FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Harvath, L Mondoro, TH Franke, PJ Aksamit, RR Lightfoot, T Leitman, SF Stroncek, DF AF Harvath, L Mondoro, TH Franke, PJ Aksamit, RR Lightfoot, T Leitman, SF Stroncek, DF TI Granulocyte concentrates: Chemotactic activity and platelet-granulocyte interactions are differentially affected by mobilization regimen and storage SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. US FDA, CBER, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 12S EP 12S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600047 ER PT J AU Rios, M Hue-Roye, K Gubin, AN Miller, JL Reid, ME AF Rios, M Hue-Roye, K Gubin, AN Miller, JL Reid, ME TI Identification of the molecular basis and PCR-RFLP assay for the dombrock polymorphism SO TRANSFUSION LA English DT Meeting Abstract C1 New York Blood Ctr, New York, NY 10021 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 13S EP 14S PG 2 WC Hematology SC Hematology GA 364CN UT WOS:000089874600053 ER PT J AU Kleinman, SH Busch, MP Kuhns, MC McNamara, AL Todd, D Watanabe, K Sharma, U Dimarco, A AF Kleinman, SH Busch, MP Kuhns, MC McNamara, AL Todd, D Watanabe, K Sharma, U Dimarco, A TI A multicenter study of anti-HBC and anti-HBS in US blood donors SO TRANSFUSION LA English DT Meeting Abstract C1 NHLBI, Retrovirus Donor Epidemiol Study, Bethesda, MD 20892 USA. Abbott Labs, Abbott Pk, IL 60064 USA. WESTAT Corp, Rockville, IL USA. WESTAT Corp, Rockville, MD 20850 USA. Blood Ctr Pacific, San Francisco, CA USA. WESTAT Corp, Victoria, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 15S EP 15S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600060 ER PT J AU Bolan, CD Cecco, S Oblitas, J Yau, YY Grammont, R Remaley, A Wesley, R Rehak, N Leitman, SF AF Bolan, CD Cecco, S Oblitas, J Yau, YY Grammont, R Remaley, A Wesley, R Rehak, N Leitman, SF TI Double-blind, placebo-controlled study of prophylactic oral calcium carbonate administration in plateletpheresis donors. SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 22S EP 23S PG 2 WC Hematology SC Hematology GA 364CN UT WOS:000089874600088 ER PT J AU Murphy, EL Bryzman, SM Glynn, SA Ameti, DI Nass, CC Ownby, HE Nemo, GJ AF Murphy, EL Bryzman, SM Glynn, SA Ameti, DI Nass, CC Ownby, HE Nemo, GJ TI Notification and medical evaluation of hepatitis C seropositive blood donors SO TRANSFUSION LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. E Bay Family Practice, Oakland, CA USA. Amer Red Cross, Blood Serv Chesapeake Reg, Baltimore, MD 20006 USA. Amer Red Cross, Blood Serv SE Michigan Reg, Detroit, MI USA. NHLBI, DBDR, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 31S EP 31S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600122 ER PT J AU Provenzano, M Kwon, S Marincola, FM Stroncek, D AF Provenzano, M Kwon, S Marincola, FM Stroncek, D TI Identification of new cytomegalovirus epitopes by direct stimulation of peripheral blood mononuclear cells SO TRANSFUSION LA English DT Meeting Abstract C1 Univ Ulsan, Seoul, South Korea. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 40S EP 40S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600155 ER PT J AU Kleinman, SH Glynn, S Williams, AE Ownby, HE Garratty, G Busch, MP AF Kleinman, SH Glynn, S Williams, AE Ownby, HE Garratty, G Busch, MP TI Incidence of syphilis infection in US blood donors SO TRANSFUSION LA English DT Meeting Abstract C1 Westat, Victoria, BC, Canada. WESTAT Corp, Rockville, MD 20850 USA. Amer Red Cross, Rockville, MD USA. Amer Red Cross, Detroit, MI USA. Amer Red Cross, Los Angeles, CA USA. Blood Ctr Pacific, San Francisco, CA USA. NHLBI, F Retrovirus Epidemiol Donor Study, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 42S EP 42S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600162 ER PT J AU Leitman, SF Kirk, AD Gladden, DS Kopp, J AF Leitman, SF Kirk, AD Gladden, DS Kopp, J TI Plasma exchange in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) following renal transplant SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD USA. RI Kirk, Allan/B-6905-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 54S EP 55S PG 2 WC Hematology SC Hematology GA 364CN UT WOS:000089874600215 ER PT J AU Todd, DS Pellett, PE Watanabe, KK Sharma, UK Ablashi, D Forghani, B Goedert, JJ Jenkins, FJ Lee, T Neipel, F Busch, MP AF Todd, DS Pellett, PE Watanabe, KK Sharma, UK Ablashi, D Forghani, B Goedert, JJ Jenkins, FJ Lee, T Neipel, F Busch, MP TI Seroprevalence of human herpesvirus 8 (HHV-8) in US blood donors using multiple serologic and PCR assays SO TRANSFUSION LA English DT Meeting Abstract C1 WESTAT Corp, Rockville, MD 20850 USA. CDC, Atlanta, GA 30333 USA. Adv Biotechnol Inc, Columbia, MD USA. CA Dept Hlth, Berkeley, CA USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Blood Ctr Pacific, San Francisco, CA USA. Univ Erlangen Nurnberg, Erlangen, Germany. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 97S EP 97S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600399 ER PT J AU Matsuo, K Procter, JL Stroncek, SF AF Matsuo, K Procter, JL Stroncek, SF TI The expression of NA antigens in people with unusual Fc-gamma-receptor-III genotypes SO TRANSFUSION LA English DT Meeting Abstract C1 Kurume Univ, Sch Med, Kurume, Fukuoka 830, Japan. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 103S EP 104S PG 2 WC Hematology SC Hematology GA 364CN UT WOS:000089874600425 ER PT J AU Kiefhaefer, K Cipolone, K Procter, JL Stroncek, DF AF Kiefhaefer, K Cipolone, K Procter, JL Stroncek, DF TI Detection of granulocyte antibodies by flow cytometry without the use of pure granulocyte isolates SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 104S EP 104S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600426 ER PT J AU Moore, S Procter, JL Cipolone, K Matsuo, K Caruccio, L Stroncek, DF AF Moore, S Procter, JL Cipolone, K Matsuo, K Caruccio, L Stroncek, DF TI Molecular analysis for Kidd (JK) polymorphisms SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Kurume Univ, Kurume, Fukuoka 830, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 117S EP 117S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600481 ER PT J AU Leitman, SF Illei, GG Tisdale, J Foley, A Popovsky, MA Balow, JE Boumpas, DT AF Leitman, SF Illei, GG Tisdale, J Foley, A Popovsky, MA Balow, JE Boumpas, DT TI Fludarabine therapy as an independent risk factor for transfusion-associated graft-versus-host disease (TA-GVHD) SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Transfus Med, Bethesda, MD USA. NIAMS, NIH, Bethesda, MD USA. NIDDK, NIH, Bethesda, MD USA. Amer Red Cross, Dedham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 SU S BP 126S EP 126S PG 1 WC Hematology SC Hematology GA 364CN UT WOS:000089874600522 ER PT J AU Seeff, LB AF Seeff, LB TI Why is there such difficulty in defining the natural history of hepatitis C? SO TRANSFUSION LA English DT Article ID NON-B-HEPATITIS; POST-TRANSFUSION HEPATITIS; NON-A; POSTTRANSFUSION HEPATITIS; FOLLOW-UP; BLOOD-TRANSFUSION; CLINICAL OUTCOMES; GLOBULIN; INFECTION; EFFICACY C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. RP Seeff, LB (reprint author), NIDDKD, NIH, 31 Ctr Dr,Room 9A18, Bethesda, MD 20892 USA. RI Jepsen, Peter/A-2593-2010 OI Jepsen, Peter/0000-0002-6641-1430 NR 23 TC 20 Z9 21 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2000 VL 40 IS 10 BP 1161 EP 1164 DI 10.1046/j.1537-2995.2000.40101161.x PG 4 WC Hematology SC Hematology GA 363PR UT WOS:000089844200004 PM 11061849 ER PT J AU Jordan, IK Natale, DA Galperin, MY AF Jordan, IK Natale, DA Galperin, MY TI Copper chaperones in bacteria: association with copper-transporting ATPases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Letter ID SUPEROXIDE-DISMUTASE C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Jordan, IK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 6 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2000 VL 25 IS 10 BP 480 EP 481 DI 10.1016/S0968-0004(00)01662-5 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 372QP UT WOS:000165245100007 PM 11203382 ER PT J AU Kobe, B Kajava, AV AF Kobe, B Kajava, AV TI When protein folding is simplified to protein coiling: the continuum of solenoid protein structures SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID RICH REPEAT PROTEINS; CRYSTAL-STRUCTURE; 3-DIMENSIONAL STRUCTURE; ANGSTROM RESOLUTION; GLOBULAR-PROTEINS; VIRULENCE FACTOR; BETA; MOTIFS; ALPHA; CLASSIFICATION AB Solenoid proteins contain repeating structural units that form a continuous superhelix. This category of proteins conveys the least complicated relationship between a sequence and the corresponding three-dimensional structure. Although solenoid proteins are divided into different classes according to commonly used classification schemes, they share many structural and functional properties. C1 Univ Queensland, Dept Biochem, Brisbane, Qld 4072, Australia. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Kobe, B (reprint author), Univ Queensland, Dept Biochem, Brisbane, Qld 4072, Australia. RI Kobe, Bostjan/D-1292-2009; Kajava, Andrey/E-1107-2014 OI Kobe, Bostjan/0000-0001-9413-9166; Kajava, Andrey/0000-0002-2342-6886 NR 49 TC 175 Z9 180 U1 2 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2000 VL 25 IS 10 BP 509 EP 515 DI 10.1016/S0968-0004(00)01667-4 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 372QP UT WOS:000165245100016 PM 11050437 ER PT J AU Rogozin, IB Lyons-Weiler, J Koonin, EV AF Rogozin, IB Lyons-Weiler, J Koonin, EV TI Intron sliding in conserved gene families SO TRENDS IN GENETICS LA English DT Article ID POSITIONS; SUPPORTS; ORIGIN C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Penn State Univ, Inst Mol Evolutionary Genet, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, Mueller Lab 328, University Pk, PA 16802 USA. RP Rogozin, IB (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 14 TC 71 Z9 75 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD OCT PY 2000 VL 16 IS 10 BP 430 EP 432 DI 10.1016/S0168-9525(00)02096-5 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 363PJ UT WOS:000089843500003 PM 11050324 ER PT J AU Moss, B Shisler, JL Xiang, Y Senkevich, TG AF Moss, B Shisler, JL Xiang, Y Senkevich, TG TI Immune-defense molecules of Molluscum contagiosum virus, a human poxvirus SO TRENDS IN MICROBIOLOGY LA English DT Review ID FACTOR RECEPTOR-1-INDUCED APOPTOSIS; DEATH EFFECTOR DOMAINS; MHC CLASS-I; INTERLEUKIN-18; INTERFERON; PROTEIN; INHIBITION; RECEPTORS; BINDING; FLIP AB Molluscum contagiosum virus encodes more than 150 proteins including some involved in host interactions that might contribute to prolonged viral replication in the skin. These include homologs of a selenocysteine-containing glutathione peroxidase, a death effector domain protein, a chemokine, a major histocompatibility complex class I molecule and an interleukin-18-binding protein. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 51 TC 31 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD OCT PY 2000 VL 8 IS 10 BP 473 EP 477 DI 10.1016/S0966-842X(00)01838-2 PG 5 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 364EU UT WOS:000089879700020 PM 11044683 ER PT J AU Lederhendler, I Schulkin, J AF Lederhendler, I Schulkin, J TI Behavioral neuroscience: challenges for the era of molecular biology SO TRENDS IN NEUROSCIENCES LA English DT Article ID GENE-EXPRESSION; PRAIRIE VOLES; VASOPRESSIN; RECEPTOR; KNOCKOUT; MONOGAMY; MEMORY; BRAIN; FEAR; MICE AB This is a great age to participate in biological inquiry. Behavioral neuroscience offers a rich perspective for molecular biologists. However, behavioral analysis is not simply an assay. Whereas molecular biology has become a unique tool in the armamentarium of behavioral neuroscience, the powerful methodology of molecular biology is no substitute for careful behavioral exploration. C1 NIMH, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Physiol & Biophys, Washington, DC USA. RP Lederhendler, I (reprint author), NIMH, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. NR 26 TC 19 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2000 VL 23 IS 10 BP 451 EP 454 DI 10.1016/S0166-2236(00)01636-2 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 364AT UT WOS:000089870400005 PM 11006460 ER PT J AU Mattson, MP Barger, SW AF Mattson, MP Barger, SW TI Silencing survival data SO TRENDS IN NEUROSCIENCES LA English DT Letter ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; INDUCED APOPTOSIS; PROTECT NEURONS; CELL-DEATH; SUPPRESSION; EXPRESSION; MICROGLIA; MECHANISM; PEPTIDE C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Arkansas Med Sci, Cent Arkansas Vet Hlth Care Syst, Little Rock, AR 72205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 21 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2000 VL 23 IS 10 BP 466 EP 467 DI 10.1016/S0166-2236(00)01622-2 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 364AT UT WOS:000089870400008 PM 11203139 ER PT J AU Chase, TN Oh, JD AF Chase, TN Oh, JD TI Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism SO TRENDS IN NEUROSCIENCES LA English DT Review ID LEVODOPA-INDUCED DYSKINESIAS; MOTOR RESPONSE ALTERATIONS; NMDA RECEPTOR SUBUNITS; LONG-TERM-MEMORY; 6-HYDROXYDOPAMINE LESIONED RATS; MESSENGER-RNA EXPRESSION; MPTP-TREATED MONKEYS; PROTEIN-KINASE-A; TYROSINE PHOSPHORYLATION; POSTSYNAPTIC DENSITY AB Characteristic changes involving interactions between dopamine and glutamate in striatal medium spiny neurons now appear to contribute to symptom production in Parkinson's disease (PD). The balance between kinase and phosphatase signaling modifies the phosphorylation state of glutamate receptors and thus their synaptic strength. Sensitization of spiny-neuron NMDA and AMPA receptors alters cortical glutamatergic input to the striatum and modifies striatal GABAergic output, and thus motor function. Conceivably, the pharmacological targeting of spiny-neuron mechanisms modified in PD will provide a safer and more effective therapy. C1 NINCDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINCDS, Expt Therapeut Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 85 TC 173 Z9 175 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2000 VL 23 IS 10 SU S BP S86 EP S91 DI 10.1016/S1471-1931(00)00018-5 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 362PT UT WOS:000089787300013 PM 11052225 ER PT J AU Gerfen, CR AF Gerfen, CR TI Molecular effects of dopamine on striatal-projection pathways SO TRENDS IN NEUROSCIENCES LA English DT Review ID EARLY GENE-EXPRESSION; GANGLIA MOTOR CONTROL; C-FOS; BASAL GANGLIA; SUBTHALAMIC NUCLEUS; SUBSTANTIA-NIGRA; MATRIX COMPARTMENTS; DEPLETED STRIATUM; GLOBUS-PALLIDUS; REGULATED GENE AB Gene regulation studies demonstrate that dopamine differentially regulates the direct and indirect projection neurons of the striatum through their respective expression of the D1 and D2 dopamine receptors. induction of immediate-early genes (IEGs) in striatal neurons is used to study dopamine-receptor-mediated neuronal plasticity. In the dopamine-depleted striatum there is a switch in receptor-mediated signal transduction mechanisms to produce a supersensitive form of D1-mediated neuronal plasticity. This switch is suggested to underlie dopamine-agonist-induced dyskinetic movements that develop during the treatment of Parkinson's disease. C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Gerfen, CR (reprint author), NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. NR 53 TC 141 Z9 148 U1 1 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2000 VL 23 IS 10 SU S BP S64 EP S70 DI 10.1016/S1471-1931(00)00019-7 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 362PT UT WOS:000089787300010 PM 11052222 ER PT J AU Walters, JR Ruskin, DN Allers, KA Bergstrom, DA AF Walters, JR Ruskin, DN Allers, KA Bergstrom, DA TI Pre- and postsynaptic aspects of dopamine-mediated transmission SO TRENDS IN NEUROSCIENCES LA English DT Review ID RAT GLOBUS-PALLIDUS; SUBTHALAMIC NUCLEUS NEURONS; BASAL GANGLIA OUTPUT; IN-VIVO; RECEPTOR STIMULATION; MULTISECOND OSCILLATIONS; NIGROSTRIATAL LESIONS; PARKINSONS-DISEASE; CELL ACTIVITY; UNIT-ACTIVITY AB Dopamine agonist administration induces changes in firing rate and pattern in basal ganglia nuclei that provide an insight into the role of dopamine in basal ganglia function. These changes support a more complex, integrated basal ganglia network than envisioned in early models. Functionally important effects on basal ganglia output involve alterations in burstiness, synchronization and oscillatory activity, as well as rate. Multisecond oscillations in basal ganglia firing rates are markedly affected by systemic administration of dopamine-receptor agonists. This suggests that coordinated changes in neuronal activity at time scales longer than commonly investigated play a role in the cognitive and motor processes that are modulated by dopamine. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Walters, JR (reprint author), NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NR 57 TC 32 Z9 34 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2000 VL 23 IS 10 SU S BP S41 EP S47 DI 10.1016/S1471-1931(00)00024-0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 362PT UT WOS:000089787300007 PM 11052219 ER PT J AU Wess, J AF Wess, J TI Physiological roles of G-protein-coupled receptor kinases revealed by gene-targeting technology - Comment SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID RHODOPSIN KINASE; KNOCKOUT MICE; DESENSITIZATION; DISRUPTION; SUBTYPES C1 NIDDKD, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 22 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2000 VL 21 IS 10 BP 364 EP 366 DI 10.1016/S0165-6147(00)01542-X PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 368ZN UT WOS:000090147500002 PM 11050310 ER PT J AU Gallo, V Ghiani, CA AF Gallo, V Ghiani, CA TI Reply: glia and neurons continue to talk SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Letter ID NERVE C1 NICHHD, Lab Cellular & Mol Neurophysiol, Sect Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Brain Res Inst, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Gallo, V (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Sect Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2000 VL 21 IS 10 BP 375 EP 375 DI 10.1016/S0165-6147(00)01544-3 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 368ZN UT WOS:000090147500012 ER PT J AU Wear, KA Stuber, AP Reynolds, JC AF Wear, KA Stuber, AP Reynolds, JC TI Relationships of ultrasonic backscatter with ultrasonic attenuation, sound speed and bone mineral density in human calcaneus SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE calcaneus; trabecular bone; backscatter; ultrasound ID CANCELLOUS BONE; HIP FRACTURE; OS CALCIS; IN-VITRO; VELOCITY; WOMEN; COEFFICIENTS; PREDICTION; SIGNALS; LIVER AB Ultrasonic attenuation and sound speed have been investigated in trabecular bone by numerous authors. Ultrasonic backscatter has received much less attention, To investigate relationships among these three ultrasonic parameters and bone mineral density (BMD), 30 defatted human calcanei were investigated in vitro. Normalized broadband ultrasonic attenuation (nBUA), sound speed (SOS), and logarithm of ultrasonic back-scatter coefficient (LBC) were measured. Bone mineral density was assessed using single-beam dual energy x-ray absorptiometry (DEXA). The correlation coefficients of least squares linear regressions of the three individual ultrasound (US) parameters with BMD were 0.84 (nBUA), 0.84 (SOS) and 0.79 (LBC). The 95% confidence intervals for the correlation coefficients were 0.69-0.92 (nBUA), 0.68-0.92 (SOS) and 0.60-0.90 (LBC). The correlations among pairs of US variables ranged from 0.63-0.79. Variations in nBUA accounted for r(2) = 62% of the variations in LBC. Variations in SOS accounted for r(2) = 40% of the variations in LBC. These results suggest that ultrasonic backscattering properties may contain substantial information Rot already contained in nBUA and SOS. A multiple regression model including all three US variables was somewhat more predictive of BMD than a model including only nBUA and SOS. (C) 2000 World federation for Ultrasound in Medicine & Biology. C1 US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20852 USA. NIH, Bethesda, MD 20892 USA. RP US FDA, Ctr Devices & Radiol Hlth, HFZ-142,122720 Twinbrook Pkwy, Rockville, MD 20852 USA. EM kaw@cdrh.fda.gov NR 42 TC 41 Z9 42 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD OCT PY 2000 VL 26 IS 8 BP 1311 EP 1316 DI 10.1016/S0301-5629(00)00267-2 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 385CA UT WOS:000165983000012 PM 11120369 ER PT J AU Sans, NA Montcouquiol, ME Raymond, J AF Sans, NA Montcouquiol, ME Raymond, J TI Postnatal developmental changes in AMPA and NMDA receptors in the rat vestibular nuclei SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE glutamate receptor; vestibular nucleus; development; non-radioactive in situ hybridization histochemistry ID METHYL-D-ASPARTATE; METABOTROPIC GLUTAMATE RECEPTORS; MESSENGER-RNA EXPRESSION; GUINEA-PIG; ULTRASTRUCTURAL-LOCALIZATION; DIFFERENTIAL EXPRESSION; SYNAPTIC TRANSMISSION; FUNCTIONAL-PROPERTIES; MOLECULAR DIVERSITY; NERVOUS-SYSTEM AB Changes in the expression of the AMPA receptor subunits GluR1-4 and of the NMDA receptor subunits NR1, NR2A-D were investigated in the developing rat medial and lateral vestibular nuclei. Analyses were performed using nonradioactive in situ hybridization and immunoblotting with subunit-specific antibodies. During the postnatal development, glutamatergic receptor subunits were differentially expressed in the vestibular nuclei. The level of expression of GluR1, GluR4 and NR1 subunits was higher in the developing brain as compared to the adult. We observed a gradual increase in GLuR2/3, NR2A, NR2B and NR2C levels of expression in the medial and lateral vestibular nuclei during the first 3 weeks of postnatal development. In situ hybridization results were consistent with immunoblot analyses. The differential expression of AMPA and NMDA receptor subunits in immature vestibular neurons is consistent with changes in glutamate receptor properties. This may be related to the postsynaptic regulation of receptor subunits associated with the synaptic plasticity of the vestibular neuron connections during specific sequences of postnatal development. (C) 2000 Elsevier Science BTV. All rights reserved. C1 Univ Montpellier 2, INSERM, U432, F-34095 Montpellier 5, France. RP Sans, NA (reprint author), NIDCD, Neurochem Lab, NIH, Bldg 36,Room 5D08,36 Convent Dr,MSC 4162, Bethesda, MD 20892 USA. NR 68 TC 39 Z9 41 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD SEP 30 PY 2000 VL 123 IS 1 BP 41 EP 52 DI 10.1016/S0165-3806(00)00082-1 PG 12 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 365BF UT WOS:000089928000005 ER PT J AU Park, S Nelson, TJ Alkon, DL Kim, J AF Park, S Nelson, TJ Alkon, DL Kim, J TI Functional characterization of the squid calexcitin-2, a calcium and GTP-binding protein SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE calcium-binding protein; calexcitin; GTP-binding protein; memory; mutagenesis ID DYNAMIN GTPASE; ALPHA(1)-ANTITRYPSIN AB Calexcitin, a calcium-binding protein, was previously cloned and functionally characterized in the squid Loligo pealei. We now report the cloning of a second form of Calexcitin, Calexcitin-3 found in the squid Todarodes pacificus optic lobe, Calexcitin-2 has a significantly different carboxyl terminal region than Calexcitin-1. It lacks the CAAX motif, which is a farnesylation site. The amino acid sequence of Calexcitin-2 shows an 84% identity with Calexcitin-1 and also displays a strong cross immunoreactivity. Western blotting shows that Calexcitin-2 was expressed exclusively in the optic lobe region of squid, but not in other body organs. Regardless of its lack of conserved regions for GTP-binding, Calexcitin-2 shows moderately low affinity GTP-binding and also shows dramatic conformational change induced by GTP-binding. Three possible GTP-binding region mutations, K142A, D144A, and K157A, did not change the GTP binding affinity. This raises the possibility that Calexcitin-2 may have a novel GTP-binding motif. C1 Inha Univ, Dept Biol, Inchon 402751, South Korea. NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Kim, J (reprint author), Inha Univ, Dept Biol, Inchon 402751, South Korea. NR 16 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD SEP 30 PY 2000 VL 33 IS 5 BP 391 EP 395 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 359EE UT WOS:000089597900006 ER PT J AU Rogan, WJ AF Rogan, WJ TI The DDT question SO LANCET LA English DT Letter ID LACTATION; DURATION C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 4 TC 4 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 SEP 30 PY 2000 VL 356 IS 9236 BP 1189 EP 1189 DI 10.1016/S0140-6736(05)72882-8 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 359CQ UT WOS:000089594300046 PM 11030315 ER PT J AU Chin, K Yu, XB Beleslin-Cokic, B Liu, C Shen, K Mohrenweiser, HW Noguchi, CT AF Chin, K Yu, XB Beleslin-Cokic, B Liu, C Shen, K Mohrenweiser, HW Noguchi, CT TI Production and processing of erythropoietin receptor transcripts in brain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE erythropoietin receptor; brain transcript; alternative splicing; upstream transcription; anemic stress; induced expression ID CENTRAL-NERVOUS-SYSTEM; ENDOTHELIAL-CELLS; GENE-EXPRESSION; NITRIC-OXIDE; IN-VITRO; RAT HIPPOCAMPAL; MICE LACKING; MOUSE-BRAIN; FACTOR AP-2; NEURONS AB The expression of erythropoietin receptor (EpoR) in brain and neuronal cells, and hypoxia-responsive production of erythropoietin (Epo) in the brain suggests that the function of Epo as a survival or viability factor may extend beyond hematopoietic tissue and erythroid progenitor cells. Epo, produced by astrocytes and neurons, can be induced by hypoxia by severalfold, and in animal models Epo administration is neuroprotective to ischemic challenge. We characterized the human EpoR transcript in brain and neuronal cells to determine its contribution in regulating the Epo response in brain. Screening of a human brain cDNA library and quantitative analysis of EpoR transcripts indicate that the EpoR gene locus is transcriptionally active in brain. In addition to the proximal promoter that is active in hematopoietic cells, a significant proportion of transcripts originates far upstream from the EpoR coding region. Unlike erythroid cells with efficient splicing of EpoR transcripts to its mature form, brain EpoR transcripts are inefficiently or alternately processed with a bias towards the 3' coding region. In human EpoR transgenic mice, anemic stress induces expression of the transgene and endogenous EpoR gene in hematopoietic tissue and brain. In culture of neuronal cells, hypoxia induces EpoR expression and increases sensitivity to Epo. Induction of EpoR expression appears to be a consequence of increased transcription from the upstream region and proximal promoter, and a shift towards increased processing efficiency. These data suggest that in contrast to erythropoiesis where erythroid progenitor cells express high levels of EpoR and are directly responsive to Epo stimulation, the neuroprotective effect of Epo and its receptor may require two molecular events: the induction of Epo production by hypoxia and an increase in EpoR expression in neuronal cells resulting in increased sensitivity to Epo. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. RP Noguchi, CT (reprint author), NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 54 TC 61 Z9 65 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 30 PY 2000 VL 81 IS 1-2 BP 29 EP 42 DI 10.1016/S0169-328X(00)00157-1 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 363LW UT WOS:000089838000004 PM 11000476 ER PT J AU Chen, W Baler, R AF Chen, W Baler, R TI The rat arylalkylamine N-acetyltransferase E-box: differential use in a master vs. a slave oscillator SO MOLECULAR BRAIN RESEARCH LA English DT Article DE E box; circadian; clock; arylalkylamine N-acetyltransferase; retina ID CIRCADIAN EXPRESSION; PINEAL-GLAND; MELATONIN SYNTHESIS; MESSENGER-RNA; CYCLIC-AMP; ADRENERGIC REGULATION; CLOCK GENE; RETINA; MECHANISM; TRANSCRIPTION AB The rat arylalkylamine N-acetyltransferase (AA-NAT) gene encodes the key enzyme whose rhythmic expression drives the nocturnal production of melatonin. It is of interest that this enzyme is expressed virtually exclusively in two phylogenetically related tissues: retinal photoreceptors, which harbor an endogenous clock, and pinealocytes which, in higher vertebrates, function strictly in response to the master oscillator in the suprachiasmatic nucleus (SCN). While much is known about AA-NAT transcriptional regulation in the rat pineal gland (a slave oscillator), a full understanding of the mechanisms controlling AA-NAT gene expression in the retina by the clock is lacking. In the present study we have identified a functional E box in the first intron of the rat AA-NAT gene which is capable of mediating transcriptional upregulation via the action of a bMAL/CLOCK heterodimer. This is the first report to characterize the AA-NAT gene as a possible direct transcriptional target of the biological clock loop in a master oscillator. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIMH, Lab Cellular & Mol Regulat, Unit Temporal Gene Express, NIH, Bethesda, MD 20892 USA. RP Baler, R (reprint author), NIMH, Lab Cellular & Mol Regulat, Unit Temporal Gene Express, NIH, Bethesda, MD 20892 USA. NR 32 TC 87 Z9 87 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 30 PY 2000 VL 81 IS 1-2 BP 43 EP 50 DI 10.1016/S0169-328X(00)00160-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 363LW UT WOS:000089838000005 ER PT J AU Chang, RCC Hudson, P Wilson, B Liu, B Abel, H Hemperly, J Hong, JS AF Chang, RCC Hudson, P Wilson, B Liu, B Abel, H Hemperly, J Hong, JS TI Immune modulatory effects of neural cell adhesion molecules on lipopolysaccharide-induced nitric oxide production by cultured glia SO MOLECULAR BRAIN RESEARCH LA English DT Article DE glia; lipopolysaccharide; neural cell adhesion molecules; nitric oxide ID N-CAM; ASTROCYTE PROLIFERATION; INJURY; BRAIN AB Activation of glial cells often occurs at sites of neuronal injury or death and where there is disruption of communication between glia and neurons. We have previously reported that neurons exert an inhibitory influence on LPS-stimulated nitric oxide (NO) production in glial cells. We hypothesized that neural cell adhesion molecules (NCAM) might mediate this inhibitory effect, and this study was designed to elucidate the role of NCAM on lipopolysaccharide (LPS)induced NO production. We found that soluble NCAMs reduced LPS-stimulated NO production by cultured glia. A monoclonal antibody that recognizes the third immunoglobulin (Ig) domain and can mimic the functions of NCAMs reduced LPS-stimulated NO production, whereas another antibody that binds to other regions of the NCAM did not modulate NO production. Using a 10-amino acid peptide from the third Ig domain of the NCAM, a peptide fragment within the region recognized by the NCAM antibody, mimics the effect of the molecule in reducing NO production. This study demonstrated that NCAMs could modulate LPS-stimulated NO production, most likely via interaction between NCAMs. These results suggest that neuron-glia interactions via NCAMs play an important role in regulating the activities of glial cells in the brain. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, Lab Pharmacol & Chem, Neuropharmacol Sect, NIH, Res Triangle Pk, NC 27709 USA. Becton Dickinson Res Ctr, Res Triangle Pk, NC USA. RP Chang, RCC (reprint author), Univ Hong Kong, Fac Med, Dept Anat, 5F Li Shu Fan Bldg,5 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. RI Chang, Raymond Chuen-Chung/C-1107-2009; liu, Bin/A-7695-2009 OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993; NR 19 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 30 PY 2000 VL 81 IS 1-2 BP 197 EP 201 DI 10.1016/S0169-328X(00)00175-3 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 363LW UT WOS:000089838000021 ER PT J AU Margolis, L Glushakova, S Chougnet, C Shearer, G Markham, P Robert-Guroff, M Benveniste, R Miller, CJ Cranage, M Hirsch, V Franchini, G AF Margolis, L Glushakova, S Chougnet, C Shearer, G Markham, P Robert-Guroff, M Benveniste, R Miller, CJ Cranage, M Hirsch, V Franchini, G TI Replication of simian immunodeficiency virus (SIV) in ex vivo lymph nodes as a means to assess susceptibility of macaques in vivo SO VIROLOGY LA English DT Article ID T-CELL ACTIVITY; RHESUS MACAQUES; INTRAVAGINAL INOCULATION; CHILDREN BORN; HIV-INFECTION; RESPONSES; VACCINE; CHALLENGE; IMMUNITY; IMMUNIZATION AB Six macaques, apparently uninfected, following low-dose exposure to the pathogenic SIVmac251 and SIVSME660 by the mucosal route, were used in a pilot study to investigate whether infectability of ex vivo lymph nodes could predict resistance and/or susceptibility to SIV infection in vivo. Of six macaques exposed to the less-pathogenic virus SIVMNE, four resisted viral infection. Analysis of the susceptibility of the PBMC of these four animals before SIVMNE challenge indicated that all of them were resistant to infection by the SIVBK28 isolate and, in three of them, this resistance was dependent on CD8+ T cells. Blocks of lymph nodes of these four macaques were resistant to SIVMNE infection ex vivo following SIVMNE viral challenge exposure. However, the same blocks from the same animals were permissive to the more virulent SIV251(32H). Accordingly, three of these macaques were readily infected following challenge exposure with SIV251(32H). Lymphoproliferative responses in blood or lymph nodes, local C-C chemokine production in the lymph-node explants, and cytotoxic T-cell activity measured throughout the study did not correlate with ex vivo resistance or susceptibility to in vivo infection. In conclusion, PBMC and lymph-node resistance or susceptibility to infection ex vivo appeared to correlate with in vivo infectivity and, thus, these approaches should be further tested for their predictive value for in vivo infection. (C) 2000 Academic Press. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Adv BioSci Labs Inc, Kensington, MD 20895 USA. Univ Calif Davis, Calif Reg Primate Res Ctr, Davis, CA 95616 USA. Ctr Appl Microbiol & Res, Salisbury, Wilts, England. NIAID, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, NIH, 41 Lib Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. NR 32 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2000 VL 275 IS 2 BP 391 EP 397 DI 10.1006/viro.2000.0528 PG 7 WC Virology SC Virology GA 360ZU UT WOS:000089697900019 PM 10998338 ER PT J AU Reichelderfer, PS Coombs, RW Wright, DJ Cohn, J Burns, DN Cu-Uvin, S Baron, PA Cohen, MH Landay, AL Beckner, SK Lewis, SR Kovacs, AA AF Reichelderfer, PS Coombs, RW Wright, DJ Cohn, J Burns, DN Cu-Uvin, S Baron, PA Cohen, MH Landay, AL Beckner, SK Lewis, SR Kovacs, AA CA WHS 001 Study Team TI Effect of menstrual cycle on HIV-1 levels in the peripheral blood and genital tract SO AIDS LA English DT Article; Proceedings Paper CT 6th Conference on Retroviruses and Opportunistic Infections CY JAN 31-FEB 04, 1999 CL CHICAGO, ILLINOIS DE female genital tract; HIV; menstrual cycle ID HUMAN-IMMUNODEFICIENCY-VIRUS; GLUCOCORTICOID RECEPTOR; RNA LEVELS; TYPE-1; AIDS; SECRETIONS; CELLS; WOMEN; COMPARTMENTALIZATION; PROGESTERONE AB Objective: To assess the variation in HIV-1 over the menstrual cycle, including RNA levels in the female genital tract, plasma HIV-1-RNA levels, CD4 cell counts, and culturable virus. Design: A prospective analysis of 55 HIV-1-infected women. Methods: Blood and genital tract specimens were collected weekly over 8 weeks, spanning two complete menstrual cycles. Applying repeated-measures models that used menses as the reference level, the variation in viral RNA levels was compared in endocervical canal fluid and cells (collected by Sno-strips and cytobrush, respectively) and ectocervicovaginal lavage (CVL) fluid. Repeated-measures models were also used to assess the variation in plasma CD4 cell counts and viral load. Results: Shedding patterns differed among the three sampling methods, independent of genital tract co-infections. Genital tract HIV-1-RNA levels from CVL fluid and endocervical canal cytobrush specimens were highest during menses and lowest immediately thereafter (P = 0.001 and P = 0.04). The HIV-I-RNA level in endocervical canal fluid was highest in the week preceding menses(P = 0.003). The menstrual cycle had no effect on blood levels of RNA (P = 0.62), culturable virus (P = 0.34), or CD4 cell counts (P = 0.55). HIV-I-RNA levels were higher in endocervical canal fluid than in peripheral blood plasma during the late luteal phase (P = 0.03). Conclusion: HIV-1-RNA levels vary with the menstrual cycle in the female genital tract but not the blood compartment. HIV-I-RNA levels are higher in endocervical canal fluid than in blood plasma. These findings may have important implications for sex-specific pathogenesis, heterosexual transmission, and contraceptive hormone interventions in HIV-l-infected women. (C) 2000 Lippincott Williams & Wilkins. C1 NICHHD, Contracept & Reprod Hlth Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. WESTAT Corp, Rockville, MD 20850 USA. Wayne State Univ, Detroit, MI USA. Miriam Hosp, Providence, RI 02906 USA. St Lukes Roosevelt Hosp Ctr, New York, NY USA. Cook Cty Hosp, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ So Calif, Los Angeles, CA USA. RP Reichelderfer, PS (reprint author), NICHHD, Contracept & Reprod Hlth Branch, NIH, 6100 Execut Blvd,Room 8B13G, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-27664, AI-30731]; NICHD NIH HHS [HD-33162] NR 34 TC 92 Z9 92 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 29 PY 2000 VL 14 IS 14 BP 2101 EP 2107 DI 10.1097/00002030-200009290-00005 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 365ZV UT WOS:000089981100005 PM 11061650 ER PT J AU An, P Martin, MP Nelson, GW Carrington, M Smith, MW Gong, K Vlahov, D O'Brien, SJ Winkler, CA AF An, P Martin, MP Nelson, GW Carrington, M Smith, MW Gong, K Vlahov, D O'Brien, SJ Winkler, CA TI Influence of CCR5 promoter haplotypes on AIDS progression in African-Americans SO AIDS LA English DT Article DE AIDS; progression; chemokine receptor; genetic epidemiology; CCR5 promoter ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 DISEASE PROGRESSION; CHEMOKINE RECEPTOR-5; INFECTION; RESISTANCE; ALLELE; GENE; MUTATION; ENTRY; POLYMORPHISM AB Objectives: To test the hypothesis that the CCR5 promoter variants in HIV-l-infected African-Americans affect the rate of progression to AIDS and to determine the extent of linkage disequilibrium between the CCR5P1 allele and the CCR5 59029A variant (referred to here as CCR5-2459A), both of which have been shown independently to accelerate AIDS progression in Caucasians. Design: We used survival analysis to assess the effects of CCR5 promoter variants in HIV-1 seroincident Caucasians and African-Americans. Subjects and methods: Genotypes were determined for 806 Caucasians and 1067 African-Americans, which included 700 seroconverters, enrolled in four HIV/AIDS natural history cohort studies. These genotypes were used to determine linkage and haplotypes for CCR2 and CCR5 alleles. Survival analysis was used to assess the effect of CCR2, CCR5,and CCR5 promoter haplotypes on progression to AIDS in seroincident African-Americans. Results: A survey of Caucasians and African-Americans demonstrated complete linkage disequilibrium between CCR5P1 and CCR5-2459A sites. The composite CCR5P1 haplotype (including the CCR5-2459A allele) is shown to be associated with rapid progression to AIDS endpoints in both African-American and Caucasian cohorts, but the effect is recessive in Caucasians and dominant in African-Americans. This is probably due to the presence of modulating genes or as yet unidentified polymorphisms that may differ between racial groups. (C) 2000 Lippincott Williams & Wilkins. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Dev Ctr, Frederick, MD 21702 USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Winkler, CA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Bldg 560,Room 11-64, Frederick, MD 21702 USA. RI Smith, Michael/B-5341-2012 FU NCI NIH HHS [N01-CO-56000] NR 28 TC 55 Z9 60 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 29 PY 2000 VL 14 IS 14 BP 2117 EP 2122 DI 10.1097/00002030-200009290-00007 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 365ZV UT WOS:000089981100007 PM 11061652 ER PT J AU Morcock, DR Kane, BP Casas-Finet, JR AF Morcock, DR Kane, BP Casas-Finet, JR TI Fluorescence and nucleic acid binding properties of the human T-cell leukemia virus-type 1 nucleocapsid protein SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY LA English DT Article DE nucleocapsid; zinc finger; human T-cell leukemia virus type 1; retrovirus; nucleic acid; fluorescence ID HUMAN-IMMUNODEFICIENCY-VIRUS; ZINC-FINGER; GENOMIC RNA; SEQUENCE; MUTANTS; HIV-1; OLIGONUCLEOTIDES; RETROVIRUSES; PARAMETERS; DOMAINS AB We used intrinsic tryptophan fluorescence to study the nucleocapsid protein from human T-cell leukemia virus-type one, HTLV-1 p15, an 85-amino-acid protein with two Trp-containing zinc-finger motifs. Fluorescence spectra suggested an interaction between the two zinc fingers and another interaction involving the C-terminal tail and the zinc fingers. Titrations with nucleic acid revealed similar, sub-micromolar affinity for poly(dT) and poly(U) in 1 mM sodium phosphate, pH 7. Double-stranded DNA bound an order of magnitude weaker, suggesting helix-destabilizing activity. Base preference of p15 was T approximate to U>I approximate to C approximate to G>A; affinity spanned about one order of magnitude. HTLV-1 p15 bound weaker and with less variation than reported values for either human or simian immunodeficiency virus homologues. The low affinity of p15 for nonspecific nucleic acids distinguishes it from other nucleocapsid proteins, and may suggest its involvement in additional steps of the virus life cycle other than RNA packaging. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. RP Casas-Finet, JR (reprint author), NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Bldg 535,4th Floor,POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 31 TC 9 Z9 9 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4838 J9 BBA-PROTEIN STRUCT M JI Biochim. Biophys. Acta-Protein Struct. Molec. Enzym. PD SEP 29 PY 2000 VL 1481 IS 2 BP 381 EP 394 DI 10.1016/S0167-4838(00)00181-3 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 362KM UT WOS:000089777200020 PM 11018730 ER PT J AU Mezey, E Chandross, KJ AF Mezey, E Chandross, KJ TI Bone marrow: a possible alternative source of cells in the adult nervous system SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE stem cell; differentiation; hematopoietic; central nervous system ID NEURAL STEM-CELLS; MAMMALIAN FOREBRAIN; ENDOTHELIAL-CELLS; VISUAL-CORTEX; GLIAL-CELLS; IN-VIVO; BRAIN; RAT; NEURONS; ASTROCYTES AB There is increasing evidence that stem cell populations can undergo a transition between mesodermal and neural ectodermal cell fates. Bone marrow-derived cells have been shown to be extremely versatile: they can become brain and liver cells and muscle, while other mesodermal derived cells have been shown to migrate into the brain and differentiate into neurons. Moreover, under the appropriate conditions, neural stem cells can differentiate into hematopoietic and muscle cell fates. It is now well established that newly differentiated cell types are continuously generated from immature stem cells throughout development and in adult mammals, including humans. This review addresses the contribution that bone marrow-derived stem cells may play during neurogenesis. We transplanted male bone marrow into female recipients to track and characterize the Y chromosome containing cells in the CNS (central nervous system) of mice. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, NIH, BNP, Bethesda, MD 20892 USA. LDN, Bethesda, MD 20892 USA. RP Mezey, E (reprint author), NINDS, NIH, BNP, Bldg 36,3D-06, Bethesda, MD 20892 USA. NR 45 TC 72 Z9 85 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 29 PY 2000 VL 405 IS 1-3 BP 297 EP 302 DI 10.1016/S0014-2999(00)00561-6 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 360PQ UT WOS:000089676800029 PM 11033336 ER PT J AU Vawter, MP AF Vawter, MP TI Dysregulation of the neural cell adhesion molecule and neuropsychiatric disorders SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Review DE schizophrenia; bipolar disorder; depression; memory; synaptic plasticity; ventricle enlargement; neurocognitive impairment ID LONG-TERM POTENTIATION; MONOZYGOTIC TWINS DISCORDANT; DEPENDENT NEURITE OUTGROWTH; PASSIVE-AVOIDANCE RESPONSE; FIRST-EPISODE PATIENTS; N-CAM; BIPOLAR DISORDER; VASE EXON; MEMORY FORMATION; NERVOUS-SYSTEM AB Cell adhesion molecule proteins play a diverse role in neural development, signal transduction, structural Linkages to extracellular and intracellular proteins, synaptic stabilization, neurogenesis, and learning. Three basic mRNA isoforms and potent posttranslational modifications differentially regulate these neurobiological properties of the neural cell adhesion molecule (N-CAM). Abnormal concentrations of N-CAM 105-115 kDa (cN-CAM), N-CAM variable alternative spliced exon (VASE), and N-CAM secreted exon (SEC) are related to schizophrenia and bipolar neuropsychiatric disorders. These N-CAM isoforms provide potential mechanisms for expression of multiple neurobiological alterations between controls and individuals with schizophrenia or bipolar illness. Multiple processes can trigger the dysregulation of N-CAM isoforms. Differences in neuropil volume, neuronal diameter, gray matter thickness, and ventricular size can be related to N-CAM neurobiological properties in neuropsychiatric disorders. Potential test of the N-CAM dysregulation hypothesis of neuropsychiatric disorder is whether ongoing dysregulation of N-CAM would cause cognitive impairments, increased lateral ventricle volume, and decreased hippocampal volume observed in schizophrenia and to a lesser extent in bipolar disorder. An indirect test of this theory conducted in animal experiments lend support to this N-CAM hypothesis. N-CAM dysregulation is consistent with a synaptic abnormality that could underlie the disconnection between brain regions consistent with neuroimaging reports. Synapse stability and plasticity may be put of the molecular neuropathology of these disorders. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDA, Addict Res Ctr, IRP, Sect Dev & Plast, Baltimore, MD 21224 USA. RP Vawter, MP (reprint author), NIDA, Addict Res Ctr, IRP, Sect Dev & Plast, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 140 TC 62 Z9 63 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 29 PY 2000 VL 405 IS 1-3 BP 385 EP 395 DI 10.1016/S0014-2999(00)00568-9 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 360PQ UT WOS:000089676800036 PM 11033343 ER PT J AU Chen, SY Sarlis, NJ Simons, SS AF Chen, SY Sarlis, NJ Simons, SS TI Evidence for a common step in three different processes for modulating the kinetic properties of glucocorticoid receptor-induced gene transcription SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREB-BINDING-PROTEIN; TYROSINE AMINOTRANSFERASE GENE; THYROID-HORMONE RECEPTOR; ESTROGEN-REGULATED RNAS; NUCLEAR RECEPTORS; HISTONE ACETYLTRANSFERASE; PROMOTER-CONTEXT; AGONIST ACTIVITY; DEPENDENT TRANSCRIPTION; COACTIVATOR COMPLEXES AB The dose-response curve of steroid hormones and the associated EC50 value are critical parameters both in the development of new pharmacologically active compounds and in the endocrine therapy of various disease states. We have recently described three different variables that can reposition the dose-response curve of agonist-bound glucocorticoid receptors (GRs): a 21-base pair sequence of the rat tyrosine aminotransferase gene called a glucocorticoid modulatory element (GME), GR concentration, and coactivator concentration, At the same time, each of these three components was found to influence the partial agonist activity of antiglucocorticoids. In an effort to determine whether these three processes proceed via independent pathways or a common intermediate, we have examined several mechanistic details. The effects of increasing concentrations of both GR and the coactivator TIF2 are found to be saturable. Furthermore, saturating levels of either GR or TIF2 inhibit the ability of each protein, and the GME, to affect further changes in the dose-response curve or partial agonist activity of antisteroids. This competitive inhibition suggests that all three modulators proceed through a common step involving a titratable factor. Support for this hypothesis comes from the observation that a fragment of the coactivator TIF2 retaining intrinsic transactivation activity is a dominant negative inhibitor of each component (GME, GR, and coactivator). This inhibition was not due to nonspecific effects on the general transcription machinery as the VP16 transactivation domain was inactive. The viral protein E1A also prevented the action of each of the three components in a manner that was independent of E1A's ability to block the histone acetyltransferase activity of CBP. Collectively, these results suggest that three different inputs (GME, GR, and coactivator) for perturbing the dose-response curve, and partial agonist activity, of GR-steroid complexes act by converging at a single step that involves a limiting factor prior to transcription initiation. C1 NIDDKD, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDKD, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bldg 8,Rm B2A-07, Bethesda, MD 20892 USA. NR 82 TC 39 Z9 39 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 29 PY 2000 VL 275 IS 39 BP 30106 EP 30117 DI 10.1074/jbc.M005418200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 358VM UT WOS:000089577900028 PM 10899170 ER PT J AU Jacobson, KA Xie, RY Young, L Chang, L Liang, BT AF Jacobson, KA Xie, RY Young, L Chang, L Liang, BT TI A novel pharmacological approach to treating cardiac ischemia - Binary conjugates of A(1) and A(3) adenosine receptor agonists SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; RAT-BRAIN; CARDIOPROTECTION; ANTAGONISTS; ACTIVATION; INHIBITION; MYOCYTES; INJURY AB Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart via activation of A(1) or A(3) receptors. However, the interaction between the two cardioprotective adenosine receptors and the question of which receptor is the more important anti-ischemic receptor remain largely unexplored. The objective of this study was to test the hypothesis that activation of both receptors exerted a cardioprotective effect that was significantly greater than activation of either receptor individually. This was accomplished by using a novel design in which new binary conjugates of adenosine A(1) and A(3) receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A(1) and A(3) receptors were created through the covalent linking of functionalized congeners of adenosine agonists, each being selective for either the A(1) or A(3) receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A(1) and A(3) receptors (K-i values of 0.7-3.5 nM) versus A(2A) receptors. The myocyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A(1) and A(3) receptors, or engineered atrial cells, in which either human A(3) receptors alone or both human A(1) and A(3) receptors were expressed. The binary agonist MRS 1741 coactivated A(1) and A(3) receptors simultaneously, with full cardioprotection (EC50 similar to 0.1 nM) dependent on expression of both receptors, Thus, co-activation of both adenosine A(1) and A(3) receptors by the binary A(1)/A(3) agonists represents a novel general cardioprotective approach for the treatment of myocardial ischemia. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Med Ctr, Dept Pharmacol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031115-24, Z01 DK031117-20, Z99 DK999999]; NHLBI NIH HHS [R01 HL048225, R01-HL48225] NR 27 TC 47 Z9 48 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 29 PY 2000 VL 275 IS 39 BP 30272 EP 30279 DI 10.1074/jbc.M001520200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 358VM UT WOS:000089577900050 PM 10887176 ER PT J AU Yoo, SH Lewis, MS AF Yoo, SH Lewis, MS TI Interaction of chromogranin B and the near N-temninal region of chromogranin B with an intraluminal loop peptide of the inositol 1,4,5-trisphosphate receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SECRETORY VESICLE MEMBRANE; PH-DEPENDENT INTERACTION; DISULFIDE-BONDED LOOP; TRISPHOSPHATE RECEPTOR; BINDING REGION; CONFORMATIONAL CHANGE; INTRACELLULAR STORES; CA2+ MOBILIZATION; CALCIUM RELEASE; MATRIX PROTEINS AB Given the interaction of the inositol 1,4,5-trisphosphate receptor (IP3R) with chromogranins A (CGA) and B (CGB), two major Ca2+ storage proteins of secretory granules that have been shown to be IP3-sensitive intracellular Ca2+ store of neuroendocrine cells, we have investigated the potential interaction of the intraluminal loop regions of the IP3R with both intact CGB and the conserved near N-terminal region of CGB. The interaction studies carried out with CGB and glutathione S-transferase fusion proteins of intraluminal loop regions of bovine type 1 IP3R showed that CGB interacts with intraluminal loop 3-2 (the second loop formed between transmembrane regions 5 and 6) of the IP3R at both pH 5.5 and 7.5. Analytical ultracentrifugation studies also indicated-that CGB interacts with the same intraluminal loop region of the IP3R and the interaction was much stronger than that between CGA and the loop. Moreover, the conserved near N-terminal region of CGB also interacted with the intraluminal loop region of the IP3R. The CGB interaction with the IP3R intraluminal loop peptide at pH 7.5 showed a Delta G(0) value of -8.1 kcal/ mol at 37 degrees C for a 1:1 stoichiometry, indicating a K-d of similar to 1.9 mu M. These results give insight into the molecular organization of the IP3-sensitive Ca2+ store. C1 Korea Adv Inst Sci & Technol, Biomed Res Ctr, Natl Creat Res Initiat Ctr Secretory Granule Res, Taejon 305701, South Korea. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Yoo, SH (reprint author), Korea Adv Inst Sci & Technol, Biomed Res Ctr, Natl Creat Res Initiat Ctr Secretory Granule Res, Taejon 305701, South Korea. NR 47 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 29 PY 2000 VL 275 IS 39 BP 30293 EP 30300 DI 10.1074/jbc.M001204200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 358VM UT WOS:000089577900053 PM 10906121 ER PT J AU Scoltock, AB Bortner, CD Bird, GS Putney, JW Cidlowski, JA AF Scoltock, AB Bortner, CD Bird, GS Putney, JW Cidlowski, JA TI A selective requirement for elevated calcium in DNA degradation, but not early events in anti-Fas-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-DEATH; DEPENDENT ENDONUCLEASE; INTRACELLULAR CALCIUM; ENDOPLASMIC-RETICULUM; CYTOSOLIC CA2+; ACTIVATION; BCL-2; SUPPRESSION; THYMOCYTES; FRAGMENTATION AB Jurkat cells undergo apoptosis in response to anti-Fas antibody through a caspase-dependent death cascade in which calcium signaling has been implicated. We have now evaluated the role of calcium during this death cascade at the single cell level in real time utilizing flow cytometric analysis and confocal microscopy. Fluo-3 and propidium iodide were employed to evaluate calcium fluxes and to discriminate between viable and non-viable cells, respectively. Anti-Fas treatment of Jurkat cells resulted in a sustained increase in intracellular calcium commencing between 1 and 2 h after treatment and persisting until subsequent loss of cell membrane integrity. The significance of this rise in calcium was evaluated by buffering intracellular calcium with BAPTA and/or removing calcium from the extracellular medium and monitoring the effects of these manipulations on calcium signaling and components of the apoptotic process. Complete inhibition of the anti-Fas induced rise in intracellular calcium required both chelation of [Ca2+](i) and removal of extracellular calcium. Interestingly, this condition did not abrogate several events in Fas-induced apoptosis including cell shrinkage, mitochondrial depolarization, annexin binding, caspase activation, and nuclear poly(A)DP-ribose polymerase cleavage. Furthermore, calcium-free conditions in the absence of anti-Fas antibody weakly induced these apoptotic components. In marked contrast, calcium depletion did not induce DNA degradation in control cells, and inhibited apoptotic DNA degradation in response to anti-Fas. These data support the concept that the rise in intracellular calcium is not a necessary component for the early signal transduction pathways in anti-Fas-induced apoptosis in Jurkat cells, but rather is necessary for the final degradation of chromatin via nuclease activation. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 35 TC 51 Z9 52 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 29 PY 2000 VL 275 IS 39 BP 30586 EP 30596 DI 10.1074/jbc.M004058200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 358VM UT WOS:000089577900092 PM 10859318 ER PT J AU Kurys, G Tagaya, Y Bamford, R Hanover, JA Waldmann, TA AF Kurys, G Tagaya, Y Bamford, R Hanover, JA Waldmann, TA TI The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED KILLER-CELLS; IL-15 MESSENGER-RNA; GROWTH-FACTOR; BETA-CHAIN; TRANSLATIONAL EFFICIENCY; ENDOPLASMIC-RETICULUM; MICROSOMAL-MEMBRANES; TRANSLOCATION; EXPRESSION; PROTEINS AB Two isoforms of interleukin (IL)-15 exist: one with a short and another with a long signal peptide (LSP). Experiments using combinations of the LSP and mature proteins IL-2, IL-15, and green fluorescent protein revealed complex pathways of intracellular trafficking. In one pathway, the LSP was unprocessed, and IL-15 was not glycosylated, remained in the cytoplasm, and was degraded. The second trafficking pathway involved endoplasmic reticulum entry, N-linked glycosylation, and alternative partial LSP processing. The third pathway involved endoplasmic reticulum entry, followed by glycosylation, complete processing, and ultimately secretion. The complex intracellular trafficking patterns of LSP-IL-15 with its impediments to secretion as well as impediments to translation may be required due to the potency of IL-15 as an inflammatory cytokine. In terms of a more positive role, we propose that intracellular infection may relieve the burdens on translation and intracellular trafficking to yield effective IL-15 expression. C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, NIH, Bldg 10,Rm 4N115,10 Ctr Dr,MSC 1374, Bethesda, MD 20892 USA. NR 29 TC 74 Z9 76 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 29 PY 2000 VL 275 IS 39 BP 30653 EP 30659 DI 10.1074/jbc.M002373200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 358VM UT WOS:000089577900101 PM 10869346 ER PT J AU Kikyo, N Wade, PA Guschin, D Ge, H Wolffe, AP AF Kikyo, N Wade, PA Guschin, D Ge, H Wolffe, AP TI Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI SO SCIENCE LA English DT Article ID RNA-POLYMERASE-II; XENOPUS-LAEVIS; HISTONE DEACETYLASE; CHROMATIN; PROTEIN; TRANSCRIPTION; BINDING; CELLS; NUCLEOPLASMIN; EXTRACTS AB Cloning by the transplantation of somatic nuclei into unfertilized eggs requires a dramatic remodeling of chromosomal architecture. Many proteins are specifically Lost from nuclei, and others are taken up from the egg cytoplasm. Recreating this exchange in vitro, we identified the chromatin-remodeling nucleosomal adenosine triphosphatase (ATPase) ISWI as a key molecule in this process. ISWI actively erases the TATA binding protein from association with the nuclear matrix. Defining the biochemistry of global nuclear remodeling may facilitate the efficiency of cloning and other dedifferentiation events that establish new stem cell lineages. C1 NIH, Mol Embryol Lab, Bethesda, MD 20892 USA. Sangarno BioSci, Point Richmond Tech Ctr, Richmond, CA 94804 USA. RP Wolffe, AP (reprint author), Sangarno BioSci, Point Richmond Tech Ctr, Richmond, CA 94804 USA. NR 28 TC 178 Z9 190 U1 0 U2 0 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 SEP 29 PY 2000 VL 289 IS 5488 BP 2360 EP 2362 DI 10.1126/science.289.5488.2360 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 359CG UT WOS:000089593500056 PM 11009424 ER PT J AU Li, Q Li, T Wu, JG AF Li, Q Li, T Wu, JG TI Comparative study on the structure of reverse micelles. 2. FT-IR, H-1 NMR, and electrical conductance of H2O/AOT/NaDEHP/n-heptane systems SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID IN-OIL MICROEMULSIONS; AEROSOL OT; PHYSICOCHEMICAL PROPERTIES; NONIONIC SURFACTANTS; CATIONIC SURFACTANTS; WATER/AOT/N-HEPTANE; AROMATIC SOLVENTS; PHASE-BEHAVIOR; TERNARY WATER; PERCOLATION AB The microstructure of mixed reverse micelles stabilized with surfactants of sodium bis(2-ethylhexyl)sulfosuccinate (aerosol OT, or AOT) and/or sodium bis(2-ethylhexyl)phosphate (NaDEHP) has been studied by means of Fourier transform infrared spectroscopy (FT-LR), proton nuclear magnetic resonance (H-1 NMR), and electrical conductometry. The O-H stretching band in IR and the chemical shift in H-1 NMR of water solubilized in the reverse micelles change concomitantly with both water content (W-0, the number of solubilized water molecules per amphipathic molecule) and relative content of surfactants (AOT and NaDEHP). As in the reverse micelles stabilized with AOT and AOT + NaDEHP (50:50), the maxima of conductivity were observed in respective conductivity vs water content (kappa-W-0) curves below the percolation threshold, while the conductivity of.NaDEHP-formed reverse micelles changed proportionally with water content. The striking point is that, at a certain water content, the conductivity of the H2O/AOT/NaDEHP/n-heptane system decreases with increasing temperature from 0 to 55 degrees C, a rare phenomenon in solution. The changes are attributed to the hydration of surfactant ions plus the morphology change of surfactant aggregates in respective systems. C1 Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. RP Li, T (reprint author), NIH, Bldg 10,Rm 9050,10 Ctr Dr, Bethesda, MD 20892 USA. NR 48 TC 76 Z9 77 U1 2 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5647 J9 J PHYS CHEM B JI J. Phys. Chem. B PD SEP 28 PY 2000 VL 104 IS 38 BP 9011 EP 9016 DI 10.1021/jp000336v PG 6 WC Chemistry, Physical SC Chemistry GA 358MG UT WOS:000089561400016 ER PT J AU Mills, JL AF Mills, JL TI Fortification of foods with folic acid. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NICHHD, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 28 PY 2000 VL 343 IS 13 BP 972 EP 972 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 357KT UT WOS:000089501400023 ER PT J AU Knapp, JI Heppner, C Hickman, AB Burns, AL Chandrasekharappa, SC Collins, FS Marx, SJ Spiegel, AM Agarwal, SK AF Knapp, JI Heppner, C Hickman, AB Burns, AL Chandrasekharappa, SC Collins, FS Marx, SJ Spiegel, AM Agarwal, SK TI Identification and characterization of JunD missense mutants that lack menin binding SO ONCOGENE LA English DT Article DE MEN1; menin; JunD; mutagenesis; two-hybrid; tumor suppressor ID ENDOCRINE-NEOPLASIA TYPE-1; C-JUN; MUTATION ANALYSIS; ACTIVATED TRANSCRIPTION; GERMLINE MUTATIONS; AP-1 COMPLEX; CELL-GROWTH; GENE; PROTEIN; FOS AB Menin, the product of the MEN1 tumor suppressor gene, binds to the AP1 transcription factor JunD and represses JunD transcriptional activity. The effects of human or mouse JunD missense mutations upon menin interaction were studied by random and alanine scanning mutagenesis of the menin binding region of JunD (amino acids 1-70). JunD mutant proteins were tested for menin binding in a reverse yeast two-hybrid assay, and for transcriptional regulation by menin in AP1-reporter assays. Random mutagenesis identified two different mutations that disrupted menin interaction at mouse JunD amino acid 42 (G42E and G42R). Mutation G42A generated by alanine scanning did not affect menin binding, likely reflecting the conserved nature of this amino acid substitution. Furthermore, by size exclusion chromatography menin co-migrated with wild type JunD but not with the JunD mutant tested (G42E). Alanine scanning mutagenesis of residues 30-55 revealed two different amino acids, P41 and P44, of mouse JunD that mere critical for interaction with menin. Mouse JunD missense mutants P41A, G42R, G42E and P44A failed to bind menin and also escaped menin's control over their transcriptional activity. At lower amounts of transfected menin, the transcriptional effect of menin on the mutants P41A, G42R and G42E was changed from repression to activation, similar to that with c-jun, In conclusion, a small N-terminal region of JunD mediates a key difference between JunD and c-jun, and a component of this difference is dependent on JunD binding to menin. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 9C-101,10 Ctr Dr,MSC 1802, Bethesda, MD 20892 USA. RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 36 TC 20 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 28 PY 2000 VL 19 IS 41 BP 4706 EP 4712 DI 10.1038/sj.onc.1203832 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 357YB UT WOS:000089528800004 PM 11032020 ER PT J AU Narayan, S Wilson, SH AF Narayan, S Wilson, SH TI Kinetic analysis of Sp1-mediated transcriptional activation of the human DNA polymerase beta promoter SO ONCOGENE LA English DT Article DE Sp1; beta-pol promoter; in vitro transcription; kinetic analysis ID PROTEIN-PROTEIN INTERACTIONS; BOX-BINDING-PROTEINS; TATA-LESS PROMOTER; PREINITIATION COMPLEX; FUNCTIONAL-ANALYSIS; II TRANSCRIPTION; TFIID COMPLEX; SP1; INITIATOR; CLONING AB In the present studies, we have examined the effect of Spl on the activation of the human DNA polymerase beta (beta-pol), a TATA-less promoter. A HeLa cell nuclear extract (NE) based in vitro runoff transcription system of core beta-pol promoter human DNA (p beta P8) three-step kinetic model of transcription initiation were used to describe the kinetic effect of Spl. The results showed that distal Spl-binding sites in the core beta-pol promoter are important for transcriptional activation of the p beta P8 promoter. A detailed kinetic analysis showed that Spl stimulates the activity of the p beta PS promoter through distal Spl-binding sites by increasing the amount of recruitment, instead of stimulating the apparent rate of RPc assembly (k(1)), There was no significant effect of Sp1 on the apparent rate of open complex (RP0) formation (k(2)) Or on the apparent rate of promoter clearance (k(3)) Of the p beta P8 promoter. These studies define the kinetic mechanisms by which Spl may regulate the rate of transcript formation of the p beta P8 promoter, and these results may have implications for Spl regulation of TATA-less promoters. C1 Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, Galveston, TX 77555 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Narayan, S (reprint author), Univ Florida, UF Shands Canc Ctr, POB 100232, Gainesville, FL 32610 USA. FU NCI NIH HHS [CA77721]; NIEHS NIH HHS [ES06492] NR 44 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 28 PY 2000 VL 19 IS 41 BP 4729 EP 4735 DI 10.1038/sj.onc.1203823 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 357YB UT WOS:000089528800007 PM 11032023 ER PT J AU Tycko, R Blanco, FJ Ishii, Y AF Tycko, R Blanco, FJ Ishii, Y TI Alignment of biopolymers in strained gels: A new way to create detectable dipole-dipole couplings in high-resolution biomolecular NMR SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID IMMUNOGLOBULIN-BINDING DOMAIN; LIQUID-CRYSTALLINE MEDIUM; STREPTOCOCCAL PROTEIN-G; MAGNETIC-FIELD; MACROMOLECULES; SYSTEM; RANGE C1 NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RI Blanco, Francisco/D-4401-2009; Ishii, Yoshitaka/F-4558-2014 OI Blanco, Francisco/0000-0003-2545-4319; Ishii, Yoshitaka/0000-0002-7724-6469 NR 25 TC 251 Z9 254 U1 1 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 27 PY 2000 VL 122 IS 38 BP 9340 EP 9341 DI 10.1021/ja002133q PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 359GP UT WOS:000089603400052 ER PT J AU Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G Colan, SD AF Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G Colan, SD CA P2C2 HIV Study Grp TI Cardiac dysfunction and mortality in HIV-infected children - The prospective (PCHIV)-C-2-H-2 multicenter study SO CIRCULATION LA English DT Article DE viruses; mortality; pediatrics; AIDS ID LEFT-VENTRICULAR STRUCTURE AB Background-Left ventricular (LV) dysfunction is common in children infected with the human immunodeficiency virus (HIV), but its clinical importance is unclear. Our objective was to determine whether abnormalities of LV structure and function independently predict all-cause mortality in HIV-infected children. Methods and Results-Baseline echocardiograms were obtained on 193 children with vertically transmitted HIV infection (median age, 2.1 years). Children were followed up for a median of 5 years. Cox regression was used to identify measures of LV structure and function predictive of mortality after adjustment for other important demographic and baseline clinical risk factors. The time course of cardiac variables before mortality was also examined. The 5-year cumulative survival was 64%. Mortality was higher in children who, at baseline, had depressed LV fractional shortening (FS) or contractility; increased LV dimension, thickness, mass, or wall stress; or increased heart rate or brood pressure (P less than or equal to 0.02 for each). Decreased LV FS (P<0.001) and increased wall thickness (P=0.004) were also predictive of increased mortality after adjustment for CD4 count (P<0.001), clinical center (P<0.001), and encephalopathy (P<0.001). FS showed abnormalities for up to 3 years before death, whereas wall thickness identified a population at risk only 18 to 24 months before death. Conclusions-Depressed LV FS and increased wall thickness are risk factors for mortality in HIV-infected children independent of depressed CD4 cell count and neurological disease. FS may be useful as a long-term predictor and wall thickness as a short-term predictor of mortality. C1 Univ Rochester, Med Ctr, Div Pediat Cardiol, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. Childrens Hosp Strong, Rochester, NY USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cardiol, Boston, MA 02115 USA. Boston Med Ctr, Dept Pediat, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Pediat, Div Pediat Cardiol, Cleveland, OH 44195 USA. Univ Calif Los Angeles, Med Ctr, Dept Pediat, Div Pediat Cardiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Columbia Univ, Coll Phys & Surg, Presbyterian Hosp, Dept Pediat,Div Pediat Cardiol, New York, NY USA. Mt Sinai Sch Med, Dept Pediat, Div Pediat Cardiol, New York, NY USA. Baylor Coll Med, Dept Pediat, Div Pediat Cardiol, Houston, TX 77030 USA. NHLBI, Bethesda, MD 20892 USA. RP Lipshultz, SE (reprint author), Univ Rochester, Med Ctr, Div Pediat Cardiol, 601 Elmwood Ave,Box 631, Rochester, NY 14642 USA. RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NCRR NIH HHS [M01 RR000645, M01 RR002172, M01 RR000071, M01 RR000188, M01 RR000533, M01 RR000865, M01 RR000043, K01 RR000188]; NHLBI NIH HHS [N01 HR096037, N01 HR096043, N01-HR-96039, N01-HR-96038] NR 14 TC 81 Z9 84 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 SEP 26 PY 2000 VL 102 IS 13 BP 1542 EP 1548 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 355YC UT WOS:000089415300022 PM 11182983 ER PT J AU Pommier, Y Laco, GS Kohlhagen, G Sayer, JM Kroth, H Jerina, DM AF Pommier, Y Laco, GS Kohlhagen, G Sayer, JM Kroth, H Jerina, DM TI Position-specific trapping of topoisomerase I-DNA cleavage complexes by intercalated benzo[a]pyrene diol epoxide adducts at the 6-amino group of adenine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEOXYADENOSINE N-6-AMINO GROUP; N-RAS CODON-61; NMR SOLUTION STRUCTURE; DG MISMATCH OPPOSITE; TRANS ADDITION; NONANUCLEOTIDE DUPLEX; SOLUTION CONFORMATION; DRUG CAMPTOTHECIN; SEQUENCE; BASE AB DNA topoisomerase I (top1) is the target of potent anticancer agents, including camptothecins and DNA intercalators, which reversibly stabilize (trap) top1 catalytic intermediates (cleavage complexes). The aim of the present study was to define the structural relationship between the site(s) of covalently bound intercalating agents, whose solution conformations in DNA are known, and the site(s) of top1 cleavage. Two diastereomeric pairs of oligonucleotide 22-mers, derived from a sequence used to determine the crystal structure of top1-DNA complexes, were synthesized. One pair contained either a trans-opened 10R- or 10S-benzo[a]pyrene 7,8-diol 9,10-epoxide adduct at the N-6-amino group of a central 2'-deoxyadenosine residue in the scissile strand, and the other pair contained the same two adducts in the non-scissile strand. These adducts were derived from the (+)-(7R,8S,9S,10R)- and (-)-(7S,8R,9R,10S)-7,8-diol 9,10-epoxides in which the benzylic 7-hydroxyl group and the epoxide oxygen are trans. On the basis of analogy with known solution conformations of duplex oligonucleotides containing these adducts, we conclude that top1 cleavage complexes are trapped when the hydrocarbon adduct is intercalated between the base pairs flanking a preexisting top1 cleavage site, or between the base pairs immediately downstream (3' relative to the scissile strand) from this site. We propose a model with the +1 base rotated out of the duplex, and in which the intercalated adduct prevents religation of the corresponding nucleotide at the 5' end of the cleaved DNA. These results suggest mechanisms whereby intercalating agents interfere with the normal function of human top1. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Rm 5D02, Bethesda, MD 20892 USA. NR 50 TC 46 Z9 48 U1 0 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 SEP 26 PY 2000 VL 97 IS 20 BP 10739 EP 10744 DI 10.1073/pnas.190312697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100016 PM 10995470 ER PT J AU Leblanc, BP Benham, CJ Clark, DJ AF Leblanc, BP Benham, CJ Clark, DJ TI An initiation element in the yeast CUP1 promoter is recognized by RNA polymerase II in the absence of TATA box-binding protein if the DNA is negatively supercoiled SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SACCHAROMYCES-CEREVISIAE; TRANSCRIPTIONAL ACTIVATION; IN-VIVO; DUPLEX DESTABILIZATION; METALLOTHIONEIN GENE; BASAL FACTORS; TEMPLATE; SUBUNIT; SITE; RECRUITMENT AB Purified RNA polymerase II initiated transcription from the yeast CUP1 promoter fused to a C-less cassette if the DNA was negatively supercoiled. Relaxed plasmid was not transcribed. Transcription did not require addition of any other transcription factors. TATA box-binding protein (TBP) was not detectable in the polymerase preparation and the TATA box was not required. Deletion analysis of the CUP1 promoter revealed that a 25-bp element containing the initiation region was sufficient for recognition by polymerase. Two transcription start sites were mapped, one of which is identical to one of the two major start sites observed in vivo. Our observations can be accounted for by using a theoretical analysis of the probability of DNA melting within the plasmid as a function of superhelix density: the CUP1 initiation element is intrinsically unstable to superhelical stress, permitting entry of the polymerase. which then scans the DNA to locate the start site. In support of this analysis, the CUP1 promoter was sensitive to mung bean nuclease. These observations and a previous theoretical analysis of yeast genes support the idea that promoters are stress points within the DNA superhelix. The role of transcription factors might be to mark the promoter and to regulate specific melting of promoter DNA. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Biomath Sci, New York, NY 10029 USA. RP Clark, DJ (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bldg 6,Room B1-12, Bethesda, MD 20892 USA. RI Benham, Craig/G-1512-2013 FU NIGMS NIH HHS [R01-GM47012] NR 42 TC 26 Z9 26 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 SEP 26 PY 2000 VL 97 IS 20 BP 10745 EP 10750 DI 10.1073/pnas.200365097 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100017 PM 10984524 ER PT J AU Takei, L Chu, RA Bai, YW AF Takei, L Chu, RA Bai, YW TI Absence of stable intermediates on the folding pathway of barnase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYDROGEN-EXCHANGE; TRANSITION-STATE; UNFOLDED STATE; RIBONUCLEASE-A; BURST PHASE; EQUILIBRIUM; BEHAVIOR; EXTRAPOLATION; DEPENDENCE; PROTEINS AB Barnase is one of the few protein models that has been studied extensively for protein folding. Previous studies led to the conclusion that barnase folds through a very stable submillisecond intermediate (approximate to 3 kcal/mol). The structure of this intermediate was characterized intensively by using a protein engineering approach. This intermediate has now been reexamined with three direct and independent methods. (i) Hydrogen exchange experiments show very small protection factors (approximate to 2) for the putative intermediate, indicating a stability of approximate to 0.0 kcal/mol. (ii) Denaturant-dependent unfolding of the putative intermediate is noncooperative and indicates a stability less than 0.0 kcal/mol. (iii) The logarithm of the unfolding rate constant of native barnase vs. denaturant concentrations is not linear. Together with the measured rate ("I" to N), this nonlinear behavior accounts for almost all of the protein stability, leaving only about 0.3 kcal/mol that could be attributed to the rapidly formed intermediate. Other observations previously interpreted to support the presence of an intermediate are now known to have alternative explanations. These results cast doubts on the previous conclusions on the nature of the early folding state in barnase and therefore should have important implications in understanding the early folding events of barnase and other proteins in general. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 4A-01, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 29 TC 24 Z9 24 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 26 PY 2000 VL 97 IS 20 BP 10796 EP 10801 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100026 ER PT J AU Motaleb, MA Corum, L Bono, JL Elias, AF Rosa, P Samuels, DS Charon, NW AF Motaleb, MA Corum, L Bono, JL Elias, AF Rosa, P Samuels, DS Charon, NW TI Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE spirochete; Lyme disease; allelic exchange; morphology ID SPIROCHETE TREPONEMA-DENTICOLA; OPERON; MUTANT; PEPTIDOGLYCAN; MORPHOLOGY; IDENTIFICATION; INACTIVATION; LEPTOSPIRA; EXPRESSION; SEQUENCE AB Bacterial shape usually is dictated by the peptidoglycan layer of the cell wall. In this paper, we show that the morphology of the Lyme disease spirochete Borrelia burgdorferi is the result of a complex interaction between the cell cylinder and the internal periplasmic flagella. a. burgdorferi has a bundle of 7-11 helically shaped periplasmic flagella attached at each end of the cell cylinder and has a flat-wave cell morphology. Backward moving, propagating waves enable these bacteria to swim in both low viscosity media and highly viscous gel-like media. Using targeted mutagenesis, we inactivated the gene encoding the major periplasmic flagellar filament protein FlaB. The resulting flaB mutants not only were nonmotile, but were rod-shaped. Western blot analysis indicated that FlaB was no longer synthesized, and electron microscopy revealed that the mutants were completely deficient in periplasmic flagella. Wild-type cells poisoned with the protonophore carbonyl cyanide-m-chlorophenyl hydrazone retained their flat-wave morphology, indicating that the periplasmic flagella do not need to be energized for the cell to maintain this shape. Our results indicate that the periplasmic flagella of a. burgdorferi have a skeletal function. These organelles dynamically interact with the rod-shaped cell cylinder to enable the cell to swim, and to confer in part its flat-wave morphology. C1 W Virginia Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Morgantown, WV 26506 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. RP Charon, NW (reprint author), W Virginia Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Box 9177, Morgantown, WV 26506 USA. RI Samuels, D Scott/B-7549-2012; OI Samuels, D Scott/0000-0001-8352-7593; Motaleb, MD Abdul/0000-0003-2761-5104 FU NIAID NIH HHS [AI29743, R01 AI029743] NR 43 TC 111 Z9 113 U1 3 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 26 PY 2000 VL 97 IS 20 BP 10899 EP 10904 DI 10.1073/pnas.200221797 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100044 PM 10995478 ER PT J AU Wada, R Tifft, CJ Proia, RL AF Wada, R Tifft, CJ Proia, RL TI Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microglia; macrophage; apoptosis; cDNA microarray; tumor necrosis factor-alpha ID CENTRAL-NERVOUS-SYSTEM; CREUTZFELDT-JAKOB-DISEASE; NEURONAL APOPTOSIS; CELL-DEATH; ALZHEIMERS-DISEASE; MOUSE MODELS; TAY-SACHS; BRAIN; EXPRESSION; DEMENTIA AB Sandhoff disease is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase and storage of G(M2) ganglioside and related glycolipids in the central nervous system. The glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. In symptomatic Sandhoff disease mice, apoptotic neuronal cell death was prominent in the caudal regions of the brain. cDNA microarray analysis to monitor gene expression during neuronal cell death revealed an upregulation of genes related to an inflammatory process dominated by activated microglia. Activated microglial expansion, based on gene expression and histologic analysis, was found to precede massive neuronal death. Extensive microglia activation also was detected in a human case of Sandhoff disease. Bone marrow transplantation of Sandhoff disease mice suppressed both the explosive expansion of activated microglia and the neuronal cell death without detectable decreases in neuronal G(M2) ganglioside storage. These results suggest a mechanism of neurodegeneration that includes a vigorous inflammatory response as an important component. Thus, this lysosomal storage disease has parallels to other neurodegenerative disorders, such as Alzheimer's and prion diseases, where inflammatory processes are believed to participate directly in neuronal cell death. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9N314, Bethesda, MD 20892 USA. RI Proia, Richard/A-7908-2012 NR 38 TC 241 Z9 249 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 26 PY 2000 VL 97 IS 20 BP 10954 EP 10959 DI 10.1073/pnas.97.20.10954 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100053 PM 11005868 ER PT J AU Mueller, E Smith, M Sarraf, P Kroll, T Aiyer, A Kaufman, DS Oh, W Demetri, G Figg, WD Zhou, XP Eng, C Spiegelman, BM Kantoff, PW AF Mueller, E Smith, M Sarraf, P Kroll, T Aiyer, A Kaufman, DS Oh, W Demetri, G Figg, WD Zhou, XP Eng, C Spiegelman, BM Kantoff, PW TI Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN BREAST-CANCER; PPAR-GAMMA; ADIPOCYTE DIFFERENTIATION; TERMINAL DIFFERENTIATION; RETINOIC ACID; COLON-CANCER; IN-VITRO; TROGLITAZONE; CELLS; THIAZOLIDINEDIONE AB Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPAR gamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPAR gamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPAR gamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPAR gamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. RP Kantoff, PW (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Oh, William/B-9163-2012; Figg Sr, William/M-2411-2016 OI Oh, William/0000-0001-5113-8147; FU NCI NIH HHS [P30CA16058, P30 CA016058] NR 25 TC 329 Z9 337 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 26 PY 2000 VL 97 IS 20 BP 10990 EP 10995 DI 10.1073/pnas.180329197 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100059 PM 10984506 ER PT J AU Smith, CB Kang, J AF Smith, CB Kang, J TI Cerebral protein synthesis in a genetic mouse model of phenylketonuria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BLOOD-BRAIN-BARRIER; PRECURSOR POOL; AMINO-ACIDS; RAT-BRAIN; PLASMA PHENYLALANINE; SYNTHESIS INVIVO; REGIONAL RATES; ADULT-RAT; DEGRADATION; HYPERPHENYLALANINEMIA AB Local rates of cerebral protein synthesis (ICPSleu) were measured with the quantitative autoradiographic [1-C-14]leucine method in a genetic mouse model (Pah(enu2)) of phenylketonuria. As in the human disease. Pah(enu2) mice have a mutation in the gene for phenylalanine hydroxylase. We compared adult homozygous (HMZ) and heterozygous (HTZ) Pah(enu2) mice with the background strain (BTBR). Arterial plasma concentrations of phenylalanine (Phe) were elevated in both HMZ and HTZ mutants by 21 times and 38%, respectively. In the total acid-soluble pool in brain concentrations of Phe were higher and other neutral amino acids lower in HMZ mice compared with either HTZ or BTBR mice indicating a partial saturation of the L-amino acid carrier at the blood brain barrier by the elevated plasma Phe concentrations. In a series of steady-state experiments, the contribution of leucine from the arterial plasma to the tRNA-bound pool in brain was found to be statistically significantly reduced in HMZ mice compared with the other groups, indicating that a greater fraction of leucine in the precursor pool for protein synthesis is derived from protein degradation. We found reductions in ICPSleu of about 20% throughout the brain in the HMZ mice compared with the other two groups, but no reductions in brain concentrations of tRNA-bound neutral amino acids. Our results in the mouse model suggest that in untreated phenylketonuria in adults, the partial saturation of the L-amino acid transporter at the blood-brain barrier may not underlie a reduction in cerebral protein synthesis. C1 NIMH, Cerebral Metab Lab, NIH, US PHS,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Cerebral Metab Lab, NIH, US PHS,Dept Hlth & Human Serv, Bldg 36,Room 1A07,36 Convent Dr, Bethesda, MD 20892 USA. NR 29 TC 38 Z9 39 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 26 PY 2000 VL 97 IS 20 BP 11014 EP 11019 DI 10.1073/pnas.97.20.11014 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358PH UT WOS:000089566100063 PM 11005872 ER PT J AU Yanovski, SZ Billington, CJ Epstein, LH Goodwin, NJ Hill, JO Pi-Sunyer, FX Rolls, BJ Stern, JS Wadden, TA Weinsier, RL Wilson, GT Wing, RR AF Yanovski, SZ Billington, CJ Epstein, LH Goodwin, NJ Hill, JO Pi-Sunyer, FX Rolls, BJ Stern, JS Wadden, TA Weinsier, RL Wilson, GT Wing, RR CA Natl Task Force Prevention Treat TI Dieting and the development of eating disorders in overweight and obese adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID LOW-CALORIE DIET; WEIGHT-LOSS TREATMENT; LONG-TERM MAINTENANCE; UNITED-STATES ADULTS; BEHAVIOR-THERAPY; BINGE EATERS; PSYCHOLOGICAL SYMPTOMS; INDIVIDUALS SUCCESSFUL; CONTROLLED TRIAL; BULIMIA-NERVOSA AB We reviewed articles evaluating the relations among dieting, weight loss treatment, weight cycling, eating disorders, and psychological functioning in overweight and obese adults. Moderate caloric (energy) restriction, in combination with behavioral weight loss treatment, does not seem to cause clinically significant binge eating in overweight adults without preexisting binge eating problems and might ameliorate binge eating, at least in the short term, in those reporting recurrent binge eating before treatment. Most studies of behavioral weight loss interventions report improvements in psychological status during weight loss. However, these improvements might return to baseline with weight regain. Weight cycling does not seem to be associated with clinically significant psychopathologic conditions, although results of cross-sectional studies show an association between weight cycling and binge eating, as well as poorer perceived health status. "Nondieting" approaches seem to lead to improvements in mood and self-esteem; however, weight loss is generally minimal. Concerns that dieting induces eating disorders or other psychological dysfunction in overweight and obese adults are generally not supported by empirical studies. Such concerns should not preclude attempts to reduce caloric intake and increase physical activity to achieve modest weight loss or prevent additional weight gain. C1 Vet Affairs Med Ctr, Minneapolis, MN USA. SUNY Buffalo, Buffalo, NY 14260 USA. Hlth Watch Informat & Promot Serv, New York, NY USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Columbia Univ, St Lukes Roosevelt Hosp Ctr, New York, NY USA. Penn State Univ, State Coll, University Pk, PA 16802 USA. Univ Calif Davis, Davis, CA 95616 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Alabama Birmingham, Birmingham, AL USA. Rutgers State Univ, Piscataway, NJ 08855 USA. Brown Univ, Providence, RI 02912 USA. NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Yanovski, SZ (reprint author), Weight Control Informat Network, 1 Win Way, Bethesda, MD 20892 USA. NR 96 TC 82 Z9 84 U1 12 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 25 PY 2000 VL 160 IS 17 BP 2581 EP 2589 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 357GX UT WOS:000089491100003 ER PT J AU Li, BQ Fu, T Yao, DY Mikovits, JA Ruscetti, FW Wang, JM AF Li, BQ Fu, T Yao, DY Mikovits, JA Ruscetti, FW Wang, JM TI Flavonoid baicalin inhibits HIV-1 infection at the level of viral entry SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE flavonoid; baicalin; HIV-1; fusion; viral entry ID HERBAL MEDICINE; GROWTH; METASTASIS; CHEMOKINES; ASSAY AB Baicalin (BA) is a flavonoid compound purified from medicinal plant Scutellaria baicalensis Georgi and has been shown to possess anti-inflammatory and anti-HIV-1 activities. In an effort to elucidate the mechanism of the anti-inflammatory effect of BG we recently found that this flavonoid compound was able to form complexes with selected chemokines and attenuated their capacity to bind and activate receptors on the cell surface. These observations prompted us to investigate whether BA could inhibit HIV-1 infection by interfering with viral entry, a process known to involve interaction between HIV-1 envelope proteins and the cellular CD4 and chemokine receptors. We found that BA at the noncytotoxic concentrations, inhibited both T cell tropic (X4) and monocyte tropic (R5) HIV-1 Env protein mediated fusion with cells expressing CD4/CXCR4 or CD4/CCR5, Furthermore, presence of BA at the initial stage of HIV-1 viral adsorption blocked the replication of HIV-1 early strong stop DNA in cells. Since BA did not inhibit binding of HIV-1 gp120 to CD4, we propose that BA may interfere with the interaction of HIV-1 Env with chemokine coreceptors and block HIV-1 entry of target cells, Therefore, BA can be used as a basis for developing novel anti-HIV-l agents. C1 NCI, Screening Technol Branch, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Shenyang Airforce Hosp, Shenyang, Liaoning Prov, Peoples R China. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte BIol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Li, BQ (reprint author), NCI, Screening Technol Branch, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. NR 28 TC 115 Z9 140 U1 0 U2 13 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 24 PY 2000 VL 276 IS 2 BP 534 EP 538 DI 10.1006/bbrc.2000.3485 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 358LB UT WOS:000089558600024 PM 11027509 ER PT J AU Sarabi, A Hoffer, BJ Olson, L Morales, M AF Sarabi, A Hoffer, BJ Olson, L Morales, M TI GFR alpha-1 is expressed in parvalbumin GABAergic neurons in the hippocampus SO BRAIN RESEARCH LA English DT Article DE GDNF; interneurons; calcium-binding protein ID CALCIUM-BINDING PROTEIN; KAINATE-INDUCED EXCITATION; C-RET PROTOONCOGENE; MICE LACKING GDNF; NEUROTROPHIC-FACTOR; RAT HIPPOCAMPUS; MESSENGER-RNAS; DOPAMINERGIC-NEURONS; IMMUNOCYTOCHEMICAL LOCALIZATION; INHIBITORY INTERNEURONS AB Glial cell line derived neurotrophic factor (GDNF) is a potent survival factor for several types of neurons. GDNF binds with high affinity to GDNF-family receptor alpha-1 (GFR alpha-1). This receptor is expressed in different areas of the brain, including the hippocampus and dentate gyrus. By using in situ hybridization and immunohistochemistry, we found that 19% to 37% of glutamic acid decarboxylase (GAD) expressing neurons co-expressed GFR alpha-1 in the hippocampus. GFR alpha-1/GAD co-expression was found mainly in the stratum (s) pyramidale (29-37%) and s. oriens (20-25%). Further characterization of GFR alpha-1 expressing interneurons, based on their calcium-binding protein immunoreactivity, demonstrated that many parvalbumin (PV) immunoreactive neurons express GFR alpha-1 in the s. pyramidale of CA1 (72%), CA2 (70%) and CA3 (70%) subfields of the hippocampus. GFR alpha-1/PV double labeled neurons were also detected in the s. oriens of CA1 (52%), CA2 (27%) and CA3 (36%) subfields. The expression of GFR alpha-1 in principal neurons and in a specific sub-population of GABAergic neurons (PV-containing neurons) suggest that GDNF might modulate, in a selective manner, functions of the entire adult hippocampus. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Natl Inst Drug Abuse, Baltimore, MD 21224 USA. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. RP Morales, M (reprint author), Natl Inst Drug Abuse, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 45 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 22 PY 2000 VL 877 IS 2 BP 262 EP 270 DI 10.1016/S0006-8993(00)02682-2 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 355MB UT WOS:000089388500017 PM 10986340 ER PT J AU Furuya, T Salstrom, JL McCall-Vining, S Cannon, GW Joe, B Remmers, EF Griffiths, MM Wilder, RL AF Furuya, T Salstrom, JL McCall-Vining, S Cannon, GW Joe, B Remmers, EF Griffiths, MM Wilder, RL TI Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; GENOME-WIDE SEARCH; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BROWN-NORWAY RATS; SUSCEPTIBILITY LOCI; MULTIPLE-SCLEROSIS; DISEASE SEVERITY; LINKAGE ANALYSIS; DIABETES-PRONE; X-CHROMOSOME AB Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease that is influenced by genetic factors including gender. Many studies suggest that the genetic risk for RA is determined by the MHC, in particular class II alleles with a 'shared epitope' (SE), and multiple non-MHC loci. Other studies indicate that RA and other autoimmune diseases, in particular insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease (ATD), share genetic risk factors. Rat collagen-induced arthritis (CIA) is an experimental model with many features that resemble RA. The spontaneous diabetes-resistant bio-breeding rat, BB(DR), is of interest because it is susceptible to experimentally induced CIA, IDDM and ATD, and it has an SE in its MHC class II allele. To explore the genetics of CIA, including potential gender influences and the genetic relationships between CIA and other autoimmune diseases, we conducted a genome-wide scan for CIA regulatory loci in the F-2 progeny of BB(DR) and CIA-resistant BN rats. We identified 10 quantitative trait loci (QTLs), including 5 new ones (Cia15, Cia16*, Cia17, Cia18* and Cia19 on chromosomes 9, 10, 18 and two on the X chromosome, respectively), that regulated CIA severity. We also identified four QTLs, including two new ones (Ciaa4* and Ciaa5* on chromosomes 4 and 5, respectively), that regulated autoantibody titer to rat type II collagen. Many of these loci appeared to be gender influenced, and most co-localized with several other autoimmune trait loci. Our data support the view that multiple autoimmune diseases may share genetic risk factors, and suggest that many of these loci are gender influenced. C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Vet Affairs Med Ctr, Res Serv, Salt Lake City, UT USA. Univ Utah, Dept Med Rheumatol, Salt Lake City, UT USA. RP Wilder, RL (reprint author), NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N240, Bethesda, MD 20892 USA. NR 67 TC 60 Z9 62 U1 0 U2 0 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 SEP 22 PY 2000 VL 9 IS 15 BP 2241 EP 2250 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 360JP UT WOS:000089664400005 PM 11001927 ER PT J AU Francis, P Chung, JJ Yasui, M Berry, V Moore, A Wyatt, MK Wistow, G Bhattacharya, SS Agre, P AF Francis, P Chung, JJ Yasui, M Berry, V Moore, A Wyatt, MK Wistow, G Bhattacharya, SS Agre, P TI Functional impairment of lens aquaporin in two families with dominantly inherited cataracts SO HUMAN MOLECULAR GENETICS LA English DT Article ID MAJOR INTRINSIC PROTEIN; WATER CHANNELS; MIP; MUTATIONS; BIOLOGY; CHIP AB Opacities in the crystalline lens of eye appear with high frequency in the general population. Dominantly inherited cataracts with differing clinical features were found in two families carrying different point mutations in the gene encoding lens water channel protein AQPO (major intrinsic protein, MIP), Families with E134G have a uni-lamellar cataract which is stable after birth, whereas families with T138R have multi-focal opacities which increase throughout life. To establish pathophysiological relevance of cataract formation, the Xenopus laevis oocyte expression system was employed to evaluate functional defects in the mutant proteins, E134G and T138R. Both substitutions cause loss of membrane water channel activity due to impaired trafficking of the mutant proteins to the oocyte plasma membrane. Although missense mutations in AQP1 and AQP2 proteins are known to result in recessive traits in vivo and in vitro, when E134G or T138R are co-expressed with wild-type AQPO protein, the mutant proteins exhibit dominant negative behaviour. To our knowledge, these studies represent the first in vitro demonstration of functionally defective AQPO protein from humans with congenital cataracts. Moreover, these observations predict that less severe defects in the AQPO protein may contribute to lens opacity in patients with common, less fulminant forms of cataracts. C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. UCL, Inst Ophthalmol, Dept Mol Genet, London EC1V 9EL, England. Moorfields Eye Hosp, London EC1V 9EL, England. Addenbrookes Hosp, Cambridge, England. NEI, NIH, Bethesda, MD 20892 USA. RP Agre, P (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, 75 N Wolfe St, Baltimore, MD 21205 USA. EM pagre@jhmi.edu RI Yasui, Masato/L-3312-2013 FU NEI NIH HHS [EY11239]; NHLBI NIH HHS [HL33991, HL48268] NR 24 TC 95 Z9 100 U1 0 U2 2 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 SEP 22 PY 2000 VL 9 IS 15 BP 2329 EP 2334 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 360JP UT WOS:000089664400015 PM 11001937 ER PT J AU Masuda, A Matsuguchi, T Yamaki, K Hayakawa, T Kubo, M LaRochelle, WJ Yoshikai, Y AF Masuda, A Matsuguchi, T Yamaki, K Hayakawa, T Kubo, M LaRochelle, WJ Yoshikai, Y TI Interleukin-15 induces rapid tyrosine phosphorylation of STAT6 and the expression of interleukin-4 in mouse mast cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN T-CELLS; BETA-CHAIN; IL-4 PRODUCTION; GROWTH-FACTOR; GM-CSF; RECEPTOR; CYTOKINE; LYMPHOKINE; DIFFERENTIATION; ACTIVATION AB Interleukin (IL)-4 plays an important role in the differentiation of naive T helper (Th) cells into Th2. Mast cells can produce a significant amount of IL-4 and have been proposed to play a major role in the induction of Th2 responses. Recently, it has been reported that mast cells have a distinct IL-15 receptor system different from that of T or natural killer cells. In the present study, we demonstrated that IL-15 induced IL-4 production from a mouse mast cell line, MC/9, and bone marrow-derived mast cells. IL-4 mRNA expression was increased by IL-15, suggesting that IL-15 promotes IL-4 expression at the transcriptional Level. In these mast cells, signal transducer and activator of transcription (STAT) 6 were rapidly tyrosine-phosphorylated in response to IL-15. In MC/9 cells, the expression of a C-terminally truncated dominant negative form of STAT6 significantly suppressed the IL-4 mRNA up-regulation by IL-15, suggesting that STAT6 activation is essential for the IL-15-mediated IL-4 production. Additionally, tyrosine phosphorylation of Tyk2 was rapidly increased by IL-15 treatment in this cell line. Altogether, our results suggest that IL-15 plays an important role in stimulating early IL-4 production in mast cells that may be responsible for the initiation of Th2 response. C1 Nagoya Univ, Sch Med, Dis Mechanism & Control Res Inst, Lab Host Def & Germfree Life,Showa Ku, Nagoya, Aichi 4668550, Japan. Nagoya Univ, Sch Med, Dis Mechanism & Control Res Inst, Dept Internal Med 2,Showa Ku, Nagoya, Aichi 4668550, Japan. Sci Univ Tokyo, Res Inst Biol Sci, Div Immunobiol, Tokyo 2780022, Japan. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Matsuguchi, T (reprint author), Nagoya Univ, Sch Med, Dis Mechanism & Control Res Inst, Lab Host Def & Germfree Life,Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. RI Masuda, Akio/H-6323-2012 NR 43 TC 44 Z9 45 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 22 PY 2000 VL 275 IS 38 BP 29331 EP 29337 DI 10.1074/jbc.M910290199 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356JH UT WOS:000089439800022 PM 10882748 ER PT J AU Henneberry, AL Wistow, G McMaster, CR AF Henneberry, AL Wistow, G McMaster, CR TI Cloning, genomic organization, and characterization of a human cholinephosphotransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CDP-CHOLINE PATHWAY; PLATELET-ACTIVATING-FACTOR; SACCHAROMYCES-CEREVISIAE; TRANSFER PROTEIN; PHOSPHATIDYLCHOLINE BIOSYNTHESIS; PHOSPHOLIPID BIOSYNTHESIS; SN-1,2-DIACYLGLYCEROL CHOLINEPHOSPHOTRANSFERASE; PHOSPHATIDYLETHANOLAMINE BIOSYNTHESIS; FINAL STEP; ETHANOLAMINEPHOSPHOTRANSFERASE AB A cholinephosphotransferase activity catalyzes the final step in the de novo synthesis of phosphatidylcholine Dia the transfer of a phosphocholine moiety from CDP choline to diacylglycerol. Ethanolaminephosphotransferase activity catalyzes a similar reaction substituting CDP ethanolamine as the phosphobase donor. We report the identification and cloning of a human cDNA (human cholinephosphotransferase (hCPT1)) that codes for a cholinephosphotransferase-specific enzyme. This was demonstrated using in vitro enzyme assays and in vivo measurement of the reconstitution of the phosphatidylcholine and phosphatidylethanolamine biosynthetic pathways in yeast cells devoid of their own endogenous cholinephosphotransferase and ethanolaminephosphotransferase activities. This contrasted with our previously cloned human choline/ethanolaminephosphotransferase cDNA that was demonstrated to code for a dual specificity choline/ethanolaminephosphotransferase. The hCPT1 and human choline/ethanolaminephosphotransferase (hCEPT1) predicted amino acid sequences possessed 60% overall identity and had only one variation in the amino acid residues within the CDP-alcohol phosphotransferase catalytic motif, In vitro assessment of hCPT1 and hCEPT1 derived cholinephosphotransferase activities also revealed differences in diradylglycerol specificities including their capacity to synthesize platelet-activating factor and platelet-activating factor precursor. Expression of the hCPT1 mRNA varied greater than 100-fold between tissues and was most abundant in testis followed by colon, small intestine, heart, prostate, and spleen. This was in marked contrast to the hCEPT1 mRNA, which has been found in similar abundance in all tissues tested to date. Both the hCPT1 and hCEPT1 enzymes were able to reconstitute the synthesis of PC in yeast to levels provided by the endogenous yeast cholinephosphotransferase; however, only hCEPT1-derived activity was able to complement the yeast CPT1 gene in its interaction with SEC14 and affect cell growth. C1 Dalhousie Univ, IWK Grace Hlth Ctr, Dept Pediat, Atlantic Res Ctr, Halifax, NS B3H 4H7, Canada. Dalhousie Univ, IWK Grace Hlth Ctr, Dept Biochem & Mol Biol, Atlantic Res Ctr, Halifax, NS B3H 4H7, Canada. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP McMaster, CR (reprint author), Dalhousie Univ, IWK Grace Hlth Ctr, Dept Pediat, Atlantic Res Ctr, Halifax, NS B3H 4H7, Canada. NR 54 TC 57 Z9 61 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 22 PY 2000 VL 275 IS 38 BP 29808 EP 29815 DI 10.1074/jbc.M005786200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356JH UT WOS:000089439800086 PM 10893425 ER PT J AU Dhanvantari, S Loh, YP AF Dhanvantari, S Loh, YP TI Lipid raft association of carboxypeptidase E is necessary for its function as a regulated secretory pathway sorting receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GPI-ANCHORED PROTEINS; INFLUENZA-VIRUS HEMAGGLUTININ; DISULFIDE-BONDED LOOP; TRANS-GOLGI NETWORK; CHROMOGRANIN-B; TRANSMEMBRANE DOMAIN; MEMBRANE DOMAINS; CELL-SURFACE; CHOLESTEROL; IDENTIFICATION AB Membrane carboxypeptidase E (CPE) is a sorting receptor for targeting prohormones, such as pro-opiomelanocortin, to the regulated secretory pathway in endocrine cells. Its membrane association is necessary for it to bind a prohormone sorting signal at the trans-Golgi network (TGN) to facilitate targeting. In this study, we examined the lipid interaction of CPE in bovine pituitary secretory granule membranes, which are derived from the TGN. We show that CPE is associated with detergent-resistant lipid domains, or rafts, within secretory granule membranes. Lipid analysis revealed that these rafts are enriched in glycosphingolipids and cholesterol. Pulse-chase and subcellular fractionation experiments in AtT-20 cells show that the association of CPE with membrane rafts occurred only after it reached the Golgi. Cholesterol depletion resulted in dissociation of CPE from secretory granule membranes and decreased the binding of prohormones to membranes, lit vivo cholesterol depletion using lovastatin resulted in the lack of sorting of CPE and its cargo to the regulated secretory pathway. We propose that the sorting receptor function of CPE necessitates its interaction with glycosphingolipid-cholesterol rafts at the TGN, thereby anchoring it in position to bind to its prohormone cargo. C1 NICHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bldg 49,Rm 5A38,MSC 4480,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Dhanvantari, Savita/B-5362-2015 NR 47 TC 87 Z9 89 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 22 PY 2000 VL 275 IS 38 BP 29887 EP 29893 DI 10.1074/jbc.M005364200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356JH UT WOS:000089439800096 PM 10896946 ER PT J AU Tong, XK Hussain, NK Adams, AG O'Bryan, JP McPherson, PS AF Tong, XK Hussain, NK Adams, AG O'Bryan, JP McPherson, PS TI Intersectin can regulate the Ras/MAP kinase pathway independent of its role in endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; EPIDERMAL GROWTH-FACTOR; NUCLEOTIDE EXCHANGE FACTOR; CLATHRIN-MEDIATED ENDOCYTOSIS; RECEPTOR INTERNALIZATION; SIGNAL-TRANSDUCTION; PHENYLARSINE OXIDE; ADAPTER PROTEIN; EPS15 HOMOLOGY; BETA-ARRESTIN AB We previously identified intersectin, a multiple EH and SH3 domain-containing protein, as a component of the endocytic machinery. Overexpression of the SH3 domains of intersectin blocks transferrin receptor endocytosis, possibly by disrupting targeting of accessory proteins of clathrin-coated pit formation. More recently, we identified mammalian Sos, a guanine-nucleotide exchange factor for Pas, as an intersectin SH3 domain-binding partner. We now demonstrate that overexpression of intersectin's SH3 domains blocks activation of Ras and MAP kinase in various cell lines. Several studies suggest that activation of MAP kinase downstream of multiple receptor types is dependent on endocytosis. Thus, the dominant-negative effect of the SH3 domains on Ras/MAP kinase activation may be indirectly mediated through a block in endocytosis. Consistent with this idea, incubating cells at 4 degrees C or with phenylarsine oxide, treatments previously established to inhibit EGF receptor endocytosis, blocks EGF-dependent activation of MAP kinase. However, under these conditions, Pas activity is unaffected and overexpression of the SH3 domains of intersectin is still able to block Pas activation. Thus, intersectin SH3 domain overexpression can effect EGF-mediated MAP kinase activation directly through a block in Pas, consistent with a functional role for intersectin in Ras activation. C1 McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP McPherson, PS (reprint author), McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. NR 54 TC 59 Z9 63 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 22 PY 2000 VL 275 IS 38 BP 29894 EP 29899 DI 10.1074/jbc.M004096200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356JH UT WOS:000089439800097 PM 10896662 ER PT J AU Chernukhin, IV Shamsuddin, S Robinson, AF Carne, AF Paul, A El-Kady, AI Lobanenkov, VV Klenova, EM AF Chernukhin, IV Shamsuddin, S Robinson, AF Carne, AF Paul, A El-Kady, AI Lobanenkov, VV Klenova, EM TI Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-MYC GENE; TRANSCRIPTION FACTOR YB-1; HUMAN POLYOMAVIRUS JC; NUCLEAR FACTOR; 5'-FLANKING SEQUENCE; PRECURSOR PROMOTER; MESSENGER-RNA; DNA-SEQUENCE; EXPRESSION; CELLS AB CTCF is a unique, highly conserved, and ubiquitously expressed 11 zinc finger (ZF) transcriptional factor with multiple DNA site specificities. It is able to bind to varying target sequences to perform different regulatory roles, including promoter activation or repression, creating hormone-responsive gene silencing elements, and functional block of enhancer-promoter interactions. Because different sets of ZFs are utilized to recognize different CTCF target DNA sites, each of the diverse DNA.CTCF complexes might engage different essential protein partners to define distinct functional readouts. To identify such proteins, we developed an affinity chromatography method based on matrix-immobilized purified recombinant CTCF. This approach resulted in isolation of several CTCF protein partners. One of these was identified as the multifunctional Y-box DNA/RNA-binding factor, YB-1, known to be involved in transcription, replication, and RNA processing. We examined CTCF/YB-1 interaction by reciprocal immunoprecipitation experiments with anti-CTCF and anti-YB-l antibodies, and found that CTCF and YB-1 form complexes in vivo. We show that the bacterially expressed ZF domain of CTCF is fully sufficient to retain YB-1 in vitro. To assess possible functional significance of CTCF/YB-1 binding, we employed the very first identified by us, negatively regulated, target for CTCF (c-myc oncogene promoter) as a model in co-transfection assays with both CTCF and YB-1 expression vectors. Although expression of YB-1 alone had no effect, co-expression with CTCF resulted in a marked enhancement of CTCF-driven c-myc transcriptional repression. Thus our findings demonstrate, for the first time, the biological relevance of the CTCF/YB-1 interaction. C1 Univ Oxford, Dept Biochem, Genet Lab, Oxford OX1 3QU, England. Inst Canc Res, Haddow Labs, Surrey, England. NIAID, Sect Mol Pathol, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Klenova, EM (reprint author), Univ Oxford, Dept Biochem, Genet Lab, S Parks Rd, Oxford OX1 3QU, England. RI Shamsuddin, Shaharum/A-7907-2011; Elkady, Ayman/J-5738-2012; OI Shamsuddin, Shaharum/0000-0001-9997-7740; Lobanenkov, Victor/0000-0001-6665-3635 NR 70 TC 71 Z9 74 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 22 PY 2000 VL 275 IS 38 BP 29915 EP 29921 DI 10.1074/jbc.M001538200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356JH UT WOS:000089439800100 PM 10906122 ER PT J AU Vos, CMP Gartner, S Ransohoff, RM McArthur, JC Wahl, L Sjulson, L Hunter, E Conant, K AF Vos, CMP Gartner, S Ransohoff, RM McArthur, JC Wahl, L Sjulson, L Hunter, E Conant, K TI Matrix metalloprotease-9 release from monocytes increases as a function of differentiation: implications for neuroinflammation and neurodegeneration SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE MMP-9; MCP-1; monocytes; CCR-2 ID BLOOD-BRAIN-BARRIER; HUMAN-IMMUNODEFICIENCY-VIRUS; LOW-DENSITY-LIPOPROTEIN; TUMOR-NECROSIS-FACTOR; CHEMOATTRACTANT PROTEIN-1; REDUCES ATHEROSCLEROSIS; CHEMOTACTIC PROTEIN-1; CHEMOKINE RECEPTOR; CCR2 EXPRESSION; DEFICIENT MICE AB Naive monocytes extravasate in response to monocyte chemoattractant-l (MCP-1) and subsequently, following differentiation within tissue, carry out effector functions. Consistent with this concept, expression of the MCP-I receptor CCR2 decreases with monocyte differentiation, as production of cytokines increases (Fantuzzi et al., 1999). Because matrix metalloproteases (MMPs) may also play an important role in the ability of monocytes to migrate into tissues and/or to promote pathogen clearance/tissue injury, we have examined production of matrix metalloprotease-9 as a function of both monocyte differentiation in vitro and expression of CCR2. Increased time in culture, which is linked to monocyte differentiation, resulted in enhanced production of MMP-9, assessed by gelatin substrate zymography. Further, CCR2-negative monocytes produced greater quantities of MMP-9 than did naive CCR2-positive cells. Our results indicate that MMP-9 release increases during monocyte differentiation, consistent with a prominent role in effector functions. Because extracellular matrix proteins are important to cell structure and survival (Wee Yong et al., 1998), increased expression of MMP-9 could contribute to tissue damage following; monocyte differentiation. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. Leiden Univ, Sylvius Labs, Leiden Amsterdam Ctr Drug Res, Dept Pharmacol, Leiden, Netherlands. Cleveland Clin, Lerner Res Inst, Dept Neurol, Cleveland, OH USA. Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Natl Inst Dent & Craniofacial Res, Immunopathol Sect, Bethesda, MD USA. RP Conant, K (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, 600 N Wolfe St, Baltimore, MD 21287 USA. FU NCRR NIH HHS [RR00722]; NIAID NIH HHS [AI35042]; NINDS NIH HHS [NS26643] NR 38 TC 31 Z9 31 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 SEP 22 PY 2000 VL 109 IS 2 BP 221 EP 227 DI 10.1016/S0165-5728(00)00308-8 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 358VC UT WOS:000089577000020 PM 10996224 ER PT J AU Stern, EL Quan, N Proescholdt, MG Herkenham, M AF Stern, EL Quan, N Proescholdt, MG Herkenham, M TI Spatiotemporal induction pattens of cytokine and related immune signal molecule mRNAs in response to intrastriatal injection of lipopolysaccharide (vol. 106, pg. 114, 2000) SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Correction ID TUMOR-NECROSIS-FACTOR; NITRIC-OXIDE SYNTHASE; MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; INTERLEUKIN-1 RECEPTOR ANTAGONIST; MICROVESSEL ENDOTHELIAL-CELLS; FACTOR-ALPHA EXPRESSION; FACTOR KAPPA-B; GENE-EXPRESSION; RAT-BRAIN AB The brain's response to a direct immune challenge was examined by in situ hybridization histochemistry. Lipopolysaccharide (bacterial endotoxin) injected acutely into rat striatum induced mRNA expression for inhibitory factor kappa B alpha, interleukin (IL)-1 beta, tumor necrosis factor-alpha, IL-6, IL-12, p35, inducible nitric oxide synthase, IL-1 receptor antagonist, and the type 1 IL-1 receptor. Expression patterns were evaluated at select time points ranging from 15 min to 3 days post-injection. Rats injected with vehicle alone were used to control for mechanical effects. Following lipopolysaccharide administration, a wave of mRNA induction within brain parenchyma radiated outward from the injection site, generally peaking in intensity at the 16-h time point. The individual profiles of cytokine mRNA induction patterns reveal that the brain's immune response to local inflammatory stimulation is quite elaborate and in many ways resembles the progression of cytokine induction customary of localized inflammation in peripheral tissues. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. NR 90 TC 0 Z9 0 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 SEP 22 PY 2000 VL 109 IS 2 BP 244 EP 260 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 358VC UT WOS:000089577000023 ER PT J AU Zhang, XC Lee, YK Kelley, JA Burke, TR AF Zhang, XC Lee, YK Kelley, JA Burke, TR TI Preparation of aryl isothiocyanates via protected phenylthiocarbamates and application to the synthesis of caffeic acid (4-isothiocyanato)phenyl ester SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HIV-1 INTEGRASE INHIBITORS; IRREVERSIBLE LIGANDS; OPIATE RECEPTORS; DELTA-OPIATE; MU-OPIATE; THIOCYANATE; TRANSFORMATION; ANALOGS; AGENTS; AMINES C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Rm 5C06, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014 NR 34 TC 21 Z9 21 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 22 PY 2000 VL 65 IS 19 BP 6237 EP 6240 DI 10.1021/jo000139s PG 4 WC Chemistry, Organic SC Chemistry GA 354PJ UT WOS:000089338600051 PM 10987967 ER PT J AU Burke, TR Liu, DG Gao, Y AF Burke, TR Liu, DG Gao, Y TI Use of a heck reaction for the synthesis of a new alpha-azido phosphotyrosyl mimetic suitably protected for peptide synthesis SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ENANTIOSELECTIVE SYNTHESIS; ASYMMETRIC-SYNTHESIS; CARBOXYLIC-ACIDS; AMINO-ACIDS; TYROSINE C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Rm 5C06, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014 NR 23 TC 36 Z9 36 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 22 PY 2000 VL 65 IS 19 BP 6288 EP 6291 DI 10.1021/jo000643x PG 4 WC Chemistry, Organic SC Chemistry GA 354PJ UT WOS:000089338600065 PM 10987981 ER PT J AU Paul, WE Mage, RG AF Paul, WE Mage, RG TI Elvin A. Kabat (1914-2000) - Obituary SO NATURE LA English DT Biographical-Item C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 21 PY 2000 VL 407 IS 6802 BP 316 EP 316 DI 10.1038/35030291 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 355NA UT WOS:000089390700030 PM 11014176 ER PT J AU Azzam, NA Hallenbeck, JM Kachar, B AF Azzam, NA Hallenbeck, JM Kachar, B TI Membrane changes during hibernation - Organelle lipids undergo rapidly reversible rearrangement as body temperature drops. SO NATURE LA English DT Article ID PHASE-TRANSITIONS C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. RP Azzam, NA (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 9 TC 24 Z9 27 U1 2 U2 8 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 21 PY 2000 VL 407 IS 6802 BP 317 EP 318 DI 10.1038/35030294 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 355NA UT WOS:000089390700031 PM 11014177 ER PT J AU Modi, S Kubo, A Oie, H Coxon, AB Rehmatulla, A Kaye, FJ AF Modi, S Kubo, A Oie, H Coxon, AB Rehmatulla, A Kaye, FJ TI Protein expression of the RB-related gene family and SV40 large T antigen in mesothelioma and lung cancer SO ONCOGENE LA English DT Article DE RB; RBL1/p107; RBL2/p130; SV40; mesothelioma ID CARCINOMA CELL-LINES; RETINOBLASTOMA PROTEIN; DIFFERENTIAL EXPRESSION; MALIGNANT MESOTHELIOMA; GROWTH SUPPRESSION; SIMIAN VIRUS-40; DNA-SEQUENCES; P107; SIMIAN-VIRUS-40; E2F AB Mutational inactivation of the RE-related gene RBL2/ p130 has been reported as a common and important prognostic factor in human lung cancer. To examine the role of the RE-related gene family in lung cancer we analysed the protein expression of the RE gene in cell Lines obtained from 83 patients with small cell lung cancer (SCLC) and 114 patients with non-SCLC that included 21 novel lung tumor samples. While we detected five new SCLC with mutant RE expression (RB inactivation in 75/83; 90.4%), we did not detect any RE mutations in the new non-SCLC cell lines (RB inactivation in 13/114 non-SCLC and mesothelioma; 11.4%), In addition, we detected expression of a full-length RBL1/p107 and RBL2/p130 species in every sample tested (RBL1 or RBL2 inactivation in 0/69) and confirmed that both RE-related gene products retain functional binding activity to the E1A viral oncoprotein. Since expression of SV40 Large T antigen (Tag) has been reported in a subset of human lung tumors where it may inactivate RBL1 and RBL2, we also examined mesothelioma and non-mesothelioma lung tumors for Tag expression. Although we detected a faint 85 kDa protein species using specific anti-Tag antibodies, this signal migrated slightly faster than Tag extracted from Cos7 cells and did not exhibit binding activity to the RE or RBL1 proteins, Finally, we subjected 11 lung cancer cell lines to nucleotide sequencing and did not detect mutations within the C-terminal RBL2 exons 19-22 as recently reported. While the RB/p16 tumor suppressor pathway is targeted for mutations in 100% of lung cancers, mutational inactivation of the related RBL1 and RBL2 genes is a rare event. C1 Natl Naval Med Ctr, Med Branch, Bethesda, MD 20889 USA. NCI, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. RP Kaye, FJ (reprint author), Natl Naval Med Ctr, Med Branch, Bldg 8,Room 5101, Bethesda, MD 20889 USA. RI kaye, frederic/E-2437-2011 NR 57 TC 31 Z9 33 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 21 PY 2000 VL 19 IS 40 BP 4632 EP 4639 DI 10.1038/sj.onc.1203815 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 356HQ UT WOS:000089438200009 PM 11030152 ER PT J AU Mautino, MR Morgan, RA AF Mautino, MR Morgan, RA TI Potent inhibition of human immunodeficiency virus type 1 replication by conditionally replicating human immunodeficiency virus-based lentiviral vectors expressing envelope antisense mRNA SO HUMAN GENE THERAPY LA English DT Article ID HIV-1 REPLICATION; TRANSDOMINANT REV; NONDIVIDING CELLS; GENE-THERAPY; LYMPHOCYTES; RNA; TRANSDUCTION; RETROVIRUS; RIBOZYME; DELIVERY AB We describe an HIV-based lentiviral vector that expresses a 1-kb antisense mRNA directed against the HIV-1 mRNAs containing env sequences. The expression of antisense env mRNAs (envAS) does not inhibit the synthesis of p24 expressed from the HIV-1 helper plasmid used to package the vector, as this helper has a deletion in the env gene. This allows the production of high-titer VSV-G pseudotyped lentiviral particles. In challenge experiments using unselected populations of SupT1 cells transduced with this vector, a complete inhibition of HIV-1 replication was observed for long periods of irt vitro culture, even at high HIV-1 infectious doses. The potent inhibition of HIV-1 replication by this vector correlated with a low occurrence of mobilization of the vector to previously untransduced cells. The infectivity of the wild-type HIV-1 that escapes inhibition was highly inhibited, suggesting that the vector is providing HIV-1 inhibition of replication not only due to its antisense effect but also by competing for encapsidation and mobilization to noninfected cells. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 32 TC 25 Z9 28 U1 0 U2 0 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 SEP 20 PY 2000 VL 11 IS 14 BP 2025 EP 2037 DI 10.1089/10430340050143444 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 359BU UT WOS:000089592300006 PM 11020801 ER PT J AU Otsu, M Sugamura, K Candotti, F AF Otsu, M Sugamura, K Candotti, F TI In vivo competitive studies between normal and common gamma chain-defective bone marrow cells: Implications for gene therapy SO HUMAN GENE THERAPY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC PROGENITOR CELLS; LYMPHOID DEVELOPMENT; MEDIATED TRANSFER; MICE; DIFFERENTIATION; TRANSPLANTATION; REPOPULATION; EXPRESSION; EXPANSION AB Corrective gene transfer into hematopoietic stem cells (HSCs) is being investigated as therapy for X-linked severe combined immunodeficiency (XSCID) and it is hoped that selective advantage of gene-corrected HSCs will help in achieving full immune reconstitution after treatment. Lines of evidence from the results of allogeneic bone marrow transplantation in patients with XSCID support this hypothesis that, however, has not been rigorously tested in an experimental system. We studied the competition kinetics between normal and XSCID bone marrow (BM) cells using a murine bone marrow transplantation (BMT) model. For easy chimerism determination, we used genetic marking with retrovirus-mediated expression of the enhanced green fluorescent protein (EGFP), We found that XSCID BR I cells were able to compete with normal BR I cells for engraftment of myeloid lineages in a dose-dependent manner, whereas we observed selective repopulation of T, B, and NK cells deriving from normal BM cells. This was true despite the evidence of competitive engraftment of XSCID lineage marker-negative/c-Kit-positive (Lin(-)/c-Kit(+)) cells in the bone marrow of treated animals. From these results we extrapolate that genetic correction of XSCID HSCs will result in selective advantage of gene-corrected lymphoid lineages with consequent restoration of lymphocyte populations and high probability of clinical benefit. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Tohoku Univ, Sch Med, Dept Microbiol, Sendai, Miyagi 9808575, Japan. RP Candotti, F (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10C103, Bethesda, MD 20892 USA. OI Otsu, Makoto/0000-0002-9769-0217 NR 28 TC 14 Z9 14 U1 0 U2 0 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 SEP 20 PY 2000 VL 11 IS 14 BP 2051 EP 2056 DI 10.1089/10430340050143462 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 359BU UT WOS:000089592300008 PM 11020803 ER PT J AU Cantrell, CL Gustafson, KR Cecere, MR Pannell, LK Boyd, MR AF Cantrell, CL Gustafson, KR Cecere, MR Pannell, LK Boyd, MR TI Chondropsins A and B: Novel tumor cell growth-inhibitory macrolide lactams from the marine sponge Chondropsis sp SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DINOFLAGELLATE AMPHIDINIUM SP; CYTOTOXIC MACROLIDES; SYMBIOTIC DINOFLAGELLATE; ZOOXANTHELLATOXIN-A; THEONELLA SP; SPECTROSCOPY; COERULEA; LACTONE; C-13; H-1 AB Antiproliferative bioassay-guided fractionation of an aqueous extract of the marine sponge Chondropsis sp. provided two novel macrolides, chondropsins A (1) and B (2). The structures were elucidated by a combination of spectroscopic analysis and chemical modification. HMBC, TOCSY, NOESY, and HSQC-TOCSY experiments were particularly useful for the structural assignments of these polyketide-derived metabolites. The chondropsins define an unprecedented class of polyunsaturated, polyhydroxylated, 35-membered macrocycles which incorporate both lactone and lactam functionalities. An additional unique feature of these compounds is a complex, amide-linked, polyketide side chain. Testing of chondropsin A (1) in the NCI 60-cell screen revealed a mean-graph profile that did not correlate significantly with the profile of any compound class represented in the NCI standard agents database. The chondropsins therefore represent an interesting new lead for cancer therapeutics research. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag, Bldg 1052,Room 121, Frederick, MD 21702 USA. NR 41 TC 23 Z9 24 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 20 PY 2000 VL 122 IS 37 BP 8825 EP 8829 DI 10.1021/ja0010711 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 356QK UT WOS:000089453800003 ER PT J AU Frisch, M Biggar, IJ Goedert, JJ AF Frisch, M Biggar, IJ Goedert, JJ TI Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; CERVICAL INTRAEPITHELIAL NEOPLASIA; HIV-INFECTION; HOMOSEXUAL MEN; SAN-FRANCISCO; BISEXUAL MEN; ANAL CANCER; WOMEN; RISK; LESIONS AB Background: Human papillomavirus (HPV)-associated anogenital malignancies occur frequently in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). The purpose of our study was to determine if the high frequency of these cancers is due to lifestyle factors associated with both HPV and HIV infections or to immunosuppression following HIV infection. Methods: We studied invasive and in situ HPV-associated cancers among 309365 U.S. patients with HIV infection/AIDS (257605 males and 51760 females) from 5 years before the date of AIDS onset to 5 years after this date. Sex-, race-, and age-standardized ratios of observed-to-expected cancers served as measures of relative risk (RR). Trend tests were used to evaluate changes in the RRs during the 10 years spanning AIDS onset. All statistical tests were two-sided. Results: All HPV-associated cancers in AIDS patients occurred in statistically significant excess compared with the expected numbers of cancers. For in situ cancers, overall risks were significantly increased for cervical (RR = 4.6; 95% confidence interval [CI] = 4.3-5.0), vulvar/vaginal (RR = 3.9; 95% CI = 2.0-7.0), anal (in females, RR = 7.8 [95% CI = 0.2-43.6]; in males, RR = 60.1 [95% CI = 49.2- 72.7]), and penile (RR = 6.9; 95% CI = 4.2-10.6) cancers, and RRs increased during the 10 years spanning AIDS onset for carcinomas in situ of the cervix (P for trend <.001), vulva/ vagina (P for trend =.04), and penis (P for trend =.04). For invasive cancers, overall risks were significantly increased for cervical (RR = 5.4; 95% CI = 3.9-7.2), vulvar/vaginal (RR = 5.8; 95% CI = 3.0-10.2), and anal (RR = 6.8; 95% CI = 2.7-14.0) cancers in females and for anal (RR = 37.9; 95% CI = 33.0-43.4), penile (RR = 3.7; 95% CI = 2.0-6.2), tonsillar (RR = 2.6; 95% CI = 1.8-3.8), and conjunctival (RR = 14.6; 95% CI = 5.8-30.0) cancers in males. However, RRs for invasive cancers changed little during the 10 years spanning AIDS onset. Conclusions: HPV-associated malignancies occur at increased rates in persons with HIV/AIDS. Increasing RRs for in situ cancers to and beyond the time of AIDS onset may reflect the gradual loss of control over HPV-infected keratinocytes with advancing immunosuppression. However, the lack of a similar increase for invasive HPV-associated cancers suggests that late-stage cancer invasion is not greatly influenced by immune status. C1 Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Frisch, M (reprint author), Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, 5 Artillerivej, DK-2300 Copenhagen S, Denmark. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 FU NCI NIH HHS [Y1CP8040-02] NR 58 TC 494 Z9 502 U1 0 U2 18 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 20 PY 2000 VL 92 IS 18 BP 1500 EP 1510 DI 10.1093/jnci/92.18.1500 PG 11 WC Oncology SC Oncology GA 353XH UT WOS:000089300400008 PM 10995805 ER PT J AU Syrjakoski, K Vahteristo, P Eerola, H Tamminen, A Kivinummi, K Sarantaus, L Holli, K Blomqvist, C Kallioniemi, OP Kainu, T Nevanlinna, H AF Syrjakoski, K Vahteristo, P Eerola, H Tamminen, A Kivinummi, K Sarantaus, L Holli, K Blomqvist, C Kallioniemi, OP Kainu, T Nevanlinna, H TI Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID OVARIAN-CANCER; GENE-MUTATIONS; LOW PROPORTION; WOMEN; PREVALENCE; FAMILIES; RISK; FREQUENCY C1 Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Oncol, Tampere, Finland. Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Oncol, FIN-00029 Helsinki, Finland. Univ Uppsala Hosp, Dept Oncol, S-75185 Uppsala, Sweden. Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. RP Nevanlinna, H (reprint author), Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, POB 140,Haartmaninkatu 2, FIN-00029 Helsinki, Finland. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 22 TC 140 Z9 143 U1 1 U2 5 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 20 PY 2000 VL 92 IS 18 BP 1529 EP 1531 DI 10.1093/jnci/92.18.1529 PG 3 WC Oncology SC Oncology GA 353XH UT WOS:000089300400012 PM 10995809 ER PT J AU Pirnia, F Breuleux, M Schneider, E Hochmeister, M Bates, SE Marti, A Hotz, MA Betticher, DC Borner, MM AF Pirnia, F Breuleux, M Schneider, E Hochmeister, M Bates, SE Marti, A Hotz, MA Betticher, DC Borner, MM TI Uncertain identity of doxorubicin-resistant MCF-7 cell lines expressing mutated p53 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID BREAST-CANCER CELLS; CASPASE-3 C1 Inselspital Bern, Inst Med Oncol, CH-3010 Bern, Switzerland. Inselspital Bern, Dept Ear Nose & Throat, CH-3010 Bern, Switzerland. Univ Bern, Dept Forens Med, CH-3012 Bern, Switzerland. Univ Bern, Dept Clin Res, CH-3012 Bern, Switzerland. New York State Dept Hlth, Wadsworth Ctr, Div Mol Med, Albany, NY USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Borner, MM (reprint author), Inselspital Bern, Inst Med Oncol, CH-3010 Bern, Switzerland. RI Borner, Markus/B-7583-2011 NR 7 TC 17 Z9 17 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 20 PY 2000 VL 92 IS 18 BP 1535 EP 1536 DI 10.1093/jnci/92.18.1535 PG 2 WC Oncology SC Oncology GA 353XH UT WOS:000089300400017 PM 10995814 ER PT J AU Simon, R AF Simon, R TI Are placebo-controled clinical trials ethical or needed when alternative treatment exists? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, 6130 Execut Blvd,Room 739, Bethesda, MD 20892 USA. NR 5 TC 37 Z9 41 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 19 PY 2000 VL 133 IS 6 BP 474 EP 475 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 354KM UT WOS:000089329700011 PM 10975967 ER PT J AU Zhu, XG Borchers, C Bienstock, RJ Tomer, KB AF Zhu, XG Borchers, C Bienstock, RJ Tomer, KB TI Mass spectrometric characterization of the glycosylation pattern of HIV-gp120 expressed in CHO cells SO BIOCHEMISTRY LA English DT Article ID ENVELOPE GLYCOPROTEIN GP120; SITE-SPECIFIC CHARACTERIZATION; HAMSTER OVARY CELLS; N-LINKED GLYCANS; V3 LOOP; HIV-1 GP120; STRUCTURAL CHARACTERIZATION; OLIGOSACCHARIDE STRUCTURES; EXOGLYCOSIDASE DIGESTION; NEUTRALIZATION SITE AB An analytical approach is reported for the characterization of the specific glycans found on highly glycosylated proteins based on a combination of specific proteolysis and deglycosylation combined with two different mass spectrometric approaches, matrix-assisted laser desorption/ionization mass spectrometry, and nanoelectrospray mass spectrometry/tandem mass spectrometry using a hybrid quadrupole-time-of-flight tandem mass spectrometer. The high resolution and mass accuracy of the mass spectrometric data obtained on the hybrid instrument combined with the high parent mass capabilities are shown to be extremely useful in the site-specific assignment of heterogeneous glycans. Using this methodology, 25 of 26 consensus glycosylation sites on HIV-1(SF2) gp120, expressed in Chinese hamster ovary cells, could be assigned. Good correlations between the relative abundances of members of heterogeneous series in the matrix-assisted laser desorption/ionization mass spectra and the nanoelectrospray mass spectra were observed, indicating that the mass spectrometric data reflected the actual abundances of the members of the series. These data were incorporated with molecular modeling based on the solved structure of a mutant truncated, highly deglycosylated gp120 to propose a structural model for the completely glycosylated form. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Comp Sci Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Tomer, KB (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013; OI Bienstock, Rachelle/0000-0001-5228-3610 NR 43 TC 175 Z9 177 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 SEP 19 PY 2000 VL 39 IS 37 BP 11194 EP 11204 DI 10.1021/bi000432m PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356GY UT WOS:000089436600004 PM 10985765 ER PT J AU Mu, L Sarafianos, SG Nicklaus, MC Russ, P Siddiqui, MA Ford, H Mitsuya, H Le, R Kodama, E Meier, C Knispel, T Anderson, L Barchi, JJ Marquez, VE AF Mu, L Sarafianos, SG Nicklaus, MC Russ, P Siddiqui, MA Ford, H Mitsuya, H Le, R Kodama, E Meier, C Knispel, T Anderson, L Barchi, JJ Marquez, VE TI Interactions of conformationally biased north and south 2 '-fluoro-2 ',3 '-dideoxynucleoside 5 '-triphosphates with the active site of HIV-1 reverse transcriptase SO BIOCHEMISTRY LA English DT Article ID NUCLEOSIDE ANALOGS; COUPLING-CONSTANTS; DRUG-RESISTANCE; SUGAR RING; DNA; STABILITY; DEAMINASE; AGENT AB Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, beta FddATP, and alpha FddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > beta FddATP > alpha FddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, alpha FddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of alpha FddATP in its preferred north conformation. The south-biased beta FddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than beta FddATP. These results highlight the opposite conformational preferences of HIV-1 RT for alpha FddATP and beta FddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme. C1 NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Med Branch,Expt Retrovirol Sect, NIH, Bethesda, MD 20892 USA. Adv Ctr Biochem Engn, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. Univ Hamburg, Inst Organ Chem, D-20146 Hamburg, Germany. RP Marquez, VE (reprint author), NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RI Kodama, Eiichi /C-4032-2009; Nicklaus, Marc/N-4183-2014; Barchi Jr., Joseph/N-3784-2014; OI Kodama, Eiichi /0000-0002-6622-2752; Sarafianos, Stefan G/0000-0002-5840-154X NR 50 TC 28 Z9 28 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 19 PY 2000 VL 39 IS 37 BP 11205 EP 11215 DI 10.1021/bi001090n PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356GY UT WOS:000089436600005 PM 10985766 ER PT J AU Tcherkasskaya, O Knutson, JR Bowley, SA Frank, MK Gronenborn, AM AF Tcherkasskaya, O Knutson, JR Bowley, SA Frank, MK Gronenborn, AM TI Nanosecond dynamics of the single tryptophan reveals multi-state equilibrium unfolding of protein GB1 SO BIOCHEMISTRY LA English DT Article ID IMMUNOGLOBULIN-BINDING DOMAIN; G B1 DOMAIN; SECONDARY STRUCTURE; NMR-SPECTROSCOPY; LOW-TEMPERATURE; MOLTEN GLOBULE; FLUORESCENCE; DENATURATION; POLYPEPTIDE; FRAGMENTS AB Unfolding of the immunoglobulin binding domain B1 of streptococcal protein G (GB1) was induced by guanidine hydrochloride (GdnHCl) and studied by circular dichroism, steady-state, and time-resolved fluorescence spectroscopy. The fluorescence methods employed the single tryptophan residue of GB1 as an intrinsic reporter. While the transitions monitored by circular dichroism and steady-state fluorescence coincided with each other, the transitions followed by dynamic fluorescence were markedly different. Specifically, fluorescence anisotropy data showed that a relaxation spectrum of tryptophan contained a slow motion with relaxation times of 9 ns in the native state and 4 ns in the unfolded state in 6 M GdnHCl. At intermediate GdnHCl concentrations of 3.8-4.2 M, however, the slow relaxation time increased to 18 ns. The fast nanosecond motion had an average time of 0.8 ns and showed no dependence on the formation of native structure. Overall, dynamic fluorescence revealed two preliminary stages in GB1 folding, which are equated with the formation of local structure in the beta(3)-strand hairpin and the initial collapse. Both stages exist without alpha-helix formation, i.e., before the appearance of any ordered secondary structure detectable by circular dichroism. Another stage in GB1 folding might exist at very low (similar to 1 M) GdnHCl concentrations. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tcherkasskaya, O (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 51 TC 21 Z9 21 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 19 PY 2000 VL 39 IS 37 BP 11216 EP 11226 DI 10.1021/bi000345u PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356GY UT WOS:000089436600006 PM 10985767 ER PT J AU Misra, S Beach, BM Hurley, JH AF Misra, S Beach, BM Hurley, JH TI Structure of the VHS domain of human Tom1 (target of myb 1): Insights into interactions with proteins and membranes SO BIOCHEMISTRY LA English DT Article ID TRANSDUCING ADAPTER MOLECULE; CRYSTAL-STRUCTURE; CELL-GROWTH; ANGSTROM RESOLUTION; HOMOLOGY DOMAIN; EPS15 HOMOLOGY; FYVE DOMAIN; EH DOMAIN; BINDING; ENDOCYTOSIS AB VHS domains are found at the N-termini of select proteins involved in intracellular membrane trafficking. We have determined the crystal structure of the VHS domain of the human Tom1 (target of myb 1) protein to 1.5 Angstrom resolution. The domain consists of eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2. We compare our structure to the recently obtained structure of tandem VHS-FYVE domains from Hrs [Mao, Y., Nickitenko, A., Duan, X., Lloyd, T. E., Wu, M. N., Bellen, H., and Quiocho, F. A. (2000) Cell 100, 447-456]. Key features of the interaction surface between the FYVE and VHS domains of Hrs, involving helices 2 and 4 of the VHS domain, are conserved in the VHS domain of Tom1, even though Tom1 does not have a FYVE domain. We also compare the structures of the VHS domains of Tom1 and Hrs to the recently obtained structure of the ENTH domain of epsin-1 [Hyman, J., Chen, H., Di Fiore, P. P., De Camilli, P., and Brunger, A. T. (2000) J. Cell Biol. 149, 537-546]. Comparison of the two VHS domains and the ENTH domain reveals a conserved surface, composed of helices 2 and 4, that is utilized for protein-protein interactions. In addition, VIIS domain-containing proteins are often localized to membranes. We suggest that the conserved positively charged surface of helix 3 in VHS and ENTH domains plays a role in membrane binding. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Misra, Saurav/0000-0002-1385-8554 NR 58 TC 48 Z9 49 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 19 PY 2000 VL 39 IS 37 BP 11282 EP 11290 DI 10.1021/bi0013546 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356GY UT WOS:000089436600012 PM 10985773 ER PT J AU Derubeis, AR Young, MF Jia, L Robey, PG Fisher, LW AF Derubeis, AR Young, MF Jia, L Robey, PG Fisher, LW TI Double FYVE-containing protein 1 (DFCP1): isolation, cloning and characterization of a novel FYVE finger protein from a human bone marrow cDNA library SO GENE LA English DT Article DE bone marrow stroma; expressed sequence tag; vesicles; zinc finger ID CRYSTAL-STRUCTURE; ZINC-FINGER; CFU-F; INVITRO; CELLS; MOTIF; BINDING; DOMAIN; MICROENVIRONMENT; EEA1 AB Double FYVE-containing protein I (DFCP1) encodes a 777 amino acid protein that contains: (1) an N-terminal Cys-His cluster with some homology to many zinc finger domains; (2) a consensus sequence consistent with an ATP/GTP binding site; and (3) a C-terminal domain unique because it contains two zinc-binding FYVE domains. The gene, ZNFN2A1 (GenBank accession no. AF251025) was localized to chromosome 14q22-q24 and shown to be composed of 11 exons. Northern blot analysis revealed the presence of three different mRNA transcripts (4.2, 3 and 1.2 kb). The two longer transcripts appear to be expressed in a variety of different tissues, especially in endocrine tissues, while the shorter messenger is limited to testis. Both of the larger transcripts are unusual due to the presence of a 463 bp long 5' UTR. Furthermore, the 4.2 kb transcript contains a non-standard polyadenylation consensus sequence while the 3 kb transcript contains a standard consensus sequence but within the open reading frame. Following in vitro transfection of a DFCP1-containing expression construct, confocal microscopy studies showed a vesicular distribution of DFCP1 suggesting that this protein, like other FYVE-containing proteins, might be involved in membrane trafficking. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 28 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD SEP 19 PY 2000 VL 255 IS 2 BP 195 EP 203 DI 10.1016/S0378-1119(00)00303-6 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 362KR UT WOS:000089777600006 PM 11024279 ER PT J AU Bernhardt, BA Biesecker, BB Mastromarino, CL AF Bernhardt, BA Biesecker, BB Mastromarino, CL TI Goals, benefits, and outcomes of genetic counseling: Client and genetic counselor assessment SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetic counseling; outcomes; qualitative research; genetic services ID INFORMATION; SATISFACTION; REPRODUCTION; EDUCATION; DECISION; SUCCESS; COUNTS; CANCER; RECALL AB Most studies of outcomes of genetic counseling have focused on client knowledge, reproductive plans and behavior, or satisfaction. Other measures of the "value" of genetic counseling are needed to guide research assessing the impact of genetic counseling on individuals and populations, as well as to improve the process of providing care. To obtain input from providers, we conducted telephone interviews with six experienced genetic counselors, and then we held a focus group with 10 additional genetic counselors from a variety of practice settings. To obtain input from consumers, telephone interviews were also conducted with 19 past clients of these participating counselors. We found that counselor goals focus on meeting clients' needs, usually educating and providing psychosocial support. Clients often had few goals going into a session because they were unaware of what would be discussed or how the session would be structured. They usually did not expect to receive "counseling," and when they did, it was a welcome surprise. Both clients and counselors commented that a positive interpersonal interaction and "connecting" are primary measures of success. All clients appreciated the large amount of time spent with the counselor, and the manner (clear, comprehensive, and unhurried) of providing information. Many clients said that genetic counseling resulted in improved communication with their partners and other family members. Clients view the counselor as an "expert" and value the counselor as an on-going resource for both information and support. These "outcomes" of genetic counseling need to be assessed, and new measures must be developed, (C) 2000 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. RP Bernhardt, BA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, 550 N Broadway,Suite 511, Baltimore, MD 21205 USA. NR 31 TC 72 Z9 73 U1 0 U2 17 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 18 PY 2000 VL 94 IS 3 BP 189 EP 197 DI 10.1002/1096-8628(20000918)94:3<189::AID-AJMG3>3.0.CO;2-E PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 349AZ UT WOS:000089022800003 PM 10995504 ER PT J AU Krakowiak, PA Nwokoro, NA Wassif, CA Battaile, KP Nowaczyk, MJM Connor, WE Maslen, C Steiner, RD Porter, FD AF Krakowiak, PA Nwokoro, NA Wassif, CA Battaile, KP Nowaczyk, MJM Connor, WE Maslen, C Steiner, RD Porter, FD TI Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: Polymerase chain reaction-based assays to simplify genotyping SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Smith-Lemli-Opitz syndrome; RSH syndrome; DHCR7; mutation analysis ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; FEMALE EXTERNAL GENITALIA; DELTA-7-STEROL REDUCTASE; METABOLISM; GENE; 7-DEHYDROCHOLESTEROL; IDENTIFICATION; DIAGNOSIS AB We report the clinical and molecular data of 16 patients with RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) with varying phenotypic severity, for which we have identified mutations in both alleles. RSH/SLOS is an autosomal recessive malformation syndrome caused by mutations in the gene encoding the sterol Delta(7)-reductase. This protein catalyzes the reduction of 7-dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis via the Kandutsch-Russell pathway. In addition to previously reported mutations (T93M, L109P, G147D, W151X, T154M, R242C, A247V, T289I, IVS8-1G-->C, Y408H, and E448K), we have identified six previously undescribed mutations (321G-->C, W177R, R242H, Y318N, L341P, and C444Y). We also report rapid polymerase chain reaction (PCR)-based assays developed to detect four of the recurring mutations (T93M, W151X, V326L, and R404C) and six other RSH/SLOS mutations (321G-->C, L109P, T154M, T289I, Y318N, and L341P). The purpose of this article is to correlate detailed clinical information with molecular data in order to improve our understanding of the genotype-phenotype correlation of RSH/SLOS and to report the development of PCR-based assays that will allow more rapid mutation analysis. Published 2000 Wiley-Liss, Inc.(dagger). C1 NICHHD, Heritable Disroders Branch, Unit Mol Dysmorphol, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Doernbecher Childrens Hosp, Child Dev & Rehabil Ctr, Dept Pediat, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Doernbecher Childrens Hosp, Child Dev & Rehabil Ctr, Dept Mol & Med Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. RP Porter, FD (reprint author), NICHD, HDB, NIH, Bldg 10,Rm 9D41,10 Ctr Dr, Bethesda, MD 20892 USA. OI Battaile, Kevin/0000-0003-0833-3259; Steiner, Robert/0000-0003-4177-4590; Wassif, Christopher/0000-0002-2524-1420 FU NCRR NIH HHS [MO1RR00334-33S3]; NICHD NIH HHS [5P30-HD33703-04] NR 43 TC 48 Z9 50 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 18 PY 2000 VL 94 IS 3 BP 214 EP 227 DI 10.1002/1096-8628(20000918)94:3<214::AID-AJMG7>3.0.CO;2-R PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 349AZ UT WOS:000089022800007 PM 10995508 ER PT J AU Du, J Feng, LY Yang, F Lu, B AF Du, J Feng, LY Yang, F Lu, B TI Activity- and Ca2+-dependent modulation of surface expression of brain-derived neurotrophic factor receptors in hippocampal neurons SO JOURNAL OF CELL BIOLOGY LA English DT Article DE TrkB receptors; tetanic stimulation; calcium influx; Ca2+/calmodulin-dependent kinase II; synaptic transmission ID NERVE GROWTH-FACTOR; LONG-TERM POTENTIATION; CORTICAL DENDRITIC GROWTH; BDNF KNOCKOUT MICE; SYNAPTIC TRANSMISSION; VISUAL-CORTEX; CREB PHOSPHORYLATION; GENE-EXPRESSION; RAT HIPPOCAMPUS; CA1 REGION AB Brain-derived neurotrophic factor (BDNF) has been shown to regulate neuronal survival and synaptic plasticity in the central nervous system (CNS) in an activity-dependent manner, but the underlying mechanisms remain unclear, Here we report that the number of BDNF receptor TrkB on the surface of hippocampal neurons can be enhanced by high frequency neuronal activity and synaptic transmission, and this effect is mediated by Ca2+ influx. Using membrane protein biotinylation as well as receptor binding assays, we show that field electric stimulation increased the number of TrkB on the surface of cultured hippocampal neurons. Immunofluorescence staining suggests that the electric stimulation facilitated the movement of TrkB from intracellular pool to the cell surface, particularly on neuronal processes. The number of surface TrkB was regulated only by high frequency tetanic stimulation, but not by low frequency stimulation. The activity de pendent modulation appears to require Ca2+ influx, since treatment of the neurons with blockers of voltage-gated Ca-2+ channels or NMDA receptors, or removal of extracellular Ca2+, severely attenuated the effect of electric stimulation. Moreover, inhibition of Ca2+/calmodulin-dependent kinase II (CaMKII) significantly reduced the effectiveness of the tetanic stimulation. These findings may help us to understand the role of neuronal activity in neurotrophin function and the mechanism for receptor tyrosine kinase signaling. C1 NICHHD, Unit Synapse Dev & Plast, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Inst Neurosci, Shanghai 200031, Peoples R China. RP Lu, B (reprint author), NICHHD, Unit Synapse Dev & Plast, Dev Neurobiol Lab, NIH, Bldg 49,Rom 5A38,49 Convent Dr, Bethesda, MD 20892 USA. RI Yang, Feng/C-9530-2011; Lu, Bai/A-4018-2012; Du, Jing/A-9023-2012 NR 55 TC 114 Z9 118 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 18 PY 2000 VL 150 IS 6 BP 1423 EP 1433 DI 10.1083/jcb.150.6.1423 PG 11 WC Cell Biology SC Cell Biology GA 356QR UT WOS:000089454500019 PM 10995446 ER PT J AU Bhandoola, A Dolnick, B Fayad, N Nussenzweig, A Singer, A AF Bhandoola, A Dolnick, B Fayad, N Nussenzweig, A Singer, A TI Immature thymocytes undergoing receptor rearrangements are resistant to an Atm-dependent death pathway activated in mature T cells by double-stranded DNA breaks SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE DNA damage; apoptosis; thymic development; actinomycin D; rearrangement ID ATAXIA-TELANGIECTASIA; POSITIVE SELECTION; DEFICIENT MICE; IMMUNE-SYSTEM; APOPTOSIS; P53; PHOSPHORYLATION; EXPRESSION; RADIATION; THYMUS AB Immature CD4(+)CD8(+) thymocytes rearrange their T cell receptor (TCR)-alpha gene locus to generate clonotypic alpha/beta TCR, after which a few cells expressing selectable TCR are signaled to further differentiate into mature T cells. Because of requirements for self-tolerance, immature CD4(+)CD8(+) thymocytes are programmed to die in the thymus in response to a variety of stimuli that do not induce death of mature T cells. We now demonstrate that, in contrast to all previously described stimuli, immature CD4(+)CD8(+) thymocytes are selectively more resistant than mature T cells to apoptotic death induced by DNA intercalating agents. Importantly, we demonstrate that DNA intercalating agents induce double-stranded DNA breaks in both immature thymocytes and mature T cells, but immature thymocytes tolerate these DNA breaks, whereas mature T cells are signaled to die by an Atm-dependent but p53-independent death mechanism. Thus, our results indicate that absence of an Aim-dependent but p53-independent pathway allows immature thymocytes to survive double-stranded DNA breaks. It is likely that the unique ability of immature thymocytes to survive DNA-damaging intercalating agents reflects their tolerance of double-stranded DNA breaks that occur normally during antigen receptor gene rearrangements. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Bhandoola, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. NR 32 TC 12 Z9 12 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 18 PY 2000 VL 192 IS 6 BP 891 EP 897 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 356EM UT WOS:000089423300012 PM 10993919 ER PT J AU Sommers, CL Dejarnette, JB Huang, K Lee, J El-Khoury, D Shores, EW Love, PE AF Sommers, CL Dejarnette, JB Huang, K Lee, J El-Khoury, D Shores, EW Love, PE TI Function of CD3 epsilon-mediated signals in T cell development SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE TCR; CD3epsilon; development; mice; cell survival ID RECEPTOR TRANSGENIC MICE; TCR ZETA-CHAIN; ANTIGEN RECEPTOR; ACTIVATION MOTIFS; ALPHA-BETA; SELECTION; GAMMA; SURVIVAL; COMPLEX; PHOSPHORYLATION AB The T cell antigen receptor (TCR) and pre-TCR complexes are composed of multiple signal-transducing subunits (CD3 gamma, CD3 delta, CD3 epsilon, and zeta) that each contain one or more copies of a semiconserved functional motif, the immunoreceptor tyrosine-based activation motif (ITAM). Although biochemical studies indicate that individual TCR-ITAMs may bind selectively or with different affinity to various effector molecules, data from other experiments suggest that at least some ITAMs are functionally equivalent. In this study, we examined the role of CD3 epsilon ITAM-mediated signals in T cell development by genetically reconstituting CD3 epsilon-deficient mice with transgenes encoding either wild-type or ITAM-mutant (signaling defective) forms of the protein. The results demonstrate that signals transduced by CD3 epsilon are not specifically required for T cell maturation but instead contribute quantitatively to TCR signaling in a manner similar to that previously observed for zeta chain. Unexpectedly, analysis of TCR-transgenic/CD3 epsilon-mutant mice reveals a potential role for CD3 epsilon signals in T cell survival. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Ctr Biol Evaluat & Res Food & Drug Adm, Div Hematol Prod, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 30 TC 37 Z9 38 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 18 PY 2000 VL 192 IS 6 BP 913 EP 919 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 356EM UT WOS:000089423300015 PM 10993922 ER PT J AU Shane, BS Smith-Dunn, DL de Boer, JG Glickman, BW Cunningham, ML AF Shane, BS Smith-Dunn, DL de Boer, JG Glickman, BW Cunningham, ML TI Mutant frequencies and mutation spectra of dimethylnitrosamine (DMN) at the lacI and cII loci in the livers of Big Blue (R) transgenic mice SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE lambda cII assay; lacI assay; Big Blue (R) transgenic mice; dimethylnitrosamine ID METHYL-N-NITROSOUREA; ESCHERICHIA-COLI; IN-VIVO; GENE-MUTATIONS; MOLECULAR ANALYSIS; ALKYLATING-AGENTS; P53 MUTATIONS; RAS ONCOGENE; DNA-REPAIR; HPRT GENE AB The lacI gene in Big Blue(R) transgenic rodents has traditionally been used as a surrogate gene for in vivo mutations. Recently, a more efficient and less expensive assay involving direct selection in the smaller lambda cIIgene has been developed. Little is known, however, about the comparative sensitivity of the two loci or their influence on the recovered mutation spectrum following mutagen treatment. We have compared the mutation frequency (MF) and mutational spectrum (MS) of lacI and cII from the same DNA samples isolated from the liver of control and dimethylnitrosamine (DMN)-treated mice. A three-fold (p<0.01) increase in the MF was observed at both loci in the DMN-treated group compared to the corresponding control groups. While the DMN-induced mutation spectrum at lacI was significantly different: from its corresponding spontaneous mutation spectrum (p<0.001), the mutation spectrum at cII (p>0.28) was not. The mutation spectra at the two loci from the DMN-treated mice resembled each other but the 4, 2.5 and 12-fold increase in the mutation frequency of A:T>T:A transversions, single base deletions and deletions of more than four base pairs, respectively, at lacI, altered the spectra significantly (p<0.007). The number of mutations of these classes at cII was also increased, but the fractions were lower than at lacI. The spontaneous mutation spectra at the cII and lacI loci resembled each other except for the seven-fold increase in G:C3.0.CO;2-D PG 10 WC Oncology SC Oncology GA 353EA UT WOS:000089260800020 PM 11002231 ER PT J AU Jacoby, RF Seibert, K Cole, CE Kelloff, G Lubet, RA AF Jacoby, RF Seibert, K Cole, CE Kelloff, G Lubet, RA TI The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis SO CANCER RESEARCH LA English DT Article ID MULTIPLE INTESTINAL NEOPLASIA; RAT COLONIC TUMORS; COLORECTAL-CANCER; ASPIRIN USE; APOPTOSIS; RISK; MICE; MECHANISMS; PIROXICAM; SULINDAC AB Epidemiological and animal studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia, We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam, Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam, To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B-2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach. C1 Univ Wisconsin, Ctr Comprehens Canc, Madison, WI 53792 USA. Univ Wisconsin, Dept Med, Gastroenterol Sect, Madison, WI 53792 USA. Searle Res & Dev, St Louis, MO 63167 USA. NCI, Div Canc Prevent, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Jacoby, RF (reprint author), H6 516 Clin Sci Ctr 5124, 600 Highland Ave, Madison, WI 53792 USA. FU NCI NIH HHS [N01 CN 65122] NR 32 TC 357 Z9 376 U1 1 U2 3 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 SEP 15 PY 2000 VL 60 IS 18 BP 5040 EP 5044 PG 5 WC Oncology SC Oncology GA 358GQ UT WOS:000089550600011 PM 11016626 ER PT J AU Hsing, AW Gao, YT Wu, G Wang, X Deng, J Chen, YL Sesterhenn, IA Mostofi, FK Benichou, J Chang, CS AF Hsing, AW Gao, YT Wu, G Wang, X Deng, J Chen, YL Sesterhenn, IA Mostofi, FK Benichou, J Chang, CS TI Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: A population-based case-control study in China SO CANCER RESEARCH LA English DT Article ID EXPRESSION; MUTATION; MEN; TRANSACTIVATION; MICROSATELLITE; AMPLIFICATION; ACTIVATION; EXPANSION; ESTROGEN; THERAPY AB The length of the polymorphic CAG trinucleotide repeat in the polyglutamine region of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Because increased androgenic activity has been linked to prostate cancer and because an ethnic variation exists in the CAG repeat length, this polymorphism has been suggested to explain part of the substantial racial difference in prostate cancer risk, We conducted a population-based case-control study in China to investigate whether CAG and other polymorphisms of the AR gene are associated with clinically significant prostate cancer in this low-risk population. Genomic DNA from 190 prostate cancer patients and 304 healthy controls was used for direct sequencing to evaluate the relationship of CAG and GGN (polyglycine) repeat length in the AR gene. Relative to western men, our study subjects had a longer CAG repeat length, with a median of 23 and only 10% of the subjects having a CAG repeat length shorter than 20, Men with a CAG repeat length shorter than 23 (median length) had a 65% increased risk of prostate cancer (odds ratio, 1.65; 95% confidence interval, 1.14-2.39), compared with men with a CAG repeat length of 23 or longer. For the GGN tract (GGT(3)GGG(1)GGT(2)GGC(n)), based on the sequencing results from 481 samples, we are the first to show that although GGC regions in the polyglycine tract are highly variable, there are no mutations or polymorphisms in the GGT and GGG regions. More than 72% of the subjects had a GGN repeat length of 23, and those with a GGN repeat length shorter than 23 had a 12% increased risk of prostate cancer (95% confidence interval, 0.71-1.78), compared with those with greater than or equal to 23 GGN repeats. Our study not only confirms that Chinese men do have a longer CAG repeat length than western men but also represents the first population-based study to show that even in a very low risk population, a shorter CAG repeat length confers a higher risk of clinically significant prostate cancer. These results imply that CAG repeat length can potentially serve as a useful marker to identify a subset of individuals at higher risk of developing clinically significant prostate cancer. Larger studies are needed to evaluate the combined effect of CAG and GGN repeats, Because of the significance of AR in prostate cancer, investigation of factors that interact with the polyglutamine region of the AR gene to alter AR function and modulate prostate cancer risk is an important area for future research. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Shanghai Canc Inst, Shanghai 200032, Peoples R China. Univ Rochester, Rochester, NY 14642 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Univ Rouen, F-76031 Rouen, France. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, EPS MSC 7234,6120 Execut Blvd, Rockville, MD 20852 USA. NR 42 TC 212 Z9 225 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2000 VL 60 IS 18 BP 5111 EP 5116 PG 6 WC Oncology SC Oncology GA 358GQ UT WOS:000089550600022 PM 11016637 ER PT J AU Chua, MS Kashiyama, E Bradshaw, TD Stinson, SF Brantley, E Sausville, EA Stevens, MFG AF Chua, MS Kashiyama, E Bradshaw, TD Stinson, SF Brantley, E Sausville, EA Stevens, MFG TI Role of CYP1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells SO CANCER RESEARCH LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; HUMAN-LIVER-MICROSOMES; AH-RECEPTOR; IN-VITRO; MDA-MB-231 CELLS; EPITHELIAL-CELLS; EXPRESSION; CYTOCHROME-P-450; METABOLISM; PROTEIN AB 2-(4-Amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) is a candidate antitumor agent with potent and selective activity against human-derived tumor cell lines in vitro and in vivo, Only sensitive cell lines (e.g., MCF-7) were able to accumulate and metabolize DF 203, forming the main inactive metabolite, 2-(4-amino-3-methylphenyl)-6-hydroxybenzothiazole (6-OH 203). selective metabolism may therefore underlie its antitumor profile. DF 203 6-hydroxylase activity by MCF-7 cells was not constitutive but induced only after pretreatment of cells with DF 203, 3-methylcholanthrene, or beta-naphthoflavone, 6-Hydroxylation was strongly inhibited by either goat antirat cytochrome P450 1A1 (CYP1A1) serum or cu-naphthoflavone. Both alpha-naphthoflavone and 6-OH 203 abrogated DF 203-induced growth inhibition. Microsomes from genetically engineered human B-lymphoblastoid cells expressing CYP1A1, CYP1B1, or CYP2D6 metabolized DF 203 to 6-OH 203, Immunoblot analysis detected significantly enhanced CYP1A1 protein in a panel of sensitive breast cancer cell lines after exposure to DF 203. Neither constitutive expression nor induction of CYP1A1 protein was detected in nonresponsive breast (HBL 100, MDA-MB-435, and MCF-7/ADR) and prostate (PC 3 and DU 145) cancer cell lines. The expression of CYP1B1 was also modulated by DF 203 in the same sensitive cell lines. However, of the two isoforms, only CYP1A1 activity was irreversibly inhibited by DF 203 and significantly inhibited by 6-OH 203, In sensitive cell lines only, [C-4]DF 203-derived radioactivity bound covalently to a M-r 50,000, protein which was immunoprecipitated by CYP1A1 antiserum. The covalent binding of [C-14]DF 203 to recombinant CYP1A1 enzyme was NADPH-dependent and reduced by 6-OH 203 and glutathione. CYP1A1 appears essential for the metabolism of DF 203 and may have a pivotal, yet undefined, role in its antitumor activity. C1 Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Stevens, MFG (reprint author), Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Univ Pk, Nottingham NG7 2RD, England. NR 41 TC 90 Z9 91 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2000 VL 60 IS 18 BP 5196 EP 5203 PG 8 WC Oncology SC Oncology GA 358GQ UT WOS:000089550600033 PM 11016648 ER PT J AU Kobayashi, H Wood, M Song, YS Appella, E Celis, E AF Kobayashi, H Wood, M Song, YS Appella, E Celis, E TI Defining promiscuous MHC class II helper T-cell epitopes for the HER2/neu tumor antigen SO CANCER RESEARCH LA English DT Article ID PULSED DENDRITIC CELLS; IN-VITRO IMMUNIZATION; PEPTIDE-BINDING REPERTOIRES; OVARIAN-CANCER; CTL EPITOPES; INFILTRATING LYMPHOCYTES; CARCINOEMBRYONIC ANTIGEN; SYNTHETIC PEPTIDE; ADOPTIVE TRANSFER; HLA-A2 MELANOMAS AB It is accepted that both helper and CTLs play a critical role in immune antitumor responses. Thus, the design of effective immune-based therapies for cancer relies in the identification of relevant tumor-associated antigens (TAAs) capable of eliciting strong helper and cytotoxic T-cell responses against tumor cells. The product of the HER2/neu oncogene is considered as a prototype TAA, because it is found overexpressed in a large variety of malignancies, whereas normal cells only produce low levels of this product. Several cytotoxic T-cell epitopes for HER2/neu have been identified that enable the design of peptide-based therapeutic vaccines for tumors expressing this TAA, Nevertheless, it is expected that inclusion of peptide epitopes capable of eliciting HER2/neu-specific T helper responses into these vaccines may enhance their effectiveness in the clinic. We describe here a strategy to identify helper T-cell epitopes for HER2/neu that focuses on peptides predicted to bind to numerous histocompatibility alleles (promiscuous epitopes), which would encourage their use in therapeutic vaccines for the general cancer patient population. Following this approach, we successfully identified several peptides that elicited T helper (CD4(+)) proliferative responses to peptides derived from HER2/neu. Most of the T-cell responses appeared to reflect a low affinity for antigen, which could be the result of immune tolerance because HER2/neu is expressed in low levels in normal cells and possibly including lymphocytes and monocytes, Interestingly, one of these peptides, HER2(883), was recognized by T cells in the context of either HLA-DR1, HLA-DR4, HLA-DR52, and HLA-DR53, indicating a high degree of histocompatibility promiscuity, Furthermore, T cells that reacted with peptide HER2(883) could also recognize antigen-presenting cells that process HER2/(neu) recombinant protein. These results may be relevant for the design of more effective therapeutic vaccines for tumors expressing the HER2/neu oncogene product. C1 Mayo Clin & Mayo Fdn, Dept Immunol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Ctr Canc, Rochester, MN 55905 USA. Mayo Grad Sch, Rochester, MN 55905 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Celis, E (reprint author), Mayo Clin & Mayo Fdn, Dept Immunol, GU421A, Rochester, MN 55905 USA. FU NCI NIH HHS [R01CA80782] NR 62 TC 100 Z9 100 U1 1 U2 3 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 SEP 15 PY 2000 VL 60 IS 18 BP 5228 EP 5236 PG 9 WC Oncology SC Oncology GA 358GQ UT WOS:000089550600037 PM 11016652 ER PT J AU Vacca, F Bagnato, A Catt, KJ Tecce, R AF Vacca, F Bagnato, A Catt, KJ Tecce, R TI Transactivation of the epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells SO CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE CELLS; RAT MESANGIAL CELLS; SWISS 3T3 CELLS; TYROSINE PHOSPHORYLATION; COUPLED RECEPTORS; DNA-SYNTHESIS; EGF RECEPTOR; C-FOS; PHOSPHATIDYLINOSITOL 3-KINASE AB Endothelin (ET)-1 is produced in ovarian carcinoma cells and is known to act through ETA receptors as an autocrine growth factor in vitro and in vivo. In OVCA 433 human ovarian carcinoma cells, ET-1 caused phosphorylation of the epidermal growth factor receptor (EGF-R) that was accompanied by phosphorylation of Shc and its recruitment complexed with Grb2. These findings suggested that an EGF-R/ras-dependent pathway may contribute to the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) 2 and mitogenic signaling induced by ET-1 in these cells. Specific inhibition of EGF-R kinase activity by tyrphostin AG1478 prevented ET-1-induced transactivation of the EGF-R, as well as Shc phosphorylation and recruitment with Grb2. Furthermore, ET-1-induced activation of Erk 2 was partially inhibited by tyrphostin AG1478. In accord with this finding, the mitogenic action of ET-1 in OVCA 433 cells was also significantly reduced by a concentration of tyrphostin AG1478 that abolished the growth response of EGF-stimulated cells. Inhibition of protein kinase C activity, which contributes to the proliferative action of ET-1 in OVCA 433 cells, had no effect on the activation of Erk 2 by ET-1, which suggests that this effect of protein kinase C does not involve ras-independent activation of Erk 2. Inhibition by wortmannin of PI3-kinase activity, which has been implicated in ET-1 and other G protein-coupled receptor (GPCR)-mediated signaling pathways, reduced Erk 2 activation by ET-1 but had no effect on ET-1-induced EGF-R and Shc phosphorylation. These findings indicate that ET-1-induced stimulation of Erk 2 phosphorylation, and mitogenic responses in OVCA 433 ovarian cancer cells are mediated in part by signaling pathways that are initiated by transactivation of the EGF-R. C1 Regina Elena Canc Inst, Lab Mol Pathol & Ultrastruct, I-00158 Rome, Italy. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Tecce, R (reprint author), Regina Elena Canc Inst, Lab Mol Pathol & Ultrastruct, I-00158 Rome, Italy. RI Vacca, Fabrizio/A-5113-2009; Bagnato, Anna/G-9747-2016 OI Bagnato, Anna/0000-0002-7269-9522 NR 61 TC 102 Z9 102 U1 0 U2 3 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 SEP 15 PY 2000 VL 60 IS 18 BP 5310 EP 5317 PG 8 WC Oncology SC Oncology GA 358GQ UT WOS:000089550600048 PM 11016663 ER PT J AU Sinal, CJ Tohkin, M Miyata, M Ward, JM Lambert, G Gonzalez, FJ AF Sinal, CJ Tohkin, M Miyata, M Ward, JM Lambert, G Gonzalez, FJ TI Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis SO CELL LA English DT Article ID FAMILIAL INTRAHEPATIC CHOLESTASIS; MICROSOMAL EPOXIDE HYDROLASE; BINDING PROTEIN GENE; RETINOID-X RECEPTOR; SALT EXPORT PUMP; CHOLESTEROL 7-ALPHA-HYDROXYLASE; FUNCTIONAL EXPRESSION; ESTROGEN-RECEPTOR; RESPONSE PATHWAY; HORMONE-RECEPTOR AB Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. RXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7 alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor. C1 NIH, Lab Metab, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Sci, NIH, Frederick, MD 21702 USA. NHLBI, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NIH, Lab Metab, Div Basic Sci, Bldg 10, Bethesda, MD 20892 USA. NR 74 TC 925 Z9 941 U1 7 U2 45 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD SEP 15 PY 2000 VL 102 IS 6 BP 731 EP 744 DI 10.1016/S0092-8674(00)00062-3 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 355PZ UT WOS:000089395200005 PM 11030617 ER PT J AU Dalgaard, JZ Klar, AJS AF Dalgaard, JZ Klar, AJS TI swi1 and swi3 perform imprinting, pausing, and termination of DNA replication in S-pombe SO CELL LA English DT Article ID FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; SWITCHING GENES; PROTEIN; CELLS; VIABILITY; MECHANISM; ASYMMETRY; BINDING AB The developmental program of cell-type switching of S. pombe requires a strand-specific imprinting event at the mating-type locus (mat1). Imprinting occurs only when mat1 is replicated in a specific direction and requires several trans-acting factors. This work shows (1) that the factors swi1p and swi3p act by pausing the replication fork at the imprinting site; and (2) that swi1p and swi3p are involved in termination at the mat1-proximal polar-terminator of replication (RTS1). A genetic screen to identify termination factors identified an allele that separated pausing/imprinting and termination functions of swi1p. These results suggest that swi1p and swi3p promote imprinting in novel ways both by pausing replication at mat1 and by terminating replication at RTS1. C1 NCI, DHHS, Div Basic Sci,Gene Regulat & Chromosome Biol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP NCI, DHHS, Div Basic Sci,Gene Regulat & Chromosome Biol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM klar@mail.ncifcfr.gov NR 32 TC 109 Z9 113 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD SEP 15 PY 2000 VL 102 IS 6 BP 745 EP 751 DI 10.1016/S0092-8674(00)00063-5 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 355PZ UT WOS:000089395200006 PM 11030618 ER PT J AU Muraoka, RS Bushdid, PB Brantley, DM Yull, FE Kerr, LD AF Muraoka, RS Bushdid, PB Brantley, DM Yull, FE Kerr, LD TI Mesenchymal expression of nuclear factor-kappa B inhibits epithelial growth and branching in the embryonic chick lung SO DEVELOPMENTAL BIOLOGY LA English DT Article ID APICAL ECTODERMAL RIDGE; N-MYC EXPRESSION; SONIC-HEDGEHOG; MOUSE LUNG; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; GENE-EXPRESSION; IMMUNE-RESPONSES; LIMB DEVELOPMENT; VERTEBRATE LIMB AB It is becoming increasingly recognized that the ubiquitous, inducible transcription factor nuclear factor-kappa B (NF-kappa B) is involved in developmental processes. For example, NF-kappa B acts as a mediator of epithelial-mesenchymal interactions in the developing chick limb. We investigated the role of NF-kappa B in directing the branching morphogenesis of the developing chick lung, a process which relies on epithelial-mesenchymal communication. High level expression of relA was found in the mesenchyme surrounding the nonbranching structures of the lung but was not detected either in the mesenchyme surrounding the branching structures of the distal lung or in the developing lung epithelium. Specific inhibition of mesenchymal NF-kappa B in lung cultures resulted in increased epithelial budding. Conversely, expression of a trans-dominant activator of NF-kappa B in the lung mesenchyme repressed budding. Ectopic expression of RelA was sufficient to inhibit the ability of the distal mesenchyme to induce epithelial bud formation. Cellular proliferation in the mesenchyme was inhibited by hyperactivation of NF-kappa B in the mesenchyme of lung cultures. Interestingly, increased NF-kappa B activity in the mesenchyme also decreased the proliferation of the associated epithelium, while inhibition of NF-kappa B activity increased cellular proliferation in lung cultures. Expression patterns of several genes which are known to influence lung branching morphogenesis were altered in response to changes in mesenchymal NF-kappa B activity, including fgf10, bmp-4, and tgf-beta 1. Thus NF-kappa B represents the first transcription factor reported to function within the lung mesenchyme to limit growth and branching of the adjacent epithelium. (C) 2000 Academic Press. C1 Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. NIH, Transplantat & Immunogenet Sect, Div Allergy Immunol & Infect Dis, Bethesda, MD 20892 USA. RP Kerr, LD (reprint author), Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, A-4314 MCN 1161 21st Ave S, Nashville, TN 37232 USA. NR 71 TC 33 Z9 33 U1 0 U2 0 PU ACADEMIC PRESS INC 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 SEP 15 PY 2000 VL 225 IS 2 BP 322 EP 338 DI 10.1006/dbio.2000.9824 PG 17 WC Developmental Biology SC Developmental Biology GA 355NY UT WOS:000089392800005 PM 10985853 ER PT J AU Piotrowski, T Nusslein-Volhard, C AF Piotrowski, T Nusslein-Volhard, C TI The endoderm plays an important role in patterning the segmented pharyngeal region in zebrafish (Danio rerio) SO DEVELOPMENTAL BIOLOGY LA English DT Article DE craniofacial development; segmentation; pharyngeal arches; endoderm; endodermal pouches; neural crest; casanova (cas); one-eyed pinhead (oep) ID BRANCHIAL ARCH MUTANTS; NEURAL CREST CELLS; WILD-TYPE; NO TAIL; HINDBRAIN REGION; EMBRYONIC AXIS; CHICK-EMBRYO; PAIRED-BOX; INNER-EAR; HOX GENES AB The development of the vertebrate head is a highly complex process involving tissues derived from all three germ layers. The endoderm forms pharyngeal pouches, the paraxial mesoderm gives rise to endothelia and muscles, and the neural crest cells, which originate from the embryonic midbrain and hindbrain, migrate ventrally to form cartilage, connective tissue, sensory neurons, and pigment cells. All three tissues form segmental structures: the hindbrain compartmentalizes into rhombomeres, the mesoderm into somitomeres, and the endoderm into serial gill slits. It is not known whether the different segmented tissues in the head develop by the same molecular mechanism or whether different pathways are employed. It is also possible that one tissue imposes segmentation on the others. Most recent studies have emphasized the importance of neural crest cells in patterning the head. Neural crest cells colonize the segmentally arranged arches according to their original position in the brain and convey positional information from the hindbrain into the periphery. During the screen for mutations that affect embryonic development of zebrafish, one mutant, called van gogh (vgo), in which segmentation of the pharyngeal region is absent, was isolated. In vgo, even though hindbrain segmentation is unaffected, the pharyngeal endoderm does not form reiterated pouches and surrounding mesoderm is not patterned correctly. Accordingly, migrating neural crest cells initially form distinct streams but fuse when they reach the arches. This failure to populate distinct pharyngeal arches is likely due to the lack of pharyngeal pouches. The results of our analysis suggest that the segmentation of the endoderm occurs without signaling from neural crest cells but that tissue interactions between the mesendoderm and the neural crest cells are required for the segmental appearance of the neural crest-derived cartilages in the pharyngeal arches. The lack of distinct patches of neural crest cells in the pharyngeal region is also seen in mutants of one-eyed pinhead and casanova, which are characterized by a lack of endoderm, as well as defects in mesodermal structures, providing evidence for the important role of the endoderm and mesoderm in governing head segmentation. (C) 2000 Academic Press. C1 NICHHD, Genet Mol Lab, Bethesda, MD 20892 USA. Max Planck Inst Entwicklungsbiol, Genet Abt, D-72076 Tubingen, Germany. RP Piotrowski, T (reprint author), NICHHD, Genet Mol Lab, Bldg 6B,Room 420, Bethesda, MD 20892 USA. NR 85 TC 146 Z9 150 U1 0 U2 7 PU ACADEMIC PRESS INC 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 SEP 15 PY 2000 VL 225 IS 2 BP 339 EP 356 DI 10.1006/dbio.2000.9842 PG 18 WC Developmental Biology SC Developmental Biology GA 355NY UT WOS:000089392800006 PM 10985854 ER PT J AU Chao, C Saito, S Kang, J Anderson, CW Appella, E Xu, Y AF Chao, C Saito, S Kang, J Anderson, CW Appella, E Xu, Y TI p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage SO EMBO JOURNAL LA English DT Article DE acetylation; DNA damage; phosphorylation; stability; transactivation ID WILD-TYPE P53; CELL-CYCLE ARREST; TRANSACTIVATION DOMAIN; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; TERMINAL DOMAIN; PROTEIN-KINASE; ES CELLS; PHOSPHORYLATION; ACTIVATION AB p53-mediated transcription activity is essential for cell cycle arrest, but its importance for apoptosis remains controversial. To address this question, we employed homologous recombination and LoxP/Cre-mediated deletion to produce mutant murine embryonic stem (ES) cells that express p53 with Gin and Ser in place of Leu25 and Trp26, respectively. p53(Gln25Ser26) was stable but did not accumulate after DNA damage; the expression of p21/Waf1 and PERP was not induced, and p53-dependent repression of MAP4 expression was abolished. Therefore, p53(Gln25Ser26) is completely deficient in transcriptional activation and repression activities. After DNA damage by UV radiation, p53(Gln25Ser26) was phosphorylated at Ser18 but was not acetylated at C-terminal sites, and its DNA binding activity did not increase, further supporting a role for p53 acetylation in the activation of sequence-specific DNA binding activity. Most importantly, p53(Gln25Ser26) mouse thymocytes and ES cells, like p53(-/-) cells, did not undergo DNA damage-induced apoptosis. We conclude that the transcriptional activities of p53 are required for p53-dependent apoptosis. C1 Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. RP Xu, Y (reprint author), Univ Calif San Diego, Dept Biol, 9500 Gilman Dr, La Jolla, CA 92093 USA. FU NCI NIH HHS [CA77563, R01 CA077563]; NIGMS NIH HHS [GM52825] NR 57 TC 192 Z9 194 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 15 PY 2000 VL 19 IS 18 BP 4967 EP 4975 DI 10.1093/emboj/19.18.4967 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 358QQ UT WOS:000089569100011 PM 10990460 ER PT J AU Tsao, LI Hayashi, T Su, TP AF Tsao, LI Hayashi, T Su, TP TI Blockade of dopamine transporter and tyrosine hydroxylase activity loss by [D-Ala(2), D-Leu(5)]enkephalin in methamphetamine-treated CD-1 mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE DADLE ([DAla(2), D-Leu(5)]enkephalin) methamphetamine; dopamine transporter ID SYNTHASE-DEFICIENT MICE; OXIDATIVE STRESS; NEUROTOXICITY; PRESERVATION; LUNG AB [D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been previously reported to prolong the survival of tissues both in the periphery and in the central nervous system. Here, we show that DADLE was able to block the protein as well as the functional loss of dopamine transporter (DAT) and tyrosine hydroxylase (TH) induced by methamphetamine. Male CD-1 mice received four injections of methamphetamine (10 mg/kg, i.p.) at 2-h intervals. DADLE (4 mg/kg, i.p.) was given 30 min before each injection of methamphetamine. Western blotting and enzymatic assays showed that DADLE blocked the protein loss and functional impairment of DAT and TH induced by methamphetamine. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 18 TC 4 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 15 PY 2000 VL 404 IS 1-2 BP 89 EP 93 DI 10.1016/S0014-2999(00)00616-6 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 355GG UT WOS:000089377500010 PM 10980266 ER PT J AU Cocchia, M Huber, R Pantano, S Chen, EY Ma, P Forabosco, A Ko, MSH Schlessinger, D AF Cocchia, M Huber, R Pantano, S Chen, EY Ma, P Forabosco, A Ko, MSH Schlessinger, D TI PLAC1, an Xq26 gene with placenta-specific expression SO GENOMICS LA English DT Article ID MOUSE INTERSPECIFIC HYBRIDS; CHICKEN CAUDAL HOMOLOG; HOMEOBOX GENE; X-CHROMOSOME; TROPHOBLAST CELLS; DNA-SEQUENCES; HPRT LOCUS; LACTOGEN-I; IMPLANTATION; DYSPLASIA AB A novel human X-linked gene shows placenta-specific expression and has been named PLAC1. The gene maps 65 kb telomeric to HPRT at Xq26 and has been completely sequenced at the cDNA and genomic levels. The mouse orthologue Plac1 maps to the syntenically equivalent region of the mouse X chromosome. In situ hybridization studies with the antisense mRNA during mouse embryogenesis detect Plac1 expression from 7.5 dpc (days postcoitum) to 14.5 dpc in ectoplacental cone, giant cells, and labyrinthine trophoblasts. The putative human and murine PLAC1 proteins are 60% identical and 77% homologous, Both include a signal peptide and a peptide sequence also found in an interaction domain of the ZP3 (zona pellucida 3) protein. These results make PLAC1 a marker for placental development, with a possible role in the establishment of the mother-fetus interface. (C) 2000 Academic Press. C1 NIA, Genet Lab, Baltimore, MD 21224 USA. PE Appl Biosyst, Foster City, CA 94404 USA. Univ Modena & Reggio Emilia, Sez Istol Embriol & Genet, Dipartimento Sci Morfol & Med Legali, I-41100 Modena, Italy. RP Schlessinger, D (reprint author), NIA, IRP, LG, NIH, 333 Cassell Dr,Suite 4000, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 38 TC 52 Z9 60 U1 1 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD SEP 15 PY 2000 VL 68 IS 3 BP 305 EP 312 DI 10.1006/geno.2000.6302 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 358GH UT WOS:000089549900009 PM 10995572 ER PT J AU Hahn, H Wojnowski, L Specht, K Kappler, R Calzada-Wack, J Potter, D Zimmer, A Muller, U Samson, E Quintanilla-Martinez, L Zimmer, A AF Hahn, H Wojnowski, L Specht, K Kappler, R Calzada-Wack, J Potter, D Zimmer, A Muller, U Samson, E Quintanilla-Martinez, L Zimmer, A TI Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-II; BECKWITH-WIEDEMANN-SYNDROME; SIGNALING PATHWAY; SONIC HEDGEHOG; GENE; EXPRESSION; CANCER; TUMORIGENESIS; RECEPTOR; DISEASE AB Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children (Dagher, R., and Helman, L, (1999) Oncologist 4, 34-44), whereas medulloblastoma, a highly malignant tumor of the cerebellum, accounts for 20% of childhood brain tumors (Goodrich, L, V,, and Scott, M. P. (1998) Neuron 21, 1243-1257), Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R, J, (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models. RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2), We have investigated the mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis, Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disomy, amplification of the Igf2 locus, or polyploidy, Since Igf2 is also overexpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They also identify Igf2 as a potential target for medulloblastoma and RMS. C1 Tech Univ Munich, Inst Pathol, GSF, Res Ctr Environm & Hlth, D-85758 Neuherberg, Germany. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. NIMH, Vet Med & Resources Branch, NIH, Bethesda, MD 20892 USA. Univ Bonn, Psychiat Clin, D-53105 Bonn, Germany. RP Tech Univ Munich, Inst Pathol, GSF, Res Ctr Environm & Hlth, D-85758 Neuherberg, Germany. EM heidi.hakn@gsf.de RI Zimmer, Andreas/B-8357-2009; OI Calzada, Julia/0000-0003-0816-9305 NR 29 TC 159 Z9 160 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 15 PY 2000 VL 275 IS 37 BP 28341 EP 28344 DI 10.1074/jbc.C000352200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354KY UT WOS:000089330700001 PM 10884376 ER PT J AU Chao, SH Fujinaga, K Marion, JE Taube, R Sausville, EA Senderowicz, AM Peterlin, BM Price, DH AF Chao, SH Fujinaga, K Marion, JE Taube, R Sausville, EA Senderowicz, AM Peterlin, BM Price, DH TI Flavopiridol inhibits P-TEFb and blocks HIV-1 replication SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; BREAST-CARCINOMA CELLS; IN-VITRO; ELONGATION COMPLEXES; TAT TRANSACTIVATION; KINASE-ACTIVITY; TRANSCRIPTION; PROTEIN; ACTIVATION; PHOSPHATASE AB Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb, The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K-i of 3 nM. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat, Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC50 of less than 10 nM. C1 Univ Iowa, Program Mol Biol, Iowa City, IA 52242 USA. Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA. Univ Calif San Francisco, Howard Hughes Med Inst, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Howard Hughes Med Inst, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. NCI, Dev Therapeut Program, Clin Trials Unit, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), Univ Iowa, Program Mol Biol, Iowa City, IA 52242 USA. RI Price, David/F-6173-2010 FU NIAID NIH HHS [AI43691]; NIGMS NIH HHS [GM35500] NR 30 TC 326 Z9 334 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 15 PY 2000 VL 275 IS 37 BP 28345 EP 28348 DI 10.1074/jbc.C000446200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354KY UT WOS:000089330700002 PM 10906320 ER PT J AU Kersten, S Mandard, S Tan, NS Escher, P Metzger, D Chambon, P Gonzalez, FJ Desvergne, B Wahli, W AF Kersten, S Mandard, S Tan, NS Escher, P Metzger, D Chambon, P Gonzalez, FJ Desvergne, B Wahli, W TI Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA PPAR-ALPHA; TIE2 RECEPTOR; GAMMA; EXPRESSION; MICE; TISSUE; ANGIOPOIETIN-1; METABOLISM; RODENTS; LIGAND AB Fasting is associated with significant changes in nutrient metabolism, many of which are governed by transcription factors that regulate the expression of rate-limiting enzymes. One factor that plays an important role in the metabolic response to fasting is the peroxisome proliferator-activated receptor alpha (PPAR alpha). To gain more insight into the role of PPAR alpha during fasting, and into the regulation of metabolism during fasting in general, a search for unknown PPAR alpha target genes was performed. Using subtractive hybridization (SABRE) comparing liver mRNA from wild-type and PPAR alpha null mice, we isolated a novel PPAR alpha target gene, encoding the secreted protein FIAF (for fasting induced adipose factor), that belongs to the family of fibrinogen/angiopoietin-like proteins. FIAF is predominantly expressed in adipose tissue and is strongly up-regulated by fasting in white adipose tissue and liver. Moreover, FIAF mRNA is decreased in white adipose tissue of PPAR gamma +/- mice. FIAF protein can be detected in various tissues and in blood plasma, suggesting that FIAF has an endocrine function. Its plasma abundance is increased by fasting and decreased by chronic high fat feeding. The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions. C1 Univ Lausanne, Inst Biol Anim, CH-1015 Lausanne, Switzerland. Univ Louis Pasteur Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch, France. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Wahli, W (reprint author), Univ Lausanne, Inst Biol Anim, CH-1015 Lausanne, Switzerland. RI Kersten, Sander/A-1116-2011; Wahli, Walter/B-1398-2009; Desvergne, Beatrice/C-8892-2016; OI Kersten, Sander/0000-0003-4488-7734; Wahli, Walter/0000-0002-5966-9089; Desvergne, Beatrice/0000-0001-5483-288X; MANDARD, Stephane/0000-0002-7298-821X NR 25 TC 294 Z9 308 U1 0 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 15 PY 2000 VL 275 IS 37 BP 28488 EP 28493 DI 10.1074/jbc.M004029200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354KY UT WOS:000089330700021 PM 10862772 ER PT J AU Sabatino, DE Wong, C Cline, AP Pyle, L Garrett, LJ Gallagher, PG Bodine, DM AF Sabatino, DE Wong, C Cline, AP Pyle, L Garrett, LJ Gallagher, PG Bodine, DM TI A minimal ankyrin promoter linked to a human gamma-globin gene demonstrates erythroid specific copy number dependent expression with minimal position or enhancer dependence in transgenic mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOCUS-CONTROL REGION; HIGH-LEVEL EXPRESSION; BETA-GLOBIN; HYPERSENSITIVE SITE; HEREDITARY SPHEROCYTOSIS; DEVELOPMENTAL REGULATION; INDEPENDENT EXPRESSION; MESSENGER-RNA; CELLS; SEQUENCE AB In red blood cells ankyrin (ANK-1) provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane. We have previously demonstrated that a 2-71-bp 5'-flanking region of the ANK-1 gene has promoter activity in erythroid, but not non-erythroid, cell lines. To determine whether the ankyrin promoter could direct erythroid-specific expression in vivo, we analyzed transgenic mice containing the ankyrin promoter fused to the human (A)gamma-globin gene. Sixteen of 17 lines expressed the transgene in erythroid cells indicating nearly position-independent expression. We also observed a significant correlation between the level of Ank/(A)gamma-globin mRNA and transgene copy number. The level of Ank/(A)gamma mRNA averaged 11% of mouse alpha-globin mRNA per gene copy at all developmental stages. The addition of the HS2 enhancer from the beta-globin locus control region to the Ank/(A)gamma-globin transgene resulted in Ank/(A)gamma-globin mRNA expression in embryonic and fetal erythroid cells in six of eight lines but resulted in absent or dramatically reduced levels of Ank/(A)gamma-globin mRNA in adult erythroid cells in eight of eight transgenic lines. These data indicate that the minimal ankyrin promoter contains all sequences necessary and sufficient for erythroid-specific, copy number-dependent, position-independent expression of the human (A)gamma-globin gene. C1 NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. George Washington Univ, Grad Program Genet, Washington, DC 20052 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, Bldg 49,Room 3A14 MSC 4442, Bethesda, MD 20892 USA. NR 40 TC 38 Z9 39 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 15 PY 2000 VL 275 IS 37 BP 28549 EP 28554 DI 10.1074/jbc.M004043200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354KY UT WOS:000089330700030 PM 10878017 ER PT J AU Hamada, M Sakulich, AL Koduru, SB Maraia, RJ AF Hamada, M Sakulich, AL Koduru, SB Maraia, RJ TI Transcription termination by RNA polymerase III in fission yeast - A genetic and biochemically tractable model system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN LA ANTIGEN; SCHIZOSACCHAROMYCES-POMBE; DNA-BINDING; INITIATION-FACTOR; ALPHA-AMANITIN; BETA' SUBUNIT; S-CEREVISIAE; PROTEIN; SEQUENCES; CLEAVAGE AB In order for RNA polymerase (pol) III to produce a sufficient quantity of RNAs of appropriate structure, initiation, termination, and reinitiation must be accurate and efficient. Termination-associated factors have been shown to facilitate reinitiation and regulate transcription in some species. Suppressor tRNA genes that differ in the dT(n) termination signal were examined for function in Schizosaccharomyces pombe, We also developed an S. pombe extract that is active for tRNA transcription that is described here for the first time. The ability of this tRNA gene to be transcribed in extracts from different species allowed us to compare termination in three model systems. Although human pol III terminates efficiently at 4 dTs and S. pombe at 5 dTs, Saccharomyces cerevisiae pol III requires 6 dTs to direct comparable but lower termination efficiency and also appears qualitatively distinct. Interestingly, this pattern of sensitivity to a minimal dT(n) termination signal was found to correlate with the sensitivity to alpha-amanitin, as S. pombe was intermediate between human and S. cerevisiae pols III. The results establish that the pols III of S. cerevisiae, S. pombe, and human exhibit distinctive properties and that termination occurs in S. pombe in a manner that is functionally more similar to human than is S. cerevisiae. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), 6 Ctr Dr,Rm 416, Bethesda, MD 20892 USA. NR 63 TC 48 Z9 48 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 15 PY 2000 VL 275 IS 37 BP 29076 EP 29081 DI 10.1074/jbc.M003980200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354KY UT WOS:000089330700095 PM 10843998 ER PT J AU Yasutomo, K Lucas, B Germain, RN AF Yasutomo, K Lucas, B Germain, RN TI TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DIFFERENTIAL AVIDITY MODEL; MARROW-DERIVED CELLS; CLASS-II MHC; T-CELLS; HEMATOPOIETIC-CELLS; NEGATIVE SELECTION; DENDRITIC CELLS; THYMIC SELECTION; ANTIGEN RECEPTOR; DEFICIENT MICE AB Thymocyte selection involves signaling by TCR engaging diverse self-peptide:MHC molecule ligands on various cell types in the cortex and medulla, Here we separately analyze early and late stages of selection to better understand how presenting cell type, ligand quality, and the timing of TCR signaling contribute to intrathymic differentiation. TCR transgenic CD4(+)CD8(+) thymocytes (double positive (DP)) from MHC-deficient mice were stimulated using various presenting cells and ligands, The resulting CD69(high) cells were isolated and evaluated for maturation in reaggregate cultures with wild-type or MHC molecule-deficient thymic stroma with or without added hemopoietic dendritic cells (DC), Production of CD4(+) T cells required TCR signaling in the reaggregates, indicating that transient recognition of self-ligands by DP is inadequate for full differentiation. DC bearing a potent agonist ligand could initiate positive selection, producing activated thymocytes that matured into agonist-responsive T cells in reaggregates lacking the same ligand, DC could also support the TCR signaling necessary for late maturation. These results argue that despite the negative role assigned to DC in past studies, neither the peptide:MHC molecule complexes present on DC nor any other signals provided by these cells stimulate only thymocyte death. These findings also indicate that unique epithelial ligands are not necessary for positive selection. They provide additional insight into the role of ligand quality in selection events and support the concept that following initiation of maturation from the DP state, persistent TCR signaling is characteristic of and perhaps required by T cells. C1 NIAID, Immunol Lab, NIH, Lymphocyte Biol Sect, Bethesda, MD 20892 USA. Inst Necker, INSERM, Unite 345, Paris, France. RP Germain, RN (reprint author), NIAID, Immunol Lab, NIH, Lymphocyte Biol Sect, Bldg 10,Room 11N311,10 Ctr Dr,MSC-1892, Bethesda, MD 20892 USA. NR 57 TC 37 Z9 38 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2000 VL 165 IS 6 BP 3015 EP 3022 PG 8 WC Immunology SC Immunology GA 384JB UT WOS:000165938100014 PM 10975810 ER PT J AU Love, PE Lee, J Shores, EW AF Love, PE Lee, J Shores, EW TI Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; ZETA-CHAIN; ANTIGEN RECEPTOR; TRANSGENIC MICE; NEGATIVE SELECTION; ACTIVATION MOTIFS; THYMIC SELECTION; LYMPHOCYTES-T; GAMMA-CHAIN; TRANSDUCTION AB Whether a developing thymocyte becomes positively or negatively selected is thought to be determined by the affinity/avidity of its TCR for MHC/peptide ligands expressed in the thymus, Presumably, differences in affinity translate into differences in the potency of the ensuing TCR-mediated signals, and these differences in signal strength determine the outcome of thymocyte selection. However, there is little direct evidence establishing a relationship between TCR-ligand affinity and signal strength during positive and negative selection. The TCR complex contains multiple signaling motifs, known as immunoreceptor tyrosine-based activation motifs (ITAMs) that are required for T cell activation. To examine the effects of TCR signal strength on selection, the signaling potential of the TCR was modified by substituting transgenic TCR 5-chains containing either three, one, or zero ITAMs for endogenous (3-ITAM) zeta -chain. These zeta -chain variants were then bred into different alpha beta TCR transgenic backgrounds. We report that reductions in TCR signaling potential have distinct effects on the selection of thymocytes expressing different TCRs, and that the requirement for zeta -chain ITAMs critically depends upon the specificity and apparently, affinity, of the TCR for its selecting ligand(s). C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. RP Shores, EW (reprint author), 1401 Rockville Pke,HFM-538, Rockville, MD 20852 USA. NR 37 TC 51 Z9 52 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2000 VL 165 IS 6 BP 3080 EP 3087 PG 8 WC Immunology SC Immunology GA 384JB UT WOS:000165938100023 PM 10975819 ER PT J AU Soldatov, NM Zhenochin, S AlBanna, B Abernethy, DR Morad, M AF Soldatov, NM Zhenochin, S AlBanna, B Abernethy, DR Morad, M TI New molecular determinant for inactivation of the human L-type alpha(1C) Ca2+ channel SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE calcium channel; inactivation; mutant; Ca2+ overloading ID BRAIN CALCIUM-CHANNEL; STRUCTURAL DETERMINANTS; SODIUM-CHANNEL; SUBUNIT GENE; PHENYLALKYLAMINES; SELECTIVITY; CALMODULIN; INHIBITION; RECEPTOR; REGION AB Molecular cloning of the human fibroblast Ca2+ channel pore-forming alpha(1C) subunit revealed (Soldatov, 1992. Proc. Natl. Acad. Sci. USA 89:4628-4632) a naturally occurring mutation g(2254) --> a that causes the replacement of the conservative alanine for threonine at the position 752 at the cytoplasmic end of transmembrane segment IIS6. Using stably transfected HEK293 cell lines, we have compared electrophysiological properties of the conventional alpha(1C,77) human recombinant L-type Ca2+ channel with those of its mutated isoform alpha(1C,94) containing the A752T replacement. Comparative quantification of steady-state availability of the current carried by alpha(1C,94) and alpha(1C,77) showed that A752T mutation prevented a large (approximate to 25%) fraction of the current carried by Ca2+ or Ba2+ from fully inactivating. This mutation, however, did not appear to alter significantly the Ca2+-dependence and kinetics of decay of the inactivating fraction of the current or its voltage-dependence. The data suggests that Ala752 at the cytoplasmic end of IIS6 might serve as a molecular determinant of the Ca2+ channel inactivation, possibly regulating the voltage-dependence of its availability. C1 NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. RP Soldatov, NM (reprint author), NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. FU NHLBI NIH HHS [HL16152]; NIA NIH HHS [AG08226] NR 27 TC 13 Z9 13 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD SEP 15 PY 2000 VL 177 IS 2 BP 129 EP 135 DI 10.1007/s002320001106 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 355BJ UT WOS:000089365500004 PM 11003687 ER PT J AU Xu, BJ Gottschalk, W Chow, A Wilson, RI Schnell, E Zang, KL Wang, DA Nicoll, RA Lu, B Reichardt, LF AF Xu, BJ Gottschalk, W Chow, A Wilson, RI Schnell, E Zang, KL Wang, DA Nicoll, RA Lu, B Reichardt, LF TI The role of brain-derived neurotrophic factor receptors in the mature hippocampus: Modulation of long-term potentiation through a presynaptic mechanism involving TrkB SO JOURNAL OF NEUROSCIENCE LA English DT Article DE TrkB; conditional mutant; CA1; long-term potentiation; presynaptic; neuronal survival ID CENTRAL-NERVOUS-SYSTEM; BDNF KNOCKOUT MICE; SYNAPTIC TRANSMISSION; PROTEIN-KINASE; CA1 REGION; ADULT-RAT; NEURONS; SYNAPSES; PLASTICITY; NT-3 AB The neurotrophin BDNF has been shown to modulate long-term potentiation (LTP) at Schaffer collateral-CA1 hippocampal synapses. Mutants in the BDNF receptor gene trkB and antibodies to its second receptor p75NTR have been used to determine the receptors and cells involved in this response. Inhibition of p75NTR does not detectably reduce LTP or affect presynaptic function, but analyses of newly generated trkB mutants implicate TrkB. One mutant has reduced expression in a normal pattern of TrkB throughout the brain. The second mutant was created by cre-loxP-mediated removal of TrkB in CA1 pyramidal neurons of this mouse. Neither mutant detectably impacts survival or morphology of hippocampal neurons. TrkB reduction, however, affects presynaptic function and reduces the ability of tetanic stimulation to induce LTP. Postsynaptic glutamate receptors are not affected by TrkB reduction, indicating that BDNF does not modulate plasticity through postsynaptic TrkB. Consistent with this, elimination of TrkB in postsynaptic neurons does not affect LTP. Moreover, normal LTP is generated in the mutant with reduced TrkB by a depolarization-low-frequency stimulation pairing protocol that puts minimal demands on presynaptic terminal function. Thus, BDNF appears to act through TrkB presynaptically, but not postsynaptically, to modulate LTP. C1 Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Howard Hughes Med Inst, Program Neurosci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. NICHHD, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Reichardt, LF (reprint author), Univ Calif San Francisco, Dept Physiol, 533 Parnassu Ave, San Francisco, CA 94143 USA. RI Lu, Bai/A-4018-2012; yu, yan/C-2322-2012 FU NIMH NIH HHS [MH 48200, P50 MH048200-100005] NR 51 TC 249 Z9 255 U1 1 U2 9 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 SEP 15 PY 2000 VL 20 IS 18 BP 6888 EP 6897 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 355GY UT WOS:000089379000019 PM 10995833 ER PT J AU Kruman, II Culmsee, C Chan, SL Kruman, Y Guo, ZH Penix, L Mattson, MP AF Kruman, II Culmsee, C Chan, SL Kruman, Y Guo, ZH Penix, L Mattson, MP TI Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium; caspase; mitochondrial transmembrane potential; NAD; PARP; stroke ID ISCHEMIC BRAIN INJURY; MANGANESE SUPEROXIDE-DISMUTASE; FIBROBLAST-GROWTH-FACTOR; STRESS-INDUCED APOPTOSIS; ENDOTHELIAL-CELL INJURY; ADP-RIBOSE POLYMERASE; CYTOCHROME-C RELEASE; ALZHEIMERS-DISEASE; MITOCHONDRIAL DEPOLARIZATION; PEROXYNITRITE PRODUCTION AB Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 65 TC 501 Z9 524 U1 1 U2 19 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 SEP 15 PY 2000 VL 20 IS 18 BP 6920 EP 6926 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 355GY UT WOS:000089379000022 PM 10995836 ER PT J AU Nomura, T Yabe, T Rosenthal, ES Krzan, M Schwartz, JP AF Nomura, T Yabe, T Rosenthal, ES Krzan, M Schwartz, JP TI PSA-NCAM distinguishes reactive astrocytes in 6-OHDA-lesioned substantia nigra from those in the striatal terminal fields SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE reactive gliosis; PSA-NCAM; NG2; GFAP; substantia nigra; striatum ID CELL-ADHESION MOLECULE; CHONDROITIN-SULFATE PROTEOGLYCAN; OLIGODENDROCYTE PRECURSOR CELLS; N-CAM; POLYSIALIC ACID; SPINAL-CORD; PROGENITOR-CELL; NERVOUS-SYSTEM; DENTATE GYRUS; OPTIC-NERVE AB 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra (SN) causes the appearance of reactive astrocytes not only in the SN but also in the striatal terminal fields, as measured by increased size of the cells and their processes, as well as enhanced expression of glial fibrillary acidic protein (GFAP) and an epitope recognized by monoclonal antibody 19D1. We now demonstrate that polysialylated neural cell adhesion molecule (PSA-NCAM) is induced on reactive astrocytes, as well as on large neurons, on the ipsilateral side of the 6-OHDA-lesioned SN. Colocalization of GFAP and PSA-NCAM was confirmed for reactive astrocytes using a confocal laser Scanning microscope. Negligible amounts of PSA-NCAM reactivity were detected contralaterally, although colocalization was noted on astrocytes with sparse, significantly thinner processes, In contrast to the increase of GFAP in the lesioned striatum, few striatal astrocytes expressed PSA-NCAM. In agreement with these results, PSA-NCAM was detected on cultured reactive astrocytes from SN but not reactive striatal astrocytes. Double immunohistochemistry for proliferating cell nuclear antigen (PCNA), a marker of dividing cells, and GFAP demonstrated that reactive astrocytes in lesioned SN were PCNA-positive whereas those in striatum were not. Although NG2 chondroitin sulfate proteoglycan expression also increased in the lesioned SN, NG2 was not colocalized with PSA-NCAM, was not expressed on astrocytes, and labeled only oligodendrocyte precursor cells. Our results suggest that PSA-NCAM can act as a marker for reactive astrocytes only at the site of the lesion and not in the terminal fields, probably because it is reexpressed only when astrocytes divide. Published 2000 Wiley-Liss, Inc.dagger C1 NINDS, NTFS, NIH, Bethesda, MD 20892 USA. RP Schwartz, JP (reprint author), NINDS, NTFS, NIH, Bldg 36,Room 4A31, Bethesda, MD 20892 USA. NR 38 TC 32 Z9 34 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP 15 PY 2000 VL 61 IS 6 BP 588 EP 596 DI 10.1002/1097-4547(20000915)61:6<588::AID-JNR2>3.0.CO;2-M PG 9 WC Neurosciences SC Neurosciences & Neurology GA 349TJ UT WOS:000089061400002 PM 10972955 ER PT J AU Lanuza, MA Li, MX Jia, M Kim, S Davenport, R Dunlap, V Nelson, PG AF Lanuza, MA Li, MX Jia, M Kim, S Davenport, R Dunlap, V Nelson, PG TI Protein kinase C-mediated changes in synaptic efficacy at the neuromuscular junction in vitro: The role of postsynaptic acetylcholine receptors SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE neuromuscular junction; synapse loss; protein kinase C; acetylcholine receptor; activity dependent; in vitro; phorbol esters ID GENE-RELATED PEPTIDE; EMBRYONIC RAT MOTONEURONS; SKELETAL-MUSCLE; PHORBOL ESTER; POLYNEURONAL INNERVATION; MAMMALIAN MUSCLE; AXON WITHDRAWAL; DOWN-REGULATION; IN-VITRO; T-CELLS AB Activation of a mouse in vitro neuromuscular synapse produces a reduction in synaptic efficacy which is greater for nonactivated than for activated inputs to the myotubes, This has been shown to require thrombin and thrombin receptor activation and to involve a protein kinase C (PKC)-mediated step. We show in the present work that phorbol ester activation of PKC produces physiological loss of synapses in a time- and dose-related manner. We observe, using quantitative imaging methods, a parallel loss of acetylcholine receptors (AChR) from synaptically functional neurite-associated receptor aggregates in nerve-muscle cocultures, Biochemical measurements of total AChR show that PKC activation reduces both AChR stability (increases receptor loss) and receptor insertion into the surface membrane. Taken together, the data suggest that PKC activation decreases the stability of AChR aggregates in the muscle surface membrane. We conclude that PKC plays a crucial role in activity-dependent synapse reduction and does so, at least in part, by altering AChR stability. Published 2000 Wiley-Liss, Inc.dagger C1 NICHHD, NIH, Neurobiol Sect, Bethesda, MD 20892 USA. Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, E-43201 Reus, Spain. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP Nelson, PG (reprint author), NICHHD, NIH, Neurobiol Sect, Bldg 49,Rm 5A38,MSC 4480, Bethesda, MD 20892 USA. NR 56 TC 33 Z9 34 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP 15 PY 2000 VL 61 IS 6 BP 616 EP 625 DI 10.1002/1097-4547(20000915)61:6<616::AID-JNR5>3.0.CO;2-N PG 10 WC Neurosciences SC Neurosciences & Neurology GA 349TJ UT WOS:000089061400005 PM 10972958 ER PT J AU Maric, D Liu, QY Grant, GM Andreadis, JD Hu, Q Chang, YH Barker, JL Pancrazio, JJ Stenger, DA Ma, W AF Maric, D Liu, QY Grant, GM Andreadis, JD Hu, Q Chang, YH Barker, JL Pancrazio, JJ Stenger, DA Ma, W TI Functional ionotropic glutamate receptors emerge during terminal cell division and early neuronal differentiation of rat neuroepithelial cells SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE neural precursor cell; neurogenesis; Ca2+ imaging; patch-clamp recording ID CEREBELLAR GRANULE CELLS; CEREBRAL-CORTEX; NMDA RECEPTORS; IN-VITRO; HIPPOCAMPAL-NEURONS; PROGENITOR CELLS; BETA-TUBULIN; GLIAL-CELLS; STEM-CELLS; POSTTRANSLATIONAL MODIFICATION AB Ionotropic glutamate receptors mediate fast forms of excitatory synaptic transmission in mature neurons and may play critical roles in neuronal development. However, the developmental stage at which neuronal cells begin to express functional receptors and their roles in lineage progression remain unclear. In the present study, neural precursor cells were isolated from the cortical neuroepithelium of embryonic day 13 rats, and rapidly expanded in serum-free medium in response to basic fibroblast growth factor, RT-PCR revealed the presence of mRNAs encoding AMPA(A), AMPA(C), KA(1), KA(2), NMDA(1), and NMDA(2D) subunits after 3 days in culture, The functional expression of AMPA/kainate and NMDA receptors was investigated using Ca2+ imaging and whole-cell patch-clamp recording techniques in cells pulse-labeled with bromodeoxyuridine (BrdU) for 1-4 hr. The recorded cells were then double-immunostained for BrdU incorporation and neuron-specific p-tubulin (TuJ1), The results show that AMPA/kainate and NMDA induced increases in cytosolic Ca2+ and inward currents only in differentiating neurons. In contrast, proliferating BrdU(+)TuJ1(-) cells failed to respond to any ionotropic glutamate receptor agonists, Interestingly, Ca2+ imaging revealed that a subpopulation of BrdU(+)TuJ1(+) cells also responded to AMPA, indicating the emergence of functional ionotropic AMPA/kainate receptors during terminal cell division and the earliest commitment to neuronal cell lineage. These in vitro results were supported by flow cytometric sorting of AMPA-responsive cells pulse-labeled with BrdU for I hr in vivo, which revealed that functional AMPA receptors appear in BrdU(+)TuJ1(+) cells under physiological conditions and may play a role in terminal cell division. (C) 2000 Wiley-Liss, Inc. C1 USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Ma, W (reprint author), USN, Res Lab, Ctr Biomol Sci & Engn, Code 6910,4555 Overlook Ave SW, Washington, DC 20375 USA. RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 FU NIAAA NIH HHS [1 R21 AA12237-01] NR 49 TC 51 Z9 52 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP 15 PY 2000 VL 61 IS 6 BP 652 EP 662 DI 10.1002/1097-4547(20000915)61:6<652::AID-JNR9>3.0.CO;2-J PG 11 WC Neurosciences SC Neurosciences & Neurology GA 349TJ UT WOS:000089061400009 PM 10972962 ER PT J AU Shao, ZY Yakel, JL AF Shao, ZY Yakel, JL TI Single channel properties of neuronal nicotinic ACh receptors in stratum radiatum interneurons of rat hippocampal slices SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID ACETYLCHOLINE-RECEPTORS; FUNCTIONAL CONTRIBUTION; ALPHA-5 SUBUNIT; SUBTYPES; DIVERSITY; BRAIN; RELEASE; BETA-2 AB 1. The single channel properties of neuronal nicotinic ACh receptors (nAChRs) were investigated in outside-out patches from CA1 stratum radiatum interneurons from thin slices of rat hippocampus. 2. The application of ACh (10 mu M to 1 mM) induced the opening of observable single channel currents with two distinct current levels, which corresponded to conductance levels of 38 +/- 3 and 62 +/- 2 pS. The 38 pS channel was observed in 10% (n = 260) of patches, whereas the 62 pS channel was observed in 4% of patches; these two channel types were most often observed independently 3. The alpha 7-selective nAChR antagonist methyllycaconitine (MLA; 50 nM) reduced the open probability of the 38 pS channel by 73%. In contrast, the 62 pS channel was unaffected by MLA, but instead was blocked by dihydro-beta-erythroidine (DH beta E; 10 mu M), a broad spectrum nAChR antagonist. 4. These data suggest that rat hippocampal CA1 stratum radiatum interneurons in the slice possess at least two different types of functional nAChRs, an alpha 7-containing subtype with a single channel conductance of 38 pS, and a non-alpha 7 subtype with a single channel conductance of 62 pS. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 TW Alexander Dr,F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 44 Z9 44 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2000 VL 527 IS 3 BP 507 EP 513 DI 10.1111/j.1469-7793.2000.00507.x PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 356HV UT WOS:000089438600009 PM 10990537 ER PT J AU Sudweeks, SN Yakel, JL AF Sudweeks, SN Yakel, JL TI Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; ACETYLCHOLINE-RECEPTORS; SYNAPTIC TRANSMISSION; ALPHA-5 SUBUNIT; INTERNEURONS; SUBTYPES; EXPRESSION; BRAIN; DIVERSITY; CHANNELS AB 1. The molecular and functional properties of neuronal nicotinic acetylcholine receptors (nAChRs) were characterized from CA1 neurons in rat hippocampal slices using single-cell reverse-transcription polymerase chain reaction (RT-PCR) in conjunction with with hole-cell patch-clamp recordings. 2. We analysed the presence of the neuronal nAChR subunit mRNAs alpha 2-7 and beta 2-4, along with the mRNA for the GABAergic markers GAD (glutamic acid decarboxylase) 65 and 67 isoforms, and VGAT (vesicular GABA transporter) in interneurons from the stratum radiatum and stratum oriens, and in CA1 pyramidal neurons. Functional nAChR-mediated currents were detected in both interneuron populations, but not in pyramidal neurons. 3. The neuronal nAChR subunit mRNAs detected in > 20% of the populations examined were alpha 4, alpha 5, alpha 7 and beta 2-4 in stratum radiatum interneurons; alpha 2, alpha 3, alpha 4, alpha 7, beta 2 and beta 3 subunits in stratum oriens interneurons; and beta 2-4 in pyramidal neurons. High levels of GABAergic marker mRNAs were detected in both interneuron populations, but not in pyramidal neurons. 4. Significant co-expression of nAChR subunits within individual neurons was detected for alpha 3 + alpha 5, alpha 4 + beta 2, alpha 4 + beta 3, alpha 7 + beta 2, beta 2 + beta 3 and beta 3 + beta 4. 5. The kinetics of the nAChR-mediated currents in response to the application of 100 mu M ACh were significantly correlated with the expression of particular nAChR subunits. The alpha 3, alpha 7 and beta 2 nAChR subunits were individually correlated with a fast rise time, the alpha 2 nAChR subunit was correlated with a medium rise time, and the alpha 4 nAChR subunit was correlated with a slow rise time. The alpha 2 and alpha 4 nAChR subunits were also significantly correlated with slow desensitization kinetics. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 TW Alexander Dr,F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. NR 49 TC 146 Z9 150 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2000 VL 527 IS 3 BP 515 EP 528 DI 10.1111/j.1469-7793.2000.00515.x PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 356HV UT WOS:000089438600010 PM 10990538 ER PT J AU Miao, FJP Janig, W Levine, JD AF Miao, FJP Janig, W Levine, JD TI Nociceptive neuroendocrine negative feedback control of neurogenic inflammation activated by capsaicin in the rat paw: role of the adrenal medulla SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SYNOVIAL PLASMA EXTRAVASATION; POSTGANGLIONIC NERVE-FIBERS; MECHANICAL HYPERALGESIA; GASTROINTESTINAL-TRACT; INTRATHECAL NICOTINE; ANESTHETIZED RATS; VAGAL AFFERENTS; BRADYKININ; INNERVATION; INHIBITION AB 1. Recently we have found that inhibition of bradykinin-induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo-pituitary-adrenal axis. 2. Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin-induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. Furthermore, we tested whether inhibition of bradykinin-induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T-1/T-2 or T-12/L-1. 3. Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin-induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. 4. The inhibition of bradykinin-induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. 5. Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus-intact and in vagotomized animals. 6. after spinalization at the segmental Level T-1/T-2, capsaicin injected into the forepaw did not depress bradykinin-induced plasma extravasation either in vagus-intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T-12/L-1 no depression was produced by capsaicin injected into the hindpaw. 7. Depression of bradykinin-induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus-intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho-adrenal system. 8. We conclude that depression of bradykinin-induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin-induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo-pituitary-adrenal axis. C1 Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. Univ Kiel, Inst Physiol, D-24098 Kiel, Germany. RP Miao, FJP (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, Box 0440, San Francisco, CA 94143 USA. FU NIAMS NIH HHS [R01 AR032634, AR-32634] NR 29 TC 18 Z9 18 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2000 VL 527 IS 3 BP 601 EP 610 DI 10.1111/j.1469-7793.2000.00601.x PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 356HV UT WOS:000089438600016 PM 10990544 ER PT J AU Fox, RJ Kasner, SE Galetta, SL Chalela, JA AF Fox, RJ Kasner, SE Galetta, SL Chalela, JA TI Treatment of Bickerstaff's brainstem encephalitis with immune globulin SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Bickerstaff's brainstem encephalitis; intravenous immunoglobulin; IVIg; anti-GQ1b antibody; ophthalmoparesis; pseodoptosis; pseudoretraction ID GUILLAIN-BARRE-SYNDROME; MILLER FISHER SYNDROME; STEM ENCEPHALITIS; ANTIBODY; PARALYSIS AB Bickerstaff's brainstem encephalitis (BBE) is an immune disorder of unknown etiology. Previous reports of successful treatment of BBE involved steroids or plasma exchange. We describe a patient with BBE who demonstrated rapid clinical recovery after treatment with intravenous immune globulin. Our findings suggest that IVIg is an alternative treatment in BBB, especially when plasma exchange is difficult or contraindicated. Our patient also demonstrated pseudoretraction and pseudoptosis during clinical recovery, an observation which supports a differential immune attack on components of the third nerve or supranuclear regions, and expands our understanding of the pathophysiology of BBE. (C) 2000 Elsevier Science B.V. AII rights reserved. C1 Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA USA. RP Chalela, JA (reprint author), NINCDS, NIH, Sect Stroke Diagnost & Therapeut, 36 Convent Dr,Room 4A03,MSC 4129, Bethesda, MD 20892 USA. RI Kasner, Scott/C-6109-2011 NR 14 TC 11 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD SEP 15 PY 2000 VL 178 IS 2 BP 88 EP 90 DI 10.1016/S0022-510X(00)00379-8 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 365KL UT WOS:000089950400002 PM 11018699 ER PT J AU Qin, ZH Wang, YM Chasea, TN AF Qin, ZH Wang, YM Chasea, TN TI A caspase-3-like protease is involved in NF-kappa B activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum SO MOLECULAR BRAIN RESEARCH LA English DT Article DE NF-kappa B; I kappa B-alpha; caspase-3; proteasome; MG-132; Ac-DEVD CHO; apoptosis ID CEREBELLAR GRANULE NEURONS; TUMOR-NECROSIS-FACTOR; TRANSCRIPTION FACTOR; NUCLEAR TRANSLOCATION; MEDIATED APOPTOSIS; ALPHA PHOSPHORYLATION; GLUTAMATE RECEPTORS; HIPPOCAMPAL-NEURONS; DNA FRAGMENTATION; CELL-DEATH AB Glutamate receptor stimulation reportedly activates NF-kappa B in vitro and in vivo, although underlying mechanisms remain to be elucidated. Here we evaluated the role of proteases in mediating N-methyl-D-aspartate (NMDA) receptor agonist-induced NF-kappa B activation and apoptosis in rat striatum. The intrastriatal infusion of quinolinic acid (QA, 60 nmol) had no effect on levels of NF-kappa B family proteins, including p65, p50, p52, c-Rel and Rel B. In contrast, QA decreased I kappa B-alpha protein levels by 60% (P<0.05); other members of the I kappa B filmily, including I kappa B-beta, I kappa B-gamma, I kappa B-epsilon and Bcl-3, were not altered. The QA-stimulated degradation of I kappa B-alpha was completely blocked by the NMDA receptor antagonist MK-801. QA-induced I kappa B-alpha degradation and NF-kappa B activation were not affected by the proteasome inhibitor MG-132 (1-4 mu g). On the other hand, the caspase-3 inhibitor Ac-DEVD . CHO (2-8 mu g) blocked QA-induced I kappa B-alpha degradation in a dose-dependent manner (P<0.05). Ac-DEVD . CHO (4 mu g) also substantially reduced QA-induced NF-kappa B activation (P<0.05), but had no effect on QA-induced AP-1 activation. Furthermore, Ac-DEVD . CHO, but not MG-132, dose-dependently attenuated QA-induced internucleosomal DNA fragmentation. These findings suggest that NF-kappa B activation by NMDA receptor stimulation involves I kappa B-alpha degradation by a caspase-3-like cysteine protease dependent mechanism. Caspase-3 thus appears to contribute to the excitotoxin-induced apoptosis in rat striatal neurons occurring at least partially as a consequence of NF-kappa B activation. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chasea, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Rm 5C 103,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 64 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 15 PY 2000 VL 80 IS 2 BP 111 EP 122 DI 10.1016/S0169-328X(00)00147-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 355JG UT WOS:000089382100001 ER PT J AU Asanuma, M Hayashi, T Ordonez, SV Ogawa, N Cadet, JL AF Asanuma, M Hayashi, T Ordonez, SV Ogawa, N Cadet, JL TI Direct interactions of methamphetamine with the nucleus SO MOLECULAR BRAIN RESEARCH LA English DT Article DE methamphetamine; nucleus; transcription factor; AP-1; CREB; confocal laser scanning microscopy ID DISMUTASE TRANSGENIC MICE; DNA-BINDING ACTIVITY; INDUCED NEUROTOXICITY; RAT-BRAIN; METHYLENEDIOXYMETHAMPHETAMINE MDMA; OXIDATIVE STRESS; DOPAMINE; ATTENUATION; INHIBITOR; RADICALS AB Possible direct effects of methamphetamine (METH) on transcription factors AP-1 and cAMP response element-binding. protein (CREB) in the nucleus were assessed by electrophoretic mobility-shift assay. In vitro addition of METH to nuclear extract from brain tissue increased DNA-binding activities of both transcription factors. In addition, injections of METH to mice induced increases in the binding of AP-I and CREB, which were depleted by preincubating the nuclear extract with anti-METH antibody. We also examined the cellular distribution of METH in mesencephalic neuronal cells using an immunofluorescence experiment with anti-METH antibody. METH-like immunoreactivity was seen to accumulate in the cytosol 4-6 h after the METH treatment. Furthermore, METH-positive signals were also observed in the nuclei of the: METH-treated cells. The present study is the first demonstration that METH can have direct effects on DNA-binding protein complex by redistributing not only in the cytosol but also into the nucleus. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Okayama Univ, Sch Med, Inst Mol & Cellular Med, Dept Neurosci, Okayama 7008558, Japan. NIDA, Mol Neuropsychiat Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Asanuma, M (reprint author), Okayama Univ, Sch Med, Inst Mol & Cellular Med, Dept Neurosci, 2-5-1 Shikatacho, Okayama 7008558, Japan. RI Hayashi, Teruo/A-9690-2008 NR 28 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 15 PY 2000 VL 80 IS 2 BP 237 EP 243 DI 10.1016/S0169-328X(00)00128-5 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 355JG UT WOS:000089382100014 ER PT J AU Radany, EH Dornfeld, KJ Sanderson, RJ Savage, MK Majumdar, A Seidman, MM Mosbaugh, DW AF Radany, EH Dornfeld, KJ Sanderson, RJ Savage, MK Majumdar, A Seidman, MM Mosbaugh, DW TI Increased spontaneous mutation frequency in human cells expressing the phage PBS2-encoded inhibitor of uracil-DNA glycosylase SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE uracil-DNA glycosylase; Ugi protein; Ung mutant; mutator phenotype ID BASE EXCISION-REPAIR; SHUTTLE VECTOR PLASMID; ESCHERICHIA-COLI; MAMMALIAN-CELLS; CYCLE REGULATION; PROTEIN MIMICRY; MESSENGER-RNA; UNG GENE; NUCLEAR; VIRUS AB The Ugi protein inhibitor of uracil-DNA glycosylase encoded by bacteriophage PBS2 inactivates human uracil-DNA glycosylases (UDG) by forming a tight enzyme:inhibitor complex. To create human cells that are impaired for UDG activity, the human glioma U251 cell line was engineered to produce active Ugi protein. In vitro assays of crude cell extracts from several Ugi-expressing clonal lines showed UDG inactivation under standard assay conditions as compared to control cells, and four of these UDG defective cell Lines were characterized for their ability to conduct in vivo uracil-DNA repair. Whereas transfected plasmid DNA containing either a U:G mispair or U:A base pairs was efficiently repaired in the control lines, uracil-DNA repair was not evident in the lines producing Ugi. Experiments using a shuttle vector to detect mutations in a target gene showed that Ugi-expressing cells exhibited a S-fold higher overall spontaneous mutation frequency compared to control cells, due to increased C:G to T:A base pair substitutions. The growth rate and cell cycle distribution of Ugi-expressing,a cells did not differ appreciably from their parental cell counterpart. Further in vitro examination revealed that a thymine DNA glycosylase (TDG) previously shown to mediate Ugi-insensitive excision of uracil bases from DNA was not detected in the parental U251 cells. However, a Ugi-insensitive UDG activity of unknown origin that recognizes U:G mispairs and to a lesser extent U:A base pairs in duplex DNA, but which was inactive toward uracil residues in single-stranded DNA, was detected under assay conditions previously shown to be efficient for detecting TDG. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Calif Irvine, Sch Med, Chao Family Comprehens Canc Ctr, Orange, CA 92868 USA. Dept Vet Affairs Med Ctr, Ann Arbor, MI 48105 USA. Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA. Oregon State Univ, Ctr Environm Hlth Sci, Corvallis, OR 97331 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Radany, EH (reprint author), Univ Calif Irvine, Coll Med, Med Sci 1 Rm B-135 Zotcode 2695, Irvine, CA 92697 USA. FU NCI NIH HHS [CA26803]; NIEHS NIH HHS [ES00210]; NIGMS NIH HHS [GM32832] NR 67 TC 24 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8777 J9 MUTAT RES-DNA REPAIR JI Mutat. Res.-DNA Repair PD SEP 15 PY 2000 VL 461 IS 1 BP 41 EP 58 DI 10.1016/S0921-8777(00)00040-9 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 358ZK UT WOS:000089586900004 PM 10980411 ER PT J AU Benoliel, R Tanaka, M Caudle, RM Iadarola, MJ AF Benoliel, R Tanaka, M Caudle, RM Iadarola, MJ TI Co-localization of N-methyl-D-aspartate receptors and substance P (neurokinin-1) receptors in rat spinal cord SO NEUROSCIENCE LETTERS LA English DT Article DE glutamate; pain; Onuf's nucleus; motorneurons; intermediolateral nucleus; sympathetic nervous system; parasympathetic nervous system; receptor co-localization ID MESSENGER-RNA; DORSAL HORN; ACID; HYPERSENSITIVITY; TRANSMISSION; NOCICEPTION; RESPONSES; ISOFORMS; NEURONS; PAIN AB Glutamate, substance P (SP), and their receptors have been implicated in the initiation and maintenance of persistent pain through an interaction at second order spinal cord neurons. Employing well-characterized antibodies to the SP receptor and the N-methyl-D-aspartate receptor (NR1 subunit, splice variant missing exon 22), we demonstrate co localization of these receptors on second order neurons at cervical, thoracic, lumbar, and sacral spinal cord levels. The co-localization was marked in lamina I of the dorsal horn at all levels and in the intermediolateral nucleus of the thoraco-lumbar spinal cord nuclei associated with autonomic function. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Neuronal Gene Express Unit, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), Natl Inst Dent & Craniofacial Res, Neuronal Gene Express Unit, Pain & Neurosensory Mech Branch, NIH, Bldg 49,Room 1A08,49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. NR 18 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 15 PY 2000 VL 291 IS 2 BP 61 EP 64 DI 10.1016/S0304-3940(00)01337-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 354EH UT WOS:000089316500001 PM 10978574 ER PT J AU Aravind, L Makarova, KS Koonin, EV AF Aravind, L Makarova, KS Koonin, EV TI Holliday junction resolvases and related nucleases: identification of new families, phyletic distribution and evolutionary trajectories SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SHORT PATCH REPAIR; PROTEIN SECONDARY STRUCTURE; ESCHERICHIA-COLI K-12; RESOLVING ENZYME CCE1; T4 ENDONUCLEASE-VII; GROUP-II INTRONS; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; RESTRICTION-ENDONUCLEASE; LAMBDA-EXONUCLEASE AB Holliday junction resolvases (HJRs) are key enzymes of DNA recombination. A detailed computer analysis of the structural and evolutionary relationships of HJRs and related nucleases suggests that the HJR function has evolved independently from at least four distinct structural folds, namely RNase H, endonuclease, endonuclease VII-colicin E and RusA. The endonuclease fold, whose structural prototypes are the phage lambda exonuclease, the very short patch repair nuclease (Vsr) and type II restriction enzymes, is shown to encompass by far a greater diversity of nucleases than previously suspected. This fold unifies archaeal HJRs, repair nucleases such as RecB and Vsr, restriction enzymes and a variety of predicted nucleases whose specific activities remain to be determined. Within the RNase H fold a new family of predicted HJRs, which is nearly ubiquitous in bacteria, was discovered, in addition to the previously characterized RuvC family. The proteins of this family, typified by Escherichia coli YqgF, are likely to function as an alternative to RuvC in most bacteria, but could be the principal HJRs in low-GC Gram-positive bacteria and Aquifex. Endonuclease VII of phage T4 is shown to serve as a structural template for many nucleases, including McrA and other type II restriction enzymes. Together with colicin E7, endonuclease VII defines a distinct metal-dependent nuclease fold. As a result of this analysis, the principal HJRs are now known or confidently predicted for all bacteria and archaea whose genomes have been completely sequenced, with many species encoding multiple potential HJRs. Horizontal gene transfer, lineage-specific gene loss and gene family expansion, and non-orthologous gene displacement seem to have been major forces in the evolution of HJRs and related nucleases. A remarkable case of displacement is seen in the Lyme disease spirochete Borrelia burgdorferi, which does not possess any of the typical HJRs, but instead encodes, in its chromosome and each of the linear plasmids, members of the lambda exonuclease family predicted to function as HJRs. The diversity of HJRs and related nucleases in bacteria and archaea contrasts with their near absence in eukaryotes. The few detected eukaryotic representatives of the endonuclease fold and the RNase H fold have probably been acquired from bacteria via horizontal gene transfer. The identity of the principal HJR(s) involved in recombination in eukaryotes remains uncertain; this function could be performed by topoisomerase IB or by a novel, so far undetected, class of enzymes. Likely HJRs and related nucleases were identified in the genomes of numerous bacterial and eukaryotic DNA viruses. Gene flow between Viral and cellular genomes has probably played a major role in the evolution of this class of enzymes. This analysis resulted in the prediction of numerous previously unnoticed nucleases, some of which are likely to be new restriction enzymes. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 97 TC 232 Z9 238 U1 1 U2 10 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 SEP 15 PY 2000 VL 28 IS 18 BP 3417 EP 3432 DI 10.1093/nar/28.18.3417 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 355JX UT WOS:000089383500002 PM 10982859 ER PT J AU Yamamoto, A Schofield, MJ Biswas, I Hsieh, P AF Yamamoto, A Schofield, MJ Biswas, I Hsieh, P TI Requirement for Phe36 for DNA binding and mismatch repair by Escherichia coli MutS protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID REPLICATION FIDELITY; HETERODUPLEX DNA; HELICASE-II; RECOMBINATION; CANCER; IDENTIFICATION; EXONUCLEASES; RECOGNITION; MUTATION; GENOME AB The MutS family of DNA repair proteins recognizes base pair mismatches and insertion/deletion mismatches and targets them for repair in a strand-specific manner, Photocrosslinking and mutational studies previously identified a highly conserved Phe residue at the N-terminus of Thermus aquaticus MutS protein that is critical for mismatch recognition in vitro, Here, a mutant Escherichia coli MutS protein harboring a substitution of Ala for the corresponding Phe36 residue is assessed for proficiency in mismatch repair in vivo and DNA binding and ATP hydrolysis in vitro. The F36A protein is unable to restore mismatch repair proficiency to a mutS strain as judged by mutation to rifampicin or reversion of a specific point mutation in lacZ, The F36A protein is also severely deficient for binding to heteroduplexes containing an unpaired thymidine or a G:T mismatch although its intrinsic ATPase activity and subunit oligomerization are very similar to that of the wildtype MutS protein. Thus, the F36A mutation appears to confer a defect specific for recognition of insertion/ deletion and base pair mismatches. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), Kagawa Med Sch, Dept Physiol 2, Kagawa 7610793, Japan. EM hsieh@nciferf.gov NR 35 TC 40 Z9 40 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2000 VL 28 IS 18 BP 3564 EP 3569 DI 10.1093/nar/28.18.3564 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 355JX UT WOS:000089383500020 PM 10982877 ER PT J AU Kim, JW Kim, HC Kim, GM Yang, JM Boeke, JD Nam, K AF Kim, JW Kim, HC Kim, GM Yang, JM Boeke, JD Nam, K TI Human RNA lariat debranching enzyme cDNA complements the phenotypes of Saccharomyces cerevisiae dbr1 and Schizosaccharomyces pombe dbr1 mutants SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SMALL NUCLEOLAR RNAS; YEAST; INTRONS; PRECURSORS; GENE AB The cDNA encoding the human RNA lariat debranching enzyme (hDBR1) was identified and cloned by searching the Expressed Sequence Tag (EST) database and screening a HeLa cDNA library, based on predicted amino acid sequence homologies with the Saccharomyces cerevisiae, Schizosaccharomyces pombe and Caenorhabditis elegans debranching enzymes. The hDBR1 cDNA expressed in Escherichia coli showed debranching activity in vitro and was also shown to be functional in an interspecies specific complementation experiment, hDBR1 cDNA in a S.cerevisiae expression vector complemented the intron accumulation phenotype of a S.cerevisiae dbr1 null mutant. Integration of the cDNA for hDBR1 into the ura4 locus of S.pombe also complemented both the intron accumulation and slow-growth phenotypes of a S.pombe dbr1 null mutant: strain, Comparison of the amino acid sequence of hDBR1 with the other DBR protein sequences showed several conserved regions, with 40, 44 and 43% identity to the S.cerevisiae, S.pombe and C.elegans debranching enzymes, respectively. C1 Inha Univ, Coll Med, Dept Biochem, Inchon, South Korea. Samsung Biomed Res inst, Clin Res Ctr, Seoul 135230, South Korea. Sungkyunkwan Univ, Sch Med, Dept Dermatol, Seoul, South Korea. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Nam, K (reprint author), NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. EM knam@box-k.nih.gov NR 20 TC 22 Z9 23 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2000 VL 28 IS 18 BP 3666 EP 3673 DI 10.1093/nar/28.18.3666 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 355JX UT WOS:000089383500033 PM 10982890 ER PT J AU Beja, O Aravind, L Koonin, EV Suzuki, MT Hadd, A Nguyen, LP Jovanovich, S Gates, CM Feldman, RA Spudich, JL Spudich, EN DeLong, EF AF Beja, O Aravind, L Koonin, EV Suzuki, MT Hadd, A Nguyen, LP Jovanovich, S Gates, CM Feldman, RA Spudich, JL Spudich, EN DeLong, EF TI Bacterial rhodopsin: Evidence for a new type of phototrophy in the sea SO SCIENCE LA English DT Article ID 16S RIBOSOMAL-RNA; ESCHERICHIA-COLI; PROTON RELEASE; PHYLOGENETIC DIVERSITY; MEMBRANE-VESICLES; BINDING-PROTEIN; BACTERIORHODOPSIN; TRANSDUCER; GENE; ARCHAEAL AB Extremely halophilic archaea contain retinal-binding integral membrane proteins called bacteriorhodopsins that function as Light-driven proton pumps. So far, bacteriorhodopsins capable of generating a chemiosmotic membrane potential in response to Light have been demonstrated only in halophilic archaea. We describe here a type of rhodopsin derived from bacteria that was discovered through genomic analyses of naturally occuring marine bacterioplankton. The bacterial rhodopsin was encoded in the genome of an uncultivated gamma-proteobacterium and shared highest amino acid sequence similarity with archaeal rhodopsins. The protein was functionally expressed in Escherichia coli and bound retinal to form an active, Light-driven proton pump. The new rhodopsin exhibited a photochemical reaction cycle with intermediates and kinetics characteristic of archaeal proton-pumping rhodopsins. Our results demonstrate that archaeal-like rhodopsins are broadly distributed among different taxa, including members of the domain Bacteria. Our data also indicate that a previously unsuspected mode of bacterially mediated Light-driven energy generation may commonly occur in oceanic surface waters worldwide. C1 Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Amersham Pharmacia Biotech, Mol Dynam, Sunnyvale, CA 94086 USA. Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. RP DeLong, EF (reprint author), Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. RI Suzuki, Marcelino/D-3329-2009 OI Suzuki, Marcelino/0000-0003-3868-6362 FU NHGRI NIH HHS [HG01775-02S1]; NIGMS NIH HHS [R01GM27750] NR 39 TC 807 Z9 856 U1 14 U2 142 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 SEP 15 PY 2000 VL 289 IS 5486 BP 1902 EP 1906 DI 10.1126/science.289.5486.1902 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 354XD UT WOS:000089355800036 PM 10988064 ER PT J AU Pickle, LW AF Pickle, LW TI Exploring spatio-temporal patterns of mortality using mixed effects models SO STATISTICS IN MEDICINE LA English DT Article ID CANCER MORTALITY; RATES AB A linear mixed effects (LME) model previously used for a spatial analysis of mortality data for a single time period is extended to include time trends and spatio-temporal interactions. This model includes functions of age and time period that can account for increasing and decreasing death rates over time and age, and a change-point of rates at a predetermined age. A geographic hierarchy is included that provides both regional and small area age-specific rate estimates, stabilizing rates based on small numbers of deaths by sharing information within a region. The proposed log-linear analysis of rates allows the use of commercially available software for parameter estimation, and provides an estimator of overdispersion directly as the residual variance. Because of concerns about the accuracy of small area rate estimates when there are many instances of no observed deaths, we consider potential sources of error, focusing particularly on the similarity of likelihood inferences using the LME model for rates as compared to an exact Poisson-normal mixed effects model for counts. The proposed LME model is applied to breast cancer deaths which occurred among white women during 1979-1996. For this example, application of diagnostics for multiparameter likelihood comparisons suggests a restriction of age to a minimum of either 25 or 35, depending on whether small area rate estimates are required. Investigation into a convergence problem led to the discovery that the changes in breast cancer geographic patterns over time are related more to urbanization than to region, as previously thought. Published in 2000 by John Wiley & Sons, Ltd. C1 Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Pickle, LW (reprint author), NCI, DCCPS, SRAB, 6130 Execut Blvd,Rm 4103, Bethesda, MD 20892 USA. NR 26 TC 10 Z9 12 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 15 PY 2000 VL 19 IS 17-18 BP 2251 EP + DI 10.1002/1097-0258(20000915/30)19:17/18<2251::AID-SIM567>3.3.CO;2-D PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 353LE UT WOS:000089275000005 PM 10960851 ER PT J AU Sharpe, LG Pilotte, NS Shippenberg, TS Goodman, CB London, ED AF Sharpe, LG Pilotte, NS Shippenberg, TS Goodman, CB London, ED TI Autoradiographic evidence that prolonged withdrawal from intermittent cocaine reduces mu-opioid receptor expression in limbic regions of the rat brain SO SYNAPSE LA English DT Article DE I-125-DAMGO; mesolimbic pathways; nucleus accumbens; limbic cortex; nucleus of the diagonal band ID MESSENGER-RNA LEVELS; NUCLEUS-ACCUMBENS; DOPAMINE TRANSPORTER; RHESUS-MONKEYS; BINDING-SITES; OPIATE; SHELL; NALTREXONE; FOOD; CORE AB Numerous reports support evidence that dopaminergic mesolimbic pathways interact with opioid systems to influence the reinforcing properties of cocaine. Withdrawal from chronic administration of cocaine in rats causes an upregulation of mesocorticolimbic mu-opioid receptors during early stages, but information about prolonged cocaine abstinence is lacking. We addressed this issue by treating rats with cocaine or saline (control) intermittently (1 mg/kg, i.v., every 12 min for 2 h daily) for 10 days followed by a 10- or 20-day withdrawal period. The animals were then decapitated and the brains removed for quantitative in vitro autoradiographic analysis of 14 brain regions with I-125-DAMGO. A separate group of animals received two consecutive cycles of the 10-day cocaine/10-day withdrawal regimen. Only the group that participated in the two consecutive cycles showed a significant effect of treatment: downregulation of mu-opiate receptors in limbic cortical layer 3 (17% lower than saline-treated controls, P = 0.03), the core of the nucleus accumbens (16% decrease, P = 0.05), and the nucleus of the diagonal band (18% decrease, P = 0.05), The mu-receptor may manifest, as do other neural markers (e.g., dopamine transporter, dopamine efflux), a biphasic temporal pattern with upregulation during early phases of cocaine withdrawal but a downregulation at later times. Published 2000 Wiley-Liss, Inc(dagger). C1 NIDA, Intramural Res Program, Behav Neurosci Branch, Baltimore, MD 21224 USA. NIDA, Div Basic Res, Bethesda, MD USA. Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Tallahassee, FL 32307 USA. NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. RP Sharpe, LG (reprint author), NIDA, Intramural Res Program, Behav Neurosci Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 47 TC 18 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 0887-4476 J9 SYNAPSE JI Synapse PD SEP 15 PY 2000 VL 37 IS 4 BP 292 EP 297 DI 10.1002/1098-2396(20000915)37:4<292::AID-SYN6>3.0.CO;2-V PG 6 WC Neurosciences SC Neurosciences & Neurology GA 339ZD UT WOS:000088507000006 PM 10891866 ER PT J AU Childs, R Chernoff, A Contentin, N Bahceci, E Schrump, D Leitman, S Read, EJ Tisdale, J Dunbar, C Linehan, WM Young, NS Barrett, AJ Clave, E Epperson, D Mayo, V AF Childs, R Chernoff, A Contentin, N Bahceci, E Schrump, D Leitman, S Read, EJ Tisdale, J Dunbar, C Linehan, WM Young, NS Barrett, AJ Clave, E Epperson, D Mayo, V TI Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BONE-MARROW TRANSPLANTATION; GRAFT-VERSUS-LEUKEMIA; MYELOABLATIVE THERAPY; BREAST-CANCER; HOST DISEASE; TUMOR; INTERLEUKIN-2; CHEMOTHERAPY; CHIMERISM; ENGRAFTMENT AB Background: Since allogeneic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematologic cancers, we sought to induce analogous graft-versus-tumor effects in patients with metastatic renal-cell carcinoma by means of nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. Methods: Nineteen consecutive patients with refractory metastatic renal-cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of a peripheral-blood stem-cell allograft from an HLA-identical sibling or a sibling with a mismatch of a single HLA antigen. Cyclosporine, used to prevent graft-versus-host disease, was withdrawn early in patients with mixed T-cell chimerism or disease progression. Patients with no response received up to three infusions of donor lymphocytes. Results: At the time of the last follow-up, 9 of the 19 patients were alive 287 to 831 days after transplantation (median follow-up, 402 days). Two had died of transplantation-related causes, and eight from progressive disease. In 10 patients (53 percent) metastatic disease regressed; 3 had a complete response, and 7 had a partial response. The patients who had a complete response remained in remission 27, 25, and 16 months after transplantation. Regression of metastases was delayed, occurring a median of 129 days after transplantation, and often followed the withdrawal of cyclosporine and the establishment of complete donor-T-cell chimerism. These results are consistent with a graft-versus-tumor effect. Conclusions: Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy. (N Engl J Med 2000;343:750-8.) (C) 2000, Massachusetts Medical Society. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Surg Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Childs, R (reprint author), NHLBI, Hematol Branch, NIH, 10-7C103,10 Ctr Dr,MSC 1652, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 29 TC 727 Z9 753 U1 0 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 14 PY 2000 VL 343 IS 11 BP 750 EP 758 DI 10.1056/NEJM200009143431101 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 352LZ UT WOS:000089221300001 PM 10984562 ER PT J AU Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G McIntosh, K Colan, SD AF Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G McIntosh, K Colan, SD CA Pediat Pulm Cardiac Complications TI Absence of cardiac toxicity of zidovudine in infants SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IDIOPATHIC DILATED CARDIOMYOPATHY; NUCLEOSIDE ANALOGS; CHILDREN; EXPOSURE AB Background: Some evidence suggests that perinatal exposure to zidovudine may cause cardiac abnormalities in infants. We prospectively studied left ventricular structure and function in infants born to mothers infected with the human immunodeficiency virus (HIV) in order to determine whether there was evidence of zidovudine cardiac toxicity after perinatal exposure. Methods: We followed a group of infants born to HIV-infected women from birth to five years of age with echocardiographic studies every four to six months. Serial echocardiograms were obtained for 382 infants without HIV infection (36 with zidovudine exposure) and 58 HIV-infected infants (12 with zidovudine exposure). Repeated-measures analysis was used to examine four measures of left ventricular structure and function during the first 14 months of life in relation to zidovudine exposure. Results: Zidovudine exposure was not associated with significant abnormalities in mean left ventricular fractional shortening, end-diastolic dimension, contractility, or mass in either non-HIV-infected or HIV-infected infants. Among infants without HIV infection, the mean fractional shortening at 10 to 14 months was 38.1 percent for those never exposed to zidovudine and 39.0 percent for those exposed to zidovudine (mean difference, -0.9 percentage point; 95 percent confidence interval, -3.1 to 1.3 percentage points; P=0.43). Among HIV-infected infants, the mean fractional shortening at 10 to 14 months was similar in those never exposed to zidovudine (35.4 percent) and those exposed to the drug (35.3 percent) (mean difference, 0.1 percentage point; 95 percent confidence interval, -3.7 to 3.9 percentage points; P=0.95). Zidovudine exposure was not significantly related to depressed fractional shortening (shortening of 25 percent or less) during the first 14 months of life. No child over the age of 10 months had depressed fractional shortening. Conclusions: Zidovudine was not associated with acute or chronic abnormalities in left ventricular structure or function in infants exposed to the drug in the perinatal period. (N Engl J Med 2000;343:759-66.) (C) 2000, Massachusetts Medical Society. C1 Univ Rochester, Med Ctr, Div Pediat Cardiol, Rochester, NY 14642 USA. Childrens Hosp Strong, Rochester, NY USA. Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Boston Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Pediat, Div Pediat Cardiol, Cleveland, OH 44195 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Univ Calif Los Angeles, Med Ctr, Dept Pediat, Div Pediat Cardiol, Los Angeles, CA USA. Presbyterian Hosp, Dept Pediat, Div Pediat Cardiol, New York, NY USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Columbia Univ, Sch Med, New York, NY USA. Baylor Coll Med, Dept Pediat, Div Pediat Cardiol, Houston, TX 77030 USA. Mt Sinai Sch Med, Dept Pediat, Div Pediat Cardiol, New York, NY USA. NHLBI, Bethesda, MD 20892 USA. RP Lipshultz, SE (reprint author), Univ Rochester, Med Ctr, Div Pediat Cardiol, 601 Elmwood Ave,Box 631, Rochester, NY 14642 USA. RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NHLBI NIH HHS [N01 HR096037, N01-HR-96038, N01-HR-96039] NR 23 TC 91 Z9 95 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 14 PY 2000 VL 343 IS 11 BP 759 EP 766 DI 10.1056/NEJM200009143431102 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 352LZ UT WOS:000089221300002 PM 10984563 ER PT J AU Mofenson, LM AF Mofenson, LM TI Perinatal exposure to zidovudine - Benefits and risks SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ORAL ZIDOVUDINE; COTE-DIVOIRE; IN-UTERO; TRANSMISSION; TRIAL; HIV-1; CHILDREN; INFANTS; WOMEN C1 NICHHD, Rockville, MD 20852 USA. RP Mofenson, LM (reprint author), NICHHD, Rockville, MD 20852 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 15 TC 21 Z9 22 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 14 PY 2000 VL 343 IS 11 BP 803 EP 805 DI 10.1056/NEJM200009143431110 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 352LZ UT WOS:000089221300010 PM 10984571 ER PT J AU Slavkin, HC Baum, BJ AF Slavkin, HC Baum, BJ TI Relationship of dental and oral pathology to systemic illness SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY HEART-DISEASE; ADULTS 30 YEARS; MYOCARDIAL-INFARCTION; UNITED-STATES; PERIODONTAL-DISEASE; ARTERY DISEASE; RISK FACTOR; INFECTION; ATHEROSCLEROSIS; CARIES C1 Off Director, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Slavkin, HC (reprint author), Off Director, Bldg 31,Room 2C39,MSC-2290, Bethesda, MD 20892 USA. NR 41 TC 52 Z9 52 U1 0 U2 1 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 SEP 13 PY 2000 VL 284 IS 10 BP 1215 EP 1217 DI 10.1001/jama.284.10.1215 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 350WL UT WOS:000089124600001 PM 10979082 ER PT J AU Elam, MB Hunninghake, DB Davis, KB Garg, R Johnson, C Egan, D Kostis, JB Sheps, DS Brinton, EA AF Elam, MB Hunninghake, DB Davis, KB Garg, R Johnson, C Egan, D Kostis, JB Sheps, DS Brinton, EA CA ADMIT Investigators TI Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease - The ADMIT Study: A randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; NICOTINIC-ACID; CHOLESTEROL; THERAPY; HYPERTRIGLYCERIDEMIA; ATHEROSCLEROSIS; DYSLIPIDEMIA; GEMFIBROZIL; MECHANISM; MELLITUS AB Context Although niacin increases low levels of high-density lipoprotein cholesterol (HDL-C), which frequently accompany diabetes, current guidelines do not recommend use of niacin in patients with diabetes because of concerns about adverse effects on glycemic control; however, this is based on limited clinical data. Objective To determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes. Design and Setting Prospective, randomized placebo-controlled clinical trial conducted in 6 clinical centers from August 1993 to December 1995. Participants A total of 468 participants, including 125 with diabetes, who had diagnosed peripheral arterial disease. Interventions After an active run-in period, participants were randomly assigned to receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61 with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active run-in and 48-week double-blind). Main Outcome Measures Plasma lipoprotein, glucose, hemoglobin A(1c) (HbA(1c)), alanine aminotransferase, and uric acid levels; hypoglycemic drug use: compliance; and adverse events, in patients with diabetes vs without who were receiving niacin vs placebo. Results Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding changes in participants receiving placebo were increases of 0% and 2% in HDL-C and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in LDL-C, Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL [0.4 and 0.3 mmol/L]; P = .04 and P<.001) in participants with and without diabetes, respectively. Levels of HbA(1c) were unchanged from baseline to follow-up in participants with diabetes treated with niacin. In participants with diabetes treated with placebo, HbA(1c) decreased by 0.3 % (P = .04 for difference). There were no significant differences in niacin discontinuation, niacin dosage, or hypoglycemic therapy in participants with diabetes assigned to niacin vs placebo. Conclusions Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. C1 Univ Tennessee, Div Clin Pharmacol, Hlth Sci Ctr, Memphis, TN 38163 USA. Memphis Vet Affairs Med Ctr, Memphis, TN USA. Univ Minnesota, Minneapolis, MN USA. Univ Washington, Seattle, WA 98195 USA. Axio Res Corp, Seattle, WA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Robert Wood Johnson Univ, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Univ N Carolina, Chapel Hill, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Elam, MB (reprint author), Univ Tennessee, Div Clin Pharmacol, Hlth Sci Ctr, 874 union Ave, Memphis, TN 38163 USA. FU NCRR NIH HHS [MO1-RROO21]; NHLBI NIH HHS [HC-25110-6, N0I-HC-35124] NR 32 TC 308 Z9 315 U1 1 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 SEP 13 PY 2000 VL 284 IS 10 BP 1263 EP 1270 DI 10.1001/jama.284.10.1263 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 350WL UT WOS:000089124600033 PM 10979113 ER PT J AU Sullivan, DM Wehr, NB Fergusson, MM Levine, RL Finkel, T AF Sullivan, DM Wehr, NB Fergusson, MM Levine, RL Finkel, T TI Identification of oxidant-sensitive proteins: TNF-alpha induces protein glutathiolation SO BIOCHEMISTRY LA English DT Article ID TYROSINE-PHOSPHATASE 1B; EPIDERMAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; HYDROGEN-PEROXIDE; S-THIOLATION; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; APOPTOSIS; CELLS; INVOLVEMENT AB Reactive oxygen species are thought to play a role in a variety of physiologic and pathophysiological processes. One possible mediator of oxidant effects at the molecular level is a subset of proteins containing reactive cysteine thiols that can be readily oxidized. The transient incorporation of glutathione into cellular proteins is an established response to oxidant stress and could provide a mechanism for reversible covalent modification in response to reactive oxygen species. To better understand the function of protein S-glutathiolation in vivo, a biotinylated membrane-permeant analogue of glutathione, biotinylated glutathione ethyl ester, was developed and used to detect proteins into which glutathione is incorporated under oxidant stress. Oxidant stress from exogenous hydrogen peroxide or generated in response to TNF-alpha was found to increase incorporation of biotinylated glutathione ethyl ester into several HeLa cell proteins. The identity of two of these proteins was determined by peptide sequencing and mass spectrometric peptide mapping. A 23 kDa S-glutathiolated protein was identified as thioredoxin peroxidase II, a member of the peroxiredoxin family of peroxidases known to play a role in redox-dependent growth factor and cytokine signal transduction. A second, 36 kDa, protein was identified as annexin II. Further investigation revealed a single reactive cysteine in the annexin II tail domain. Deletion of the identified cysteine was found to abolish S-glutathiolation of annexin II. These findings demonstrate a specific posttranslational modification associated with an endogenously generated oxidant stress and suggest a mechanism by which TNF-alpha might selectively regulate protein function in a redox-dependent fashion. C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Biochem, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Mol Biol Lab, NIH, Bldg 10,Room 6N240,10 Ctr Dr, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 29 TC 163 Z9 164 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 12 PY 2000 VL 39 IS 36 BP 11121 EP 11128 DI 10.1021/bi0007674 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 353RX UT WOS:000089290200022 PM 10998251 ER PT J AU Hirtz, D Ashwal, S Berg, A Bettis, D Camfield, C Camfield, P Crumrine, P Elterman, R Schneider, S Shinnar, S AF Hirtz, D Ashwal, S Berg, A Bettis, D Camfield, C Camfield, P Crumrine, P Elterman, R Schneider, S Shinnar, S TI Practice parameter: Evaluating a first nonfebrile seizure in children - Report of the Quality Standards Subcommittee of the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society SO NEUROLOGY LA English DT Article ID 1ST UNPROVOKED SEIZURE; TONIC-CLONIC SEIZURE; COMPUTED-TOMOGRAPHY; GENERALIZED SEIZURE; ADULT PATIENTS; NEW-ONSET; EMERGENCY; RECURRENCE; EEG; DISORDERS AB Objective: The Quality Standards Subcommittee of the American Academy of Neurology develops practice parameters as strategies for patient management based on analysis of evidence. For this practice parameter, the authors reviewed available evidence on evaluation of the first nonfebrile seizure in children in order to make practice recommendations based on this available evidence. Methods: Multiple searches revealed relevant literature and each article was reviewed, abstracted, and classified. Recommendations were based on a three-tiered scheme of classification of the evidence. Results: Routine EEG as part of the diagnostic evaluation was recommended; other studies such as laboratory evaluations and neuroimaging studies were recommended as based on specific clinical circumstances. Conclusions: Further studies are needed using large, well-characterized samples and standardized data collection instruments. Collection of data regarding appropriate timing of evaluations would be important. C1 NINDS, NIH, Bethesda, MD 20892 USA. Loma Linda Univ, Sch Med, Dept Pediat, Loma Linda, CA USA. No Illinois Univ, Dept Biol Sci, De Kalb, IL 60115 USA. Izaak Walton Killam Hosp Children, Dept Pediat Neurol, Halifax, NS B3J 3G9, Canada. Childrens Hosp Pittsburgh, Dept Neurol, Pittsburgh, PA USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. RP Hirtz, D (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. NR 65 TC 173 Z9 180 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 12 PY 2000 VL 55 IS 5 BP 616 EP 623 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 357EC UT WOS:000089484700005 PM 10980722 ER PT J AU Terwindt, GM Ferrari, MD Tijhuis, M Groenen, SMA Picavet, HSJ Launer, LJ AF Terwindt, GM Ferrari, MD Tijhuis, M Groenen, SMA Picavet, HSJ Launer, LJ TI The impact of migraine on quality of life in the general population - The GEM study SO NEUROLOGY LA English DT Article ID HEALTH SURVEY SF-36; OF-LIFE; MEDICAL OUTCOMES; FUNCTIONAL STATUS; CARE USE; HEADACHE; EPIDEMIOLOGY; DISABILITY; INSTRUMENT; COHORT AB Objective: To assess health-related quality of life (HRQOL) in migraineurs in the general population. Design: Cross-sectional study within the context of a population-based study monitoring health characteristics of the Dutch adult population in two municipalities representative of the general population in the Netherlands. Migraine was assessed in a multistaged procedure that included a semistructured clinical interview by telephone. Final diagnosis met 1988 International Headache Society criteria. HRQOL was measured with the self-administered RAND 36-item Health Survey (RAND-36), including physical functioning, social functioning, role limitations, and physical perception. HRQOL of migraineurs was compared with that of nonmigraineurs. To compare and study the effect of comorbidity, the authors also identified subjects with asthma or chronic musculoskeletal pain. There were 5998 people with complete data, 620 of whom had migraine in the last year. Results: Compared with nonmigraineurs, significantly more migraineurs had asthma (OR = 1.6; 95% CI 1.1, 2.4) or chronic musculoskeletal pain (OR = 1.7; 95% CI 1.5, 2.1). Migraineurs reported diminished functioning and well-being on all eight domains as compared with nonmigraineurs. HRQOL was inversely related to attack frequency (p < 0.0002). Migraineurs had a poorer HRQOL than did those reporting asthma, except for dimensions concerning physical functioning and general health perception, but they had a better HRQOL than did subjects with chronic musculoskeletal pain. Comorbidity of asthma or chronic musculoskeletal pain in migraine further reduced HRQOL. Conclusions: Migraineurs report more asthma and chronic musculoskeletal pain. Compared with nonmigraineurs and to others with chronic conditions, migraineurs report compromised physical, mental, and social functioning, particularly those with a high frequency of attack. C1 NIA, EDBP, NIH, Bethesda, MD 20892 USA. Natl Inst Publ Hlth, Bilthoven, Netherlands. Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. RP Launer, LJ (reprint author), NIA, EDBP, NIH, Gateway Bldg,Room 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. NR 38 TC 221 Z9 223 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 12 PY 2000 VL 55 IS 5 BP 624 EP 629 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 357EC UT WOS:000089484700006 PM 10980723 ER PT J AU Leonardi, A Chariot, A Claudio, E Cunningham, K Siebenlist, U AF Leonardi, A Chariot, A Claudio, E Cunningham, K Siebenlist, U TI CIKS, a connection to I kappa B kinase and stress-activated protein kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IKK-BETA SUBUNIT; UBIQUITIN LIGASE; ALPHA PROTEOLYSIS; SIGNAL; PHOSPHORYLATION; RECEPTOR; COMPLEX; IDENTIFICATION; DEGRADATION; MICE AB Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF-kappa B and AP-1/ATF families, Activation of NF-kappa B factors is thought to be mediated primarily via I kappa B kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs). IKK alpha and IKK beta are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-kappa B essential modulator)/IKK gamma. The latter protein is essential for activation of the IKKs. but its mechanism of action is not known. Here we describe the molecular cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKK gamma in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-kappa B-dependent reporter. Activation of NF-kappa B is prevented in the presence of kinase-deficient. interfering mutants of the IKKs. CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways. functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI leonardi, antonio/A-2887-2009; OI LEONARDI, Antonio/0000-0001-8636-9623 NR 50 TC 107 Z9 114 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 SEP 12 PY 2000 VL 97 IS 19 BP 10494 EP 10499 DI 10.1073/pnas.190245697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 354QP UT WOS:000089341400038 PM 10962033 ER PT J AU Cleghorn, FR Jack, N Carr, JK Edwards, J Mahabir, B Sill, A McDanal, CB Connolly, SM Goodman, D Bennetts, RQ O'Brien, TR Weinhold, KJ Bartholomew, C Blattner, WA Greenberg, ML AF Cleghorn, FR Jack, N Carr, JK Edwards, J Mahabir, B Sill, A McDanal, CB Connolly, SM Goodman, D Bennetts, RQ O'Brien, TR Weinhold, KJ Bartholomew, C Blattner, WA Greenberg, ML TI A distinctive clade BHIV type 1 is heterosexually transmitted in Trinidad and Tobago SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HOMOSEXUAL MEN; HIV TYPE-1; ENVELOPE; AIDS; PREVALENCE; DIVERSITY; SEQUENCES; TRANSMISSION; POPULATION AB HIV-1 transmission worldwide is predominantly associated with heterosexual activity, and non-clade B viruses account for the most spread. The HIV-1 epidemic in Trinidad/Tobago and the Caribbean shares many features with such heterosexual epidemics, including a prominent role for coincident sexually transmitted diseases. This study evaluates the molecular epidemiology of HIV-1 in Trinidad/ Tobago during a period when abrupt transition from homosexual to heterosexual transmission occurred in the absence of injecting drug use, concomitant with a rapid rise in HIV-1 prevalence in the heterosexual population. Of 31 viral isolates studied during 1987-1995, all cluster with subtype B reference strains. In the analysis of full env genes from 22 early seroconverters, the Trinidad isolates constitute a significant subcluster within the B subtype, The Trinidad V3 consensus sequence differs by a single amino acid from the prototype B V3 consensus and demonstrates stability over the decade of this study. In the majority of isolates, the Vs loop of env contains a signature threonine deletion that marks the lineage of the Trinidad HIV-I clade B epidemic from pre-1984. No phenotypic features, including syncitium induction, neutralization profiles, and chemokine receptor usage, distinguish this virus population from other subtype a viruses. Thus, although the subtype B HIV-1 viruses being transmitted in Trinidad are genetically distinguishable from other subtype B viruses, this is probably the result of a strong founder effect in a geographically circumscribed population rather than genetic selection for heterosexual transmission. These results demonstrate that canonical clade B HIV-1 can generate a typical heterosexual epidemic. C1 Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, Baltimore, MD 21201 USA. Med Res Fdn Trinidad & Tobago, Port Of Spain, Trinid & Tobago. Henry M Jackson Fdn, Rockville, MD 20852 USA. Minist Hlth Trinidad & Tobago, Port Of Spain, Trinid & Tobago. NCI, Viral Epidemiol Branch, NIH, Rockville, MD 20895 USA. Duke Univ, Dept Surg, Durham, NC 27710 USA. RP Cleghorn, FR (reprint author), Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, MBC Room 449N,725 W Lombard St, Baltimore, MD 21201 USA. FU NIAID NIH HHS [P30-AI28662, R01-AI32393, R01-AI40017] NR 34 TC 40 Z9 40 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 12 PY 2000 VL 97 IS 19 BP 10532 EP 10537 DI 10.1073/pnas.97.19.10532 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 354QP UT WOS:000089341400045 PM 10984542 ER PT J AU Wilkin, DJ Liberfarb, R Davis, J Levy, HP Cole, WG Francomano, CA Cohn, DH AF Wilkin, DJ Liberfarb, R Davis, J Levy, HP Cole, WG Francomano, CA Cohn, DH TI Rapid determination of COL2A1 mutations in individuals with Stickler syndrome: Analysis of potential premature termination codons SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Stickler syndrome; COL2A1; mutation; premature termination codon ID II PROCOLLAGEN GENE; HEREDITARY ARTHRO-OPHTHALMOPATHY; SYNDROME ARTHROOPHTHALMOPATHY; LINKAGE; FAMILY; PHENOTYPES; EXCLUSION; COLLAGEN; 2A1 AB Stickler syndrome is one of the milder phenotypes resulting from mutations in the gene that encodes type-II collagen, COL2A1, All COL2A1 mutations known to cause Stickler syndrome result in the formation of a premature termination codon within the type-II collagen gene. COL2A1 has 10 inframe CGA codons, which can mutate to TGA STOP codons via a methylationdeamination mechanism. We have analyzed these sites in genomic DNA from a panel of 40 Stickler syndrome patients to test the hypothesis that mutations that cause Stickler syndrome preferentially occur at these bases. Polymerase chain reaction (PCR) amplification of genomic DNA containing each of the in-frame CGA codons was done by one of two methods: either using primers that amplify DNA that includes the CGA codon, or using allele-specific primers that either amplify normal sequence containing a CGA codon or amplify a mutant sequence containing a TGA codon, Analysis of PCR products by restriction endonuclease digestion or sequencing demonstrated the presence of a normal or mutated codon, TGA mutations were identified in eight patients, at five of the 10 in-frame CGA codons, The identification of these mutations in eight of 40 patients demonstrates that these sites are common sites for mutations in individuals with Stickler syndrome and, we propose, should be analyzed as a first step in the search for mutations that result in this disorder. Published 2000 Wiley-Liss, Inc.(dagger). C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Genet & Teratol Unit, Boston, MA 02114 USA. Hosp Sick Children, Div Orthopaed, Toronto, ON M5G 1X8, Canada. Univ Calif Los Angeles, Sch Med, Dept Pediat,Cedars Sinai Res Inst, Steven Spielberg Pediat Res Ctr, Los Angeles, CA 90024 USA. RP Wilkin, DJ (reprint author), Fed Bur Invest Acad, Forens Sci Res Unit, Bldg 12,FSRU, Quantico, VA 22135 USA. NR 31 TC 13 Z9 15 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 11 PY 2000 VL 94 IS 2 BP 141 EP 148 DI 10.1002/1096-8628(20000911)94:2<141::AID-AJMG6>3.0.CO;2-A PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 345TN UT WOS:000088831400006 PM 10982970 ER PT J AU Liang, HL Ding, MZ Nakamura, R Bressler, SL AF Liang, HL Ding, MZ Nakamura, R Bressler, SL TI Causal influences in primate cerebral cortex during visual pattern discrimination SO NEUROREPORT LA English DT Article DE adaptive multivariate autoregression model (AMVAR); bottom-up; causal influences; feedback; feedforward; local field potentials (LFP); short-time directed transfer function (STDTF); top-down; visual cortex ID CORTICAL AREAS; INFORMATION-FLOW; ATTENTION; FEEDBACK; SYSTEM; CONNECTIONS; MODEL AB Anatomical studies of the visual cortex demonstrate the existence of feedforward, feedback and lateral pathways among multiple cortical areas. Yet relatively little evidence has previously been available to show the causal influences of these areas on one another during visual information processing. We simultaneously recorded event-related local field potentials (LFPs) from surface-to-depth bipolar electrodes at six sites in the ventral region of the right hemisphere visual cortex in a highly trained macaque monkey during performance of a visual pattern discrimination task. Applying a new statistical measure, the short-time directed transfer function (STDTF), to the LFP data set, we charted the changing strength and direction of causal influence between these cortical sites on a fraction-of-a-second time scale. We present results showing, for the first time, the dynamics of distinct feedforward, feedback and lateral influences in the ventral portion of the primate visual cortex during visual pattern processing. NeuroReport 11:2875-2880 (C) 2000 Lippincott Williams & Wilkins. C1 Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Liang, HL (reprint author), Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, 777 Glades Rd, Boca Raton, FL 33431 USA. FU NIMH NIH HHS [MH-58190-02] NR 30 TC 46 Z9 48 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 11 PY 2000 VL 11 IS 13 BP 2875 EP 2880 DI 10.1097/00001756-200009110-00009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 354ZC UT WOS:000089360300009 PM 11006957 ER PT J AU Yefimov, S Sjomeling, C Yergey, AL Li, T Chrambach, A AF Yefimov, S Sjomeling, C Yergey, AL Li, T Chrambach, A TI Recovery of sodium dodecyl sulfate-proteins from gel electrophoretic bands in a single electroelution step for mass spectrometric analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE gel electrophoresis; electroelution; mass spectrometry; single-step elution; protein transfer ID APPARATUS AB Mass spectrometric analysis of proteins derived from bands in gel electrophoresis is incompatible with the covalent fluorescent labeling of the protein. Thus, if one wishes to take advantage of the capacity for computer-directed electroelution of electrophoresis apparatus with intermittent fluorescent scanning of the migration path, the protein must be labeled fluorescently in a noncovalent, reversible fashion. This was recently achieved by staining of SDS-proteins with Cascade blue and electrophoresis in barbital buffer. However, the method was not a practical one for the purpose of isolating proteins from gel electrophoretic bands and their transfer into the mass spectrometer for three reasons: (i) Ten consecutive electroelution steps were required to obviate pH changes in the electroelution chamber; (ii) electroeluates from six gel electrophoretic lanes needed to be pooled; (iii) excessive protein loads ranging from 7 to 33 mu g/pool were required. The present study reports the solution to those three problems. Mass spectrometric (MALDI-TOF) characterization of five proteins was demonstrated (i) after a single electroelution step; (ii) using electroelution from a single gel of 0.3-cm(2) cross-sectional area; and (iii) using a protein load of 2 (in one case 4) mu g. However, the migration rates of the Cascade blue-SDS-protein-barbital complexes derived from proteins with widely varying molecular weights proved to be the same. Thus, despite the three advances made, the method to date remains restricted to samples of single proteins. C1 NICHHD, Macromol Anal Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, NIH, Bldg 10,Room 9D50, Bethesda, MD 20892 USA. NR 11 TC 11 Z9 11 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 10 PY 2000 VL 284 IS 2 BP 288 EP 295 DI 10.1006/abio.2000.4736 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 355HL UT WOS:000089380200013 PM 10964411 ER PT J AU Zhou, W Tomer, KB Khaledi, MG AF Zhou, W Tomer, KB Khaledi, MG TI Evaluation of the binding between potential anti-HIV DNA-based drugs and viral envelope glycoprotein gp120 by capillary electrophoresis with laser-induced fluorescence detection SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE phosphorothioate oligodeoxynucleotide; HIV envelope glycoprotein gp120; affinity-capillary electrophoresis; laser-induced fluorescence detection ID IMMUNODEFICIENCY-VIRUS TYPE-1; LOOP DOMAIN V3; PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES; DEXTRAN SULFATE; AFFINITY; PROTEIN; RECEPTOR; CD4; INFECTION; IDENTIFICATION AB The fusion of the human immunodeficiency virus (HIV) with the target cell was assisted by the interaction between the viral envelope glycoprotein HIV-1 gp120 and a chemokine receptor. Studies have shown that the efficiency of the binding depends on the presence of the V3 loop of the gp120 which is known to interact with polyanions, such as phosphorothioate oligodeoxynucleotides (Sd, potential anti-HIV drugs). In this study, capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was used to systematically evaluate binding between Sd and HIV-1 gp120. A 25-mer fluorescently tagged phosphorothioate oligodeoxynucleotide (GEM) was employed as a probe to study this interaction. The dissociation constant (K-d) between GEM and gp120 was determined to be 0.98 nM by Scatchard analysis. The competition constants (K-c) of a set of Sd that compete with GEM for binding to gp120 were also determined. The results showed that the interaction had a strong dependence on the sulfur phosphorothioate backbone. Chain length and the sequence of Sd also affect the ability of binding to gp120. The ability to study the protein-drug binding in the solution with minimal sample consumption makes CE-LIF very attractive for biological studies. (C) 2000 Academic Press. C1 N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Khaledi, MG (reprint author), N Carolina State Univ, Dept Chem, Box 8204, Raleigh, NC 27695 USA. RI Tomer, Kenneth/E-8018-2013 NR 40 TC 19 Z9 20 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 10 PY 2000 VL 284 IS 2 BP 334 EP 341 DI 10.1006/abio.2000.4651 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 355HL UT WOS:000089380200019 PM 10964417 ER PT J AU Sher, L AF Sher, L TI Selenium and human health SO LANCET LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Bldg 10,Room 3S-231,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 10 Z9 10 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 SEP 9 PY 2000 VL 356 IS 9233 BP 943 EP 943 DI 10.1016/S0140-6736(05)73927-1 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 353DP UT WOS:000089259800052 PM 11036922 ER PT J AU Luzzio, FA Thomas, EM Figg, WD AF Luzzio, FA Thomas, EM Figg, WD TI Thalidomide metabolites and analogs. Part 2: Cyclic derivatives of 2-N-phthalimido-2S,3S (3-hydroxy) ornithine SO TETRAHEDRON LETTERS LA English DT Article DE amino acids and derivatives; azides; hydroxylation; imides; lactams ID ACTIVATION AB E-(5-N-phthaloyl)-2-pentenoic acid benzyl ester was dihydroxylated by a Sharpless AD-mix protocol followed by mononosylation of the resultant 2R,3S diol. Azide displacement of the mononosylate followed by protection with the TBDMS group gave the epsilon-N-phthaloyl-substituted-beta-tert-butyldimethylsilyloxy-alpha-azidocarboxylic acid benzylester. Hydrazinolysis resulted in removal of the phthalimide group with concomitant lactamization to the 4-silyloxy-3-azidopiperidinones. Staudinger reduction of the azidopiperidinones followed by N-phthaloylation and hydrolysis of the silyl group afforded the 4'-hydroxylated-6'-deoxythalidomide derivatives. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Louisville, Dept Chem, Louisville, KY 40292 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Luzzio, FA (reprint author), Univ Louisville, Dept Chem, Louisville, KY 40292 USA. RI Figg Sr, William/M-2411-2016 NR 25 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD SEP 9 PY 2000 VL 41 IS 37 BP 7151 EP 7155 DI 10.1016/S0040-4039(00)01204-1 PG 5 WC Chemistry, Organic SC Chemistry GA 351YM UT WOS:000089187800003 ER PT J AU Biswas, MHU Amin, ARMR Islam, MA Hasan, CM Gustafson, KR Boyd, MR Pannell, LK Rashid, MA AF Biswas, MHU Amin, ARMR Islam, MA Hasan, CM Gustafson, KR Boyd, MR Pannell, LK Rashid, MA TI Monocillinols A and B, novel fungal metabolites from a Monocillium sp. SO TETRAHEDRON LETTERS LA English DT Article DE fungal metabolites; monocillinols; Monocillium sp. ID CHROMOPHORE AB Monocillinols A (1) and B (2), two novel isomeric fungal metabolites, have been isolated from the chloroform extract of the culture filtrate of a Monocillium sp. The structures of 1 and 2 were elucidated by interpretation of their spectral data. Published by Elsevier Science Ltd. C1 Rajshahi Univ, Dept Pharm, Rajshahi 6250, Bangladesh. Univ Dhaka, Dept Pharm, Dhaka 1000, Bangladesh. NCI, Lab Drug Discovery Res & Dev, DTP, DCTD,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Rashid, MA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. NR 11 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD SEP 9 PY 2000 VL 41 IS 37 BP 7177 EP 7180 DI 10.1016/S0040-4039(00)01252-1 PG 4 WC Chemistry, Organic SC Chemistry GA 351YM UT WOS:000089187800008 ER PT J AU Hatano, H Miller, KD Yoder, CP Yanovski, JA Sebring, NG Jones, EC Davey, RT AF Hatano, H Miller, KD Yoder, CP Yanovski, JA Sebring, NG Jones, EC Davey, RT TI Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy SO AIDS LA English DT Article DE metabolic abnormalities; hyperlipidemia; hypercholesterolemia; insulin resistance; fat redistribution; lipodystrophy; lipohypertrophy; lipoatrophy; HAART; antiretroviral therapy ID INHIBITOR-ASSOCIATED LIPODYSTROPHY; IMPAIRED GLUCOSE-TOLERANCE; BETA-CELL FUNCTION; HIV-INFECTED MEN; PROTEASE INHIBITORS; FASTING HYPERINSULINEMIA; COMPUTED-TOMOGRAPHY; INSULIN-RESISTANCE; DIABETES-MELLITUS; HOMEOSTASIS MODEL AB Background: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. Setting: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. Method: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. Results: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194 +/- 47.3 versus 159 +/- 29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114 +/- 32.6 versus 96 +/- 24.7 mg/dl; P = 0.0013), triglycerides (261 +/- 244.3 versus 185 +/- 165.4 mg/dl; P= 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15 +/- 7.9 versus 5 +/- 2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45 +/- 34.1 versus 62 +/- 32.2 mu g/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. Conclusions: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term. (C) 2000 Lippincott Williams & Wilkins. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. NICHHD, Dept Nutr, NIH, Bethesda, MD 20892 USA. NICHHD, Dept Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Davey, RT (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Room 11C103, Bethesda, MD 20892 USA. NR 40 TC 56 Z9 57 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 8 PY 2000 VL 14 IS 13 BP 1935 EP 1942 DI 10.1097/00002030-200009080-00008 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 351VZ UT WOS:000089180700008 PM 10997397 ER PT J AU Cawley, NX Normant, E Chen, A Loh, YP AF Cawley, NX Normant, E Chen, A Loh, YP TI Oligomerization of pro-opiomelanocortin is independent of pH, calcium and the sorting signal for the regulated secretory pathway SO FEBS LETTERS LA English DT Article DE pro-opiomelanocortin; oligomerization; aggregation; prohormone sorting ID GRANULE CONTENT PROTEINS; CARBOXYPEPTIDASE-E; CHROMOGRANIN-A; DEPENDENT AGGREGATION; MEMBRANE-PROTEINS; ACIDIC PH; RECEPTOR; BINDING; PROOPIOMELANOCORTIN; IDENTIFICATION AB Studies indicate that pro-opiomelanocortin (POMC) is sorted to the regulated secretory pathway by binding to a sorting receptor identified as membrane-bound carboxypeptidase E (CPE) [Cool et al, (1997) Cell 88, 73-83]. The efficiency of this sorting mechanism could be enhanced if POMC molecules were to self-associate to form oligomers, prior or subsequent to binding to CPE. Using cross-linking and gel filtration techniques, we demonstrated that POMC forms oligomers at both neutral and acidic pHs and calcium was not necessary. Delta N-POMC, which Lacks the IV-terminal sorting signal for the regulated secretory pathway, also formed similar oligomers, indicating that the sorting and oligomerization domains are different. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NICHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bldg 49,Rm 5A38, Bethesda, MD 20892 USA. NR 29 TC 15 Z9 15 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 SEP 8 PY 2000 VL 481 IS 1 BP 37 EP 41 DI 10.1016/S0014-5793(00)01961-X PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 353TX UT WOS:000089292500008 PM 10984611 ER PT J AU Osheroff, WP Beard, WA Yin, S Wilson, SH Kunkel, TA AF Osheroff, WP Beard, WA Yin, S Wilson, SH Kunkel, TA TI Minor groove interactions at the DNA polymerase beta active site modulate single-base deletion error rates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; DIFFERENT SEQUENCE CONTEXTS; ESCHERICHIA-COLI; TEMPLATE-PRIMER; NUCLEOTIDE INCORPORATION; MUTATIONAL SPECIFICITY; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURES; III HOLOENZYME; FIDELITY AB The structures of open and closed conformations of DNA polymerase beta (pol beta) suggests that the rate of single-nucleotide deletions during synthesis may be modulated by interactions in the DNA minor groove that align the templating base with the incoming dNTP. To test this hypothesis, we measured the single-base deletion error rates of wild-type pol beta and lysine and alanine mutants of Arg(283), whose side chain interacts with the minor groove edge of the templating nucleotide at the active site. The error rates of both mutant enzymes are increased > 100-fold relative to wild-type pol beta, Template engineering experiments performed to distinguish among three possible models for deletion formation suggest that most deletions in repetitive sequences by pol beta initiate by strand slippage. However, pol beta also generates deletions by a different mechanism that is strongly enhanced by the substitutions at Arg283. Analysis of error specificity suggests that this mechanism involves nucleotide misinsertion followed by primer relocation, creating a misaligned intermediate. The structure of pol beta bound to non-gapped DNA also indicates that the templating nucleotide and its downstream neighbor are out of register in the open conformation and this could facilitate misalignment (dNTP or primer terminus) with the next template base. C1 NIEHS, Mol Genet Lab, NIH, 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, Res Triangle Pk, NC 27709 USA. NR 44 TC 48 Z9 48 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28033 EP 28038 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100068 PM 10851238 ER PT J AU Warner, GJ Berry, MJ Moustafa, ME Carlson, BA Hatfield, DL Faust, JR AF Warner, GJ Berry, MJ Moustafa, ME Carlson, BA Hatfield, DL Faust, JR TI Inhibition of selenoprotein synthesis by selenocysteine tRNA([Ser]Sec) lacking isopentenyladenosine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSFER-RNA MODIFICATION; HAMSTER OVARY CELLS; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; TRANSFER RNASEC; MAMMALIAN-CELLS; CODON; GENE; IDENTIFICATION; UGA AB A common posttranseriptional modification of tRNA is the isopentenylation of adenosine at position 37, creating isopentenyladenosine (i(6)A), The role of this modified nucleoside in protein synthesis of higher eukaryotes is not well understood. Selenocysteyl (Sec) tRNA (tRNA([Ser]Sec)) decodes specific UGA codons and contains i(6)A. To address the role of the modified nucleoside in this tRNA, we constructed a site-specific mutation, which eliminates the site of isopentenylation, in the Xenopus tRNA([Ser]Sec) gene. Transfection of the mutant tRNA([Ser]Sec) gene resulted in 80% and 95% reduction in the expression of co-transfected selenoprotein genes encoding type I and II iodothyronine deiodinases, respectively. A similar decrease in type I deiodinase synthesis was observed when transfected cells were treated with lovastatin, an inhibitor of the biosynthesis of the isopentenyl moiety, Neither co-transfection with the mutant tRNA gene nor lovastatin treatment reduced type I deiodinase mRNA levels. Also, mutant tRNA expression did not alter initiation of translation or degradation of the type I deiodinase protein. Furthermore, isopentenylation of tRNA([Ser]Sec) was not required for synthesis of Sec on the tRNA, We conclude that isopentenylation of tRNA([Ser]Sec) is required for efficient translational decoding of UGA and synthesis of selenoproteins. C1 Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Harvard Inst Med,Dept Med,Thyroid Div, Boston, MA 02115 USA. NCI, Div Basic Sci, Basic Res Lab, Bethesda, MD 20892 USA. RP Faust, JR (reprint author), Tufts Univ, Sch Med, Dept Physiol, 136 Harrison Ave, Boston, MA 02111 USA. FU NIDDK NIH HHS [DK07542] NR 47 TC 41 Z9 41 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28110 EP 28119 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100077 PM 10821829 ER PT J AU Ghirlando, R Trainor, CD AF Ghirlando, R Trainor, CD TI GATA-1 bends DNA in a site-independent fashion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ERYTHROID TRANSCRIPTION FACTOR; BINDING DOMAIN; FINGER; PROMOTER; COMPLEX; ZINC; EXPRESSION; PROTEINS; CGATA-1; FAMILY AB The DNA binding domain of GATA-1 consists of two adjacent homologous zinc fingers, of which only the C-terminal finger binds DNA independently. Solution structure studies have shown that the DNA is bent by about 15 degrees in the complex formed with the single C-terminal finger of GATA-1, The N-terminal finger stabilizes DNA binding at some sites. To determine whether it contributes to DNA bending, we have performed circular permutation DNA bending experiments with a variety of DNA-binding sites recognized by GATA-1, By using a series of full-length GATA-1, double zinc finger, and single C-terminal finger constructs, we show that GATA-1 bends DNA by about 24 degrees, irrespective of the DNA-binding site. We propose that the N- and C-terminal fingers of GATA-1 adopt different orientations when bound to different cognate DNA sites. Furthermore, we characterize circular permutation bending artifacts arising from the reduced gel mobility of the protein-DNA complexes. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ghirlando, R (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Ghirlando, Rodolfo/A-8880-2009 NR 26 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28152 EP 28156 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100082 PM 10862761 ER PT J AU Trainor, CD Ghirlando, R Simpson, MA AF Trainor, CD Ghirlando, R Simpson, MA TI GATA zinc finger interactions modulate DNA binding and transactivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; LOCUS-CONTROL REGION; EPSILON-GLOBIN GENE; REGULATORY GENE; COFACTOR FOG; MICE LACKING; PROTEIN; EXPRESSION; PROMOTER; FAMILY AB GATA-1 and other vertebrate GATA factors contain a DNA binding domain composed of two adjacent homologous zinc fingers. Whereas only the C-terminal finger of GATA-1 is capable of independent binding to the GATA recognition sequence, double GATA sites that require both fingers for high affinity interaction are found in several genes. We propose a mechanism whereby adjacent zinc fingers interact to influence the binding and transactivation properties of GATA-1 at a subset of DNA-binding sites. By using two such double GATA sites we demonstrate that the N-terminal finger and adjacent linker region can alter the binding specificity of the C-terminal finger sufficiently to prevent it from recognizing some consensus GATA sequences. Therefore, the two zinc fingers form a composite binding domain having a different DNA binding specificity from that shown by the constituent single C-terminal finger. Furthermore, we compare two of these double sites and show that high affinity binding of GATA-1 to a reporter gene does not necessarily induce transactivation, namely the sequence of the DNA-binding site can alter the ability of GATA-1 to stimulate transcription. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Trainor, CD (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Ghirlando, Rodolfo/A-8880-2009 FU NHLBI NIH HHS [HL03601] NR 55 TC 69 Z9 71 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28157 EP 28166 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100083 PM 10862757 ER PT J AU Rumsey, SC Daruwala, R Al-Hasani, H Zarnowski, MJ Simpson, IA Levine, M AF Rumsey, SC Daruwala, R Al-Hasani, H Zarnowski, MJ Simpson, IA Levine, M TI Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACILITATIVE GLUCOSE TRANSPORTERS; GROWTH-FACTOR-I; ASCORBIC-ACID; VITAMIN-C; DIABETES-MELLITUS; HUMAN NEUTROPHILS; CELL-SURFACE; SUGAR-TRANSPORT; SKELETAL-MUSCLE; INSULIN AB Dehydroascorbic acid (DHA), the first stable oxidation product of vitamin C, was transported by GLUT1 and GLUT3 in Xenopus laevis oocytes with transport rates similar to that of P-deoxyglucose (2-DG), but due to inherent difficulties with GLUT4 expression in oocytes it was uncertain whether GLUT4 transported DHA (Rumsey, S, C., Kwon, O., Xu, G. W., Burant, C. F., Simpson, I., and Levine, M. (1997) J. Biol. Chem. 272, 18982-18989). We therefore studied DHA and 2-DG transport in rat adipocytes, which express GLUT4. Without insulin, rat adipocytes transported 2-DG 2-3-fold faster than DHA. Preincubation with insulin (0.67 mu M) increased transport of each substrate similarly: 7-10-fold for 2-DG and 6-8-fold for DHA, Because intracellular reduction of DHA in adipocytes was complete before and after insulin stimulation, increased transport of DHA was not explained by increased internal reduction of DHA to ascorbate, To determine apparent transport kinetics of GLUT4 for DHA, GLUT4 expression in Xenopus oocytes was reexamined. Preincubation of oocytes for >4 h with insulin (1 mu M) augmented GLUT4 transport of 2-DG and DKA by up to 5-fold. Transport of both substrates was inhibited by cytochalasin B and displayed saturable kinetics. GLUT4 had a higher apparent transport affinity (K-m of 0.98 versus 5.2 mM) and lower maximal transport rate (V-max of 66 versus 880 pmol/oocyte/10 min) for DHA compared with 2-DG. The lower transport rate for DHA could not be explained by binding differences at the outer membrane face, as shown by inhibition with ethylidene glucose, or by transporter trans-activation and therefore was probably due to substrate-specific differences in transporter/substrate translocation or release. These novel data indicate that the insulin-sensitive transporter GLUT4 transports DHA in both rat adipocytes and Xenopus oocytes, Alterations of this mechanism in diabetes could have clinical implications for ascorbate utilization. C1 NIDDK, Digest Dis Branch, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Diabet Branch, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. Mead Johnson Nutr, Evansville, IN USA. RP Levine, M (reprint author), NIDDK, Digest Dis Branch, Mol & Clin Nutr Sect, NIH, Bldg 10 Rm 4D52 MSC 1372, Bethesda, MD 20892 USA. NR 44 TC 111 Z9 116 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28246 EP 28253 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100095 PM 10862609 ER PT J AU Vial, D Okazaki, H Siraganian, RP AF Vial, D Okazaki, H Siraganian, RP TI The NH2-terminal region of focal adhesion kinase reconstitutes high affinity IgE receptor-induced secretion in mast cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; DROSOPHILA-MELANOGASTER; PROTEIN; MIGRATION; DOMAIN; FAK; PP125(FAK); SRC; ASSOCIATION AB Focal adhesion kinase (FAK) is tyrosine-phosphorylated by adherence of cells and also by Fc epsilon RI aggregation in RBL-2H3 mast cells. Using phosphorylation site-specific antibodies, we observed that Fc epsilon RI activation in these cells led to an increase in FAK phosphorylation at the same tyrosine residues that are phosphorylated by integrin-induced activation. Previous studies in the 3B6 line, a FAK-deficient variant of the RBL-2H3 cells, suggest that FAK plays a role in Fc epsilon RI-induced secretion. Stable cell lines expressing either full-length or truncated forms of FAK were isolated after transfection of the FAK-deficient 3B6 variant cells. The NH2 domain of FAK, which lacks the enzymatic and the COOH-terminal regions, was sufficient to reconstitute secretion. The different truncated forms of FAK were still tyrosine-phosphorylated after Fc epsilon RI aggregation. Therefore, the kinase domain and the COOH-terminal region are not essential for Fc epsilon RI-induced tyrosine phosphorylation of FAK or for secretion. Taken together, our data demonstrate that the reconstitution of secretion is dissociated from FAK activation and that the NH2-terminal region of FAK is the only critical element that may play a role in Fc epsilon RI-induced secretion by acting as an adaptor or linker molecule. C1 NIDCR, OIIB, Receptors & Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. RP Vial, D (reprint author), NIDCR, OIIB, Receptors & Signal Transduct Sect, NIH, Bldg 10,Rm 1N106, Bethesda, MD 20892 USA. NR 35 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28269 EP 28275 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100098 PM 10862765 ER PT J AU Robyr, D Gegonne, A Wolffe, AP Wahli, W AF Robyr, D Gegonne, A Wolffe, AP Wahli, W TI Determinants of vitellogenin B1 promoter architecture - HNF3 and estrogen responsive transcription within chromatin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THYROID-HORMONE RECEPTOR; XENOPUS-LAEVIS; CRYSTAL-STRUCTURE; IN-VIVO; HISTONE ACETYLTRANSFERASE; INDEPENDENT ACTIVATION; INVITRO TRANSCRIPTION; GLOBULAR DOMAIN; DISTAL PROMOTER; LINKER HISTONES AB The liver-specific vitellogenin B1 promoter is efficiently activated by estrogen within a nucleosomal environment after microinjection into Xenopus laevis oocytes, consistent with the hypothesis that significant nucleosome remodeling over this promoter is not a prerequisite for the activation by the estrogen receptor (ER alpha). This observation lead us to investigate determinants other than ER alpha of chromatin structure and transcriptional activation of the vitellogenin B1 promoter in this system and in vitro. We find that the liver-enriched transcription factor HNF3 has an important organizational role for chromatin structure as demonstrated by DNase I-hypersensitive site mapping. Both HNF3 and the estrogen receptor activate transcription synergistically and are able to interact with chromatin reconstituted in vitro with three positioned nucleosomes. We propose that HNF3 is the cellular determinant which establishes a promoter environment favorable to a rapid transcriptional activation by the estrogen receptor. C1 Univ Lausanne, Inst Biol Anim, CH-1015 Lausanne, Switzerland. NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wahli, W (reprint author), Univ Lausanne, Inst Biol Anim, Batiment Biol, CH-1015 Lausanne, Switzerland. RI Wahli, Walter/B-1398-2009 OI Wahli, Walter/0000-0002-5966-9089 NR 69 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 8 PY 2000 VL 275 IS 36 BP 28291 EP 28300 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352CN UT WOS:000089197100101 PM 10854430 ER PT J AU Kroth, H Yagi, H Seidel, A Jerina, DM AF Kroth, H Yagi, H Seidel, A Jerina, DM TI New and highly efficient synthesis of cis- and trans-opened benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the exocyclic N-2-amino group of deoxyguanosine SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; DIOL-EPOXIDE; NUCLEOSIDE ADDUCTS; SEQUENCE CONTEXT; N-6-AMINO GROUP; DNA-ADDUCTS; MOUSE SKIN; DEOXYADENOSINE; CARCINOGEN; P53 AB describe a new and facile method for the synthesis of both cis- and trans-opened N-2-deoxyguanosine (dG) adducts of (+/-)-7 alpha,8 beta-dihydoxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and (+/-)-7 alpha,8 beta-dihydoxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene at C-10. The key step in our approach is the direct coupling of O-6-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine with these epoxides followed by the separation of the mixtures of cis- and trans-diastereomers produced. Overall coupling yields ranged from 45 to 65%. Stereochemistry of addition of the N-2-exocyclic amino group of dG (cis-trans, similar to 1:1) was assigned by NMR, and the absolute configuration of the dG adducts was unequivocally assigned by CD spectroscopy after separation of each individual diastereomer and cleavage of the allyl protecting group. A strong CD band at 279 nm in the O-6-protected adduct was found to be diagnostic for configuration at C-IO, with a negative band correlating with 10R configuration. The synthetic methodology described allows easy access to cis- and trans-opened N-2-dG adducts which are valuable building blocks for the synthesis of adduct-containing oligonucleotides far physical and biochemical studies. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Biochem Inst Environm Carcinogens, D-22927 Grosshansdorf, Germany. RP Jerina, DM (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8A,Rm 1A-15, Bethesda, MD 20892 USA. NR 43 TC 21 Z9 21 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 8 PY 2000 VL 65 IS 18 BP 5558 EP 5564 DI 10.1021/jo000522x PG 7 WC Chemistry, Organic SC Chemistry GA 354BP UT WOS:000089310200014 PM 10970294 ER PT J AU Hrabie, JA Arnold, EV Citro, ML George, C Keefer, LK AF Hrabie, JA Arnold, EV Citro, ML George, C Keefer, LK TI Reaction of nitric oxide at the beta-carbon of enamines. A new method of preparing compounds containing the diazeniumdiolate functional group SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID CONVENIENT; OXIDATION; CHEMISTRY; RELEASE; OLEFINS AB The reaction of nitric oxide (NO) with enamines has been investigated. Unlike previously reported reactions of NO as a free radical with alkenes, the electrophilic addition of NO to the beta-carbon of enamines results in the formation of compounds containing the diazeniumdiolate functional group (-[N(O)NO]-). This reaction between NO;and enamines has been shown to be quite general and a variety of enamine-derived diazeniumdiolates have been isolated and characterized. While enamines derived from aldehydes and ketones whose structures allow for sequential multiple electrophilic additions tended to undergo overreaction leading to unstable products, it has been shown that this complication may be overcome by suitable choice of reaction solvent. The products obtained may exist as zwitterionic iminium salts or as neutral species depending upon the structure of the parent enamine. The diazeniumdiolate derived from 1-(N-morpholino)cyclohexene is unique among the new compounds in that it spontaneously releases NO upon dissolution in buffered aqueous solution at pH 7.4 and 37 degrees C, While the total quantity of NO released by this material (ca. 7% of the theoretical 2 moles) is apparently limited by a competing reaction in which it hydrolyzes to an alpha-diazeniumdiolated carbonyl compound and the parent amine, this feature may prove to be of great value in the development of multiaction pharmaceuticals based upon this new type of NO-releasing compound. Reports of enzymatic (oxidative) release of NO from previously known carbon-bound diazeniumdiolates also suggest that analogues of these compounds may be useful as pharmaceutical agents. This new method of introducing the relatively rarely studied diazeniumdiolate functional group into organic compounds should lead to further research into its chemical and biological properties. C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Hrabie, JA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01CO56000] NR 52 TC 31 Z9 31 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 8 PY 2000 VL 65 IS 18 BP 5745 EP 5751 DI 10.1021/jo000600g PG 7 WC Chemistry, Organic SC Chemistry GA 354BP UT WOS:000089310200039 PM 10970319 ER PT J AU Hrinczenko, BW Schechter, AN Wojtkowski, TL Pannell, LK Cashon, RE Alayash, AI AF Hrinczenko, BW Schechter, AN Wojtkowski, TL Pannell, LK Cashon, RE Alayash, AI TI Nitric oxide-mediated heme oxidation and selective beta-globin nitrosation of hemoglobin from normal and sickle erythrocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE nitric oxide; hemoglobin; sickle cell anemia ID S-NITROSOHEMOGLOBIN; BIOCHEMICAL-CHARACTERIZATION; MASS-SPECTROMETRY; OXYGEN-AFFINITY; NO; MYOGLOBIN AB Nitric oxide (NO) has been reported to modulate the oxygen affinity of blood from sickle cell patients (SS), but not that of normal adult blood (AA), with little or no heme oxidation, However, we had found that the NO donor compounds 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO) and S-nitrosocysteine (CysNO) caused increased oxygen affinity of red cells from both AA and SS individuals and also caused significant methemoglobin (metHb) formation. Rapid kinetic experiments in which HbA(0), AA, or SS erythrocytes were mixed with CysNO or DEANO showed biphasic time courses indicative of initial heme oxidation followed by reductive heme nitrosylation, respectively. Hemolysates treated with CysNO showed by electrospray mass spectrometry a peak corresponding to a 29 mass unit increase (consistent with NO binding) of both the beta(A) and beta(S) chains but not of the alpha chains, Therapeutic use of NO in sickle cell disease may ultimately require further optimization of these competing reactions, i.e., heme reactivity (nitrosylation or oxidation) versus direct S-nitrosation of hemoglobin on the P-globin, (C) 2000 Academic Press. C1 US FDA, Ctr Biol Evaluat & Res, Lab Plasma Derivat, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Struct Mass Spect Grp, NIH, Bethesda, MD 20892 USA. Univ Maine, Dept Biochem Microbiol & Mol Biol, Orono, ME 04469 USA. RP Alayash, AI (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Plasma Derivat, 8800 Rockville Pike,NIH Campus,Bldg 29,Room 112, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 18 TC 14 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 7 PY 2000 VL 275 IS 3 BP 962 EP 967 DI 10.1006/bbrc.2000.3413 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 353FV UT WOS:000089264900041 PM 10973828 ER PT J AU Chen, C Kim, MG Lyu, MS Kozak, CA Schwartz, RH Flomerfelt, FA AF Chen, C Kim, MG Lyu, MS Kozak, CA Schwartz, RH Flomerfelt, FA TI Characterization of the mouse gene, human promoter and human cDNA of TSCOT reveals strong interspecies homology SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE thymus; epithelium; TSCOT; transgenic mouse; mouse chromosome 4; transmembrane protein ID THYMIC STROMAL CELLS; POSITIVE SELECTION; TRANSCRIPTION; MICE; DIFFERENTIATION; TRANSPORTER; EXPRESSION; RECEPTOR; MHC AB The regulation of gene expression in thymic epithelial cells is critical for T cell development. The mouse thymic epithelial gene Tscot encodes a protein with weak homology to bacterial 12 transmembrane co-transporters. Using competitive reverse transcription-polymerase chain reaction (RT-PCR), we show that low level Tscot expression is detectable in several other tissues. Tscot was mapped to chromosome 4 and was also detected in other mammalian species by Southern blotting. The human cDNA clone showed 77% amino acid identity with the mouse sequence. The highest conservation was in the TM regions and in a small segment of the central cytoplasmic loop. Genomic clones spanning 17164 bases of the Tscot gene revealed four exons with nine of the TM domains encoded in the first exon. The major transcriptional start site in mouse was identified by a primer extension analysis and confirmed by RT-PCR. Comparison of 1.7 kb of the human and mouse promoters identified six conserved possible regulatory elements, one containing a potential binding site for an interferon oc inducible factor. Finally, as a functional test, 3 kb of the murine promoter was used to create a transgenic mouse that expresses enhanced green fluorescent protein message strongly in the thymus, weakly in the kidney and undetectably in the spleen, liver and heart. (C) 2000 Published by Elsevier Science B.V. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Inst Mol Biol & Genet, Natl Creat Res Initiat Ctr Genet Reprogramming, Seoul, South Korea. NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Room 111,Bldg 4, Bethesda, MD 20892 USA. NR 29 TC 9 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD SEP 7 PY 2000 VL 1493 IS 1-2 BP 159 EP 169 DI 10.1016/S0167-4781(00)00177-9 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 353UV UT WOS:000089294600019 PM 10978518 ER PT J AU Oh, S Hahn, H Torrey, TA Shin, H Choi, W Lee, YM Morse, HC Kim, W AF Oh, S Hahn, H Torrey, TA Shin, H Choi, W Lee, YM Morse, HC Kim, W TI Identification of the human homologue of mouse KIF4, a kinesin superfamily motor protein SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE kinesin; KIF4; cDNA library screening; reverse transcription polymerase chain reaction; genomic KIF4 gene; tissue-specific expression ID SQUID GIANT-AXON; HEAVY-CHAIN; BINDING; ORGANELLE; TRANSPORT; GAG AB A combination of RT-PCR with cDNA library screening led to the identification of the human homologue of murine KIF4 (mKIF4), a microtubule-based motor protein. The nucleotide sequence of human KIF4 (hKIF4) comprised part of the 5' untranslated region (UTR), a long open reading frame (ORF) encoding 1232 amino acids, and the entire 3' UTR. Homologies with mKIF4 were 82% and 85% for nucleotides and amino acids, respectively. A single transcript of 5.0 kb was highly expressed in hematopoietic tissues including fetal liver, spleen, and thymus, and adult thymus and bone marrow. Comparison of the ORF with that of mKIF4 revealed some dissimilarities in the putative cargo binding domain which might affect binding specificities. (C) 2000 Published by Elsevier Science B.V. C1 Ajou Univ, Inst Med Sci, Suwon 442749, South Korea. Ewha Womans Univ, Dept Biol Sci, Seoul 120750, South Korea. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, W (reprint author), Ajou Univ, Inst Med Sci, Suwon 442749, South Korea. OI Morse, Herbert/0000-0002-9331-3705 NR 19 TC 10 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD SEP 7 PY 2000 VL 1493 IS 1-2 BP 219 EP 224 DI 10.1016/S0167-4781(00)00151-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 353UV UT WOS:000089294600028 PM 10978527 ER PT J AU Schatzkin, A Lanza, E Freedman, L AF Schatzkin, A Lanza, E Freedman, L TI High-fiber diet and colorectal adenomas - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Bar Ilan Univ, IL-52900 Ramat Gan, Israel. RP Schatzkin, A (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 7 PY 2000 VL 343 IS 10 BP 737 EP 738 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 350KU UT WOS:000089100500018 ER PT J AU Doong, H Price, J Kim, YS Gasbarre, C Probst, J Liotta, LA Blanchette, J Rizzo, K Kohn, E AF Doong, H Price, J Kim, YS Gasbarre, C Probst, J Liotta, LA Blanchette, J Rizzo, K Kohn, E TI CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70 SO ONCOGENE LA English DT Article DE calcium; EGF; phospholipase C; Hsp70/Hsc70; signal transduction ID SIGNAL-TRANSDUCTION; BCL-2-BINDING PROTEIN; MOLECULAR CHAPERONES; CALCIUM INFLUX; SH3 DOMAINS; CELL-DEATH; RECEPTOR; ACTIVATION; INHIBITION; C-GAMMA-1 AB CAIR-1/BAG-3 forms an EGF-regulated ternary complex with Hsp70/Hsc70 and latent phospholipase C-gamma (PLC-gamma). The expression of CAIR-1, CAI stressed-1, was induced in A2058 human melanoma cells by continuous exposure to CAI, an inhibitor of non voltage-gated calcium influx. CAIR-1 sequence is identical, save 2 amino acids, to BAG-3 also cloned recently as Bis, a member of the bcl-2-associated athanogene family. We show that CAIR-I/BAG-3 binds to Hsp70/Hsc70 in intact cells and this binding is increased by short term exposure to CAI (P<0.007). CAIR-1/BAG-3 is phosphorylated in vivo in the absence of stimulation. Basal phosphorylation is inhibited by treatment with d-erythrosphingosine (d-ES), a broad inhibitor of the protein kinase C family. CAIR-1/BAG-3 contains several PXXP SH3 binding domains leading to the hypothesis that it is a partner protein of phospholipase C-gamma. PLC-gamma is bound to CAIR-1/BAG-3 in unstimulated cells, It is increased by CAI or d-ES (P=0.05) treatment, and abrogated by EGF (r(2)=0.99); d-ES treatment blocks the EGF-mediated dissociation, We show that CAIR-1/BAG-3 binds to PLC-gamma and Hsp701/Hsc70 through separate and distinct domains. Hsp70/Hsc70 binds to the BAG domain of BAGs-1 and -3, CAIR-1/BAG-3 from control and EGF-treated cell lysates bound selectively to the SH3 domain of PLC-gamma, but not its N-SH2 or C-SH2 domains, Confirming the SH3 interaction, PLC-gamma was pulled down by CAIR-1/BAG-3 PXXP-GST fusions, but GST-PXXP constructs confronted with lysates from EGF-treated cells did not bind PLC-gamma as was seen in intact cells. Hsp70/Hsc70 was brought down by the PLC-gamma SH3 construct equally from native and EGF-treated cells, but did not bind the PXXP construct under either condition. We propose that CAIR-1/BAG-3 may act as a multifunctional signaling protein linking the Hsp70/Hsc70 pathway with those necessary for activation of the EGF receptor tyrosine kinase signaling pathways. C1 NCI, Mol Signaling Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Kohn, E (reprint author), 10 Ctr Dr,10-2A33, Bethesda, MD 20892 USA. NR 34 TC 106 Z9 110 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 7 PY 2000 VL 19 IS 38 BP 4385 EP 4395 DI 10.1038/sj.onc.1203797 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 353JW UT WOS:000089271900009 PM 10980614 ER PT J AU de Caestecker, MP Piek, E Roberts, AB AF de Caestecker, MP Piek, E Roberts, AB TI Role of transforming growth factor-beta signaling in cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID TUMOR-SUPPRESSOR GENE; II RECEPTOR GENE; INTESTINAL EPITHELIAL-CELLS; FACTOR (TGF)-BETA RECEPTORS; HUMAN-CHROMOSOME 18Q21.1; HUMAN COLORECTAL-CANCER; FAMILY MEDIATOR SMAD1; CYCLIN D1 EXPRESSION; CREB BINDING-PROTEIN; MAD-RELATED PROTEIN AB Signaling from transforming growth factor-beta (TGF-beta) through its unique transmembrane receptor serine-threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF-beta by mutational inactivation or dysregulated expression of components in its signaling pathway. Decreased receptor function and altered ratios of the TGF-beta type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF-beta and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF-beta signaling by tumor cells, In addition, several proteins recently have been identified that can modulate the Smad-signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF-beta signaling, Understanding the interplay between these signaling cascades as well as the complex patterns of cross-talk with other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF-beta in carcinogenesis. C1 NCI, Div Basic Sci, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Roberts, AB (reprint author), NIH, Bldg 41,Rm C629,41 Library Dr,MSC 5055, Bethesda, MD 20892 USA. NR 219 TC 363 Z9 374 U1 2 U2 13 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 6 PY 2000 VL 92 IS 17 BP 1388 EP 1402 DI 10.1093/jnci/92.17.1388 PG 15 WC Oncology SC Oncology GA 349QV UT WOS:000089057800009 PM 10974075 ER PT J AU Rowland, JH Desmond, KA Meyerowitz, BE Belin, TR Wyatt, GE Ganz, PA AF Rowland, JH Desmond, KA Meyerowitz, BE Belin, TR Wyatt, GE Ganz, PA TI Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-22, 1996 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Clin Oncol ID QUALITY-OF-LIFE; BODY-IMAGE; PSYCHOLOGICAL EVALUATION; PSYCHOSOCIAL OUTCOMES; GEOGRAPHIC-VARIATION; CONSERVING TREATMENT; AUTOLOGOUS TISSUES; DYADIC ADJUSTMENT; MASTECTOMY; WOMEN AB Background: Tissue-sparing approaches to primary treatment and reconstructive options provide improved cosmetic outcomes for women with breast cancer. Earlier research has suggested that conservation or restitution of the breast might mitigate the negative effects of breast cancer on women's sexual well-being. Few studies, however, have compared psychosocial outcomes of women who underwent lumpectomy, mastectomy alone, or mastectomy with reconstruction. To address some of these issues, we examined women's adaptation to surgery in two large cohorts of breast cancer survivors. Methods: A total of 1957 breast cancer survivors (1-5 years after diagnosis) from two major metropolitan areas were assessed in two waves with the use of a self-report questionnaire that included a number of standardized measures of health-related quality of life, body image, and physical and sexual functioning. All P values are two-sided. Results: More than one half (57%) of the women underwent lumpectomy, 26% had mastectomy alone, and 17% had mastectomy with reconstruction. As in earlier studies, women in the mastectomy with reconstruction group were younger than those in the lumpectomy or mastectomy-alone groups (mean ages = 50.3, 55.9, and 58.9, respectively; P = .0001); they were also more likely to have a partner and to be college educated, affluent, and white. Women in both mastectomy groups complained of more physical symptoms related to their surgeries than women in the lumpectomy group. However, the groups did not differ in emotional, social, or role function. Of interest, women in the mastectomy with reconstruction group were most likely to report that breast cancer had had a negative impact on their sex lives (45.4% versus 29.8% for lumpectomy and 41.3% for mastectomy alone; P = .0001). Conclusions: The psychosocial impact of type of primary surgery for breast cancer occurs largely in areas of body image and feelings of attractiveness, with women receiving lumpectomy experiencing the most positive outcome, Beyond the first year after diagnosis, a woman's quality of life is more likely influenced by her age or exposure to adjuvant therapy than by her breast surgery. C1 NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Rowland, JH (reprint author), NIH, 6130 Execut Blvd,Rm 4089, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01CA63028] NR 57 TC 285 Z9 295 U1 2 U2 19 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 6 PY 2000 VL 92 IS 17 BP 1422 EP 1429 DI 10.1093/jnci/92.17.1422 PG 8 WC Oncology SC Oncology GA 349QV UT WOS:000089057800012 PM 10974078 ER PT J AU Goldstein, DS Holmes, C Li, ST Bruce, S Metman, LV Cannon, RO AF Goldstein, DS Holmes, C Li, ST Bruce, S Metman, LV Cannon, RO TI Cardiac sympathetic denervation in Parkinson disease SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MULTIPLE SYSTEM ATROPHY; METAIODOBENZYLGUANIDINE MYOCARDIAL SCINTIGRAPHY; AUTONOMIC FAILURE; PLASMA DIHYDROXYPHENYLALANINE; HUMAN-HEART; NOREPINEPHRINE; 6-FLUORODOPAMINE; DEGENERATION; DYSFUNCTION; DEATH AB Background: In Parkinson disease, orthostatic hypotension can result from L-dopa treatment or from sympathetic neurocirculatory failure. The latter is detected by abnormal blood pressure responses to the Valsalva maneuver and can be associated with loss of functional cardiac sympathetic nerve terminals. Objective: To determine the frequency of cardiac sympathetic denervation in Parkinson disease, with or without sympathetic neurocirculatory failure, and its association with disease duration, severity, and L-dopa treatment. Design: Intergroup comparisons in resting patients. Setting: National Institutes of Health Clinical Center, Bethesda, Maryland. Patients: 29 patients with Parkinson disease (9 with sympathetic neurocirculatory failure, 10 who had stopped receiving or had never been treated with L-dopa), 24 patients with multiple-system atrophy (17 with sympathetic neurocirculatory failure, 8 receiving L-dopa), 7 patients with pure autonomic failure, 33 controls with episodic or persistent orthostatic intolerance without sympathetic neurocirculatory failure, and 19 normal volunteers. Measurements: Beat-to-beat blood pressure responses to the Valsalva maneuver, Interventricular septal 6-[F-18]fluorodopamine-derived radioactivity, cardiac extraction fraction of [H-3]norepinephrine, appearance rate of norepinephrine in coronary sinus plasma (cardiac norepinephrine spillover) and venous-arterial differences in levels of dihydroxyphenylglycol (DHPG) and endogenous L-dopa. Results: Of the 29 patients with Parkinson disease, 9 with sympathetic neurocirculatory failure and 11 without had low septal 6-[F-18]fluorodopamine-derived radioactivity (2861 +/- 453 Bq/mL per MBq/kg and 5217 +/- 525 Bq/mL per MBq/kg, respectively). All 6 patients with Parkinson disease and decreased 6-[F-18]fluorodopamine-derived radioactivity who underwent right-heart catheterization had a decreased cardiac extraction fraction of [H-3]norepinephrine and virtually no cardiac norepinephrine spillover or venous-arterial increments in plasma levels of DHPG and L-dopa. Sympathetic neurocirculatory failure and decreased 6-[F-18]fluorodopamine-derived radioactivity were unrelated to disease duration, disease severity, or L-dopa treatment. Conclusions: Many patients with Parkinson disease-including all those with sympathetic neurocirculatory failure-have evidence of cardiac sympathetic denervation. This suggests that loss of catecholamine innervation in Parkinson disease occurs in the nigrostriatal system in the brain and in the sympathetic nervous system in the heart. C1 NINDS, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Goldstein, DS (reprint author), NINDS, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 36 TC 210 Z9 216 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 5 PY 2000 VL 133 IS 5 BP 338 EP 347 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 350QD UT WOS:000089111900003 PM 10979878 ER PT J AU Ondrey, F Griffith, A Van Waes, C Rudy, S Peters, K McCullagh, L Biesecker, LG AF Ondrey, F Griffith, A Van Waes, C Rudy, S Peters, K McCullagh, L Biesecker, LG TI Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE hypothalamic hamartoma; polydactyly; multiple abnormalities; imperforate anus; GLI3 ID BIFID EPIGLOTTIS; GREIG-SYNDROME; GLI3; HYPOPITUITARISM; MUTATIONS AB Pallister-Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis, The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families. Published 2000 Wiley-Liss, Inc.dagger C1 Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Biesecker, LG (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. NR 21 TC 20 Z9 21 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 4 PY 2000 VL 94 IS 1 BP 64 EP 67 DI 10.1002/1096-8628(20000904)94:1<64::AID-AJMG13>3.0.CO;2-D PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 344FU UT WOS:000088749200013 PM 10982485 ER PT J AU Wood, JD Nucifora, FC Duan, K Zhang, CY Wang, JX Kim, Y Schilling, G Sacchi, N Liu, JM Ross, CA AF Wood, JD Nucifora, FC Duan, K Zhang, CY Wang, JX Kim, Y Schilling, G Sacchi, N Liu, JM Ross, CA TI Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription SO JOURNAL OF CELL BIOLOGY LA English DT Article DE trinucleotide repeats; neurodegenerative diseases; cerebellar nuclei; nuclear matrix; myeloid leukemia ID REPEAT NEURODEGENERATIVE DISEASES; ACUTE MYELOGENOUS LEUKEMIA; HUNTINGTONS-DISEASE; FUSION TRANSCRIPT; TRANSGENIC MICE; MOUSE MODEL; PROTEIN; POLYGLUTAMINE; LOCALIZATION; T(8-21) AB Dentato-rubral and pallido-luysian atrophy (DRPLA) is one of the family of neurodegenerative diseases caused by expansion of a polyglutamine tract. The drp1a gene product, atrophin-1, is widely expressed, has no known function or activity, and is found in both the nuclear and cytoplasmic compartments of neurons. Truncated fragments of atrophin-1 accumulate in neuronal nuclei in a transgenic mouse model of DRPLA, and may underlie the disease phenotype. Using the yeast two-hybrid system, we identified ETO/MTG8, a component of nuclear receptor corepressor complexes, as an atrophin-1-interacting protein. When cotransfected into Neuro-2a cells, atrophin-1 and ETO/MTG8 colocalize in discrete nuclear structures that contain endogenous mSin3A and histone deacetylases. These structures are sodium dodecyl sulfate-soluble and associated with the nuclear matrix. Cotransfection of ETO/MTG8 with atrophin-1 recruits atrophin-1 to the nuclear matrix, while atrophin-1 and ETO/MTG8 cofractionate in nuclear matrix preparations from brains of DRPLA transgenic mice. Furthermore, in a cell transfection-based assay, atrophin-1 represses transcription. Together, these results suggest that atrophin-1 associates with nuclear receptor corepressor complexes and is involved in transcriptional regulation. Emerging links between disease-associated polyglutamine proteins, nuclear receptors, translocation-leukemia proteins, and the nuclear matrix may have important repercussions for the pathobiology of this family of neurodegenerative disorders. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21205 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Milan, Sch Med, Dept Biol & Genet, I-20133 Milan, Italy. RP Wood, JD (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, 720 Rutland Ave,Ross 618, Baltimore, MD 21205 USA. RI Wood, Jonathan/A-5060-2009; Kim, Yujin/P-4270-2014 OI Kim, Yujin/0000-0003-4290-0974 FU NINDS NIH HHS [R01 NS034172, NS16375, NS34172, NS38144, P01 NS016375, R01 NS038144] NR 44 TC 73 Z9 79 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 4 PY 2000 VL 150 IS 5 BP 939 EP 948 DI 10.1083/jcb.150.5.939 PG 10 WC Cell Biology SC Cell Biology GA 353ZN UT WOS:000089305500002 PM 10973986 ER PT J AU Ishizuya-Oka, A Li, Q Amano, T Damjanovski, S Ueda, S Shi, YB AF Ishizuya-Oka, A Li, Q Amano, T Damjanovski, S Ueda, S Shi, YB TI Requirement for matrix metalloproteinase stromelysin-3 in cell migration and apoptosis during tissue remodeling in Xenopus laevis SO JOURNAL OF CELL BIOLOGY LA English DT Article DE apoptosis; matrix metalloproteinase; Xenopus laevis; thyroid hormone; metamorphosis ID HORMONE RESPONSE GENES; THYROID-HORMONE; EXTRACELLULAR-MATRIX; CONNECTIVE-TISSUE; SMALL-INTESTINE; EXPRESSION PATTERN; BASEMENT-MEMBRANE; EPITHELIAL-CELLS; TAIL RESORPTION; TRANSGENIC MICE AB The matrix metalloproteinase (MMP) stromelysin-3 (ST3) was originally discovered as a gene whose expression was associated with human breast cancer carcinomas and with apoptosis during organogenesis and tissue remodeling. It has been shown previously, in our studies as well as those by others, that ST3 mRNA is highly upregulated during apoptotic tissue remodeling during Xenopus laevis metamorphosis, Using a function-blocking antibody against the catalytic domain of Xenopus ST3, we demonstrate here that Sn protein is specifically expressed in the cells adjacent to the remodeling extracellular matrix (ECM) that lies beneath the apoptotic larval intestinal epithelium in X. laevis in vivo, and during thyroid hormone-induced intestinal remodeling in organ cultures. More importantly addition of this antibody, but not the preimmune antiserum or unrelated antibodies, to the medium of intestinal organ cultures leads to an inhibition of thyroid hormone-induced ECM remodeling, apoptosis of the larval epithelium, and the invasion of the adult intestinal primodia into the connective tissue, a process critical for adult epithelial morphogenesis. On the other hand, the antibody has little effect on adult epithelial cell proliferation. Furthermore, a known MMP inhibitor can also inhibit epithelial transformation in vitro. These results indicate that ST3 is required for cell fate determination and cell mi,oration during morphogenesis, most likely through ECM remodeling. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Dokkyo Univ, Sch Med, Dept Histol & Neurobiol, Mibu, Tochigi 32102, Japan. RP Shi, YB (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. RI Damjanovski, Sashko/N-8728-2015 NR 71 TC 88 Z9 88 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 4 PY 2000 VL 150 IS 5 BP 1177 EP 1188 DI 10.1083/jcb.150.5.1177 PG 12 WC Cell Biology SC Cell Biology GA 353ZN UT WOS:000089305500020 PM 10974004 ER PT J AU Moir, S Malaspina, A Li, YX Chun, TW Lowe, T Adelsberger, J Baseler, M Ehler, LA Liu, SY Davey, RT Mican, JAM Fauci, AS AF Moir, S Malaspina, A Li, YX Chun, TW Lowe, T Adelsberger, J Baseler, M Ehler, LA Liu, SY Davey, RT Mican, JAM Fauci, AS TI B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HIV-1; B cell; viral reservoir; complement; CD21 ID FOLLICULAR DENDRITIC CELLS; ANTIBODY-DEPENDENT ENHANCEMENT; TYPE-1 INFECTION; HIV-1 INFECTION; COMPLEMENT; LYMPHOCYTES; ANTIGEN; PLASMA; SUSCEPTIBILITY; INDIVIDUALS AB The impact of HIV-associated immunopathogenesis on B cells has been largely associated with indirect consequences of viral replication. This study demonstrates that HIV interacts directly with B cells in both lymphoid tissues and peripheral blood. B cells isolated from lymph node and peripheral blood mononuclear cells (PBMCs) of 4 and 23 chronically infected patients, respectively, demonstrated similar capacities to pass virus to activated HIV-negative PBMCs when compared with CD4(+) cells from the same patients. However, in contrast to T cells, virus associated with B cells was surface bound, as shown by its sensitivity to pronase and the staining pattern revealed by in situ amplification of HIV-1 RNA. Cell sorting and ligand displacing approaches established that CD21 was the HIV-binding receptor on B cells, and that this association was mediated through complement-opsonized virus. These B cells were also found to express significantly lower levels of CD21 compared with HIV-negative individuals, suggesting a direct perturbing effect of HIV on B cells. These findings suggest that B cells, although they themselves are not readily infected by HIV, are similar to follicular dendritic cells in their capacity to serve as extracellular reservoirs for HIV-1. Furthermore, B cells possess the added capability of circulating in peripheral blood and migrating through tissues where they can potentially interact with and pass virus to T cells. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Adv BioSci Labs Inc, Kensington, MD 20895 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A02, Bethesda, MD 20892 USA. NR 40 TC 140 Z9 145 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 4 PY 2000 VL 192 IS 5 BP 637 EP 645 DI 10.1084/jem.192.5.637 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353FW UT WOS:000089265000005 PM 10974030 ER PT J AU Park, LS Martin, U Garka, K Gliniak, B Di Santo, JP Muller, W Largaespada, DA Copeland, NG Jenkins, NA Farr, AG Ziegler, SF Morrissey, PJ Paxton, R Sims, JE AF Park, LS Martin, U Garka, K Gliniak, B Di Santo, JP Muller, W Largaespada, DA Copeland, NG Jenkins, NA Farr, AG Ziegler, SF Morrissey, PJ Paxton, R Sims, JE TI Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytokine receptors; interleukin 2 receptor; interleukin 7 receptor; cytokine; DNA sequence ID GAMMA-CHAIN; CHROMOSOMAL LOCALIZATION; GENE-EXPRESSION; IL-1 RECEPTOR; B-CELLS; CYTOKINE; SUPERFAMILY; FAMILY; MICE; COMPONENT AB The,cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of murine, but not human myelomonocytic cell Lines by radioligand binding. cDNA clones encoding the receptor were isolated from a murine T helper cell cDNA library. TSLP receptor (TSLPR) is a member of the hematopoietin receptor family. Transfection of TSLPR cDNA resulted in only low affinity binding. Cotransfection of the interleukin 7 (IL-7)R alpha chain cDNA resulted in conversion to high affinity binding. TSLP did not activate cells from IL7R alpha(-/-) mice, but did activate cells h-om gamma c(-/-) mice. Thus, the functional TSLPR requires the IL-7R alpha chain, but not the gamma c chain for signaling. C1 Immunex Res & Dev Corp, Dept Biochem, Seattle, WA 98101 USA. Immunex Res & Dev Corp, Dept Biol Sci, Seattle, WA 98101 USA. Immunex Res & Dev Corp, Dept Mol Biol, Seattle, WA 98101 USA. Inst Pasteur, Dept Immunol, F-75724 Paris, France. Inst Genet, D-50931 Cologne, Germany. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. Virginia Mason Res Ctr, Seattle, WA 98101 USA. RP Sims, JE (reprint author), Immunex Res & Dev Corp, Dept Biochem, 51 Univ St, Seattle, WA 98101 USA. RI Largaespada, David/C-9832-2014; Di Santo, James/M-4298-2014; OI Di Santo, James/0000-0002-7146-1862; Muller, Werner/0000-0002-1297-9725 NR 37 TC 242 Z9 248 U1 0 U2 4 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 SEP 4 PY 2000 VL 192 IS 5 BP 659 EP 669 DI 10.1084/jem.192.5.659 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353FW UT WOS:000089265000007 PM 10974032 ER PT J AU Sims, JE Williams, DE Morrissey, PJ Garka, K Foxworthe, D Price, V Friend, SL Farr, A Bedell, MA Jenkins, NA Copeland, NG Grabstein, K Paxton, RJ AF Sims, JE Williams, DE Morrissey, PJ Garka, K Foxworthe, D Price, V Friend, SL Farr, A Bedell, MA Jenkins, NA Copeland, NG Grabstein, K Paxton, RJ TI Molecular cloning and biological characterization of a novel murine lymphoid growth factor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytokine; B lymphocyte; growth factor; lymphocyte differentiation; DNA sequence ID GENETIC-LINKAGE MAP; BONE-MARROW; IN-VITRO; B-LYMPHOPOIESIS; STROMAL CELLS; KIT-LIGAND; INTERLEUKIN-7; EXPRESSION; RECEPTOR; CHROMOSOME-18 AB Using a bioassay consisting of the proliferation of a murine B cell line, a cDNA of a gene whose product supports the growth of that cell line was isolated from a thymic stromal cell line. This factor, termed thymic stromal lymphopoietin (TSLP), isa protein of 140 amino acids. The gene encoding TSLP was mapped to murine chromosome 18. Purified recombinant TSLP supported the growth of pre-B cell colonies in vitro, but had no myelopoietic activity. TSLP had comitogenic activity for fetal thymocytes, but was not as potent as interleukin 7 in lobe submersion cultures. Injection of TSLP into neonatal mice induced the expansion of B220(+)BP-1(+) pre-B cells. C1 Immunex Res & Dev Corp, Dept Mol Biol, Seattle, WA 98101 USA. Immunex Res & Dev Corp, Dept Biol Sci, Seattle, WA 98101 USA. Immunex Res & Dev Corp, Dept Prot Chem, Seattle, WA 98101 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, Frederick, MD 21702 USA. RP Sims, JE (reprint author), Immunex Res & Dev Corp, Dept Mol Biol, 51 Univ St, Seattle, WA 98101 USA. FU NIAID NIH HHS [R01 AI024137, AI24137, AI44160] NR 35 TC 147 Z9 156 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 4 PY 2000 VL 192 IS 5 BP 671 EP 680 DI 10.1084/jem.192.5.671 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353FW UT WOS:000089265000008 PM 10974033 ER PT J AU Zhang, SL Fukuda, S Lee, Y Hangoc, G Cooper, S Spolski, R Leonard, WJ Broxmeyer, HE AF Zhang, SL Fukuda, S Lee, Y Hangoc, G Cooper, S Spolski, R Leonard, WJ Broxmeyer, HE TI Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Flt3; signal transducer and activator of transfection 5 signal transduction; hematopoiesis; gene knockout ID COLONY-STIMULATING FACTOR; RECEPTOR TYROSINE KINASE; EPIDERMAL GROWTH-FACTOR; HEMATOPOIETIC PROGENITOR CELLS; FLT3 LIGAND; GENE-EXPRESSION; BINDING-SITE; ALPHA CHAIN; IN-VITRO; C-KIT AB The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1-4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a(-/-) mice, bur did stimulate/costimulate proliferation of these cells from Stat5a(+/+), Stat5b(-/-), and Stat5b(+/+) mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function. C1 Indiana Univ, Sch Med, Dept Microbiol Immunol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN 46206 USA. NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Broxmeyer, HE (reprint author), Indiana Univ, Sch Med, Dept Microbiol Immunol, Bldg R4,Rm 302,1044 W Walnut St, Indianapolis, IN 46202 USA. FU NHLBI NIH HHS [R01 HL056416, R01 HL56416]; NIDDK NIH HHS [R01 DK053674, R01 DK53674] NR 55 TC 147 Z9 149 U1 0 U2 6 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 SEP 4 PY 2000 VL 192 IS 5 BP 719 EP 728 DI 10.1084/jem.192.5.719 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353FW UT WOS:000089265000012 PM 10974037 ER PT J AU London, SJ Romieu, I AF London, SJ Romieu, I TI Health costs due to outdoor air pollution by traffic SO LANCET LA English DT Editorial Material ID UNITED-STATES; MORTALITY C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Pan Amer Hlth Org, Mexico City, DF, Mexico. RP London, SJ (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. OI London, Stephanie/0000-0003-4911-5290 NR 12 TC 9 Z9 9 U1 1 U2 4 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 2 PY 2000 VL 356 IS 9232 BP 782 EP 783 DI 10.1016/S0140-6736(00)02646-5 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 350LF UT WOS:000089101800002 PM 11022919 ER PT J AU Houn, F Bright, RA Bushar, HF Croft, BY Finder, CA Gohagan, JK Jennings, RJ Keegan, P Kessler, LG Kramer, BS Martynec, LO Robinowitz, M Sacks, WM Schultz, DG Wagner, RF AF Houn, F Bright, RA Bushar, HF Croft, BY Finder, CA Gohagan, JK Jennings, RJ Keegan, P Kessler, LG Kramer, BS Martynec, LO Robinowitz, M Sacks, WM Schultz, DG Wagner, RF TI Study design in the evaluation of breast cancer imaging technologies SO ACADEMIC RADIOLOGY LA English DT Article DE breast cancer; diagnosis; efficacy; regulatory requirements; screening; technology evaluation ID DIAGNOSTIC-ACCURACY; ROC METHODOLOGY AB Rationale and Objectives. Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. Materials and Methods. The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. Conclusion, Boast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy leg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected). C1 US FDA, Rockville, MD 20852 USA. NCI, Bethesda, MD 20892 USA. RP Houn, F (reprint author), US FDA, 5600 Fishers Ln,HFD-103, Rockville, MD 20852 USA. RI Croft, Barbara/D-1248-2013; Bright, Roselie/D-2240-2016 OI Croft, Barbara/0000-0003-2544-150X; NR 41 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 2000 VL 7 IS 9 BP 684 EP 692 DI 10.1016/S1076-6332(00)80524-3 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 351DU UT WOS:000089143200002 PM 10987329 ER PT J AU Kannan, N Schneider, TD Vishveshwara, S AF Kannan, N Schneider, TD Vishveshwara, S TI Logos for amino-acid preferences in different backbone packing density regions of protein structural classes SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID GLOBULAR-PROTEINS; RECOGNITION; SEQUENCES; PATTERNS; TURNS AB A protein sequence can be classified into one of four structural classes, namely alpha, beta, alpha + beta and alpha/beta, based on its amino-acid composition. The present study aims at understanding why a particular sequence with a given amino-acid composition should fold into a specific structural class. In order to answer this question, each amino acid in the protein sequence was classified to a particular neighbor density based on the number of spatial residues surrounding it within a distance of 6.5 Angstrom. Each of the four structural classes showed a unique preference of amino acids in each of the neighbor densities. Residues which show a high compositional bias in a structural class are also found to occur in high neighbor densities. This high compositional bias towards specific residues in the four different structural classes of proteins appears to be caused by structural and functional requirements. The distribution of amino acids in different neighbor densities is graphically presented in a novel logo form which incorporates several features such as composition, the frequency of occurrence and color code for amino acids. The spatial neighbors of the residues in different neighbor densities and their secondary structural location are also represented in the form of logos. This representation helped in the identification of specific details of the whole data which may otherwise have gone unnoticed. It is suggested that the data presented in this study may be useful in knowledge-based structure modelling and de novo protein design. C1 Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Vishveshwara, S (reprint author), Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. OI Schneider, Thomas/0000-0002-9841-1531 NR 27 TC 6 Z9 6 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD SEP PY 2000 VL 56 BP 1156 EP 1165 DI 10.1107/S0907444900008969 PN 9 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 347AM UT WOS:000088904100009 PM 10957634 ER PT J AU Schiffman, M Adrianza, ME AF Schiffman, M Adrianza, ME CA ALTS Grp TI ASCUS-LSIL Triage Study - Design, methods and characteristics of trial participants SO ACTA CYTOLOGICA LA English DT Article; Proceedings Paper CT International Consensus Conference on the Fight Against Cervical Cancer CY MAR 18-22, 2000 CL CHICAGO, ILLINOIS SP IAC Task Force DE cervix neoplasms; Papanicolaou smear; mass screening; ASCUS-LSIL Triage Study ID HUMAN-PAPILLOMAVIRUS DNA; CERVICAL INTRAEPITHELIAL NEOPLASIA; CYTOLOGICALLY NORMAL WOMEN; CANCER DETECTION; NATURAL-HISTORY; INFECTION; RISK; CERVICOGRAPHY; PERSISTENCE; DIAGNOSES AB OBJECTIVE: To describe the design and methods of the ASCUS-LSIL Triage Study (ALTS), a multicenter, randomized clinical trial designed to evaluate three alternative methods of managing low grade (LSIL) and equivocal (ASCUS) cervical cytologic diagnoses. STUDY DESIGN: Nonpregnant women, 18+ years old, with ASCUS or LSIL, no prior hysterectomy or ablative therapy to the cervix, were referred to one of four clinical centers around the United States. Eligible and consenting participants were administered a risk-factor questionnaire and underwent a pelvic examination, collection of cervical specimens for liquid-based cytology and human papillomavirus (HPV) testing and Cervicography(TM) (National Testing Laboratories, Fenton, Missouri, U.S.A.). Patients were randomized to one of three arms: (1) immediate referral for colposcopy at enrollment, (2) follow-up with cytology only, and (3) use of HPV DNA testing to triage to colposcopy. All women are followed every six months for two years with pelvic examinations, cytologic and masked HPV testing, and masked Cervicography(TM). Digital cervical images and cytology and histology slides are externally reviewed to maximize patient safety. RESULTS: We enrolled and randomized 3,488 eligible women with ASCUS and 1,572 women with LSIL. CONCLUSION: The successful enrollment, randomization and high rates of follow-up are encouraging. The study will help clarify the optimal strategies for managing low grade cervical abnormalities. C1 NCI, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. RP Schiffman, M (reprint author), NCI, Interdisciplinary Studies Sect, Environm Epidemiol Branch, 6120 Execut Plaza S,Room 7066, Rockville, MD 20852 USA. FU NCI NIH HHS [CN-55153, CN-55154, CN-55155] NR 45 TC 170 Z9 173 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA P.O. DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD SEP-OCT PY 2000 VL 44 IS 5 BP 726 EP 742 PG 17 WC Pathology SC Pathology GA 356ZC UT WOS:000089473200004 PM 11015972 ER PT J AU Pequegnat, W Stover, E AF Pequegnat, W Stover, E TI Behavioral prevention is today's AIDS vaccine! SO AIDS LA English DT Article; Proceedings Paper CT Consensus Development Conference on Interventions to Prevent HIV Risk Behaviors CY FEB 11-13, 1997 CL BETHESDA, MD SP NIH DE HIV; AIDS; behavioral prevention; behavior change ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED TRIAL; HIV RISK-REDUCTION; CONDOM USE; CITIES AB Introduction: Behavioral prevention is currently the only effective way to stem the further spread of HIV, This article reviews the pro-active programmatic model of behavioral research that has led to the development and testing of successful HIV/STD preventive interventions in the last fifteen years. Objective: To present (1) a model of behavioral prevention adapting phases of clinical trials research: Phase I: Discovery; Phase II: Exploratory; Phase Iii: Efficacy; and Phase IV: Effectiveness; and (2) a theoretical framework For behavioral prevention; and (3) A Lifespan Model of Health Promotion and Disease Prevention which can be used to design HIV/STD prevention programs across the lifespan, at different levels (e.g., individual, couple, family, community, societal) using different intervention modalities. Conclusions: Behavioral prevention is effective with different age groups and at different levels of intervention when the prevention program has a theoretical basis. Behavioral prevention works now and can be mobilized within a community to address all of the factors associated with the rapid development of an epidemic. Behavioral prevention is cost effective and can be delivered in communities that have limited resources. (C) 2000 Lippincott Williams & Wilkins. C1 NIMH, Ctr Mental Hlth Res AIDS, NIH, Bethesda, MD 20892 USA. RP Pequegnat, W (reprint author), NIMH, Ctr Mental Hlth Res AIDS, NIH, 6001 Execut Blvd,Room 6205,MSC 9619, Bethesda, MD 20892 USA. EM Wpequegn@nih.gov NR 42 TC 24 Z9 24 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP PY 2000 VL 14 SU 2 BP S1 EP S7 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 366QK UT WOS:000090015900001 PM 11061636 ER PT J AU Wiener, LS Battles, HB Heilman, N AF Wiener, LS Battles, HB Heilman, N TI Public disclosure of a child's HIV infection: Impact on children and families SO AIDS PATIENT CARE AND STDS LA English DT Article ID AIDS; PHYSICIANS; ATTITUDES AB As an increasing number of children infected with HIV live to older ages, the question of disclosure of the diagnosis (to the child and to others) becomes more crucial. Disclosure of a child's HIV diagnosis is a controversial and emotionally laden issue. One reason that families avoid disclosure is their fear of the negative impact on the child and family that the stigma associated with AIDS can bring. At the other end of the spectrum, are those families that choose to publicly disclose an HIV diagnosis. There are a number of reasons that a family may choose to go public with their child's diagnosis, although this has never been systematically assessed. The dearth of literature and research regarding the emotional impact of public life on a child as well as the interest of a number of non-public HIV-infected children to "go public" served as an impetus to conduct a study that directly examined the impact public disclosure has on the HIV-infected child and family. Specifically, findings pertaining to the decision making process, the impact public disclosure has had on the child's family, and the child's sense of self-worth at the time of the study and then again 4 years later are reviewed. Findings and implications for future research as well as interventions and strategies aimed at counseling families considering "going public" and helping to normalize the public child's life are discussed. C1 NCI, Pediat AIDS Working Grp, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. Good Samaritan Hosp, Puyallup, WA USA. RP Wiener, LS (reprint author), NCI, Pediat AIDS Working Grp, HIV AIDS Malignancy Branch, Bldg 10-13N240,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 19 Z9 19 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD SEP PY 2000 VL 14 IS 9 BP 485 EP 497 DI 10.1089/108729100438863 PG 13 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 359UP UT WOS:000089630700005 PM 11051631 ER PT J AU Isaki, L Kresina, TF AF Isaki, L Kresina, TF TI Directions for biomedical research in alcohol and HIV: Where are we now and where can we go? SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; BLOOD MONONUCLEAR-CELLS; TUMOR-NECROSIS-FACTOR; NEW-YORK-CITY; LIVER-TRANSPLANTATION; TUBERCULOSIS-CONTROL; TYPE-1 REPLICATION; ETHANOL EXPOSURE; DRUG-USERS C1 NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. RP Kresina, TF (reprint author), NIAAA, Biomed Res Branch, Div Basic Res, NIH, Room 402,6000 Execut Blvd, Bethesda, MD 20892 USA. NR 77 TC 13 Z9 13 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2000 VL 16 IS 13 BP 1197 EP 1207 DI 10.1089/08892220050116961 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 347HC UT WOS:000088921400001 PM 10957717 ER PT J AU Pilon, AA Marchand, C Kavlick, MF Bajaj, K Owen, J Mitsuya, H Pommier, Y AF Pilon, AA Marchand, C Kavlick, MF Bajaj, K Owen, J Mitsuya, H Pommier, Y TI Mutations in the HIV type 1 integrase of patients receiving long-term dideoxynucleoside therapy do not confer resistance to zidovudine SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; GENE-EXPRESSION; CELLS; DNA; REPLICATION; INVIVO AB Metabolites of AZT can inhibit HIV-1 integrase in vitro (Mazumder A, et al., Proc Natl Acad Sci USA 1994; 91: 5771-5775). To determine if long-term dideoxynucleoside therapy can lead to the emergence of HIV-1 AZT-resistant variants containing mutations in the integrase, we have sequenced the proviral DNA encoding the HIV-1 integrase of nine HIV-1-infected patients at different time points during treatment. Four of the nine patients developed mutations during the course of treatment. Although most mutations occurred at nonconserved amino acids, one patient developed a mutation at codon (R166T), a residue that is conserved among all integrases from known HIV-1 isolates. This mutation was introduced in the recombinant HIV-1 integrase protein to determine if it could confer resistance to AZT in vitro. We show that the R166T integrase mutant is still proficient at carrying 3'-processing and 3'-end-joining but that the enzyme is not resistant to AZT-TP. Our results suggest that it is unlikely that integrase inhibition contributes to the antiviral activity of AZT. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment, Med Branch, Expt Retrovirol Sect,NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Rm 5D02, Bethesda, MD 20892 USA. RI Marchand, Christophe/D-8559-2016 NR 23 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2000 VL 16 IS 14 BP 1417 EP 1422 DI 10.1089/08892220050140964 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 359CC UT WOS:000089593100010 PM 11018861 ER PT J AU Ferrari, G Kostyu, DD Cox, J Dawson, DV Flores, J Weinhold, KJ Osmanov, S AF Ferrari, G Kostyu, DD Cox, J Dawson, DV Flores, J Weinhold, KJ Osmanov, S TI Identification of highly conserved and broadly cross-reactive HIV type 1 cytotoxic T lymphocyte epitopes as candidate immunogens for inclusion in Mycobacterium bovis BCG-vectored HIV vaccines SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LOW VIRAL LOAD; PRIMARY INFECTION; DENDRITIC CELLS; IN-VITRO; PROTECTIVE IMMUNITY; PERIPHERAL-BLOOD; CTL EPITOPES; RESPONSES; IMMUNODOMINANT AB One of the fundamental goals of current strategies to develop an efficacious vaccine for AIDS is the elicitation of cytotoxic T lymphocyte (CTL) reactivities capable of recognizing cells infected with different subtypes of the human immunodeficiency virus type 1 (HIV-1). In efforts to explore new vaccine candidates by the UNAIDS/WHO Vaccine Committee, we review the most recent data concerning CTL epitopes that are conserved among the different HIV-1 subtypes. Moreover, we examine HLA allelic frequencies in several different populations, to determine those that could contribute to the goal of a cumulative phenotype frequency (CP) of at least 80%. By analyzing conserved epitopes in the context of HLA restricting alleles, we define a set of HIV-1 gene regions that may have the greatest potential to induce cross-clade reactive CTLs. The absence of well-defined correlates of immune protection that link CTL epitopes to delayed disease progression and/or prevention of infection does not permit an assignment of rank order of the most relevant component of a candidate vaccine. Thus far, most of the studies conducted in clade B-infected patients to define conserved and immunodominant epitopes indicate gag and pol gene products to be the most conserved among the HIV-1 subtypes. Moreover, anti-Pol and -Gag CTL responses appear to correlate inversely with disease progression, suggesting that they should be among the first choice of antigens to be included in a candidate vaccine construct aimed at induction of broad CTL responses. The impact of a clade B-based vaccine as a worldwide candidate capable of inducing protective immune responses can be determined only after "in vivo" studies. Meanwhile, extensive parallel studies in populations infected with non-clade B HIV-1 subtypes should define the patterns of immunodominant epitopes and HLA for comparison with the data already collected in clade B-infected subjects. C1 Duke Univ, Med Ctr, Dept Surg, Durham, NC 27707 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27707 USA. Henry H Jackson Fdn, Rockville, MD USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Epidemiol & Biostat, Cleveland, OH USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Joint United Nat Programme HIV AIDS, Geneva, Switzerland. RP Ferrari, G (reprint author), Duke Univ, Med Ctr, Dept Surg, DUMC 2926,SORF Bldg,LaSalle St Ext, Durham, NC 27710 USA. RI Ferrari, Guido/A-6088-2015 FU NIAID NIH HHS [N01-AI65305] NR 62 TC 44 Z9 49 U1 0 U2 2 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 SEP PY 2000 VL 16 IS 14 BP 1433 EP 1443 DI 10.1089/08892220050140982 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 359CC UT WOS:000089593100012 PM 11018863 ER PT J AU Cohen, SG Rizzo, PL AF Cohen, SG Rizzo, PL TI Asthma among the famous - A continuing series SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD SEP-OCT PY 2000 VL 21 IS 5 BP 323 EP 334 DI 10.2500/108854100778248278 PG 12 WC Allergy SC Allergy GA 368JV UT WOS:000090114600011 PM 11061044 ER PT J AU McCrae, RR AF McCrae, RR TI This issue is devoted to personality traits and culture: New perspectives on some classic issues - Introduction SO AMERICAN BEHAVIORAL SCIENTIST LA English DT Editorial Material ID PSYCHOLOGY C1 NIA, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0002-7642 J9 AM BEHAV SCI JI Am. Behav. Sci. PD SEP PY 2000 VL 44 IS 1 BP 7 EP 9 DI 10.1177/00027640021956053 PG 3 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 413UR UT WOS:000167630400001 ER PT J AU McCrae, RR AF McCrae, RR TI Trait psychology and the revival of personality and culture studies SO AMERICAN BEHAVIORAL SCIENTIST LA English DT Article; Proceedings Paper CT 106th Annual Convention of the American-Psychological-Association CY AUG 14-18, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Psychol Assoc ID 5-FACTOR MODEL; NATURAL-LANGUAGE; CHINESE; OPENNESS; SCIENCE AB Personality and culture studies have largely disappeared since the 1960s, but progress in trait psychology makes their revival feasible. A review of evidence on the consensual validity longitudinal stability, heritability, and structure of personality traits suggests new approaches to old issues. At the transcultural level claims of universality are addressed. At the intercultural level, associations are sought between mean levels of personality traits and corresponding culture-level variables; cultural institutions may be either causes or effects of personality. At the intracultural level culture-specific manifestations of universal traits are documented. The new discipline of personality traits and culture draws on multiple methodologies to understand human nature in social context. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, NIH, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 89 TC 55 Z9 55 U1 4 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0002-7642 J9 AM BEHAV SCI JI Am. Behav. Sci. PD SEP PY 2000 VL 44 IS 1 BP 10 EP 31 DI 10.1177/00027640021956062 PG 22 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 413UR UT WOS:000167630400002 ER PT J AU Bordi, C Azzoni, C Ferraro, G Corleto, VD Gibril, F Delle Fave, G Lubensky, IA Venzon, DJ Jensen, RT AF Bordi, C Azzoni, C Ferraro, G Corleto, VD Gibril, F Delle Fave, G Lubensky, IA Venzon, DJ Jensen, RT TI Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger-Ellison syndrome SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE endoscopy; biopsy sampling; Zollinger-Ellison syndrome; enterochromaffin-like cells; ECL cells; gastric carcinoids; multiple endocrine neoplasia; type 1 ID LONG-TERM TREATMENT; OMEPRAZOLE THERAPY; ENDOCRINE-CELLS; NEUROENDOCRINE CARCINOMA; GASTRIN; CLASSIFICATION; TUMORS; HYPERGASTRINEMIA; LANSOPRAZOLE; STOMACH AB To investigate the optimum number of biopsy specimens to be obtained for enterochromaffin-like (ECL) cell monitoring in hypergastrinemic patients and ECL cell regional variations potentially influencing the results, qualitative ECL cell changes were assessed in 149 patients with Zollinger-Ellison syndrome using jumbo biopsy specimens and a systematic sampling procedure of 4 areas each from the lesser or greater curvature of the gastric body. Of 1,176 specimens examined, 1,101 were adequate. The correlation was excellent between different sites within the greater or lesser curvature. In contrast, a normal ECL cell pattern was more frequent in the lesser curvature, whereas linear hyperplasia was more frequent in the greater curvature. Dysplastic lesions and carcinoid tumors in endoscopically unremarkable mucosa were detected in 3.4% and 1.2% of biopsy specimens, respectively, and were equally distributed between the lesser and greater curvature. Their chances of being diagnosed were related to the number of specimens examined Extensive sampling of both the lesser and greater curvature is recommended for early diagnosis of dysplastic and/or carcinoid lesions in patients at risk. In contrast, limited sampling in the greater curvature seems to be adequate in patients with no risk for carcinoid development. C1 Univ Parma, Dept Pathol & Lab Med, Sez Anat Patol, I-43100 Parma, Italy. Univ Roma La Sapienza, Sch Med 2, Dept Digest Dis, Rome, Italy. Univ Roma La Sapienza, Dept Cell Biotechnol & Hematol, Rome, Italy. NIH, Digest Dis Branch, Bethesda, MD 20892 USA. NCI, Dept Pathol, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Bordi, C (reprint author), Univ Parma, Dept Pathol & Lab Med, Sez Anat Patol, I-43100 Parma, Italy. RI Venzon, David/B-3078-2008 NR 33 TC 23 Z9 26 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2000 VL 114 IS 3 BP 419 EP 425 PG 7 WC Pathology SC Pathology GA 349ZN UT WOS:000089075700013 PM 10989643 ER PT J AU Kipnis, V Carroll, RJ Freedman, LS Li, L AF Kipnis, V Carroll, RJ Freedman, LS Li, L TI Re: "Implications of a new dietary measurement error model for estimation of relative risk: Application to four calibration studies'' - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID COVARIANCE STRUCTURE MODELS C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, IL-52900 Ramat Gan, Israel. Univ Kentucky, Dept Family Practice, Lexington, KY 40506 USA. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NR 5 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 1 PY 2000 VL 152 IS 5 BP 495 EP 496 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 349BM UT WOS:000089024000018 ER PT J AU Chen, F Pau, AK Piscitelli, SC AF Chen, F Pau, AK Piscitelli, SC TI Update on preventing vertical transmission of HIV type 1 SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; 1-INFECTED PREGNANT-WOMEN; PERINATAL TRANSMISSION; ZIDOVUDINE PROPHYLAXIS; PHARMACOKINETICS; LAMIVUDINE; NEVIRAPINE; EXPOSURE; INFANTS; INHIBITORS C1 NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. RP Piscitelli, SC (reprint author), NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bldg 10,Room 1N257, Bethesda, MD 20892 USA. NR 38 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD SEP 1 PY 2000 VL 57 IS 17 BP 1616 EP 1623 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 350DR UT WOS:000089085900016 PM 10984815 ER PT J AU Yasunaga, S Grati, M Chardenoux, S Smith, TN Friedman, TB Lalwani, AK Wilcox, ER Petit, C AF Yasunaga, S Grati, M Chardenoux, S Smith, TN Friedman, TB Lalwani, AK Wilcox, ER Petit, C TI OTOF encodes multiple long and short isoforms: Genetic evidence that the long ones underlie recessive deafness DFNB9 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GIRDLE MUSCULAR-DYSTROPHY; INNER-EAR; MUTATIONS; INSIGHTS; PROTEIN; DOMAIN; FORM AB We have recently reported that OTOF underlies an autosomal recessive form of prelingual sensorineural deafness, DFNB9. The isolated 5-kb cDNA predicted a 1,230 amino acid (aa) C-terminus membrane-anchored cytosolic protein with three C2 domains. This protein belongs to a family of mammalian proteins sharing homology with the Caenorhabditis elegans fer-1. The two other known members of this family, dysferlin and myoferlin, both have six predicted C2 domains. By northern blot analysis, a 7-kb otoferlin mRNA could be detected in the human brain. We isolated the corresponding cDNA, which is expected to encode a 1,977-aa-long form of otoferlin with six C2 domains. A 7-kb cDNA derived from the murine orthologous gene, Otof, was also identified in the inner ear and the brain. The determination of the exon-intron structure of the human and murine genes showed that they are composed of 48 coding exons and extend similar to 90 kb and similar to 80 kb, respectively. Alternatively spliced transcripts could be detected that predict several long isoforms (six C2 domains) in humans and mice and short isoforms (three C2 domains) only in humans. Primers were designed to explore the first 19 OTOF exons, henceforth permitting exploration of the complete coding sequence of the gene in DFNB9 patients. In a southwestern Indian family affected by DFNB9, a mutation in the acceptor splice site of intron 8 was detected, which demonstrates that the long otoferlin isoforms are required for inner ear function. C1 Inst Pasteur, CNRS URA 1968, Unite Genet Deficits Sensoriels, F-75724 Paris 15, France. Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD USA. RP Petit, C (reprint author), Inst Pasteur, CNRS URA 1968, Unite Genet Deficits Sensoriels, 25 Rue Dr Roux, F-75724 Paris 15, France. RI Grati, M'hamed/C-9563-2011 FU NIDCD NIH HHS [T32 DC000035, T32 DC000038, ZO1 DC 00035, ZO1 DC 00038] NR 18 TC 103 Z9 114 U1 0 U2 7 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 2000 VL 67 IS 3 BP 591 EP 600 DI 10.1086/303049 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 348TJ UT WOS:000089002300006 PM 10903124 ER PT J AU Griffith, AJ Chowdhry, AA Kurima, K Hood, LJ Keats, B Berlin, CI Morell, RJ Friedman, TB AF Griffith, AJ Chowdhry, AA Kurima, K Hood, LJ Keats, B Berlin, CI Morell, RJ Friedman, TB TI Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HEARING-LOSS; SENSORINEURAL DEAFNESS; GENE GJB2; MUTATIONS; POPULATIONS; FAMILIES; FORM AB Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles. C1 Natl Inst Deafness & Other Commun Disorders, Genet Mol Lab, NIH, Rockville, MD USA. Natl Inst Deafness & Other Commun Disorders, Neuro Otol Branch, NIH, Rockville, MD USA. Louisiana State Univ, Hlth Sci Ctr, Kresge Hearing Res Lab, Dept Otohinolaryngol & Biocommun, New Orleans, LA USA. Louisiana State Univ, Hlth Sci Ctr, Dept Biometry & Genet, New Orleans, LA USA. RP Griffith, AJ (reprint author), NIH, NIDCD, 5 Res Court,Room 2A-02, Rockville, MD 20850 USA. OI Morell, Robert/0000-0003-1537-7356 FU NIDCD NIH HHS [R01-DC03679, T32 DC000035, Z01-DC00054-01, R01 DC003679, T32 DC000054, Z01-DC00035-03] NR 21 TC 46 Z9 48 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 2000 VL 67 IS 3 BP 745 EP 749 DI 10.1086/303045 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 348TJ UT WOS:000089002300020 PM 10903123 ER PT J AU Hagan, DM Ross, AJ Strachan, T Lynch, SA Ruiz-Perez, V Wang, YM Scambler, P AF Hagan, DM Ross, AJ Strachan, T Lynch, SA Ruiz-Perez, V Wang, YM Scambler, P TI Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene (vol 66, pg 1504, 2000) SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Correction C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Hagan, DM (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,Room 10-C-101C, Bethesda, MD 20892 USA. RI Scambler, Peter/C-4998-2008; Ruiz-Perez, Victor /K-6066-2014 OI Scambler, Peter/0000-0002-1487-4628; Ruiz-Perez, Victor /0000-0003-0635-3619 NR 1 TC 2 Z9 2 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 2000 VL 67 IS 3 BP 769 EP 769 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 348TJ UT WOS:000089002300025 ER PT J AU Silbergeld, EK Waalkes, M Rice, JM AF Silbergeld, EK Waalkes, M Rice, JM TI Lead as a carcinogen: Experimental evidence and mechanisms of action SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Lead Exposure, Reproductive Toxicity, and Carcinogenicity CY JUN 07-09, 1999 CL GARGNANO, ITALY SP US Natl Inst Environm Hlth Sci, US Natl Inst Occupat Safety & Hlth, Univ Brescia, Inst Occupat Hlth, Int Agcy Res Canc, Lyon DE lead; cancer; genotoxicity ID HEAVY-METALS; ZINC-FINGER; TOXICITY; ACETATE; CALCIUM; CELLS; DNA; RATS; MUTAGENESIS; CANCER AB Recent epidemiological and experimental work confirms that inorganic lead compounds are associated with increased risks of tumorigenesis. In animals, these risks can be induced at doses that are not associated with organ toxicity and in mice that do not produce alpha-2 urinary globulin in the kidney. Thus the mechanisms of lead carcinogenicity are unlikely to be fully explained as toxicity-related sequelae of high dose exposure or as a rat-specific response involving overexpression of a renal protein. Plausible mechanisms of lead carcinogenicity include direct DNA damage, clastogenicity, or inhibition of DNA synthesis or repair Lead may also generate reactive oxygen species and cause oxidative damage to DNA. Recent data indicate that lead can substitute for zinc in several proteins that function as transcriptional regulators, including protamines, Lead further reduces the binding of these proteins to recognition elements in genomic DNA, which suggests an epigenetic involvement of lead in altered gene expression. These events may be of particular relevance in transplacental exposures and Inter cancer. Am. J. Ind. Med. 38:316-323, 2000. Published 2000 Wiley-Liss, Inc.(dagger) C1 Univ Maryland, Program Human Hlth & Environm, Baltimore, MD 21201 USA. NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. Int Agcy Res Canc, Unit Carcinogen Identificat & Evaluat, Lyon, France. RP Silbergeld, EK (reprint author), Univ Maryland, Program Human Hlth & Environm, 10 S Pine St,MSTF 9-36, Baltimore, MD 21201 USA. NR 74 TC 114 Z9 123 U1 3 U2 21 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 SEP PY 2000 VL 38 IS 3 BP 316 EP 323 DI 10.1002/1097-0274(200009)38:3<316::AID-AJIM11>3.0.CO;2-P PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 341HE UT WOS:000088584300011 PM 10940970 ER PT J AU Quintanilla-Vega, B Hoover, D Bal, W Silbergeld, EK Waalkes, MP Anderson, LD AF Quintanilla-Vega, B Hoover, D Bal, W Silbergeld, EK Waalkes, MP Anderson, LD TI Lead effects on protamine-DNA binding SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Lead Exposure, Reproductive Toxicity, and Carcinogenicity CY JUN 07-09, 1999 CL GARGNANO, ITALY SP US Natl Inst Environm Hlth Sci, US Natl Inst Occupat Safety & Hlth, Univ Brescia, Inst Occupat Hlth, Int Agcy Res Canc, Lyon DE protamines; sperm chromatin; lead toxicity; reproductive toxicity ID SPERM CHROMATIN; PROTEIN INTERACTIONS; EXPOSED HUMANS; P2 PROTAMINES; SEMEN QUALITY; METALS; MEN; RAT; REPRODUCTION; FERTILITY AB Background Lead impairs male fertility and may affect offspring of exposed males, bur the mechanisms for this impairment are not completely cleat: Protamine P1 and P2 families pack and protect mammalian sperm DNA, Human HP2 is a zinc-protein and may have art important role in fertility. As lean has affinity for zinc-containing proteins, we evaluated its ability in vitro to bind to HP2 and its effects on HP2-DNA binding, Methods and Results UV/VIS spectroscopic data indicated that HP2 binds both Pb2+ and Zn2+ (as chloride salts). They also provided evidence that thiol groups mainly participate for Zn2+-binding; however HP2 has additional binding sites for Pb2+. The mobility shift assay showed that lead interaction with HP2 caused a dose-dependent decrease on HP2 binding to DNA, suggesting that lead may alter chromatin stability, Conclusions These in vitro results demonstrate that lead can interact with HP2 altering the DNA-protamine binding. This chemical interaction of lead with protamines may result in chromatin alterations, which in turn may lead to male fertility problems and eventually to DNA damage. Am. J. Ind. Med. 38:324-329, 2000. (C) 2000 Wiley-Liss, Inc. C1 Inst Politecn Nacl, CINVESTAV, Secc Toxicol Ambiental, Mexico City 07300, DF, Mexico. NIEHS, NCI, Res Triangle Pk, NC 27709 USA. Univ Maryland, Sch Med, Program Human Hlth & Environm, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Univ Wroclaw, Dept Chem, PL-50138 Wroclaw, Poland. NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. RP Quintanilla-Vega, B (reprint author), Inst Politecn Nacl, CINVESTAV, Secc Toxicol Ambiental, POB 14-740, Mexico City 07000, DF, Mexico. NR 51 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD SEP PY 2000 VL 38 IS 3 BP 324 EP 329 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 341HE UT WOS:000088584300012 PM 10940971 ER PT J AU Ho, NC McInerney, A Levy, H Francomano, CA Elkayam, O AF Ho, NC McInerney, A Levy, H Francomano, CA Elkayam, O TI Minocycline-induced generalized postinflammatory elastolysis SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter ID CUTIS LAXA C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Ichilov Hosp, Tel Aviv Souraski Med Ctr, Dept Rheumatol, IL-64239 Tel Aviv, Israel. RP Ho, NC (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NR 10 TC 3 Z9 3 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD SEP PY 2000 VL 109 IS 4 BP 340 EP 341 DI 10.1016/S0002-9343(00)00499-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 354XM UT WOS:000089356600015 PM 11203144 ER PT J AU Grether, JK Hoogstrate, J Walsh-Greene, E Nelson, KB AF Grether, JK Hoogstrate, J Walsh-Greene, E Nelson, KB TI Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE magnesium; tocolysis; cerebral palsy ID BIRTH-WEIGHT INFANTS; INTRAVENTRICULAR HEMORRHAGE; DEVELOPMENTAL DISABILITY; INTRAVENOUS MAGNESIUM; PEDIATRIC MORTALITY; PRETERM LABOR; BRAIN; EFFICACY; MODULATION; MANAGEMENT AB OBJECTIVE: Our aim was to examine magnesium sulfate tocolysis and cerebral palsy in infants born prematurely to women without preeclampsia. STUDY DESIGN: We conducted a retrospective case-control study of infants with birth weights <1500 g and of infants with birth weights from 1500 to 1999 g who were born at <33 weeks' gestation. The study infants were born in level 2 or level 3 hospitals from 1988 through 1994 to women without preeclampsia, were delivered >3 hours after admission, and had survived to age 2 years. RESULTS: Among 170 children with cerebral palsy and 288 control subjects, similar proportions of case mothers (58%) and control mothers (62%) had received magnesium sulfate tocolysis. In women with some tocolytic treatment, these proportions were 78% and 76%, respectively. The duration of treatment with magnesium was comparable for case and control women, as were the intervals from beginning and termination of treatment to delivery. Adjustment for gestational age, birth weight, and other variables did not alter this result. CONCLUSION: Magnesium exposure was not associated with a lower risk of cerebral palsy in infants born prematurely to women without preeclampsia. The difference between this finding and that in our previous study showing an apparent neuroprotective effect of magnesium is not explained by the more restrictive selection criteria used here and may be related to a number of changes in medical practice between the 2 periods. C1 March Dimes Birth Defects Fdn, Calif Birth Defects Monitoring Program, Calif Dept Hlth Serv, Oakland, CA 94606 USA. NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. RP Grether, JK (reprint author), March Dimes Birth Defects Fdn, Calif Birth Defects Monitoring Program, Calif Dept Hlth Serv, 1830 Embarcadero,Suite 100, Oakland, CA 94606 USA. FU NINDS NIH HHS [NS35573-01] NR 49 TC 49 Z9 51 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2000 VL 183 IS 3 BP 717 EP 725 DI 10.1067/mob.2000.106581 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 355UP UT WOS:000089407200032 PM 10992199 ER PT J AU Mercer, BM Goldenberg, RL Meis, PJ Moawad, AH Shellhaas, C Das, A Menard, MK Caritis, SN Thurnau, GR Dombrowski, MP Miodovnik, M Roberts, JM McNellis, D AF Mercer, BM Goldenberg, RL Meis, PJ Moawad, AH Shellhaas, C Das, A Menard, MK Caritis, SN Thurnau, GR Dombrowski, MP Miodovnik, M Roberts, JM McNellis, D CA Natl Inst Child Hlth Human Dev TI The Preterm Prediction Study: Prediction of preterm premature rupture of membranes through clinical findings and ancillary testing SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE prediction; premature rupture of membranes; prematurity; preterm birth ID BACTERIAL VAGINOSIS; FETAL MEMBRANES; RISK-FACTORS; HISTOLOGIC CHORIOAMNIONITIS; AMNIOTIC MEMBRANES; BIRTH; PREGNANCY; DELIVERY; INFECTION; FIBRONECTIN AB OBJECTIVE: Our objective was to determine the relative importance of demographic characteristics, clinical risk factors, and ancillary screening tests in the prediction of preterm birth as a result of premature rupture of membranes. STUDY DESIGN: A total of 2929 women were evaluated in 10 centers at 23 to 24 weeks' gestation. Demographic and clinical characteristics were ascertained. Cervicovaginal fetal fibronectin and bacterial vaginosis were evaluated. Cervical length was measured by vaginal ultrasonography. Patients were evaluated for spontaneous preterm birth caused by preterm premature rupture of membranes at <37 and <35 weeks' gestation. Multivariate analyses were performed separately for nulliparous women and multiparous women. RESULTS: Premature rupture of membranes at <37 weeks' gestation complicated 4.5% of pregnancies, accounting for 32.6% of preterm births. Univariate analysis revealed low body mass index, pulmonary disease, contractions within 2 weeks, short cervix (less than or equal to 25 mm), positive results of fetal fibronectin screening, bacterial vaginosis, and a previous preterm birth caused by premature rupture of membranes tin multiparous women) to be significantly associated with preterm birth caused by premature rupture of membranes in the current gestation. Short cervix, previous preterm birth caused by premature rupture of membranes in multiparous women, and presence of fetal fibronectin were the strongest predictors for both preterm birth caused by premature rupture of membranes at <37 and <35 weeks' gestation. Women with positive fetal fibronectin screening results and a short cervix had greater risks both of preterm birth caused by premature rupture of membranes at <37 weeks' gestation (relative risk, 4.9) and of preterm birth caused by premature rupture of membranes at <35 weeks' gestation (relative risk, 13.5) than did those without these risk factors. Multiparous women with all three risk factors had a 31.3-fold increased risk of preterm birth caused by premature rupture of membranes at <35 weeks' gestation. CONCLUSION: The combination of short cervical length, previous preterm birth caused by preterm premature rupture of membranes, and positive fetal fibronectin screening results was highly associated with preterm delivery caused by preterm premature rupture of membranes in the current gestation. C1 Univ Tennessee, Memphis, TN 38163 USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. NICHHD, Bethesda, MD 20892 USA. Univ Oklahoma, Oklahoma City, OK USA. Univ Alabama, Birmingham, AL USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Wayne State Univ, Detroit, MI USA. RP Mercer, BM (reprint author), Univ Tennessee, Memphis, TN 38163 USA. RI Shellhaas, Cynthia/E-4077-2011; OI caritis, steve/0000-0002-2169-0712 FU NICHD NIH HHS [HD21410, HD21414, HD21434] NR 25 TC 119 Z9 122 U1 0 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2000 VL 183 IS 3 BP 738 EP 745 DI 10.1067/mob.2000.106766 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 355UP UT WOS:000089407200035 PM 10992202 ER PT J AU Hogg, BB Hauth, JC Meis, PJ Roberts, JM Meikle, S AF Hogg, BB Hauth, JC Meis, PJ Roberts, JM Meikle, S TI What is the meaning of authorship? Reply SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter ID WOMEN C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35249 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27157 USA. Magee Womens Hosp, Magee Womens Res Inst, Dept Obstet & Gynecol, Pittsburgh, PA 15213 USA. NICHHD, NIH, Bethesda, MD 20893 USA. RP Hogg, BB (reprint author), Univ Alabama, Dept Obstet & Gynecol, 619 19th St S, Birmingham, AL 35249 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2000 VL 183 IS 3 BP 775 EP 776 DI 10.1067/mob.2000.106029 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 355UP UT WOS:000089407200042 ER PT J AU Zhang, J Klebanoff, MA Levine, RJ AF Zhang, J Klebanoff, MA Levine, RJ TI Effects of smoking on blood pressure during pregnancy on balance are negative - Reply SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NICHHD, Dept Epidemiol, Stat & Prevent Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Dept Epidemiol, Stat & Prevent Branch, NIH, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2000 VL 183 IS 3 BP 776 EP 777 DI 10.1067/mob.2000.106715 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 355UP UT WOS:000089407200044 ER PT J AU Robertson, SC Colborn, AP AF Robertson, SC Colborn, AP TI Can we improve outcomes research by expanding research methods? SO AMERICAN JOURNAL OF OCCUPATIONAL THERAPY LA English DT Editorial Material C1 NIH, Occupat Therapy Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Occupat Therapy Serv, Washington, DC 20307 USA. RP Robertson, SC (reprint author), 5618 Greentree Rd, Bethesda, MD 20817 USA. NR 18 TC 3 Z9 3 U1 0 U2 1 PU AMER OCCUPATIONAL THERAPY ASSOC, INC PI BETHESDA PA 4720 MONTGOMERY LANE, BETHESDA, MD 20814-3425 USA SN 0272-9490 J9 AM J OCCUP THER JI Am. J. Occup. Ther. PD SEP-OCT PY 2000 VL 54 IS 5 BP 541 EP 543 DI 10.5014/ajot.54.5.541 PG 3 WC Rehabilitation SC Rehabilitation GA 356CT UT WOS:000089427300013 PM 11006815 ER PT J AU Prajna, NV Ellwein, LB Selvaraj, S Manjula, K Kupfer, C AF Prajna, NV Ellwein, LB Selvaraj, S Manjula, K Kupfer, C TI The Madurai Intraocular Lens Study IV: Posterior capsule opacification SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; EXTRACAPSULAR CATARACT-EXTRACTION; VISUAL-ACUITY; OUTCOMES; IMPLANTATION; DESIGN; COUNTY; CHINA; NEPAL AB PURPOSE: To estimate the cumulative incidence of posterior capsule opacification 4 years after surgery in patients who participated in the Madurai Intraocular Lens Study and had extracapsular cataract extraction with posterior chamber intraocular lens implantation, METHODS: In the Madurai Intraocular Lens Study, 1,700 patients with best-corrected visual acuity 20/120 or worse in the better eye had extracapsular cataract extraction with posterior chamber intraocular lens implantation, and 1,474 (86.7%) of these completed the 1-year follow-up examination. From this group of 1,474 pseudophakic patients, 400 were randomly selected for reexamination 4 years after the original surgery. The eye that was operated on was examined by an ophthalmologist who was involved in the 1-year follow-up examinations and posterior capsule opacification grading. A grading of I to III was used to reflect the degree of opacification. With grades II and III, posterior capsule opacification detectable with an undilated pupil was present in the central axis, RESULTS: Three hundred twenty-seven (81.8%) of the selected population were examined between October 1997 and December 1998. Thirty-four (8.5%) were confirmed as being deceased, and 39 (9.8%) were unavailable for follow-up. The median age was 60 years, and 57.2% were women. The 4-year incidence of grade II or III posterior capsule opacification, including eyes already treated with laser capsulotomy, was 13.1% (95% confidence interval [CI], 9.7% to 17.3%). Each year of increased age was associated with a decreased risk of posterior capsule opacification (odds ratio, 0.96; 95% CI, 0.92 to 1.00). Based on best-corrected visual acuity of 20/40 or worse without co-existing pathology, the 4-year incidence of posterior capsule opacification was 13.5%. CONCLUSION: Because patients with relatively mature cataracts routinely receive extracapsular cataract extraction with posterior chamber intraocular lens implantation instead of the traditional intracapsular extraction, the subsequent need for laser capsulotomy may be less than that anticipated, based on previous reports, (C) 2000 by Elsevier Science Inc. All rights reserved. C1 NEI, Bethesda, MD 20892 USA. Aravind Eye Hosp, Madurai, Tamil Nadu, India. Postgrad Inst Ophthalmol, Madurai, Tamil Nadu, India. RP Ellwein, LB (reprint author), NEI, Bldg 31,Room 6A04,31 Ctr Dr, Bethesda, MD 20892 USA. FU NEI NIH HHS [N01EY2103] NR 21 TC 19 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD SEP PY 2000 VL 130 IS 3 BP 304 EP 309 DI 10.1016/S0002-9394(00)00481-5 PG 6 WC Ophthalmology SC Ophthalmology GA 360DF UT WOS:000089650600007 PM 11020409 ER PT J AU Richter, J Wagner, U Kononen, J Fijan, A Bruderer, J Schmid, U Ackermann, D Maurer, R Alund, G Knonagel, H Rist, M Wilber, K Anabitarte, R Hering, F Hardmeier, T Schonenberger, A Flury, R Jager, P Fehr, JL Schraml, P Moch, H Mihatsch, MJ Gasser, T Kallioniemi, OP Sauter, G AF Richter, J Wagner, U Kononen, J Fijan, A Bruderer, J Schmid, U Ackermann, D Maurer, R Alund, G Knonagel, H Rist, M Wilber, K Anabitarte, R Hering, F Hardmeier, T Schonenberger, A Flury, R Jager, P Fehr, JL Schraml, P Moch, H Mihatsch, MJ Gasser, T Kallioniemi, OP Sauter, G TI High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; TRANSITIONAL-CELL CARCINOMA; CHROMOSOMAL IMBALANCES; TRANSCRIPTION FACTOR; PHASE-TRANSITION; EXPRESSION; ONCOGENE; PROTEIN; PROGRESSION; NEOPLASMS AB Studies by comparative genomic hybridization revealed that the 19q13 chromosomal region is frequently amplified in bladder cancer. The cyclin E gene (CCNE), coding for a regulatory subunit of cyclin-dependent kinase 2, has been mapped to 19q13. To investigate the role of cyclin E alterations in bladder cancer, a tissue microarray of 2,317 specimens from 1,842 bladder cancer patients was constructed and analyzed for CCNE amplification by fluorescence in situ hybridization and for cyclin-E protein overexpression by immunohistochemistry. Fluorescence in situ hybridization analysis showed amplification in only 30 of the 1,561 evaluable tumors (1.9%), Amplification was significantly associated with stage and grade (P < 0.0005 each). Immunohistochemically detectable cyclin E expression was strong in 233 (12.4%), weak in 354 (18.9%), and negative in 1,286 of the 1,873 interpretable tumors. The majority (62.1%) of CCNE-amplified tumors were strongly immunohistochemistry-positive (P < 0.0001), The frequency of protein expression increased from stage pTa (22.2%) to pT1 (45.5%; P < 0.0001) but then decreased for stage pT2-4 (29.4%; P < 0.0001 for pT1 versus pT2-4). Low cyclin E expression was associated with poor overall survival in all patients (P < 0.0001), but had no prognostic impact independent of stage. It is concluded that cyclin E overexpression is characteristic to a subset of bladder carcinomas, especially at the stage of early invasion, This analysis of the prognostic impact of CCNE gene amplification and protein expression in >1,500 arrayed bladder cancers was accomplished in a period of 2 weeks, illustrating how the tissue microarray technology remarkably facilitates the evaluation of the clinical relevance of molecular alterations in cancer. C1 Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Univ Basel, Urol Clin, CH-4003 Basel, Switzerland. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Cantonal Hosp St Gallen, Inst Pathol, St Gallen, Switzerland. Cantonal Hosp St Gallen, Urol Clin, St Gallen, Switzerland. City Hosp Triemli, Urol Clin, Zurich, Switzerland. City Hosp Triemli, Inst Pathol, Zurich, Switzerland. Limmattal Hosp, Urol Clin, Schlieren, Switzerland. Clara Hosp, Basel, Switzerland. Vysis Inc, Downers Grove, IL USA. Cantonal Hosp Baden, Urol Clin, Baden, Switzerland. Cantonal Hosp Baden, Inst Pathol, Baden, Switzerland. Cantonal Hosp Munsterlingen, Urol Clin, Munsterlingen, Switzerland. Cantonal Hosp Munsterlingen, Inst Pathol, Munsterlingen, Switzerland. Cantonal Hosp Winterthur, Inst Pathol, Winterthur, Switzerland. Cantonal Hosp Winterthur, Urol Clin, Winterthur, Switzerland. Cantonal Hosp Schaffhausen, Urol Clin, Schaffhausen, Switzerland. RP Sauter, G (reprint author), Univ Basel, Inst Pathol, Schoenbeinstr 40, CH-4003 Basel, Switzerland. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 30 TC 204 Z9 229 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2000 VL 157 IS 3 BP 787 EP 794 DI 10.1016/S0002-9440(10)64592-0 PG 8 WC Pathology SC Pathology GA 352GP UT WOS:000089207200012 PM 10980118 ER PT J AU Hesse, M Cheever, AW Jankovic, D Wynn, TA AF Hesse, M Cheever, AW Jankovic, D Wynn, TA TI NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; SCHISTOSOMA-MANSONI EGGS; AIRWAY INFLAMMATION; INTERFERON-GAMMA; TNF-ALPHA; AUTOIMMUNE-DISEASE; MURINE MACROPHAGES; HEPATIC-FIBROSIS; LPR/LPR MICE; IFN-GAMMA AB Mice sensitized with Schistosoma mansoni eggs and IL-12 develop liver granulomas, on subsequent infection, which are smaller and less fibrotic than those in nonsensitized mice. The protective response is accompanied by a shift in the type-2 cytokine profile to one dominated by type-1 cytokines. The deviated response is associated with marked increases in inducible nitric oxide synthase (NOS-2) activity. Here, we demonstrate, by using NOS-2-deficient mice, that the anti-inflammatory and anti-fibrotic effects of the type-1 response are completely NOS-2-dependent. Strikingly, despite developing a polarized type-1 cytokine response that was similar in magnitude, the egg/IL-12-sensitized NOS-deficient mice developed granulomas 8 times larger than WT mice did. There was also no decrease in hepatic fibrosis in the sensitized mutant animals. Interferon-gamma-deficient mice failed to exhibit the exacerbated inflammatory response, despite displaying a marked deficiency in nitric oxide production. However, immune deviation was unsuccessful in the latter animals, which suggested that the increase in inflammation in NOS-deficient mice resulted from a polarized but nitric oxide-deficient type-1 response. These results reveal a beneficial role for NOS-2 in the regulation of inflammation and suggest that the ultimate success of Th2-to-Th1 immune deviation strategies will rely on the efficient activation of NOS-2 expression in downstream effector cells. C1 NIAID, Schistosomiasis Immunol & Pathol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Schistosomiasis Immunol & Pathol Unit, Parasit Dis Lab, NIH, Bldg 7,Room 318, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 40 TC 82 Z9 90 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2000 VL 157 IS 3 BP 945 EP 955 DI 10.1016/S0002-9440(10)64607-X PG 11 WC Pathology SC Pathology GA 352GP UT WOS:000089207200027 PM 10980133 ER PT J AU Seo, MS Okamoto, N Vinores, MA Vinores, SA Hackett, SF Yamada, H Yamada, E Derevjanik, NL LaRochelle, W Zack, DJ Campochiaro, PA AF Seo, MS Okamoto, N Vinores, MA Vinores, SA Hackett, SF Yamada, H Yamada, E Derevjanik, NL LaRochelle, W Zack, DJ Campochiaro, PA TI Photoreceptor-specific expression of platelet-derived growth factor-B results in traction retinal detachment SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PIGMENTED EPITHELIAL-CELLS; PROLIFERATIVE VITREORETINOPATHY; ENDOTHELIAL-CELLS; PDGF-B; EXPERIMENTAL-MODEL; TRANSGENIC MICE; OPTIC-NERVE; MOUSE; RECEPTORS; BETA AB Expression of platelet-derived growth factor (PDGF)A and PDGF-B is increased in patients with proliferative retinopathies in which traction retinal detachments occur. Previous studies have demonstrated that increased expression of PDGF-A in the retina of transgenic mice results in retinal gliosis due to proliferation of astrocytes with different retinal phenotypes based on the time of onset and location of the PDGF-A production. hi this study, we investigated the effects of PDGF-B in the retina using gain-of-function transgenic mice that express PDGF-B in photoreceptors. These mice show proliferation of astrocytes, pericytes, and, to a lesser extent, endothelial cells, resulting in ectopic cells on the surface and extending into the retina. The sheets of cells exert traction on the retina resulting in traction retinal detachments similar to those seen in humans with proliferative retinopathies. These studies suggest that PDGF-B has more dramatic effects in the retina than PDGF-A, because it acts on additional cell types, in particular on pericytes, which have a highly developed contractile apparatus. These studies in the retina suggest a means that could be used in. other tissues throughout the body to achieve graded PDGF effects. They also provide a new model of traction retinal detachment that can be used to investigate new treatments for patients with proliferative retinopathies. C1 Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21287 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Campochiaro, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Maumenee 719,600 N Wolfe St, Baltimore, MD 21287 USA. OI Zack, Don/0000-0002-7966-1973 FU NEI NIH HHS [EY05951, EY10017, EY12609, P30 EY001765, R01 EY005951, R01 EY009769, R01 EY010017, R01 EY012609] NR 42 TC 55 Z9 57 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2000 VL 157 IS 3 BP 995 EP 1005 DI 10.1016/S0002-9440(10)64612-3 PG 11 WC Pathology SC Pathology GA 352GP UT WOS:000089207200032 PM 10980138 ER PT J AU Holland, EC Li, Y Celestino, J Dai, CK Schaefer, L Sawaya, RA Fuller, GN AF Holland, EC Li, Y Celestino, J Dai, CK Schaefer, L Sawaya, RA Fuller, GN TI Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PROLIFERATION; RECEPTOR; MICE AB The cells of origin for oligodendrogliomas and astrocytomas are not known but are presumed to be oligodendrocyte and astrocyte precursors, respectively. In this paper we report the generation of mixed gliomas from in vivo transformation of glial fibrillary acidic protein (GFAP)-positive cells (differentiated astrocytes) with polyoma virus middle T antigen (MTA). MTA is a powerful oncogene that activates a number of signal transduction pathways, including those proposed to be involved in gliomagenesis, and has been shown to induce tumors in many cell types. We have achieved transfer of MTA expression specifically to GFAP(+) cells in vivo using somatic cell, gene transfer, and find resultant formation of anaplastic gliomas with mixed astrocytoma and oligodendroglioma morphological features. We conclude that GFAP-expressing astrocytes, with appropriate signaling abnormalities, can serve as the cell of origin for oligodendrogliomas, astrocytomas, or mixed gliomas. C1 Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Grad Program Genes & Dev, Houston, TX 77030 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Holland, EC (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, 1515 Holcombe Blvd, Houston, TX 77030 USA. OI Li, Yi/0000-0002-9976-518X; Fuller, Gregory/0000-0001-9447-2647 NR 21 TC 58 Z9 58 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2000 VL 157 IS 3 BP 1031 EP 1037 DI 10.1016/S0002-9440(10)64615-9 PG 7 WC Pathology SC Pathology GA 352GP UT WOS:000089207200035 PM 10980141 ER PT J AU Kowaltowski, AJ Smaili, SS Russell, JT Fiskum, G AF Kowaltowski, AJ Smaili, SS Russell, JT Fiskum, G TI Elevation of resting mitochondrial membrane potential of neural cells by cyclosporin A, BAPTA-AM, and Bcl-2 SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE calcium; mitochondrial permeability transition; energy metabolism ID PERMEABILITY TRANSITION PORE; CYTOCHROME-C; CALCIUM SIGNALS; CA2+; RELEASE; APOPTOSIS; DEPOLARIZATIONS; MECHANISM; PROTECTS; INJURY AB This study tested the hypothesis that the activity of the mitochondrial membrane permeability transition pore (PTP) affects the resting mitochondrial membrane potential (Delta Psi) of normal, healthy cells and that the anti-apoptotic gene product Bcl-2 inhibits the basal activity of the PTP. Delta Psi was measured by both fluorometric and nonfluorometric methods with SY5Y human neuroblastoma cells and with GT1-7 hypothalamic cells and PC12 pheochromocytoma cells in the absence and presence of Bcl-2 gene overexpression. The resting Delta Psi of Bcl-2 nonexpressing PC12 and wild-type SY5Y cells was increased significantly by the presence of the PTP inhibitor cyclosporin A (CsA) or by intracellular Ca2+ chelation through exposure to the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). The Delta Psi of Bcl-2-overexpressing PC12 cells was larger than that of Bcl-2-negative cells and not significantly increased by CsA or by Ca2+ chelation. CsA did not present a significant effect on the Delta Psi monitored in unstressed GT1-7 cells but did inhibit the decrease in Delta Psi elicited by the addition of t-butyl hydroperoxide, an oxidative inducer of the mitochondrial permeability transition. These results support the hypothesis that an endogenous PTP activity can contribute to lowering the basal Delta Psi of some cells and that Bcl-2 can regulate the endogenous activity of the mitochondrial PTP. C1 Univ Maryland, Dept Anesthesiol, Baltimore, MD 21201 USA. Univ Estadual Campinas, Fac Ciencias Med, Dept Patol Clin, Campinas, SP, Brazil. NICHHD, Sect Neuronal Secretory Syst, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo, Brazil. RP Fiskum, G (reprint author), Univ Maryland, Dept Anesthesiol, 685 W Baltimore St, Baltimore, MD 21201 USA. RI Kowaltowski, Alicia/H-8698-2012 FU NINDS NIH HHS [NS-34152] NR 54 TC 34 Z9 35 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP PY 2000 VL 279 IS 3 BP C852 EP C859 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 344EQ UT WOS:000088745000030 PM 10942734 ER PT J AU Mott, DM Hoyt, C Caspari, R Stone, K Pratley, R Bogardus, C AF Mott, DM Hoyt, C Caspari, R Stone, K Pratley, R Bogardus, C TI Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE fatty acid oxidation; skeletal muscle; insulin resistance ID HUMAN SKELETAL-MUSCLE; DEPENDENT DIABETES-MELLITUS; NONDIABETIC PIMA-INDIANS; CARBOHYDRATE-METABOLISM; GLUCOSE-TRANSPORT; CELL-CULTURES; NIDDM; GLUCOSE-6-PHOSPHATE; PATHOGENESIS; PHOSPHATASE AB Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 mu M palmitate in cultured myoblasts correlated with the fasting glucose (r = 0.71, P = 0.001), log fasting insulin (r = 0.52, P = 0.03), and insulin-mediated glucose storage rate (r = -0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 mu M palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 mu M palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix, AZ 85016 USA. RP Mott, DM (reprint author), NIDDKD, Clin Diabet & Nutr Sect, 4212 N 16th St,Rm 541, Phoenix, AZ 85016 USA. NR 34 TC 7 Z9 7 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD SEP PY 2000 VL 279 IS 3 BP E561 EP E569 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 345TB UT WOS:000088830300011 PM 10950823 ER PT J AU Szebeni, J Baranyi, L Savay, S Bodo, M Morse, DS Basta, M Stahl, GL Bunger, R Alving, CR AF Szebeni, J Baranyi, L Savay, S Bodo, M Morse, DS Basta, M Stahl, GL Bunger, R Alving, CR TI Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE hypersensitivity reactions; anaphylatoxin; hemoglobin; IgM-enriched intravenous immunoglobulin; hemodynamics ID ANTI-CHOLESTEROL ANTIBODIES; ENCAPSULATED HEMOGLOBIN; IN-VITRO; ALTERNATIVE PATHWAY; ACTIVATION; ANAPHYLATOXINS; AMPHOTERICIN; DOXORUBICIN; INHIBITION; IMMUNITY AB Intravenous injection of liposomes can cause significant pulmonary hypertension in pigs, a vasoconstrictive response that provides a sensitive model for the cardiopulmonary distress in humans caused by some liposomal drugs. The reaction was recently shown to be a manifestation of "complement activation-related pseudoallergy" (CARPA; Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bunger R, and Alving CR. Circulation 99: 2302-2309, 1999). In the present study we demonstrate that the composition, size, and administration method of liposomes have significant influence on pulmonary vasoactivity, which varied between instantaneously lethal (following bolus injection of 5 mg lipid) to nondetectable (despite infusion of a 2,000-fold higher dose). Experimental conditions augmenting the pulmonary hypertensive response included the presence of dimyristoyl phosphatidylglycerol, 71 mol% cholesterol, distearoyl phosphatidylcholine, and hemoglobin in liposomes, increased vesicle size and polydispersity, and bolus injection vs. slow infusion. The vasoactivity of large multilamellar liposomes was reproduced with human C3a, C5a, and xenoreactive immunoglobulins, and it correlated with the complement activating and natural antibody binding potential of vesicles. Unilamellar, monodisperse liposomes with 0.19 +/- 0.10 mm mean diameter had no significant vasoactivity. These data indicate that liposome-induced pulmonary hypertension in pigs is multifactorial, it is due to natural antibody-triggered classic pathway complement activation and it can be prevented by appropriate tailoring of the structure and administration method of vesicles. C1 Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Membrane Biochem, Washington, DC 20307 USA. Natl Stroke Prevent Fdn, Bethesda, MD 20814 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Anesthesia, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. RP Szebeni, J (reprint author), Walter Reed Army Inst Res, Dept Membrane Biochem, 503 Robert Grant Rd, Silver Spring, MD 20910 USA. FU NHLBI NIH HHS [R0 76HB] NR 41 TC 72 Z9 73 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2000 VL 279 IS 3 BP H1319 EP H1328 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 355HC UT WOS:000089379400055 PM 10993799 ER PT J AU Kim, GH Martin, SW Fernandez-Llama, P Masilamani, S Packer, RK Knepper, MA AF Kim, GH Martin, SW Fernandez-Llama, P Masilamani, S Packer, RK Knepper, MA TI Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE sodium-proton exchange; sodium-potassium-2 chloride cotransport; distal convoluted tubule; collecting duct; amiloride-sensitive epithelial sodium channel ID THICK ASCENDING LIMB; CORTICAL COLLECTING TUBULE; BRUSH-BORDER VESICLES; METABOLIC-ACIDOSIS; PROXIMAL TUBULE; CL COTRANSPORTER; ALPHA-SUBUNIT; H+ EXCHANGE; RAT; SODIUM AB Increased systemic acid intake is associated with an increase in apical Na/H exchange in the renal proximal tubule mediated by the type 3 Na/H exchanger (NHE3). Because NHE3 mediates both proton secretion and Na absorption, increased NHE3 activity could inappropriately perturb Na balance unless there are compensatory changes in Na handling. In this study, we use semiquantitative immunoblotting of rat kidneys to investigate whether acid loading is associated with compensatory decreases in the abundance of renal tubule Na transporters other than NHE3. Long-term (i.e., 7-day) acid loading with NH(4)Cl produced large decreases in the abundances of the thiazide-sensitive Na-Cl cotransporter (TSC/NCC) of the distal convoluted tubule and both the beta- and gamma-subunits of the amiloride-sensitive epithelial Na channel (ENaC) of the collecting duct. In addition, the renal cortical abundance of the proximal type 2 Na-dependent phosphate transporter (NaPi-2) was markedly decreased. In contrast, abundances of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb and the alpha-subunit of ENaC were unchanged. A similar profile of changes was seen with short-term (16-h) acid loading. Longterm (7-day) base loading with NaHCO(3) resulted in the opposite pattern of response with marked increases in the abundances of the beta- and gamma-subunits of ENaC and NaPi-2. These adaptations may play critical roles in the maintenance in Na balance when changes in acid-base balance occur. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Biol Sci, Washington, DC 20052 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [ZO1-HL-01282-09] NR 50 TC 53 Z9 53 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 SEP PY 2000 VL 279 IS 3 BP F459 EP F467 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 349FX UT WOS:000089033900007 PM 10966925 ER PT J AU Kwon, TH Laursen, UH Marples, D Maunsbach, AB Knepper, MA Frokiaer, J Nielsen, S AF Kwon, TH Laursen, UH Marples, D Maunsbach, AB Knepper, MA Frokiaer, J Nielsen, S TI Altered expression of renal AQPs and Na+ transporters in rats with lithium-induced NDI SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin; nephrogenic diabetes insipidus; sodium transport; urinary concentration mechanism; water transport ID AQUAPORIN-2 WATER CHANNEL; KIDNEY COLLECTING DUCT; INDUCED DOWN-REGULATION; K-CL COTRANSPORTER; MOLECULAR-CLONING; DIABETES-INSIPIDUS; PLASMA-MEMBRANE; NAPI-II; VASOPRESSIN; INTOXICATION AB Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H exchanger (NHE3), type 2 Na-Pi cotransporter (NaPi-2), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), and thiazide-sensitive Na-Cl cotransporter (TSC) were examined in rats treated with Li orally for 4 wk: protocol 1, high doses of Li (high Na+ intake), and protocol 2, low doses of Li (identical food and normal Na+ intake in Li-treated and control rats). Both protocols resulted in severe polyuria. Semiquantitative immunoblotting revealed that whole kidney abundance of AQP2 was dramatically reduced to 6% (protocol 1) and 27% (protocol 2) of control levels. In contrast, the abundance of AQP1 was not decreased. Immunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked increase in urinary Na+ excretion in both protocols. However, the expression of several major Na+ transporters in the proximal tubule, loop of Henle, and distal convoluted tubule was unchanged in protocol 2, whereas in protocol 1 significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 expression was associated with chronic Li treatment. In conclusion, severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria. In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na+ transporters do not participate in the development of Li-induced polyuria. C1 Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Univ Leeds, Sch Biomed Sci, Leeds LS2 9NQ, W Yorkshire, England. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Aarhus Univ Hosp, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Inst Expt Clin Res, DK-8200 Aarhus N, Denmark. RP Nielsen, S (reprint author), Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 63 TC 100 Z9 103 U1 0 U2 3 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 SEP PY 2000 VL 279 IS 3 BP F552 EP F564 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 349FX UT WOS:000089033900017 PM 10966935 ER PT J AU Saito, K Fujigaki, S Heyes, MP Shibata, K Takemura, M Fujii, H Wada, H Noma, A Seishima, M AF Saito, K Fujigaki, S Heyes, MP Shibata, K Takemura, M Fujii, H Wada, H Noma, A Seishima, M TI Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aminocarboxymuconate-semialdehyde decarboxylase; L-tryptophan 2,3-dioxygenase; kynureninase; pyrazinamide ID RAT-BRAIN; PATHWAY METABOLISM; IMMUNE ACTIVATION; AMINO-ACIDS; TRYPTOPHAN; BLOOD; QUANTIFICATION; HEPATOCYTES; FAILURE; REGIONS AB Marked increases in metabolites of the L-tryptophan-kynurenine pathway, L-kynurenine and quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with renal insufficiency. The mechanisms responsible for their accumulation after renal insufficiency were investigated. In patients with chronic renal insufficiency, elevated levels of serum L-kynurenine and Quin were reduced by hemodialysis. In renal-insufficient rats, Quin and L-kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of renal insufficiency. Urinary excretion of Quin (3.5-fold) and L-kynurenine (2.8-fold) was also increased. Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphoribosyltransferase were unchanged, but the activities of kynureninase, 3-hydroxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum L-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency. The accumulation of CSF L-kynurenine is caused by the entry of increased serum L-kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain. C1 Gifu Univ, Sch Med, Dept Lab Med, Gifu 5008705, Japan. Univ Shiga Prefecture, Hikone 5228533, Japan. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Saito, K (reprint author), Gifu Univ, Sch Med, Dept Lab Med, Gifu 5008705, Japan. EM saito@cc.gifu-u.ac.jp NR 39 TC 76 Z9 77 U1 0 U2 9 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 SEP PY 2000 VL 279 IS 3 BP F565 EP F572 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 349FX UT WOS:000089033900018 PM 10966936 ER PT J AU Kumra, S Giedd, JN Vaituzis, AC Jacobsen, LK McKenna, K Bedwell, J Hamburger, S Nelson, JE Lenane, M Rapoport, JL AF Kumra, S Giedd, JN Vaituzis, AC Jacobsen, LK McKenna, K Bedwell, J Hamburger, S Nelson, JE Lenane, M Rapoport, JL TI Childhood-onset psychotic disorders: Magnetic resonance imaging of volumetric differences in brain structure SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CHRONIC-SCHIZOPHRENIA; ADOLESCENT ONSET; MRI; ABNORMALITIES; MORPHOLOGY; CLOZAPINE; SIZE; AGE AB Objective: Although childhood-onset schizophrenia is rare, children with brief psychotic symptoms and prominent emotional disturbances commonly present diagnostic and treatment problems. Quantitative anatomic brain magnetic resonance images (MRIs) of a subgroup of children with psychotic disorder not otherwise specified were compared with those of children with childhood-onset schizophrenia and healthy comparison subjects. Method: Anatomic MRIs were obtained for 71 patients (44 with childhood-onset schizophrenia and 27 with psychotic disorder not otherwise specified) and 106 healthy volunteers. Most patients had been treated with neuroleptics. Volumetric measurements for the cerebrum, anterior frontal region, lateral ventricles, corpus callosum, caudate, putamen, globus pallidus, and midsagittal thalamic area were obtained. Results: Patients had a smaller total cerebral volume than healthy comparison subjects. Analysis of covariance for total cerebral volume and age found that lateral ventricles were larger in both patient groups than in healthy comparison subjects and that schizophrenia patients had a smaller midsagittal thalamic area than both subjects with psychotic disorder not otherwise specified and healthy comparison subjects. Conclusions: Pediatric patients with psychotic disorder not otherwise specified showed a pattern of brain volumes similar to those found in childhood-onset schizophrenia. Neither group showed a decrease in volumes of temporal robe structures. Prospective longitudinal magnetic resonance imaging and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Yale Univ, Sch Med, New Haven, CT USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N202,10 Ctr Dr MSC1600, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 46 TC 51 Z9 52 U1 4 U2 8 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2000 VL 157 IS 9 BP 1467 EP 1474 DI 10.1176/appi.ajp.157.9.1467 PG 8 WC Psychiatry SC Psychiatry GA 349QH UT WOS:000089056800017 PM 10964864 ER PT J AU Judd, LL Paulus, MJ Schettler, PJ Akiskal, HS Endicott, J Leon, AC Maser, JD Mueller, T Solomon, DA Keller, MB AF Judd, LL Paulus, MJ Schettler, PJ Akiskal, HS Endicott, J Leon, AC Maser, JD Mueller, T Solomon, DA Keller, MB TI Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DISORDER; SYMPTOMS; RELAPSE; REMISSION AB Objective: This study investigated the influence of incomplete recovery from first lifetime major depressive episodes on longterm outcome. Method: After their first lifetime major depressive episode, patients were divided into asymptomatic (N=70) and residual subthreshold depressive symptom (N=26) recovery groups and compared on longitudinal course during up to 12 years of prospective naturalistic follow-up. Results: Patients with residual subthreshold depressive symptoms during recovery had significantly more severe and chronic future courses. Those with residual symptoms relapsed to major and minor depressive episodes faster and had more recurrences, shorter well intervals, and fewer symptom-free weeks during follow-up than asymptomatic patients. Conclusions: Resolution of major depressive episodes with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course. When ongoing subthreshold symptoms continue after major depressive episodes, the illness is still active, and continued treatment is strongly recommended. C1 Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. NIMH, Collaborat Program Psychobiol Depress, Bethesda, MD 20892 USA. VA Med Ctr, Psychiat Serv, San Diego, CA USA. RP Judd, LL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. RI Page, Andrew/G-5438-2012 OI Page, Andrew/0000-0003-3133-2844 FU NIMH NIH HHS [R01 MH025478] NR 9 TC 311 Z9 318 U1 1 U2 7 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2000 VL 157 IS 9 BP 1501 EP 1504 DI 10.1176/appi.ajp.157.9.1501 PG 4 WC Psychiatry SC Psychiatry GA 349QH UT WOS:000089056800022 PM 10964869 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI Safe motherhood means: Social equity for women ... SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Hist Med Div, Non Book Collect, Bethesda, MD 20894 USA. RP Theerman, P (reprint author), Natl Lib Med, Hist Med Div, Non Book Collect, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2000 VL 90 IS 9 BP 1382 EP 1382 DI 10.2105/AJPH.90.9.1382 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 348RJ UT WOS:000089000000004 PM 10983188 ER PT J AU Banzett, RB Dempsey, JA O'Donnell, DE Wamboldt, MZ AF Banzett, RB Dempsey, JA O'Donnell, DE Wamboldt, MZ TI Symptom perception and respiratory sensation in asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article; Proceedings Paper CT Workshop on Symptom Perception and Respiratory Sensation in Asthma CY SEP 22-23, 1998 CL BETHESIA, MARYLAND ID NEAR-FATAL ASTHMA; INSPIRATORY RESISTIVE LOADS; BRONCHIAL-ASTHMA; BRONCHOCONSTRICTION; BREATHLESSNESS; HYPERINFLATION; METHACHOLINE; CHILDHOOD; DYSPNEA C1 Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Wisconsin, Dept Prevent Med, Madison, WI 53706 USA. Queens Univ, Dept Med, Kingston, ON K7L 3N6, Canada. Natl Jewish Med & Res Ctr, Denver, CO USA. RP Banzett, RB (reprint author), NHLBI, Div Lung Dis, 6701 Rockledge Dr,Room 10210, Bethesda, MD 20892 USA. NR 38 TC 114 Z9 115 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 SEP PY 2000 VL 162 IS 3 BP 1178 EP 1182 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 355AM UT WOS:000089363500074 PM 10988151 ER PT J AU Gardner, EL AF Gardner, EL TI What we have learned about addiction from animal models of drug self-administration SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Review ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS DOPAMINE; FREELY MOVING RATS; CONDITIONED PLACE PREFERENCE; CORTICOTROPIN-RELEASING FACTOR; DISCRETE TRIALS PROCEDURE; COCAINE-SEEKING BEHAVIOR; BRAIN-STIMULATION REWARD; STRESS-INDUCED RELAPSE; IN-VIVO MICRODIALYSIS AB Self-administration of addictive drugs in laboratory animals has been widely used for decades as a tool for studying behavioral, neurobiological, and genetic factors in addiction. From such studies has come an enormous amount of information on brain mechanisms involved in addiction, on vulnerability factors in the addictive process, and on possible pharmacotherapeutic treatments for addiction. Modifications of the laboratory animal self-administration paradigm including progressive ratio break-point models and the "reinstatement" model of relapse to drug-seeking behavior-are currently increasing our knowledge of incentive motivational factors in addiction and of the mechanisms underlying relapse to drug self-administration behavior. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gardner, EL (reprint author), NIDA, Intramural Res Program, NIH, Bldg C,Room 272,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 306 TC 66 Z9 66 U1 3 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD FAL PY 2000 VL 9 IS 4 BP 285 EP 313 DI 10.1080/105504900750047355 PG 29 WC Substance Abuse SC Substance Abuse GA 383VV UT WOS:000165905700004 PM 11155784 ER PT J AU Frank, SM Satitpunwaycha, P Bruce, SR Holmes, CS Goldstein, DS AF Frank, SM Satitpunwaycha, P Bruce, SR Holmes, CS Goldstein, DS TI Sympathoneural and adrenomedullary responses to cold stress in awake humans SO ANESTHESIOLOGY LA English DT Meeting Abstract C1 NIH, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2000 VL 93 IS 3A SU S MA A355 BP U149 EP U149 PG 1 WC Anesthesiology SC Anesthesiology GA 351BU UT WOS:000089136800340 ER PT J AU Satitpunwaycha, P Frank, SM Bruce, SR Holmes, CS Goldstein, DS AF Satitpunwaycha, P Frank, SM Bruce, SR Holmes, CS Goldstein, DS TI Cardiac parasympathetic function during normothermic and hypothermic intravascular volume loading SO ANESTHESIOLOGY LA English DT Meeting Abstract C1 NIH, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2000 VL 93 IS 3A SU S MA A169 BP U135 EP U135 PG 1 WC Anesthesiology SC Anesthesiology GA 351BU UT WOS:000089136800164 ER PT J AU Gastwirth, JL Freidlin, B AF Gastwirth, JL Freidlin, B TI On power and efficiency robust linkage tests for affected sibs SO ANNALS OF HUMAN GENETICS LA English DT Article ID DISEASE SUSCEPTIBILITY LOCI; PAIR LINKAGE; COMPLEX TRAITS; CONTINGENCY-TABLES; SURVIVAL; STATISTICS; STRATEGIES; MODELS AB For diseases that do not follow a clear Mendelian pattern of inheritance nonparametric tests applied to affected sibs have been shown to be robust to the inherent uncertainty about the precise underlying genetic model. It is known that the weights optimizing the power of tests using IBD alleles shared by affected sib pairs or triples depend on the underlying model. We show how efficiency robustness techniques, used in other areas of statistics, provide a systematic approach for constructing a robust linear combination of the statistics that are optimal for the individual members of a family of plausible genetic models. The method depends on the correlation matrix of the optimal tests as these correlations reflect ho how different the models are. When the minimal correlation is less than 0.5, an alternate robust procedure is proposed. The methods apply to combining data from sibships of different sizes. C1 NCI, Div Canc Genet & Epidemiol, EPS 8105, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagnost, Bethesda, MD 20892 USA. RP Gastwirth, JL (reprint author), George Washington Univ, Dept Stat, Washington, DC 20052 USA. NR 43 TC 24 Z9 24 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2000 VL 64 BP 443 EP 453 DI 10.1046/j.1469-1809.2000.6450443.x PN 5 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 390QD UT WOS:000166307100008 PM 11281282 ER PT J AU Lippa, CF Swearer, JM Kane, KJ Nochlin, D Bird, TD Ghetti, B Nee, LE St George-Hyslop, P Pollen, DA Drachman, DA AF Lippa, CF Swearer, JM Kane, KJ Nochlin, D Bird, TD Ghetti, B Nee, LE St George-Hyslop, P Pollen, DA Drachman, DA TI Familial Alzheimer's disease: Site of mutation influences clinical phenotype SO ANNALS OF NEUROLOGY LA English DT Article ID GENE; CHROMOSOME-1; ONSET; LOCUS AB Alzheimer's disease (AD) is caused by multiple genetic and/or environmental etiologies. Because differences in the genetically determined pathogenesis may cause differences in the phenotype, we examined age at onset and age at death in 90 subjects with dominantly inherited AD due to different mutations (amyloid precursor protein, presenilin-1, and presenilin-2 genes). We found that among patients with dominantly inherited AD, genetic factors influence both age at onset and age at death. C1 Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. Med Coll Penn & Hahnemann Univ, Dept Neurol, Philadelphia, PA 19102 USA. Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. Vet Affairs Med Ctr, Dept Neurol, Seattle, WA 98108 USA. Indiana Univ, Dept Pathol, Med Ctr, Indianapolis, IN 46204 USA. NINDS, Family Studies Unit, Bethesda, MD 20892 USA. Univ Toronto, Dept Med Neurol, Toronto, ON, Canada. RP Swearer, JM (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, 55 Lake Ave N, Worcester, MA 01655 USA. FU NIA NIH HHS [AG05134, AG05136, AG13623] NR 11 TC 42 Z9 43 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2000 VL 48 IS 3 BP 376 EP 379 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 349BU UT WOS:000089024600013 PM 10976645 ER PT J AU Kenney, K Brechtel, C Takahashi, H Kurohara, K Anderson, P Gibbs, CJ AF Kenney, K Brechtel, C Takahashi, H Kurohara, K Anderson, P Gibbs, CJ TI An enzyme-linked immunosorbent assay to quantify 14-3-3 proteins in the cerebrospinal fluid of suspected Creutzfeldt-Jakob disease patients SO ANNALS OF NEUROLOGY LA English DT Article ID VARIANT CJD; DIAGNOSIS AB The detection of 14-3-3 protein by Western immunoblot is a sensitive and specific cerebrospinal fluid marker of Creutzfeldt-Jakob disease (CJD). We developed a quantitative enzyme-linked immunosorbent assay (ELISA) that reliably detects 14-3-3 in cerebrospinal fluid. In a prospective study of 147 cerebrospinal fluid samples, the mean 14-3-3 concentration among pathologically confirmed CJD patients (28.0 +/- 20.6 ng/ml, n = 41) is significantly higher than the mean in the cerebrospinal fluid of those with other neurological disorders (3.1 +/- 2.9 ng/ml, n = 84). At a cutoff value of 8.3 ng/ml, the ELISA has a sensitivity of 92.7% and a specificity of 97.6%. The 14-3-3 ELISA supports a diagnosis of CJD in patients who fulfill clinical criteria for possible CJD. C1 NINDS, LCNSS, BNP, DIR,NIH, Bethesda, MD 20892 USA. Natl Inst Infect Dis, Dept Pathol, Tokyo, Japan. RP Gibbs, CJ (reprint author), NINDS, LCNSS, BNP, DIR,NIH, Bldg 36,Rm 4A-05,MSC 4122,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 14 TC 53 Z9 55 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2000 VL 48 IS 3 BP 395 EP 398 DI 10.1002/1531-8249(200009)48:3<395::AID-ANA18>3.0.CO;2-A PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 349BU UT WOS:000089024600018 PM 10976650 ER PT J AU Auerbach, JD AF Auerbach, JD TI Feminism and federally funded social science: Notes from inside SO ANNALS OF THE AMERICAN ACADEMY OF POLITICAL AND SOCIAL SCIENCE LA English DT Article AB In order for feminist social science research to influence the transformation of society toward more equitable gender arrangements, it must both be undertaken and be applied in the policy arena. For these to happen, feminist social scientists must be active players in the research policy and funding enterprise, particularly at the federal level. The discussion of how feminist social science has had an impact, and can have an even greater one, both on and through federally funded research is framed in two larger contexts: the broader federal science and technology (S&T) enterprise and the impact of feminism on society generally. A selective review of developments in both the representation of women in S&T and attention to issues of gender in the content of scientific research demonstrates that, although much progress has been made, much remains to be done. Some strategies for furthering the feminist project through the federal research enterprise are offered. C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Auerbach, JD (reprint author), NIH, Off AIDS Res, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0002-7162 J9 ANN AM ACAD POLIT SS JI Ann. Am. Acad. Polit. Soc. Sci. PD SEP PY 2000 VL 571 BP 30 EP 41 DI 10.1177/0002716200571001003 PG 12 WC Political Science; Social Sciences, Interdisciplinary SC Government & Law; Social Sciences - Other Topics GA 341ZH UT WOS:000088620500003 ER PT J AU Wu, CO Yu, KF Chiang, CT AF Wu, CO Yu, KF Chiang, CT TI A two-step smoothing method for varying-coefficient models with repeated measurements SO ANNALS OF THE INSTITUTE OF STATISTICAL MATHEMATICS LA English DT Article DE bandwidth; kernel; longitudinal data; mean squared error; ultrasound measurement; varying coefficient models ID LONGITUDINAL DATA; CURVES AB Datasets involving repeated measurements over time are common in medical trials and epidemiological cohort studies. The outcomes and covariates are usually observed from randomly selected subjects, each at a set of possibly unequally spaced time design points. One useful approach for evaluating the effects of covariates is to consider linear models at a specific time, but the coefficients are smooth curves over time. We show that kernel estimators of the coefficients that are based on ordinary local least squares may be subject to large biases when the covariates are time-dependent. As a modification, we propose a two-step kernel method that first centers the covariates and then estimates the curves based on some local least squares criteria and the centered covariates. The practical superiority of the two-step kernel method over the ordinary least squares kernel method is shown through a fetal growth study and simulations. Theoretical properties of both the two-step and ordinary least squares kernel estimators are developed through their large sample mean squared risks. C1 Johns Hopkins Univ, Dept Math Sci, Baltimore, MD 21218 USA. NICHHD, Dept Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. Tunghai Univ, Dept Stat, Taichung 40704, Taiwan. OI Chiang, Chin-Tsang/0000-0001-7957-7061 NR 15 TC 17 Z9 18 U1 1 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0020-3157 J9 ANN I STAT MATH JI Ann. Inst. Stat. Math. PD SEP PY 2000 VL 52 IS 3 BP 519 EP 543 DI 10.1023/A:1004125621021 PG 25 WC Statistics & Probability SC Mathematics GA 358XB UT WOS:000089581500011 ER PT J AU Izbicka, E Sommer, E Skopinska-Rozewska, E Davidson, K Wu, RS Orlowski, T Pastewka, K AF Izbicka, E Sommer, E Skopinska-Rozewska, E Davidson, K Wu, RS Orlowski, T Pastewka, K TI Tetracationic porphyrins inhibit angiogenesis induced by human tumor cells in vivo SO ANTICANCER RESEARCH LA English DT Article DE porphyrin; angiogenesis; tumor; mouse; in vivo ID IN-VIVO; CATIONIC PORPHYRINS; INTERACTIVE AGENTS; QUADRUPLEX DNA; APOPTOSIS; GROWTH; ENDOSTATIN; VITRO AB Background: Cationic porphyrin TMPyP4, but not its isomer TMPyP2, inhibits telomerase in tumor cells in vitro and induces chromosome destabilization in vivo. Materials and Methods: To examine the effects of these porphyrins on tumor induced angiogenesis, 25-200 mug TMPyP4 or TMPyP2 were injected daily for 3 days in mice with intradermally implanted primary human tumor cells. Alternatively tumor cells were exposed for 90 minutes to 2.5-20 muM porphyrins prior to implantation in mice. Results: Either subcutaneous injections (greater than or equal to 50 mug/mouse) ol preincubation with greater than or equal to5 muM porphyrins significantly inhibited angiogenesis. Conclusion: Antiangiogenic activity is apparently unrelated to the ability of the porphyrins to inhibit telomerase. C1 Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78245 USA. Inst TB & Lung Dis, Dept Immunol, Warsaw, Poland. Inst TB & Lung Dis, Dept Surg, Warsaw, Poland. NIH, Bethesda, MD 20892 USA. Postgrad Med Ctr, Dept Urol, Warsaw, Poland. RP Izbicka, E (reprint author), Inst Drug Dev, Canc Therapy & Res Ctr, 14960 Omicron Dr, San Antonio, TX 78245 USA. NR 18 TC 5 Z9 5 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 2000 VL 20 IS 5A BP 3205 EP 3210 PG 6 WC Oncology SC Oncology GA 367BQ UT WOS:000090042100059 PM 11062744 ER PT J AU Aquino, A Prete, SP Guadagni, F Greiner, JW Giuliani, A Orlando, L Masci, G De Santis, S Bonmassar, E Graziani, G AF Aquino, A Prete, SP Guadagni, F Greiner, JW Giuliani, A Orlando, L Masci, G De Santis, S Bonmassar, E Graziani, G TI Effect of 5-fluorouracil on carcinoembryonic antigen expression and shedding at clonal level in colon cancer cells SO ANTICANCER RESEARCH LA English DT Article DE carcinoembryonic antigen; 5-fluorouracil; colon cancer ID COLORECTAL-CANCER; MONOCLONAL-ANTIBODY; GAMMA-INTERFERON; CARCINOMA CELLS; TUMOR-CELLS; VACCINE; CEA; GENE; EPITOPES; TISSUES AB Background: The carcinoembryonic antigen (CEA) is a tumor marker largely utilized for the detection of minimal disease or as a target of immunotherapeutic approaches. In preclinical models CEA has been found to be upregulated after exposure of cancer cells to 5-fluorouracil (5-FU). In the present study, the clonal distribution of CEA and its regulation by 5-FU at clonal level was investigated using human HT-29 colon cancer cells. Materials and Methods: The extent of CEA expression was measured in terms of: (a) antigen levels on plasma membrane by flow cytometry; (b) cytoplasm and membrane protein, by Western blot analysis; (c) transcript, by Northern blot analysis; (d) CEA shedding by radioimmunossay. Results: CEA protein and gene transcript were variably expressed among different clones. In all cases 5-FU was able to increase the percentage of CEA-positive cells, the amount of antigen either in the membrane ol cytosolic fractions, and the corresponding transcript. Moreover, a mal ked increase of CEA shedding was found in drug-treated cells with respect to that of controls. The increase of CEA induced by the antimetabolite was nor the result of a selection mechanism based on preferential killing of CEA negative cells. The antimetabolite was capable of enhancing antigen expression also in other CEA-positive tumor cell lines with different basal levels of the marker Conclusions: The present findings could be of potential value to increase the sensitivity, of diagnostic processes based on detection of CEA positive tumor cells. Moreover, the antimetabolite might be included in immunotherapeutic protocols to facilitate recognition of CEA-positive cancer cells by immune responses. C1 Regina Elena Canc Inst, Clin Pathol Lab, Rome, Italy. Univ Roma Tor Vergata, Dept Neurosci, Sect Pharmacol & Med Oncol, I-00133 Rome, Italy. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. CNR, Inst Expt Med, Rome, Italy. IRCCS, IDI, Rome, Italy. RP Guadagni, F (reprint author), Regina Elena Canc Inst, Clin Pathol Lab, Rome, Italy. RI Graziani, Grazia/G-5747-2012; Guadagni, Fiorella/J-4432-2013; OI Guadagni, Fiorella/0000-0003-3652-0457; GRAZIANI, GRAZIA/0000-0002-0221-768X NR 30 TC 14 Z9 15 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 2000 VL 20 IS 5B BP 3475 EP 3484 PG 10 WC Oncology SC Oncology GA 379GR UT WOS:000165634100017 PM 11131650 ER PT J AU Darley-Usmar, V Starke-Reed, PE AF Darley-Usmar, Victor Starke-Reed, Pamela E. TI Antioxidants: Strategies for Interventions in Aging and Age-Related Diseases A Workshop Sponsored by the National Institute on Aging and by the Office of Dietary Supplements SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Editorial Material AB The role of free radicals in aging has been a long-standing theory that has now been extended to include both reactive oxygen and nitrogen species. The original concepts that overwhelming oxidative stress depleted antioxidants and thus damaged intracellular targets is being supplanted by the hypothesis that the reactive species play an essential role in signal transduction. The concept that the cell establishes a redox tone that is altered during the aging process places the oxidative and nitrosative modifications that occur during aging in a new and exciting context. Some highlights of this recent workshop convened by The National Institute on Aging and the Office of Dietary Supplements at the National Institutes of Health are discussed. Antiox. & Redox Signal. 2, 375-378. C1 [Darley-Usmar, Victor] Univ Alabama, Dept Pathol, Birmingham, AL 35295 USA. [Starke-Reed, Pamela E.] NIDDK, Div Nutr Res Coordinat, NIH, Bethesda, MD 20892 USA. RP Darley-Usmar, V (reprint author), Univ Alabama, Dept Pathol, Volker Hall G019,1670 Univ Blvd, Birmingham, AL 35295 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FAL PY 2000 VL 2 IS 3 BP 375 EP 377 DI 10.1089/15230860050192143 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V10ZB UT WOS:000207500800001 PM 11229350 ER PT J AU Luo, YQ Roth, GS AF Luo, Yongquan Roth, George S. TI The Roles of Dopamine Oxidative Stress and Dopamine Receptor Signaling in Aging and Age-Related Neurodegeneration SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review AB Aging is accompanied by a decline of functions controlled by the central dopaminergic system, such as reduced locomotor activity, motivation, impairment of memory formation, and learning deficits. The molecular mechanisms underlying age-related impairment of dopaminergic functions are unknown. Current literature and our own recent work, which are reviewed and summarized in the present paper, suggest that dopamine oxidative stress and its subsequent signaling may contribute to the aging of dopaminergic system. Antiox. Redox Signal. 2, 449-460. C1 [Luo, Yongquan; Roth, George S.] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Luo, YQ (reprint author), NIA, Gerontol Res Ctr, NIH, NIA 4C01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM luoyq@helix.nih.gov NR 88 TC 45 Z9 46 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FAL PY 2000 VL 2 IS 3 BP 449 EP 460 DI 10.1089/15230860050192224 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V10ZB UT WOS:000207500800009 PM 11229358 ER PT J AU Wong, CM Chun, ACS Kok, KH Zhou, Y Fung, PCW Kung, HF Jeang, KT Jin, DY AF Wong, Chi-Ming Chun, Abel C. S. Kok, K. H. Zhou, Yuan Fung, Peter C. W. Kung, Hsiang-Fu Jeang, Kuan-Teh Jin, Dong-Yan TI Characterization of Human and Mouse Peroxiredoxin IV: Evidence for Inhibition by Prx-IV of Epidermal Growth Factor- and p53-Induced Reactive Oxygen Species SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article AB The aim of this study was to identify and characterize human and mouse Prx-IV. We identified mouse peroxiredoxin IV (Prx-IV) by virtue of sequence homology to its human ortholog previously called AOE372. Mouse Prx-IV conserves an amino-terminal presequence coding for signal peptide. The amino acid sequences of mature mouse and human Prx-IV share 97.5% identity. Phylogenetic analysis demonstrates that Prx-IV is more closely related to Prx-I/-II/-III than to Prx-V/-VI. Previously, we mapped the mouse Prx-IV gene to chromosome X by analyzing two sets of multiloci genetic crosses. Here we performed further comparative analysis of mouse and human Prx-IV genomic loci. Consistent with the mouse results, human Prx-IV gene localized to chromosome Xp22.135-136, in close proximity to SAT and DXS7178. A bacterial artificial chromosome (BAC) clone containing the complete human Prx-IV locus was identified. The size of 7 exons and the sequences of the splice junctions were confirmed by PCR analysis. We conclude that mouse Prx-IV is abundantly expressed in many tissues. However, we could not detect Prx-IV in the conditioned media of NIH-3T3 and Jurkat cells. Mouse Prx-IV was specifically found in the nucleus-excluded region of cultured mouse cells. Intracellularly, overexpression of mouse Prx-IV prevented the production of reactive oxygen species induced by epidermal growth factor or p53. Taken together, mouse Prx-IV is likely a cytoplasmic or organellar peroxiredoxin involved in intracellular redox signaling. Antiox. Redox Signal. 2, 507-518. C1 [Wong, Chi-Ming; Chun, Abel C. S.; Zhou, Yuan; Kung, Hsiang-Fu; Jin, Dong-Yan] Univ Hong Kong, Inst Mol Biol, Pokfulam, Hong Kong, Peoples R China. [Kok, K. H.; Fung, Peter C. W.] Univ Hong Kong, Dept Med, Div Med Phys, Pokfulam, Hong Kong, Peoples R China. [Jeang, Kuan-Teh; Jin, Dong-Yan] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jin, DY (reprint author), Univ Hong Kong, Inst Mol Biol, 8-F Kadoorie Biological Sci Bldg,Pokfulam Rd, Pokfulam, Hong Kong, Peoples R China. EM dyjin@hkucc.hku.hk RI Jeang, Kuan-Teh/A-2424-2008; Wong, Chi-Ming/A-7627-2013 OI Wong, Chi-Ming/0000-0002-0025-7135 FU Committee on Research and Conference; University of Hong Kong; HKU Foundation FX We gratefully acknowledge the Baylor College of Medicine Human Genome Sequencing Center for generating and disseminating DNA sequence and chromosomal mapping data. We thank Tony K.T. Chin, H.H. Kwok, Oscar G.W. Wong, and H.W. Wu for critically reading the manuscript, and Lan Lin for assistance in manuscript preparation. This work was supported in part by a research initiation grant (to D.-Y.J.) from the Committee on Research and Conference Grants, the University of Hong Kong and an HKU Foundation grant (to P.C.W.F.). NR 41 TC 46 Z9 50 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FAL PY 2000 VL 2 IS 3 BP 507 EP 518 DI 10.1089/15230860050192288 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V10ZB UT WOS:000207500800015 PM 11229364 ER PT J AU Pommier, Y Marchand, C Neamati, N AF Pommier, Y Marchand, C Neamati, N TI Retroviral integrase inhibitors year 2000: update and perspectives SO ANTIVIRAL RESEARCH LA English DT Review DE retroviruses; integrase inhibitors; resistance; structure of integrases ID VIRUS TYPE-1 INTEGRASE; DNA MINOR-GROOVE; L-CHICORIC ACID; HIV-1 INTEGRASE; IN-VITRO; REVERSE-TRANSCRIPTASE; POTENT INHIBITORS; CATALYTIC DOMAIN; REPLICATION; PROTEASE AB HIV-1 integrase is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. A number of inhibitors have been reported in the past 8 years. This review focuses on the recent developments in the past 2 years. There are now several inhibitors with known sites of actions and antiviral activity. The challenge is to convert these leads into drugs that will selectively target integrase in vivo, and can be added to our antiviral armamentarium. (C) 2000 Published by Elsevier Science B.V. C1 NCI, Div Basic Sci, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NIH, Rm 5D02,Bldg 37, Bethesda, MD 20892 USA. RI Marchand, Christophe/D-8559-2016 NR 57 TC 98 Z9 103 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD SEP PY 2000 VL 47 IS 3 BP 139 EP 148 DI 10.1016/S0166-3542(00)00112-1 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 360FG UT WOS:000089655300001 PM 10974366 ER PT J AU Aspiras, MB Kazmerzak, KM Kolenbrander, PE McNab, R Hardegen, N Jenkinson, HF AF Aspiras, MB Kazmerzak, KM Kolenbrander, PE McNab, R Hardegen, N Jenkinson, HF TI Expression of green fluorescent protein in Streptococcus gordonii DL1 and its use as a species-specific marker in coadhesion with Streptococcus oralis 34 in saliva-conditioned biofilms in vitro SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID LACTIC-ACID BACTERIA; ESCHERICHIA-COLI; ACTINOMYCES-VISCOSUS; GENE-EXPRESSION; INTRAGENERIC COAGGREGATION; INSERTIONAL INACTIVATION; APATITIC SURFACES; GFP; COMMUNITY; PROMOTER AB Streptococcus gordonii is one of the predominant streptococci in the biofilm ecology of the oral cavity, It interacts with other bacteria through receptor-adhesin complexes formed between cognate molecules on the surfaces of the partner cells. To study the spatial organization of S. gordonii DL1 in oral biofilms, we used green fluorescent protein (GFP) as a species-specific marker to identify S. gordonii In a two-species in vitro oral biofilm Boo-cell system, To drive expression of gfp, we isolated and characterized an endogenous S. gornonii promoter, PhppA, which is situated upstream of the chromosomal hppA gene encoding an oligopeptide-binding lipoprotein. A chromosomal chloramphenicol acetyltransferase (cat) gene fusion with PhppA was constructed and used to demonstrate that PhppA was highly active throughout the growth of bacteria in batch culture. A promoterless 0,8-kb gfp ('gfp) cassette was PCR amplified from pBJ169 and subcloned to replace the cat cassette downstream of the S. gordonii-derived PhppA in pMH109-HPP, generating pMA1. Subsequently, the PhppA-'gfp cassette was PCR amplified from pMA1 and subcloned into pDL277 and pVA838 to generate the Escherichia coli-S, gordonii shuttle vectors pMA2 and pMA3, respectively. Each vector was transformed into S, gordonii DL1 aerobically to ensure GFP expression, Flow cytometric analyses of aerobically grown transformant cultures were performed over a 24-h period, and results showed that GFP could be successfully expressed in S. gordonii DL1 from PhppA and that S. gordonii DL1 transformed with the PhppA-'gfp fusion plasmid stably maintained the fluorescent phenotype, Fluorescent S. gordonii DL1 transformants were used to elucidate the spatial arrangement of S, gordonii DL1 alone in biofilms or with the coadhesion partner Streptococcus oralis 34 in two-species biofilms in a saliva-conditioned in vitro flowcell system. These results show for the first time that GFP expression in oral streptococci can be used as a species-specific marker in model oral biofilms. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Otago, Sch Dent, Dunedin, New Zealand. Univ Bristol, Dept Oral & Dental Sci, Bristol, Avon, England. RP Kolenbrander, PE (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 310,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. OI Jenkinson, Howard/0000-0002-9195-7945 NR 58 TC 22 Z9 23 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD SEP PY 2000 VL 66 IS 9 BP 4074 EP 4083 DI 10.1128/AEM.66.9.4074-4083.2000 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 350NZ UT WOS:000089109200059 PM 10966431 ER PT J AU Wang, YX Walsh, PJ AF Wang, YX Walsh, PJ TI High ammonia tolerance in fishes of the family Batrachoididae (Toadfish and Midshipmen) SO AQUATIC TOXICOLOGY LA English DT Article DE Opsanus beta; Opsanus tau; Porichthys notatus; ammonia toxicity; urea; glutamine synthetase; glutamate dehydrogenase; 96-h LC50 ID PULSATILE UREA EXCRETION; OPSANUS-BETA; RAINBOW-TROUT; MARINE FISH; NITROGEN-METABOLISM; TOXICITY; TELEOST; EVOLUTION; SURVIVAL; TRANSPORT AB Three fish species of the family Batrachoididae, the gulf toadfish (Opsanus bera), the oyster toadfish (Opsanus tali), and the plainfin midshipman (Porichthys notatus) demonstrated exceptionally high tolerances to elevated water ammonia with 96-h LC50 values of 9.75, 19.72 and 6 mM total ammonia, respectively. Using pH values we calculated the corresponding unionized ammonia (NH3) values to be 519, 691 and 101 mu M, respectively. These values are well above typical values for most teleost fishes, but close to those of ureotelic fish examined to date. Following sublethal high ammonia exposure (HAE) blood and tissue (brain, liver and muscle) sampling confirmed that internal ammonia levels rose substantially in all three species, suggesting that they were not simply avoiding toxicity by impermeance to ammonia. The three species of batrachoidids can be characterized in the following manner with respect to the inabilities to synthesize and excrete urea, based on these studies and prior research: O. beta (fully ureotelic) > O. tau (moderately ureotelic) > P. notatus (ammoniotelic). While some of the high ammonia tolerance for O. beta and O. tau can be explained by their ability to detoxify it to urea, other mechanisms must be at play for P. notatus. Further experiments determined that ail three species possess rather high activities of glutamine synthetase (GSase) in brain especially (60-180 U g(-1)), that glutamine accumulates in many tissues, and that LC50 values are correlated positively with brain GSase activity. Taken together, our results suggest that alternative/additional mechanisms for ammonia detoxification via urea synthesis must be considered to explain the exceptionally high ammonia tolerance of this group. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS,Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Wang, YX (reprint author), Univ Waterloo, Dept Kinesiol, 200 Univ Ave W, Waterloo, ON N2L 3G1, Canada. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 46 TC 61 Z9 68 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-445X J9 AQUAT TOXICOL JI Aquat. Toxicol. PD SEP PY 2000 VL 50 IS 3 BP 205 EP 219 DI 10.1016/S0166-445X(99)00101-0 PG 15 WC Marine & Freshwater Biology; Toxicology SC Marine & Freshwater Biology; Toxicology GA 346RV UT WOS:000088885600005 ER PT J AU Freedman, DM Cantor, KP Ward, MH Helzlsouer, KJ AF Freedman, DM Cantor, KP Ward, MH Helzlsouer, KJ TI A case-control study of nitrate in drinking water and non-Hodgkin's lymphoma in Minnesota SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article ID CANCER; RISK AB Nitrate in drinking water has been implicated as a possible risk factor for non-Hodgkin's lymphoma. The authors examined the association between non-Hodgkin's lymphoma and waterborne nitrate through a population-based case-control study of white men in Minnesota. The authors, by linking residential histories with community water records, estimated average long-term exposure to nitrate in drinking water from 1947 to 1975 for 73 cases diagnosed between 1980 and 1982 and for 147 controls who used community water supplies. No association was found between nitrate levels in community water supplies and non-Hodgkin's lymphoma within the range of study exposures (median of highest exposure category = 2.4 mg nitrate/l [range = 0.1-7.2 mg/l]). The findings provide some safety assurance for those who use water systems that have nitrate levels that are less than 2.4 mg/l. C1 NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Freedman, DM (reprint author), NCI, Radiat Epidemiol Branch, EPS 7087,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 24 TC 11 Z9 11 U1 0 U2 0 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0003-9896 J9 ARCH ENVIRON HEALTH JI Arch. Environ. Health PD SEP-OCT PY 2000 VL 55 IS 5 BP 326 EP 329 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 368VY UT WOS:000090139200007 PM 11063407 ER PT J AU Weickert, TW Goldberg, TE Gold, JM Bigelow, LB Egan, MF Weinberger, DR AF Weickert, TW Goldberg, TE Gold, JM Bigelow, LB Egan, MF Weinberger, DR TI Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Society-of-Neuroscience CY OCT 25-30, 1997 CL NEW ORLEANS, LOUISIANA SP Soc Neurosci ID MONOZYGOTIC TWINS DISCORDANT; ADULT READING TEST; RISK; DECLINE; IQ; INTELLIGENCE; PERFORMANCE; CHILDHOOD; DISORDERS; DEMENTIA AB Background: Although intellectual and neurocognitive deficits accompany schizophrenia, there are inconsistencies in the literature concerning issues of intellectual decline, premorbid deficits, a modal deficit pattern, and preserved abilities. Methods: A battery of neuropsychological tests was administered once to 117 consecutively admitted patients with chronic schizophrenia and a group of 27 healthy control subjects to examine patterns of premorbid and current intellect (measured by means of reading scores and IQ, respectively) and the attendant cognitive profiles in schizophrenia using classification methods based on clinically derived (IQ levels) and atheoretical (cluster) techniques. Results: Sixty patients (51%) with schizophrenia who displayed a general intellectual decline of 10 points or greater from estimated premorbid levels also exhibited deficits of executive function, memory, and attention. Twenty-eight patients (23%) with consistently low estimated premorbid intellect and current intellectual levels who displayed no evidence of IQ decline exhibited language and visual processing deficits in addition to deficits present in the intellectually declining group. The remaining 29 patients (25%) who displayed average estimated premorbid intellectual levels did not show IQ decline and exhibited a cognitive profile similar to normal, with the exception of executive function and attention impairment. Atheoretical analyses support the findings from clinically derived subgroups. Conclusions: These results suggest that IQ decline, although modal in schizophrenia, is not universally characteristic and that executive function and attention deficits may be core features of schizophrenia, independent of IQ variations. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, NIH, MSC 1379,10 Ctr Dr, Bethesda, MD 20892 USA. NR 58 TC 306 Z9 308 U1 1 U2 10 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 SEP PY 2000 VL 57 IS 9 BP 907 EP 913 DI 10.1001/archpsyc.57.9.907 PG 7 WC Psychiatry SC Psychiatry GA 351VU UT WOS:000089179500012 PM 10986554 ER PT J AU Conwit, RA Stashuk, D Suzuki, H Lynch, N Schrager, M Metter, EJ AF Conwit, RA Stashuk, D Suzuki, H Lynch, N Schrager, M Metter, EJ TI Fatigue effects on motor unit activity during submaximal contractions SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE fatigue; electromyography; action potentials; isometric contraction; rehabilitation ID ISOMETRIC CONTRACTIONS; MUSCLE; BICEPS; TASK AB Objective: To examine motor unit changes during the development of fatigue in healthy subjects. Design: Automated decomposition-enhanced spike-triggered averaging was used to characterize motor unit size and firing rate in the dominant vastus medialis during maintained contractions at 10% and 30% of maxima voluntary contraction (MVC). Setting: Academic outpatient neuromuscular clinic. Participants: Healthy laboratory personnel. Main Outcome Measures: Surface electromyogram, surface-detected motor unit action potential amplitude (S-MUAP), mean firing rate, force (MVC), motor unit index. Results: Surface electromyogram values and S-MUAP amplitudes increased during both 10% and 30% MVC fatiguing contractions, while mean firing rates decreased. A motor unit index, indicating the degree of motor unit pool activation, increased similarly to S-MUAP size, implying that new and larger units were recruited to maintain the contraction. Repeated contractions led to earlier motor unit changes and fatigue. Conclusion: During submaximal fatiguing contractions, additional motor units are activated to maintain strength. These changes begin early, within the first minute, particularly after a previous fatiguing effort. C1 Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland, College Pk, MD 20742 USA. Univ Waterloo, Dept Syst Design Engn, Waterloo, ON N2L 3G1, Canada. Dokkyo Univ, Sch Med, Dept Rehabil Med, Dokkyo, Japan. RP Conwit, RA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. NR 27 TC 10 Z9 11 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2000 VL 81 IS 9 BP 1211 EP 1216 DI 10.1053/apmr.2000.6975 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 350PM UT WOS:000089110400015 PM 10987164 ER PT J AU Song, XY Zeng, L Jin, WW Pilo, CM Frank, ME Wahl, SM AF Song, XY Zeng, L Jin, WW Pilo, CM Frank, ME Wahl, SM TI Suppression of streptococcal cell wall-induced arthritis by human chorionic gonadotropin SO ARTHRITIS AND RHEUMATISM LA English DT Article ID GROWTH-FACTOR-BETA; NITRIC-OXIDE PRODUCTION; RHEUMATOID-ARTHRITIS; TRANSFORMING GROWTH-FACTOR-BETA-1; BONE-RESORPTION; IMMUNE-RESPONSE; SYNOVIAL-CELLS; PREGNANCY; DISEASE; EXPRESSION AB Objective. To determine whether human chorionic gonadotropin (HCG) contributes to pregnancy-associated immunosuppression, as observed clinically by an amelioration of symptoms in human autoimmune diseases, including rheumatoid arthritis, during pregnancy. Methods. Administration of HCG was initiated 2 days prior to an arthritogenic dose of streptococcal cell wall (SCW) in nonpregnant female rats, and the development and severity of SCW-induced arthritis was monitored. Inflammatory mediators, including plasma nitrite/nitrate and cytokine levels, were measured. Inducible nitric oxide synthase (iNOS) protein and cytokine messenger RNA expression in joint tissue were compared between treated and untreated arthritic animals. Results. Systemic administration of HCG resulted in a dose-dependent reduction in the clinical arthritis index. Consistent with the amelioration of clinical symptoms, HCG significantly reduced the inflammatory cell infiltration, pannus formation, and bone and cartilage degradation. Mechanistically, HCG therapy was associated with suppression of the overzealous production of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-1 beta, which contribute to synovial pathology in animals with SCW-induced arthritis. Circulating nitric oxide and the amount of iNOS protein were also reduced. Furthermore, circulating transforming growth factor beta levels were elevated by the HCG, all of which suggest monocytes/macrophages as a potential target. Conclusion. These findings indicate that HCG exerts a protective effect in this experimental arthritis model, through modulation of inflammatory mediators. C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Wahl, SM (reprint author), Bldg 30,Room 332,30 convent Dr,MSC 4352, Bethesda, MD 20892 USA. NR 50 TC 20 Z9 20 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 BP 2064 EP 2072 DI 10.1002/1529-0131(200009)43:9<2064::AID-ANR18>3.0.CO;2-Z PG 9 WC Rheumatology SC Rheumatology GA 357JC UT WOS:000089493900019 PM 11014358 ER PT J AU Cannon, GW Remmers, EF Wilder, RL Griffiths, MM AF Cannon, GW Remmers, EF Wilder, RL Griffiths, MM TI Genes controlling adjuvant-induced arthritis have different effects on arthritis severity in male and female (DAxF344)F2 hybrid rats. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 Univ Utah, Vet Adm Med Ctr, Salt Lake City, UT 84148 USA. NIH, NIAMS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 7 BP S52 EP S52 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800008 ER PT J AU Carpten, J Suson, S Robbins, C Goldbach-Mansky, R Trent, J AF Carpten, J Suson, S Robbins, C Goldbach-Mansky, R Trent, J TI CACP gene mutations mediating a familial synovial hyperplasia syndrome do not account for synovial hyperplasia in RA. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 NIH, NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 8 BP S52 EP S52 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800009 ER PT J AU Furuya, T Salstrom, JL McCall-Vining, S Cannon, GW Joe, B Remmers, EF Griffiths, MM Wilder, RL AF Furuya, T Salstrom, JL McCall-Vining, S Cannon, GW Joe, B Remmers, EF Griffiths, MM Wilder, RL TI Genetic dissection of collagen-induced arthritis in BB(DR) x BN in rats: Important gender-influences on autosomal regulatory QTLS. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 NIH, NIAMS, Bethesda, MD 20892 USA. Univ Utah, Vet Adm Med Ctr, Salt Lake City, UT 84132 USA. Univ Utah, Salt Lake City, UT 84132 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 15 BP S53 EP S53 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800016 ER PT J AU Griffiths, MM Wang, JP Joe, B Dracheva, S Kawahito, Y Shepard, JS Cannon, GW Remmers, EF Wilder, RL AF Griffiths, MM Wang, JP Joe, B Dracheva, S Kawahito, Y Shepard, JS Cannon, GW Remmers, EF Wilder, RL TI Identification of a new non-MHC QTL (CIAA3) on chromosome 9 that regulates the production of IGG anti-collagen antibody in DA x BN intercross rats. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 Univ Utah, Salt Lake City, UT 84112 USA. NIH, NIAMS, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 18 BP S53 EP S53 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800019 ER PT J AU Jawaheer, D Seldin, MF Amos, CI Chen, W Monteiro, J Criswell, L Albani, S Nelson, L Clegg, DO Pope, R Schroeder, HW Bridges, SL Pisetsky, DS Kastner, D Wilder, R Pincus, T Callahan, L Gregersen, PK AF Jawaheer, D Seldin, MF Amos, CI Chen, W Monteiro, J Criswell, L Albani, S Nelson, L Clegg, DO Pope, R Schroeder, HW Bridges, SL Pisetsky, DS Kastner, D Wilder, R Pincus, T Callahan, L Gregersen, PK CA N Amer Rheumatoid Arthritis Cons TI A genome wide screen for allele sharing in the first 300 sibling pairs of the NARAC collection. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 N Shore Univ Hosp, Manhasset, NY 11030 USA. Univ Calif Davis, Davis, CA 95616 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Calif San Diego, San Diego, CA 92103 USA. FHCC, Seattle, WA USA. Univ Utah, Salt Lake City, UT USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Alabama, Birmingham, AL USA. Duke Univ, Durham, NC USA. NIAMS, Bethesda, MD USA. Vanderbilt Univ, Nashville, TN USA. Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 20 BP S54 EP S54 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800021 ER PT J AU Joe, B Remmers, EF Dobbins, DE Salstrom, JL Furuya, T Dracheva, S Gulko, PS Cannon, GW Griffiths, MM Wilder, RL AF Joe, B Remmers, EF Dobbins, DE Salstrom, JL Furuya, T Dracheva, S Gulko, PS Cannon, GW Griffiths, MM Wilder, RL TI Genetic dissection of collagen-induced arthritis in chromosome 10 QTL congenic rats: Evidence for more than one regulatory locus and sex influences. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. Columbia Univ Coll Phys & Surg, Div Autoimmune & Mol Dis, New York, NY 10032 USA. Univ Utah, Vet Aff Med Ctr, Dept Med Rheumatol, Salt Lake City, UT 84132 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 22 BP S54 EP S54 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800023 ER PT J AU Joe, B Remmers, EF Cannon, GW Griffiths, MM Wilder, RL AF Joe, B Remmers, EF Cannon, GW Griffiths, MM Wilder, RL TI Collagen-induced arthritis severity loci on rat chromosome 10 (RNO10) also regulate disease in three other experimentally induced models of arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Vet Aff Med Ctr, Dept Med Rheumatol, Salt Lake City, UT 84132 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2000 VL 43 IS 9 SU S MA 21 BP S54 EP S54 PG 1 WC Rheumatology SC Rheumatology GA 357JU UT WOS:000089495800022 ER PT J AU Ichikawa, T Hosoki, S Suzuki, H Akakura, K Igarashi, T Furuya, Y Oshimura, M Rinker-Schaeffer, CW Nihei, N Barrett, JC Isaacs, JT Ito, H AF Ichikawa, T Hosoki, S Suzuki, H Akakura, K Igarashi, T Furuya, Y Oshimura, M Rinker-Schaeffer, CW Nihei, N Barrett, JC Isaacs, JT Ito, H TI Mapping of metastasis suppressor genes for prostate cancer by microcell-mediated chromosome transfer SO ASIAN JOURNAL OF ANDROLOGY LA English DT Review DE prostate cancer; metastasis; metastasis suppressor gene; chromosome ID ALLELIC LOSS; SHORT ARM; LONG ARM; LOCI; PROGRESSION; 8P; HETEROZYGOSITY; LOCALIZATION; REGION; HUMAN-CHROMOSOME-8 AB To identify the metastasis suppressor genes for prostate cancer. Methods: A copy of human chromosomes was introduced into the highly metastatic Dunning R-3327 rat prostate cancer cells by the use of microcell-mediated chromosome transfer. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained the metastasis suppressor gene(s) for prostate cancer. To determine portions of human chromosomes introduced, G-banding chromosomal analysis, fluorescence in sial hybridization analysis, and polymerase chain reaction analysis were performed. Results: Each of microcell hybrid clones containing human chromosomes 7, 8, 10, 11, 12, or 17 showed decreased ability to metastasize to the lung without any loss of tumorigenicity. This demonstrates that these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in the human chromosome ?, 10, Il, 12, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis suppressor genes on human chromosomes were located on 7q21-22, 7q31.2-32, 8p21-12, 10q11-22, 11p13-11.2, 12p11-q13, 12q24-ter, and 17pter-q23. KA11 and MKK4/SEK1 were identified as metastasis suppressor genes from 11p11.2 and 17p12, respectively. Conclusion: This assay system is useful to identify metastasis suppressor gene (s) for prostate cancer. C1 Chiba Univ, Sch Med, Dept Urol, Chuo Ku, Chiba 2608670, Japan. Teikyo Univ, Sch Med, Ichihara Hosp, Dept Urol, Ichihara 2990111, Japan. Tottori Univ, Sch Med, Dept Mol & Cell Genet, Yonago, Tottori 6838503, Japan. Univ Chicago, Dept Surg, Urol Sect, Chicago, IL 60637 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. RP Ichikawa, T (reprint author), Chiba Univ, Sch Med, Dept Urol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. NR 30 TC 12 Z9 13 U1 0 U2 0 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD SEP PY 2000 VL 2 IS 3 BP 167 EP 171 PG 5 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 375PF UT WOS:000165409900002 PM 11225974 ER PT J AU Jang, KL McCrae, RR Livesley, WJ Riemann, R Angleitner, A AF Jang, KL McCrae, RR Livesley, WJ Riemann, R Angleitner, A TI Sources of structure: Genetic, environmental, and artifactual influences on the covariance of personality traits SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 2A1, Canada. NIH, NIA, Gerontol Res Ctr, Baltimore, MD USA. Univ Bielefeld, Dept Psychol, Bielefeld, Germany. NR 0 TC 0 Z9 0 U1 2 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 2000 VL 30 IS 5 BP 408 EP 409 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 405KR UT WOS:000167159000048 ER PT J AU Sirota, LA Hamer, DH AF Sirota, LA Hamer, DH TI Power and robustness of candidate gene study designs SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 NCI, NIH, Biochem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 2000 VL 30 IS 5 BP 418 EP 419 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 405KR UT WOS:000167159000088 ER PT J AU Katz, JL Alling, JL AF Katz, JL Alling, JL TI Discriminative stimulus effects of putative D3 dopamine receptor agonists in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE dopamine; D3 receptors; D2 receptors; behaviour; drug discrimination; rat ID WILD-TYPE MICE; D-AMPHETAMINE; SKF 38393; COCAINE; 7-OH-DPAT; MEDIATION; D-2 AB Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001-0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001-0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms. (C) 2000 Lippincott Williams & Wilkins. C1 NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. OI Katz, Jonathan/0000-0002-1068-1159 NR 31 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2000 VL 11 IS 6 BP 483 EP 493 PG 11 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 360XP UT WOS:000089692900005 PM 11103914 ER PT J AU Yilmaz, O Kanit, L Okur, BE London, ED Pogun, S AF Yilmaz, O Kanit, L Okur, BE London, ED Pogun, S TI Nitric oxide synthetase inhibition hinders facilitation of active avoidance learning by nicotine in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE nicotine; nitric oxide; nitric oxide synthetase; learning; active avoidance; L-N-omega-nitroarginine; rat ID LONG-TERM POTENTIATION; 14-UNIT T-MAZE; SEX-DIFFERENCES; L-ARGININE; BRAIN; MEMORY AB Nicotine produces dose-dependent enhancement of performance in an active avoidance test, and also increases the levels of NO2- and NO3-, which are stable metabolites of nitric oxide (NO), in various brain regions of rats. On the basis of these two observations, we hypothesized that the beneficial effect of nicotine on learning could result from increased NO in relevant brain regions. We therefore tested active avoidance performance in rats given L-N-omega-nitroarginine (L-NA) to inhibit NO synthetase (NOS) prior to nicotine administration, Male Sprague-Dawley rats received L-NA (30 or 50 mg/kg), nicotine (0.4 mg/kg), saline or combinations of these treatments before learning trials. Rats were also tested on the inclined plane, to assess the possible effects due to impairment of motor function by drug treatments on active avoidance learning. L-NA treatment impaired the acquisition of active avoidance learning, and this defect was partially overcome by the co-administration of nicotine. Nicotine facilitated learning and significantly increased the number of correct responses. The threshold for the effect of NOS inhibition on performance exceeded 30 mg/kg L-NA, whereas 50 mg/kg impaired learning and also eliminated the nicotine-induced enhancement of learning. On the fifth day of learning trials, no facilitation of learning by nicotine was observed in rats receiving either dose of L-NA. Our results suggest that NO is involved in the facilitation of active avoidance learning by nicotine. (C) 2000 Lippincott Williams & Wilkins. C1 Ege Univ, Sch Med, Ctr Brain Res, Dept Physiol, TR-35100 Izmir, Turkey. Ege Univ, TUBITAK Basic Neurosci Res Unit, TR-35100 Izmir, Turkey. NIDA, Brain Imaging Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pogun, S (reprint author), Ege Univ, Sch Med, Ctr Brain Res, Dept Physiol, TR-35100 Izmir, Turkey. RI Pogun, Sakire/A-5816-2010 NR 24 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2000 VL 11 IS 6 BP 505 EP 510 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 360XP UT WOS:000089692900007 PM 11103916 ER PT J AU Gao, ZG Jiang, QL Jacobson, KA IJzerman, AP AF Gao, ZG Jiang, QL Jacobson, KA IJzerman, AP TI Site-directed mutagenesis studies of human A(2A) adenosine receptors - Involvement of Glu(13) and His(278) in ligand binding and sodium modulation SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE A(2A) adenosine receptor; mutation; glutamic acid; histidine; sodium ions ID PROTEIN-COUPLED RECEPTORS; RAT-BRAIN; ANTAGONIST; RECOGNITION; PURINOCEPTORS; RADIOLIGAND; INHIBITION; AMILORIDE; RESIDUES; DOMAINS AB To provide insights into interactions between ligands and A(2A) adenosine receptors, site-directed mutagenesis was used to test the roles of a glutamic acid residue in the first transmembrane domain (Glu13) and a histidine residue in the seventh transmembrane domain (His278). The two residues, which have been suggested to be closely linked in molecular modeling studies, were mutated to glutamine (E13Q) and tyrosine (H278Y), respectively. Saturation experiments revealed that [H-3]ZM241385 (4-(2-[7-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5] triazin-5-yl-amino]ethyl)phenol) bound wild-type and mutant receptors in membranes from COS-7 cells expressing human A(2A) adenosine receptors with high affinity and low non-specific binding. It was found from the competition experiments that the affinity of the A(2A) adenosine receptor agonists for the mutant receptors was 3- to 200-fold lower than for the wild-type receptor. Among antagonist competitors of binding at E13Q and H278Y mutant receptors, there was variation in the affinity depending on their different structures, although changes were relatively minor (<3-fold) except in the case of theophylline, whose affinity was decreased approximately 20 times on the H278Y mutant. The possible involvement of the two residues in sodium ion regulation was also tested. The agonist competition curves for [H-3]ZM241385 were shifted to the right in both wild-type and mutant receptors in the presence of 1 M sodium ions, but the extent of shift (2- to 27-fold) in wild-type receptor was generally larger than for the mutant receptors. Sodium ions also decreased [H-3]ZM241385 dissociation from both wild-type and mutant receptors, being more influential on the former than the latter. The results suggest that the two closely linked residues Glu13 and His278 in A(2A) adenosine receptor are most important for agonist recognition and are partly responsible for the allosteric regulation by sodium ions. BIOCHEM PHARMACOL 60;5:661-668, 2000. (C) 2000 Elsevier Science Inc. C1 Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands. NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20982 USA. RP IJzerman, AP (reprint author), Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, POB 9502, NL-2300 RA Leiden, Netherlands. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 33 TC 57 Z9 57 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 1 PY 2000 VL 60 IS 5 BP 661 EP 668 DI 10.1016/S0006-2952(00)00357-9 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 359DV UT WOS:000089597000007 PM 10927024 ER PT J AU Goel, A Colcher, D Koo, JS Booth, BJM Pavlinkova, G Batra, SK AF Goel, A Colcher, D Koo, JS Booth, BJM Pavlinkova, G Batra, SK TI Relative position of the hexahistidine tag effects binding properties of a tumor-associated single-chain Fv construct SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE single chain Fv; yeast; histidine tag; immobilized metal affinity chromatography; BIAcore ID CHELATE AFFINITY-CHROMATOGRAPHY; MONOCLONAL-ANTIBODY; ESCHERICHIA-COLI; BIOCHEMICAL-CHARACTERIZATION; EXPRESSION SYSTEMS; CRYSTAL-STRUCTURE; SWISS-MODEL; PROTEINS; PURIFICATION; FRAGMENT AB Hexahistidine tag (His-tag) is the most widely used tag for affinity purification of recombinant proteins for their structural and functional analysis. In the present study, single chain Fv (scFv) constructs were engineered form the monoclonal antibody (MAb) CC49 which is among the most extensively studied MAb for cancer therapy. For achieving efficient purification of scFvs by immobilized metal-ion affinity chromatography (IMAC), a His-tag was placed either at the C-terminal (scFv-His(6)) or N-terminal (His(6)-scFv) of the coding sequence. Solid-phase radioimmunoassay for scFv-His(6) showed only 20-25% binding whereas both His(6)-scFv and scFv (no His-tag) showed 60-65% binding. Surface plasmon resonance studies by BIAcore revealed the binding affinity constant (K-A) for His(6)-scFv and scFv as 1.19X10(6) M-1 and 3.27X10(6) M-1, respectively. No KA value could be calculated for scFv-His(6) due to poor binding kinetics (k(on) and k(off)). Comparative homology modeling for scFv and scFv-His(6) showed that the C-terminal position of the His-tag partially covered the antigen-binding site of the protein. The study demonstrates that the C-terminal position of His-tag on the CC49 scFv adversely affects the binding properties of the construct. The results emphasize the importance of functional characterization of recombinant proteins expressed with purification tags. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. Coulter Pharmaceut Inc, San Francisco, CA 94080 USA. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. RP Batra, SK (reprint author), Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, 984525 Nebraska Med Ctr, Omaha, NE 68198 USA. RI Pavlinkova, Gabriela /G-9304-2014 OI Pavlinkova, Gabriela /0000-0002-5689-6577 NR 60 TC 52 Z9 59 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD SEP 1 PY 2000 VL 1523 IS 1 BP 13 EP 20 DI 10.1016/S0304-4165(00)00086-6 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 364XZ UT WOS:000089920500003 PM 11099853 ER PT J AU Shears, SB AF Shears, SB TI Transcriptional regulation: a new dominion for inositol phosphate signaling? SO BIOESSAYS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; ARGININE METABOLISM; EXPRESSION; SEQUENCES; FAMILY; GENES; CAR1 AB The diverse phosphorylation patterns of the six-carbon inositol ring generates a mesmerizing wealth of inositol phosphates but we have little insight into the precise cellular roles of most members of this family. Therefore, new information on these roles is very welcome. The discovery by two independent groups((1,2)) that the Arg82 transcriptional regulator from Saccharomyces cerevisiae has inositol phosphate kinase activity is intriguing in this respect. One group proposes that these events directly affect the function of a specific, multimeric transcriptional complex.((2)) It will be argued here, however, that available data do not entirely support such a direct role for Arg82 in transcription. The potential relevance of these findings to higher organisms will also be discussed. BioEssays 22:786-789, 2000. published 2000 John Wiley & Sons, Inc. C1 NIEHS, Inositide Signaling Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 21 Z9 22 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD SEP PY 2000 VL 22 IS 9 BP 786 EP 789 DI 10.1002/1521-1878(200009)22:9<786::AID-BIES3>3.0.CO;2-0 PG 4 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 347XV UT WOS:000088955200003 PM 10944580 ER PT J AU Kikyo, N Wolffe, AP AF Kikyo, N Wolffe, AP TI The secret for cloning: reprogramming the nucleus SO BIOFUTUR LA French DT Article ID TRANSPLANTATION; CHROMATIN; FETAL; CELLS C1 NIH, Inst Natl Sante Enfant & Dev, Lab Embyrol Mol, Bethesda, MD 20205 USA. Sangamo Biosci Inc, Richmond, CA USA. RP Kikyo, N (reprint author), NIH, Inst Natl Sante Enfant & Dev, Lab Embyrol Mol, Bethesda, MD 20205 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0294-3506 J9 BIOFUTUR JI Biofutur PD SEP PY 2000 VL 2000 IS 203 BP 36 EP 39 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 366BV UT WOS:000089985700007 ER PT J AU Afshari, CA Hamadeh, H AF Afshari, CA Hamadeh, H TI Promises of toxicogenomics SO BIOFUTUR LA French DT Article ID TOXICOLOGY C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Afshari, CA (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0294-3506 J9 BIOFUTUR JI Biofutur PD SEP PY 2000 VL 2000 IS 203 BP 40 EP 43 DI 10.1016/S0294-3506(00)80120-9 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 366BV UT WOS:000089985700008 ER PT J AU Steinbach, OC Wolffe, AP Rupp, RAW AF Steinbach, OC Wolffe, AP Rupp, RAW TI Histone deacetylase activity is required for the induction of the MyoD muscle cell lineage in Xenopus SO BIOLOGICAL CHEMISTRY LA English DT Article DE activin; FGF; mesoderm; myogenesis; trichostatin A; Wnt ID CHROMATIN STRUCTURE; MESODERM INDUCTION; EARLY RESPONSE; EMBRYOS; TRANSCRIPTION; ACETYLATION; EXPRESSION; ACTIVATION; GENES; H1 AB Acetylation of nucleosome core histones, which is positively correlated with transcriptional activity, is developmentally regulated in Xenopus. Here we have used the specific histone deacetylase (HDAC)-inhibitor trichostatin A (TSA) to induce precocious histone hyperacetylation in the early frog embryo in order to investigate the potential role of the endogenous changes in chromatin acetylation for the temporally programmed induction of skeletal myogenesis. We show that TSA-treatment (i) selectively blocked the transcriptional induction of the myoD gene, and (ii) severely reduced subsequent muscle differentiation. Both phenotypes required TSA application before gastrulation. This indicates that HDAC activity is required early for the formation of the frog embryonic musculature, apparently for the induction of the MyoD-dependent muscle cell lineage. C1 Max Planck Gesell, Friedrich Miescher Lab, D-72076 Tubingen, Germany. NIH, Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Rupp, RAW (reprint author), Max Planck Gesell, Friedrich Miescher Lab, D-72076 Tubingen, Germany. NR 33 TC 14 Z9 16 U1 0 U2 1 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD SEP-OCT PY 2000 VL 381 IS 9-10 BP 1013 EP 1016 DI 10.1515/BC.2000.124 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 365GX UT WOS:000089944100026 PM 11076034 ER PT J AU Crook, JM Tomaskovic-Crook, E Copolov, DL Dean, B AF Crook, JM Tomaskovic-Crook, E Copolov, DL Dean, B TI Decreased muscarinic receptor binding in subjects with schizophrenia: A study of the human hippocampal formation SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; muscarinic receptors; human hippocampus; [H-3]pirenzepine ID RAT HIPPOCAMPUS; CHOLINERGIC HYPERACTIVITY; POSTMORTEM BRAIN; IN-VIVO; ACETYLCHOLINE; DOPAMINE; MODEL; PHARMACOLOGY; INNERVATION; ANTAGONISM AB Background: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients, The present study tested the hypothesis that [H-3]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia, Methods: We have used quantitative autoradiography to measure [H-3]pirenzepine binding to M-1 and M-4 receptors in the hippocampal formation from 15 schizophrenic and IS nonschizophrenic subjects. Results: The mean density of [H-3]pirenzepine binding was reduced in all regions studied including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [H-3]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects, Conclusions: These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia. (C) 2000 Society of Biological Psychiatry. C1 Mental Hlth Res Inst, Div Mol Schizophrenia, Rebecca L Cooper Res Labs, Parkville, Vic, Australia. Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. Univ Melbourne, Royal Melbourne Hosp, Dept Psychiat, Parkville, Vic 3052, Australia. RP NIMH, Clin Brain Disorders Branch, Bldg 10,Rm 4N312,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Tomaskovic-Crook, Eva/C-9339-2016; OI Tomaskovic-Crook, Eva/0000-0002-7818-9013; Dean, Brian/0000-0001-7773-4473 NR 42 TC 141 Z9 142 U1 1 U2 5 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 SEP 1 PY 2000 VL 48 IS 5 BP 381 EP 388 DI 10.1016/S0006-3223(00)00918-5 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 352RY UT WOS:000089232700005 PM 10978721 ER PT J AU Fillmore, CM Fears, TR Hoover, RN Falk, RT Vaught, JB Chandler, DW Stanczyk, FZ Galmarini, M Ziegler, RG AF Fillmore, CM Fears, TR Hoover, RN Falk, RT Vaught, JB Chandler, DW Stanczyk, FZ Galmarini, M Ziegler, RG TI Biomarkers (sex-hormone binding globulin (SHBG), bioavailable oestradiol, and bioavailable testosterone) and processing of blood samples in epidemiological studies SO BIOMARKERS LA English DT Article DE EDTA plasma; sex-hormone binding globulin; bioavailable oestradiol; bioavailable testosterone; blood processing ID REPRODUCIBILITY C1 NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, NIH, Bethesda, MD 20892 USA. BioReliance Corp, Rockville, MD 20850 USA. Endocrine Sci, Calabasas Hills, CA 91301 USA. Univ So Calif, Womens & Childrens Hosp, Reprod Endocrine Res Lab, Los Angeles, CA 90033 USA. Quest Diagnost, San Juan Capistrano, CA 92690 USA. RP Fillmore, CM (reprint author), NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, NIH, Execut Plaza N,6120 Execut Blvd,Mailstop 7240, Bethesda, MD 20892 USA. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 7 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD SEP-OCT PY 2000 VL 5 IS 5 BP 395 EP 398 PG 4 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 358UJ UT WOS:000089575300006 PM 23886025 ER PT J AU Albert, PS Follmann, DA AF Albert, PS Follmann, DA TI Modeling repeated count data subject to informative dropout SO BIOMETRICS LA English DT Article DE approximate conditional model; generalized estimating equations; generalized linear mixed models; nonignorable missingness; shared random effects ID LONGITUDINAL DATA; LINEAR-MODEL; REGRESSION AB In certain diseases, outcome is the number of morbid events over the course of follow-up. In epilepsy, e.g., daily seizure counts are often used to reflect disease severity. Follow-up of patients in clinical trials of such diseases is often subject to censoring due to patients dying or dropping out. If the sicker patients tend to be censored in such trials, estimates of the treatment effect that do not incorporate the censoring process may be misleading. We extend the shared random effects approach of Wu and Carroll (1988, Biometrics 44, 175-188) to the setting of repeated counts of events. Three strategies are developed. The first is a likelihood-based approach for jointly modeling the count and censoring processes. A shared random effect is incorporated to introduce dependence between the two processes. The second is a likelihood-based approach that conditions on the dropout times in adjusting for informative dropout. The third is a generalized estimating equations (GEE) approach, which also conditions on the dropout times but makes fewer assumptions about the distribution of the count process. Estimation procedures for each of the approaches are discussed, and the approaches are applied to data from an epilepsy clinical trial. A simulation study is also conducted to compare the various approaches. Through analyses and simulations, we demonstrate the flexibility of the likelihood-based conditional model for analyzing data from the epilepsy trial. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biometr Res Branch, EPN Room 739, Bethesda, MD 20892 USA. NR 20 TC 34 Z9 34 U1 1 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2000 VL 56 IS 3 BP 667 EP 677 DI 10.1111/j.0006-341X.2000.00667.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 349WX UT WOS:000089069500003 PM 10985201 ER PT J AU Van Goor, F LeBeau, AP Krsmanovic, LZ Sherman, A Catt, KJ Stojilkovic, SS AF Van Goor, F LeBeau, AP Krsmanovic, LZ Sherman, A Catt, KJ Stojilkovic, SS TI Amplitude-dependent spike-broadening and enhanced Ca2+ signaling in GnRH-secreting neurons SO BIOPHYSICAL JOURNAL LA English DT Article ID CA1 PYRAMIDAL NEURONS; SPONTANEOUS ACTION-POTENTIALS; CEREBELLAR PURKINJE NEURONS; CALCIUM CHANNELS; SODIUM-CHANNEL; NA+ CHANNELS; HIPPOCAMPAL-NEURONS; POTASSIUM CURRENT; SINOATRIAL NODE; WAVE-FORM AB In GnRH-secreting (GT1) neurons, activation of Ca2+-mobilizing receptors induces a sustained membrane depolarization that shifts the profile of the action potential (AP) waveform from sharp, high-amplitude to broad, low-amplitude spikes. Here we characterize this shift in the firing pattern and its impact on Ca2+ influx experimentally by using prerecorded sharp and broad APs as the voltage-clamp command pulse. As a quantitative test of the experimental data, a mathematical model based on the membrane and ionic current properties of GT1 neurons was also used. Both experimental and modeling results indicated that inactivation of the tetrodotoxin-sensitive Na+ channels by sustained depolarization accounted for a reduction in the amplitude of the spike upstroke. The ensuing decrease in tetraethylammonium-sensitive K+ current activation slowed membrane repolarization, leading to AP broadening. This change in firing pattern increased the total L-type Ca2+ current and facilitated AP-driven Ca2+ entry. The leftward shift in the current-voltage relation of the L-type Ca2+ channels expressed in GT1 cells allowed the depolarization-induced AP broadening to facilitate Ca2+ entry despite a decrease in spike amplitude. Thus the gating properties of the L-type Ca2+ channels expressed in GT1 neurons are suitable for promoting AP-driven Ca2+ influx in receptor- and non-receptor-depolarized cells. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20892 USA. RP Van Goor, F (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. NR 45 TC 27 Z9 27 U1 0 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2000 VL 79 IS 3 BP 1310 EP 1323 PG 14 WC Biophysics SC Biophysics GA 349TD UT WOS:000089060900014 PM 10968994 ER PT J AU Leikina, E Markovic, I Chernomordik, LV Kozlov, MM AF Leikina, E Markovic, I Chernomordik, LV Kozlov, MM TI Delay of influenza hemagglutinin refolding into a fusion-competent conformation by receptor binding: A hypothesis SO BIOPHYSICAL JOURNAL LA English DT Article ID MEDIATED MEMBRANE-FUSION; PLANAR BILAYER-MEMBRANES; VIRUS HEMAGGLUTININ; LOW-PH; CELL-SURFACE; SIALIC-ACID; DISULFIDE BONDS; MECHANISM; HEMIFUSION; KINETICS AB Two subunits of influenza hemagglutinin (HA), HA1 and HA2, represent one of the best-characterized membrane fusion machines. While a low pH conformation of HA2 mediates the actual fusion, HA1 establishes a specific connection between the viral and cell membranes via binding to the sialic acid-containing receptors, Here we propose that HA1 may also be involved in modulating the kinetics of HA refolding, We hypothesized that binding of the HA1 subunit to its receptor restricts the major refolding of the low pH-activated HA to a fusion-competent conformation and, in the absence of fusion, to an HA-inactivated state. Dissociation of the HA1-receptor connection was considered to be a slow kinetic step. To verify this hypothesis, we first analyzed a simple kinetic scheme accounting for the stages of dissociation of the HA1/receptor bonds, inactivation and fusion, and formulated experimentally testable predictions. Second, we verified these predictions by measuring the extent of fusion between HA-expressing cells and red blood cells. Three experimental approaches based on 1) the temporal inhibition of fusion by lysophosphatidylcholine, 2) rapid dissociation of the HA1-receptor connections by neuraminidase treatment, and 3) substitution of membrane-anchored receptors by a water-soluble sialyllactose all provided support for the proposed role of the release of HA1-receptor connections. Possible biological implications of this stage in HA refolding and membrane fusion are being discussed. C1 NICHHD, NIH, Lab Cellular & Mol Biophys, Sect Membrane Biol, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Chernomordik, LV (reprint author), NICHHD, NIH, Lab Cellular & Mol Biophys, Sect Membrane Biol, Bldg 10,Room 10D-04,10 Ctr Dr, Bethesda, MD 20892 USA. NR 52 TC 24 Z9 24 U1 0 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2000 VL 79 IS 3 BP 1415 EP 1427 PG 13 WC Biophysics SC Biophysics GA 349TD UT WOS:000089060900023 PM 10969003 ER PT J AU Hu, YC Kaufman, J Cho, MW Golding, H Shiloach, J AF Hu, YC Kaufman, J Cho, MW Golding, H Shiloach, J TI Production of HIV-1 gp120 in packed-bed bioreactor using the vaccinia virus/T7 expression system SO BIOTECHNOLOGY PROGRESS LA English DT Article ID POLYMERASE SYSTEM; RNA-POLYMERASE; CELLS; TYPE-1 AB The HeLa cell-vaccinia virus system is an attractive method for producing recombinant mammalian proteins with proper post-translation modifications. This approach is especially important for the production of HIV-1 envelope glycoprotein, gp120, since more than half of its total mass is due to carbohydrates. A recombinant vaccinia virus/T7 RNA polymerase expression system was developed to express and produce large amounts of gp120 tagged with six histidine residues. In this system, the expressed T7 RNA polymerase from one virus drives the transcription of the gp120 encoded in the second virus. During the process development phase, the following parameters were studied: infection time, infection duration, multiplicity of infection, ratio of the two viruses, medium composition, and medium replacement strategy during the infection phase. The chosen production method was based on using the packed-bed bioreactor. The HeLa cells were immobilized on fibrous disks (Fibra-Cel) packed in an internal basket positioned in a vertically mixed bioreactor (Celligen Plus), and 25 g of carriers were packed in a 1.6-L (working volume) reactor. The process included a growth stage followed by a production stage. In the growth stage, the bed was perfused with a serum-containing medium, allowing the cells to grow to saturation, and in the production stage, done using serum-free medium, the cells were infected with the two recombinant viruses. The expressed protein was secreted, collected from the culture fluid, and purified. The specific production was found to be between 2 and 3 mu g of protein/10(6) cells, and the volumetric production was around 10 mg/50 g carriers. C1 NIDDK, Biotechnol Unit, LCDB, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, LCDB, NIH, Bldg 6,Rm B1-33, Bethesda, MD 20892 USA. NR 22 TC 16 Z9 19 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD SEP-OCT PY 2000 VL 16 IS 5 BP 744 EP 750 DI 10.1021/bp000112u PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 362UX UT WOS:000089797600011 PM 11027165 ER PT J AU Hough, CJ Chuang, DM AF Hough, CJ Chuang, DM TI The mitochondrial hypothesis of bipolar disorder SO BIPOLAR DISORDERS LA English DT Editorial Material ID MOOD-STABILIZING AGENTS; LITHIUM; EXCITOTOXICITY; EXPRESSION; NEURONS; BCL-2; CNS C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Hough, CJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 18 TC 31 Z9 33 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD SEP PY 2000 VL 2 IS 3 BP 145 EP 147 PN 1 PG 3 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 428PN UT WOS:000168470200001 PM 11256681 ER PT J AU Visconti, R Gadina, M Chiariello, M Chen, EH Stancato, LF Gutkind, JS O'Shea, JJ AF Visconti, R Gadina, M Chiariello, M Chen, EH Stancato, LF Gutkind, JS O'Shea, JJ TI Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity SO BLOOD LA English DT Article ID ACTIVATED PROTEIN-KINASE; P38 MAP KINASE; HEMATOPOIETIC GROWTH-FACTORS; RAS-DEPENDENT ACTIVATION; C-JUN PROMOTER; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAY; T-CELLS; COUPLED RECEPTORS; NATURAL-KILLER AB Interleukin-12 (IL-12) is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses, The transcription factor STAT4 (signal transducer and activator of transcription 4) is an important element in mediating IL-12 signals, as evidenced by the fact that STAT4(-/-) mice display impaired responsiveness to IL-12 and deficient Th1 differentiation. STAT4 is inducibly phosphorylated on tyrosine and serine in response to IL-12, but the kinase(s) responsible for the latter event is unknown. Here we show that IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity. In addition, we show that mutation of tyrosine 693 abrogates IL-12-induced STAT4 tyrosine phosphorylation and transcriptional activity. Although the site surrounding serine 721 is an optimum consensus sequence for mitogen-activated family of protein kinases (MAPKs)-mediated phosphorylation, we demonstrate that IL-12 does not induce extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) activation in T and natural killer (NK) cells and that IL-12-induced STAT4 transcriptional activity is not affected by these kinases, Rather, we show that IL-12 induces p38 activation, Moreover, we demonstrate that p38 alpha and its upstream activator, MKK6, phosphorylate STAT4 on serine 721, and are required for STAT4 full transcriptional activity induced by IL-12, establishing the MKK6/p38 alpha/STAT4 pathway as an important mediator of IL-12 actions. (C) 2000 by The American Society of Hematology. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. Howard Hughes Med Inst, NIH Res Scholars Program, NIH, Bethesda, MD 20817 USA. RP Visconti, R (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Arthritis & Rheumatism Branch, NIH, Bldg 10,Room 9N252,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Visconti, Roberta/C-5299-2009; Chiariello, Mario/O-3642-2014 OI Chiariello, Mario/0000-0001-8434-5177 NR 73 TC 89 Z9 93 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 SEP 1 PY 2000 VL 96 IS 5 BP 1844 EP 1852 PG 9 WC Hematology SC Hematology GA 358VR UT WOS:000089578300034 PM 10961885 ER PT J AU Anagnostopoulos, I Hansmann, ML Franssila, K Harris, M Harris, NL Jaffe, ES Han, J van Krieken, JM Poppema, S Marafioti, T Franklin, J Sextro, M Diehl, V Stein, H AF Anagnostopoulos, I Hansmann, ML Franssila, K Harris, M Harris, NL Jaffe, ES Han, J van Krieken, JM Poppema, S Marafioti, T Franklin, J Sextro, M Diehl, V Stein, H CA European Task Force Lymphoma TI European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes SO BLOOD LA English DT Article ID EPSTEIN-BARR-VIRUS; B-CELL LYMPHOMA; REED-STERNBERG CELLS; TRANSFORMED GERMINAL-CENTERS; LATENT MEMBRANE-PROTEIN; MONOCLONAL-ANTIBODIES; INSITU HYBRIDIZATION; PARAFFIN SECTIONS; H VARIANTS; T-CELLS AB Paraffin blocks and clinical data from 521 patients with lymphocyte predominance Hodgkin disease (LPHD) diagnosed between 1970 and 1994 were collected from 16 European and United States oncological centers to establish the pathologic and clinical characteristics of a large patient cohort, to determine how frequent T-cell-rich large B-cell lymphoma (TCRLBCL) is among LPHD, and to find differential diagnostic criteria distinguishing between the 2 lymphoma categories. For this purpose, conventionally and immunohistologically stained sections were reviewed by a panel of hematopathologists, The diagnosis of LPHD was confirmed in only 219 of the 388 assessable cases (56.5%), This low confirmation rate was due mainly to the presence of a new variant of classical Hodgkin disease (CHD), which resembled, in terms of nodular growth and lymphocyte-richness, nodular LPHD and, in terms of the immunophenotype of the tumor cells, CHD and was designated nodular lymphocyte-rich CHD (NLRCHD). The nodules of LRCHD consisted - as in nodular LPHD - predominantly of B cells but differed from those present in LPHD in that they represented expanded mantle zones with atrophic germinal centers. Clinically, patients with LPHD and NLRCHD showed similar disease characteristics at presentation but differed in the frequency of multiple relapses and prognosis after relapse. Patients with LPHD and NLRCHD clearly differed from patients with CHD with nodular sclerosis or mixed cellularity, as they presented with an earlier disease stage and infrequent mediastinal involvement. As 97% of the LPHD cases showed a complete or partial nodular growth pattern, their differentiation from TCRLBCL was a rare problem in the present series, (C) 2000 by The American Society of Hematology. C1 Free Univ Berlin, Klinikum Benjamin Franklin, Inst Pathol, D-12200 Berlin, Germany. Univ Frankfurt, Senkenberg Ctr Pathol, D-6000 Frankfurt, Germany. Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. Christie Hosp, Dept Pathol, Manchester, Lancs, England. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NCI, Bethesda, MD 20892 USA. Univ Nijmegen, Ctr Med, Dept Pathol, Nijmegen, Netherlands. Univ Groningen, Fac Med Sci, Dept Pathol, Groningen, Netherlands. Univ Cologne, Clin Internal Med 1, Cologne, Germany. RP Stein, H (reprint author), Free Univ Berlin, Klinikum Benjamin Franklin, Inst Pathol, Hindenburgdamm 30, D-12200 Berlin, Germany. RI Marafioti, Teresa/B-4493-2009; Poppema, Sibrand/D-1204-2012; van Krieken, Joannes/D-4138-2009 OI van Krieken, Joannes/0000-0001-6544-1040 NR 55 TC 134 Z9 140 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2000 VL 96 IS 5 BP 1889 EP 1899 PG 11 WC Hematology SC Hematology GA 358VR UT WOS:000089578300040 PM 10961891 ER PT J AU Yao, L Pike, SE Setsuda, J Parekh, J Gupta, G Raffeld, M Jaffe, ES Tosato, G AF Yao, L Pike, SE Setsuda, J Parekh, J Gupta, G Raffeld, M Jaffe, ES Tosato, G TI Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12 SO BLOOD LA English DT Article ID CHEMOKINE RECEPTOR CXCR3; LEWIS-LUNG-CARCINOMA; ENDOTHELIAL-CELLS; MATRIX METALLOPROTEINASES; T-CELLS; B-CELLS; GROWTH; REGRESSION; MIG; ANGIOSTATIN AB Solid tumors are dependent on preexisting vasculature and neovascularization for their growth. Successful cancer therapies targeting the tumor vasculature would be expected to block the existing tumor blood supply and to prevent tumor neovascularization. We tested the antitumor activity of experimental therapy with 2 distinct antiangiogenic drugs. Vasostatin inhibits endothelial cell growth and neovascularization, and interleukin-12 (IL-12) targets the tumor vasculature acting through interferon-gamma (IFN-gamma) and the downstream chemokines interferon-inducible protein-10 (IP-10) and monokine induced by IFN-gamma. Individually, vasostatin and IL-12 produced distinct efficacy profiles in trials aimed at reducing tumor growth in athymic mice. In combination, these inhibitors halted the growth of human Burkitt lymphoma, colon carcinoma, and ovarian carcinoma. Thus, cancer therapy that combines distinct inhibitors of angiogenesis is a novel, effective strategy for the experimental treatment of cancer. (C) 2000 by The American Society of Hematology. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Ctr Biol Evaluat & Res, Rockville, MD USA. NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NIH Bethesda Campus,Bldg 10,Rm 12N226,8800 Rockvi, Bethesda, MD 20892 USA. FU PHS HHS [IRA AWD-7] NR 49 TC 75 Z9 87 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2000 VL 96 IS 5 BP 1900 EP 1905 PG 6 WC Hematology SC Hematology GA 358VR UT WOS:000089578300041 PM 10961892 ER PT J AU Liyanage, M Weaver, Z Barlow, C Coleman, A Pankratz, DG Anderson, S Wynshaw-Boris, A Ried, T AF Liyanage, M Weaver, Z Barlow, C Coleman, A Pankratz, DG Anderson, S Wynshaw-Boris, A Ried, T TI Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice SO BLOOD LA English DT Article ID ATAXIA-TELANGIECTASIA GENE; THYMIC LYMPHOMA; PROPHASE-I; LEUKEMIA; MUTATIONS; DEFECTS; RECOMBINATION; CHROMOSOMES; DISRUPTION; PATHWAYS AB Atm-deficient mice (Atm(-/-)) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm(-/-) mice. All Atm(-/-) tumors are of thymic lymphoblastoid origin, display an immature CD3(-) and CD4(+)/CD8(+) phenotype, and arise coincident with V(D)J recombination, Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptor alpha/delta (Tcr alpha/delta) locus, suggesting the involvement of V(D)J recombination in these translocations, In addition, 11.5% of Atm(-/-) peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at the Tcr alpha/delta locus occur early during tumor development in the absence of ATM, However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcr alpha/delta locus but not for V(D)J recombination at other loci, The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks, (C) 2000 by The American Society of Hematology. C1 NCI, Dept Genet, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Weaver, Z (reprint author), NCI, Dept Genet, Div Clin Sci, NIH, 9 Mem Dr,Bldg 9,Rm 1N-105,MSC 0913, Bethesda, MD 20892 USA. NR 32 TC 114 Z9 114 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2000 VL 96 IS 5 BP 1940 EP 1946 PG 7 WC Hematology SC Hematology GA 358VR UT WOS:000089578300047 PM 10961898 ER PT J AU Collins, RH Goldstein, S Giralt, S Levine, J Porter, D Drobyski, W Barrett, J Johnson, M Kirk, A Horowitz, M Parker, P AF Collins, RH Goldstein, S Giralt, S Levine, J Porter, D Drobyski, W Barrett, J Johnson, M Kirk, A Horowitz, M Parker, P TI Donor leukocyte infusions in acute lymphocytic leukemia SO BONE MARROW TRANSPLANTATION LA English DT Article DE acute lymphocytic leukemia; donor leukocyte infusions; adoptive immunotherapy ID BONE-MARROW TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; VERSUS-HOST DISEASE; EXTRAMEDULLARY RELAPSE; COMPLETE REMISSION; CHRONIC GRAFT; TRANSFUSIONS; CELLS AB Donor leukocyte infusion (DLI) has well-documented activity in CML but the role of DLI in other diseases is less well defined, To evaluate the strategy in acute lymphocytic leukemia (ALL) we evaluated 44 ALL patients from 27 centers who were treated with DLI, Patients with persistent or recurrent disease received DLI from the original marrow donor (30 matched related, four mismatched family, and 10 matched unrelated). Chemotherapy was given before DLI to 28 patients. Of 15 patients who received no pre-DLI chemotherapy, two achieved complete remissions, lasting 1112 and 764+ days. In four patients who received DLI as consolidation of remission induced by chemotherapy or immunosuppression-withdrawal, duration of remission post DI,I was 65, 99, 195 and 672+ days. Of 25 patients who received DLI in the nadir after chemotherapy, 13 survived greater than or equal to 30 days post DLI but did not achieve remission, seven died within less than 30 days post DLI, and five entered remissions that lasted 42, 68, 83, 90, 193 days. Seven patients who did not respond to the initial DLI received a second DLI; none of these patients attained durable remission, Eighteen of 37 evaluable patients developed acute GVHD and five of 20 evaluable patients developed chronic GVHD. Overall actuarial survival is 13% at 3 years. In conclusion, DLI has limited benefit in ALL. New approaches are needed in this group of patients. C1 Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. Baylor Sammons Canc Ctr, Dallas, TX USA. H Lee Moffit Canc Ctr & Res Inst, Tampa, FL USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. NHLBI, Bethesda, MD 20892 USA. Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Milwaukee, WI 53226 USA. RP Collins, RH (reprint author), Univ Texas, SW Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. NR 37 TC 144 Z9 151 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD SEP PY 2000 VL 26 IS 5 BP 511 EP 516 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 351UF UT WOS:000089176000007 PM 11019840 ER PT J AU Stinson, TJ Adams, JR Bishop, MR Kruse, S Tarantolo, S Bennett, CL AF Stinson, TJ Adams, JR Bishop, MR Kruse, S Tarantolo, S Bennett, CL TI Economic analysis of a phase III study of G-CSF vs placebo following allogeneic blood stem cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Article DE costs; allogeneic peripheral blood stem cell transplant; granulocyte colony-stimulating factor; cost-effectiveness ID COLONY-STIMULATING FACTOR; BONE-MARROW TRANSPLANTATION; HIGH-DOSE THERAPY; PERIPHERAL-BLOOD; AUTOLOGOUS TRANSPLANTATION; NEUTROPHIL RECOVERY; HOST DISEASE; MALIGNANCIES; LEUKEMIA; OUTCOMES AB Hematopoietic colony-stimulating factors (CSF) decrease the duration of neutropenia following stem cell transplantation (SCT, With CSF-mobilized allogeneic blood SCT (alloBSCT), the yields of CD34(+) cells are several-fold higher than in other SCT settings, raising concern that post-transplant CSF use may be unnecessary. In this study, we estimate the resource and cost implications associated with CSF use following alloBSCT, A cost identification analysis was conducted for 44 patients on a randomized, double-blind placebo-controlled trial of G-CSF following alloBSCT, Study drug was given daily until an absolute neutrophil count (ANC) greater than or equal to 1000 cells/mu l. Billing information from the time of transplant to day +100 was analyzed. The median number of days to an ANC greater than or equal to 500 cells/mu l was shorter in the G-CSF arm, 10.5 days vs 15 days (P < 0.001), while platelet recovery and rates of acute graft-versus-host disease (GVHD) and survival were similar. Resource use was similar, including days hospitalized, days on antibiotics, blood products transfused and outpatient visits. Total median post-transplant costs were $76 577 for G-CSF patients and $78 799 for placebo patients (P=0.93), G-CSF following allogeneic blood SCT decreased the median duration of absolute neutropenia and did not incur additional costs, but did not result in shorter hospitalizations, or less frequent antibiotic use. C1 Chicago VA Hlth Care Syst Lakeside Div, Chicago, IL 60611 USA. Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. Univ Nebraska, Med Ctr, Dept Internal Med, Sect Oncol & Hematol, Omaha, NE USA. NCI, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. RP Bennett, CL (reprint author), Chicago VA Hlth Care Syst Lakeside Div, Med Sci Res Bldg Rm 205,400 E Ontario, Chicago, IL 60611 USA. RI Bennett, Charles/C-2050-2008 NR 23 TC 19 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD SEP PY 2000 VL 26 IS 6 BP 663 EP 666 DI 10.1038/sj.bmt.1702579 PG 4 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 357LJ UT WOS:000089502900013 PM 11041569 ER PT J AU Hallett, M AF Hallett, M TI Disorder of movement preparation in dystonia SO BRAIN LA English DT Editorial Material C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NR 11 TC 35 Z9 35 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2000 VL 123 BP 1765 EP 1766 DI 10.1093/brain/123.9.1765 PN 9 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 349XD UT WOS:000089070100001 PM 10960042 ER PT J AU Parchi, P Capellari, S Gibbs, CJ Ghetti, B Brown, P Gambetti, P AF Parchi, P Capellari, S Gibbs, CJ Ghetti, B Brown, P Gambetti, P TI Transmission to non-human primates indicates that the same strain of prion can be associated with sporadic, familial, and latrogenic forms of prion disease SO BRAIN PATHOLOGY LA English DT Meeting Abstract C1 NINDS, NIH, CNS Studies Lab, Bethesda, MD USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. RI capellari, sabina/F-5545-2012; Parchi, Piero/L-9833-2015 OI Parchi, Piero/0000-0002-9444-9524 NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT SOC NEUROPATHOLOGY PI PITTSBURGH PA 200 LOTHROP ST A506, PITTSBURGH, PA 15213 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD SEP PY 2000 VL 10 IS 4 BP 608 EP 609 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 334YB UT WOS:000088213000249 ER PT J AU Wong, K Weibel, TD Weiss, MD Kaneski, C Mixon, TH Abu-Asab, M Tsokos, M Quarles, RH Schiffmann, R AF Wong, K Weibel, TD Weiss, MD Kaneski, C Mixon, TH Abu-Asab, M Tsokos, M Quarles, RH Schiffmann, R TI Two novel dysmylinating disorders with abnormal myelin protein fractions SO BRAIN PATHOLOGY LA English DT Meeting Abstract C1 Armed Forces Inst Pathol, Washington, DC 20306 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT SOC NEUROPATHOLOGY PI PITTSBURGH PA 200 LOTHROP ST A506, PITTSBURGH, PA 15213 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD SEP PY 2000 VL 10 IS 4 BP 644 EP 644 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 334YB UT WOS:000088213000322 ER PT J AU Budka, H Liberski, PP Williams, ES Guiroy, DC Walis, A AF Budka, H Liberski, PP Williams, ES Guiroy, DC Walis, A TI Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease SO BRAIN PATHOLOGY LA English DT Meeting Abstract C1 Univ Vienna, Vienna, Austria. Med Acad, Lodz, Poland. Univ Wyoming, Laramie, WY 82071 USA. NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU INT SOC NEUROPATHOLOGY PI PITTSBURGH PA 200 LOTHROP ST A506, PITTSBURGH, PA 15213 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD SEP PY 2000 VL 10 IS 4 BP 660 EP 661 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 334YB UT WOS:000088213000358 ER PT J AU Liberski, P Bratosiewicz, J Barcikowska, M Cervenakova, L Brown, P AF Liberski, P Bratosiewicz, J Barcikowska, M Cervenakova, L Brown, P TI A case of Gerstmann-Straussler-Scheinker disease (GSS) with Met to Thr mutation at codon 232 of the PRNP gene SO BRAIN PATHOLOGY LA English DT Meeting Abstract C1 Med Acad Lodz, Dept Biol Mol, Lodz, Poland. Polish Acad Sci, Med Res Ctr, Warsaw, Poland. NIH, NINDS, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU INT SOC NEUROPATHOLOGY PI PITTSBURGH PA 200 LOTHROP ST A506, PITTSBURGH, PA 15213 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD SEP PY 2000 VL 10 IS 4 BP 669 EP 669 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 334YB UT WOS:000088213000376 ER PT J AU McKay, R AF McKay, R TI Building brains with stem cells SO BRAIN PATHOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT SOC NEUROPATHOLOGY PI PITTSBURGH PA 200 LOTHROP ST A506, PITTSBURGH, PA 15213 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD SEP PY 2000 VL 10 IS 4 BP 723 EP 723 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 334YB UT WOS:000088213000481 ER PT J AU Ahlbom, A Day, N Feychting, M Roman, E Skinner, J Dockerty, J Linet, M McBride, M Michaelis, J Olsen, JH Tynes, T Verkasalo, PK AF Ahlbom, A Day, N Feychting, M Roman, E Skinner, J Dockerty, J Linet, M McBride, M Michaelis, J Olsen, JH Tynes, T Verkasalo, PK TI A pooled analysis of magnetic fields and childhood leukaemia SO BRITISH JOURNAL OF CANCER LA English DT Article DE EMF; cancer; childhood leukaemia; meta-analysis; pooled analysis; epidemiology ID VOLTAGE POWER-LINES; CHILDREN; LEUKEMIA; CANCER; RISK; CANADA; EXPOSURE; ONTARIO AB Previous studies have suggested an association between exposure to 50-60 Hz magnetic fields (EMF) and childhood leukaemia. We conducted a pooled analysis based on individual records from nine studies, including the most recent ones. Studies with 24/48-hour magnetic field measurements or calculated magnetic fields were included. We specified which data analyses we planned to do and how to do them before we commenced the work. The use of individual records allowed us to use the same exposure definitions, and the large numbers of subjects enabled more precise estimation of risks at high exposure levels. For the 3203 children with leukaemia and 10 338 control children with estimated residential magnetic field exposures levels < 0.4 mu T we observed risk estimates near the no effect level, while for the 44 children with leukaemia and 62 control children with estimated residential magnetic field exposures greater than or equal to 0.4 mu T the estimated summary relative risk was 2.00 (1.27-3.13), P value = 0.002). Adjustment for potential confounding variables did not appreciably change the results. For North American subjects whose residences were in the highest wire code category, the estimated summary relative risk was 1.24 (0.82-1.87). Thus, we found no evidence in the combined data for the existence of the so-called wire-code paradox. In summary, the 99.2% of children residing in homes with exposure levels < 0.4 mu T had estimates compatible with no increased risk, while the 0.8% of children with exposures greater than or equal to 0.4 mu T had a relative risk estimate of approximately 2, which is unlikely to be due to random variability. The explanation for the elevated risk is unknown, but selection bias may have accounted for some of the increase. (C) 2000 Cancer Research Campaign. C1 Karolinska Inst, Div Epidemiol, Natl Inst Environm Med, S-10401 Stockholm, Sweden. Univ Cambridge, Strangeways Res Lab, Cambridge, England. Univ Leeds, Leukaemia Res Fund, Ctr Clin Epidemiol, Leeds, W Yorkshire, England. Univ Oxford, Childhood Canc Res Grp, Oxford OX1 2JD, England. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. British Columbia Canc Agcy, Canc Control Res Programme, Vancouver, BC, Canada. Inst Epidemiol Canc Res, Oslo, Norway. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. Finnish Canc Registry, Helsinki, Finland. Turku Univ, Dept Publ Hlth, Turku, Finland. RP Ahlbom, A (reprint author), Karolinska Inst, Div Epidemiol, Natl Inst Environm Med, S-10401 Stockholm, Sweden. NR 17 TC 383 Z9 410 U1 1 U2 34 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP PY 2000 VL 83 IS 5 BP 692 EP 698 DI 10.1054/bjoc.2000.1376 PG 7 WC Oncology SC Oncology GA 347CH UT WOS:000088909400024 PM 10944614 ER PT J AU Sandor, V Senderowicz, A Mertins, S Sackett, D Sausville, E Blagosklonny, MV Bates, SE AF Sandor, V Senderowicz, A Mertins, S Sackett, D Sausville, E Blagosklonny, MV Bates, SE TI P21-dependent G(1) arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228 SO BRITISH JOURNAL OF CANCER LA English DT Article DE experimental therapeutic; cell cycle; cyclin; p21; cytotoxicity ID CHROMOBACTERIUM-VIOLACEUM NO-968; RETINOBLASTOMA PROTEIN; CANCER-CELLS; RESTRICTION POINT; PROMYELOCYTIC LEUKEMIA; REPRESS TRANSCRIPTION; GROWTH ARREST; DEPSIPEPTIDE; BUTYRATE; P53 AB Depsipeptide, FR901228, a novel cyclic peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is currently in phase I clinical trials. Here we demonstrate that, in addition to G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In vitro kinase assays demonstrated no direct inhibition of CDK activity, however, an inhibition was observed in CDKs extracted from cells exposed to FR901228. Cyclin D1 protein disappeared between 6 and 12 hours after treatment with FR901228, whereas cyclin E was upregulated. While it did not induce wt p53, FR901228 did induce p21(WAF1/CIP1) in a p53-independent manner. Cell clones lacking p21 were not arrested in G1 phase, but continued DNA synthesis and were arrested in G2/M phase following FR901228 treatment. Finally, FR901228 blunted ERK2/MAPK activation by EGF whereas early signal transduction events remained intact since overall cellular tyrosine phosphorylation after EGF stimulation was unaffected. Thus, FR901228, while not directly inhibiting kinase activity, causes cyclin D1 downregulation and a p53-independent p21 induction, leading to inhibition of CDK and dephosphorylation of Rb resulting in growth arrest in the early G1 phase. In contrast to the GI arrest, the G2/M arrest is p21-independent, but is associated with significant cytotoxicity. (C) 2000 Cancer Research Campaign. C1 NCI, Med Branch, DSC, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Branch, DSC, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 46 TC 201 Z9 213 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP PY 2000 VL 83 IS 6 BP 817 EP 825 DI 10.1054/bjoc.2000.1327 PG 9 WC Oncology SC Oncology GA 353FG UT WOS:000089263700018 PM 10952788 ER PT J AU Egwuagu, CE Charukamnoetkanok, P Gery, I AF Egwuagu, CE Charukamnoetkanok, P Gery, I TI Susceptibility to ocular autoimmune disease SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Letter C1 NEI, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD SEP PY 2000 VL 84 IS 9 BP 1084 EP 1084 PG 1 WC Ophthalmology SC Ophthalmology GA 354CK UT WOS:000089312100049 PM 10966976 ER PT J AU Apasov, SG Chen, JF Smith, PT Schwarzschild, MA Fink, JS Sitkovsky, MV AF Apasov, SG Chen, JF Smith, PT Schwarzschild, MA Fink, JS Sitkovsky, MV TI Study of A(2A) adenosine receptor gene deficient mice reveals that adenosine analogue CGS 21680 possesses no A(2A) receptor-unrelated lymphotoxicity SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE adenosine; purinergic receptors; T-lymphocytes; cytotoxicity ID T-CELL DEVELOPMENT; PURINERGIC RECEPTOR; EXTRACELLULAR ATP; DNA FRAGMENTATION; HUMAN THYMOCYTES; FLOW-CYTOMETRY; APOPTOSIS; DEATH; INHIBITION; AGONISTS AB 1 Cell surface A(2A) adenosine receptor (A(2A)R) mediated signalling affects a variety of important processes and adenosine analogues possess promising pharmacological properties. 2 Demonstrating the receptor specificity of potentially lymphotoxic adenosine-based drugs facilitates their development for clinical applications. 3 To distinguish between the receptor-dependent and -independent lymphotoxicity and apoptotic activity of adenosine and its analogues we used lymphocytes from A(2A)R-deficient mice. 4 Comparison of A(2A)R-expressing (+/+) and A(2A)R-deficient (-/-) cells in cyclic AMP accumulation assays confirmed that the A(2A)R agonist CGS 21680 is indeed selective for A(2A) receptors in T-lymphocytes. 5 Incubation of A2AR-expressing thymocytes with extracellular adenosine or CGS 21680 bz vitro results in the death of about 7-15% of thymocytes. In contrast, no death was induced in parallel assays in cells from A(2A)R-deficient mice, providing genetic evidence that CGS 21680 does not display adenosine receptor-independent intracellular cytotoxicity. 6 The A(2A) receptor-specific lymphotoxicity of CGS 21650 is also demonstrated in a long-term (6-day) in vitro model of thymocyte positive selection where addition of A(2A)R antagonist ZM 241,385 did block the effects of CGS 21680, allowing the survival of T cells. 7 The use of cells from adenosine receptor-deficient animals is proposed as a part of the screening process for potential adenosine-based drugs for their receptor-independent cytotoxicity and lymphotoxicity. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp E, Dept Neurol, Mol Neurobiol Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NIDA NIH HHS [DA07496] NR 41 TC 20 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2000 VL 131 IS 1 BP 43 EP 50 DI 10.1038/sj.bjp.0703532 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 351WK UT WOS:000089181900008 PM 10960067 ER PT J AU Fee, E AF Fee, E TI How to have theory in an epidemic: Cultural chronicles of AIDS. SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Book Review C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Fee, E (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD FAL PY 2000 VL 74 IS 3 BP 658 EP 659 DI 10.1353/bhm.2000.0116 PG 2 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 355LW UT WOS:000089388000047 ER PT J AU Keating, GA Sinha, R Layton, D Salmon, CP Knize, MG Bogen, KT Lynch, CF Alavanja, M AF Keating, GA Sinha, R Layton, D Salmon, CP Knize, MG Bogen, KT Lynch, CF Alavanja, M TI Comparison of heterocyclic amine levels in home-cooked meats with exposure indicators (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE cooked meat; doneness; exposure; heterocyclic amines ID WELL-DONE; COLORECTAL ADENOMAS; VARYING DEGREES; BREAST-CANCER; RED MEAT; RISK; PRODUCTS; CONSUMPTION; TEMPERATURE; COLON AB Objective: To compare indicators of heterocyclic amine (HCA) exposure with HCA concentrations in home-cooked meat samples. Methods: Pan-fried hamburger and steak samples were obtained from individuals stating a preference for medium, well done and very well done meat. Concentrations of DiMeIQx, IFP, MeIQx and PhIP were determined by HPLC. Results: HCA concentrations at the three doneness levels were not significantly different using the participants' self-reported doneness preference to categorize samples. Using doneness levels determined at the time the meat was cooked and photograph analysis to categorize samples, HCA concentrations increased with doneness level and significant differences were observed between the very well done and lower doneness levels. When assigned to doneness levels by photograph analysis, mean concentrations (ng/g cooked meat) of DiMeIQx, IFP, MeIQx, and PhIP were 0.18, 0.16, 0.65 and 0.47 in well done hamburger and 0.61, 0.74, 1.88 and 2.04 in very well done hamburger. In steak, mean concentrations were 0.24, 0.10, 0.79 and 0.59 in well done steak and 0.45, 0.14, 1.87 and 0.62 in very well done steak. Conclusions: HCA levels in home-cooked meat samples were significantly different when samples were visually classified for doneness, but not when self-reported doneness preference was used to classify doneness. C1 Univ Calif Lawrence Livermore Natl Lab, Hlth & Ecol Assessment Div, Livermore, CA 94551 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. Univ Iowa, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Keating, GA (reprint author), Univ Calif Lawrence Livermore Natl Lab, Hlth & Ecol Assessment Div, Box 808,L-396, Livermore, CA 94551 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NCI NIH HHS [CA55861] NR 19 TC 33 Z9 33 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2000 VL 11 IS 8 BP 731 EP 739 DI 10.1023/A:1008935407971 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355XC UT WOS:000089413000008 PM 11065010 ER PT J AU Goldstein, AM Martinez, M Tucker, MA Demenais, F AF Goldstein, AM Martinez, M Tucker, MA Demenais, F TI Gene-covariate interaction between dysplastic nevi and the CDKN2A gene in American melanoma-prone families SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GERMLINE MUTATIONS; SPORADIC MELANOMA; LOD SCORES; MODELS; SEGREGATION; LINKAGE; RISK; CDK4; P16(INK4); INDUCTION AB The CDKN2A gene has been implicated in cutaneous malignant melanoma pathogenesis. Although CDKN2A mutations confer substantial risk for melanoma, clinicoepidemiological covariates including dysplastic nevi (DN), total nevi, and solar injury also enhance melanoma risk. To examine the relationship between CDKN2A and these three risk factors, we conducted combined segregation/linkage analysis using the class D regressive logistic model, as implemented in the computer program REGRESS, Genetic and covariate data were collected on 20 American melanoma-prone Families, 13 of which had cosegregating CDKN2A mutations. Two types of analyses were conducted, The missing-indicator method used a missing-value indicator, set to 1 for unknown and 0 for known covariate status, and a second variable set to 1 For exposed and D for unexposed or unknown. The second method, complete-eases method, coded subjects with missing covariates as unknown for the affection status. The results for both analyses were very similar. Overall, there was a significant Improvement in the likelihood when DN, total nevi or both covariates were added to the base model, which included dominant transmission of the CDKN2A gene and a linear increase of risk with the logarithm of age on the logit scale. In contrast, inclusion of solar injury did not significantly improve the likelihood for the base model. Significant evidence for a gene-covariate interaction was detected between DN and CDKN2A when DN was the only covariate! in the model (missing-indicator method or complete-cases method) or when both DN and total nevi were in the model (complete-cases method only). Interestingly, in both methods, the odds ratio (OR) for DN was greater in subjects without mutations (OR, 20.1; 95% confidence interval, 4.8-92.8) versus those with CDKN2A mutations (OR, 3.3; 95% confidence interval, 1.1-10.0; complete-cases method). The CDKN2A-DN interaction illustrates the complex etiology of melanoma and needs to be confirmed in a larger sample of families. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Hop St Louis, INSERM, Paris, France. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S,Room 7004,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. RI Demenais, Florence/G-3298-2013; Tucker, Margaret/B-4297-2015; Martinez, Maria/B-3111-2013 OI Demenais, Florence/0000-0001-8361-0936; Martinez, Maria/0000-0003-2180-4537 NR 33 TC 25 Z9 26 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2000 VL 9 IS 9 BP 889 EP 894 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355NW UT WOS:000089392600005 PM 11008905 ER PT J AU Chow, CK Venzon, D Jones, EC Premkumar, A O'Shaughnessy, J Zujewski, J AF Chow, CK Venzon, D Jones, EC Premkumar, A O'Shaughnessy, J Zujewski, J TI Effect of tamoxifen on mammographic density SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER RISK; PARENCHYMAL PATTERNS; CLASSIFICATION; INDEX; AGE AB There are strong data showing that increased breast cancer risk is associated with increased mammographic density. Tamoxifen has been shown to decrease the risk of invasive breast cancer and decrease breast density. We sought to demonstrate and calculate the extent of change in mammographic density in women who have taken tamoxifen for up to 2 years, We evaluated mammograms from 28 high-risk women who were taking tamoxifen, Four different methods of evaluation were used: (a) two qualitative methods (Wolfe criteria and the American College of Radiology Breast Imaging and Reporting Data System criteria); (b) one semiquantitative method (mammograms were assigned one of five semiquantitative scores by visual inspection); and (c) one quantitative method (computer-aided calculation of fibroglandular area from digitized mammograms). The Wolfe criteria showed a 0.03 category decrease per year (P = 0.50), The American College of Radiology Breast Imaging and Reporting Data System criteria showed a 0.1 category decrease per year (P = 0.12). Semiquantitative criteria showed a 0.2 category decrease per year (P = 0.039), Digitized scores showed a 4.3% decrease per year (P = 0.0007), In conclusion, tamoxifen causes a decrease in mammographic density with use, an effect that is better quantitated with semiquantitative criteria or digitized images. Density change might become useful as a surrogate end point for the effect of tamoxifen and other chemopreventive? measures, although our data do not predict an individual's degree of risk reduction. C1 NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NIH, Biostat & Data Management Sect, Div Clin Serv, NCI, Bethesda, MD 20892 USA. NIH, Med Branch, Div Clin Sci, NCI, Bethesda, MD 20892 USA. RP Chow, CK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 25 TC 73 Z9 75 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2000 VL 9 IS 9 BP 917 EP 921 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355NW UT WOS:000089392600009 PM 11008909 ER PT J AU Crane, LA Leakey, TA Ehrsam, G Rimer, BK Warnecke, RB AF Crane, LA Leakey, TA Ehrsam, G Rimer, BK Warnecke, RB TI Effectiveness and cost-effectiveness of multiple outcalls to promote mammography among low-income women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; INTERVENTIONS; SURVIVAL AB A multiple outcall approach based on the Transtheoretical Model was used to entourage mammography behavior in low-income women in the state of Colorado. Women (n = 983) were recruited in person at grocery and discount stores and were then called over the telephone to receive the multiple outcall intervention. These women were compared with 3,080 women who were recruited by telephone and randomly assigned to three study groups: health survey only (control); single outcall; or advance card + single outcall, Subsequent mammography behavior was assessed through a telephone interview conducted 6 months after initiation of the protocol. After controlling for baseline differences between groups in age, education, income, health status, and previous mammography behavior, the multiple outcall intervention was significantly related to mammography behavior among women nonadherent at baseline (odds ratio, 2.58; 95% confidence interval, 1.45-4.60), Furthermore, women who received the multiple outcall intervention had higher "stage of change" at follow-up and more positive attitudes toward mammography. Cost-effectiveness analysis indicated that although the multiple outcall intervention was more costly to deliver ($14.84 per subject compared with about $7.00 for the single outcall interventions), it cost considerably less per subject converted from nonadherent to adherent. Despite study design limitations, the multiple outcall intervention appears to be an effective method of promoting mammography among previously nonadherent women. The results suggest that a combined approach, in which nonadherent women receive multiple calls promoting screening behavior, followed by single calls at the appropriate intervals to promote repeat screening, may be a useful strategy in defined populations. C1 Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. AMC Canc Res Ctr, Ctr Behav Studies, Denver, CO 80214 USA. Duke Comprehens Canc Ctr, Durham, NC 27705 USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Univ Illinois, Ctr Hlth Policy, Chicago, IL 60607 USA. Univ Illinois, Ctr Hlth Serv Res, Chicago, IL 60607 USA. RP Crane, LA (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Box C-245,4200 E 9th ave, Denver, CO 80262 USA. FU NCI NIH HHS [P01-CA57586] NR 24 TC 24 Z9 24 U1 2 U2 3 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 SEP PY 2000 VL 9 IS 9 BP 923 EP 931 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355NW UT WOS:000089392600010 PM 11008910 ER PT J AU Lipkus, IM Kuchibhatla, M McBride, CM Bosworth, HB Pollak, KI Siegler, IC Rimer, BK AF Lipkus, IM Kuchibhatla, M McBride, CM Bosworth, HB Pollak, KI Siegler, IC Rimer, BK TI Relationships among breast cancer perceived absolute risk, comparative risk, and worries SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article AB When trying to predict breast cancer screening, it may be important to understand the relationships between perceived breast cancer risks and worries about getting breast cancer. This study examines the extent to which women's worries about breast cancer correlate with perceptions of both absolute (assessment of own) and comparative (self versus other) 10-year and lifetime risks. As part of a larger randomized intervention trial concerning hormone replacement therapy, 581 women participated in a telephone baseline survey to assess their perceptions of breast cancer risks and worries, Worries about getting breast cancer in the next 10 Sears and in one's lifetime were related positively to both absolute and comparative 10-year and lifetime risks. The magnitude of these relationships did not differ by time frame. Worry about breast cancer is a function of both how a woman views her own risk and how she compares her risk with that of other women. Some practitioners may encourage women to get screened for breast cancer by using emotional appeals, such as heightening women's worries about breast cancer by using risk information. Our data suggest that they should give careful consideration how best to combine, if at all, information about absolute and comparative risks. For example, if the motivation to screen Is based on a sequential assessment of risk beginning with comparative and then absolute risk, creating communications that heighten perceived risk on both of these risk dimensions may be needed to evoke sufficient worry to initiate breast cancer screening. C1 Duke Univ, Med Ctr, Durham, NC 27701 USA. NCI, Bethesda, MD 20892 USA. RP Lipkus, IM (reprint author), Duke Univ, Med Ctr, 905 W Main St,Box 34,South Bldg, Durham, NC 27701 USA. FU NCI NIH HHS [5U19CA72099-04] NR 13 TC 97 Z9 97 U1 0 U2 7 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 SEP PY 2000 VL 9 IS 9 BP 973 EP 975 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355NW UT WOS:000089392600017 PM 11008917 ER PT J AU London, SJ Yuan, JM Coetzee, GA Gao, YT Ross, RK Yu, MC AF London, SJ Yuan, JM Coetzee, GA Gao, YT Ross, RK Yu, MC TI CYP1A1 I462V genetic polymorphism and lung cancer risk in a cohort of men in Shanghai, China SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID S-TRANSFERASE GENES; METABOLIZING-ENZYMES; JAPANESE POPULATION; CIGARETTE-SMOKING; GLUTATHIONE; SUSCEPTIBILITY; GSTM1; ASSOCIATION; CARCINOMAS; BIOMARKERS AB Cytochrome P450 (CYP) CYP1A1 activates tobacco-related carcinogens, A point mutation at codon 462 in exon 7 of CYP1A1 results in a substitution of isoleucine by valine near the heme binding site, This mutation is rare in Caucasians but common in Japanese populations, in which association with increased risk of lung cancer has been reported. There are few data in other Asian populations. We investigated this I462V polymorphism using DNA from 214 incident cases of lung cancer and 669 controls in a prospective cohort study of 18,244 middle-aged and older men in Shanghai, China, The valine allele frequency was 0.138 among the control population. The I462V genotype was not appreciably associated with lung cancer risk overall. There was some suggestion that having at least one valine allele might be related to increased risk of lung cancer among smokers of <20 cigarettes/day (odds ratio, 1.72; 95% confidence interval, 0.82-3.62), particularly among those with homozygous deletion of GSTM1 (odds ratio, 2.80; 95% confidence interval, 1.07-7.33), which is involved in the detoxification of activated tobacco carcinogens. In this Chinese cohort, with CYP1A1 valine allele frequency intermediate between Japanese and Caucasian populations, the I462V polymorphism is not related to lung cancer overall, but it might play a role at lower levels of cigarette smoking among subjects with impaired carcinogen detoxification as assessed by the GSTM1-null genotype. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Shanghai Canc Inst, Shanghai 200032, Peoples R China. RP London, SJ (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI Yuan, Jian-Min/0000-0002-4620-3108; London, Stephanie/0000-0003-4911-5290 FU NCI NIH HHS [R01 CA043092, R01 CA043092-20, R01 CA43092, R35 CA53890]; NIEHS NIH HHS [5P30 ES07048] NR 24 TC 34 Z9 40 U1 2 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 SEP PY 2000 VL 9 IS 9 BP 987 EP 991 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 355NW UT WOS:000089392600020 PM 11008920 ER PT J AU Campbell, I Magliocco, A Moyana, T Zheng, CY Xiang, J AF Campbell, I Magliocco, A Moyana, T Zheng, CY Xiang, J TI Adenovirus-mediated p16(INK4) gene transfer significantly suppresses human breast cancer growth SO CANCER GENE THERAPY LA English DT Article DE p16; adenovirus; apoptosis; breast cancer ID CELL-CYCLE CONTROL; RETINOBLASTOMA PROTEIN; TUMOR-REGRESSION; P16 PROTEIN; IN-VIVO; EXPRESSION; APOPTOSIS; THERAPY; ARREST; PROLIFERATION AB The p16(INK4) tumor suppressor gene encodes a protein that inhibits cyclin-dependent kinase 4, and its homologous deletion is common in human breast cancer. p16(INK4) gene transfer has been reported to be efficacious in inducing growth inhibition of various human tumors such as brain, lung, prostate, and esophageal cancers. However, the efficiency of the p16(INK4) gene with regard to growth inhibition of human breast cancer has not been studied extensively. To examine its tumor-suppressive function and its potential in breast cancer gene therapy, the wild-type p16(INK4) gene was expressed in an adenovirus-mediated gene delivery system and introduced into breast cancer cell lines that do not express p16(INK4) protein. Expression of the introduced p16(INK4) blocked tumor cell entry into the S phase of the cell cycle, induced tumor cell apoptosis, and inhibited tumor cell proliferation both in vitro and in vivo. These results strongly suggest that p1(INK4) is a tumor suppressor gene and suggest that ii has potential utility in breast cancer gene therapy. C1 Univ Saskatchewan, Saskatoon Canc Ctr, Dept Microbiol, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Saskatoon Canc Ctr, Dept Pathol, Saskatoon, SK S7N 4H4, Canada. Univ Calgary, Dept Pathol, Calgary, AB, Canada. NIDR, Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Xiang, J (reprint author), Univ Saskatchewan, Saskatoon Canc Ctr, Dept Microbiol, Saskatoon, SK S7N 4H4, Canada. NR 41 TC 17 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD SEP PY 2000 VL 7 IS 9 BP 1270 EP 1278 DI 10.1038/sj.cgt.7700226 PG 9 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 359LK UT WOS:000089612200008 PM 11023200 ER PT J AU Danforth, DN AF Danforth, DN TI Comments on skin-sparing mastectomy and immediate breast reconstruction: A critical analysis of local recurrence SO CANCER JOURNAL LA English DT Editorial Material ID CANCER C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Danforth, DN (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B38, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PONE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. Sci. Am. PD SEP-OCT PY 2000 VL 6 IS 5 BP 285 EP 286 PG 2 WC Oncology SC Oncology GA 372HT UT WOS:000165228800004 PM 11079166 ER PT J AU Chulada, PC Thompson, MB Mahler, JF Doyle, CM Gaul, BW Lee, C Tiano, HF Morham, SG Smithies, O Langenbach, R AF Chulada, PC Thompson, MB Mahler, JF Doyle, CM Gaul, BW Lee, C Tiano, HF Morham, SG Smithies, O Langenbach, R TI Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice SO CANCER RESEARCH LA English DT Article ID COLON CARCINOGENESIS; KNOCKOUT MICE; CYCLOOXYGENASE-2; CANCER; ASPIRIN; MOUSE; CHEMOPREVENTION; PROSTAGLANDINS; EXPRESSION; SYNTHASE-2 AB Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2, rather than COX-1, as the isoform involved in colon carcinogenesis. In the present study, we show that homologous disruption of either Ptgs-1 or Ptgs-2 (genes coding for COX-1 or COX-2, respectively) reduced polyp formation in Min/+ mice by similar to 80%, Only COX-1 protein was immunohistochemically detected in normal intestinal tissue, whereas both COX-1 and variable levels of COX-2 protein were detected in polyps. Prostaglandin E-2 was increased in polyps compared with normal tissue, and both COX-1 and COX-2 contributed to the PGE(2) produced. The results indicate that COX-1, as well as COX-2, plays a key role in intestinal tumorigenesis and that COX-1 may also be a chemotherapeutic target for nonsteroidal anti-inflammatory drugs. C1 NIEHS, Lab Expt Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Expt Pathol Labs, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. RP Chulada, PC (reprint author), NIEHS, Lab Expt Carcinogenesis & Mutagenesis, NIH, 111 alexander Dr, Res Triangle Pk, NC 27709 USA. NR 26 TC 362 Z9 378 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 SEP 1 PY 2000 VL 60 IS 17 BP 4705 EP 4708 PG 4 WC Oncology SC Oncology GA 352FM UT WOS:000089203900009 PM 10987272 ER PT J AU Liu, XF Helman, LJ Yeung, C Bera, TK Lee, B Pastan, I AF Liu, XF Helman, LJ Yeung, C Bera, TK Lee, B Pastan, I TI XAGE-1, a new gene that is frequently expressed in Ewing's sarcoma SO CANCER RESEARCH LA English DT Article ID CYTOLYTIC T-LYMPHOCYTES; CANCER/TESTIS ANTIGENS; MAGE GENE; IDENTIFICATION; PROSTATE; FAMILY; SEQUENCE; GAUGE; TRANSCRIPT; HOMOLOGY AB Our previous expressed sequence tag database analysis indicates that XAGE-1 is frequently found in Ewing's sarcoma and alveolar rhabdomyosarcoma (U. Brinkmann et al,, Cancer Res., 59: 1445-1448, 1999), Using Northern blots and RNA dot blots, we have now found that XAGE-1 is highly expressed in normal testis, in seven of eight Ewing's cell lines, in four of nine Ewing's sarcoma patient samples, and in one of one alveolar rhabdomyosarcoma patient sample. The gene is located on the X chromosome. The full-length cDNA contains 611 bp and predicts a protein of M-r 16,300 with a potential transmembrane domain at the NH2 terminus, XAGE-1 shares homology with GAGE/PAGE proteins in the COOH-terminal end. These findings could be valuable for cancer diagnosis and cancer immunotherapy. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E16,37 Convent Dr 4255, Bethesda, MD 20892 USA. NR 25 TC 52 Z9 61 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 SEP 1 PY 2000 VL 60 IS 17 BP 4752 EP 4755 PG 4 WC Oncology SC Oncology GA 352FM UT WOS:000089203900018 PM 10987281 ER PT J AU Rusyn, I Yamashina, S Segal, BH Schoonhoven, R Holland, SM Cattley, RC Swenberg, JA Thurman, RG AF Rusyn, I Yamashina, S Segal, BH Schoonhoven, R Holland, SM Cattley, RC Swenberg, JA Thurman, RG TI Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators SO CANCER RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE-C; NF-KAPPA-B; KUPFFER CELLS; RAT-LIVER; HEPATOCYTE PROLIFERATION; DNA-SYNTHESIS; WY-14,643; INCREASES; 8-HYDROXYDEOXYGUANOSINE AB It was shown that 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643), a potent peroxisome proliferator, caused rapid oxidant-dependent activation of nuclear factor kappa B (NF-kappa B) in Kupffer cells in vivo and activated superoxide production by isolated Kupffer cells, Here, we tested the hypothesis that NADPH oxidase (NADPH OX) is the source of oxidants increased by Wy-14,643. Indeed, both activation of NF-kappa B and increases in cell proliferation due to a single dose of Wy-14,643 (100 mg/kg) were prevented completely when rats were pretreated with diphenyleneiodonium (1 mg/kg), an inhibitor of NADPH OX. p47(phox) is a critical subunit of NADPH OX: therefore, p47(phox) knockout mice were used to specifically address the hypothesis of NADPH OX involvement. In livers of wild-type mice, Wy-14,643 activated NF-kappa B, followed by an increase in mRNA for tumor necrosis factor alpha. Importantly, these changes did not occur in p47(phox) knockouts, Moreover, when Kupffer cells were treated with Wy-14,643 in vitro, superoxide production was increased in cells from wild-type but not p47(phox)-null mice. Finally, when mice were fed a Wy-14,643-containing (0.1%) diet for 7 days, the increase in liver weight and cell proliferation caused by Wy-14,643 in wild-type mice was blocked in p47(phox)-null mice. Combined, these results are consistent with the hypothesis that Wy-14,643 activates NADPH OX, which Leads to NF-kappa B-mediated production of mitogens that causes hepatocellular proliferation characteristic of this class of nongenotoxic carcinogens. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365, Chapel Hill, NC 27599 USA. RI Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [ES-04325] NR 42 TC 38 Z9 38 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2000 VL 60 IS 17 BP 4798 EP 4803 PG 6 WC Oncology SC Oncology GA 352FM UT WOS:000089203900026 PM 10987289 ER PT J AU Clarke, K Lee, FT Brechbiel, MW Smyth, FE Old, LJ Scott, AM AF Clarke, K Lee, FT Brechbiel, MW Smyth, FE Old, LJ Scott, AM TI In vivo biodistribution of a humanized anti-Lewis Y monoclonal antibody (hu3S193) in MCF-7 xenografted BALB/c nude mice SO CANCER RESEARCH LA English DT Article ID HER2/NEU-OVEREXPRESSING METASTATIC BREAST; CANCER-CELLS; PHASE-II; IN-VITRO; MOUSE; RADIOIMMUNOTHERAPY; PHARMACOKINETICS; METABOLISM; SURFACE; GROWTH AB The biodistribution characteristics of a humanized anti-Lewis(y) antibody (hu3S193) radiolabeled to three radioisotopes, I-125, In-111, and Y-90, were examined in a BALB/c nude mouse xenograft model of breast cancer. The immunoreactivity of both I-125- and In-111-bound hu3S193 exceeded 50% and was 20% for Y-90. In vivo, labeled antibody was shown by gamma camera imaging and immunohistochemical and autoradiographic techniques to localize to Lewis(y)-expressing breast xenografts with minimal normal tissue uptake. Maximal radioisotope uptake peaked at 48 h for all three isotopes; however, the percentage of injected dose/gram and tumor retention were greater for In-111- and Y-90-bound antibody than for I-125-bound antibody. Although immunoreactivity of In-111- and I-125-labeled hu3S193 in serum was stable over a 5-day period, the amount of unlabeled In-111 in serum was lower than I-125, which together with higher tumor uptake indicates better retention of In-111-labeled hu3S193 and catabolites within the tumor cells. Superior tumor uptake and retention of In-125-labeled hu3S193 and similar blood clearance compared with I-125-labeled hu3S193, suggest that radiometals are the preferred radioisotope for this antibody-antigen system. Humanized 3S193 is a promising new construct for the targeting and potential therapy of Lewis(y)-expressing tumors. C1 Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Melbourne Branch, Tumour Targeting Program, Heidelberg, Vic 3084, Australia. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York, NY 10021 USA. RP Scott, AM (reprint author), Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Melbourne Branch, Tumour Targeting Program, Heidelberg, Vic 3084, Australia. NR 44 TC 39 Z9 41 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 SEP 1 PY 2000 VL 60 IS 17 BP 4804 EP 4811 PG 8 WC Oncology SC Oncology GA 352FM UT WOS:000089203900027 PM 10987290 ER PT J AU Sodhi, A Montaner, S Patel, V Zohar, M Bais, C Mesri, EA Gutkind, JS AF Sodhi, A Montaner, S Patel, V Zohar, M Bais, C Mesri, EA Gutkind, JS TI The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1 alpha SO CANCER RESEARCH LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; FACTOR-I; TRANSCRIPTIONAL ACTIVITY; PERMEABILITY FACTOR; GENE-EXPRESSION; TUMOR-GROWTH; DNA-BINDING; ANGIOGENESIS; CELLS; TRANSACTIVATION AB The elucidation of the molecular mechanisms governing the transition from a nonangiogenic to an angiogenic phenotype is central for understanding and controlling malignancies, Viral oncogenes represent powerful tools for disclosing transforming mechanisms, and they may also afford the possibility of investigating the relationship between transforming pathways and angiogenesis. In this regard, we have recently observed that a constitutively active G protein-coupled receptor (GPCR) encoded by the Kaposi's sarcoma-associated herpes virus (KSHV)/human herpes virus 8 is oncogenic and stimulates angiogenesis by increasing the secretion of vascular endothelial growth factor (VEGF), which is a key angiogenic stimulator and a critical mitogen for the development of Kaposi's sarcoma. Here we show that the KSHV GPCR enhances the expression of VEGF by stimulating the activity of the transcription factor hypoxia-inducible factor (HIF)-1 alpha, which activates transcription from a hypoxia response element within the 5'-flanking region of the VEGF promoter. Stimulation of HIF-1 alpha by the KSHV GPCR involves the phosphorylation of its regulatory/inhibitory domain by the p38 and mitogen-activated protein kinase (MAPK) signaling pathways, thereby enhancing its transcriptional activity, Moreover, specific inhibitors of the p38 (SKF86002) and MAPK (PD98059) pathways are able to inhibit the activation of the transactivating activity of HIF-1 alpha induced by the KSHV GPCR, as well as the VEGF expression and secretion in cells overexpressing this receptor. These findings suggest that the KSHV GPCR oncogene subverts convergent physiological pathways leading to angiogenesis and provide the first insight into a mechanism whereby growth factors and oncogenes acting upstream from MAPK, as well as inflammatory cytokines and cellular stresses that activate p38, can interact with the hypoxia-dependent machinery of angiogenesis, These results may also help to identify novel targets for the development of antiangiogenic therapies aimed at the treatment of Kaposi's sarcoma and other neoplastic diseases. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. Cornell Univ, Coll Med, Dept Med, Div Hematol Oncol,Lab Viral Oncogenesis, New York, NY 10021 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 FU NIAID NIH HHS [AI-39192] NR 53 TC 320 Z9 333 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2000 VL 60 IS 17 BP 4873 EP 4880 PG 8 WC Oncology SC Oncology GA 352FM UT WOS:000089203900038 PM 10987301 ER PT J AU Mori, N Ueda, A Ikeda, S Yamasaki, Y Yamada, Y Tomonaga, M Morikawa, S Geleziunas, R Yoshimura, T Yamamoto, N AF Mori, N Ueda, A Ikeda, S Yamasaki, Y Yamada, Y Tomonaga, M Morikawa, S Geleziunas, R Yoshimura, T Yamamoto, N TI Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappa B sites SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR INDUCTION; HTLV-I; CLINICAL ENTITY; RECEPTOR-ALPHA; IKK-ALPHA; EXPRESSION; KINASE; BETA; ONCOPROTEIN; RETROVIRUS AB Infection by human T-cell leukemia virus type (HTLV)I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis, Leukocytes are attracted to sites of inflammation by chemokines, One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines, We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia, The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell Line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-kappa B sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-kappa B binding to both MCP-1 kappa B sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappa B, Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases. C1 Nagasaki Univ, Inst Trop Med, Dept Prevent Med & AIDS Res, Nagasaki 8528523, Japan. Nagasaki Univ, Sch Med, Dept Lab Med, Nagasaki 8528501, Japan. Nagasaki Univ, Sch Med, Inst Atom Dis, Dept Hematol, Nagasaki 8528523, Japan. City Sasebo Gen Hosp, Dept Internal Med, Sasebo 8578511, Japan. Kokura Mem Hosp, Dept Internal Med, Kitakyushu, Fukuoka 8028555, Japan. Shimane Med Univ, Dept Pathol, Unit 1, Izumo, Shimane 6938501, Japan. Yokohama City Univ, Sch Med, Dept Internal Med 1, Yokohama, Kanagawa 2360004, Japan. Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA. NCI, Immunopathol Sect, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Mori, N (reprint author), Nagasaki Univ, Inst Trop Med, Dept Prevent Med & AIDS Res, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. NR 47 TC 18 Z9 19 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 SEP 1 PY 2000 VL 60 IS 17 BP 4939 EP 4945 PG 7 WC Oncology SC Oncology GA 352FM UT WOS:000089203900047 PM 10987310 ER PT J AU Ottaggio, L Bozzo, S Moro, F Sparks, A Campomenosi, P Miele, M Bonatti, S Fronza, G Lane, DP Abbondandolo, A AF Ottaggio, L Bozzo, S Moro, F Sparks, A Campomenosi, P Miele, M Bonatti, S Fronza, G Lane, DP Abbondandolo, A TI Defective nuclear localization of p53 protein in a Chinese hamster cell line is associated with the formation of stable cytoplasmic protein multimers in cells with gene amplification SO CARCINOGENESIS LA English DT Article ID SUBCELLULAR-LOCALIZATION; PHOSPHORYLATION; INHIBITION; GROWTH; SIGNAL; EXPORT; SEQUESTRATION; TRANSPORT; EXCLUSION; BINDING AB Many p53 functions require p53 transport into the nucleus, Mutant p53 also generally accumulates in the nucleus of transformed or neoplastic cells. However, examples of cytoplasmic accumulation of wild-type or mutant p53 have also been reported. Various explanations have been provided for defective nuclear localization. Here we propose a novel example of cytoplasmic p53 localization which occurs in cells showing gene amplification and appears to be due to the formation of stable p53 multimers, We studied a methotrexate-resistant Chinese hamster cell line (MTX M) carrying amplified dihydrofolate reductase genes and derived from a cell line with p53 nuclear accumulation. MTX M showed cytoplasmic p53 localization and, on immunoblots, several extra bands in the high molecular weight region, besides the expected 53 kDa band. p53 localization and the appearance of high molecular weight bands appeared to be correlated with the degree of DNA amplification. However, amplification of dihydrofolate reductase itself was not involved. Changing the p53 phosphorylation status quantitatively influenced the formation of high molecular weight bands. Cell fusion experiments demonstrated that p53 cytoplasmic localization in MTX M is a dominant phenotype. This result suggests that the defect causing lack of nuclear Localization in this cell line does not reside in the nucleus. In the cytoplasm of MTX M and of wild-type/MTX M heterodikaryons p53 gives rise to protein complexes that are unable to re-enter the nucleus. The formation of such protein complexes is dependent on the amplification of an unknown gene product. C1 Natl Canc Inst, IST, Mutagenesis Lab, I-16132 Genoa, Italy. Univ Dundee, Dept Biochem, CRC Labs, Dundee DD1 4HN, Scotland. CNR, Inst Mutagenesis & Differentiat, I-56100 Pisa, Italy. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. RP Ottaggio, L (reprint author), Natl Canc Inst, IST, Mutagenesis Lab, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. RI Lane, David/C-4920-2008; Campomenosi, Paola/C-9729-2011; OI Campomenosi, Paola/0000-0002-8853-1134 NR 30 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2000 VL 21 IS 9 BP 1631 EP 1638 DI 10.1093/carcin/21.9.1631 PG 8 WC Oncology SC Oncology GA 352FU UT WOS:000089204500001 PM 10964093 ER PT J AU Yang, K Lamprecht, SA Liu, YH Shinozaki, H Fan, KH Leung, D Newmark, H Steele, VE Kelloff, GJ Lipkin, M AF Yang, K Lamprecht, SA Liu, YH Shinozaki, H Fan, KH Leung, D Newmark, H Steele, VE Kelloff, GJ Lipkin, M TI Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon SO CARCINOGENESIS LA English DT Article ID ABERRANT CRYPT FOCI; CELL-CYCLE; DIETARY FLAVONOIDS; CANCER-CELLS; INDUCED APOPTOSIS; EPITHELIAL-CELLS; PROTEIN-KINASES; DNA-DAMAGE; IN-VIVO; INHIBITORS AB In this study we investigated the chemopreventive effects of quercetin and rutin when added to standard AIN-76A diet and fed to normal and azoxymethane (AOM)-treated mice. Early changes in colonic mucosa were analyzed, including colonic cell proliferation, apoptotic cell death, cyclin D-1 expression and focal areas of dysplasia (FAD), The findings show that the number of colonic epithelial cells per crypt column increased (P < 0.01) in each normal mouse group fed the flavonoids; AOM administration increased colonic crypt cell proliferation and resulted in a marked rise of bromodeoxyuridine-labeled cells in the lower proliferative zone of the crypt, Both supplementary dietary quercetin and rutin increased the apoptotic index and caused a redistribution of apoptotic cells along the crypt axis in normal mice fed a standard AIN-76A diet. The number of apoptotic cells/column and apoptotic indices markedly increased (P < 0.01) in the AOM-treated group compared with untreated animals; apoptotic cells expanded throughout the colonic crypts after flavonoid supplementation and AOM administration. Positive cyclin D1 expression was detected in mice on diets supplemented either with quercetin (P < 0.01) or rutin (P < 0.05). AOM administration resulted in the formation of FAD, Both the number of mice exhibiting FAD and the total numer of FAD observed were significantly reduced (P < 0.01) in AOM-treated animals fed flavonoids compared with mice maintained on the standard AIN-76A diet. Surprisingly, however, quercetin alone was able to induce FAD in 22% of normal mice fed the standard AIN-76A diet. C1 Rockefeller Univ, Strang Canc Res Lab, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Lipkin, M (reprint author), Rockefeller Univ, Strang Canc Res Lab, 1230 York Ave, New York, NY 10021 USA. RI LEUNG, Denis Heng Yan/D-1439-2009 FU NCI NIH HHS [CA29502, CN55114-72] NR 64 TC 105 Z9 110 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2000 VL 21 IS 9 BP 1655 EP 1660 DI 10.1093/carcin/21.9.1655 PG 6 WC Oncology SC Oncology GA 352FU UT WOS:000089204500004 PM 10964096 ER PT J AU Patel, AC Anna, CH Foley, JF Stockton, PS Tyson, FL Barrett, JC Devereux, TR AF Patel, AC Anna, CH Foley, JF Stockton, PS Tyson, FL Barrett, JC Devereux, TR TI Hypermethylation of the p16(Ink4a) promoter in B6C3F1 mouse primary lung adenocarcinomas and mouse lung cell lines SO CARCINOGENESIS LA English DT Article ID TUMOR-SUPPRESSOR GENE; CPG ISLAND METHYLATION; DNA METHYLATION; FREQUENT LOSS; CHROMOSOME 9P21; HUMAN CANCERS; EXPRESSION; CARCINOMAS; DELETION; REGION AB Primary lung tumors from B6C3F1 mice and mouse lung cell lines were examined to investigate the role of transcriptional silencing of the p16(Ink4a) tumor suppressor gene by DNA hypermethylation during mouse lung carcinogenesis. Hypermethylation (greater than or equal to 50% methylation at two or more of the CpG sites examined) of the p16(Ink4a) promoter region was detected in DNA from 12 of 17 (70%) of the B6C3F1 primary mouse lung adenocarcinomas examined, whereas hypermethylation was not detected in normal B6C3F1, C57BL/6 and C3H/He mouse lung tissues. Immunohistochemistry performed on the B6C3F1 lung adenocarcinomas revealed heterogeneous expression of the p16 protein within and among the tumors. Laser capture microdissection was employed to collect cells from immunostained sections of four tumors displaying areas of relatively high and low p16 expression. The methylation status of the microdissected samples was assessed by sodium bisulfite genomic sequencing. The pattern of p16 expression correlated inversely with the DNA methylation pattern at promoter CpG sites in nine of 11 (82%) of the microdissected areas displaying variable p16 expression. To provide further evidence that hypermethylation is involved in the loss of p16(Ink4a) gene expression, three mouse lung tumor cell lines (C10, sp6c and CMT64) displaying complete methylation at seven promoter CpG sites and no p16(Ink4a) expression were treated with the demethylating agent, 5-aza-2'-deoxycytidine. Reexpression of p16(Ink4a) and partial demethylation of the p16(Ink4a) promoter were observed in two cell lines (C10 and sp6c) following treatment. These are the first reported studies to provide strong evidence that DNA methylation is a mechanism for p16 inactivation in mouse lung tumors. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Div Extramural Res & Training, Chem Exposures & Mol Biol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. RP Devereux, TR (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,Mail Drop D4-04, Res Triangle Pk, NC 27709 USA. NR 48 TC 37 Z9 37 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2000 VL 21 IS 9 BP 1691 EP 1700 DI 10.1093/carcin/21.9.1691 PG 10 WC Oncology SC Oncology GA 352FU UT WOS:000089204500009 PM 10964101 ER PT J AU Joazeiro, CAP Weissman, AM AF Joazeiro, CAP Weissman, AM TI RING finger proteins: Mediators of ubiquitin ligase activity SO CELL LA English DT Review ID GROWTH-FACTOR RECEPTOR; C-CBL C1 Salk Inst Biol Studies, Mol Biol & Virol Lab, La Jolla, CA 92037 USA. NCI, Lab Immune Cell Biol, Div Basic Sci, Bethesda, MD 20892 USA. RP Joazeiro, CAP (reprint author), Salk Inst Biol Studies, Mol Biol & Virol Lab, La Jolla, CA 92037 USA. NR 21 TC 840 Z9 879 U1 3 U2 47 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD SEP 1 PY 2000 VL 102 IS 5 BP 549 EP 552 DI 10.1016/S0092-8674(00)00077-5 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 350ML UT WOS:000089105200003 PM 11007473 ER PT J AU Carrol, SL Horowits, R AF Carrol, SL Horowits, R TI Myofibrillogenesis and formation of cell contacts mediate the localization of N-RAP in cultured chick cardiomyocytes SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE myofibril; vinculin; alpha-actinin; premyofibril; nascent myofibril ID NEBULIN-RELATED PROTEIN; CARDIAC MYOCYTES; STRIATED-MUSCLE; THIN-FILAMENTS; Z-LINE; ACTIN; NEBULETTE; TITIN; TROPOMYOSIN; MYOFIBRILS AB The expression of N-RAP was investigated in immuofluorescently stained embryonic chick cardiomyocyte cultures. After 1 day in culture, the cardiomyocytes were spherical and N-RAP, titin, alpha-actinin, and vinculin were all diffusely distributed. As the cardiomyocytes spread and formed myofibrils and cell contacts, N-RAP became localized to distinct areas in the cells. During myofibrillogenesis, N-RAP was found concentrated in premyofibrils. As the premyofibrils transformed into bundles of mature myofibrils, N-RAP became concentrated at the longitundal ends of the cells, and was not found in the mature sarcomeres. At sites of cell-cell contacts, N-RAP was localized to the cell junction even in cells without any significant myofibril formation. As the cell-cell contacts became more extensive and formed structures resembling the intercalated disks found in hearts, N-RAP became even more specifically concentrated at these junctions. The results show that myofibrillogenesis and cell contact formation can each independently target N-RAP to the longitudinal ends of cardiomyocytes. (dagger)Published 2000 Wiley-Liss, Inc. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Horowits, R (reprint author), NIAMSD, Phys Biol Lab, NIH, Bldg 6,Room 408,MSC 2755, Bethesda, MD 20892 USA. NR 24 TC 23 Z9 23 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 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD SEP PY 2000 VL 47 IS 1 BP 63 EP 76 DI 10.1002/1097-0169(200009)47:1<63::AID-CM6>3.0.CO;2-M PG 14 WC Cell Biology SC Cell Biology GA 358NA UT WOS:000089563100006 PM 11002311 ER PT J AU Yang, YL Li, XM AF Yang, YL Li, XM TI The IAP family: endogenous caspase inhibitors with multiple biological activities SO CELL RESEARCH LA English DT Review DE apoptosis; ubiquitination; IAP; caspase; TNF receptor; TGF-beta receptor; cell cycle; RING finger ID NF-KAPPA-B; APOPTOSIS PROTEIN XIAP; GROWTH-FACTOR RECEPTOR; INDUCED CELL-DEATH; C-CBL; BACULOVIRAL-INHIBITOR; RING FINGER; SURVIVIN; ACTIVATION; GENE AB IAPs (inhibitors of apoptosis) are a family of proteins containing one or more characteristic BIR domains. These proteins have multiple biological activities that include binding and inhibiting caspases, regulating cell cycle progression, and modulating receptor-mediated signal transduction. Our recent studies found the IAP family members XIAP and c-IAP1 are ubiquitinated and degraded in proteasomes in response to apoptotic stimuli in T cells, and their degradation appears to be important for T cells to commit to death. In addition to three BIR domains, each of these IAPs also contains a RING finger domain. We found this region confers ubiquitin protease ligase (E3) activity to IAPs, and is responsible for the auto-ubiquitination and degradation of IAPs after an apoptotic stimulus. Given the fact that IAPs can bind a variety of proteins, such as caspases and TRAFs, it will be of interest to characterize potential substrates of the E3 activity of IAPs and the effects of ubiquitination by IAPs on signal transduction, cell cycle, and apoptosis. C1 NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Yang, YL (reprint author), NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bldg 10,Room 1B-49, Bethesda, MD 20892 USA. NR 49 TC 176 Z9 185 U1 0 U2 7 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD SEP PY 2000 VL 10 IS 3 BP 169 EP 177 DI 10.1038/sj.cr.7290046 PG 9 WC Cell Biology SC Cell Biology GA 360ER UT WOS:000089653900003 PM 11032169 ER PT J AU Cunningham, J Oiwa, Y Nagy, D Podsakoff, G Colosi, P Bankiewicz, KS AF Cunningham, J Oiwa, Y Nagy, D Podsakoff, G Colosi, P Bankiewicz, KS TI Distribution of AAV-TK following intracranial convection-enhanced delivery into rats SO CELL TRANSPLANTATION LA English DT Article; Proceedings Paper CT 6th Annual Meeting of the American-Society-for-Neural-Transplantation-and-Repair (ASNTR) CY APR, 1999 CL CLEARWATER, FLORIDA SP Amer Soc Neural Transplantat & Repair DE adeno-associated virus; thymidine kinase (ACC-TK); intracranial delivery; convection-enhanced delivery ID ADENOASSOCIATED VIRUS VECTORS; GENE-EXPRESSION; IN-VIVO; VIRAL-ANTIGENS; BRAIN; TRANSDUCTION; INFUSION; THERAPY; NEURONS; VOLUME AB Adeno-associated virus (AAV)-based vectors are being tested in animal models as viable treatments for glioma and neurodegenerative disease and could potentially be employed to target a variety of central nervous system disorders. The relationship between dose of injected vector and its resulting distribution in brain tissue has not been previously reported nor has the most efficient method of delivery been determined. Hen we report that convection-enhanced delivery (CED) of 2.5 x 10(8), 2.5 x 10(9), or 2.5 x 10(10) particles of AAV-thymidine kinase (AAV-TK) into rat brain revealed a clear dose response. In the high-dose group, a volume of 300 mm(3) of brain tissue was partially transduced. Results showed that infusion pump and subcutaneous osmotic pumps were both capable of delivering vector via CED and that total particle number was the most important determining factor in obtaining efficient expression. Results further showed differences in histopathology between the delivery groups. While administration of vector using. infusion pump had relatively benign effects, the use of osmotic pumps resulted in notable toxicity to the surrounding brain tissue. To determine tissue distribution of vector following intracranial delivery, PCR analysis was performed on tissues from rats that received high doses of AAV-TK. three weeks following CED, vector could be detected in both hemispheres of the brain, spinal cord, spleen, and kidney. C1 NINDS, Mol Therapeut Sect, LMMN, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Ctr Funct Imaging, Berkeley, CA 94720 USA. RP Bankiewicz, KS (reprint author), NINDS, Mol Therapeut Sect, LMMN, NIH, 36 Convent Dr,Bldg 36,Room 5W21,MSC 4164, Bethesda, MD 20892 USA. NR 28 TC 58 Z9 61 U1 0 U2 3 PU COGNIZANT COMMUNICATION CORP PI ELMSFORD PA 3 HARTSDALE ROAD, ELMSFORD, NY 10523-3701 USA SN 0963-6897 J9 CELL TRANSPLANT JI Cell Transplant. PD SEP-OCT PY 2000 VL 9 IS 5 BP 585 EP 594 PG 10 WC Cell & Tissue Engineering; Medicine, Research & Experimental; Transplantation SC Cell Biology; Research & Experimental Medicine; Transplantation GA 380LE UT WOS:000165702700004 PM 11144956 ER PT J AU Bankiewicz, KS Bringas, J Pivirotto, P Kutzscher, E Nagy, D Emborg, ME AF Bankiewicz, KS Bringas, J Pivirotto, P Kutzscher, E Nagy, D Emborg, ME TI Technique for bilateral intracranial implantation of cells in monkeys using an automated delivery system SO CELL TRANSPLANTATION LA English DT Article; Proceedings Paper CT 6th Annual Meeting of the American-Society-for-Neural-Transplantation-and-Repair (ASNTR) CY APR, 1999 CL CLEARWATER, FLORIDA SP Amer Soc Neural Transplantat & Repair DE cell therapy; primates; crafting; CNS; magnetic resonance imaging ID NERVE GROWTH-FACTOR; PRIMATE BRAIN; NEURAL TRANSPLANTATION; MAGNETIC-RESONANCE; GENE-TRANSFER; RAT-BRAIN; GRAFTS; FIBROBLASTS; STEREOTAXIS; TOMOGRAPHY AB Intracerebral grafting combined with gene transfer may provide a powerful technique for local delivery of therapeutic agents into the CNS. The present study was undertaken to: (i) develop a reliable and reproducible automated cell implantation system, (ii) determine optimal implantation parameters of cells into the striatum, (iii) determine upper safe limits of cellular implantation into the neostriatum of monkeys. Autologous fibroblasts were infused into six sites of the striatum in nonhuman primates (Macaca mulatta, n = 11). Twenty-six-gauge cannulae were inserted vertically through cortical entry sites into the striatum (two sites in the caudate nucleus and four sites in the putamen) at predefined coordinates based on magnetic resonance imaging (MRI). The cannulae were guided by an electronically operated, hydraulic micropositioner and withdrawn at controlled rates, while cells (5, 10, 20, 40, or 80 mul/site) were infused simultaneously. Varying infusion rates and cell concentrations were also evaluated. Visualization and evaluation of graft placement were performed using contrast MRI at 3-5 days postsurgery. Animals were monitored for signs of clinical complications and sacrificed 2 weeks following surgery. Postimplantation MRI revealed a tissue mass effect of the implant with shifting of midline, edema, and infiltration of the white tracts at 40 and 80 mul/site. In addition, these animals developed transient hemiparesis contralateral to the implant site. MRI of animals grafted with 20 mul/site exhibited columnar-shaped implants and evidence of infiltration into white matter tracts possibly due to a volume effect. No clinical side effects were seen in this group. At 14 days post surgery, MRI scans showed consistent columnar grafts (measuring approximately 5 mm in height) throughout the striatum in animals implanted with 5 or 10 mul/site. No signs of clinical side effects were associated with these volumes and postmortem histological examination confirmed MRI observations. Optimal surgical parameters for delivery of cells into the striatum consist of a graft volume of 10 mul/site, an infusion rate of 1.6 mul/min, a cell concentration of 2.0 x 10(5) cells/mul. and a cannula withdrawal rate of 0.75 mm/min. These results show that infusion of cells into the striatum can be done in a safe and routine manner. C1 NINDS, Mol Therapeut Sect, LMMN, NIH, Bethesda, MD 20892 USA. Cromedica Inc, Victoria, BC, Canada. Pacific Neurosci Inst, Orinda, CA USA. UC Berkeley, LBNL, Ctr Funct Imaging, Berkeley, CA USA. Rush Presbyterian St Lukes Med Ctr, Res Ctr Brain Repair, Chicago, IL 60612 USA. RP Bankiewicz, KS (reprint author), NINDS, Mol Therapeut Sect, LMMN, NIH, 36 Convent Dr,Bldg 36,Rm 5W21,MSC 4164, Bethesda, MD 20892 USA. NR 28 TC 12 Z9 12 U1 0 U2 0 PU COGNIZANT COMMUNICATION CORP PI ELMSFORD PA 3 HARTSDALE ROAD, ELMSFORD, NY 10523-3701 USA SN 0963-6897 J9 CELL TRANSPLANT JI Cell Transplant. PD SEP-OCT PY 2000 VL 9 IS 5 BP 595 EP 607 PG 13 WC Cell & Tissue Engineering; Medicine, Research & Experimental; Transplantation SC Cell Biology; Research & Experimental Medicine; Transplantation GA 380LE UT WOS:000165702700005 PM 11144957 ER PT J AU Lewis, JW Beauchamp, MS DeYoe, EA AF Lewis, JW Beauchamp, MS DeYoe, EA TI A comparison of visual and auditory motion processing in human cerebral cortex SO CEREBRAL CORTEX LA English DT Review ID SUPERIOR TEMPORAL SULCUS; POSITRON-EMISSION TOMOGRAPHY; SPATIAL WORKING-MEMORY; VENTRAL INTRAPARIETAL AREA; POSTERIOR PARIETAL CORTEX; PRIMATE PREFRONTAL CORTEX; TOP-DOWN MODULATION; HUMAN-BRAIN; MACAQUE MONKEY; FUNCTIONAL-ANATOMY AB Visual and auditory motion information can be used together to provide complementary information about the movement of objects. To investigate the neural substrates of such cross-modal integration, functional magnetic resonance imaging was used to assess brain activation while subjects performed separate visual and auditory motion discrimination tasks. Areas of unimodal activation included the primary and/or early sensory cortex for each modality plus additional sites extending toward parietal cortex. Areas conjointly activated by both tasks included lateral parietal cortex, lateral frontal cortex, anterior midline and anterior insular cortex. The parietal site encompassed distinct, but partially overlapping, zones of activation in or near the intraparietal sulcus (IPS). A subsequent task requiring an explicit cross-modal speed comparison revealed several foci of enhanced activity relative to the unimodal tasks. These included the IPS, anterior midline, and anterior insula but not frontal cortex. During the unimodal auditory motion task, portions of the dorsal visual motion system showed signals depressed below resting baseline. Thus, interactions between the two systems involved either enhancement or suppression depending on the stimuli present and the nature of the perceptual task. Together these results identify human cortical regions involved in polysensory integration and the attentional selection of cross-modal motion information. C1 Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. NIH, Bethesda, MD 20892 USA. RP Lewis, JW (reprint author), Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NEI NIH HHS [EY10244, EY0676702]; NIMH NIH HHS [MH15358] NR 143 TC 240 Z9 241 U1 4 U2 22 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2000 VL 10 IS 9 BP 873 EP 888 DI 10.1093/cercor/10.9.873 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 348JJ UT WOS:000088981500005 PM 10982748 ER PT J AU Behar, TN Schaffner, AE Scott, CA Greene, CL Barker, JL AF Behar, TN Schaffner, AE Scott, CA Greene, CL Barker, JL TI GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex SO CEREBRAL CORTEX LA English DT Article ID DEVELOPING CEREBRAL-CORTEX; CENTRAL-NERVOUS-SYSTEM; CAJAL-RETZIUS CELLS; NEURONAL MIGRATION; ORGANOTYPIC CULTURES; CALCIUM TRANSIENTS; CORTICAL-NEURONS; IN-VITRO; BRAIN; ORGANIZATION AB Recent studies indicate that GABA acts as a chemoattractant during rat cortical histogenesis. In vivo, GABA localizes in appropriate locations for a chemoattractant, along migratory routes and near target destinations for migrating cortical neurons. In vitro, GABA induces dissociated embryonic cortical neurons to migrate. Here, embryonic rat cortical slices were cultured in the presence or absence of GABA receptor (GABA-R) antagonists to assess GABA's Effects on neuronal migration in situ. Gestational day 18 (E18) cortical slices were incubated overnight in bromodeoxyuridine (BrdU)-containing medium to label ventricular zone (vz) cells as they underwent terminal mitosis. The slices were then cultured in BrdU-free medium with or without GABA-R antagonists. In control slices, most BrdU(+) cells were observed in the cortical plate (cp) after 48 h. in contrast, cultures maintained in either saclofen (a GABA(B)-R antagonist) or picrotoxin (a GABA(A/C)-R antagonist) had few BrdU-labeled cp cells. However, the effects of the two antagonists were distinct. In the picrotoxin-treated slices, nearly half of all BrdU(+) cells remained in the vz and subventricular zone (svz), whereas saclofen treatment resulted in an accumulation of BrdU(+) cells in the intermediate zone (iz). Bicuculline, a GABA(A)-R antagonist, did not block, but rather enhanced migration of BrdU(+) cells into the cp. These results provide evidence that picrotoxin-sensitive receptors promote the migration of vz/svz cells into the it, while saclofen sensitive receptors signal cells to migrate into the cp. Thus, as cortical cells differentiate, changing receptor expression appears to modulate migratory responses to GABA. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Behar, TN (reprint author), Bldg 36,Room 2C02,36 Convent Dr, Bethesda, MD 20892 USA. NR 44 TC 137 Z9 141 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2000 VL 10 IS 9 BP 899 EP 909 DI 10.1093/cercor/10.9.899 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 348JJ UT WOS:000088981500007 PM 10982750 ER PT J AU Bal, W Wojcik, J Maciejczyk, M Grochowski, P Kasprzak, KS AF Bal, W Wojcik, J Maciejczyk, M Grochowski, P Kasprzak, KS TI Induction of a secondary structure in the N-terminal pentadecapeptide of human protamine HP2 through Ni(II) coordination. An NMR study SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID HUMAN-SPERM PROTAMINES; AMINO-ACID-SEQUENCE; CRYSTAL-STRUCTURE; 2 FORMS; SPECTROSCOPY; BINDING; DNA; COPPER(II); CHROMATIN; NICKEL(II) AB A solution structure of the Ni(II) complex with the N-terminal pentadecapeptide of human protamine HP2 (HP2(1-15)) was elucidated with the use of a range of one- and two-dimensional H-1 NMR techniques and molecular modeling. A striking double-loop conformation was found, exhibiting the interactions of the aromatic ring of the Tyr(8) residue with the Ni(II) coordination site at Arg(1), Thr(2), and His(3) residues and the side chain of the Arg(15) residue. In such a conformation, a tendency was found for all five positively charged arginine side chains to locate on one side of the molecule, making possible efficient contacts with the DNA double helix. These structural features, induced indirectly by Ni(II) coordination, are discussed in terms of a possible physiological function of the N-terminus of HP2 as a metal-binding site. C1 Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland. Polish Acad Sci, Inst Biochem & Biophys, Warsaw, Poland. Interdisciplinary Ctr Math & Computat Modeling, Warsaw, Poland. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Univ Wroclaw, Fac Chem, F Joliot Curie 14, PL-50383 Wroclaw, Poland. EM wbal@wchuwr.chem.uni.wroc.pl NR 48 TC 28 Z9 28 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2000 VL 13 IS 9 BP 823 EP 830 DI 10.1021/tx000060i PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 356RZ UT WOS:000089457800003 PM 10995254 ER PT J AU Vepachedu, SR Ya, N Yagi, H Sayer, JM Jerina, DM AF Vepachedu, SR Ya, N Yagi, H Sayer, JM Jerina, DM TI Marked differences in base selectivity between DNA and the free nucleotides upon adduct formation from bay- and fjord-region diol epoxides SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID COVALENT NUCLEOSIDE ADDUCTS; DEOXYADENOSINE ADDUCTS; 7,8-DIOL 9,10-EPOXIDES; 3,4-DIOL 1,2-EPOXIDES; CATALYZED-HYDROLYSIS; CYTOSINE BASES; BENZOPHENANTHRENE; ADENINE; ACID; STEREOCHEMISTRY AB Distributions of adducts formed from each of the four optically active isomers of 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BcPh and BaP diol epoxides) on reaction with an equimolar mixture of deoxyadenosine and deoxyguanosine 5'-monophosphates were compared with the known adduct distributions from these diol epoxides (DEs) upon reaction with calf thymus DNA in vitro. In the presence of an equimolar (100 mM total) mixture of dAMP and dGMP, the efficiency of formation of all types of adducts relative to tetraols is comparable for both the BaP (similar to 40-60%) and BcPh (similar to 30-40%) diol epoxides. This is in contrast to the partitioning between tetraols and adducts observed with DNA, where the BcPh DEs form adducts much more efficiently than the BaP DEs. Preference for trans versus cis ring opening by the exocyclic amino groups of the free nucleotides in the dAMP/dGMP mixture is greater for the DE diastereomer in which the benzylic hydroxyl group and the epoxide oxygen are trans (DE-2). This is qualitatively similar to the preferences for trans versus cis adduct formation on reaction of these isomers with DNA, as well as trans versus cis tetraol formation on their acid hydrolysis. For the BcPh DE isomers, competitive reaction between dGMP and dAMP gives 40-62% of the total exocyclic amino group adducts as dA adducts. A similar distribution of dG versus dA adducts had previously been observed on reaction of the BcPh DEs with DNA, except in the case of (+)3(R),4(S)-dihydroxy-1(R),2(S)-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene, which gives similar to 85 dA adducts on reaction with DNA. With the BaP DEs, 60-77% of the exocyclic amino group adducts formed upon competitive reaction with the free nucleotides are derived from dGMP. The observed dG selectivity of these BaP DEs is much smaller with the nucleotide mixture than it is with DNA, leading to the conclusion that DNA structure has a much larger modifying effect on the base selectivity of the BaP relative to the BcPh DEs. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Sayer, JM (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 10 Z9 10 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2000 VL 13 IS 9 BP 883 EP 890 DI 10.1021/tx000073w PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 356RZ UT WOS:000089457800010 PM 10995261 ER PT J AU Lorber, M Pinsky, P AF Lorber, M Pinsky, P TI An evaluation of three empirical air-to-leaf models for polychlorinated dibenzo-p-dioxins and dibenzofurans SO CHEMOSPHERE LA English DT Article DE air-to-leaf vapor transfer; dioxins; furans; scavenging model ID DRY DEPOSITION; CHLORINATED DIOXINS; GRASS; PHOTODEGRADATION; ATMOSPHERE; VALIDATION; PARTICLE; WET; GAS AB Three empirical air-to-leaf models for estimating grass concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (abbreviated dioxins and furans) from air concentrations of these compounds are described and tested against two field data sets. All are empirical in that they are founded on simplistic bioconcentration and related approaches which rely on field data for their parameterization. One of the models, identified as the EPA Model, partitions the total air concentration into vapor and particle phases, and separately models the impact of both. A second model addresses only the vapor phase: grass concentrations are modeled as a function of vapor deposition. For the third model, it is assumed that the grass plants "scavenge" a fixed Volume of air of dioxins, and hence grass concentrations are modeled as a simple product of total air concentration and a constant scavenging coefficient. Field data from two sites, a rural and an industrial site in the United Kingdom, included concurrent measurements of dioxins in air and field grass, and dioxin and furan depositions, for one 6-week sampling period. Principal findings include: (1) the EPA Model underpredicted grass concentrations at the rural field site by a factor of 2, while the Scavenging Model underpredicted grass concentrations by a factor of 3.8, and the Vapor Deposition Model significantly underpredicted grass concentrations (by a factor greater than 10), (2) the presence of high soil concentrations for some of the dioxins and furans at the industrial sire appears to have caused higher grass concentrations and confounded the air-to-plant modeling exercise, (3) the Scavenging Model could be calibrated to the data set; however, a key premise of this model - that vapor and particle phase dioxins equally impact the plants, is nor supported by the field data, (4) measured depositions are highly correlated to but systematically lower than modeled depositions, which could be due ro modeling assumptions or a systematic measurement bias. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 US EPA, Natl Ctr Environm Assessment 8623D, Washington, DC 20460 USA. NIH, Bethesda, MD 20892 USA. RP Lorber, M (reprint author), US EPA, Natl Ctr Environm Assessment 8623D, 401 M St SW, Washington, DC 20460 USA. NR 29 TC 10 Z9 10 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD SEP PY 2000 VL 41 IS 6 BP 931 EP 941 DI 10.1016/S0045-6535(99)00318-5 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA 317VU UT WOS:000087248300018 PM 10864167 ER PT J AU Masur, H Shelhamer, JH AF Masur, H Shelhamer, JH TI Pneumocystis pneumonia - Miles to go SO CHEST LA English DT Editorial Material ID CARINII PNEUMONIA C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIH, Ctr Clin, Dept Crit Care Med, 10 Ctr Dr,Room 7D43, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD SEP PY 2000 VL 118 IS 3 BP 575 EP 577 DI 10.1378/chest.118.3.575 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 355KA UT WOS:000089383800005 PM 10988173 ER PT J AU LaCroix, S Stewart, JA Thouless, ME Black, JB AF LaCroix, S Stewart, JA Thouless, ME Black, JB TI An immunoblot assay for detection of immunoglobulin M antibody to human herpesvirus 6 SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID INFECTION EXANTHEM SUBITUM; MEASLES; HUMAN-HERPESVIRUS-6; CHILDREN; IDENTIFICATION; DIAGNOSIS; RUBELLA; INFANTS; PCR; MENINGOENCEPHALITIS AB We identified the human herpesvirus 6 (HHV-6)-dominant immunoglobulin M (IgM)-reactive virion protein as being the same 101-kDa protein (101K) previously identified as the major IgG immunoreactive protein and a specific serologic marker of HHV-6 infection. An immunoblot assay (IB) to detect HHV-6-specific IgM antibodies against the 101K protein in human serum samples was developed. The assay was validated by using acute- and convalescent-phase serum collected from children under 2 years of age in which we previously detected IgG seroconversion to the HHV-6 101K protein. Of 32 serum pairs which previously demonstrated IgG seroconversion to the 101K protein, 29 had IgM reactivity to the same protein in the acute-phase sample and the remaining 3 had reactivity in the convalescent-phase sample. We also detected HHV-6 IgM activity in sera collected from individuals greater than or equal to 4 years of age who were also IgM seropositive to measles or rubella. Results of cross-adsorption studies using measles virus-, rubella virus-, and HHV-6-infected cells as the adsorbing antigen indicated no cross-reactivity between measles or rubella IgM and HHV-6 IgM in human serum samples. The IgM IB detected HHV-6-specific IgM antibody to the 101K protein in 78% (63 of 81) of tested acute-phase serum collected from young children with an undifferentiated rash illness by using a single serum dilution. C1 Publ Hlth Lab, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Black, JB (reprint author), NCI, NIH, 31 Ctr Dr,Bldg 31,Room 3A44, Bethesda, MD 20892 USA. NR 34 TC 7 Z9 8 U1 0 U2 0 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 SEP PY 2000 VL 7 IS 5 BP 823 EP 827 DI 10.1128/CDLI.7.5.823-827.2000 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 352UC UT WOS:000089235400020 PM 10973462 ER PT J AU Kobayashi, H Ishizuka, T Okayama, Y AF Kobayashi, H Ishizuka, T Okayama, Y TI Human mast cells and basophils as sources of cytokines SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Review ID COLONY-STIMULATING FACTOR; FC-EPSILON-RI; LYMPHOCYTE CHEMOATTRACTANT FACTOR; PERENNIAL ALLERGIC RHINITICS; MESSENGER-RNA EXPRESSION; MIXED LEUKOCYTE-CULTURES; NECROSIS-FACTOR-ALPHA; HUMAN BLOOD BASOPHILS; HUMAN IGE SYNTHESIS; CD8(+) T-CELLS C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA. Gunma Univ, Sch Med, Fac Med, Dept Internal Med 1, Maebashi, Gumma 371, Japan. RP Okayama, Y (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C 206,10 Ctr Dr,MSC 1888, Bethesda, MD USA. NR 59 TC 60 Z9 63 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD SEP PY 2000 VL 30 IS 9 BP 1205 EP 1212 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 348PP UT WOS:000088994100005 PM 10971465 ER PT J AU Nesterova, M Noguchi, K Park, YG Lee, YN Cho-Chung, YS AF Nesterova, M Noguchi, K Park, YG Lee, YN Cho-Chung, YS TI Compensatory stabilization of RII beta protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase a RI alpha protein SO CLINICAL CANCER RESEARCH LA English DT Article ID HL-60 LEUKEMIA; CANCER-CELLS; SUBUNIT; DIFFERENTIATION; OLIGODEOXYNUCLEOTIDE; EXPRESSION; SITE; OLIGONUCLEOTIDES; ACTIVATION; HOLOENZYME AB The cyclic AMP-dependent protein kinase (PKA) exists in two isoforms, PKA-I (type I) and PKA-II (type II), that contain an identical catalytic (C) subunit but distinct regulatory (R) subunits, RI and RII, respectively. Increased expression of RIalpha/PKA-I has been shown in human cancer cell lines, in primary tumors, in cells after transformation, and in cells upon stimulation of growth. We have shown previously that a single-injection RIalpha antisense treatment results in a reduction in RIalpha and PKA-I expression and sustained inhibition of human colon carcinoma growth in athymic mice (M. Nesterova and Y.S. Cho-Chung, Nat. Med., 1: 528-533, 1995). Growth inhibition accompanied reduction in RIalpha/PKA-I expression and compensatory increases in RIIbeta protein and PKA-IIbeta, the RIIbeta-containing holoenzyme, Here, we report that these in vivo findings are consistent with observations made in cancer cells in culture. We demonstrate that the antisense depletion of RIalpha in cancer cells results in increased RIIbeta protein without increasing the rate of RIIbeta synthesis or RIIbeta mRNA levels, Pulse-chase experiments revealed a 3-6-fold increase in the half-life of RIIbeta protein in antisense-treated colon and prostate carcinoma cells with little or no change in the half-lives of RIalpha, RIIalpha, and C-alpha proteins. Compensation by RIIbeta stabilization may represent a novel biochemical adaptation mechanism of the cell in response to sequence-specific loss of RIalpha expression, which leads to sustained down-regulation of PKA-I activity and inhibition of tumor growth. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B05,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 28 Z9 29 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3434 EP 3441 PG 8 WC Oncology SC Oncology GA 352NK UT WOS:000089224600009 PM 10999726 ER PT J AU Liu, J Nau, MM Yeh, JC Allegra, CJ Chu, E Wright, JJ AF Liu, J Nau, MM Yeh, JC Allegra, CJ Chu, E Wright, JJ TI Molecular heterogeneity and function of EWS-WT1 fusion transcripts in desmoplastic small round cell tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID ZINC-FINGER GENE; WILMS-TUMOR; EWINGS-SARCOMA; DNA-BINDING; CHIMERIC TRANSCRIPTS; RESPONSE GENE; EWS GENE; CHROMOSOME-TRANSLOCATION; GENOMIC STRUCTURE; WT1 GENE AB Desmoplastic small round cell tumor (DSRCT) is a primitive sarcoma with a consistent cytogenetic abnormality, t(11;22)(p13;q12). This chromosomal translocation generates a chimeric transcript that is formed by fusion of the 5' region of the Ewing's sarcoma gene, EWS, with the 3' DNA-binding segment of WT1, the Wilms' tumor suppressor gene. We collected 14 DSRCT tumor samples and examined the hybrid transcripts. We identified: (a) combinatorial heterogeneity of EWS exons fused to WT1 including use of EWS exons 7, 8, and 9; (b) subpopulations of variant transcripts in 6 of 14 tumors characterized by aberrant splicing resulting in loss of EWS exon 6 or WT1 exon 9; (c) multiple cDNA products with large internal deletions; and (d) insertion of small stretches of heterologous DNA at the fusion site or exon splice region in transcripts from two tumors. Most of the splice variants were in-frame, and in vitro translated fusion proteins with intact DNA-binding motifs formed complexes with a WT 1 response element in gel mobility assays. Each of the chimeric proteins retains the ability to bind to the GC and TC elements of the early transcription factor EGR-1 as well as WT1 consensus sequences. We present evidence that various EWS-WT1 proteins up-regulated EGR-1 promoter activity and that this up-regulation is specifically dependent upon the absence of the exon 9 KTS domain of WT1. The molecular diversity and functionality exhibited by these fusion transcripts may have significant biological implications for their transactivating and tumorigenic potential. C1 Vet Affairs Connecticut Healthcare Syst, Canc Ctr 111D, W Haven, CT 06516 USA. Yale Univ, Sch Med, Yale Canc Ctr, Dept Med & Pharmacol, New Haven, CT 06520 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20889 USA. RP Liu, J (reprint author), Vet Affairs Connecticut Healthcare Syst, Canc Ctr 111D, 950 Campbell Ave, W Haven, CT 06516 USA. FU NCI NIH HHS [CA 16359, CA 75712] NR 54 TC 36 Z9 37 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3522 EP 3529 PG 8 WC Oncology SC Oncology GA 352NK UT WOS:000089224600022 PM 10999739 ER PT J AU Karkera, JD Ayache, S Ransome, RJ Jackson, MA Elsayem, AF Sridhar, R Detera-Wadleigh, SD Wadleigh, RG AF Karkera, JD Ayache, S Ransome, RJ Jackson, MA Elsayem, AF Sridhar, R Detera-Wadleigh, SD Wadleigh, RG TI Refinement of regions with allelic loss on chromosome 18p11.2 and 18q12.2 in esophageal squamous cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; TUMOR PROGRESSION; GASTRIC-CANCER; FRAGILE SITES; HUMAN GENES; HETEROZYGOSITY; 18Q; ADENOCARCINOMA; IDENTIFICATION; PURIFICATION AB Esophageal cancer ranks among the 10 most common cancers worldwide and is almost invariably fatal. The detailed genetic repertoire involved in esophageal carcinogenesis has not been defined. We have shown previously that the esophageal squamous cell carcinoma genome exhibits a frequent loss of heterozygosity (LOH) in the pericentromeric region of chromosome 18. To construct a fine deletion map, we screened 76 new samples composed of microdissected esophageal squamous cell carcinoma and matched morphologically normal epithelial cells using closely spaced markers. Maximal LOH frequency (54%) was displayed by D18S542 on 18p11.2. The pattern of LOH in selected patients indicated that the short region of overlap extends 3 cM on either side of D18S542. On the long arm of chromosome 18, the highest frequency of allelic loss (42%) was detected by D18S978 on 18q12.2-q21.1. This analysis revealed a short region of overlap of similar to 0.8 cM. These findings further implicate unreported tumor suppressor genes encoded by 18p11.2 and 18q12.2 in esophageal squamous cell carcinogenesis and they indicate a refinement of their map location. C1 Dept Vet Affairs Med Ctr, Med Oncol Sect, Washington, DC 20422 USA. Howard Univ, Dept Pathol, Washington, DC 20060 USA. Howard Univ, Dept Med, Washington, DC 20060 USA. Howard Univ, Dept Radiat Therapy, Washington, DC 20060 USA. Howard Univ, Ctr Canc, Washington, DC 20060 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Wadleigh, RG (reprint author), Dept Vet Affairs Med Ctr, Med Oncol Sect, 50 Irving St NW, Washington, DC 20422 USA. NR 38 TC 11 Z9 11 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3565 EP 3569 PG 5 WC Oncology SC Oncology GA 352NK UT WOS:000089224600028 PM 10999745 ER PT J AU Clarke, K Lee, FT Brechbiel, MW Smyth, FE Old, LJ Scott, AM AF Clarke, K Lee, FT Brechbiel, MW Smyth, FE Old, LJ Scott, AM TI Therapeutic efficacy of anti-Lewis(y) humanized 3S193 radioimmunotherapy in a breast cancer model: Enhanced activity when combined with taxol chemotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODIES; ANTITUMOR-ACTIVITY; TUMOR XENOGRAFTS; CHIMERIC L6; MOUSE MODEL; PHASE-II; MCF-7; MICE; A33 AB Monoclonal antibody therapy may provide new treatment options in the management of metastatic breast cancer by selectively targeting tumors and producing a therapeutic effect, by delivering radiation or other toxins directly to tumor cells, or by producing an intrinsic immune inflammatory response. The effect of I-131-labeled humanized anti-Lewis(y) monoclonal antibody 3S193 (hu3S193) was compared with that of placebo and radiolabeled huA33 control antibody in a series of radioimmunotherapy experiments in a MCF-7 xenografted BALB/c nude mouse breast cancer model. The maximum tolerated dose of I-131-labeled antibody occurred at 200 mu Ci/mouse, at which dose level three of six mice that received I-131-hu3S193 showed significant tumor growth inhibition in contrast to no responses in the comparable I-131-huA33 control treatment arm. Breast cancer is an ideal model to test the efficacy of combined modalities given its known sensitivity to both radiotherapy and chemotherapy. The synergy between radioimmunotherapy and chemotherapy was therefore also explored using a combination of I-131-labeled hu3S193 antibody and Taxol using subtherapeutic doses of each agent. The combination of Taxol and 100 mu Ci of I-131-hu3S193 produced significant tumor inhibition in 80% of mice, whereas no responses were seen with either treatment modality alone or the combination of Taxol and I-131-huA33. These results support a potential therapeutic role of radiolabeled hu3S193 in the treatment of breast cancer, including combination therapy with Taxol, and warrants further investigation of this promising new agent. C1 Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Tumour Targeting Program, Melbourne Branch, Heidelberg, Vic 3084, Australia. NIH, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York Branch, New York, NY 10021 USA. RP Scott, AM (reprint author), Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Tumour Targeting Program, Melbourne Branch, Heidelberg, Vic 3084, Australia. NR 29 TC 45 Z9 46 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3621 EP 3628 PG 8 WC Oncology SC Oncology GA 352NK UT WOS:000089224600037 PM 10999754 ER PT J AU Wang, DL Marko, M Dahl, AR Engelke, KS Placke, ME Imondi, AR Mulshine, JL De Luca, LM AF Wang, DL Marko, M Dahl, AR Engelke, KS Placke, ME Imondi, AR Mulshine, JL De Luca, LM TI Topical delivery of 13-cis-retinoic acid by inhalation up-regulates expression of rodent lung but not liver retinoic acid receptors SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-INHIBITION; BETA EXPRESSION; CANCER; MICE; PREVENTION; CARCINOMA; INCREASES; BINDING; TISSUE; TUMORS AB Chemopreventive retinoids may be more effective if delivered to the lung epithelium by inhalation, 13-cis-Retinoic acid (13-cis-RA) was comparable to all-trans-retinoic acid (RA) in inducing transglutaminase II (TGase II) in cultured human cells. Inhaled 13-cis-RA had a significant stimulatory activity on TGase II in rat lung (P < 0.001) but not in liver tissue (P < 0.544), Furthermore, inhaled 13-cis-RA at daily deposited doses of 1.9 mg/kg/day up-regulated the expression of lung retinoic acid receptors (RARs) alpha, beta, and gamma at day 1 (RAR alpha by 3.4-fold, RAR beta by 7.2-fold, and RAR alpha by 9.7-fold) and at day 17 (RAR alpha by 4.2-fold, RAR beta by 10.0-fold, and RAR gamma by 12.9-fold). At a lower aerosol concentration, daily deposited doses of 0.6 mg/kg/day were also effective at 28 days. Lung RAR alpha was induced by 4.7-fold, RAR beta by 8.0-fold, and RAR gamma by 8.1-fold. Adjustment of dose by exposure duration was also effective; thus, inhalation of an aerosol concentration of 62.2 mu g/liter, for durations from 5 to 240 min daily for 14 days, induced all RARs from 30.6- to 74-fold at the shortest exposure time. None of the animals exposed to I3-ris-RA aerosols showed RAR induction in livers. By contrast, a diet containing pharmacological RA (30 mu g/g of diet) failed to induce RARs in SENCAR mouse lung, although it induced liver RARs (RAR alpha, 21.8-fold; RAR beta, 13.5-fold; RAR gamma, 12.5-fold); it also failed to induce lung TGase II. A striking increase of RAR alpha expression was evident in the nuclei of hepatocytes, Pharmacological dietary RA stimulated RAR alpha, RAR beta, and RAR gamma as early as day 1 by 2-, 4-, and 2.1-fold, respectively, without effect on lung RARs, Therefore, 13-cis-RA delivered to lung tissue of rats is a potent stimulant of lung but not liver RARs, Conversely, dietary RA stimulates liver but not lung RARs, These data support the concept that epithelial delivery of chemopreventive retinoids to lung tissue is a more efficacious way to attain up-regulation of TGase II and the retinoid receptors and possibly to achieve chemoprevention. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Med Branch, Bethesda, MD 20892 USA. Battelle Mem Inst, Columbus, OH 43201 USA. RP De Luca, LM (reprint author), NIH, Bldg 37,Room 3A-17,37 Convent Dr, Bethesda, MD 20892 USA. EM luigi_de_luca@nih.gov NR 32 TC 18 Z9 19 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3636 EP 3645 PG 10 WC Oncology SC Oncology GA 352NK UT WOS:000089224600039 PM 10999756 ER PT J AU Long, L Berg, SL Roy, SK McCully, CL Song-Yoo, HW Moschel, RC Balis, FM Dolan, ME AF Long, L Berg, SL Roy, SK McCully, CL Song-Yoo, HW Moschel, RC Balis, FM Dolan, ME TI Plasma and cerebrospinal fluid pharmacokinetics of O-6-benzylguanine and analogues in nonhuman primates SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; HUMAN TUMOR-CELLS; ALKYLATING-AGENTS; DEPLETION; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA; O-6-BENZYL-2'-DEOXYGUANOSINE; DERIVATIVES; METABOLISM; XENOGRAFTS; DNA AB O-6-Benzylguanine (BG) is a potent, specific inactivator of the DNA repair protein, O-6-alkylguanine-DNA alkyltransferase, that enhances the sensitivity of tumor cell lines and tumor xenografts to chloroethylnitrosoureas. To search for BG analogues with greater penetration into the cerebrospinal fluid (CSF), we evaluated plasma and CSF pharmacokinetics of BG, 8-aza-O-6-benzylguanine (8-azaBG), O-6-benzyl-8-bromoguanine (8-BrBG), O-6-benzyl-8-oxoguanine (8-oxoBG), O-6-benzyl-8-trifluoromethylguanine (8-tfmBG), and O-6-benzyl-2'-deoxyguanosine (B2dG) after i.v. administration of 200 mg/m(2) of drug through an indwelling Ommaya reservoir in a nonhuman primate model. BG and its analogues were quantified in plasma and CSF using reverse-phase high-performance liquid chromatography assays. The plasma clearances of the four 8-substituted BG analogues were similar (0.04-0.06 1h/kg), but half-lives ranged from <2 to >24 h, BG was converted to g-oxoBG, an equally potent O-6-alkylguanine-DNA alkyltransferase inactivator, and the elimination of 8-oxoBG was much slower than that of BG, As a result, the plasma area under the curve of 8-oxoBG was 3.5-fold greater than that of BG, B2dG was metabolized to BG and 8-oxoBG, but this pathway accounted for only 20% of B2dG elimination. The CSF penetration percentages (based on the ratio of AUG,,,: AUC(plasma)) for BG, 8-azaBG, 8-oxoBG, 8-tfmBG, 8-BrBG, and B2dG were 3.2, 0.18, 4.1, 1.4, <0.3, and 2.0%, respectively. The CSF penetration of BG and its active metabolite 8-oxoBG is greater than the penetration of 8-azaBG, 8-BrBG, 8-tfmBG, and B2dG. C1 Univ Chicago, Hematol Oncol Sect, Dept Med, Ctr Canc Res, Chicago, IL 60637 USA. Univ Chicago, Comm Clin Pharmacol, Chicago, IL 60637 USA. Baylor Coll Med, Texas Childrens Hosp, Texas Childrens Canc Ctr, Houston, TX 77030 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Chem Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Dolan, ME (reprint author), Univ Chicago, Hematol Oncol Sect, Dept Med, Ctr Canc Res, 5841 S Maryland Ave,Box MC2115, Chicago, IL 60637 USA. FU NCI NIH HHS [CA57725] NR 25 TC 4 Z9 4 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3662 EP 3669 PG 8 WC Oncology SC Oncology GA 352NK UT WOS:000089224600042 PM 10999759 ER PT J AU Kinsella, TJ Schupp, JE Davis, TW Berry, SE Hwang, HS Warren, K Balis, F Barnett, J Sands, H AF Kinsella, TJ Schupp, JE Davis, TW Berry, SE Hwang, HS Warren, K Balis, F Barnett, J Sands, H TI Preclinical study of the systemic toxicity and pharmacokinetics of 5-iodo-2-deoxypyrimidinone-2 '-deoxyribose as a radiosensitizing prodrug in two, non-rodent animal species: Implications for phase I study design SO CLINICAL CANCER RESEARCH LA English DT Article ID COLON-CANCER-CELLS; ALDEHYDE OXIDASE; HALOGENATED PYRIMIDINES; GLIOBLASTOMA-MULTIFORME; ANAPLASTIC ASTROCYTOMA; THYMIDINE REPLACEMENT; RADIATION-THERAPY; DNA INCORPORATION; MISMATCH REPAIR; IODODEOXYURIDINE AB We have demonstrated previously an improved therapeutic index for oral 5-iodo-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continuous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent using three different human tumor xenografts in athymic mice. IPdR is a prodrug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for greater than or equal to 1 h after p.o. IPdR, Athymic mice tolerated oral IPdR at up to 1500 mg/kg/day given four times per day for 6-14 days without significant systemic toxicities. In anticipation of an investigational new drug application for the first clinical Phase I and pharmacology study of oral IPdR in humans, we studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species. For the IPdR systemic toxicity and toxicology study, twenty-four male or female ferrets were randomly assigned to four IPdR dosage groups receiving 0, 15, 150, and 1500 mg/kg/day by oral gavage x 14 days prior to sacrifice on study day 15, All ferrets survived the 14-day treatment. Ferrets receiving 1500 mg/kg/day showed observable systemic toxicities with diarrhea, emesis, weight loss, and decreased motor activity beginning at days 5-8 of the 14-day schedule. Overall, both male and female ferrets receiving IPdR at 1500 mg/kg/day experienced significant weight loss (9 and 19%, respectively) compared with controls after the 14-day treatment, No weight loss or other systemic toxicities were observed in other IPdR dosage groups, Grossly, no anatomical lesions were noted at complete necropsy, although liver weights were increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microscopic changes in liver consisting of minimal to moderate cytoplasmic vacuolation of hepatocytes, which either occurred in the periportal area (high dosage group) or diffusely throughout the liver (lower dosage groups). Female ferrets in the highest IPdR dose group also showed decreased kidney and uterus weights at autopsy without any associated histological changes. No histological changes were found in central nervous system tissues. No significant abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was decreased to approximately 50 and 30% of control ferrets in the two higher IPdR dosage groups, respectively, after the 14-day treatment period, The % IUdR-DNA incorporation in ferret bone marrow at the completion of IPdR treatment was less than or equal to 0.05% in the two lower dosage groups and congruent to 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liver was less than or equal to 0.05% in all IPdR dosage groups, In a pharmacokinetic study in four Rhesus monkeys, we determined the plasma concentrations of IPdR after a single i.v. bolus of 50 mg/kg over 20 min, Using a two-compartment model to fit the plasma pharmacokinetic data, we found that IPdR was cleared in these non-human primates in a biexponential manner with an initial rapid distributive phase (mean T(1/2)alpha = 6.5 min), followed by an elimination phase with a mean T(1/2)beta of 63 min. The mean maximum plasma concentration of IPdR was 124 +/- 43 mu M with a mean total body clearance of 1.75 +/- 0.95 I/h/kg. IPdR was below detection (<0.5 mu M) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day schedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previously in athymic mice. However, no significant hematological, biochemical, or histopathological changes were found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent in ferret liver, suggesting partial enzyme saturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied to the design of an initial clinical Phase I study of p.o. IPdR as a radiosensitizer. C1 Univ Hosp Cleveland, Ireland Canc Ctr, Dept Radiat Oncol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Radiat Oncol, Cleveland, OH 44106 USA. NCI, Clin Pharmacol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Argus Res Labs, Horsham, PA 19044 USA. SuperGen Pharmaceut, San Ramon, CA 94583 USA. RP Kinsella, TJ (reprint author), Univ Hosp Cleveland, Ireland Canc Ctr, Dept Radiat Oncol, LTR 6068,Room B-181,11100 Euclid Ave, Cleveland, OH 44106 USA. FU NCI NIH HHS [R44-CA76835, R0-1 CA50595] NR 37 TC 14 Z9 15 U1 2 U2 4 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 SEP PY 2000 VL 6 IS 9 BP 3670 EP 3679 PG 10 WC Oncology SC Oncology GA 352NK UT WOS:000089224600043 PM 10999760 ER PT J AU Wu, K Kim, HT Rodriquez, JL Munoz-Medellin, D Mohsin, SK Hilsenbeck, SG Lamph, WW Gottardis, MM Shirley, MA Kuhn, JG Green, JE Brown, PH AF Wu, K Kim, HT Rodriquez, JL Munoz-Medellin, D Mohsin, SK Hilsenbeck, SG Lamph, WW Gottardis, MM Shirley, MA Kuhn, JG Green, JE Brown, PH TI 9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice SO CLINICAL CANCER RESEARCH LA English DT Article ID 9-CIS RETINOIC ACID; SQUAMOUS-CELL CARCINOMA; ACUTE PROMYELOCYTIC LEUKEMIA; BREAST-CANCER CELLS; 2ND PRIMARY TUMORS; PHASE-I TRIAL; ALL-TRANS; 13-CIS-RETINOIC ACID; INTERFERON ALPHA-2A; LGD1069 TARGRETIN AB Retinoids have been investigated as potential agents for the prevention and treatment of human cancers, These compounds play an important role in regulating cell growth, differentiation, and apoptosis, 9-cis-Retinoic acid (9cRA) is a naturally occurring ligand with a high affinity for both the retinoic acid receptors and the retinoid X receptors, We hypothesized that treatment with 9cRA would prevent mammary tumorigenesis in transgenic mice that spontaneously develop mammary tumors. To test this hypothesis, C3(1)-SV40 T antigen (Tag) mice, which develop mammary tumors by the age of 6 months, were treated daily p.o. with vehicle or two different dose Levels of 9cRA (10 or 50 mg/kg) from 5 weeks to 6 months of age, Tumor size and number were measured twice each week, and histological samples of normal and malignant tissue were obtained from each mouse at time of sacrifice. Our results demonstrate that 9cRA suppresses mammary tumorigenesis in C3(1)-SV40 Tag-transgenic mice, Time to tumor development was significantly delayed in treated mice; median time to tumor formation for vehicle-treated mice was 140 days versus 167 days for mice treated with 50 mg/kg 9cRA (P = 0.05), In addition, the number of tumors per mouse was reduced by >50% in mice treated with 9cRA (3.43 for vehicle, 2.33 For 10 mg/kg 9cRA, and 1.13 for 50 mg/kg 9cRA, P less than or equal to 0.002), Histological analysis of the mammary glands from vehicle and treated mice demonstrated that 9cRA treatment also did not affect normal mammary gland development, Immunohistochemical staining of normal and malignant breast tissue and Western blot analysis demonstrated that SV40 Tag expression was not affected by treatment with retinoids, Single doses of 10 and 50 mg/kg resulted in peak plasma concentrations of 3.4 and 6.71 mu M, respectively. Daily doses of 9cRA for 28 days resulted in plasma concentrations of 0.86 and 1.68 mu M, respectively, concentrations consistent with that seen in humans treated with 9cRA in clinical trials. These results demonstrate that 9cRA suppresses mammary carcinogenesis in transgenic mice without any major toxicity and suggest that retinoids are promising agents for the prevention of human breast cancer. C1 Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Med Oncol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. Ligand Pharmaceut Inc, Dept Retinoid Res, San Diego, CA 92121 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Brown, PH (reprint author), Baylor Coll Med, Breast Ctr, 1 Baylor Plaza,MS 600, Houston, TX 77030 USA. FU NCI NIH HHS [P30CA54174, SR01CA78480, CA 54174] NR 53 TC 52 Z9 53 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2000 VL 6 IS 9 BP 3696 EP 3704 PG 9 WC Oncology SC Oncology GA 352NK UT WOS:000089224600046 PM 10999763 ER PT J AU Le, YY Jiang, S Hu, JY Gong, WH Su, SB Dunlop, NM Shen, WP Li, BQ Wang, JM AF Le, YY Jiang, S Hu, JY Gong, WH Su, SB Dunlop, NM Shen, WP Li, BQ Wang, JM TI N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes SO CLINICAL IMMUNOLOGY LA English DT Article DE N36 peptide; HIV-1 gp 41; chemoattractant receptor; phagocyte ID IMMUNODEFICIENCY-VIRUS TYPE-1; SERUM AMYLOID-A; FORMYL PEPTIDE RECEPTOR; POLYMORPHONUCLEAR LEUKOCYTES; TRANSMEMBRANE GLYCOPROTEIN; PULMONARY TUBERCULOSIS; SUPEROXIDE PRODUCTION; COUPLED RECEPTOR; ATOMIC-STRUCTURE; MONOCYTES AB Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral fusion with human host cells. In this study we show that N36, a synthetic peptide derived from the N-terminus of gp41, induced directional migration and calcium mobilization in human monocytes and neutrophils, The activity of N36 on phagocytes was pertussis toxin sensitive, suggesting involvement of a Gi-coupled seven-transmembrane receptor(s), Since high concentrations of the bacterial chemotactic peptide fMet-Leu-Phe (fMLF) partially desensitized the calcium mobilizing activity of N36 in phagocytes, we postulated that N36 might use a low-affinity fMLF receptor. By using cells stably expressing fMLF receptor FPR or FPRL1, we demonstrate that N36 uses FPRL1 as a functional receptor. Our results suggest that HIV-1 gp41 may contain a fragment(s) that activates the innate host immune cells through FPRL1, Since the activation of FPRL1 in monocytes has been shown to heterologously desensitize chemokine receptors, the reduced phagocyte response to chemoattractants seen in AIDS patients may be attributed, at least in part, to heterologous desensitization. (C) 2000 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Ft Detrick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Ft Detrick, MD 21702 USA. New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA. RP Wang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Bldg 560,Room 31-40, Ft Detrick, MD 21702 USA. RI Jiang, Shibo/L-4500-2014 FU NCI NIH HHS [N01-CO-56000] NR 37 TC 26 Z9 29 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD SEP PY 2000 VL 96 IS 3 BP 236 EP 242 DI 10.1006/clim.2000.4896 PG 7 WC Immunology SC Immunology GA 353XC UT WOS:000089299900009 PM 10964542 ER PT J AU Gilron, I Max, MB Lee, G Booher, SL Sang, CN Chappell, AS Dionne, RA AF Gilron, I Max, MB Lee, G Booher, SL Sang, CN Chappell, AS Dionne, RA TI Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID IONOTROPIC GLUTAMATE RECEPTORS; SPINAL-CORD; CENTRAL SENSITIZATION; NOCICEPTIVE RESPONSE; KAINATE; HYPERALGESIA; AMPA; NMDA; RAT; FORMALIN AB Background: Previous studies suggest that 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA)/kainate antagonists reduce experimentally induced pain. There have been no studies of AMPA/kainate antagonists in clinical pain. Methods: Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 30 mg) and placebo in a randomized, double-blind, parallel-group study after oral surgery (n = 70). Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. Results: High-dose LY293558 and ketorolac tromethamine were superior to placebo (P < .05) for pain evoked by mouth opening and one of several measures of spontaneous pain: SPID240 +/- SEM for pain evoked by mouth opening was highest for ketorolac tromethamine (151 +/- 58), intermediate for high-dose LY293558 (-45 +/- 35), and least for low-dose LY293558 (-151 +/- 39) and placebo (-162 +/- 50). High-dose LY293558 was superior to placebo at individual time points (45 to 240 minutes) for pain evoked by mouth opening but not for spontaneous pain. The spontaneous summed pain intensity difference over 240 minutes (SPID240 +/- SEM) was highest for ketorolac tromethamine (303 +/- 84), intermediate for high-dose LY293558 (-51 +/- 40) and low-dose LY293558 (-96 +/- 45), and least for placebo (-180 +/- 24), LY293558 was well tolerated, with dose-dependent and reversible side effects including hazy vision in 20% of patients and sedation in 15%. Conclusions: This is the first evidence that an AMPA/kainate antagonist reduces clinical pain. Tests of evoked pain may be more sensitive to certain analgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful compounds otherwise missed if only spontaneous pain is evaluated. C1 Natl Inst Dental & Cranofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Gilron, I (reprint author), Natl Inst Dental & Cranofacial Res, Pain & Neurosensory Mech Branch, NIH, Rm 3C-434, Bethesda, MD 20892 USA. NR 30 TC 49 Z9 50 U1 1 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2000 VL 68 IS 3 BP 320 EP 327 DI 10.1067/mcp.2000.108677 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 358LR UT WOS:000089560000012 PM 11014414 ER PT J AU Li, AG Hou, YS Wall, GW Trent, A Kimball, BA Pinter, PJ AF Li, AG Hou, YS Wall, GW Trent, A Kimball, BA Pinter, PJ TI Free-air CO2 enrichment and drought stress effects on grain filling rate and duration in spring wheat SO CROP SCIENCE LA English DT Article ID TRITICUM-AESTIVUM L; WINTER-WHEAT; TEMPERATURE; GROWTH; GENOTYPES; FIELD; YIELD AB Wheat grain weight is a function of rate and duration of grain growth and is affected by photosynthate supply. Drought stress reduces photosynthate production because of stomatal closure. However, this might be partially overcome by an increase in air CO2 concentration. This study was conducted to evaluate elevated CO2 and drought stress effects on grain-filling rate and duration for spring wheat (Triticum aestivum L.), Spring wheat (cv. Yecora Roja) was grown at two CO2 concentrations, 550 (elevated) or 370 (ambient) pmol mol(-1) and two water treatments in a Free-Air CO2 Enrichment (FACE) system at the University of Arizona Maricopa Agricultural Center. Plant samples were collected every 3 to 4 d from 6 d after anthesis until plant maturity. Main stem spikes were separated into upper, middle, and lower sections. Grain weight data for the intact main stem spike, each of its sections, and intact tiller spikes were fitted to a cumulative logistic model. Both elevated CO2 and water treatments significantly influenced the grain-filling processes. Under drought stress conditions, elevated CO2 increased grain weight in the upper and lower sections of the main stem spike by 10 and 24%, respectively. In well-watered plants, final grain weight in the midsection of the main stem spike was 8% higher than that measured under drought stress conditions. Grain weight increase under elevated CO2 was due to a faster rate of grain filling. Effects of elevated CO2 on the statistically derived duration of grain tilling were inconclusive because of the confounding effect of blower-induced temperature changes on the process. An increase in grain weight of well-watered plants was due to a longer grain-tilling period. Later-formed tiller spikes were more responsive to elevated CO2 and drought stress than main stem spikes. Information from this study will help us understand the grain growth of wheat and provide information to establish grain growth mechanism. C1 NEI, NIH, Bethesda, MD 20892 USA. Washington State Univ, USDA ARS, Weed Sci Lab, Pullman, WA 99164 USA. USDA ARS, US Water Conservat Lab, Phoenix, AZ 85040 USA. Univ Idaho, Dept Plant Soil & Entomol Sci, Moscow, ID 83844 USA. RP Li, AG (reprint author), NEI, NIH, Bld 6 Rm 304,6 Ctr Dr, Bethesda, MD 20892 USA. NR 29 TC 24 Z9 36 U1 2 U2 11 PU CROP SCIENCE SOC AMER PI MADISON PA 677 S SEGOE ROAD, MADISON, WI 53711 USA SN 0011-183X J9 CROP SCI JI Crop Sci. PD SEP-OCT PY 2000 VL 40 IS 5 BP 1263 EP 1270 PG 8 WC Agronomy SC Agriculture GA 359LP UT WOS:000089612600010 ER PT J AU Longo, DL AF Longo, DL TI Lymphomas: complexity, not chaos SO CURRENT OPINION IN ONCOLOGY LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; EXPRESSION C1 NIA, NIH, Baltimore, MD 21224 USA. RP Longo, DL (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 6 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2000 VL 12 IS 5 BP 379 EP 382 DI 10.1097/00001622-200009000-00001 PG 4 WC Oncology SC Oncology GA 442BH UT WOS:000169265000001 PM 10975543 ER PT J AU Baris, D Zahm, SH AF Baris, D Zahm, SH TI Epidemiology of lymphomas SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID NON-HODGKINS-LYMPHOMA; HEPATITIS-C VIRUS; EPSTEIN-BARR-VIRUS; MULTICENTER CASE-CONTROL; AIDS-RELATED LYMPHOMA; HAIR DYE USE; BONE-MARROW TRANSPLANTATION; PRIMARY EFFUSION LYMPHOMA; SOFT-TISSUE SARCOMA; FRANCISCO BAY AREA AB Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the US, with about 55,000 new cases estimated for the year 2000. According to the new Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 1997, the age-adjusted incidence rates rose by about 80%, with an annual percentage increase of nearly 3%, which is faster than for the majority of cancers. The increasing incidence of NHL is largely unexplained. AIDS-related NHL accounts for some but not all of the increase. The American Cancer Society predicts about 7,400 new cases of Hodgkin Disease (HD) in the year 2000 in the US. The incidence of HD is consistently lower than that of NHL, and has decreased about 16% since the 1970s. Only a small portion of the decrease in HD incidence can be explained by misdiagnosis of HD as NHL. Further research is needed on the cofactors that predispose AIDS cases to lymphoma, as well as other possible causes of NHL such as immunosuppression, genetics, viruses, medical conditions, pesticides, solvents, hair dyes, and diet. Further evaluation of the role of viruses, occupational exposures, and genetics in the etiology of HD should prove valuable. Curr Opin Oncol 2000, 12:383-394 (C) 2000 Lippincott Williams & Wilkins. C1 NCI, Div Canc Epidemiol & Genet, EPS 8122, Bethesda, MD 20892 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8122, 6120 Execut Blvd, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 171 TC 75 Z9 79 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2000 VL 12 IS 5 BP 383 EP 394 DI 10.1097/00001622-200009000-00002 PG 12 WC Oncology SC Oncology GA 442BH UT WOS:000169265000002 PM 10975544 ER PT J AU Little, RF Yarchoan, R Wilson, WH AF Little, RF Yarchoan, R Wilson, WH TI Systemic chemotherapy for HIV-associated lymphoma in the era of highly active antiretroviral therapy SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID NON-HODGKINS-LYMPHOMA; LARGE-CELL LYMPHOMA; ACQUIRED IMMUNODEFICIENCY SYNDROME; COLONY-STIMULATING FACTOR; INTENSIVE CHEMOTHERAPY; M-BACOD; INFUSIONAL CYCLOPHOSPHAMIDE; COMBINATION CHEMOTHERAPY; MALIGNANT-LYMPHOMA; RANDOMIZED TRIAL AB Treatment of AIDS-associated non-Hodgkin lymphoma poses a complex and multifaceted challenge for the physician. Treatment responses to cytotoxic chemotherapy are relatively poor, relapse rates are high. and AIDS progression continues to be a major concern in patients receiving dose-intensive anti-lymphoma therapy. The recent advances in anti-HIV therapy have not seen a clear counterpart in improved anti-lymphoma therapy, but trials are underway that may help move this field forward. For patients who achieve a complete and durable response to anti-lymphoma therapy, potent antiretroviral therapy may help improve the prognosis from AIDS progression. Major questions persist, however, on the role of chemotherapy dose intensity, the best use of antiretroviral therapy during the administration of lymphoma therapy, and the optimal design of studies that can address these questions. Curt Opin Oncol 2000, 12:438-444 (C) 2000 Lippincott Williams & Wilkins, Inc. C1 NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Little, RF (reprint author), Bldg 10 Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 56 TC 15 Z9 15 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2000 VL 12 IS 5 BP 438 EP 444 DI 10.1097/00001622-200009000-00009 PG 7 WC Oncology SC Oncology GA 442BH UT WOS:000169265000009 PM 10975551 ER PT J AU Cornelison, TL AF Cornelison, TL TI Human papillomavirus genotype 16 vaccines for cervical cancer prophylaxis and treatment SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID VIRUS-LIKE PARTICLES; ANTITUMOR IMMUNITY; NEUTRALIZING ANTIBODIES; HUMAN KERATINOCYTES; NASAL IMMUNIZATION; TYPE-16 HPV-16; DNA VACCINE; CELL-CYCLE; HPV16; MICE AB More than 11% of the global cancer incidence in females is due to human papillomavirus (HPV) infections, with HPV genotype 16 the most prevalent viral type to infect the cervix. Vaccine strategies currently target HPV 16 genes E6 and E7, constitutively expressed in cervical cancer cells, acid L1 and L2, HPV surface antigens. Recent developments in HPV vaccine research are reviewed. Most studies focus on vaccine models showing improved immunogenicity or dual induction of both humeral and cellular systems. Preclinical studies show that (1) L1/E7 chimeric viral-like proteins induce both neutralizing Lf antibodies and E7-specific T cells; (2) rerouting a cytosolic tumor antigen into the endosomal/lysosomal compartment can improve the therapeutic potency of DNA vaccines; and (3) accelerated E7 protein degradation leads to enhanced antigen presentation in the context of major histocompatability complex class I. Clinical studies show that (1) HPV 16 E7 peptide vaccination can be safely delivered to patients with terminal disease; and (2) HPV-16 capsid proteins harbor at least one HLA-A*201 restricted cytotoxic T lymphocyte (CTL) epitope. Curr Opin Oncol 2000. 12:466-473 (C) 2000 Lippincott Williams & Wilkins. Inc. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Johns Hopkins Hosp & Med Inst, Dept Gynecol & Obstet, Kelly Gynecol Oncol Serv, Baltimore, MD 21287 USA. RP Cornelison, TL (reprint author), NCI, Div Canc Prevent, Execut Plaza N,Suite 300,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2000 VL 12 IS 5 BP 466 EP 473 DI 10.1097/00001622-200009000-00014 PG 8 WC Oncology SC Oncology GA 442BH UT WOS:000169265000014 PM 10975555 ER PT J AU Yang, X van Beest, M Clevers, H Jones, T Hursh, DA Mortin, MA AF Yang, X van Beest, M Clevers, H Jones, T Hursh, DA Mortin, MA TI decapentaplegic is a direct target of dTcf repression in the Drosophila visceral mesoderm SO DEVELOPMENT LA English DT Article DE decapentaplegic (dpp); T cell factor (Tcf); lymphocyte enhancer binding factor (Lef); transforming growth factor beta; transcriptional repression; wingless; WNT signalling ID TRANSCRIPTION FACTOR LEF-1; BETA-CATENIN; MIDGUT MORPHOGENESIS; GENE-EXPRESSION; WINGLESS SIGNAL; HOMEOTIC GENES; GERM LAYERS; FACTOR TCF; ARMADILLO; XENOPUS AB Drosophila T cell factor (dTcf) mediates transcriptional activation in the presence of Wingless signalling and repression in its absence. Wingless signalling is required for the correct expression of decapentaplegic (dpp), a Transforming Growth Factor beta family member, in parasegments 3 and 7 of the Drosophila visceral mesoderm. Here we demonstrate that a dpp enhancer element, which directs expression of a reporter gene in the visceral mesoderm in a pattern indistinguishable from dpp, has two functional dTcf binding sites. Mutations that reduce or eliminate Wingless signalling abolish dpp reporter gene expression in parasegment 3 and reduce it in parasegment 7 while ectopic expression of Wingless signalling components expand reporter gene expression anteriorly in the visceral mesoderm. However, mutation of the dTcf binding sites in the dpp enhancer results in ectopic expression of reporter gene expression throughout the visceral mesoderm, with no diminution of expression in the endogenous sites of expression. These results demonstrate that the primary function of dTcf binding to the dpp enhancer is repression throughout the visceral mesoderm acid that activation by Wingless signalling is probably not mediated via these dTcf binding sites to facilitate correct dpp expression in the visceral mesoderm. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ Utrecht Hosp, Ctr Biomed Genet, Dept Immunol, NL-3584 CX Utrecht, Netherlands. American Univ, Dept Biol, Washington, DC 20016 USA. RP Mortin, MA (reprint author), NCI, Biochem Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. RI Mortin, Mark/B-4251-2008 NR 41 TC 40 Z9 40 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 0950-1991 J9 DEVELOPMENT JI Development PD SEP PY 2000 VL 127 IS 17 BP 3695 EP 3702 PG 8 WC Developmental Biology SC Developmental Biology GA 356EE UT WOS:000089430700005 PM 10934014 ER PT J AU Glantz, MD Leshner, AI AF Glantz, MD Leshner, AI TI Drug abuse and developmental psychopathology SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Review ID ADOLESCENT SUBSTANCE USE; PROBLEM-BEHAVIOR; USE DISORDERS; HIGH-RISK; PSYCHIATRIC COMORBIDITY; ANTISOCIAL-BEHAVIOR; FUTURE-DIRECTIONS; MIDDLE CHILDHOOD; MENTAL-DISORDERS; FAMILY AB Drug abuse research and theory has become much more sophisticated over the last 2 decades, and some of the advancements parallel concepts that are part of the developmental psychopathology approach. The application of the developmental psychopathology perspective to recent drug abuse research findings can provide a greater understanding of that information and point to important areas of future research. Among the drug abuse research areas discussed here and viewed from this perspective are antecedent and co-occurring psychopathological conditions and other problem behaviors; the diversity of the nature of, paths to, and processes and outcomes related to drug abuse; the role of intermediary influences. the interaction of individual and environmental predisposing and protective factors; the role of families and other social institutions in intervention; and developmental stage characteristics. Directions for future research are also discussed. C1 Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Glantz, MD (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, 6001 Execut Blvd,Suite 5153 MSC 9589, Bethesda, MD 20892 USA. NR 117 TC 36 Z9 37 U1 5 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FAL PY 2000 VL 12 IS 4 BP 795 EP 814 DI 10.1017/S0954579400004120 PG 20 WC Psychology, Developmental SC Psychology GA 390PA UT WOS:000166304500012 PM 11202044 ER PT J AU Hastings, PD Zahn-Waxler, C Robinson, J Usher, B Bridges, D AF Hastings, PD Zahn-Waxler, C Robinson, J Usher, B Bridges, D TI The development of concern for others in children with behavior problems SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article ID VICARIOUS EMOTIONAL RESPONSIVENESS; PRO-SOCIAL DEVELOPMENT; PROSOCIAL BEHAVIOR; RATING-SCALE; INDIVIDUAL-DIFFERENCES; REARING PRACTICES; YOUNG-CHILDREN; HEART-RATE; EMPATHY; MOTHERS AB The development of concern for others and externalizing problems were examined in young children with normative, subclinical, or clinical levels of behavior problems. There were no group differences in observable concern for others at 4-5 years of age, Children with clinical behavior problems decreased significantly in their concern by 6-7 years of age and were reported to have less concern at 6-7 years by mothers, teachers, and the children themselves, relative to other groups. Boys with clinical problems were more callous to others' distress at both time points. Girls showed more concern than boys across risk, time, and measures. Greater concern at 4-5 years predicted decreases in the stability and severity of externalizing problems by 6-7 years, and greater concern at 6-7 years predicted decreases in the stability of problems by 9-10 years. Finally, maternal socialization approaches predicted later concerned responding. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Colorado, Prevent Res Ctr Family & Child Hlth, Boulder, CO 80309 USA. Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. RP Hastings, PD (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 15-K,Room 100,15 North Dr, Bethesda, MD 20892 USA. NR 83 TC 142 Z9 146 U1 1 U2 38 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD SEP PY 2000 VL 36 IS 5 BP 531 EP 546 DI 10.1037//0012-1649.36.5.531 PG 16 WC Psychology, Developmental SC Psychology GA 349LW UT WOS:000089047400001 PM 10976595 ER PT J AU Lindsay, RS Hanson, RL Bennett, PH Knowler, WC AF Lindsay, RS Hanson, RL Bennett, PH Knowler, WC TI Secular trends in birth weight, BMI, and diabetes in the offspring of diabetic mothers SO DIABETES CARE LA English DT Article ID GLUCOSE-TOLERANCE; FETAL HYPERINSULINISM; PREGNANCY; CHILDREN; OBESITY AB OBJECTIVE - The offspring of mothers who had diabetes during pregnancy experience increased risk later of diabetes and obesity later. We hypothesized that, in light of the historical improvements in the management of diabetes during pregnancy, these late consequences of the early environment might be diminishing with time. RESEARCH DESIGN AND METHODS - Birth weight and information on BMI and glucose tolerance have been collected as part of the epidemiological survey of the Gila River Indian Community in Arizona. We examined birth weight, BMI, and diabetes in offspring of mothers with type 2 diabetes during pregnancy born in four 10-year time intervals since 1955 compared with offspring whose mothers either had not developed diabetes or were prediabetic (i.e., developed diabetes after the index pregnancy). RESULTS - Offspring of diabetic mothers (ODM) were heavier at birth, had a higher BMI at all ages throughout childhood, and had an increased incidence rate of diabetes in childhood and early adulthood (7- to 20-fold, offspring of nondiabetic mothers [ONDM]; 3- to 5-fold, offspring of prediabetic mothers [OPDM]). Relative differences in birth weight and BMI between ODM and ONDM were greatest for those born before 1965. In those born after 1965, despite secular trends to higher BMI and diabetes incidence in the ONDM, differences in BMI and birth weight of ODM versus ONDM and OPDM appeared to have been maintained. CONCLUSIONS - With the possible exception of individuals born before 1965, the increased risk of diabetes and obesity experienced by ODM does not seem to be diminishing with time. C1 NIDDK, NIH, Phoenix, AZ 85014 USA. RP Lindsay, RS (reprint author), NIDDK, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 12 TC 51 Z9 53 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2000 VL 23 IS 9 BP 1249 EP 1254 DI 10.2337/diacare.23.9.1249 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 348UT UT WOS:000089005400008 PM 10977014 ER PT J AU Gregg, EW Breckles, GLA Williamson, DF Leveille, SG Langlois, JA Engelgau, MM Narayan, KMV AF Gregg, EW Breckles, GLA Williamson, DF Leveille, SG Langlois, JA Engelgau, MM Narayan, KMV TI Diabetes and physical disability among older US adults SO DIABETES CARE LA English DT Article ID MEDICAL CONDITIONS; RISK-FACTORS; FALLS; EXERCISE; COMPLICATIONS; ASSOCIATION; PREDICTORS; PREVALENCE; AGREEMENT; MELLITUS AB OBJECTIVE - To estimate the prevalence of physical disability associated with diabetes among U.S. adults greater than or equal to 60 years of age. RESEARCH DESIGN AND METHODS - We analyzed data from a nationally representative sample of 6,588 community-dwelling men and women greater than or equal to 60 years of age who participated in the Third National Health and Nutrition Examination Survey Diabetes and comorbidities (coronary heart disease, intermittent claudication, stroke, arthritis, and visual impairment) were assessed by questionnaire. Physical disability was assessed by self-reported ability to walk one-fourth of a mile, climb 10 steps, and do housework. Walking speed. lower-extremity function, and balance were assessed using physical performance rests. RESULTS - Among subjects greater than or equal to 60 years of age with diabetes, 32% of women and 15% of men reported an inability to walk one-fourth of a mile, climb stairs, or do housework compared with 14% of women and 8% of men without diabetes. Diabetes was associated with a 2- to 3-fold increased odds of not being able to do each task among both men and women and up to a 3.6-fold increased risk of not being able to do all 3 tasks. Among women, diabetes was also associated with slower walking speed, inferior lower-extremity function, decreased balance, and an increased risk of falling. Of the >5 million U.S. adults greater than or equal to 60 years of age with diabetes, 1.2 million are unable to do major physical tasks. CONCLUSIONS - Diabetes is associated with a major burden of physical disability in older U.S. adults, and these disabilities are likely to substantially impair their quality of life. C1 Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30341 USA. Ctr Dis Control & Prevent, Div Acute Crae Rehabil & Disabil Res, Atlanta, GA 30341 USA. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. RP Gregg, EW (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, 4770 Buford Highway NE,Mailstop K-68, Atlanta, GA 30341 USA. RI Narayan, K.M. Venkat /J-9819-2012 OI Narayan, K.M. Venkat /0000-0001-8621-5405 NR 29 TC 252 Z9 256 U1 2 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2000 VL 23 IS 9 BP 1272 EP 1277 DI 10.2337/diacare.23.9.1272 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 348UT UT WOS:000089005400012 PM 10977018 ER PT J AU Celi, FS Negri, C Tanner, K Raben, N De Pablo, F Rovira, A Pallardo, LF Martin-Vaquero, P Stern, MP Mitchell, BD Shuldiner, AR AF Celi, FS Negri, C Tanner, K Raben, N De Pablo, F Rovira, A Pallardo, LF Martin-Vaquero, P Stern, MP Mitchell, BD Shuldiner, AR TI Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE genetics; insulin resistance; noninsulin dependent diabetes mellitus; obesity; single-stranded conformational polymorphisms ID PIMA-INDIANS; BETA(3)-ADRENERGIC-RECEPTOR GENE; POLYGENIC DISEASE; COMMON VARIANT; NIDDM; POLYMORPHISMS; RESISTANCE; ONSET; MICE; DISRUPTION AB Background Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays an important role in insulin signaling. Mutations in the IRS-1 gene are associated in some populations with obesity and Type 2 diabetes. Methods To determine whether variation in the IRS-1 gene contributes to genetic susceptibility to insulin resistance and Type 2 diabetes in Mexican Americans, the entire coding region of the IRS-1 gene was screened for variation in 31 unrelated subjects with Type 2 diabetes using single-stranded conformational polymorphism analysis (SSCP) and dideoxy sequence analysis. Variants encoding amino acid substitutions were genotyped in 27 unrelated nondiabetic Mexican Americans and in all family members of subjects containing these variants, and association analyses were performed. To trace the ancestral origins of the variants, Iberian Caucasians and Pima Indians were also genotyped. Results Eight single base changes were found: four silent polymorphisms and four missense mutations (Ala94Thr, Ala512Pro, Ser892Gly and Gly971Arg). Allele frequencies were 0.009, 0.017, 0.017 and 0.043, respectively. There were no significant associations of any of these variants with diabetes, glucose or insulin levels during an oral glucose tolerance test, or with body mass index (BMI) in Mexican American families except for a modest association between the Ala94Thr variant and decreased BMI (30.4 kg/m(2) vs 24.0 kg/m(2); p=0.035). None of these four missense mutations were detected in Pima Indians. In Iberian Caucasians, neither Ala94Thr nor Ser892Gly were detected, and Ala512Pro was detected in only 0/60 diabetic patients and 1/60 nondiabetic controls. Gly971Arg was relatively more common in Iberian Caucasians with 12/58 diabetic patients and 7/60 nondiabetic controls being heterozygous for this variant (p = 0.21 for comparison between diabetic and nondiabetic subjects). Conclusions Ala94Thr, Ala512Pro and Ser892Gly mutation are rare in the populations studied. Gly971Arg, is more common in Mexican Americans and Caucasians, but is not a major contributor to genetic susceptibility to Type 2 diabetes. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Univ Rome La Sapienza, Dipartimento Med Sperimentale & Patol, Rome, Italy. Johns Hopkins Univ, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Baltimore, MD 21224 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. CSIC, Ctr Invest Biol, Madrid, Spain. Fdn Jimenez Diaz, Serv Endocrinol, E-28040 Madrid, Spain. Hosp Univ La Paz, Unidad Diabet, Madrid, Spain. Univ Texas, Hlth Sci Ctr, Dept Med, Div Clin Epidemiol, San Antonio, TX 78284 USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA. RP Shuldiner, AR (reprint author), Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, 725 W Lombard St,Room S-422, Baltimore, MD 21201 USA. OI Mitchell, Braxton/0000-0003-4920-4744 NR 52 TC 17 Z9 19 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1520-7552 J9 DIABETES METAB RES JI Diabetes-Metab. Res. Rev. PD SEP-OCT PY 2000 VL 16 IS 5 BP 370 EP 377 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 366VJ UT WOS:000090026700008 PM 11025561 ER PT J AU Hsu, IC Shih, WK Lovchik, J Wang, YH Kong, D AF Hsu, IC Shih, WK Lovchik, J Wang, YH Kong, D TI Mismatch cleavage detects pathogenic microorganisms SO DIAGNOSTIC MOLECULAR PATHOLOGY LA English DT Article DE mismatch cleavage; mutY; Chlamydia trachomatis; human immunodeficiency virus type 1; mismatch repair enzyme ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYSTIC-FIBROSIS GENE; CHLAMYDIA-TRACHOMATIS; REPAIR ENZYMES; DNA; MUTATIONS; SEQUENCE; ELECTROPHORESIS; POLYMERASE; SUBTYPE AB When a DNA probe hybridizes a DNA target and generates a G/A mismatch in the probe-target DNA heteroduplex, the mismatch enzyme, mutY, will cut the A base at the site of the mismatch. This specific cleavage at the mismatched A on the known probe will reveal the complementary DNA sequences of the targets. This study shows mismatch cleavage assays identify the complementary sequence of cryptic plasmid target in the extract of chlamydia infected cells in culture. In addition, the specific cleavage at a single base permits differentiation of two sequences with one base difference. This was shown in differentiating the subtypes of human immunodeficiency virus (HIV) type 1. The addition of amines in the assays increases the sensitivity by freeing the target for recycling. The combined assay system of high sensitivity and demonstrated specificity allows further evaluation for direct identification of pathogenic microorganisms in patient samples. C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Dept Pathol, Toxicol Program, Baltimore, MD 21201 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD USA. RP Hsu, IC (reprint author), Univ Maryland, Sch Med, Dept Pathol, 10 S Pine St, Baltimore, MD 21201 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1052-9551 J9 DIAGN MOL PATHOL JI Diagn. Mol. Pathol. PD SEP PY 2000 VL 9 IS 3 BP 172 EP 176 DI 10.1097/00019606-200009000-00008 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pathology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pathology GA 348UX UT WOS:000089005800008 PM 10976725 ER PT J AU Chen, LP Hardwick, JP McPhie, P Sitkovsky, MV Jacobson, KA AF Chen, LP Hardwick, JP McPhie, P Sitkovsky, MV Jacobson, KA TI Purification and recognition of recombinant mouse P2X(1) receptors expressed in a baculovirus system SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE ion channels; nucleotides; affinity chromatography; agonist; binding site ID GATED ION CHANNELS; POLYACRYLAMIDE-GEL ELECTROPHORESIS; EXTRACELLULAR ATP; NADPH-P450 OXIDOREDUCTASE; ENDOPLASMIC-RETICULUM; STRUCTURAL MOTIF; CATION CHANNELS; P-2X RECEPTORS; PROTEIN; ACTIVATION AB The hexahistidine-tagged mouse P2X(1) receptor (H-mP2X(1)R), an ATP-gated ion channel receptor, was expressed in a baculovirus system using the pAcHLT-B transfer vector containing a hexahistidine tag. Both widely used denaturing (8M urea) acid nondenaturing (such as 1% Triton X-100) solubilization conditions were compared, resulting in about 30% of the P2X(1) receptors being solubilized (S1). However, at pH 13 most of the n-mP2X(1)R from the initially insoluble pellet fraction was solubilized (S2) and remained in the soluble fraction (S3) after dialyzing against a nondenaturing buffer. H-mP2X(1)Rs were purified sequentially through cobalt and ATP affinity columns. Receptors purified from S3 had higher purity than those from S1 (i.e., similar to 90% vs. similar to 75%). Circular dichroism spectra indicated identical protein secondary structures of the receptors from both sources. Autoradiographic data showed that the purified receptors from S3 had higher affinity for 8-azido-ATP-gamma-P-32 than the receptors from S1. The binding of 8-azido-ATP-gamma-P-32 to H-mP2X(1)R was inhibited by ATP-gamma -S, alpha,beta -me-ATP, and PPADS, but not by a nucleoside analog (N-6-methyl-2'-deoxy-adenosine). In the presence of 2 mM Ca2+ or Mg2+ the binding was increased, but not when using a partially purified receptor fraction, in which unidentified proteins bound 8-azido ATP-gamma-P-32 or were phosphorylated at 4 degreesC in the presence of 2 mM Mg2+. These data suggest that the decrease in potency of ATP in the presence of Ca2+ and Mg2+, as observed in functional studies, is not due to a direct effect of the cations on the binding of ATP to the receptor. Both cyanogen bromide and hydroxylamine cleavage further confirmed the peptide structure of the purified H-mP2X1R. Autoradiographic analysis of the cleavage products showed that 8-azido-ATP-gamma-P-32 was crosslinked to the carboxyl side of the extracellular domain of the receptor. Drug Dev. Res. 51:7-19, 2000. Published 2000 Wiley-Liss, Inc.dagger C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NE Ohio Univ, Coll Med, Rootstown, OH 44272 USA. NIDDKD, Pharmacol Sect, Biochem Pharmacol Lab, Bethesda, MD 20892 USA. NIAID, LI, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031115-24, Z99 DK999999] NR 49 TC 2 Z9 2 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD SEP PY 2000 VL 51 IS 1 BP 7 EP 19 DI 10.1002/1098-2299(20000901)51:1<7::AID-DDR2>3.0.CO;2-W PG 13 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 366FN UT WOS:000089994300002 PM 22745520 ER PT J AU Puri, RK AF Puri, RK TI IL-4 receptor-directed cytotoxin for therapy of AIDS-associated KS tumors SO DRUG NEWS & PERSPECTIVES LA English DT Article ID CIRCULARLY PERMUTED INTERLEUKIN-4; KAPOSIS-SARCOMA CELLS; COMMON GAMMA-CHAIN; PSEUDOMONAS EXOTOXIN; CARCINOMA-CELLS; FUNCTIONAL COMPONENT; CHIMERIC TOXIN; EXPRESSION; GROWTH; PHOSPHORYLATION AB AIDS-associated Kaposi's sarcoma (AIDS-KS) represents one of the most common malignancies associated with human immunodeficiency virus infection. To target effective therapeutic agents, we have discovered that AIDS-KS cells express high-affinity receptors for interleukin-4 (IL-4), a pleiotropic immune regulatory cytokine. Molecular studies have revealed that AIDS-KS cells express type II IL-4 receptors, in which IL-4 forms a productive complex with primary IL-4 binding protein (IL-4R beta, also known as IL-4R alpha) and a shared subunit between IL-4 and IL-13R systems (IL-13R alpha', also known as IL-13R alpha1). A recombinant fusion protein composed of IL-4 and a mutated form of a powerful bacterial toxin called Pseudomonas exotoxin (PE)-the fusion protein is termed IL4(38-37)-PE38KDEL or cpIL4-PE-was found to be highly and specifically cytotoxic to AIDS-KS cells in vitro. Normal human immune cells (e.g., resting T and B cells and monocytes) or endothelial cells, a possible precursor of AIDS-KS, expressed low numbers of IL-4R and showed little or no sensitivity to cpIL4-PE. Administration of cpIL4-PE in nude mice with established subcutaneously growing AIDS-KS tumors produced remarkable antitumor activity in a dose-dependent manner with the highest dose exhibiting complete responses without any visible toxicity. KS tumors produced metabolic changes including cachexia, hypoglycemia and lymphopenia, all of which were prevented by cpIL4-PE treatment. These studies indicate that cpIL4-PE is a promising experimental therapeutic agent for treatment of AIDS-KS. (C) 2000 Prous Science. Ail rights reserved. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bethesda, MD 20892 USA. NR 38 TC 3 Z9 4 U1 0 U2 0 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0214-0934 J9 DRUG NEWS PERSPECT JI Drug News Perspect. PD SEP PY 2000 VL 13 IS 7 BP 395 EP 402 DI 10.1358/dnp.2000.13.7.858492 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 378JP UT WOS:000165581500002 PM 12937611 ER PT J AU Raymond, GJ Bossers, A Raymond, LD O'Rourke, KI McHolland, LE Bryant, PK Miller, MW Williams, ES Smits, M Caughey, B AF Raymond, GJ Bossers, A Raymond, LD O'Rourke, KI McHolland, LE Bryant, PK Miller, MW Williams, ES Smits, M Caughey, B TI Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease SO EMBO JOURNAL LA English DT Article DE cell-free conversion; chronic wasting disease (CWD); prion protein (PrP); scrapie; transmissible spongiform encephalopathy (TSE) ID PROTEASE-RESISTANT FORMS; PRION PROTEIN; NEUROBLASTOMA-CELLS; NATURAL SCRAPIE; PRP; CONVERSION; BSE; VARIANT AB Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of deer and elk, and little is known about its transmissibility to other species. An important factor controlling interspecies TSE susceptibility is prion protein (PrP) homology between the source and recipient species/genotypes. Furthermore, the efficiency with which the protease-resistant PrP (PrP-res) of one species induces the in vitro conversion of the normal PrP (PrP-sen) of another species to the protease-resistant state correlates with the cross-species transmissibility of TSE agents. Here we show that the CWD-associated PrP-res (PrPCWD) of cervids readily induces the conversion of recombinant cervid PrP-sen molecules to the protease-resistant state in accordance with the known transmissibility of CWD between cervids, In contrast, PrPCWD-induced conversions of human and bovine PrP-sen were much less efficient, and conversion of ovine PrP-sen was intermediate. These results demonstrate a barrier at the molecular level that should limit the susceptibility of these non-cervid species to CWD. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Washington State Univ, USDA ARS, ADRU, Pullman, WA 99164 USA. USDA ARS, Arthropod Borne Anim Dis Res Lab, Laramie, WY 82071 USA. Colorado Div Wildlife, Wildlife Res Ctr, Ft Collins, CO 80526 USA. Univ Wyoming, Dept Vet Sci, Laramie, WY 82070 USA. ID Lelystad Inst Anim Sci & Hlth, Lelystad, Netherlands. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RI smits, mari/J-4892-2013; OI smits, mari/0000-0002-3493-291X; Bossers, Alex/0000-0002-6586-717X NR 21 TC 168 Z9 174 U1 5 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 1 PY 2000 VL 19 IS 17 BP 4425 EP 4430 DI 10.1093/emboj/19.17.4425 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 353LL UT WOS:000089275600001 PM 10970836 ER PT J AU Ginat, S Maslen, CL Conner, WE Porter, FD Steiner, RD AF Ginat, S Maslen, CL Conner, WE Porter, FD Steiner, RD TI Smith-Lemli-Opitz syndrome: A multiple malformation/mental retardation syndrome caused by defective cholesterol synthesis SO ENDOCRINOLOGIST LA English DT Review ID CULTURED SKIN FIBROBLASTS; ION MASS-SPECTROMETRY; SONIC-HEDGEHOG GENE; PRENATAL-DIAGNOSIS; AMNIOTIC-FLUID; DELTA(7)-REDUCTASE ACTIVITY; DELTA-7-STEROL REDUCTASE; HIRSCHSPRUNG DISEASE; RSH SYNDROME; 7-DEHYDROCHOLESTEROL AB Smith-Lemli-Opitz syndrome (SLOS) is a genetic condition characterized by dysmorphic facies, mental retardation and multiple malformations. A specific defect in cholesterol metabolism, 7-de hydrocholesterol-Delta (7) reductase (DKCR7) defficiency due to mutation of the DHCR7 gene is the underlying cause of this syndrome. DHCR7 is a microsomal enzyme that catalyzes the conversion of 7-dehydrocholesterol (7DHC) to cholesterol. Hence, affected individuals exhibit low plasma cholesterol and high 7DHC levels. The phenotype most likely results from the combination of cholesterol deficiency and 7DHC accumulation. Diagnosis is based on clinical findings with confirmation by plasma sterol analysis. Prenatal diagnosis may be performed by sterol analysis of amniotic auid/amniocytes or chorionic villi, or enzyme assay of chorionic villi. Maternal serum estriol and urine sterol analyses provide the opportunity for noninvasive prenatal diagnostic testing. Preliminary evidence from animal and human studies shows that dietary cholesterol supplementation may be beneficial for SLOS patients, but issues including prenatal onset of damage plus poor transport of cholesterol across the blood-brain barrier may limit treatment efficacy. The incidence of SLOS has been estimated to be one in 20,000 to one in 60,000 making it one of the most common autosomal recessive disorders. Recent studies suggest that the carrier frequency is much higher than the disease incidence would suggest. C1 Oregon Hlth Sci Univ, CDRC F, Div Endocrinol Diabet & Clin Nutr, Dept Med, Portland, OR 97207 USA. Oregon Hlth Sci Univ, Doernbecher Mem Hosp Children, Child Dev & Rehabil Ctr, Dept Pediat, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Doernbecher Mem Hosp Children, Child Dev & Rehabil Ctr, Dept Mol & Med Genet, Portland, OR 97201 USA. NICHD, Heritable Disorders Branch, NIH, Bethesda, MD USA. RP Steiner, RD (reprint author), Oregon Hlth Sci Univ, CDRC F, Div Endocrinol Diabet & Clin Nutr, Dept Med, 707 SW Gaines,POB 574, Portland, OR 97207 USA. OI Steiner, Robert/0000-0003-4177-4590 NR 129 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-2144 J9 ENDOCRINOLOGIST JI Endocrinologist PD SEP PY 2000 VL 10 IS 5 BP 300 EP 313 DI 10.1097/00019616-200010050-00004 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 365UX UT WOS:000089969800004 ER PT J AU Melner, MH Korach, KS AF Melner, MH Korach, KS TI Editorial: A new database for tissue-specific gene expression and function in the ovary SO ENDOCRINOLOGY LA English DT Editorial Material C1 Vanderbilt Univ, Sch Med, Dept Ob Gyn, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Melner, MH (reprint author), Vanderbilt Univ, Sch Med, Dept Ob Gyn, B1100 Med Ctr N,1161 21st Ave S, Nashville, TN 37232 USA. EM mike.melner@mcmail.vanderbilt.edu NR 4 TC 2 Z9 2 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2000 VL 141 IS 9 BP 3051 EP 3051 DI 10.1210/en.141.9.3051 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346LE UT WOS:000088872200001 PM 10965871 ER PT J AU Hoare, SRJ Rubin, DA Juppner, H Usdin, TB AF Hoare, SRJ Rubin, DA Juppner, H Usdin, TB TI Evaluating the ligand specificity of zebrafish parathyroid hormone (PTH) receptors: Comparison of PTH, PTH-related protein, and tuberoinfundibular peptide of 39 residues SO ENDOCRINOLOGY LA English DT Article ID SUPRAOPTIC NUCLEUS; FISH; EXPRESSION; IDENTIFICATION; AGONIST; TISSUES; RAT AB Homologs of mammalian PTH1 and PTH2 receptors, and a novel PTH3 receptor have been identified in zebrafish (zPTH1, zPTH2, and zPTH3). zPTH1 receptor ligand specificity is similar to that of mammalian PTH1 receptors. The zPTH2 receptor is selective for PTH over PTH-related protein (PTHrP); however, PTH produces only modest cAMP accumulation. A PTH2 receptor-selective peptide, tuberoinfundibular peptide of 39 residues (TIP39), has recently been purified from bovine hypothalamus. The effect of TIP39 has not previously been examined on zebrafish receptors. The zPTH3 receptor was initially described as PTHrP selective based on comparison with the effects of human PTH. We have now examined the Ligand specificity of the zebrafish PTH-recognizing receptors expressed in COS-7 cells using a wide range of ligands. TIP39 is a potent agonist for stimulation of cAMP accumulation at two putative splice variants of the zPTH2 receptor (EC50, 2.6 and 5.2 nM); in comparison, PTH is a partial agonist [maximal effect (E-max) of PTH peptides ranges from 28-49% of the TIP39 E-max]. As TIP39 is much more efficacious than any known PTH-like peptide, a homolog of TIP39 may be the zPTH2 receptor's endogenous ligand. At the zPTH3 receptor, rat PTH-(1-34) and rat PTH-(1-84) (EC50, 0.22 and 0.45 nM) are more potent than PTHrP (EC50, 1.5 nM), and rPTH-(1-34) binds with high affinity (3.2 nM). PTH has not been isolated from fish. PTHrP-like peptides, which have been identified in fish, may be the natural ligands for zPTH1 and zPTH3 receptors. C1 NIMH, Cell Biol Unit, Genet Lab, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Usdin, TB (reprint author), NIMH, Cell Biol Unit, Genet Lab, NIH, Bldg 36,Room 3D06,36 Convent Dr,MSC4094, Bethesda, MD 20892 USA. EM usdin@codon.nih.gov NR 22 TC 36 Z9 36 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2000 VL 141 IS 9 BP 3080 EP 3086 DI 10.1210/en.141.9.3080 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346LE UT WOS:000088872200007 PM 10965877 ER PT J AU Klotz, DM Hewitt, SC Korach, KS Diaugustine, RP AF Klotz, DM Hewitt, SC Korach, KS Diaugustine, RP TI Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: Requirement of estrogen receptor-alpha SO ENDOCRINOLOGY LA English DT Article ID MESSENGER-RIBONUCLEIC-ACID; POSTMENOPAUSAL WOMEN; ENDOMETRIAL CANCER; BREAST-CANCER; IGF-I; TISSUE DISTRIBUTION; CELL-GROWTH; RAT UTERUS; ER ALPHA; EXPRESSION AB Recent data indicate that insulin-like growth factor I (IGF-I) may have a function in mediating the mitogenic effects of 17 beta-estradiol (E-2) in the uterus and in regulating the growth of uterine neoplasms. This study was designed to determine whether synthetic and plant-derived chemicals that interact with estrogen receptor-alpha (ER alpha) and elicit estrogenic responses also mimic E-2 by activating the uterine IGF-I signaling pathway. Ovariectomized adult female mice were treated with both environmental and clinically relevant chemicals previously reported to display estrogenic and/or antiestrogenic properties, and their uteri were evaluated for an activated IGF-I signaling pathway. Diethylstilbestrol, 4-hydroxytamoxifen, the raloxifene analog LY353381, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), bisphenol A, and genistein were shown to mimic E-2 in the uterus by increasing the level of IGF-I messenger RNA, inducing IGF-I receptor (TGF-IR) tyrosine phosphorylation, stimulating the formation of IGF-IR signaling complexes, and increasing both proliferating cell nuclear antigen expression and the number of mitotic cells in the epithelium. The dose of chemical necessary to activate IGF-I signaling varied, with the order of potency: E-2 = diethylstilbestrol > LY353381 > 1-hydroxytamoxifen > genistein > HPTE > bisphenol A. Administration of the chemicals to ER alpha knockout mice did not activate IGF-IR, indicating that ER alpha is required for activation of uterine IGF-IR by these diverse chemicals. This study demonstrates that several chemicals shown previously to display estrogenic activities also mimic E-2 by activating uterine IGF-I signaling. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Diaugustine, RP (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,Mail Drop D4-04, Res Triangle Pk, NC 27709 USA. EM diaugus2@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 56 TC 86 Z9 93 U1 2 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2000 VL 141 IS 9 BP 3430 EP 3439 DI 10.1210/en.141.9.3430 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346LE UT WOS:000088872200046 PM 10965916 ER PT J AU Moline, JM Golden, AL Bar-Chama, N Smith, E Rauch, ME Chapin, RE Perreault, SD Schrader, SM Suk, WA Landrigan, PJ AF Moline, JM Golden, AL Bar-Chama, N Smith, E Rauch, ME Chapin, RE Perreault, SD Schrader, SM Suk, WA Landrigan, PJ TI Exposure to hazardous substances and male reproductive health: A research framework SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE hazardous substances; male reproductive health; research; semen quality ID IN-SITU HYBRIDIZATION; GERM-CELL CANCER; TESTICULAR CANCER; SEMEN QUALITY; SPERM COUNTS; DANISH MEN; CHROMOSOMAL-ABNORMALITIES; OCCUPATIONAL HAZARDS; INCREASING INCIDENCE; EUROPEAN COUNTRIES AB 0The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism mw have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving. C1 Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Urol, New York, NY USA. Texas Tech Univ, Hlth Sci Ctr, Inst Environm & Human Hlth, Lubbock, TX 79430 USA. NIEHS, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27711 USA. NIOSH, Cincinnati, OH 45226 USA. RP Moline, JM (reprint author), Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Community & Prevent Med, Box 1057,1 Gustave Levy Pl, New York, NY 10029 USA. RI Schrader, Steven/E-8120-2011; OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES07198] NR 112 TC 57 Z9 58 U1 0 U2 2 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 SEP PY 2000 VL 108 IS 9 BP 803 EP 813 DI 10.1289/ehp.00108803 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 360BW UT WOS:000089647400017 PM 11017884 ER PT J AU Jirles, B AF Jirles, B TI Further challenges SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Jirles, B (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2000 VL 108 IS 9 BP A394 EP A394 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 360BW UT WOS:000089647400003 PM 11185380 ER PT J AU Van Houten, B Phelps, J Barnes, M Suk, WA AF Van Houten, B Phelps, J Barnes, M Suk, WA TI Evaluating scientific impact SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Van Houten, B (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. NR 6 TC 3 Z9 3 U1 1 U2 3 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 SEP PY 2000 VL 108 IS 9 BP A392 EP A393 DI 10.1289/ehp.108-a392 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 360BW UT WOS:000089647400001 PM 11017900 ER PT J AU Duell, EJ Millikan, RC Savitz, DA Newman, B Smith, JC Schell, MJ Sandler, DP AF Duell, EJ Millikan, RC Savitz, DA Newman, B Smith, JC Schell, MJ Sandler, DP TI A population based case-control study of farming and breast cancer in North Carolina SO EPIDEMIOLOGY LA English DT Article DE agriculture; breast neoplasms; environment; pesticides; DDT; women's health ID UNITED-STATES; FEMALE FARMERS; PESTICIDE USE; VITAMIN-D; RISK; MORTALITY; WOMEN; EXPOSURE; EPIDEMIOLOGY; AGRICULTURE AB We examined the role of farming and pesticide exposure among 862 cases and 790 controls in a population-based, case control study of breast cancer conducted in North Carolina between 1993 and 1996. We obtained exposure information through personal interview. Increasing duration of farming was inversely associated with breast cancer risk; odds ratios (95% confidence intervals) were 1.2 (0.8-1.7), 0.8 (0.5-1.2), 0.7 (0.5-1.1), and 0.6 (0.4-0.9) for 1-10, 11-17, 18-23, and >23 years of farming, respectively, relative to nonfarmers. Inverse associations persisted when farming was restricted to calendar time periods of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) use or to farming at ages 9-16. Among women who farmed, odds ratios (ORs) were elevated for those who reported being present in fields during or shortly after pesticide application (OR = 1.8, 95% CI = 1.1-2.8) and for those who reported not using protective clothing while applying pesticides (OR = 2.0; 95% CI = 1.0-4.3), but not among those who reported using protective clothing (OR = 0.8; 95% CI = 0.4-1.8). We conclude that residence or work on farms may be associated with a reduced risk of breast cancer. Nevertheless, our results suggest a possible increased risk of breast cancer among a subgroup of farming women who were most likely to be exposed to pesticides. C1 Univ N Carolina, Dept Epidemiol, Sch Publ Hlth, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. RP Millikan, RC (reprint author), Univ N Carolina, Dept Epidemiol, Sch Publ Hlth, CB 7400, Chapel Hill, NC 27599 USA. OI Sandler, Dale/0000-0002-6776-0018 FU NCI NIH HHS [CA09330, CA58223]; NIEHS NIH HHS [ES07128] NR 48 TC 39 Z9 40 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2000 VL 11 IS 5 BP 523 EP 531 DI 10.1097/00001648-200009000-00007 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 346DB UT WOS:000088854500007 PM 10955404 ER PT J AU Werhahn, KJ Noachtar, S Arnold, S Pfander, M Henkel, A Winkler, PA Luders, HO AF Werhahn, KJ Noachtar, S Arnold, S Pfander, M Henkel, A Winkler, PA Luders, HO TI Tonic seizures: Their significance for lateralization and frequency in different focal epileptic syndromes SO EPILEPSIA LA English DT Article DE focal epilepsy; tonic seizure; lateralization; seizure semiology ID TEMPORAL-LOBE EPILEPSY; SENSORIMOTOR AREA EPILEPSY; COMPLEX PARTIAL SEIZURES; CLINICAL CHARACTERISTICS; LOCALIZING VALUE; ICTAL SEMIOLOGY; MANIFESTATIONS; LOCALIZATION; CLASSIFICATION; PATTERNS AB Purpose: To determine whether the clinical features of tonic seizures (TSZ) are useful for lateralization of epileptic syndromes and the differential diagnosis of focal epileptic syndromes. Methods: From a group of 481 patients, 123 patients with TSZ (44 females; mean age, 22.9 years; mean age at onset, 7 years; mean duration of epilepsy, 16 years) were selected. A total of 1595 epileptic seizures, documented during video-electroencephalographic monitoring, were analyzed. Patients who had had surgery for epilepsy previously were excluded. Seizures were classified using a semiological seizure classification. Epilepsy syndromes were classified using all test data (electroencephalography, magnetic resonance imaging, computed tomography, positron emission tomography, and single-photon emission tomography). Data were compared using X-2 analysis or the Fisher exact test. Results: More patients with TSZ had extratemporal than temporal lobe epilepsies (79% vs. 1.7%; p < 0.0001) among those with an epilepsy localized to one lobe (n = 306). In the 123 patients, TSZ were part of 170 different seizure evolutions. Seizure evolutions began with TSZ as the first seizure type more often in patients with frontal lobe epilepsy (FLE) compared with patients with parieto-occipital lobe epilepsy (POLE) (40% in POLE vs. 67% in FLE; p < 0.05). In contrast, TSZ in POLE were more likely to be preceded by auras (50% in POLE vs. 26% in FLE; p < 0.05). TSZ were bilateral in 129 (76%) and unilateral in 41 (24%) seizure evolutions. Unilateral TSZ correctly lateralized the epilepsy syndrome to the contralateral hemisphere. Conclusion: Analysis of seizure semiology and evolution in patients with TSZ is helpful for differentiating between focal epilepsies of temporal, frontal, and parieto-occipital origin. Unilateral TSZ provide useful information for the lateralization of the epileptic syndrome. C1 Univ Munich, Dept Neurol, D-8000 Munich, Germany. Univ Munich, Dept Neurosurg, D-8000 Munich, Germany. Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Werhahn, KJ (reprint author), NINDS, NIH, Human Cort Physiol Sect, Bldg 10,Room 5N234, Bethesda, MD 20892 USA. NR 47 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD SEP PY 2000 VL 41 IS 9 BP 1153 EP 1161 DI 10.1111/j.1528-1157.2000.tb00320.x PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 350YA UT WOS:000089128200009 PM 10999554 ER PT J AU Spanaki, MV Kopylev, L Liow, K DeCarli, C Fazilat, S Gaillard, WD Theodore, WH AF Spanaki, MV Kopylev, L Liow, K DeCarli, C Fazilat, S Gaillard, WD Theodore, WH TI Relationship of seizure frequency to hippocampus volume and metabolism in temporal lobe epilepsy SO EPILEPSIA LA English DT Article DE epilepsy; seizure frequency; hippocampus; MRI; PET ID POSITRON EMISSION TOMOGRAPHY; RECURRENT SEIZURES; NEURONAL LOSS; SCLEROSIS; ATROPHY; DAMAGE AB Purpose: To examine the relationship between frequency of complex partial (CPS) and secondarily generalized tonic-clonic seizures (sGTCS) on hippocampal volume (HV) temporal lobe metabolism. Methods: We performed volumetric magnetic resonance imaging (MRI) and positron emission tomography with (18)fluorodeoxyglucose ((18)FDG-PET) in 32 patients with epilepsy. Temporal lobe foci were localized by ictal video-EEG. Results: We did not find any association between CPS frequency or lifetime number of sGTCS and HV or metabolism ipsilateral to electroencephalographic focus. Conclusion: The progress of metabolic or pathologic abnormalities of temporal lobe epilepsy may not be altered by adequate seizure control. The presence of an epileptic focus might be associated with progressive neuronal injury even in clinically well-controlled patients. C1 NINDS, Clin Epilepsy Sect, ERB, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Theodore, WH (reprint author), NINDS, Clin Epilepsy Sect, ERB, Bldg 10,Room 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA. RI DeCarli, Charles/B-5541-2009 NR 15 TC 22 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD SEP PY 2000 VL 41 IS 9 BP 1227 EP 1229 DI 10.1111/j.1528-1157.2000.tb00330.x PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 350YA UT WOS:000089128200019 PM 10999564 ER PT J AU Werhahn, KJ Lieber, J Classen, J Noachtar, S AF Werhahn, KJ Lieber, J Classen, J Noachtar, S TI Motor cortex excitability in patients with focal epilepsy SO EPILEPSY RESEARCH LA English DT Article DE motor cortex; intracortical excitability; focal epilepsy; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; CORTICAL EXCITABILITY; CORTICOCORTICAL INHIBITION; GENERALIZED EPILEPSY; BRAIN-STIMULATION; UNIT RESPONSES; SURFACE EMG; GUINEA-PIG; HUMANS; PROJECTIONS AB We studied the excitability of the motor cortex using, transcranial magnetic stimulation (TMS) in patients with temporal and extratemporal epilepsy. We applied single and paired-pulse TMS to 15 patients with temporal (n = 7). extratemporal (n = 6) and focal epilepsy lateralised to one hemisphere (n = 2). Patients had no antiepileptic drugs in the last 48 h and were seizure free for 4 h prior to testing. We determined the threshold for EMG responses at rest (RMT), the cortically evoked silent period (CSSP) and intracortical inhibition (ICI, intervals of 2-4 ms) and facilitation (ICF, 7-15 ms) and compared the results to those obtained in 17 normal controls. ICI and ICF was reduced in both hemispheres (P < 0.01, ANOVA) compared to the controls. In the hemisphere of seizure origin ('abnormal') there was a reduction of ICF (P < 0.01) and normal ICI, in the 'normal' hemisphere there was a reduced ICI (P < 0.01) and a slight reduction of ICF (P < 0.05). ICF on the 'abnormal' side was reduced (P < 0.05) compared to the 'normal' hemisphere. RMT was increased in two patients, but group comparison of RMT and CSSP showed no significant differences between patients and controls. The results suggest a remote effect of epileptic activity onto the motor cortex leading to an alteration of activity in local inhibitory circuits. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Munich, Dept Neurol, D-8000 Munich, Germany. Univ Rostock, Dept Neurol, Rostock, Germany. RP Werhahn, KJ (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 47 TC 65 Z9 65 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD SEP PY 2000 VL 41 IS 2 BP 179 EP 189 DI 10.1016/S0920-1211(00)00136-4 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 338NQ UT WOS:000088426500007 PM 10940619 ER PT J AU Dunn, BK McCaskill-Stevens, W Ford, LG AF Dunn, BK McCaskill-Stevens, W Ford, LG TI Breast cancer prevention: the next steps SO EUROPEAN JOURNAL OF CANCER LA English DT Article ID HEALTHY POSTMENOPAUSAL WOMEN; SURGICAL-ADJUVANT-BREAST; RALOXIFENE; TAMOXIFEN; TRIAL; REDUCTION; RISK C1 NCI, Early Detect & Community Oncol Program, Rockville, MD 20852 USA. RP Ford, LG (reprint author), NCI, Early Detect & Community Oncol Program, Execut Plaza N,Room 300,6130 Execut Blvd, Rockville, MD 20852 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2000 VL 36 SU 4 BP S53 EP S54 PG 2 WC Oncology SC Oncology GA 382TM UT WOS:000165840000024 PM 11056319 ER PT J AU Dunn, BK Ford, LG AF Dunn, BK Ford, LG TI Breast cancer prevention: results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention trial (NSABP P-1: BCPT) SO EUROPEAN JOURNAL OF CANCER LA English DT Article ID TAMOXIFEN; STATISTICS; MORTALITY C1 NCI, Early Detect & Community Oncol Program, Rockville, MD 20852 USA. RP Ford, LG (reprint author), NCI, Early Detect & Community Oncol Program, Execut Plaza N,Room 300,6130 Execut Blvd, Rockville, MD 20852 USA. NR 12 TC 5 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2000 VL 36 SU 4 BP S49 EP S50 PG 2 WC Oncology SC Oncology GA 382TM UT WOS:000165840000021 PM 11056316 ER PT J AU Fan, QR Long, EO Wiley, DC AF Fan, QR Long, EO Wiley, DC TI A disulfide-linked natural killer cell receptor dimer has higher affinity for HLA-C than wild-type monomer SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE natural killer cell; inhibitory receptor; dimerization; HLA-C ID HUMAN GROWTH-HORMONE; INHIBITORY RECEPTOR; CRYSTAL-STRUCTURE; CLASS-I; ERYTHROPOIETIN RECEPTOR; EXTRACELLULAR DOMAIN; EPO RECEPTOR; COMPLEX; ACTIVATION AB Inhibitory receptors on the surface of natural killer (NK) cells recognize specific MHC class I molecules on target cells and prevent the target cell lysis by NK cells. The killer cell immunoglobulin-related receptors (KIR), KIR2D, found in human, specifically interact with polymorphic HLA-C molecules. The crystal structure of the inhibitory receptor, KIR2DL1, revealed a relationship to the hematopoietic receptor family, suggesting that the signaling mechanism of KIR2D molecules may resemble that of the hematopoietic receptors, and involve KIR2D dimerization. We have engineered a disulfide-linked dimer of KIR2DL1 by introducing a free cysteine at the C-terminal stem region of the receptor. The disulfide-linked KIR2DL1 dimer binds to HLA-Cw4 at a molar ratio of one dimer to one HLA-Cw4 molecule. Furthermore. the covalently-linked KIR2DL1 dimer binds more tightly to HLA-Cw4 than the wild-type monomer, suggesting the occurrence of a second binding event that increases the overall affinity of KIR dimer for HLA-C. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Wiley, DC (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 22 TC 13 Z9 13 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2000 VL 30 IS 9 BP 2692 EP 2697 DI 10.1002/1521-4141(200009)30:9<2692::AID-IMMU2692>3.0.CO;2-0 PG 6 WC Immunology SC Immunology GA 352NB UT WOS:000089223800030 PM 11009104 ER PT J AU Allen, DD Martin, J Arriagada, C Cardenas, AM Rapoport, SI Caviedes, R Caviedes, P AF Allen, DD Martin, J Arriagada, C Cardenas, AM Rapoport, SI Caviedes, R Caviedes, P TI Impaired cholinergic function in cell lines derived from the cerebral cortex of normal and trisomy 16 mice SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine; Alzheimer's disease; cell line; choline; Down's syndrome ID EMBRYONIC BRAIN-DEVELOPMENT; ROOT GANGLION NEURONS; ALZHEIMERS-DISEASE; DOWNS-SYNDROME; ANIMAL-MODEL; MOUSE; ABNORMALITIES; CURRENTS; FETUSES AB Murine trisomy 16 is an animal model of human Down's syndrome. We have successfully established permanently growing cell lines from the cerebral cortex of normal and trisomy 16 foetal mice using an original procedure. These lines, named CNh (derived from a normal animal) and CTb (derived from a trisomic foetus), express neuronal markers. Considering that Down's syndrome exhibits cholinergic deficits, we examined cholinergic function in these lines, using incorporation of [H-3]-choline and fractional release studies. After 1, 3 and 5 min of [H-3]-choline incubation, CTb cell uptake was lower by similar to 50% compared to controls. Hemichollinium-3 significantly reduced the incorporation of [H-3]-choline in both CNh and CTb cells at high concentration (10 mu M), suggesting high-affinity choline transport. However, CTb cells exhibited greater sensitivity to the blocker. For fractional release experiments, the cells were stimulated by K+ depolarization, glutamate or nicotine. When depolarized, CTb cells showed a 68% reduction in fractional release of [H-3]-acetylcholine compared to CNh cell line, and a 45% reduction when stimulated by nicotine. Interestingly, glutamate induced similar levels of release in both cell types. The results indicate the existence of cholinergic dysfunction in CTb cells when compared to CNh, similar to that reported for primary cultures of trisomy 16 brain tissue (Fiedler et al., 1994, Brain Res., 658, 27-32). Thus, the CTb cell line may serve as a model for the study of Down's syndrome pathophysiology. C1 Univ Chile, Fac Med, ICBM, Morphol Program, Santiago, Chile. Texas Tech Univ, Sch Pharm, Dept Pharmaceut Sci, HSC, Amarillo, TX 79106 USA. Univ Valprariso, Sch Med, Valparaiso, Chile. NIA, LNS, NIH, Bethesda, MD 20892 USA. Ctr Estudios Cient Santiago, Santiago 9, Chile. RP Caviedes, P (reprint author), Univ Chile, Fac Med, ICBM, Pharmacol Program, Casilla 70000,Correo 7, Santiago, Chile. NR 23 TC 25 Z9 25 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 2000 VL 12 IS 9 BP 3259 EP 3264 DI 10.1046/j.1460-9568.2000.00221.x PG 6 WC Neurosciences SC Neurosciences & Neurology GA 361JA UT WOS:000089718900019 PM 10998109 ER PT J AU Kobayashi, H Sato, N Saga, T Nakamoto, Y Ishimori, T Toyama, S Togashi, K Konishi, J Brechbiel, MW AF Kobayashi, H Sato, N Saga, T Nakamoto, Y Ishimori, T Toyama, S Togashi, K Konishi, J Brechbiel, MW TI Monoclonal antibody-dendrimer conjugates enable radiolabeling of antibody with markedly high specific activity with minimal loss of immunoreactivity SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE antibody; indium; gadolinium; dendrimer ID BIODISTRIBUTION; RADIOIMMUNOTHERAPY AB For the purpose of radioimmunotherapy, labelling of monoclonal antibody with high specific activity is often necessary, especially when using a radionuclide with a shorter half-life. Polyamine dendrimers (PAMAM) are novel synthetic polymeric molecules with large numbers of amine residues on their spherical surface. In order to bind large numbers of radiometals to single antibody molecules, the generation-4 PAMAM (G4), which has 64 amines, was conjugated with 43 molecules of 2-(p-isothiocyanatobenzyl)-6-methyl-diethylene triamine penta-acetic acid (1B4M), a derivative of DTPA. This product [G4-(1B4M)(43)] was then conjugated with OST7, a murine monoclonal IgC(1). We evaluated the achievable specific activity for In-111 labeling, immunoreactivity, biodistribution, and tumor targeting in mice of the In-111- or Gd-153-OST7-G4-(1B4M)(43) as compared with radiolabeled OST7-1B4M or 56C-1B4M. The maximum specific activity of In-111-OST7-G4-(1B4M)(43) and In-111-OST7-1B4M was 470 and 8.7 GBq/mg (12,700 and 263 mCi/mg), respectively. Immunoreactivity of radiolabeled OST7-G4-(1B4M)(43) and OST7-1B4M, as determined by the binding to KT005 cells expressing the antigen, was respectively 91% and 84% of that of I-125-labelled OST7, Biodistribution studies for preparations with maximum specific activity in normal mice 3 h after injection showed that In-111- or Gd-153-OST7-C4(1B4M),, cleared faster from the blood and accumulated more in the liver than did In-111- or Gd-153-OST7-1B4M. The dendrimer 1B4M [G4-(1B4M)(64)] itself showed similar saturation effects with metals. The radioactivity in all the other organs reflected the rapid clearance of radioactivity from the blood. Gd-153-OST7-G4-(1B4M)(43) showed specific accumulation ill the KT005 tumor. In conclusion, we could successfully bind 49 times as many metal atoms to an antibody molecule as is possible with conventional metal labeling for indium and gadolinium, and did so with minimal loss of immunoreactivity. When we achieved radiolabeling with maximum specific activity, Gd conjugate showed better biodistribution than In conjugate. C1 Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Hitachi Med Co, Kyoto, Japan. Kyoto Univ, Grad Sch Med, Dept Nucl Med & Med Imaging, Kyoto, Japan. Kyoto Univ, Inst Virus Res, Kyoto 606, Japan. NCI, Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imaging, Kyoto 6068507, Japan. NR 10 TC 74 Z9 76 U1 1 U2 12 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD SEP PY 2000 VL 27 IS 9 BP 1334 EP 1339 DI 10.1007/s002590000293 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 352EN UT WOS:000089201700010 PM 11007515 ER PT J AU Jimenez-Asensio, J Garland, D AF Jimenez-Asensio, J Garland, D TI A lens glutathione S-transferase, class mu, with thiol-specific antioxidant activity SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE glutathione S-transferase; oxidation; metal-catalysed oxidation; thiol-specific antioxidant; lens; bovine; cDNA; protein ID CATALYTIC MECHANISM; SACCHAROMYCES-CEREVISIAE; PEROXIDASE-ACTIVITY; PROTEIN OXIDATION; HYDROGEN-PEROXIDE; ESCHERICHIA-COLI; ENZYME; PURIFICATION; RECOMBINANT; ISOENZYMES AB A protein that protected against the thiol-mediated metal-catalysed oxidative inactivation of enzymes but did not protect against the ascorbate-dependent oxidation system was extensively purified from bovine lens. The protein was a homodimer (pI 7) of 26 kDa subunits. Sixty per cent of the protein sequence was obtained by Edman sequencing and by sequence comparison was determined to be a class mu glutathione S-transferase (GST). The sequence of the enzyme is homologous to, but not identical to, that of any other class mu GST in the databanks. The complete protein sequence was derived from sequencing the cDNA and is the first complete sequence of a class mu GST from a bovine tissue. The enzyme was cloned and expressed in E. coli. The recombinant GST also protected against the thiol-mediated oxidative inactivation of enzymes but with lower activity than the native enzyme did and the recombinant GST had a comparable higher K-m for GSH. The native and recombinant enzymes possessed similar low level peroxidase activity utilizing alkyl and cumene peroxides as substrates, but exhibited little activity against hydrogen peroxide. C1 NEI, NIH, Bethesda, MD 20892 USA. RP NEI, NIH, Bethesda, MD 20892 USA. EM dgarland@helix.nih.gov NR 41 TC 3 Z9 4 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD SEP PY 2000 VL 71 IS 3 BP 255 EP 265 DI 10.1006/exer.2000.0876 PG 11 WC Ophthalmology SC Ophthalmology GA 356GQ UT WOS:000089435900006 PM 10973735 ER PT J AU Bohr, VA Cooper, M Orren, D Machwe, A Piotrowski, J Sommers, J Karmakar, P Brosh, R AF Bohr, VA Cooper, M Orren, D Machwe, A Piotrowski, J Sommers, J Karmakar, P Brosh, R TI Werner syndrome protein: biochemical properties and functional interactions SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT Biological Aging - Euroconference on Molecular, Cellular and Tissue Gerontology CY MAY 06-10, 2000 CL SPA, BELGIUM SP Int Assoc Gerontol, UN Programme Ageing DE Werner syndrome protein; replication protein; DNA repair ID DNA HELICASE; SYNDROME CELLS; SYNDROME GENE; EXONUCLEASE; REPAIR; WRN; APOPTOSIS; LINES AB Werner syndrome is a premature aging syndrome displaying numerous signs and symptoms found in normal aging. The disease is associated with a mutation in the WRN gene. We have purified the Warner protein (WRN) and studied its biochemical activities and its protein interactions. WRN is a helicase and an exonuclease and also has an associated ATPase activity. WRN interacts physically and functionally with replication protein A (RPA), which stimulates its helicase activity. We have studied the WRN exonuclease activity and found that it can be blocked by certain DNA lesions and not by others. Thus, while WRN does not bind to DNA damage, it may have properties that allow it to sense the presence of damage in DNA. More recently we have found other protein interactions that involve physical and functional interactions with WRN, which could suggest a role for WRN in DNA repair. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 32 Z9 32 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD SEP PY 2000 VL 35 IS 6-7 SI SI BP 695 EP 702 DI 10.1016/S0531-5565(00)00145-5 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 367ZQ UT WOS:000090093100005 PM 11053659 ER PT J AU Duan, WZ Guo, ZH Mattson, MP AF Duan, WZ Guo, ZH Mattson, MP TI Participation of Par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid SO EXPERIMENTAL NEUROLOGY LA English DT Article DE apoptosis; caspase; huntingtin; Huntington's disease; 3-nitropropionic acid; PARP; trinucleotide ID PROTEIN-KINASE-C; PROSTATE APOPTOSIS RESPONSE-4; HUNTINGTONS-DISEASE STRIATUM; CELL-DEATH; TRINUCLEOTIDE REPEAT; DNA FRAGMENTATION; OXIDATIVE STRESS; IN-VIVO; POLY(ADP-RIBOSE) POLYMERASE; SUCCINATE-DEHYDROGENASE AB Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed SNP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD. (C) 2000 Academic Press. C1 Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Duan, WZ (reprint author), Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RI Mattson, Mark/F-6038-2012 NR 70 TC 29 Z9 31 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2000 VL 165 IS 1 BP 1 EP 11 DI 10.1006/exnr.2000.7434 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 353VC UT WOS:000089295300001 PM 10964480 ER PT J AU Pfutzner, W Vogel, JC AF Pfutzner, W Vogel, JC TI Advances in skin gene therapy SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE DNA vaccination; epidermis; genetic skin diseases; skin gene therapy ID RECOMBINANT ADENOASSOCIATED VIRUS; JUNCTIONAL EPIDERMOLYSIS-BULLOSA; PRIMARY HUMAN KERATINOCYTES; TISSUE-SPECIFIC EXPRESSION; CELLULAR IMMUNE-RESPONSES; EPIDERMAL STEM-CELLS; LONG-TERM EXPRESSION; IN-VIVO; TRANSGENIC MICE; RETROVIRAL VECTORS AB Specific anatomical and biological properties make the skin a very interesting target organ for gene therapy approaches. Different cell types of the epidermis, such as keratinocytes, melanocytes, or dendritic cells, can be genetically modified to treat a broad spectrum of diseases, including genetically inherited skin disorders, tumour diseases, metabolic disorders and infectious diseases. The easy accessibility of skin suggests that different methods for gene delivery can be pursued, depending on the desired application. The approach used to deliver DNA to the skin will influence not only the efficiency of DNA delivery, but also the level and duration of transgene expression. Furthermore, the desired biological effect will also influence the decision of which gene transfer method is the best choice. Among the current challenges of cutaneous gene therapy are: optimising the efficiency of direct in vivo gene delivery; targeting specific epidermal cells, including keratinocyte stem cells; achieving sustained gene expression and regulating gene expression in vivo. This review summarises recent advances in the field of skin gene therapy and evaluates possible strategies to overcome obstacles and achieve successful clinical applications of skin gene therapy. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Pfutzner, W (reprint author), NCI, Dermatol Branch, NIH, 6130 Execut Blvd, Bethesda, MD 20892 USA. NR 115 TC 18 Z9 18 U1 0 U2 2 PU ASHLEY PUBL LTD PI LONDON PA 1ST FL, THE LIBRARY, 1 SHEPHERDS HILL HIGHGATE, LONDON N6 5QJ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD SEP PY 2000 VL 9 IS 9 BP 2069 EP 2083 DI 10.1517/13543784.9.9.2069 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347PL UT WOS:000088938300008 PM 11060793 ER PT J AU Steele, VE Holmes, CA Hawk, ET Kopelovich, L Lubet, RA Crowell, JA Sigman, CC Kelloff, GJ AF Steele, VE Holmes, CA Hawk, ET Kopelovich, L Lubet, RA Crowell, JA Sigman, CC Kelloff, GJ TI Potential use of lipoxygenase inhibitors for cancer chemoprevention SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE cancer; chemopreventive agents; lipoxygenase; mechanisms ID EPIDERMAL GROWTH-FACTOR; PROTEIN-KINASE-C; LEUKOTRIENE BIOSYNTHESIS INHIBITOR; PERITONEAL POLYMORPHONUCLEAR LEUKOCYTES; 12-LIPOXYGENASE MESSENGER-RNA; ARACHIDONIC-ACID METABOLISM; HUMAN PROSTATE-CANCER; METHYL-N-NITROSOUREA; TUMOR-CELL INVASION; LOW-FAT DIETS AB Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast rumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene induced lung tumours in strain A/J mice and hormone-induced prostate tumours in rats). In this way, compounds are identified for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors. C1 NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Steele, VE (reprint author), NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. NR 143 TC 31 Z9 33 U1 4 U2 6 PU ASHLEY PUBL LTD PI LONDON PA 1ST FL, THE LIBRARY, 1 SHEPHERDS HILL HIGHGATE, LONDON N6 5QJ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD SEP PY 2000 VL 9 IS 9 BP 2121 EP 2138 DI 10.1517/13543784.9.9.2121 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347PL UT WOS:000088938300012 PM 11060797 ER PT J AU Machwe, A Orren, DK Bohr, VA AF Machwe, A Orren, DK Bohr, VA TI Accelerated methylation of ribosomal RNA genes during the cellular senescence of Werner syndrome fibroblasts SO FASEB JOURNAL LA English DT Article DE life span; aging; population doubling; rDNA ID REPLICATIVE LIFE-SPAN; AGE-DEPENDENT LOSS; DNA METHYLATION; HUMAN-CELLS; RESTRICTION ENDONUCLEASE; SYNDROME PROTEIN; HELICASE; SEQUENCES; SGS1; RDNA AB Ribosomal DNA (rDNA) metabolism has been implicated in cellular and organismal aging. The role of rDNA in premature and normal human aging was investigated by measuring rDNA gene copy number, the level of rDNA methylation, and rRNA expression during the in vitro senescence of primary fibroblasts from normal (young and old) donors and from Werner syndrome (WS) patients, In comparison to their normal counterparts, WS fibroblasts grew slowly and reached senescence after fewer doublings. The rDNA copy number did not change significantly throughout the life span of both normal and WS fibroblasts, However, in senescent WS and normal old fibroblasts, we detected rDNA species with unusually slow electrophoretic mobility, Cellular aging in Saccharomyces cerevisiae is accompanied by the formation and accumulation of rDNA circles. Our analysis revealed that the rDNA species observed in this study were longer, linear rDNA molecules attributable to the inhibition of EcoRI cleavage by methylation. Furthermore, isoschizomeric restriction analysis confirmed that in vitro senescence of fibroblasts is accompanied by significant increases in cytosine methylation within rDNA genes, This increased methylation is maximal during the abbreviated life span of WS fibroblasts. Despite increased methylation of rDNA in senescent cells, the steady-state levels of 28S rRNA remained constant over the life span of both normal and WS fibroblasts. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 56 TC 29 Z9 32 U1 0 U2 1 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 SEP PY 2000 VL 14 IS 12 BP 1715 EP 1724 DI 10.1096/fj.99-0926com PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 352JU UT WOS:000089212400010 PM 10973920 ER PT J AU Zhou, J Ng, S Adesanya-Famuiya, O Anderson, K Bondy, CA AF Zhou, J Ng, S Adesanya-Famuiya, O Anderson, K Bondy, CA TI Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression SO FASEB JOURNAL LA English DT Article DE breast cancer; androgen; tamoxifen; monkey ID BREAST-CANCER RISK; POSTMENOPAUSAL WOMEN; MENSTRUAL-CYCLE; HORMONE LEVELS; PRIMATE OVARY; ANDROGEN; TAMOXIFEN; SERUM; THERAPY; GROWTH AB This study investigated the effect of sex steroids and tamoxifen on primate mammary epithelial proliferation and steroid receptor gene expression. Ovariectomized rhesus monkeys were treated with placebo, 17 beta estradiol (E2) alone or in combination with progesterone (E2/P) or testosterone (E2/T), or tamoxifen for 3 days. E2 alone increased mammary epithelial proliferation by similar to six-fold (P<0.0001) and increased mammary epithelial estrogen receptor (ER alpha) mRNA expression by similar to 50% (P<0.0001; ER beta mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2-induced proliferation by similar to 40% (P<0.002) and entirely abolished E2-induced augmentation of ER alpha expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a similar to threefold increase in mammary epithelial proliferation (P<0.01), but tamoxifen also reduced ER alpha expression below placebo level.. Androgen receptor (AR) mRNA was detected in mammary epithelium by in situ hybridization. AR mRNA levels were not altered by E2 alone but were significantly reduced by E2/T and tamoxifen treatment. Because combined E2/T and tamoxifen had similar effects on mammary epithelium, we investigated the regulation of known sex steroid-responsive mRNAs in the primate mammary epithelium. E2 alone had no effect on apolipoprotein D (ApoD) or IGF binding protein 5 (IGFBP5) expression, but E2/T and tamoxifen treatment groups both demonstrated identical alterations in these mRNAs (ApoD was decreased and IGFBP5 was increased). These observations showing androgen-induced down-regulation of mammary epithelial proliferation and ER expression suggest that combined estrogen/androgen hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement. In addition, these novel findings on tamoxifen's androgen-like effects on primate mammary epithelial sex steroid receptor expression suggest that tamoxifen's protective action on mammary gland may involve androgenic effects. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Rm 10N262, Bethesda, MD 20892 USA. NR 29 TC 133 Z9 138 U1 2 U2 3 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 SEP PY 2000 VL 14 IS 12 BP 1725 EP 1730 DI 10.1096/fj.99-0863com PG 6 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 352JU UT WOS:000089212400011 PM 10973921 ER PT J AU Frattarelli, JL Lauria-Costa, DF Miller, BT Bergh, PA Scott, RT AF Frattarelli, JL Lauria-Costa, DF Miller, BT Bergh, PA Scott, RT TI Basal antral follicle number and mean ovarian diameter predict cycle cancellation and ovarian responsiveness in assisted reproductive technology cycles SO FERTILITY AND STERILITY LA English DT Article DE in vitro fertilization; basal antral follicle count; ovarian diameter/size; pregnancy rates; cancellation rates; ovarian response; ovarian reserve; predictive value; clinical outcome; review ID IN-VITRO FERTILIZATION; CITRATE CHALLENGE TEST; DAY 3 ESTRADIOL; INVITRO FERTILIZATION; TRANSVAGINAL SONOGRAPHY; OVULATION INDUCTION; HORMONE AGONIST; POOR-PROGNOSIS; GONADOTROPIN; STIMULATION AB Objective: To determine the predictive value and define threshold levels for basal antral follicle number and mean ovarian diameter in patients undergoing ART cycles. Design: Retrospective, Setting: Tertiary care center. Patients: Two hundred seventy-eight patients who had ovarian measurements performed an cycle day 3 before beginning treatment with gonadotropins. Intervention: Pretreatment ovarian ultrasound measurements. Main Outcome Measure: Number of oocytes retrieved, hormone levels, and cycle outcomes. Results: A direct linear correlation was observed between mean ovarian diameter and basal follicle number. Roth measures demonstrated a positive linear correlation with recovered oocytes, basal E-2, and peak E-2. Both demonstrated a negative lineal correlation with ampules of gonadotropins administered, days of stimulation, patient age. cycle day 3 FSH, and FSH:LH ratio. An antral follicle count of less than or equal to 10 or a mean ovarian diameter of <20 mm was associated with an increased risk of cycle cancellation. Conclusions: Ovarian diameter and basal antral follicle number identify patients who may respond poorly to ART stimulation. These ovarian measures con-elate well with ART screening and stimulation parameters. This knowledge allows physicians to evaluate and counsel patients immediately before an ART stimulation and to optimize stimulation protocols. (Fertil Steril(R) 2000:74:512-17. (C) 2000 by American Society for Reproductive Medicine.). C1 Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Walter Red Army Med Ctr, NIH,Combined Fed Program Reprod Endocrinol, Bethesda, MD 20814 USA. St Barnabas Med Ctr, Inst Reprod Med & Sci, Livingston, NJ USA. RP Frattarelli, JL (reprint author), Tripler Army Med Ctr, Dept Obstet & Gynecol, 1 Jarrett White Rd, Tripler AMC, HI 96859 USA. NR 23 TC 80 Z9 86 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2000 VL 74 IS 3 BP 512 EP 517 DI 10.1016/S0015-0282(00)00708-1 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 353BV UT WOS:000089254600016 PM 10973648 ER PT J AU Frattarelli, JL Bergh, PA Drews, MR Sharara, FI Scott, RT AF Frattarelli, JL Bergh, PA Drews, MR Sharara, FI Scott, RT TI Evaluation of basal estradiol levels in assisted reproductive technology cycles SO FERTILITY AND STERILITY LA English DT Article DE assisted reproductive technology; in vitro fertilization; estradiol; follicle-stimulating hormone; ovarian reserve; pregnancy rates; cancellation rates; review ID FOLLICLE-STIMULATING-HORMONE; IN-VITRO FERTILIZATION; CITRATE CHALLENGE TEST; GENERAL INFERTILITY POPULATION; DAY 3 ESTRADIOL; OVARIAN RESERVE; INVITRO FERTILIZATION; PROGNOSTIC ASSESSMENT; OVULATION INDUCTION; POOR-PROGNOSIS AB Objective: To determine if basal E-2 screening increases the diagnostic accuracy of basal FSH screening and to determine whether basal E-2 levels correlate with outcome in ART cycles. Design: Retrospective. Setting: Tertiary care center. Patient(s): Two thousand six hundred thirty-four infertility patients. Intervention(s): Cycle outcome was evaluated after grouping patients by basal E-2 levels beginning at <20 pp/mL and extending to >100 pg/mL at 10 pg/mL increments. Main Outcome Measure(s): Retrieved oocytes, pregnancy rate, and cancellation rate. Result(s): Cancellation rates were significantly increased in patients with basal E-2 levels of <20 pg/mL or greater than or equal to 80 pg/mL. Basal E-2 levels neither predicted pregnancy outcome nor correlated with ovarian response in those patients not canceled. Conclusion(s): Patients with basal E-2 levels of <20 pg/mL or greater than or equal to 80 pg/mL had an increased risk for cancellation. Basal E-2 was predictive of stimulation parameters in patients 40 years or older. For those patients who proceeded to retrieval, there were no differences in pregnancy or delivery rates relative to basal E-2 levels. This suggests that irrespective of basal E-2 levels patients who produce mure than three maturing follicles in response to stimulation have adequate ovarian reserve as evidenced by their pregnancy rates. (Fertil Steril(R) 2000:74:518-24. (C) 2000 by American Society for Reproductive Medicine.). C1 Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Walter Reed Army Med Ctr, NIH,Combined Fed Program Reprod Endocrinol, Bethesda, MD USA. St Barnabas Med Ctr, Inst Reprod Med & Sci, Livingston, NJ USA. Reprod Med Associates New Jersey, Morristown, NJ USA. Univ Maryland, Baltimore, MD 21201 USA. RP Frattarelli, JL (reprint author), Tripler Army Med Ctr, Dept Obstet & Gynecol, 1 Jarrett White Rd, Tripler AMC, HI 96859 USA. NR 25 TC 34 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2000 VL 74 IS 3 BP 518 EP 524 DI 10.1016/S0015-0282(00)00693-2 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 353BV UT WOS:000089254600017 PM 10973649 ER PT J AU Everhart, JE AF Everhart, JE TI Recent developments in the epidemiology of Helicobacter pylori SO GASTROENTEROLOGY CLINICS OF NORTH AMERICA LA English DT Review ID PEPTIC-ULCER DISEASE; HEPATITIS-A VIRUS; HOUSEFLIES MUSCA-DOMESTICA; GASTRIC-CANCER; UNITED-STATES; RISK-FACTORS; SOCIOECONOMIC-STATUS; FOLLOW-UP; DEVELOPING-COUNTRIES; DUODENAL-ULCER AB Helicobacter pylori is found commonly throughout the world irrespective of how exotic the location. H. pylori remains among the most universal of infections; however, our understanding of some features of infection has changed. Infection can be gained and lost at rates higher than previously realized. Oral-oral and oral-fecal infection has declined rapidly in developed countries, which probably has contributed to declines in duodenal ulcer disease and gastric cancer. The full health implications of the potential elimination of infection are unknown. C1 NIDDK, Epidemiol & Clin Trials Branch, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. RP Everhart, JE (reprint author), NIDDK, Epidemiol & Clin Trials Branch, Div Digest Dis & Nutr, 2 Democracy Plaza,Room 673,6707 Democracy Blvd MS, Bethesda, MD 20892 USA. NR 143 TC 158 Z9 167 U1 0 U2 7 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8553 J9 GASTROENTEROL CLIN N JI Gastroenterol. Clin. North Am. PD SEP PY 2000 VL 29 IS 3 BP 559 EP + DI 10.1016/S0889-8553(05)70130-8 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 361FQ UT WOS:000089712800003 PM 11030073 ER PT J AU Coleman, AE Ried, T Janz, S AF Coleman, AE Ried, T Janz, S TI Chromosomes 1 and 5 harbor plasmacytoma progressor genes in mice SO GENES CHROMOSOMES & CANCER LA English DT Article ID MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; C-MYC; TRANSLOCATIONS; HYBRIDIZATION; MONOSOMY-13; ABERRATIONS AB Mouse spectral karyotyping (SKY) was employed to analyze 29 primary BALB/c plasmacytomas (PCTs) for the presence of chromosomal aberrations that took place subsequent to the Myc-activating T(12F1;15D2) or T(6C1;15D2) translocations, the initiating oncogenic mutations in plasmacytomagenesis. Recurrent amplifications of chromosome (Chr) 1 (48% prevalence) and promiscuous non-reciprocal translocations of Chr 5 (52% prevalence) suggested the existence of important PCT progressor genes on bands I B/C and 5F. The additional occurrence of sporadic aberrations (93% prevalence) most likely reflected the general instability of the PCT genome. This instability, however, was not consistent, as two PCTs lacked secondary cytogenetic changes detectable by SKY. Our findings led us to conclude that BALB/c PCTs show a remarkably similar degree of cytogenetic heterogeneity to human multiple myeloma, despite being genetically defined (inbred mouse strain) and uniformly initiated (deregulation of Myc). Genes Chromosomes Cancer 29:70-74, 2000. Published 2000 Wiley-Liss, Inc.dagger. C1 NCI, Div Basic Sci, Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Dept Genet, NIH, Bethesda, MD 20892 USA. RP Janz, S (reprint author), NCI, Div Basic Sci, Genet Lab, NIH, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 21 TC 7 Z9 7 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD SEP PY 2000 VL 29 IS 1 BP 70 EP 74 DI 10.1002/1098-2264(2000)9999:9999<::AID-GCC1009>3.0.CO;2-C PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 342KQ UT WOS:000088644100010 PM 10918396 ER PT J AU Pfendler, KC Yoon, J Taborn, GU Kuehn, MR Iannaccone, PM AF Pfendler, KC Yoon, J Taborn, GU Kuehn, MR Iannaccone, PM TI Nodal and Bone Morphogenetic Protein 5 interact in murine mesoderm formation and implantation SO GENESIS LA English DT Article DE gastrulation; mouse; mesoderm; nodal; Bmp-5; implantation; double mutants ID EARLY EMBRYONIC LETHALITY; EARLY MOUSE EMBRYO; IMMUNOHISTOCHEMICAL LOCALIZATION; CARBOHYDRATE ANTIGENS; FAMILY MEMBERS; BMP FAMILY; GASTRULATION; EXPRESSION; GENE; BETA AB Mice mutant for the TGF-beta family member, nodal, lack mesoderm and die between E8.5 and E9.5. The short ear-lethal (se(l)) mutation, a deletion that eliminates Bmp-5, causes a strikingly similar gastrulation defect. Here we analyze se(l);nodal compound mutants and find a dosage effect. Embryos homozygous for one mutation show distinct gastrulation stage defects that depend on whether they are heterozygous or homozygous for the other mutation. Embryos mutant for nodal or se(l);nodal compound mutants fail to execute an antigenic shift indicative of mesoderm differentiation and ectoderm cells are shunted into an apoptotic pathway, Furthermore, we find a novel phenotype in se(l);nodal double mutant litters, in which two to four genetically different embryos are contained within the same deciduum. Both the gastrulation and implantation phenotypes can also arise in short ear-viable (se(v)) and se(v):nodal mutant mice. These data indicate that loss of Bmp-5 may underlie the se(l) gastrulation phenotype and suggest that nodal and Bmp-5 interact during murine mesoderm formation. Our data also reveal an unsuspected role for Bmp-5 in implantation and the decidual response in the mouse. (C) 2000 Wiley-Liss, Inc. C1 Northwestern Univ, Sch Med, Dept Pediat, Chicago, IL 60614 USA. Childrens Mem Hosp, Childrens Mem Inst Educ & Res, Dev Biol Program, Chicago, IL 60614 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Iannaccone, PM (reprint author), Northwestern Univ, Sch Med, Dept Pediat, 2300 Childrens Plaza,Box 204, Chicago, IL 60614 USA. RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 NR 71 TC 18 Z9 19 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD SEP PY 2000 VL 28 IS 1 BP 1 EP 14 DI 10.1002/1526-968X(200009)28:1<1::AID-GENE10>3.0.CO;2-X PG 14 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 370GJ UT WOS:000165114900001 PM 11020711 ER PT J AU Gajewski, K Choi, CY Kim, Y Schulz, RA AF Gajewski, K Choi, CY Kim, Y Schulz, RA TI Genetically distinct cardial cells within the Drosophila heart SO GENESIS LA English DT Article DE asymmetric cell division; cardiogenesis; D-mef2; Seven Up; Tinman; transcriptional enhancer ID D-MEF2 TRANSCRIPTION FACTOR; GENE-EXPRESSION; HOMEOBOX GENES; TINMAN; MESODERM; MYOGENESIS; FATES; MEF2; 7-UP; DIFFERENTIATION AB Although often viewed as a simple pulsating tube, the Drosophila dorsal vessel is intricate in terms of its structure, cell types, and patterns of gene expression. Two nonidentical groups of cardial cells are observed in segments of the heart based on the differential expression of:transcriptional regulators. These include sets of four cell pairs that express the homeodomain protein Tinman (Tin), alternating with groups of two cell pairs that express the orphan steroid hormone receptor Seven Up (Svp). Here we show that these myocardial cell populations are distinct in terms of their formation and gene expression profiles, The Svp-expressing cells are generated by asymmetric cell divisions of precursor cells based on decreases or increases in their numbers in numb or sanpodo mutant embryos. In contrast, the numbers of Tin-expressing cardial cells are unchanged in these genetic backgrounds, suggesting they arise from symmetric cell divisions. One function for Svp in the two pairs of cardial cells is to repress the expression of the tin gene and at least one of its targets, the beta3 tubulin gene. Further differences in the cells are substantiated by the identification of separable enhancers for D-mef2 gene transcription in the distinct cardioblast sets. Taken together, these results demonstrate a greater cellular and genetic complexity of the Drosophila heart than previously appreciated, (C) 2000 Wiley-Liss, Inc. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Grad Program Genes & Dev, Houston, TX 77030 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Schulz, RA (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Grad Program Genes & Dev, Box 117,1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [CA16672]; NHLBI NIH HHS [HL59151] NR 39 TC 52 Z9 54 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD SEP PY 2000 VL 28 IS 1 BP 36 EP 43 DI 10.1002/1526-968X(200009)28:1<36::AID-GENE50>3.0.CO;2-4 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 370GJ UT WOS:000165114900005 PM 11020715 ER PT J AU Rose, PS Levy, HP Ahn, NU Sponseller, PD Magyari, T Davis, J Francomano, CA AF Rose, PS Levy, HP Ahn, NU Sponseller, PD Magyari, T Davis, J Francomano, CA TI A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome SO GENETICS IN MEDICINE LA English DT Article DE Marfan syndrome; fibrillin; dural ectasia; Berlin diagnostic criteria; Ghent diagnostic criteria ID MUTATIONS; GENE; FBN1 AB Purpose: To compare the Berlin and Ghent diagnostic criteria for Marfan syndrome and evaluate the utility of screening for dural ectasia in the diagnosis of Marfan syndrome. Methods: Review of clinical and radiographic data on 73 patients evaluated for Marfan syndrome at the National Institutes of Health. Results: Nineteen percent of patients diagnosed under the Berlin criteria failed to meet the Ghent standard. Dural ectasia was the second most common major diagnostic manifestation, and screening for dural ectasia established the diagnosis of Marfan syndrome in 23% of patients under the Ghent criteria. Conclusions: Some patients are appropriately excluded from the diagnosis of Marfan syndrome by the Ghent criteria. Determination of dural ectasia is valuable in the diagnosis of Marfan syndrome. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Dept Orthopaed Surg, Baltimore, MD 21287 USA. RP Rose, PS (reprint author), NHGRI, NIH, 10 Ctr Dr,Bldg 10,Room 10C101,MSC 1852, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 18 TC 24 Z9 26 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD SEP-OCT PY 2000 VL 2 IS 5 BP 278 EP 282 DI 10.1097/00125817-200009000-00002 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 409PZ UT WOS:000167393200002 PM 11399208 ER PT J AU Chen, AS Kovach, MJ Herman, K Avakian, A Frank, W Forrester, S Lin, JP Kimonis, V AF Chen, AS Kovach, MJ Herman, K Avakian, A Frank, W Forrester, S Lin, JP Kimonis, V TI Clinical heterogeneity in autosomal dominant optic atrophy in two 3q28-qter linked central Illinois families SO GENETICS IN MEDICINE LA English DT Article DE optic atrophy; dominant; chromosome 3q; linkage; sex-influenced variation ID DIACYLGLYCEROL KINASE; LINKAGE ANALYSIS; GENETIC-HETEROGENEITY; CHROMOSOME 3Q; OPA1; LOCUS; REFINEMENT; PEDIGREES; INTERVAL; REGION AB Purpose: To examine the clinical and genetic heterogeneity of autosomal dominant optic atrophy among two unrelated central Illinois families. Methods: Forty-three individuals from two pedigrees had complete eye examinations. Linkage analysis was performed with microsatellite markers from the region 3q28-29. Results: Visual acuity in 21 affected individuals ranged from 20/25 to 20/800. Vision loss was more severe in males than females (P = 0.02). Color vision testing revealed generalized dyschromatopsia. Both visual acuity and color vision deteriorated with age. Linkage was established to chromosome 3q28-29 (LODmax = 4.68 for D3S2305). Conclusion: Autosomal dominant optic atrophy linked to chromosome 3q28-29 shows intrafamilial phenotypic variation as well as sex-influenced severity in two Midwestern families. C1 So Illinois Univ, Sch Med, Dept Pediat, Div Genet & Metab, Springfield, IL 62794 USA. Illinois State Police, Forens Sci Command, Res & Dev Lab, Div Forens Serv, Springfield, IL USA. SIU Eye Ctr, Springfield, IL USA. NHLBI, Off Biostat, NIH, Bethesda, MD 20892 USA. RP Kimonis, V (reprint author), So Illinois Univ, Sch Med, Dept Pediat, Div Genet & Metab, POB 19658, Springfield, IL 62794 USA. NR 22 TC 5 Z9 5 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 SEP-OCT PY 2000 VL 2 IS 5 BP 283 EP 289 DI 10.1097/00125817-200009000-00003 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 409PZ UT WOS:000167393200003 PM 11399209 ER PT J AU Guttmacher, AE Collins, FS AF Guttmacher, AE Collins, FS TI Genetics resources on the Web (GROW) SO GENETICS IN MEDICINE LA English DT Article C1 NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. RP Guttmacher, AE (reprint author), NIH, Natl Ctr Human Genome Res, Bldg 31,Room 4B09, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 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 SEP-OCT PY 2000 VL 2 IS 5 BP 296 EP 299 DI 10.1097/00125817-200009000-00005 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 409PZ UT WOS:000167393200005 ER PT J AU Loging, WT Lal, A Siu, IM Loney, TL Wikstrand, CJ Marra, MA Prange, C Bigner, DD Strausberg, RL Riggins, GJ AF Loging, WT Lal, A Siu, IM Loney, TL Wikstrand, CJ Marra, MA Prange, C Bigner, DD Strausberg, RL Riggins, GJ TI Identifying potential tumor markers and antigens by database mining and rapid expression screening SO GENOME RESEARCH LA English DT Article ID GENE-EXPRESSION; DENDRITIC CELLS; CDNA-LIBRARY; NEUROMEDIN-B; ANNEXIN-I; CANCER; SPARC; CLONING; PROTEIN; TISSUE AB Genes expressed specifically in malignant tissue may have potential as therapeutic targets but have been difficult to locate for most cancers. The information hidden within certain public databases can reveal RNA transcripts specifically expressed in transformed tissue. To be useful, database information must be verified and a more complete pattern of tissue expression must be demonstrated. We tested database mining plus rapid screening by fluorescent-PCR expression comparison (F-PEC) as an approach to locate candidate brain tumor antigens. Cancer Genome Anatomy Project (CGAP) data was mined for genes highly expressed in glioblastoma multiforme. From 13 mined genes, seven showed potential as possible tumor markers or antigens as determined by further expression profiling. Now that large-scale expression information is readily available for many of the commonly occurring cancers, other candidate tumor markers or antigens could be located and evaluated with this approach. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA. Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, IMAGE Consortium, Livermore, CA 94550 USA. NCI, Canc Genome Anat Project, Off Director, Bethesda, MD 20892 USA. RP Riggins, GJ (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. RI Marra, Marco/B-5987-2008 NR 47 TC 70 Z9 75 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD SEP PY 2000 VL 10 IS 9 BP 1393 EP 1402 DI 10.1101/gr.138000 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 353BY UT WOS:000089254900014 PM 10984457 ER PT J AU Tian, HJ Brody, LC Landers, JP AF Tian, HJ Brody, LC Landers, JP TI Rapid detection of deletion, insertion, and substitution mutations via heteroduplex analysis using capillary- and microchip-based electrophoresis SO GENOME RESEARCH LA English DT Article ID STRAND CONFORMATION POLYMORPHISM; POLYMERASE-CHAIN-REACTION; INDUCED FLUORESCENCE DETECTION; SILICON-GLASS CHIPS; PCR AMPLIFICATION; GEL-ELECTROPHORESIS; BRCA1 MUTATIONS; POINT MUTATIONS; OVARIAN-CANCER; ASHKENAZI JEWS AB In this report, we explore the potential of capillary and microchip electrophoresis for heteroduplex analysis-(HDA) based mutation detection. Fluorescent dye-labeled primers (6-FAM-tagged) were used to amplify the DNA fragments ranging from 130 to 400 bp. The effects of DNA fragment length, matrix additives, pH, and salt were evaluated for capillary electrophoresis- (CE) and/or microchip electrophoresis-based HDA, using six heterozygous mutations, 185delAG, E1250X(3867GT), R1443G (4446CG), 5382insC, 5677insA in BRCA1 and 6174delT in BRCA2. For this system, the effective Fragment size for CE-based HDA was found in the range of 200-300 bp, however, the effective range was 150-260 bp for microchip-based HDA. Sensitivity studies show CE-based HDA could detect a mutated DNA present at only 1%-10% of the total DNA. Discrimination between wild-type and deletion or insertion mutations in BRCA1 and BRCA2 with CE-based HDA could be achieved in <8 min, while the substitution mutations required 14 min of analysis time. For each mutation region, 15 samples were run to confirm the accuracy and reproducibility of the method. Using the method described, two previously reported mutations, E1038G (3232AG, missense) and 4427 C/T (4427CT, polymorphism), were detected in the tested samples and confirmed by DNA sequencing. Translation of the CE-based methodology to the microchip Format allowed the analysis time for each mutation to be decreased to 130 sec. Based on the results obtained with this model system, it is possible that CE-based HDA methodologies can be developed and used effectively in genetic testing. The fast separation time and automated operation afforded with CE instrumentation provide a powerful system for screening mutations that include small deletions, insertions, and point mutations. Translation to the microchip platform, especially to a multichannel microchip system, would allow for screening mutations with high throughput. C1 Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. Univ Virginia, Dept Pathol, Charlottesville, VA 22901 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. NIH, Natl Ctr Human Genome Res, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Landers, JP (reprint author), Univ Virginia, Dept Chem, Mccormick Rd, Charlottesville, VA 22901 USA. NR 58 TC 71 Z9 74 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD SEP PY 2000 VL 10 IS 9 BP 1403 EP 1413 DI 10.1101/gr.132700 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 353BY UT WOS:000089254900015 PM 10984458 ER PT J AU Eggers, PW AF Eggers, PW TI Medicare's end stage renal disease program SO HEALTH CARE FINANCING REVIEW LA English DT Article ID POLICY AB Perhaps no other Federal Government program can lay claim to have saved as many lives as the Medicare end stage renal disease (ESRD) program. Since its inception in 1973, as a result of the Social Security Amendments of 1972 (Public Law 92-603, section 2991), over 1 million persons have received life-saving renal replacement therapy under this program. Prior to the enactment of this legislation, treatment was limited to a very few patients due to its extremely high cost and the limited number of dialysis machines. In the 1960s, it was not uncommon for hospitals that had dialysis machines to appoint special committees to review applicants for dialysis and decide who should receive treatment, the others were left to die of renal failure. Public Law 92-603 removed this odious task from the nephrology community. A person with ESRD is entitled to Medicare if he/she is fully or currently insured for benefits under Social Security, or is a spouse or dependent of an insured person. consequently, entitlement is less than universal, with 92 percent of all persons with ESRD qualifying for Medicare coverage. C1 NIDDKD, Bethesda, MD 20892 USA. RP Eggers, PW (reprint author), NIDDKD, 6707 Democracy Blvd,Room 615, Bethesda, MD 20892 USA. NR 13 TC 12 Z9 12 U1 0 U2 0 PU HEALTH CARE FINANCING REVIEW PI BALTIMORE PA 7500 SECURITY BLVD, C-3-11-07, BALTIMORE, MD 21224-1850 USA SN 0195-8631 J9 HEALTH CARE FINANC R JI Health Care Finan. Rev. PD FAL PY 2000 VL 22 IS 1 BP 55 EP 60 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 401YA UT WOS:000166955600006 ER PT J AU Petralia, RS Rubio, ME Wang, YX Wenthold, RJ AF Petralia, RS Rubio, ME Wang, YX Wenthold, RJ TI Differential distribution of glutamate receptors in the cochlear nuclei SO HEARING RESEARCH LA English DT Article; Proceedings Paper CT Symposium on Molecular Mechanisms in Central Auditory Function and Plasticity CY JUN 25-27, 1999 CL PARK CITY, UT DE AMPA; NMDA; kainate; metabotropic; endbulb; fusiform cell ID CENTRAL-NERVOUS-SYSTEM; SUBUNIT MESSENGER-RNAS; IN-SITU HYBRIDIZATION; UNIPOLAR BRUSH CELLS; D-ASPARTATE RECEPTOR; AUDITORY BRAIN-STEM; AMPA RECEPTORS; MONOCLONAL-ANTIBODY; GLIAL LOCALIZATIONS; CA2+ PERMEABILITY AB Glutamate receptors are the major excitatory neurotransmitter receptors of the mammalian central nervous system, and include AMPA. kainate, delta, NMDA, and metabotropic types. In the cochlear nucleus (CN), the AMPA receptor subunits GluR2-4 are found in major kinds of neurons, while GluR1 subunit distribution is more restricted. GluR2 is low in the anteroventral CN, suggesting that many AMPA receptors here are calcium-permeable. Delta receptors are most prevalent in cartwheel cells in the dorsal CN. Of the NMDA receptors, NR1 is widespread while the NR2 subunits show more restricted distributions. Of the metabotropic glutamate receptors, mGluR1 alpha is most prevalent in the dorsal CN, and mGluR2 is concentrated in Golgi cells and unipolar brush cells. AMPA receptors in endbulb synapses in the anteroventral CN are mainly GluR3+4 complexes: probably an adaptation for rapid auditory neurotransmission. Glutamate receptors are differentially distributed in synapses of fusiform cells of the dorsal CN; GluR4 and mGluR1 alpha are present only at basal dendrite synapses (auditory nerve), while other glutamate receptors occupy both apical and basal synapses. Analysis of cytoplasmic distribution suggests that a selective targeting mechanism may restrict movement of GluR4 and mGluR1 alpha to basal dendrites, although other targeting mechanisms may be present. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDCD, NIH, Bethesda, MD 20892 USA. RP Petralia, RS (reprint author), NIDCD, NIH, 36-5D08,36 Convent Dr MSC 4162, Bethesda, MD 20892 USA. NR 56 TC 45 Z9 45 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD SEP PY 2000 VL 147 IS 1-2 BP 59 EP 69 DI 10.1016/S0378-5955(00)00120-9 PG 11 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 352HV UT WOS:000089210200006 PM 10962173 ER PT J AU Baumert, TF Wellnitz, S Aono, S Satoi, J Herion, D Gerlach, JT Pape, GR Lau, JYN Hoofnagle, JH Blum, HE Liang, TJ AF Baumert, TF Wellnitz, S Aono, S Satoi, J Herion, D Gerlach, JT Pape, GR Lau, JYN Hoofnagle, JH Blum, HE Liang, TJ TI Antibodies against hepatitis C virus-like particles and viral clearance in acute and chronic hepatitis C SO HEPATOLOGY LA English DT Article; Proceedings Paper CT 6th International Symposium on HCV and Related Viruses CY JUN 06-09, 1999 CL BETHESDA, MARYLAND ID NONSTRUCTURAL PROTEIN-3; STRUCTURAL PROTEINS; INSECT CELLS; E2 PROTEIN; NON-A; INFECTION; INTERFERON; RESPONSES; THERAPY; SEROREACTIVITY AB We recently described the efficient assembly of hepatitis C virus (HCV) structural proteins into HCV-like particles (HCV-LPs) in insect cells. These noninfectious HCV-LPs have similar morphologic and biophysical properties as putative virions isolated from HCV-infected humans and can induce a broadly directed immune response in animal models. The HCV envelope proteins of HCV-LPs are presumably presented in a native, virion-like conformation and may therefore interact with antienvelope antibodies directed against conformational epitopes, In this study, HCV-LPs were used as capture antigens in an enzyme-linked immunosorbent assay (ELISA) to detect and quantify antibodies against HCV structural proteins in patients with acute and chronic hepatitis C, High titers of anti-HCV-LP antibodies were detected in patients chronically infected with HCV genotypes 1 to 6. In contrast to individuals with chronic hepatitis C, patients with acute self-limited hepatitis C displayed only a transient and weak seroreactivity against HCV-LPs. Patients with chronic HCV infection successfully treated with interferon demonstrated a gradual decline of anti-HCV-LP titers during or subsequent to viral clearance. Sustained interferon responders were characterized by significantly higher pretreatment levels of anti-HCV-LP antibodies as compared with nonresponders (P = .0001). In conclusion, HCV infection is associated with limited humoral immunity against the envelope proteins present on the HCV-LPs. An HCV-LP-based ELISA may be a useful diagnostic tool to distinguish acute hepatitis C from chronic HCV infection with exacerbation, and to predict viral clearance in response to interferon. C1 Univ Freiburg, Dept Med 2, Sch Med, D-79106 Freiburg, Germany. NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Munich, Klinikum Grosshadern, Dept Med 2, D-8000 Munich, Germany. Univ Florida, Sect Hepatobiliary Dis, Gainesville, FL USA. RP Baumert, TF (reprint author), Univ Freiburg, Dept Med 2, Sch Med, Hugstetter Str 55, D-79106 Freiburg, Germany. NR 42 TC 53 Z9 56 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 SEP PY 2000 VL 32 IS 3 BP 610 EP 617 DI 10.1053/jhep.2000.9876 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 350FV UT WOS:000089091000024 PM 10960457 ER PT J AU Forns, X Payette, PJ Ma, XY Satterfield, W Eder, G Mushahwar, IK Govindarajan, S Davis, HL Emerson, SU Purcell, RH Bukh, J AF Forns, X Payette, PJ Ma, XY Satterfield, W Eder, G Mushahwar, IK Govindarajan, S Davis, HL Emerson, SU Purcell, RH Bukh, J TI Vaccination of chimpanzees with plasmid DNA encoding the hepatitis C virus (HCV) envelope E2 protein modified the infection after challenge with homologous monoclonal HCV SO HEPATOLOGY LA English DT Article ID IMMUNE-RESPONSES; GLYCOPROTEIN COMPLEXES; HYPERVARIABLE REGION-1; GENETIC IMMUNIZATION; STRUCTURAL PROTEINS; HYPERIMMUNE SERUM; ANTIBODY; INTERFERON-ALPHA-2B; PREVENTION; RIBAVIRIN AB Hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. Development of vaccines to prevent HCV infection, or at least prevent progression to chronicity, is a major goal. In mice and rhesus macaques, a DNA vaccine encoding cell-surface HCV-envelope 2 (E2) glyco-protein stimulated stronger immune responses than a vaccine encoding intracellular E2. Therefore, we used DNA encoding surface-expressed E2 to immunize chimpanzees 2768 and 3001. Chimpanzee 3001 developed anti-E2 after the second immunization and antibodies to hypervariable region 1 (HVR1) after the third immunization. Although chimpanzee 2768 had only low levels of anti-E2 after the third immunization, an anamnestic response occurred after HCV challenge. CTL responses to E2 were not detected before challenge, but a strong response was detected after HCV challenge in chimpanzee 2768. An E2-specific CD4+ response was detected in chimpanzee 2768 before challenge and in both chimpanzees postchallenge. Three weeks after the last immunization, animals were challenged with 100 50% chimpanzee-infectious doses (CID50) of homologous monoclonal HCV. As a control, a naive chimpanzee was inoculated with 3 CID50 of the challenge virus. The vaccine did not generate sterilizing immunity because both vaccinated chimpanzees were infected. However, both vaccinated chimpanzees resolved the infection early whereas the control animal became chronically infected. Compared with the control animal, hepatitis appeared earlier in the course of the infection in both vaccinated chimpanzees. Therefore, DNA vaccine encoding cell surface-expressed E2 did not elicit sterilizing immunity in chimpanzees against challenge with a monoclonal homologous virus, but did appear to modify the infection and might have prevented progression to chronicity. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Loeb Res Inst, Ottawa, ON, Canada. MD Anderson Canc Ctr, Bastrop, TX USA. Hans Popper Primate Res Ctr, Orth At Donau, Austria. Abbott Labs, Virus Discovery Grp, N Chicago, IL 60064 USA. Univ So Calif, Rancho Los Amigos Med Ctr, Liver Res Lab, Downey, CA 90242 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 7,Room 201,7 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000]; PHS HHS [N01-A1-45180, N01-A1-52705] NR 48 TC 108 Z9 116 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 2000 VL 32 IS 3 BP 618 EP 625 DI 10.1053/jhep.2000.9877 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 350FV UT WOS:000089091000025 PM 10960458 ER PT J AU Kawakami, K Joshi, BH Puri, RK AF Kawakami, K Joshi, BH Puri, RK TI Sensitization of cancer cells to interleukin 13-Pseudomonas exotoxin-induced cell death by gene transfer of interleukin 13 receptor alpha chain SO HUMAN GENE THERAPY LA English DT Article ID HUMAN GLIOMA-CELLS; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; SIGNAL-TRANSDUCTION; IL-13 RECEPTOR; RETROVIRAL VECTORS; (IL)-13 BINDING; CARCINOMA-CELLS; CLONING; TOXIN AB We have demonstrated that primary interleukin 13 (IL-13) binding protein IL-13 receptor (IL-13R) alpha chain plays an important role in IL-13 binding and internalization in the IL-13R system, Although IL-13R alpha chain is expressed on many cancer cell lines, some cancer types do not express or express low levels of this receptor chain. Consequently, these cells show no or low sensitivity to the cytotoxic effect of a recombinant chimeric protein composed of IL-13 and a mutated form of a Pseudomonas exotoxin, IL13-PE38QQR. Here we demonstrate that pancreatic cancer, renal cell carcinoma, head and neck cancer, and glioblastoma cell lines that were genetically altered to express high levels of IL-13R alpha chain increase their binding affinity for IL-13, and increase their sensitivity to IL13-PE38QQR by at least 6-fold to 1000-fold compared with mock-transfected control cells. This observation was made by protein synthesis inhibition assay and confirmed by clonogenic assay. Our studies provide a proof of principle for a novel strategy for cancer therapy that combines gene transfer and targeted cytotoxin therapy. C1 NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 39 TC 39 Z9 42 U1 0 U2 0 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 SEP 1 PY 2000 VL 11 IS 13 BP 1829 EP 1835 DI 10.1089/10430340050129459 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 352AX UT WOS:000089193300002 PM 10986556 ER PT J AU Chinnasamy, N Chinnasamy, D Toso, JF Lapointe, R Candotti, F Morgan, RA Hwu, P AF Chinnasamy, N Chinnasamy, D Toso, JF Lapointe, R Candotti, F Morgan, RA Hwu, P TI Efficient gene transfer to human peripheral blood monocyte-derived dendritic cells using human immunodeficiency virus type 1-based lentiviral vectors SO HUMAN GENE THERAPY LA English DT Article ID THERAPEUTIC ANTITUMOR IMMUNITY; IN-VIVO; DEFECTIVE FUNCTION; NONDIVIDING CELLS; HIV-1 INFECTION; T-LYMPHOCYTES; ANTIGEN GENE; TRANSDUCTION; VACCINATION; PROGENITORS AB Dendritic cells (DCs) are potent antigen-presenting cells and are capable of activating naive T cells, Gene transfer of tumor antigen and cytokine genes into DCs could be an important strategy for immunotherapeutic applications. Dendritic cells derived from peripheral blood monocytes do not divide and are therefore poor candidates for gene transfer by Moloney murine leukemia virus (Mo-MuLV)-based retroviral vectors, Lentiviral vectors are emerging as a powerful tool for gene delivery into dividing and nondividing cells, A three-plasmid expression system pseudotyped with the envelope from vesicular stomatitis virus (VSV-G) was used to generate lentiviral vector particles expressing enhanced green fluorescent protein (EGFP), Peripheral blood monocyte-derived DCs were cultured in the presence of GM-CSF and IL-4 and transduced with lentiviral or Mo-MuLV-based vectors expressing EGFP, FAGS analysis of lentiviral vector-transduced DCs derived either from normal healthy volunteers or from melanoma patients demonstrated transduction efficiency ranging from 70 to 90% compared with 2-8% using Mo-MuLV-based vectors pseudotyped with VSV-G, Comparison of lentiviral vectors expressing EGFP driven by CMV or human PGK promoters showed similar levels of transgene expression. Lentiviral vector preparations produced in the absence of HIV accessory proteins transduced DCs at efficiencies equal to vectors produced with accessory proteins, Alu-HIV-1 LTR PCR demonstrated the genomic integration of the lentiviral vector in the transduced DCs, Transduced cells showed characteristic dendritic cell phenotype and strong allostimulatory capacity and maintained the ability to respond to activation signals such as CD40 ligand and lipopolysaccharide. These results provide evidence that lentiviral vectors are efficient tools for gene transfer and expression in monocyte-derived DCs that could be useful for immunotherapeutic applications. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, DCS, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 34 TC 73 Z9 75 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 SEP 1 PY 2000 VL 11 IS 13 BP 1901 EP 1909 DI 10.1089/10430340050129512 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 352AX UT WOS:000089193300008 PM 10986562 ER PT J AU Ravnik-Glavac, M Dean, M Glavac, D AF Ravnik-Glavac, M Dean, M Glavac, D TI Two novel missense mutations (R766M and R792G) in exon 13 of the CFTR gene in a patient with congenital bilateral absence of the vas deferens SO HUMAN HEREDITY LA English DT Article ID CYSTIC-FIBROSIS C1 Univ Ljubljana, Fac Med, Inst Pathol, Mol Genet Lab, SI-1000 Ljubljana, Slovenia. Univ Ljubljana, Fac Med, Inst Biochem, SI-1000 Ljubljana, Slovenia. NCI, NIH, Lab Genom Divers, Bethesda, MD USA. RP Ravnik-Glavac, M (reprint author), Univ Ljubljana, Fac Med, Inst Pathol, Mol Genet Lab, Korytkova 2, SI-1000 Ljubljana, Slovenia. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 3 TC 2 Z9 3 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5652 J9 HUM HERED JI Hum. Hered. PD SEP-OCT PY 2000 VL 50 IS 5 BP 318 EP 319 DI 10.1159/000022934 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 331PH UT WOS:000088027100005 PM 10878476 ER PT J AU Blazevic, V Mac Trubey, C Shearer, GM AF Blazevic, V Mac Trubey, C Shearer, GM TI Comparison of in vitro immunostimulatory potential of live and inactivated influenza viruses SO HUMAN IMMUNOLOGY LA English DT Article DE influenza; vaccine; interferon-gamma; interferon-alpha; costimulatory molecules ID RESPONSES; VACCINE; ACTIVATION AB Live influenza viruses, heat-inactivated virus, and a trivalent formalin-inactivated influenza vaccine were analyzed for their in vitro stimulatory properties on immune cells from healthy donors. Lymphocyte proliferation induced by each influenza antigen was comparable. Influenza vaccine stimulated significantly lower production of interferon-gamma (IFN-gamma) compared with live and heat inactivated viruses, whereas both vaccine and heat-inactivated influenza induced lower levels of IFN-alpha compared with live virus. Furthermore, only live virus generated influenza-specific cytotoxic T lymphocyte (CTL) activity. A significant increase in monocyte expression of CD80, CD86, CD40, and human leukocyte antigen-DR (HLA-DR) was also induced by live influenza virus. Our results suggest that immunization with live influenza vaccines might induce immune responses that would not be induced by conventional inactivated vaccines, including CTL generation, antiviral IFN-gamma and IFN-alpha cytokine production, and increased antigen presentation and costimulatory capacity on antigen presenting cells (APC). Human Immunology 61: 845-849 (2000). (C) American Society for Histocompatibility and Immunogenetics, 2000. Published by Elsevier Science Inc. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 14 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD SEP PY 2000 VL 61 IS 9 BP 845 EP 849 DI 10.1016/S0198-8859(00)00170-1 PG 5 WC Immunology SC Immunology GA 367DT UT WOS:000090047000001 PM 11053627 ER PT J AU McCampbell, A Taylor, JP Taye, AA Robitschek, J Li, M Walcott, J Merry, D Chai, YH Paulson, H Sobue, G Fischbeck, KH AF McCampbell, A Taylor, JP Taye, AA Robitschek, J Li, M Walcott, J Merry, D Chai, YH Paulson, H Sobue, G Fischbeck, KH TI CREB-binding protein sequestration by expanded polyglutamine SO HUMAN MOLECULAR GENETICS LA English DT Article ID ANDROGEN RECEPTOR; NUCLEAR-LOCALIZATION; TRANSCRIPTION FACTOR; CBP; AGGREGATION; COACTIVATOR; HUNTINGTIN; ACTIVATION; SURVIVAL; DISEASE AB Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion, In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3, We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA, Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture, These data support a CBP-sequestration model of polyglutamine expansion disease. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Sch Med, Dept Neurol, Showa Ku, Aichi, Japan. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Iowa, Coll Med, Dept Neurol, Iowa City, IA 52242 USA. RP McCampbell, A (reprint author), NINDS, Neurogenet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3B11, Bethesda, MD 20892 USA. NR 27 TC 367 Z9 376 U1 0 U2 5 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 SEP 1 PY 2000 VL 9 IS 14 BP 2197 EP 2202 DI 10.1093/hmg/9.14.2197 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 351WF UT WOS:000089181300016 PM 10958659 ER PT J AU Dmitrieva, RI Bagrov, AY Lalli, E Sassone-Corsi, P Stocco, DM Doris, PA AF Dmitrieva, RI Bagrov, AY Lalli, E Sassone-Corsi, P Stocco, DM Doris, PA TI Mammalian bufadienolide is synthesized from cholesterol in the adrenal cortex by a pathway that is independent of cholesterol side-chain cleavage SO HYPERTENSION LA English DT Article DE preeclampsia; adrenal gland; chromatography; steroids; bufadienolides; cholesterol ID DIGITALIS-LIKE COMPOUNDS; SODIUM-PUMP INHIBITORS; ENDOGENOUS OUABAIN; CARDIAC-GLYCOSIDES; BLOOD-PRESSURE; K+-ATPASE; RAT AORTA; CELLS; MARINOBUFAGENIN; BIOSYNTHESIS AB An increasing body of evidence suggests that an endogenous mammalian bufadienolide (BD) may be involved in the regulation of Na+,K+-ATPase activity and the pathogenesis of arterial hypertension. We developed a purification scheme for marinobufagenin (MBG), an amphibian cardiotonic ED, and applied it to purify and characterize material in human plasma, culture medium conditioned by Y-1 adrenocortical cells, and rat adrenal tissue. MBG immunoreactivity purified from plasma and measured by ELISA showed important similarities (chromatography and antibody cross-reactivity) to material secreted into cell culture medium by Y-1 cells. This observation indicates that circulating mammalian ED may have an adrenocortical origin. Release of mammalian ED from adrenocortical cells grown in the absence of exogenous cholesterol was reduced by treatment of cultures with mevastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Supplementation of the serum and cholesterol-free cell culture medium with the LDL fraction of human plasma increased the production of MBG material in the presence of mevastatin, supporting its origin from cholesterol. We used Y-1 cell lines transfected with genes shown to inhibit steroidogenesis through cholesterol side-chain cleavage (Y-1/DAX and Y-1/RIAB) to investigate the dependence of MBG biosynthesis on side-chain cleavage. Our results indicate that the mammalian ED is synthesized in the adrenal cortex from cholesterol and shares important similarities with the amphibian ED MEG, that its biosynthesis is independent of transfer of cholesterol to the side-chain cleavage enzyme complex mediated by steroidogenic acute regulatory protein, and that neither cAMP nor protein kinase A appears to be a critical component of the pathway controlling its biosynthesis. C1 Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. Univ Louis Pasteur Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, Strasbourg, France. Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA. RP Doris, PA (reprint author), Univ Texas, Hlth Sci Ctr, Inst Mol Med, 2121 Holcombe Blvd, Houston, TX 77030 USA. RI Sassone-Corsi, Paolo/H-6182-2011; Lalli, Enzo/F-7052-2013; OI Lalli, Enzo/0000-0002-0584-5681; Dmitrieva, Renata/0000-0002-3073-7914 FU NIDDK NIH HHS [R01-DDK45538] NR 50 TC 48 Z9 49 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2000 VL 36 IS 3 BP 442 EP 448 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 354MG UT WOS:000089333800024 PM 10988279 ER PT J AU Lichtstein, D McGowan, MH Russell, P Carper, DA AF Lichtstein, D McGowan, MH Russell, P Carper, DA TI Digitalis and digitalislike compounds down-regulate gene expression of the intracellular signaling protein 14-3-3 in rat lens SO HYPERTENSION RESEARCH LA English DT Article; Proceedings Paper CT International Symposium on Natriuretic and Digitalislike Factors CY AUG 24, 1999 CL HOKKAIDO, JAPAN DE digitalis; bufalin; Na+,K+-ATPase; gene expression; 14-3-3 protein ID IDENTIFICATION; OUABAIN; ATPASE AB Na+,K+-ATPase activity in the epithelial layer is fundamental to the maintenance of ionic concentration gradients and transparency of the lens. Recently we have identified endogenous digitalislike compounds (DLC), 19-norbufalln and its peptide derivatives, in human cataractous lenses (Lichtstein et al, Eur J Biochem 216: 261-263, 1993). Lenses were treated with 10 nM ouabain, bufalin or 19-norbufalin derivative for 24 h and were compared to control lenses. Differential display analysis revealed that one of the downregulated genes was 14-3-3 theta. Down-regulation was confirmed by Northern blot and by RT-PCR analysis. RT-PCR of additional 14-3-3 isoforms revealed that the eta and gamma isoforms of 14-3-3 are also down-regulated by ouabain, bufalin and 19-norbufalin derivative, whereas the zeta isoform is down-regulated only by bufalin, These results demonstrate that one of the consequences of Na+,K+-ATPase inhibition by exogenous or endogenous inhibitors is the down-regulation of mRNA transcripts encoding several isoforms of 14-3-3. Since the 14-3-3 proteins are multifunctional regulatory proteins, the reduction in the abundance of various isoforms will have profound effects on cell function. Furthermore, These results, together with the demonstration of digitalislike compounds in the normal lens, and their increased level in human cataractous lenses, strongly suggests their involvement in the molecular mechanisms responsible for cataract formation. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. NEI, Lab Mech Ocular Dis, Bethesda, MD 20892 USA. RP Lichtstein, D (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, POB 12272, IL-91120 Jerusalem, Israel. NR 17 TC 11 Z9 11 U1 0 U2 0 PU JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE PI TOYONAKA PA OSAKA, 14TH FL, SENRI LIFE SCI CENTER BLDG, 4-2 SHINSENRI- HIGASHI-MACHI 1 CHOME, TOYONAKA, 565-0082, JAPAN SN 0916-9636 J9 HYPERTENS RES JI Hypertens. Res. PD SEP PY 2000 VL 23 SU S BP S51 EP S53 DI 10.1291/hypres.23.Supplement_S51 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 364CJ UT WOS:000089874200009 PM 11016820 ER PT J AU Brigger, P Hoeg, J Unser, M AF Brigger, P Hoeg, J Unser, M TI B-Spline snakes: A flexible tool for parametric contour detection SO IEEE TRANSACTIONS ON IMAGE PROCESSING LA English DT Article ID FOURIER DESCRIPTORS; ACTIVE CONTOURS; SHAPE ESTIMATION; IMAGE CONTOURS; MODELS; RECOGNITION; ALGORITHM; CURVES; DESIGN AB We present a novel formulation for B-spline snakes that can be used as a tool for fast and intuitive contour outlining. We start with a theoretical argument in favor of splines in the traditional formulation by showing that the optimal, curvature-constrained snake is a cubic spline, irrespective of the form of the external energy held, Unfortunately, such regularized snakes suffer from slow convergence speed because of a large number of control points, as well as from difficulties in determining the weight factors associated to the internal energies of the curve. We therefore propose an alternative formulation in which the intrinsic scale of the spline model is adjusted a priori; this Leads to a reduction of the number of parameters to be optimized and eliminates the need for internal energies (i.e., the regularization term), In other words, we are now controlling the elasticity of the spline implicitly and rather intuitively by varying the spacing between the spline knots. The theory is embedded into a multiresolution formulation demonstrating improved stability in noisy image environments. Validation results are presented, comparing the traditional snake using internal energies and the proposed approach without internal energies, showing the similar performance of the latter, Several biomedical examples of applications are included to illustrate the versatility of the method. C1 NIH, Biomed Engn & Instrumentat Branch, Natl Ctr Res Resources, Bethesda, MD 20892 USA. Ecole Polytech Fed Lausanne, Biomed Imaging Grp, CH-1015 Lausanne, Switzerland. RI Unser, Michael/A-1550-2008 NR 51 TC 162 Z9 176 U1 2 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 1057-7149 J9 IEEE T IMAGE PROCESS JI IEEE Trans. Image Process. PD SEP PY 2000 VL 9 IS 9 BP 1484 EP 1496 DI 10.1109/83.862624 PG 13 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 347EL UT WOS:000088914400003 PM 18262987 ER PT J AU Tomasello, E Desmoulins, PO Chemin, K Guia, S Cremer, H Ortaldo, J Love, P Kaiserlian, D Vivier, E AF Tomasello, E Desmoulins, PO Chemin, K Guia, S Cremer, H Ortaldo, J Love, P Kaiserlian, D Vivier, E TI Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice SO IMMUNITY LA English DT Article ID PROTEIN-TYROSINE KINASE; ACTIVATING RECEPTORS; SIGNAL-TRANSDUCTION; CUTTING EDGE; IN-VIVO; COMPLEX; CYTOTOXICITY; LY-49D; DAP12; ZETA AB KARAP/DAP12 is a transmembrane polypeptide with an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). KARAP/DAP12 is associated with several activating cell surface receptors in hematopoietic cells. Here, we report that knockin mice bearing a nonfunctional KARAP/DAP12 ITAM present altered innate immune responses. Although in these mice NK cells are present and their repertoire of inhibitory MHC class I receptors is intact, the NK cell spectrum of natural cytotoxicity toward tumor cell targets is restricted. KARAP/DAP12 loss-of-function mutant mice also exhibit a dramatic accumulation of dendritic cells in muco-cutaneous epithelia, associated with an impaired hapten-specific contact sensitivity. Thus, despite its homology with CD3 zeta and FcR gamma, KARAP/DAP12 plays a specific role in innate immunity, emphasizing the nonredundancy of these ITAM-bearing polypeptides in hematopoietic cells. C1 INSERM, U404, Lyon 07, France. CNRS Marseille Luminy, INSERM, Ctr Immunol, F-13288 Marseille 09, France. Lab Genet & Physiol Dev, Marseille 09, France. NCI, Expt Immunol Lab, DBS, FCRDC, Frederick, MD 21702 USA. NICHD, Sect Cellular & Dev Biol, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Inst Univ France, Paris, France. RP Kaiserlian, D (reprint author), INSERM, U404, Lyon 07, France. RI KAISERLIAN, Dominique/G-3325-2013; OI Tomasello, Elena/0000-0002-6839-5219 NR 50 TC 134 Z9 138 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP PY 2000 VL 13 IS 3 BP 355 EP 364 DI 10.1016/S1074-7613(00)00035-2 PG 10 WC Immunology SC Immunology GA 359NF UT WOS:000089616400008 PM 11021533 ER PT J AU Zhang, YH Boesen, CC Radaev, S Brooks, AG Fridman, WH Sautes-Fridman, C Sun, PD AF Zhang, YH Boesen, CC Radaev, S Brooks, AG Fridman, WH Sautes-Fridman, C Sun, PD TI Crystal structure of the exctracellular domain of a human Fc gamma RIII SO IMMUNITY LA English DT Article ID LOW-AFFINITY RECEPTOR; INHIBITORY RECEPTOR; EPSILON-RI; PROTEIN STRUCTURES; BINDING-SITE; CLASS-I; IGE; IDENTIFICATION; ACTIVATION; COMPLEX AB Fc receptors play a major role in immune defenses against pathogens and in inflammatory processes. The crystal structure of a human immunoglobulin receptor, Fc gamma RIIIb, has been determined to 1.8 Angstrom resolution. The overall fold consists of two immunoglobulinlike domains with an acute interdomain hinge angle of approximately 50 degrees. Trp-113, wedged between the N-terminal D1 and the C-terminal D2 domains, appears to further restrict the hinge angle. The putative Pc binding region of the receptor carries a net positive charge complementary to the negative-charged receptor binding regions on Fc. A1:1 binding stoichiometry between the receptor and Fc was measured by both the equilibrium and nonequilibrium size-exclusion chromatography. Two separate parallel dimers are observed in the crystal lattice, offering intriguing models for receptor aggregation. C1 NIAID, Struct Biol Sect, NIH, Rockville, MD 20852 USA. Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. Inst Curie, Lab Cellular & Clin Immunol, INSERM, U255, F-75005 Paris, France. RP Sun, PD (reprint author), NIAID, Struct Biol Sect, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 33 TC 59 Z9 62 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP PY 2000 VL 13 IS 3 BP 387 EP 395 DI 10.1016/S1074-7613(00)00038-8 PG 9 WC Immunology SC Immunology GA 359NF UT WOS:000089616400011 PM 11021536 ER PT J AU Joe, B Remmers, EF Dobbins, DE Salstrom, JL Furuya, T Dracheva, S Gulko, PS Cannon, GW Griffiths, MM Wilder, RL AF Joe, B Remmers, EF Dobbins, DE Salstrom, JL Furuya, T Dracheva, S Gulko, PS Cannon, GW Griffiths, MM Wilder, RL TI Genetic dissection of collagen-induced arthritis in Chromosome 10 quantitative trait locus speed congenic rats: evidence for more than one regulatory locus and sex influences SO IMMUNOGENETICS LA English DT Article DE autoimmunity; rheumatoid arthritis; inbred DA rats; inbred F344 rats; genetic maps ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RADIATION HYBRID MAP; NON-MHC GENES; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; AUTOIMMUNE-DISEASES; HISTOCOMPATIBILITY COMPLEX; MULTIPLE-SCLEROSIS; ANIMAL-MODELS AB Rat Chromosome 10 (RNO10) harbors Cia5, a non-MHC quantitative trait locus (QTL) that regulates the severity of type II collagen-induced arthritis (CIA) in DAxF344 and DAxBN F2 rats. CIA is an animal model with many features that resemble rheumatoid arthritis. To facilitate analysis of Cia5 independently of the other CIA regulatory loci on other chromosomes, DA recombinant QTL speed congenic rats, DA.F344(Cia5), were generated. These QTL congenic rats have a large chromosomal segment containing Cia5 (interval size less than or equal to 80.1 cM) from CIA-resistant F344 rats introgressed into their genome. Phenotypic analyses of these rats for susceptibility and severity of CIA confirmed that Cia5 is an important disease-modifying locus. CIA severity was significantly lower in the Cia5 congenic rats than in DA controls. We also generated DA Cia5 speed sub-congenic rats, DA.F344(Cia5a), which had a smaller segment of the F344 genome, Cia5a, comprising only the distal q-telomeric end (interval size less than or equal to 22.5 cM) of Cia5, introgressed into their genome, DA,F344(Cia5a) sub-congenic rats also exhibited reduced CIA disease severity compared with the parental DA rats, The regulatory effects in both congenic strains were sex influenced. The disease-ameliorating effect of the larger fragment, Cia5, was greater in males than in females, but the effect of the smaller fragment, Cia5a, was greater in females. We also present an improved genetic linkage map covering the Cia5/Cia5a region, which we have integrated with two rat radiation hybrid maps. Comparative homology analysis of this genomic region with mouse and human chromosomes was also undertaken. Regulatory loci for multiple autoimmune/inflammatory diseases in rats (RNO10), mice (MMU11), and humans (HSA17 and HSA5q23-q31) map to chromosomal segments homologous to Cia5 and Cia5a. C1 NIAMSD, Arthritis & Rheumatism Branch, Inflammatory Joint Dis Sect, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. Columbia Univ Coll Phys & Surg, Div Autoimmune & Mol Dis, New York, NY 10032 USA. Univ Utah, Res Serv, Vet Affairs Med Ctr, Salt Lake City, UT 84132 USA. Univ Utah, Dept Med Rheumatol, Salt Lake City, UT 84132 USA. RP Wilder, RL (reprint author), NIAMSD, Arthritis & Rheumatism Branch, Inflammatory Joint Dis Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 9N240, Bethesda, MD 20892 USA. NR 58 TC 32 Z9 32 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD SEP PY 2000 VL 51 IS 11 BP 930 EP 944 DI 10.1007/s002510000231 PG 15 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 354PQ UT WOS:000089339200006 PM 11003387 ER PT J AU Osawa, M Miyoshi, S Copeland, NG Gilbert, DJ Jenkins, NA Hiroyama, T Motohashi, T Nakamura, Y Iwama, A Nakauchi, H AF Osawa, M Miyoshi, S Copeland, NG Gilbert, DJ Jenkins, NA Hiroyama, T Motohashi, T Nakamura, Y Iwama, A Nakauchi, H TI Characterization of the mouse interleukin-13 receptor alpha 1 gene SO IMMUNOGENETICS LA English DT Article DE interleukin-13 receptor alpha 1; gene structure; soluble receptor; chromosomal mapping ID B-CELLS; CHROMOSOMAL LOCALIZATION; IL-13 RECEPTOR; T-CELLS; CYTOKINE RECEPTORS; SUBUNIT GENE; MURINE; ORGANIZATION; EXPRESSION; COMPONENT AB Interleukin (IL)-13 is a pleiotropic immune regulatory cytokine that shares structural and biological characteristics with IL-4. The receptor for IL-13 is comprised of the IL-4 receptor alpha (IL-4R alpha) subunit and a low-affinity IL-13-binding subunit, IL-13R alpha 1. An additional receptor, IL-13R alpha 2, binds to IL-13 with high affinity, but lacks the cytoplasmic domain for signaling. In this study, we isolated the mouse IL-13R alpha 1 gene (I113ra1) of approximately 56 kb that spans the entire coding region. The mouse I113ra1 gene is composed of 11 exons, and shows striking similarity in genomic structure to the previously reported class I cytokine receptor genes. Motifs characteristic of the cytokine receptor family are similarly organized on the genome, including conserved cysteines, a WSxWS motif, and Box1, indicating closely related genetic evolution of the cytokine receptor superfamily. Alternative mRNA splicings were demonstrated to generate variant transcripts that encode soluble IL-13Ra1, The mouse Il13ra1 gene was mapped to the proximal region of the mouse X chromosome, and was closely linked to the DXPas3 locus by interspecific backcross analysis. Il13ra1 mRNA was co-ex-pressed with Il4ra mRNA in mouse myeloid and natural killer cells on which IL-13 has been known to act, whereas the Il13ra2 mRNA was not detected in these cells, indicating that IL-13R alpha 1 is the major component of the IL-13 receptor complex in lymphohematopoietic cells. C1 Univ Tsukuba, Inst Basic Med Sci, Dept Immunol, Tsukuba, Ibaraki 3058575, Japan. JST, CREST, Tsukuba, Ibaraki 3058575, Japan. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Adv Biosci Labs,Mammalian Genet Lab, Frederick, MD USA. RP Nakauchi, H (reprint author), Univ Tsukuba, Inst Basic Med Sci, Dept Immunol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan. RI Nakamura, Yukio/A-5263-2016 NR 38 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD SEP PY 2000 VL 51 IS 11 BP 974 EP 981 DI 10.1007/s002510000225 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 354PQ UT WOS:000089339200010 PM 11003391 ER PT J AU Sotsios, Y Blair, PJ Westwick, J Ward, SG AF Sotsios, Y Blair, PJ Westwick, J Ward, SG TI Disparate effects of phorbol esters, CD3 and the costimulatory receptors CD2 and CD28 on RANTES secretion by human T lymphocytes SO IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; CELL ACTIVATION; ANTIGEN RECEPTOR; NUCLEAR FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE PHOSPHORYLATION; EXPRESSION; PATHWAYS; PROTEIN; CTLA-4 AB This study has examined the stimuli required for secretion of regulated upon activation, normal T-cell expressed, presumed secreted (RANTES) from T lymphocytes and found that stimuli such as phorbol 12-myristate 13-acetate (PMA), which are unable to support T-cell proliferation and interleukin-2 (IL-2) production, are nevertheless able to elicit strong secretion of RANTES. Conversely, stimuli such as CD2 and CD28 ligation, which are able to support T-cell proliferation, are unable to elicit RANTES secretion. Coligation of CD3 and CD28 drives T-cell proliferation to a similar degree as CD2 and CD28 coligation, yet also supports modest RANTES secretion. Furthermore, CD28 ligation enhances the secretion of RANTES stumulated by PMA and this costimulatory effect is abrogated by the phosphoinositide 3-kinase inhibitor wortmannin. Our data also indicate that the observed effects of PMA on RANTES secretion are probably due to activation of protein kinase C (PKC) isoenzymes, since RANTES secretion was unaffected by the non-PKC activating 4 alpha-phorbol ester, whilst the general PKC inhibitor Ro-32-0432 inhibits PMA-stimulated RANTES secretion. Moreover, the effect of PMA appears to be chemokine-specific because PMA was unable to increase secretion of the related CC chemokine MIP-1 alpha. Under stimulation conditions where increases in [Ca2+](i) occur (e.g. PMA plus ionomycin or CD3 plus CD28 ligation) RANTES secretion can be severely reduced compared with the levels observed in response to the phorbol ester PMA. Hence, whilst PKC-dependent pathways are sufficient for strong RANTES secretion, a calcium-dependent factor is activated which negatively regulates RANTES secretion. This correlates well with the observation that ligation of cytolytic T lymphocyte-associated antigen-4 (CTLA-4) (expression of which has been reported to be dependent on a sustained calcium signal), inhibits RANTES secretion induced by CD3/CD28, but has no effect on PMA-stimulated RANTES secretion. C1 Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. USN, Med Res Ctr, NIDDK,T Cell Funct Sect, Navy Transplantat & Autoimmun Branch, Bethesda, MD USA. RP Ward, SG (reprint author), Univ Bath, Dept Pharm & Pharmacol, Claverton Down, Bath BA2 7AY, Avon, England. NR 45 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD SEP PY 2000 VL 101 IS 1 BP 30 EP 37 DI 10.1046/j.1365-2567.2000.00072.x PG 8 WC Immunology SC Immunology GA 354KG UT WOS:000089329200004 PM 11012750 ER PT J AU Nakagawa, Y Takeshita, T Berzofsky, JA Takahashi, H AF Nakagawa, Y Takeshita, T Berzofsky, JA Takahashi, H TI Analysis of the mechanism for extracellular processing in the presentation of human immunodeficiency virus-1 envelope protein-derived peptide to epitope-specific cytotoxic T lymphocytes SO IMMUNOLOGY LA English DT Article ID CLASS-I MOLECULES; CONVERTING ENZYME; ANTIGENIC PEPTIDES; MHC MOLECULE; EXPRESSION; RECOMBINANT; TRANSPORTER; RECOGNITION; PLASMA; CELLS AB An immunodominant epitope of human immunodeficiency virus-1 (HIV-1) gp160 recognized by D-d class I major histocompatibility complex (MHC) molecule-restricted, CD8(+) cytotoxic T lymphocytes (CTL) was originally identified as a peptide composed of 15 amino acids (P18IIIB: RIQRGPGRAFVTIGK). However, further study has indicated that a 10-mer peptide, I-10 (RGPGRAFVTI), within P18IIIB is the minimal-sized epitope and the trimming step(s) of two carboxyl terminal amino acids (GK) is essential to produce I-10 from P18IIIB. In the processing, angiotensin-1-converting enzyme (ACE), found in sera, plays a central role in generating I-10. Target cells could be sensitized with I-10 under conditions where ACE activity in the sera was abrogated. In contrast, in the case of P18IIIB, requiring further processing to delete the C-terminus of two amino acids in order to act, sensitization of target cells was completely abrogated under the conditions. Pretreatment of target cells with brefeldin A (BFA), preventing the presentation of endogenous antigens from the class I MHC molecule pathway, did not inhibit the presentation of P18IIIB. Moreover, glutaraldehyde-fixed cells, which can not process native protein, though they could present the exogenously added peptides, were also sensitized by P18IIIB. These results clearly demonstrate that the fine processing to produce I-10 occurred in the extracellular milieu. Furthermore, our result suggests that the longer P18IIIB can bind to the class I molecules on the cell surface, and then be trimmed by ACE while it is bound. The mechanisms behind the extracellular processing outlined in this paper will offer important information for designing peptide-based vaccines to elicit MHC molecule-restricted effectors. C1 Nippon Med Sch, Dept Microbiol & Immunol, Bunkyo Ku, Tokyo 1138602, Japan. Nippon Med Sch, Dept Obstet & Gynecol, Bunkyo Ku, Tokyo 1138602, Japan. NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Takahashi, H (reprint author), Nippon Med Sch, Dept Microbiol & Immunol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan. NR 25 TC 17 Z9 18 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD SEP PY 2000 VL 101 IS 1 BP 76 EP 82 DI 10.1046/j.1365-2567.2000.00092.x PG 7 WC Immunology SC Immunology GA 354KG UT WOS:000089329200010 PM 11012756 ER PT J AU Yamashiro, S Kamohara, H Yoshimura, T AF Yamashiro, S Kamohara, H Yoshimura, T TI Alteration in the responsiveness to tumour necrosis factor-alpha is crucial for maximal expression of monocyte chemoattractant protein-1 in human neutrophils SO IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA; POLYMORPHONUCLEAR NEUTROPHILS; CDNA CLONING; RECEPTORS; LEUKOCYTES; INDUCTION AB We previously reported delayed expression of monocyte chemoattractant protein-1 (MCP-1) in human neutrophils cultured with a cytokine-rich crude supernatant of phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PHA-sup). Tumour necrosis factor-alpha (TNF-alpha) contained in the PHA-sup played a key role in this event, but there appeared to be another factor(s) in the same supernatant that co-operated with TNF-alpha for maximal MCP-1 expression. In the present study, we reduced TNF-alpha concentrations in the PHA-sup to minimal levels using anti-TNF-alpha affinity columns (TNF-depleted-sup) and investigated the co-operation between TNF-alpha and TNF-depleted-sup. Nine hours of preincubation with TNF-depleted-sup altered the responsiveness of neutrophils to TNF-alpha and enabled TNF-alpha to increase the level of MCP-1 expression to a maximal level within 4 hr. The priming effect was not due to the increased expression of cell-surface TNF receptors. However, the activation of primed cells by TNF-alpha was clearly through TNF receptor-p55. Finally, the activity in the TNF-depleted-sup that co-operated with TNF-alpha was eluted at 60 000 MW on high-performance liquid chromatography-gel filtration. Thus, delayed neutrophil expression of MCP-1 is regulated by a cytokine-dependent mechanism that induces neutrophils to enter a 'mature' stage. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21701 USA. RP Yoshimura, T (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Bldg 559,Room 1, Frederick, MD 21701 USA. NR 19 TC 5 Z9 6 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD SEP PY 2000 VL 101 IS 1 BP 97 EP 103 DI 10.1046/j.1365-2567.2000.00085.x PG 7 WC Immunology SC Immunology GA 354KG UT WOS:000089329200013 PM 11012759 ER PT J AU Cheever, AW Hoffmann, KF Wynn, TA AF Cheever, AW Hoffmann, KF Wynn, TA TI Immunopathology of schistosomiasis mansoni in mice and men SO IMMUNOLOGY TODAY LA English DT Letter ID NECROSIS-FACTOR-ALPHA; INFECTIONS; RESPONSES; GAMMA C1 Biomed Res Inst, Rockville, MD 20852 USA. NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cheever, AW (reprint author), Biomed Res Inst, 12111 Parklawn Dr, Rockville, MD 20852 USA. RI Wynn, Thomas/C-2797-2011 NR 18 TC 58 Z9 64 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0167-5699 J9 IMMUNOL TODAY JI Immunol. Today PD SEP PY 2000 VL 21 IS 9 BP 465 EP 466 DI 10.1016/S0167-5699(00)01626-1 PG 2 WC Immunology SC Immunology GA 353KU UT WOS:000089274000015 PM 10953099 ER PT J AU Li, BQ Fu, T Gong, WH Dunlop, N Kung, HF Yan, YD Kang, J Wang, JM AF Li, BQ Fu, T Gong, WH Dunlop, N Kung, HF Yan, YD Kang, J Wang, JM TI The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines SO IMMUNOPHARMACOLOGY LA English DT Article DE flavonoid; baicalin; chemokines; receptors; anti-inflammation ID MULTIPLE LEUKOCYTE RECEPTORS; PROTEIN-3 MCP3 INTERACTS; HERBAL MEDICINE; CELL-LINES; IDENTIFICATION; INHIBITION; GROWTH; CCR5; INTERLEUKIN-8; ANTAGONISTS AB Baicalin (BA) is a flavonoid compound purified from the medicinal plant Scutellaria baicalensis Georgi acid has been reported to possess anti-inflammatory and anti-viral activities. In order to elucidate the mechanism(s) of action of BA, we tested whether BA could interfere with chemokines or chemokine receptors, which are critical mediators of inflammation and infection. We observed that BA inhibited the binding of a number of chemokines to human leukocytes or cells transfected to express specific chemokine receptors. This was associated with a reduced capacity of the chemokines to induce cell migration. Go-injection of BA with CXC chemokine interleukin-8 (IL-8) into rat skin significantly inhibited IL-8 elicited neutrophil infiltration. BA did not directly compete with chemokines for binding to receptors, but rather acted through its selective binding to chemokine ligands. This conclusion was supported by the fact that BA cross-linked to oxime resin bound chemokines of the CXC (stromal cell-derived factor (SDF)-1 alpha, IL-8), CC (macrophage inflammatory protein (MIP)-1 beta, monocyte chemotactic protein (MCP)-2), and C (lymphotactin (Ltn)) subfamilies, BA did not interact with CX3C chemokine fractalkine/neurotactin or other cytokines, such as TNF-alpha and IFN-gamma, indicating that its action is selective. These results suggest that one possible anti-inflammatory mechanism of BA is to bind a variety of chemokines and limit their biological function. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Biochem Physiol, Div Basic Sci, Frederick, MD 21702 USA. Shenyang AF Hosp, Shenyang, Liaoning, Peoples R China. New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Li, BQ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Bldg 560,Room 31-40, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 45 TC 132 Z9 144 U1 2 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0162-3109 J9 IMMUNOPHARMACOLOGY JI Immunopharmacology PD SEP PY 2000 VL 49 IS 3 BP 295 EP 306 DI 10.1016/S0162-3109(00)00244-7 PG 12 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 358QK UT WOS:000089568600008 PM 10996027 ER PT J AU Hu, EG Chen, J Battey, JF Gu, XX AF Hu, EG Chen, J Battey, JF Gu, XX TI Enhancement of clearance of bacteria from murine lungs by immunization with detoxified lipooligosaccharide from Moraxella catarrhalis conjugated to proteins SO INFECTION AND IMMUNITY LA English DT Article ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; BRANHAMELLA-CATARRHALIS; OTITIS-MEDIA; IMMUNE-RESPONSE; LIPOPOLYSACCHARIDE ANTIGENS; PULMONARY CLEARANCE; MOUSE MODEL; CHILDREN; VACCINE; EPIDEMIOLOGY AB Moraxella catarrhalis strain 25238 detoxified lipooligosaccharide (dLOS)-protein conjugates induced a significant rise of bactericidal anti-LOS antibodies in animals. This study reports the effect of active or passive immunization with the conjugates or their antiserum on pulmonary clearance of M. catarrhalis in an aerosol challenge mouse model. Mice were injected subcutaneously with dLOS-tetanus toxoid (dLOS-TT), dLOS-high-molecular-weight proteins (dLOS-HMP) from nontypeable Haemophilus influenzae (NTHi), or nonconjugated materials in Ribi adjuvant and then challenged with M. catarrhalis strain 2-5238 or O35E or NTHi strain 12. Immunization with dLOS-TT or dLOS-HMP generated a significant rise of serum anti-LOS immunoglobulin G and 68% and 35 to 41% reductions of bacteria in lungs compared with the control (P < 0.01) following challenge with homologous strain 25238 and heterologous strain O35E, respectively. Serum anti-LOS antibody levels correlated with its bactericidal titers against M. catarrhalis and bacterial CFU in lungs. Additionally, immunization with dLOS-HMP generated a 54% reduction of NTHi strain 12 compared with the control (P < 0.01). Passive immunization with a rabbit antiserum against dLOS-TT conferred a significant reduction of strain 25238 CFU in lungs in a dose- and time-dependent pattern compared with preimmune serum-treated mice. Kinetic examination of lung tissue sections demonstrated that antiserum-treated mice initiated and offset inflammatory responses more rapidly than preimmune serum-treated mice. These data indicate that LOS antibodies (whether active or passive) play a major role in the enhancement of pulmonary clearance of different test strains of M. catarrhalis in mice. In addition, dLOS-HMP is a potential candidate for a bivalent vaccine against M. catarrhalis and NTHi infections. C1 NIDCD, Immunol Lab, NIH, Rockville, MD 20850 USA. RP Gu, XX (reprint author), NIDCD, Immunol Lab, NIH, 5 Res Court,2A31, Rockville, MD 20850 USA. EM guxx@nidcd.nih.gov NR 45 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2000 VL 68 IS 9 BP 4980 EP 4985 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 346KM UT WOS:000088870200020 ER PT J AU Porcella, SF Fitzpatrick, CA Bono, JL AF Porcella, SF Fitzpatrick, CA Bono, JL TI Expression and immunological analysis of the plasmid-Borne mlp genes of Borrelia burgdorferi strain B31 SO INFECTION AND IMMUNITY LA English DT Article ID OUTER SURFACE-PROTEINS; LYME-DISEASE; OSPC GENE; CIRCULAR PLASMIDS; MOLECULAR-CLONING; ESCHERICHIA-COLI; RNA-POLYMERASE; LIPOPROTEIN; SEQUENCE; RECOMBINATION AB A lipoprotein gene family first identified in Borrelia burgdorferi strain 297, designated 2.9 LP and recently renamed mlp, was found on circular and linear plasmids in the genome sequence of B. burgdorferi strain B31-M1. Sequence analyses of the B31 mlp genes and physically linked variant gene families indicated that mlp gene heterogeneity is unique and unrelated to location or linkage to divergent sequences. Evidence of recombination between B31 mlp alleles was also detected. Northern blot analysis of cultured strain B31 indicated that the mlp genes were not expressed at a temperature (23 degrees C) characteristic of that of ticks in the environment. In striking contrast, expression of many mlp genes increased substantially when strain B31 was shifted to 35 degrees C, a temperature change mimicking that occurring in the natural transmission cycle of the spirochete from tick to mammal. Primer extension analysis of the mlp mRNA transcripts suggested that sigma 70-like promoters are involved in mlp expression during temperature shift conditions. Antibodies were made against strain B31 Mlp proteins within the first 4 weeks after experimental mouse infection. Importantly, Lyme disease patients also had serum antibodies reactive with purified recombinant Mlp proteins from strain B31, a result indicating that humans are exposed to Mlp proteins during infection. Taken together, the data indicate that strain B31 mlp genes encode a diverse array of lipoproteins which may participate in early infection processes in the mammalian host. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Porcella, SF (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM sporcella@nih.gov NR 54 TC 25 Z9 25 U1 1 U2 2 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 SEP PY 2000 VL 68 IS 9 BP 4992 EP 5001 DI 10.1128/IAI.68.9.4992-5001.2000 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 346KM UT WOS:000088870200022 PM 10948116 ER PT J AU Kossaczka, Z Shiloach, J Johnson, V Taylor, DN Finkelstein, RA Robbins, JB Szu, SC AF Kossaczka, Z Shiloach, J Johnson, V Taylor, DN Finkelstein, RA Robbins, JB Szu, SC TI Vibrio cholerae O139 conjugate vaccines: Synthesis and immunogenicity of V-cholerae O139 capsular polysaccharide conjugates with recombinant diphtheria toxin mutant in mice SO INFECTION AND IMMUNITY LA English DT Article ID NORTH-AMERICAN VOLUNTEERS; IMMUNOLOGICAL PROPERTIES; VIRULENCE DETERMINANTS; EXPERIMENTAL CHALLENGE; BENGAL; LIPOPOLYSACCHARIDE; PROTECTION; ANTIBODY; TETRAFLUOROBORATE; ANTIBACTERIAL AB Epidemiologic and experimental data provide evidence that a critical level of serum immunoglobulin G (IgG) antibodies to the surface polysaccharide of Vibrio cholerae O1 (lipopolysaccharide) and of Vibrio cholerae O139 (capsular polysaccharide [CPS]) is associated with immunity to the homologous pathogen. The immunogenicity of polysaccharides, especially in infants, may be enhanced by their covalent attachment to proteins (conjugates). Two synthetic schemes, involving 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) as activating agents, mere adapted to prepare four conjugates of V. cholerae O139 CPS with the recombinant diphtheria toxin mutant, CRMH21G. Adipic acid dihydrazide was used as a linker. When injected subcutaneously into young outbred mice by a clinically relevant dose and schedule, these conjugates elicited serum CPS antibodies of the IgG and IgM classes with vibriocidal activity to strains of capsulated V. cholerae O139. Treatment of these sera with 2-mercaptoethanol (2-ME) reduced, but did not eliminate, their vibriocidal activity, These results indicate that the conjugates elicited Ige with vibriocidal activity. Conjugates also elicited high levels of serum diphtheria toxin IgG. Convalescent sera from 20 cholera patients infected with V. cholerae O139 had vibriocidal titers ranging from 100 to 3,200: absorption with the CPS reduced the vibriocidal titer of all sera to less than or equal to 50. Treatment with 2-ME reduced the titers of 17 of 20 patients to less than or equal to 50. These data show that, like infection with V. cholerae O1, infection with V. cholerae O139 induces vibriocidal antibodies specific to the surface polysaccharide of this bacterium (CPS) that are mostly of IgM class. Based on these data, clinical trials with the V. cholerae O139 CPS conjugates with recombinant diphtheria toxin are planned. C1 NICHHD, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. RP Kossaczka, Z (reprint author), NICHHD, NIH, Bldg 6,Rm 424, Bethesda, MD 20892 USA. NR 45 TC 38 Z9 40 U1 0 U2 2 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 SEP PY 2000 VL 68 IS 9 BP 5037 EP 5043 DI 10.1128/IAI.68.9.5037-5043.2000 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 346KM UT WOS:000088870200028 PM 10948122 ER PT J AU Lira, R Doherty, M Modi, G Sacks, D AF Lira, R Doherty, M Modi, G Sacks, D TI Evolution of lesion formation, parasitic load, immune response, and reservoir potential in C57BL/6 mice following high- and low-dose challenge with Leishmania major SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL CUTANEOUS LEISHMANIASIS; NITRIC-OXIDE SYNTHASE; T-CELLS; DENDRITIC CELLS; IL-12 INDUCTION; RESISTANT MICE; INFECTION; MACROPHAGES; PROMASTIGOTES; HOST AB A model of cutaneous leishmaniasis using 10(2) Leishmania major metacyclic promastigotes inoculated into the footpads of genetically resistant C57BL/6 mice was studied in order to more accurately reproduce the evolution of lesion formation and the kinetics of parasite growth and immune response as they might occur in naturally exposed reservoirs and in human hosts. In contrast to the more conventional experimental model employing 10(6) metacyclic promastigotes, in which the rapid development of footpad lesions was associated with an increasing number of amastigotes in the site, the low-dose model revealed a remarkably "silent" phase of parasite growth, lasting approximately 6 weeks, during which peak parasitic loads were established in the absence of any overt pathology. Footpad swelling was observed after 6 weeks, coincident with the onset of parasite clearance and with production of high levels of interleukin-12 (IL-12) and gamma interferon (IFN-gamma) in draining lymph nodes. Low-dose challenge of IL-12- and IFN-gamma-depleted or -deficient mice provided strong evidence that the induction or expression of cellular immunity is essentially absent during the first 6 to 8 weeks of intracellular growth, since the concentration of amastigotes in the site nas not enhanced compared to that for wild-type animals during this time. By monitoring the ability of infected mice to transmit parasites to vector sand flies, it was observed that following low-dose challenge, footpads without apparent lesions provided an efficient source of parasites for exposed flies and that the low-dose challenge actually extended the duration of parasite transmissibility during the course of infection. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm 126,Ctr Dr MSC 0425, Bethesda, MD 20892 USA. NR 38 TC 36 Z9 37 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2000 VL 68 IS 9 BP 5176 EP 5182 DI 10.1128/IAI.68.9.5176-5182.2000 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 346KM UT WOS:000088870200047 PM 10948141 ER PT J AU Hilden, S AF Hilden, S TI Review of urology grant applications at NIH SO INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH LA English DT Article; Proceedings Paper CT 2nd Fall Meeting of the Society-for-the-Study-of-Impotence CY SEP 15-17, 2000 CL CLEVELAND, OHIO SP Soc Study Impotence C1 NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Hilden, S (reprint author), NIH, Ctr Sci Review, Rm 4218,6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0955-9930 J9 INT J IMPOT RES JI Int. J. Impot. Res. PD SEP PY 2000 VL 12 SU 3 BP S40 EP S41 DI 10.1038/sj.ijir.3900559 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 354UG UT WOS:000089347600008 PM 11002398 ER PT J AU Wang, Y Detrick, B Yu, ZX Zhang, Y Chesky, L Hooks, JJ AF Wang, Y Detrick, B Yu, ZX Zhang, Y Chesky, L Hooks, JJ TI The role of apoptosis within the retina of coronavirus-infected mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CYTOTOXIC T-LYMPHOCYTE; CELL-DEATH; PHOTORECEPTOR DEGENERATION; MEDIATED CYTOTOXICITY; INDUCED RETINOPATHY; MESSENGER-RNA; TNF-ALPHA; IN-VIVO; PERFORIN; FAS AB PURPOSE. To evaluate the possible roles of apoptosis in the murine retinopathy induced by coronavirus. METHODS. Mice were inoculated with virus intravitreally. Mouse eyes harvested at varying times after inoculation were evaluated for apoptotic and immunologic events by hematoxylin and eosin staining, immunohistochemical staining, in situ terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) assay, and electron microscopy. Isolated retinas were analyzed for infectious virus and for expression of apoptosis-associated genes. RESULTS. The number of apoptotic events was significantly elevated in infected eyes from BALB/c and CD-1 mouse strains, reaching a maximum at days 6 through 10, and returning to normal levels at day 20. The majority of apoptotic cells were observed in the outer nuclear layer of the infected retina. In contrast, few apoptotic cells were observed in normal or mock-injected mouse eyes. Apoptotic events within the retina were associated with the presence of viral antigen, infiltration of CD8(+) T cells, and clearance of infectious virus. Reverse transcription-polymerase chain reaction (RT-PCR) analysis identified the upregulation of Fas ligand (FasL) and granzyme B mRNAs within the infected retinas. The development of apoptosis, regulative gene expression, and viral clearance were similar in both retinal degeneration-susceptible (BALB/c) and -resistant (CD-1) mice. CONCLUSIONS. Retinal apoptosis was associated with retinal inflammation, a decrease in infectious virus, and upregulation of genes associated with CTL killing. These studies indicate that retinal apoptosis may be one of the host mechanisms that contribute to limiting this retinal infection. C1 NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Inst Med, Dept Pathol, Baltimore, MD USA. RP Hooks, JJ (reprint author), NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bldg 10,Room 6N228,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jjhooks@helix.nih.gov NR 51 TC 9 Z9 10 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2000 VL 41 IS 10 BP 3011 EP 3018 PG 8 WC Ophthalmology SC Ophthalmology GA 350FA UT WOS:000089089100026 PM 10967058 ER PT J AU Magabo, KS Horwitz, J Piatigorsky, J Kantorou, M AF Magabo, KS Horwitz, J Piatigorsky, J Kantorou, M TI Expression of beta B-2-crystallin mRNA and protein in retina, brain, and testis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALPHA-B-CRYSTALLIN; EXTRALENTICULAR EXPRESSION; GENE-EXPRESSION; BETA-CRYSTALLIN; A-CRYSTALLIN; BOVINE LENS; BETA-B2-CRYSTALLIN; PHOSPHORYLATION; SEQUENCE; TISSUES AB PURPOSE. To evaluate the expression of beta B-2-crystallin mRNA and protein in rat, bovine, and human nonlens and nonocular tissues. METHODS. beta B-2-crystallin mRNA levels were detected by RT-PCR. beta B-2-crystallin protein was purified from rat and bovine tissues by FPLC chromatography. FPLC fractions were analyzed by immunoblotting. The identity of beta B-2-crystallin protein, isolated from the retina, was confirmed by protein microsequencing. RESULTS. beta B-2-crystallin transcript: was detected in rat brain, rat testis, and human retina by RT-PCR. beta B-2-crystallin transcript was not found in rat lung, heart, ovary, spleen, thymus, kidney, and liver or in human brain and testis. beta B-2-crystallin protein was partially purified from and its identity confirmed in rat brain. rat testis, and bovine retina. The bovine retinal protein was further confirmed to be authentic beta B-2-crystallin by protein microsequencing. CONCLUSIONS. These results establish that beta B-2-crystallin mRNA and protein are expressed in tissues outside of the lens and outside of the eye including retina, brain, and testis. Extralenticular and extraocular expression of beta B-2-crystallin, coupled with its participation in phosphorylation pathways, suggests that it has nonrefractive functions in these tissues. C1 W Virginia Univ, Dept Biol, Morgantown, WV 26505 USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. RP Kantorou, M (reprint author), W Virginia Univ, Dept Biol, 320 Brooks Hall,Beechurst Ave, Morgantown, WV 26505 USA. EM mkantoro@wvu.edu FU NEI NIH HHS [EY38972, EY13022, R01 EY003897, R01 EY013022, R01 EY013022-01, R37 EY003897] NR 23 TC 48 Z9 50 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2000 VL 41 IS 10 BP 3056 EP 3060 PG 5 WC Ophthalmology SC Ophthalmology GA 350FA UT WOS:000089089100032 PM 10967064 ER PT J AU Lanford, RJ Shailam, R Norton, CR Gridley, T Kelley, MW AF Lanford, RJ Shailam, R Norton, CR Gridley, T Kelley, MW TI Expression of Math1 and HES5 in the cochleae of wildtype and Jag2 mutant mice SO JARO LA English DT Article DE Notch; Jagged2; lateral inhibition; inner ear; hair cell ID LOOP-HELIX FACTORS; DEVELOPING NERVOUS-SYSTEM; PRONEURAL GENE; INNER-EAR; NEURAL DEVELOPMENT; DROSOPHILA HAIRY; NEURONAL DIFFERENTIATION; TRANSCRIPTION FACTORS; NEUROGENIC GENES; MAMMALIAN HAIRY AB The sensory epithelium within the mammalian cochlea (the organ of Corti) is a strictly ordered cellular array consisting of sensory hair cells and nonsensory supporting cells. Previous research has demonstrated that Notch-mediated lateral inhibition plays a key role in the determination of cell types within this array. Specifically genetic deletion of the Notch ligand, Jagged2, results in a significant increase in the number of hair cells that develop within the sensory epithelium, presumably as a result of a decrease in Notch activation. In contrast, the downstream mediators and targets of the Notch pathway in the inner ear have not been determined but they may include genes encoding the proneural gene Math1 as well as the HES family of inhibitory bHLH proteins. To determine die potential roles of these genes in cochlear development, in situ hybridization for Math1 and HES5 was performed on the cochleae of wildtype vs. Jagged2 mutants (Jag2(Delta DSL)). Results in wild-type cochleae show that expression of Math1 transcripts in the duct begins on E13 and ultimately becomes restricted to hair cells in the sensory epithelium. In contrast, expression of HES5 begins on E15 and becomes restricted to supporting cells in the epithelium. Results in Jag2 mutant cochleae suggest that Math1 transcripts are ultimately maintained in a larger number of cells as compared with wildtype, while transcripts for HES5 are dramatically reduced throughout the epithelium. These results are consistent with the hypothesis that activation of Notch via Jagged2 acts to inhibit expression of Math1 in cochlear progenitor cells, possibly through the activity of HES5. C1 Georgetown Univ, Sch Med, Dept Cell Biol, Washington, DC 20007 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Lanford, RJ (reprint author), NIDCD, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 59 TC 17 Z9 18 U1 3 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1525-3961 J9 JARO JI JARO PD SEP PY 2000 VL 1 IS 2 BP 161 EP 171 DI 10.1007/sl01620010023 PG 11 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 425FA UT WOS:000168279000005 ER PT J AU Cachau, R Howard, E Barth, P Mitschler, A Chevrier, B Lamour, V Joachimiak, A Sanishvili, R Van Zandt, M Sibley, E Moras, D Podjarny, A AF Cachau, R Howard, E Barth, P Mitschler, A Chevrier, B Lamour, V Joachimiak, A Sanishvili, R Van Zandt, M Sibley, E Moras, D Podjarny, A TI Model of the catalytic mechanism of human aldose reductase based on quantum chemical calculations SO JOURNAL DE PHYSIQUE IV LA English DT Article; Proceedings Paper CT Conference on X-Rays and Matter (RX 99) CY DEC 07-10, 1999 CL ECOLE NATL SUPER ARTS & IND, STRASBOURG, FRANCE HO ECOLE NATL SUPER ARTS & IND ID CRYSTAL-STRUCTURE; INHIBITORS; BINDING; SITE AB Aldose Reductase is an enzyme involved in diabetic complications, thoroughly studied for the purpose of inhibitor development. The structure of an enzyme-inhibitor complex solved at sub-atomic resolution has been used to develop a model for the catalytic mechanism. This model has been refined using a combination of Molecular Dynamics and Quantum calculations. It shows that the proton donation, the subject of previous controversies, is the combined effect of three residues: Lys 77, Tyr 48 and His 110. Lys 77 polarises the Tyr 48 OH group, which donates the proton to His 110, which becomes doubly protonated. His 110 then moves and donates the proton to the substrate. The key information from the sub-atomic resolution structure is the orientation of the ring and the single protonation of the His 110 in the enzyme-inhibitor complex. This model is in full agreement with all available experimental data. C1 IGBMC, UPR Biol Struct, F-67404 Illkirch, France. NCI, SAIC, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. Univ Louis Pasteur Strasbourg 1, Inst Chim, Lab Chim Organ Biol, F-67008 Strasbourg, France. Argonne Natl Lab, Biosci Div, Argonne, IL USA. Inst Diabet Discovery Inc, Branford, CT USA. RP Cachau, R (reprint author), IGBMC, UPR Biol Struct, 1 Rue Laurent Fries, F-67404 Illkirch, France. NR 22 TC 27 Z9 27 U1 0 U2 0 PU E D P SCIENCES PI LES ULIS CEDEXA PA 7, AVE DU HOGGAR, PARC D ACTIVITES COURTABOEUF, BP 112, F-91944 LES ULIS CEDEXA, FRANCE SN 1155-4339 J9 J PHYS IV JI J. Phys. IV PD SEP PY 2000 VL 10 IS P10 BP 3 EP 13 DI 10.1051/jp4:20001001 PG 11 WC Physics, Multidisciplinary SC Physics GA 367HE UT WOS:000090055000001 ER PT J AU Greenspan, D Komaroff, E Redford, M Phelan, JA Navazesh, M Alves, MEAF Kamrath, H Mulligan, R Barr, CE Greenspan, JS AF Greenspan, D Komaroff, E Redford, M Phelan, JA Navazesh, M Alves, MEAF Kamrath, H Mulligan, R Barr, CE Greenspan, JS CA WIHS TI Oral mucosal lesions and HIV viral load in the women's interagency HIV study (WIHS) SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE oral candidiasis; hairy leukoplakia; women; HIV; AIDS ID HAIRY LEUKOPLAKIA; BISEXUAL MEN; INFECTED PATIENTS; PREDICTIVE VALUE; SAN-FRANCISCO; CANDIDIASIS; MANIFESTATIONS; AIDS; PROGRESSION; COHORTS AB The prevalence of oral lesions was assessed in a five-center subset of the Women's Interagency HIV Study (WIHS) and correlated with other features of HIV disease. Oral examinations were performed by dental examiners on 729 women (577 HIV-positive and 152 HIV-negative) during baseline examination. Significant differences between the groups were found for the following oral lesions: pseudomembranous candidiasis, 6.1% and 2.0%, respectively; erythematous candidiasis, 6. 41% and 0.7%, respectively; all oral candidiasis, pseudomembranous and/or erythematous, 13.7% and 3.3%, respectively. Hairy leukoplakia was observed in 6.1% of HIV-positive women. No significant differences were found for recurrent aphthous ulcers, herpes simplex lesions, or papillomas. Kaposi's sarcoma was seen in 0.5% of HIV-positive and 0% of HIV-negative women. Using multiple logistic regression models controlling for use of antiretrovirals and antifungals, in HIV-positive women the presence of oral candidiasis was associated with a CD4 count <200 cells/l, cigarette smoking, and heroin/methadone use; the presence of hairy leukoplakia was not related to CD4 count but was associated with high viral load. Oral candidiasis and hairy leukoplakia are confirmed as being common features of HIV infection in women and appear to be associated with HIV viral load, immunosuppression, and various other behaviorally determined variables. C1 Univ Calif San Francisco, Dept Stomatol, San Francisco, CA 94143 USA. New England Res Inst, Watertown, MA 02172 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Dept Vet Affairs Med Ctr, Northport, NY USA. Univ So Calif, Los Angeles, CA USA. Univ Illinois, Chicago, IL USA. Univ Connecticut, Farmington, CT USA. RP Greenspan, D (reprint author), Univ Calif San Francisco, Dept Stomatol, S 612,513 Parnassus Ave, San Francisco, CA 94143 USA. FU NIAID NIH HHS [U01 AI34989] NR 37 TC 68 Z9 69 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD SEP 1 PY 2000 VL 25 IS 1 BP 44 EP 50 DI 10.1097/00126334-200009010-00006 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 373FB UT WOS:000165276800006 PM 11064503 ER PT J AU Nettesheim, P Koo, JS Gray, T AF Nettesheim, P Koo, JS Gray, T TI Regulation of differentiation of the tracheobronchial epithelium SO JOURNAL OF AEROSOL MEDICINE-DEPOSITION CLEARANCE AND EFFECTS IN THE LUNG LA English DT Article; Proceedings Paper CT 2nd World Congress on Cilia, Mucus, and Mucociliary Interactions CY JUN 12, 1999 CL VIENNA, AUSTRIA DE squamous; mucus; vitamin A; retinoid receptors ID RETINOIC ACID RECEPTOR; MUCIN GENE-EXPRESSION; VITAMIN-A; CELLS; IDENTIFICATION; RESTORATION; PHENOTYPE; SYNTHASE; PATHWAY; MARKERS AB The study of differentiation has been the domain of embryologists and developmental biologists and, in the pulmonary field, the concern of neonatologists. Why should those of us who are neither be interested in differentiation of the epithelium lining the conducting airways? The reason is that injury to the airway epithelium and disruption of its steady state and its normal differentiation are common occurrences in both acute episodes of infection and during chronic diseases such as chronic obstructive pulmonary disease and asthma. Thus, it is important to know how injury is repaired and which are the critical mechanisms that control and regulate differentiation. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP Gray, T (reprint author), NIEHS, Pulm Pathobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 43 TC 9 Z9 9 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0894-2684 J9 J AEROSOL MED JI J. Aerosol Med.-Depos. Clear. Eff. Lung PD FAL PY 2000 VL 13 IS 3 BP 207 EP 218 DI 10.1089/jam.2000.13.207 PG 12 WC Public, Environmental & Occupational Health; Respiratory System SC Public, Environmental & Occupational Health; Respiratory System GA 368HY UT WOS:000090112600006 PM 11066024 ER PT J AU Akiskal, HS Bourgeois, ML Angst, J Post, R Moller, HJ Hirschfeld, R AF Akiskal, HS Bourgeois, ML Angst, J Post, R Moller, HJ Hirschfeld, R TI Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article; Proceedings Paper CT 1st International Exchange on Bipolar Disorders Meeting (IEBD) CY FEB 01-04, 1998 CL BARCELONA, SPAIN DE bipolar spectrum; epidemiology; bipolar I; bipolar III; bipolar III; antidepressant-induced hypomania; rapid-cyclings; mixed state; life charting ID MANIC-DEPRESSIVE ILLNESS; ANTIDEPRESSANT-ASSOCIATED MANIA; CYCLING AFFECTIVE-DISORDER; MIXED AFFECTIVE STATES; II-DISORDER; MAJOR DEPRESSION; UNITED-STATES; OUTPATIENT DEPRESSION; ATYPICAL DEPRESSION; UNIPOLAR DEPRESSION AB Until recently it was believed that no more than 1% of the general population has bipolar disorder. Emerging transatlantic data are beginning to provide converging evidence for a higher prevalence of up to at least 5%. Manic states, even those with mood-incongruent features, as well as mixed (dysphoric) mania, are now formally included in both ICD-10 and DSM-IV. Mixed states occur in an average of 40% of bipolar patients over a lifetime; current evidence supports a broader definition of mixed states consisting of full-blown mania with two or more concomitant depressive symptoms. The largest increase in prevalence rates, however, is accounted for by 'softer' clinical expressions of bipolarity situated between the extremes of full-blown bipolar disorder where the person has at least one manic episode (bipolar I) and strictly defined unipolar major depressive disorder without personal or family history for excited periods. Bipolar II is the prototype for these intermediary conditions with major depressions and history of spontaneous hypomanic episodes; current evidence indicates that most hypomanias pursue a recurrent course and that their usual duration is 1-3 days, falling below the arbitrary 4-day cutoff required in DSM-IV. Depressions with antidepressant-associated hypomania (sometimes referred to as bipolar III) also appear, on the basis of extensive international research neglected by both ICD-IO and DSM-IV, to belong to the clinical spectrum of bipolar disorders. Broadly defined, the bipolar spectrum in studies conducted during the last decade accounts for 30-55% of all major depressions. Rapid-cycling, defined as alternation of depressive and excited (at least four per year), more often arise from a bipolar II than a bipolar I baseline; such cycling does not in the main appear to be a distinct clinical subtype - but rather a transient complication in 20% in the long-term course of bipolar disorder. Major depressions superimposed on cyclothymic oscillations represent a more severe variant of bipolar IT, often mistaken for borderline or other personality disorders in the dramatic cluster. Moreover, atypical depressive features with reversed vegetative signs, anxiety states, as well as alcohol and substance abuse comorbidity, is common in these and other bipolar patients. The proper recognition of the entire clinical spectrum of bipolarity behind such 'masks' has important implications for psychiatric research and practice. Conditions which require further investigation include: (1) major depressive episodes where hyperthymic traits - lifelong hypomanic features without discrete hypomanic episodes - dominate the intermorbid or premorbid phases; and (2) depressive mixed states consisting of few hypomanic symptoms (i.e., racing thoughts, sexual arousal) during full-blown major depressive episodes - included in Kraepelin's schema of mixed states, but excluded by DSM-IV. These do not exhaust all potential diagnostic entities for possible inclusion in the clinical spectrum of bipolar disorders: the present review did not consider cyclic, seasonal, irritable-dysphoric or otherwise impulse-ridden, intermittently explosive or agitated psychiatric conditions for which the bipolar connection is less established. The concept of bipolar spectrum as used herein denotes overlapping clinical expressions, without necessarily implying underlying genetic homogeneity. in the course of the illness of the same patient, one often observes the varied manifestations described above - whether they be formal diagnostic categories or those which have remained outside the official nosology. Some form of life charting of illness with colored graphic representation of episodes, stressors, and treatments received call be used to document the uniquely varied course characteristic of each patient, thereby greatly enhancing clinical evaluation. (C) 2000 Elsevier Science BN. All rights reserved. C1 Univ Calif San Diego, Int Mood Ctr, La Jolla, CA 92093 USA. Univ Bordeaux, Bordeaux, France. Univ Zurich, Hosp Psychiat, Zurich, Switzerland. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Munich, Hosp Psychiat, D-80539 Munich, Germany. Univ Texas, Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77550 USA. RP Akiskal, HS (reprint author), VA Psychiat Serv 116A, 3550 La Jolla Village Dr, San Diego, CA 92161 USA. NR 148 TC 379 Z9 388 U1 8 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD SEP PY 2000 VL 59 SU 1 BP S5 EP S30 DI 10.1016/S0165-0327(00)00203-2 PG 26 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 401PA UT WOS:000166935400002 PM 11121824 ER PT J AU Saini, SS Klion, AD Holland, SM Hamilton, RG Bochner, BS MacGlashan, DW AF Saini, SS Klion, AD Holland, SM Hamilton, RG Bochner, BS MacGlashan, DW TI The relationship between serum IgE and surface levels of Fc epsilon R on human leukocytes in various diseases: Correlation of expression with Fc epsilon RI on basophils but not on monocytes or eosinophils SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE IgE receptors; IgE antibody; basophils; monocytes; eosinophils ID IMMUNOGLOBULIN-E; MAST-CELLS; IN-VITRO; MEDIATOR RELEASE; DOWN-REGULATION; RECEPTOR; ALPHA; ACTIVATION; ANTIBODY; GAMMA AB Background: Expression of receptors for IgE (Fc epsilon R) have been mainly studied on mast cells and blood basophils in the context of allergic disease, Some reports have noted limited expression of Fc epsilon R on other leukocytes, including blood monocytes and eosinophils in certain patients. An association between human blood basophil expression of Fc epsilon RI alpha and serum IgE has been noted among allergic subjects. Objective: Recent evidence supports regulation of Fc epsilon RI alpha by free IgE on both mast cells and basophils. We hypothesized that this relationship would exist across an extremely wide range of IgE levels for human basophils, irrespective of underlying disease. We further examined whether a similar relationship existed between serum IgE and Fc epsilon RI alpha or Fc epsilon RII (CD23) expression on monocytes and eosinophils in these same subjects. Methods: Blood was obtained from nonallergic subjects (n = 3) and subjects with allergic asthma (n = 5), atopic dermatitis (n = 3), hypereosinophilic syndromes (n = 7), hyper-IgE syndrome (n = 6), helminth infestation (n = 6), or IgE myeloma (n = 1). Levels of serum IgE were determined by using RIA and ranged from 3 to 4.7 mg/mL. Levels of cell surface Fc epsilon RI alpha, Fc epsilon RII, and IgE were measured by using immunofluorescence and now cytometry. Results: Basophil surface IgE density and Fc epsilon RI alpha expression correlated with serum IgE levels (r = 0.67 and r = 0.46, respectively; P < .01; n = 31) regardless of the disease state. In contrast, monocyte Fc epsilon RI alpha expression did not correlate with serum IgE (r = 0.09, P > .5, n = 29), and low-level eosinophil Fc epsilon RI alpha expression was only detected in a single asthmatic subject. CD23 expression was not detected on basophils or eosinophils, except for the eosinophils from the donor with IgE myeloma, CD23 was present on monocytes from some donors but did not correlate with serum IgE levels. Conclusions: In a variety of disease states, Fc epsilon RI alpha expression by basophils, but not monocytes or eosinophils, correlated with serum IgE levels across a 6-log range of IgE. These data support the concept of in vivo regulation of Fc epsilon RI alpha on basophils by serum IgE and further demonstrate that this is independent of allergic disease per se. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Immunol, Baltimore, MD 21205 USA. NIH, Bethesda, MD 20892 USA. RP Saini, SS (reprint author), Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. FU NIAID NIH HHS [K08 AI001564, K08 AI001564-04, K08 AI001564-03, AI01564, AI42220, AI07290] NR 44 TC 71 Z9 75 U1 0 U2 1 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 SEP PY 2000 VL 106 IS 3 BP 514 EP 520 DI 10.1067/mai.2000.108431 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 356YN UT WOS:000089471900015 PM 10984372 ER PT J AU Giacoia, GP AF Giacoia, GP TI Incentive to study drugs in children and other governmental initiatives: Will patients with asthma benefit? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE pediatric drug trials; pediatric labeling; Pediatric Pharmacology Research Unit Network; Pediatric Rule of 1998; biomarkers ID CHILDHOOD; GENE AB This article summarizes current regulations that have been developed to facilitate the performance of pediatric drug trials and their impact on children, particularly those children affected with asthma, in addition, other initiatives that have been developed by the federal government in response to the unexplained increase of asthma occurrence during the last 15 years will be reviewed. In the face of an asthma epidemic, a comprehensive approach is needed to determine the causes for the increase in the prevalence rate and the role of aeroallergens and other environmental and genetic factors and to identify effective preventive measures. Clearly, facilitating drug trials to prove the safety and effectiveness of drugs is of paramount importance. C1 NICHHD, Pediat Pharmacol Res Unit Network, Bethesda, MD 20892 USA. Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. RP Giacoia, GP (reprint author), NICHHD, Ctr Res Mothers & Children, Room 4B11B,6100 Executive Blvd, Bethesda, MD 20892 USA. NR 29 TC 3 Z9 3 U1 1 U2 1 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 SEP PY 2000 VL 106 IS 3 SU S BP S118 EP S124 DI 10.1067/mai.2000.109417 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 357XB UT WOS:000089525400002 PM 10984391 ER PT J AU Suarez-Quian, CA Goldstein, SR Bonner, RF AF Suarez-Quian, CA Goldstein, SR Bonner, RF TI Laser capture microdissection: A new tool for the study of spermatogenesis SO JOURNAL OF ANDROLOGY LA English DT Review ID MOLECULAR ANALYSIS; GENE-EXPRESSION; SINGLE CELLS; TISSUE; CONSTRUCTION; POPULATIONS; MICRO C1 Georgetown Univ, Med Ctr, Dept Cell Biol, Washington, DC 20007 USA. NIH, Instrumentat Res & Dev Resource Bioengn & Phys Sc, Off Res Serv, Bethesda, MD 20892 USA. NICHHD, NIH, Sect Med Biophys, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Suarez-Quian, CA (reprint author), Georgetown Univ, Med Ctr, Dept Cell Biol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NICHD NIH HHS [R01 HD23484] NR 30 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD SEP-OCT PY 2000 VL 21 IS 5 BP 601 EP 608 PG 8 WC Andrology SC Endocrinology & Metabolism GA 349BG UT WOS:000089023500001 PM 10975404 ER PT J AU Primm, TP Andersen, SJ Mizrahi, V Avarbock, D Rubin, H Barry, CE AF Primm, TP Andersen, SJ Mizrahi, V Avarbock, D Rubin, H Barry, CE TI The stringent response of Mycobacterium tuberculosis is required for long-term survival SO JOURNAL OF BACTERIOLOGY LA English DT Article ID STREPTOMYCES-COELICOLOR A3(2); DEPLETION-INDUCED DORMANCY; RELA/SPOT-HOMOLOGOUS GENE; ESCHERICHIA-COLI; GUANOSINE TETRAPHOSPHATE; FATTY-ACID; STREPTOCOCCUS-EQUISIMILIS; FUNCTIONAL-ANALYSIS; STATIONARY-PHASE; CALMETTE-GUERIN AB The stringent response utilizes hyperphosphorylated guanine [(p)ppGpp] as a signaling molecule to control bacterial gene expression involved in long-term survival under starvation conditions. In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium tuberculosis contains a single homolog of these proteins (Rel(Mtb)) and responds to nutrient starvation by producing (p)ppGpp. A rel(Mtb) knockout strain was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The rel(Mtb) mutant displayed a significantly slower aerobic growth rate than the wild type in synthetic liquid media, whether rich or minimal. The growth rate of the wild type was equivalent to that of the mutant when citrate or phospholipid was employed as the sole carbon source. These two organisms also showed identical growth rates within a human macrophage-like cell line. These results suggest that the in vivo carbon source does not represent a stressful condition for the bacilli, since it appears to be utilized in a similar Rel(Mtb)-independent manner. In vitro growth in liquid media represents a condition that benefits from Rel(Mtb)-mediated adaptation. Long-term survival of the rel(Mtb) mutant during in vitro starvation or nutrient run out in normal media was significantly impaired compared to that in the wild type. In addition, the mutant was significantly less able to survive extended anerobic incubation than the wild-type virulent organism. Thus, the Rel(Mtb) protein is required for long-term survival of pathogenic mycobacteria under starvation conditions. C1 NIAID, TB Res Sect, LHD, NIH, Rockville, MD 20852 USA. Univ Penn, Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. Univ Witwatersrand, Sch Med, MRC,S African Inst Med Res, SAIMR,WITS,Mol Mycobacteriol Res Unit, Johannesburg, South Africa. Univ Witwatersrand, Sch Med, Dept Mol Med & Hematol, Johannesburg, South Africa. RP Rubin, H (reprint author), NIAID, TB Res Sect, LHD, NIH, Twinbrook 2,Room 239,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [R01 AI043420, R01-AI43420] NR 80 TC 199 Z9 212 U1 1 U2 22 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2000 VL 182 IS 17 BP 4889 EP 4898 DI 10.1128/JB.182.17.4889-4898.2000 PG 10 WC Microbiology SC Microbiology GA 343LG UT WOS:000088703400029 PM 10940033 ER PT J AU Chang, YC Penoyer, LA AF Chang, YC Penoyer, LA TI Properties of various RHO1 mutant alleles of Cryptococcus neoformans SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GTP-BINDING PROTEIN; SACCHAROMYCES-CEREVISIAE; CELL-WALL; 1,3-BETA-D-GLUCAN SYNTHASE; CANDIDA-ALBICANS; GLUCAN SYNTHASE; YEAST PROTEIN; KINASE-C; MORPHOGENESIS; GENE AB The RHO1 homologue of Cryptococcus neoformans complemented Saccharomyces cerevisiae rho1 mutations. The results of overexpression and site-specific mutagenesis of CnRHO1 in C. neoformans and S. cerevisiae indicated that although CnRHO1 could functionally substitute for the RHO1 gene of S. cerevisiae, mutants of cnrho1 manifested unique features in certain aspects. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Chang, YC (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11C304, Bethesda, MD 20892 USA. NR 37 TC 15 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2000 VL 182 IS 17 BP 4987 EP 4991 DI 10.1128/JB.182.17.4987-4991.2000 PG 5 WC Microbiology SC Microbiology GA 343LG UT WOS:000088703400040 PM 10940044 ER PT J AU Evans, RL Park, K Turner, RJ Watson, GE Nguyen, HV Dennett, MR Hand, AR Flagella, M Shull, GE Melvin, JE AF Evans, RL Park, K Turner, RJ Watson, GE Nguyen, HV Dennett, MR Hand, AR Flagella, M Shull, GE Melvin, JE TI Severe impairment of salivation in Na+/K+/2Cl(-) cotransporter (NKCC1)-deficient mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PAROTID ACINAR-CELLS; NHE3 NA+/H+ EXCHANGER; NA+-K+-2CL(-) COTRANSPORTER; FLUID SECRETION; UP-REGULATION; MUSCARINIC STIMULATION; MOLECULAR-CLONING; CHROMOSOMAL LOCALIZATION; TARGETED DISRUPTION; CL COTRANSPORTER AB The salivary fluid secretory mechanism is thought to require Na+/K+/2Cl(-) cotransporter-mediated Cl- uptake. To directly test this possibility we studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of Na+/R+/2Cl(-) cotransporter isoform 1 (Nkcc1), the gene encoding the salivary Na+/K+/2Cl(-) cotransporter. In wildtype mice NKCC1 was localized to the basolateral membranes of parotid acinar cells, whereas expression was not detected in duct cells. The lack of functional NKCC1 resulted in a dramatic reduction (>60%) in the volume of saliva secreted in response to a muscarinic agonist, the primary in situ salivation signal, Consistent with defective Cl- uptake, a loss of bumetanide-sensitive Cl- influx was observed in parotid acinar cells from mice lacking NKCC1. Cl-/HCO3- exchanger activity was increased in parotid acinar cells isolated from knockout mice suggesting that the residual saliva secreted by mice lacking NKCC1 is associated with anion exchanger-dependent Cl- uptake. Indeed, expression of the Cl-/HCO3- exchanger AE2 was enhanced suggesting that this transporter compensates for the loss of functional Na+/K+/2Cl(-) cotransporter. Furthermore, the ability of the parotid gland to conserve NaCl was abolished in NKCC1-deficient mice. This deficit was not associated with changes in the morphology of the ducts, but transcript levels for the alpha-, beta-, and gamma-subunits of the epithelial Na+ channel were reduced. These data directly demonstrate that NKCC1 is the major Cl- uptake mechanism across the basolateral membrane of acinar cells and is critical for driving saliva secretion in vivo. C1 Univ Rochester, Med Ctr, Ctr Oral Biol, Aab Inst Biomed Sci, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Eastman Dept Dent, Rochester, NY 14642 USA. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Dept Pediat Dent, Farmington, CT 06030 USA. Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. RP Melvin, JE (reprint author), Univ Rochester, Med Ctr, Ctr Oral Biol, Aab Inst Biomed Sci, Box 611,601 Elmwood Ave, Rochester, NY 14642 USA. FU NIDCR NIH HHS [DE08921, DE13539]; NIDDK NIH HHS [DK50594] NR 48 TC 88 Z9 92 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 26720 EP 26726 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800009 PM 10831596 ER PT J AU Carew, MA Yang, XN Schultz, C Shears, SB AF Carew, MA Yang, XN Schultz, C Shears, SB TI myo-inositol 3,4,5,6-tetrakisphosphate inhibits an apical calcium-activated chloride conductance in polarized monolayers of a cystic fibrosis cell line SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMARY-TUMOR CELLS; MYOINOSITOL 1,3,4,5,6-PENTAKISPHOSPHATE; ACINAR-CELLS; SECRETION; AGONIST; PHOSPHATES; CHANNELS; TRANSPORT; EPITHELIA; MEMBRANE AB Does inositol 3,4,5,6 tetrakisphosphate (Ins(3,4,5,6)P-4) inhibit apical Ca2+-activated Cl- conductance (CaCC)? We studied this question using human CFPAC-1 pancreatoma cells grown in polarized monolayers. Cellular Ins(3,4,5,6)P-4 levels were acutely sensitive to purinergic receptor activation, rising 3-fold within 1 min of agonist addition. Intracellular Ins(3,4,5,6)P-4, levels were therefore specifically elevated, independently of receptor activation, by incubating cells with a cell-permeant bioactivable analogue, 1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis(acetoxymethyl)ester (Bt(2)Ins (3,4,5,6)P-4/AM). The latter inhibited Ca2+-activated Cl- secretion by 60%. We next used nystatin to selectively permeabilize the basolateral membrane to monovalent anions and cations, thereby preventing this membrane from electrochemically dominating ion movements through the apical membrane. Thus, we studied autonomous regulation of apical Cl- channels in situ. The properties of Cl- flux across the apical membrane were those expected of CaCC: niflumic acid sensitivity, outward rectification, and 2-fold greater permeability of I- over Cl-. Following nystatin-treatment, we elevated intracellular levels of Ins(3,4,5,6)P-4, with either purinergic agonists or with Bt(2)Ins(3,4,5,6)P-4/AM. Both protocols inhibited Ca2+-activated Cl- secretion (up to 70%). These studies provide the first demonstration that, in a physiologically relevant context of a polarized monolayer, there is an apical, Ins(3,4,5,6)P-4-inhibited CaCC. C1 NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Bremen, Inst Organ Chem, UFT, D-28359 Bremen, Germany. RP Carew, MA (reprint author), NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Schultz, Carsten/0000-0002-5824-2171 NR 47 TC 46 Z9 47 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 26906 EP 26913 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800034 PM 10842174 ER PT J AU Rigourd, M Lanchy, JM Le Grice, SFJ Ehresmann, B Ehresmann, C Marquet, R AF Rigourd, M Lanchy, JM Le Grice, SFJ Ehresmann, B Ehresmann, C Marquet, R TI Inhibition of the initiation of HIV-1 reverse transcription by 3 '-azido-3 '-deoxythymidine - Comparison with elongation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; STATE KINETIC CHARACTERIZATION; BINDING-SITE COMPLEMENTARY; STRAND DNA-SYNTHESIS; AZT RESISTANCE; TRANSFER-RNAS; TEMPLATE-PRIMER; TYPE-1; MECHANISM; POLYMERIZATION AB Initiation of human immunodeficiency virus-1 reverse transcription requires formation of a complex containing the viral RNA, primer tRNA(3)(Lys), and reverse transcriptase, Initiation, corresponding to addition of the first six nucleotides to tRNA(3)(Lys), is distinguished from elongation by its high specificity and low efficiency (processivity), Here, we compared the inhibition of initiation and elongation of reverse transcription by 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP), the active form of 3'-azido-3'-deoxythymidine. We report the first detailed study of nucleotide binding, discrimination, and pyrophosphorolysis by the authentic initiation complex, We showed that the initiation and elongation complexes bound AZTTP and dTTP with the same affinity, while the polymerization rates were reduced by 148-160-fold during initiation. The pyrophosphorolysis rate of dTTP was reduced by the same extent, indicating that the polymerization equilibrium is the same in the two phases. The efficient unblocking of the 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP)-terminated primer by pyrophosphorolysis significantly relieved inhibition of DNA synthesis during elongation in the presence of physiological pyrophosphate concentrations. Remarkably, although pyrophosphorolysis of dTMP and AZTMP were equally efficient during elongation, reverse transcriptase was almost totally unable to unblock the AZTMP-terminated primer during initiation. As a result, inhibition of reverse transcription by AZTTP was more efficient during initiation than elongation of reverse transcription, despite a reduced selectivity of incorporation. C1 Inst Biol Mol & Cellulaire, CNRS, UPR 9002, F-67084 Strasbourg, France. NCI, Frederick Canc Res & Dev Ctr, Resistance Mechanisms Lab, NIH, Frederick, MD 21702 USA. RP Marquet, R (reprint author), Inst Biol Mol & Cellulaire, CNRS, UPR 9002, 15 Rue Rene Descartes, F-67084 Strasbourg, France. OI Marquet, Roland/0000-0002-4209-3976 NR 45 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 26944 EP 26951 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800038 PM 10864929 ER PT J AU Gadina, M Sudarshan, C Visconti, R Zhou, YJ Gu, HH Neel, BG O'Shea, JJ AF Gadina, M Sudarshan, C Visconti, R Zhou, YJ Gu, HH Neel, BG O'Shea, JJ TI The docking molecule Gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL PROLIFERATION; RECEPTOR-BETA-CHAIN; COLONY-STIMULATING FACTOR; TYROSINE PHOSPHORYLATION; IL-2 RECEPTOR; TRANSDUCTION PATHWAYS; KINASE ACTIVATION; JANUS KINASE; PROTEIN; SHC AB Interleukin (IL)-2, a critical cytokine with indispensable functions in regulating lymphoid homeostasis, induces the activation of several biochemical pathways. Precisely how these pathways are linked and how they relate to the biological action of IL-2 is incompletely understood. We previously identified SHP-2 (Src homology 2 domain containing phosphatase 2) as an important intermediate in IL-S-dependent MAPK activation and showed its association with a 98-kDa phosphoprotein in response to IL-2. Were, we demonstrate that Gaba, a recently identified adapter molecule, is the major SHP-2 and phosphatidylinositol 31-kinase-associated 98 kDa protein in normal, IL-a-activated lymphocytes. We further demonstrate that phosphorylation of both Gab2 and SHP-2 is largely dependent upon tyrosine 338 of the IL-2 receptor beta chain. Gaba can be a substrate of all the three major classes of non-receptor tyrosine kinases associated with the IL-SR, but in terms of IL-2 signaling, JAK3 but not Lck or Syk is essential for Gabs phosphorylation, We also demonstrate that only IL-2 and IL-15, but not other gamma c cytokines induce Gabs phosphorylation; the ability to phosphorylate Gaba correlates with Shc phosphorylation and ERK1/ERK2 activation. Finally, we also show that Gaba levels are regulated by T cell activation, and resting T cells express little Gaba. Therefore, up-regulation and activation of Gaba may be important in linking the IL-2 receptor to activation of MAPK and may be an important means of achieving specificity in cytokine signaling. C1 NIAMS, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol Oncol,Dept Med, Boston, MA 02115 USA. RP Gadina, M (reprint author), Bldg 10,Rm 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. RI Visconti, Roberta/C-5299-2009 FU NCI NIH HHS [CA72144] NR 40 TC 77 Z9 77 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 26959 EP 26966 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800040 PM 10849428 ER PT J AU Shahs, FS Curr, KA Hamburgh, ME Parniak, M Mitsuya, H Arnez, JG Prasad, VR AF Shahs, FS Curr, KA Hamburgh, ME Parniak, M Mitsuya, H Arnez, JG Prasad, VR TI Differential influence of nucleoside analog-resistance mutations K65R and L74V on the overall mutation rate and error specificity of human immunodeficiency virus type 1 reverse transcriptase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-POLYMERASE-I; MISPAIR EXTENSION; DRUG-RESISTANT; WILD-TYPE; HIV-1; FIDELITY; PROCESSIVITY; BINDING; MUTANTS; M184V AB Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variants with the K65R or L74V substitution display resistance to several nucleoside analogs. An in vitro dNTP exclusion assay revealed an increased fidelity for K65R RT compared with wild-type RT, but little change for L74V RT. When the forward mutation rates were measured via a gap-filling assay, the K65R variant displayed an 8-fold decrease in the overall mutation rate (1.0 x 10(-8) versus 8.6 x 10(-5) for wild-type HIV-1 RT), whereas the rate for the L74V variant was closer to that for wild-type RT (5.0 x 10(-3)). The increase in overall fidelity observed for K65R RT is the largest reported for any drug-resistant HIV-1 RT variant. Nucleotide sequence analysis of locZ alpha mutants generated by variant RTs indicated that K65R RT displays uniform reduction in most types of errors, whereas L74V RT does not. Modeling the substitutions into the x-ray structure of the ternary complex revealed that the major influence of Leu(74) in stabilizing the templating base is unaffected by Val substitution, whereas the K65R substitution appears to increase the stringency of dNTP binding. It is speculated that the increased fidelity of K65R RT is due to an altered interaction with the dNTP substrate. C1 Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. Childrens Hosp Montefiore, Div Pediat Infect Dis, Bronx, NY 10467 USA. McGill Univ, AIDS Ctr, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. NCI, Expt Retrovirol Sect, NIH, Bethesda, MD 20892 USA. RP Prasad, VR (reprint author), Albert Einstein Coll Med, Dept Microbiol & Immunol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NIAID NIH HHS [AI40375, T32-AI07501]; NIGMS NIH HHS [T32-GM07491] NR 41 TC 58 Z9 58 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27037 EP 27044 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800051 PM 10833521 ER PT J AU Akiyama, TE Ward, JM Gonzalez, FJ AF Akiyama, TE Ward, JM Gonzalez, FJ TI Regulation of the liver fatty acid-binding protein gene by hepatocyte nuclear factor 1 alpha (HNF1 alpha) - Alterations in fatty acid homeostasis in HNF1 alpha-deficient mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; ACYL-COA OXIDASE; BETA-OXIDATION; RAT-LIVER; PEROXISOME PROLIFERATORS; LIPOPROTEIN-LIPASE; DIABETIC RAT; EXPRESSION; SEQUENCE; MOUSE AB Hepatocyte nuclear factor 1 alpha (HNF1 alpha)-null mice have enlarged fatty livers and alterations in the expression of genes encoding enzymes involved in the synthesis, catabolism, and transport of fatty acids. Elevations in the expression of genes encoding fatty acid synthetic enzymes (fatty acid synthase and acyl-CoA carboxylase) and peroxisomal B-oxidation enzymes (CYP4A3, bifunctional enzyme, and thiolase) were observed in the livers of HNF1 alpha-null mice, whereas hepatic mitochondrial p-oxidation gene (medium and short chain acyl-CoA dehydrogenase) expression levels remain unchanged relative to HNF1 alpha-heterozygous controls. An elevation in the levels of fatty acid transporter gene expression was also observed. In contrast, there was a marked reduction of liver fatty acid-binding protein (L-FABP) gene expression in the livers of HNF1 alpha-null mice. Isolation and sequence analysis of the 5'-flanking region of the mouse L-FABP gene revealed the presence of two HNF1 alpha regulatory elements. The results of transient transfection studies indicate that HNF1 alpha is required to transactivate the expression of the L-FABP promoter. Taken together, these data define a critical role for HNF1 alpha in the pathogenesis of a phenotype marked by fatty infiltration of the liver and in the regulation of the L-FABP gene, the expression of which may have a direct impact on the maintenance of fatty acid homeostasis. C1 NIH, Lab Metab, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Off Lab Anim Sci, Vet & Tumor Pathol Sect,NIH, Frederick, MD 21702 USA. RP Gonzalez, FJ (reprint author), NIH, Lab Metab, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 73 Z9 75 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27117 EP 27122 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800061 PM 10852923 ER PT J AU Jones, CE Mueser, TC Nossal, NG AF Jones, CE Mueser, TC Nossal, NG TI Interaction of the bacteriophage T4 gene 59 helicase loading protein and gene 41 helicase with each other and with fork, flap, and cruciform DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLAR BRANCH MIGRATION; DOUBLE-STRAND BREAKS; 4-WAY JUNCTION DNA; REPLICATION COMPLEX; ASSEMBLY PROTEIN; PRIMASE-HELICASE; BINDING; RECOMBINATION; POLYMERASE; PURIFICATION AB Bacteriophage T4 gene 59 helicase loading protein accelerates the loading of T4 gene 41 DNA helicase and is required for recombination-dependent DNA replication late in T4 phage infection. The crystal structure of 59 protein revealed a two-domain alpha-helical protein, whose N-terminal domain has strong structural similarity to the DNA binding domain of high mobility group family proteins (Mueser, T. C., Jones, C. E., Nossal, N. G., and Hyde, C, C, (2000) J. Mel. Biol, 296, 597-612), We have previously shown that 59 protein binds preferentially to fork DNA, Here we show that 59 protein binds to completely duplex forks but cannot load the helicase unless there is a single-stranded gap of more than 5 nucleotides on the fork arm corresponding to the lagging strand template. Consistent with the roles of these proteins in recombination, we find that 59 protein binds to and stimulates 41 helicase activity on Holliday junction DNA, and on a substrate that resembles a strand invasion structure. 59 protein forms a stable complex with wild type 41 helicase and fork DNA in the presence of adenosine 5'-O-(thiotriphosphate). The unwinding activity of 41 helicase missing 20 C-terminal amino acids is not stimulated by 59 protein, and it does not form a complex with 59 protein on fork DNA. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Nossal, NG (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bldg 8,Rm 2A19, Bethesda, MD 20892 USA. NR 51 TC 35 Z9 35 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27145 EP 27154 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800065 PM 10871615 ER PT J AU Taggart, C Cervantes-Laurean, D Kim, G McElvaney, NG Wehr, N Moss, J Levine, RL AF Taggart, C Cervantes-Laurean, D Kim, G McElvaney, NG Wehr, N Moss, J Levine, RL TI Oxidation of either methionine 351 or methionine 358 in alpha(1)-antitrypsin causes loss of anti-neutrophil elastase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN ALPHA-1-PROTEINASE INHIBITOR; CYSTIC-FIBROSIS; SERINE PROTEINASES; ESCHERICHIA-COLI; REACTIVE-CENTER; ALPHA-1-ANTITRYPSIN; EMPHYSEMA; RESIDUES; DEFICIENCY; INACTIVATION AB Hydrogen peroxide is a component of cigarette smoke known to be essential for inactivation of alpha(1)-antitrypsin, the primary inhibitor of neutrophil elastase, To establish the molecular basis of the inactivation of alpha(1)-antitrypsin, we determined the sites oxidized by hydrogen peroxide, Two of the nine methionines were particularly susceptible to oxidation, One was methionine 358, whose oxidation was known to cause loss of antielastase activity. The other, methionine 351, was as susceptible to oxidation as methionine 358, Its oxidation also resulted in loss of anti-elastase activity, an effect not previously recognized, The equal susceptibility of methionine 358 and methionine 351 to oxidation was confirmed by mass spectrometry. To verify this finding, we produced recombinant alpha(1)-antitrypsins in which one or both of the susceptible methionines were mutated to valine, M351V and M358V were not as rapidly inactivated as wild-type alpha 1-antitrypsin, but only the double mutant M351V/M358V was markedly resistant to oxidative inactivation. We suggest that inactivation of alpha(1)-antitrypsin by oxidation of either methionine 351 or 358 provides a mechanism for regulation of its activity at sites of inflammation. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Royal Coll Surg Ireland, Div Pulm, Dublin 9, Ireland. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Rm 106,MSC 0320, Bethesda, MD 20892 USA. RI McElvaney, Noel/A-6809-2010; Taggart, Clifford/G-4492-2014; Levine, Rodney/D-9885-2011 NR 53 TC 163 Z9 172 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27258 EP 27265 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800079 PM 10867014 ER PT J AU Hoare, SRJ Clark, JA Usdin, TB AF Hoare, SRJ Clark, JA Usdin, TB TI Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor - N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CROSS-LINKING; TRANSMEMBRANE RESIDUES; EXTRACELLULAR LOOP; CHIMERIC RECEPTORS; AMINO-TERMINUS; AGONIST; LIGAND; ACTIVATION; CALCITONIN; EXPRESSION AB Tuberoinfundibular peptide of 39 residues (TIP39) and the parathyroid hormone-a (PTH2) receptor form part of an extended family of related signaling molecules that includes the PTH1 receptor, which responds to PTH and PTH-related protein. TIP39 does not appreciably activate the PTH1 receptor, but in this study it is shown to bind the receptor with moderate affinity (59 nM), In this study, we investigated the molecular determinants of both ligand and receptor for the PTH2 receptor selectivity of TIP39 and quantitatively evaluated the role of molecular elements in the binding of TIP39 to the PTH2 and PTH1 receptors, A chimeric receptor composed of the N-terminal extracellular domain of the PTH1 receptor and the remainder (juxtamembrane domain) of the PTH2 receptor (P2-NP1) was fully activated by TIP39 (E-max = 98% of the rPTH-(1-34), E-max, EC50 = 2.0 nnr). This receptor chimera bound TIP39 with an equivalent affinity to the wild-type PTH2 receptor (2.3 and 2.0 nM, respectively). The reciprocal chimeric receptor (P1-NP2) was not activated by TIP39 and bound the ligand with an affinity equivalent to that of the PTH1 receptor. Thus, the juxtamembrane receptor domain specifies the signaling and binding selectivity of TIP39 for the PTH2 receptor over the PTH1 receptor. Removing six N-terminal residues of TIP39 eliminated activation of the PTH2 receptor and reduced binding affinity 70-fold. In contrast, this truncation increased affinity for the PTH1 receptor 10-fold, reversing the PTH2/PTH1 receptor binding selectivity and resulting in a high affinity interaction of TIP-(7-39) with the PTH1 receptor (6 mM), These findings can be explained by a strong interaction between the N-terminal region of TIP39 and the juxtamembrane domain of the PTH2 receptor, with the corresponding domain of the PTH1 receptor acting as a selectivity barrier against high affinity binding of TIP39, As a result, TIP-(7-39) is a highly potent, selective antagonist for the PTH1 receptor. C1 NIMH, Cell Biol Unit, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIH, Rm 3D06,Bldg 36,36 Convent Dr MSC4094, Bethesda, MD 20892 USA. NR 41 TC 44 Z9 45 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27274 EP 27283 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800081 PM 10854439 ER PT J AU Piserchio, A Usdin, T Mierke, DF AF Piserchio, A Usdin, T Mierke, DF TI Structure of tuberoinfundibular peptide of 39 residues SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN PARATHYROID-HORMONE; PTH-RELATED PEPTIDE; NMR-SPECTROSCOPY; RECEPTOR INTERACTIONS; COUPLING-CONSTANTS; AMINO-TERMINUS; CROSS-LINKING; PROTEIN; LIGAND; AGONIST AB The recently identified natural peptide ligand, tuberoinfundibular peptide of 39 residues (TIP39) for the parathyroid hormone-2 (PTHS) receptor has been structurally characterized by high resolution NMR, circular dichroism, and computer simulations. The structural features of TIP39, determined in the presence of a zwitterionic lipid to mimic the membrane environment of the G-protein-coupled PTH2 receptor, consist of two a-helices, Ala(5)-Arg(21) and Leu(26)-Val(35). Although TIP39 shares limited sequence homology with parathyroid hormone (PTH), a comparison of the structural features of TIP39 and PTH illustrates a similar topological display of residues of the N-terminal helix important for PTH2 receptor activation. The C-terminal helix of TIP39 differs from that of PTH with respect to size and amphipathicity, suggesting an altered mode of binding for TIP39, consistent with the receptor chimera and ligand truncation studies presented in the accompanying paper (Hoare, S. R. J., Clark, J, A, and Usdin, T. B. (2000) J. Biol. Chen. 275, 27274-27283). The structural characterization of TIP39 also provides some insight into the lack of affinity of this novel ligand for the PTH1 receptor. C1 Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Div Biol & Med, Providence, RI 02912 USA. Brown Univ, Dept Chem, Providence, RI 02912 USA. NIMH, Genet Lab, Cell Biol Unit, Bethesda, MD 20892 USA. RP Mierke, DF (reprint author), Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Box G-B4, Providence, RI 02912 USA. FU NCRR NIH HHS [RR-00995]; NIGMS NIH HHS [GM54082] NR 54 TC 34 Z9 34 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27284 EP 27290 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800082 PM 10856302 ER PT J AU Adams, A Thorn, JM Yamabhai, M Kay, BK O'Bryan, JP AF Adams, A Thorn, JM Yamabhai, M Kay, BK O'Bryan, JP TI Intersectin, an adaptor protein involved in clathrin-mediated endocytosis, activates mitogenic signaling pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE KINASE SUBSTRATE; GROWTH-FACTOR RECEPTOR; XENOPUS OOCYTES; EH-DOMAIN; MEIOTIC MATURATION; ONCOGENE PRODUCT; EPS15 HOMOLOGY; RAS PROTEINS; TRANSFORMATION; COMPONENTS AB Intersectin is a member of a growing family of adaptor proteins that possess conserved Eps15 homology (EH) domains as well as additional protein recognition motifs. In general, EH domain-containing proteins play an integral role in clathrin-mediated endocytosis. Indeed, intersectin functions in the intermediate stages of clathrin-coated vesicle assembly. However, recent evidence suggests that components of the endocytic machinery also regulate mitogenic signaling pathways. In this report, we provide several lines of evidence that intersectin has the capacity to activate mitogenic signaling pathways. First, intersectin overexpression activated the Elk-l transcription factor in an MAPK-independent manner, This ability resides within the EH domains, as expression of the tandem EH domains was sufficient to activate Elk-l. Second, intersectin cooperated with epidermal growth factor to potentiate Elk-l activation; however, a similar level of Elk-l activation was obtained by expression of the tandem EH domains suggesting that the coiled-coil region and SH3 domains act to regulate the EH domains. Third, intersectin expression was sufficient to induce oncogenic transformation of rodent fibroblasts. And finally, intersectin cooperated with progesterone to accelerate maturation of Xenopus laevis oocytes. Together, these data suggest that intersectin links endocytosis with regulation of pathways important for cell growth and differentiation. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Wisconsin, Dept Pharmacol, Madison, WI 53706 USA. RP O'Bryan, JP (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,Bldg 101,Rm F336,MD F3-06, Res Triangle Pk, NC 27709 USA. NR 39 TC 60 Z9 66 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27414 EP 27420 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800100 PM 10851244 ER PT J AU Tanimura, A Tojyo, Y Turner, RJ AF Tanimura, A Tojyo, Y Turner, RJ TI Evidence that type I, II, and III inositol 1,4,5-trisphosphate receptors can occur as integral plasma membrane proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; OPERATED HTRP3 CHANNELS; IP3 RECEPTOR; CARCINOMA-CELLS; RAT-LIVER; LOCALIZATION; ACTIVATION; IDENTIFICATION; RETICULUM; NEURONS AB A number of previous reports have suggested that inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are present in the plasma membranes of cells. We confirm this directly in the present study by demonstrating that a significant proportion of the IP,Rs found in A431 cells, Jurkat cells, and rat parotid acini can be biotinylated by the extracellular application of sulfo-N-hydroxysuccinimide-biotin to intact cells. This labeling cannot be accounted for by the reaction of sulfo-N-hydroxysuccinimide-biotin with intracellular IP(3)Rs since calnexin and the SERCA2 ATPase, both integral membrane proteins of the endoplasmic reticulum, are not labeled under the same experimental conditions. individual IP3R subtypes were detected using subtype-specific antibodies. A431 cells expressed only the type-3 IP3R, and 23% of this protein was in the biotinylated (plasma membrane) fraction. Jurkat cells and rat parotid cells expressed all three IP3R subtypes. Contrary to earlier results suggesting that only the type-3 IP3R might localize to the plasma membrane, we found that significant amounts (5-14%) of all three subtypes could be identified in the biotinylated fractions of Jurkat and rat parotid cells. Our results suggest a role for IP,Rs in plasma membrane as well as intracellular membrane function. C1 Hlth Sci Univ Hokkaido, Sch Dent, Dept Dent Pharmacol, Ishikari, Hokkaido 0610293, Japan. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Tanimura, A (reprint author), Hlth Sci Univ Hokkaido, Sch Dent, Dept Dent Pharmacol, Ishikari, Hokkaido 0610293, Japan. NR 32 TC 48 Z9 50 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 1 PY 2000 VL 275 IS 35 BP 27488 EP 27493 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351EL UT WOS:000089144800108 PM 10874040 ER PT J AU Ameye, L Aria, D Chen, X Gehron Robey, P Chakravarti, S Oldberg, A Young, MF AF Ameye, L Aria, D Chen, X Gehron Robey, P Chakravarti, S Oldberg, A Young, MF TI Biglycan and fibromodulin double-knockout mice develop ectopic sesamoid bones and premature osteoarthritis in the knee joint. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. Case Western Reserve Univ, Dept Med & Genet, Cleveland, OH 44106 USA. Univ Lund, Dept Cell & Mol Biol, Lund, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1189 BP S185 EP S185 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400190 ER PT J AU Atti, E Paschalis, EP Gomez, S Wahl, SM Boskey, AL AF Atti, E Paschalis, EP Gomez, S Wahl, SM Boskey, AL TI The role of TGF-beta in bone development: an FTIR imaging analysis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Hosp Special Surg, New York, NY 10021 USA. Univ Cadiz, Dipartimento Anat Patol, Cadiz, Spain. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU145 BP S366 EP S366 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400918 ER PT J AU Barnes, GL Sommer, B Young, MF Einhorn, TA Gerstenfeld, LC AF Barnes, GL Sommer, B Young, MF Einhorn, TA Gerstenfeld, LC TI Molecular regulators of bone sialoprotein expression in human metastatic breast cancer cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Boston Univ, Sch Med, Dept Orthopaed Surg, Musculoskeletal Res Lab, Boston, MA 02118 USA. NIDCR, NIH, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1249 BP S200 EP S200 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400250 ER PT J AU Chen, X Xu, T Young, M AF Chen, X Xu, T Young, M TI Age-related osteoporosis in biglycan deficient mice is related to a defect in osteoblast differentiation. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Glaxo Wellcome Inc, Mol Pharmacol, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1130 BP S171 EP S171 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400131 ER PT J AU Chesnut, CH Lee, MH Gill, RK Gafni, RI Baron, J Langman, CB Patel, SB Cowell, CT Key, LL Bell, NH AF Chesnut, CH Lee, MH Gill, RK Gafni, RI Baron, J Langman, CB Patel, SB Cowell, CT Key, LL Bell, NH TI High turnover idiopathic juvenile osteoporosis does not map to the osteoprotegerin/osteoclastogenesis inhibitory factor gene locus. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Chicago, IL USA. New Childrens Hosp, Parramatta, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SA362 BP S302 EP S302 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400657 ER PT J AU Chung, U Wei, W Schipani, E Hunzelman, J Weinstein, L Kronenberg, H AF Chung, U Wei, W Schipani, E Hunzelman, J Weinstein, L Kronenberg, H TI In vivo function of stimulatory G protein (Gs) in the growth plate. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. NIH, NIDDK, Metab Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1149 BP S175 EP S175 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400150 ER PT J AU Collins, MT Chebli, C Jones, JM Bianco, P Robey, PG AF Collins, MT Chebli, C Jones, JM Bianco, P Robey, PG TI A case of tumor-induced osteomalacia demonstrating biochemical evidence of bone healing in with aggressive medical treatment. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Natl Insts Hlth, CSDB, Bethesda, MD USA. Natl Insts Hlth, NIDCR, Bethesda, MD USA. Natl Insts Hlth, CC, Bethesda, MD USA. Univ Aquila, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU109 BP S358 EP S358 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400882 ER PT J AU Corsi, A Collins, MT Mankani, M Robey, PG Bianco, P AF Corsi, A Collins, MT Mankani, M Robey, PG Bianco, P TI Core biopsy studies of fibrous dysplasia of bone: Evidence for impaired mineralization of lesional bone and for hormonal dependency of turnover within the lesion. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. NIDCR, NIH, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA M115 BP S485 EP S485 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401409 ER PT J AU Engsig, MT Kirkegaard, T Henriksen, K Pedersen, AC Ovejero, MC Birkedal-Hansen, H Holmbeck, K Foged, NT Delaisse, M AF Engsig, MT Kirkegaard, T Henriksen, K Pedersen, AC Ovejero, MC Birkedal-Hansen, H Holmbeck, K Foged, NT Delaisse, M TI Osteoclast recruitment is regulated by membrane-type 1 matrix metalloproteinase (MT1-MMP). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 OsteoPro AS, Herlev, Denmark. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1177 BP S182 EP S182 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400178 ER PT J AU Genco, R Adams, D Jeffcoat, M Klokkevold, P Page, R Cizza, G Kimberlin, M Lombardi, A Meng, L Santora, A Shih, W AF Genco, R Adams, D Jeffcoat, M Klokkevold, P Page, R Cizza, G Kimberlin, M Lombardi, A Meng, L Santora, A Shih, W TI Safety and tolerability of once-weekly alendronate 70 mg is comparable to that of placebo in men and women with periodontal disease. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 SUNY Buffalo, Buffalo, NY 14260 USA. OHSU, Portland, OR USA. Univ Alabama, Birmingham, AL USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Washington, Seattle, WA USA. NIH, Bethesda, MD 20892 USA. Merck Res Labs, Clin Res, Rahway, NJ USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA M131 BP S489 EP S489 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401425 ER PT J AU Greendale, GA Huang, M FitzGerald, G Sowers, M Sternfeld, B Seeman, T Sherman, S AF Greendale, GA Huang, M FitzGerald, G Sowers, M Sternfeld, B Seeman, T Sherman, S TI Dietary genistein and BMD in premenopausal and early perimenopausal African-American and Caucasian women. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Dept Med, Div Geriatr, Los Angeles, CA 90024 USA. New England Res Inst, Cambridge, MA USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Kaiser Permanente, Div Res, Oakland, CA USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU327 BP S411 EP S411 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401100 ER PT J AU Greendale, GA Huang, M FitzGerald, G Sowers, M Sternfeld, B Seeman, T Sherman, S AF Greendale, GA Huang, M FitzGerald, G Sowers, M Sternfeld, B Seeman, T Sherman, S TI Dietary genistein and BMD in premenopausal and early perimenopausal Chinese and Japanese women. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Dept Med, Div Geriatr, Los Angeles, CA 90024 USA. New England Res Inst, Cambridge, MA USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Kaiser Permanente, Div Res, Oakland, CA USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU326 BP S410 EP S410 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401099 ER PT J AU Gronthos, S Shi, S Robey, PG AF Gronthos, S Shi, S Robey, PG TI Comparison of gene expression profiles between human bone marrow stromal cells and human bone cells by microarray (genefilters) analysis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Craniofacial Skeletal Dis Branch, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU219 BP S384 EP S384 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400992 ER PT J AU Hoare, SRJ Gardella, TJ Usdin, TB AF Hoare, SRJ Gardella, TJ Usdin, TB TI Measuring ligand affinity for the G-protein-coupled and uncoupled states of the parathyroid hormone 1 (PTH1) receptor: Implications for the development of therapeutic ligands. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SA461 BP S319 EP S319 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400723 ER PT J AU Kiel, DP Hannan, MT Cupples, LA Wilson, PWF Levy, D Clouse, ME Krueger-Lovy, K O'Donnell, CJ AF Kiel, DP Hannan, MT Cupples, LA Wilson, PWF Levy, D Clouse, ME Krueger-Lovy, K O'Donnell, CJ TI Low bone mineral density (BMD) is associated with coronary artery calcification. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Div Aging, HRCA Res & Training Inst, Boston, MA 02115 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1087 BP S160 EP S160 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400088 ER PT J AU Kurland, ES Seltzer, B Kulak, CAM Scussheim, D Shane, E Rogers, J Bilezikian, JP Rosen, CJ AF Kurland, ES Seltzer, B Kulak, CAM Scussheim, D Shane, E Rogers, J Bilezikian, JP Rosen, CJ TI Gender specific effects of an IGF-I gene polymorphism on bone density and serum IGF-I in relatives of men with idiopathic osteoporosis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Fed Univ Parana, Hosp Clin, Parana, Brazil. NIH, Bethesda, MD 20892 USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. St Joseph Hosp, Maine Ctr Osteoporosis Res & Educ, Bangor, ME USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU122 BP S361 EP S361 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400895 ER PT J AU Kuznetsov, SA Majolagbe, A Cherman, N Fisher, LW Riminucci, M Bianco, P Robey, PG AF Kuznetsov, SA Majolagbe, A Cherman, N Fisher, LW Riminucci, M Bianco, P Robey, PG TI The lethal nature of activating GNAS1 mutations in the post-natal organism: Selective age-dependent loss of mutated osteoprogenitor cells in fibrous dysplasia. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Bethesda, MD 20892 USA. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1102 BP S164 EP S164 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400103 ER PT J AU LaCroix, AZ Cauley, JA Jackson, R McGowan, J Pettinger, M Hsia, J Chen, Z Lewis, C Bauer, DC Daugherty, S McNeeley, SG Passaro, M AF LaCroix, AZ Cauley, JA Jackson, R McGowan, J Pettinger, M Hsia, J Chen, Z Lewis, C Bauer, DC Daugherty, S McNeeley, SG Passaro, M TI Does statin use reduce risk of fracture in postmenopausal women? Results from the Women's Health Initiative Observational Study (WHI-OS). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Washington, Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat CCC, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. NIH, NIAMS, Bethesda, MD 20892 USA. George Washington Univ, Washington, DC USA. Arizona Prevent Ctr, Tucson, AZ USA. Univ Alabama, Birmingham, AL USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Nevada, Reno, NV 89557 USA. Wayne State Univ, Detroit, MI USA. Howard Univ, Ctr Canc, Washington, DC 20059 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 34 Z9 35 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1066 BP S155 EP S155 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400067 ER PT J AU Nuckolls, GH Kane, A Shum, L Slavkin, HC AF Nuckolls, GH Kane, A Shum, L Slavkin, HC TI Lovastatin promotes cartilage growth but inhibits endochondral ossification of the cranial base in organ culture. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIAMS, Craniofacial Dev, NIH, Bethesda, MD USA. Warren Grant Magnuson Clin Ctr, Lab Diag Radiol Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU390 BP S426 EP S426 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401163 ER PT J AU Riminucci, M Yamada, S Festuccia, C Holmbeck, K Birkedal-Hansen, H Robey, PG Bianco, P AF Riminucci, M Yamada, S Festuccia, C Holmbeck, K Birkedal-Hansen, H Robey, PG Bianco, P TI Collagenolytic properties of GNAS1-mutated osteogenic cells from fibrous dysplasia and their in vivo correlate. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. NIH, NIDCR, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA F129 BP S212 EP S212 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400298 ER PT J AU Schroder, C Segovis, C Barsony, J AF Schroder, C Segovis, C Barsony, J TI Active vitamin D metabolites are stored and released from the adipose tissue. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDDK, LCBB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SA443 BP S316 EP S316 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400711 ER PT J AU Schwartz, AV Sellmeyer, DE Nevitt, MC Resnick, HE Margolis, KL Hillier, TA Black, DM Ensrud, KE Cummings, SR AF Schwartz, AV Sellmeyer, DE Nevitt, MC Resnick, HE Margolis, KL Hillier, TA Black, DM Ensrud, KE Cummings, SR CA Study Osteoporotic Fractures Res G TI Older women with diabetes have a higher rate of bone loss at the hip. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, Coordinating Ctr, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1199 BP S188 EP S188 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400200 ER PT J AU Schwartzberg, PL Xing, L Venegas, A Boyce, B Varmus, H AF Schwartzberg, PL Xing, L Venegas, A Boyce, B Varmus, H TI Genetic evidence for a role for the Src tyrosine kinase in cell survival and signaling from the TNF family receptor RANK. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Natl Human Genome Inst, Genet Dis Res Branch, NIH, Bethesda, MD USA. Univ Rochester, Dept Pathol, Rochester, NY 14627 USA. NCI, Varmus Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA F261 BP S220 EP S220 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400331 ER PT J AU Shi, S Gronthos, S Mankani, M Brahim, J Robey, PG AF Shi, S Gronthos, S Mankani, M Brahim, J Robey, PG TI Comparison of human dental pulp cells (DPCs) and human bone marrow stromal cells (BMSCs) by in vitro and in vivo differentiation. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA M187 BP S501 EP S501 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401479 ER PT J AU Sun, B Mitnick, M Rudikoff, S Troiano, N Insogna, K AF Sun, B Mitnick, M Rudikoff, S Troiano, N Insogna, K TI Interleukin-6 knock-out mice have secondary hyperparathyroidism and increased bone density. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Yale Univ, Sch Med, New Haven, CT USA. Natl Canc Inst, Bethesda, MD USA. Yale Univ, Sch Med, New Haven, CT 06510 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA F168 BP S215 EP S215 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400309 ER PT J AU Taaffe, DR Lang, T Fuerst, T Cauley, J Nevitt, M Tylavsky, F Harris, T AF Taaffe, DR Lang, T Fuerst, T Cauley, J Nevitt, M Tylavsky, F Harris, T TI Cross-sectional geometry and bone density of the femoral midshaft: Gender and race effects in older adults. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Memphis, TN USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SU364 BP S419 EP S419 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401137 ER PT J AU Tylavsky, EA Kritchevsky, S Newman, A Cauley, JA Visser, M Harris, TB AF Tylavsky, EA Kritchevsky, S Newman, A Cauley, JA Visser, M Harris, TB TI Does bone mineral content and density depend on weight history? SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Pittsburgh, PA USA. Vrije Univ Amsterdam, EMGO Inst, Amsterdam, Netherlands. NIA, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA M354 BP S540 EP S540 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898401646 ER PT J AU Vogt, MT Rubash, HE Scott, J Cauley, JA AF Vogt, MT Rubash, HE Scott, J Cauley, JA TI Surgical management and post-operative mortality of hip fracture patients. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA USA. Harvard Univ, Sch Med, Boston, MA USA. NIH, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA SA319 BP S293 EP S293 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400620 ER PT J AU Xing, LP Carlso, L Story, B Tai, Z Sibenlist, U Boyce, B AF Xing, LP Carlso, L Story, B Tai, Z Sibenlist, U Boyce, B TI NF-kappa B expression is required for IL-1-induced bone resorption. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Rochester, Rochester, NY USA. NIH, Bethesda, MD 20892 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2000 VL 15 SU 1 MA 1063 BP S154 EP S154 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400064 ER PT J AU Zhang, Y Kiel, D Ellison, C Schatskin, A Kreger, B Dorgan, J Cupples, A Felson, DT AF Zhang, Y Kiel, D Ellison, C Schatskin, A Kreger, B Dorgan, J Cupples, A Felson, DT TI Bone mass and the risk of prostate cancer among men: The Framingham Study. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Boston Univ, Arthrit Ctr, Boston, MA USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Boston Univ, Boston, MA 02215 USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 10 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2000 VL 15 SU 1 MA 1083 BP S159 EP S159 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 346YJ UT WOS:000088898400084 ER PT J AU Begg, L Adams, RC AF Begg, L Adams, RC TI Nutrition-related education, research training, and career development opportunities at the National Cancer Institute SO JOURNAL OF CANCER EDUCATION LA English DT Editorial Material C1 NCI, Canc Training Branch, NIH, Bethesda, MD 20892 USA. RP Begg, L (reprint author), NCI, Canc Training Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD FAL PY 2000 VL 15 IS 3 BP 121 EP 122 PG 2 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 459DX UT WOS:000170236700003 PM 11019754 ER PT J AU Duncan, MK Kozmik, Z Cveklova, K Piatigorsky, J Cvekl, A AF Duncan, MK Kozmik, Z Cveklova, K Piatigorsky, J Cvekl, A TI Overexpression of PAX6(5a) in lens fiber cells results in cataract and upregulation of alpha 5 beta 1 integrin expression SO JOURNAL OF CELL SCIENCE LA English DT Article DE paired domain; homeodomain; lens; transgenic; cataract ID DNA-BINDING SUBDOMAINS; A-CRYSTALLIN GENE; PAIRED DOMAIN; TRANSCRIPTIONAL REGULATION; CADHERIN EXPRESSION; TRANSGENIC MICE; HUMAN EYE; PAX-6; PROMOTER; ADHESION AB The PAX6 gene, a key regulator of eye development, produces two major proteins that differ in paired domain structure: PAX6 and PAX6(5a). It is known that an increase in the PAX6(5a) to PAX6 ratio leads to multiple ocular defects in humans. Here, transgenic mice were created that overexpress human PAX6(5a) in the lens, These mice develop cataracts with abnormalities in fiber cell shape as well as fiber cell/lens capsule and fiber cell/fiber cell interactions. While the structure of the actin cytoskeleton appeared relatively normal, the cataractous lens expresses increased amounts of paxillin and p120(ctn) as well as large aggregates of alpha 5 beta 1 integrin in the dysgenic fiber cells, The elevated amounts of these proteins in the transgenic lens correlated well with elevated levels of their respective mRNAs, To investigate the role of Pax-6(5a) in the upregulation of these genes, a series of gel shift experiments using truncated proteins and consensus oligonucleotides demonstrated the complexity of Pax-6 and Pax-6(5a) binding to DNA, aiding our identification of potential binding sites in the human alpha 5- and beta 1-integrin promoters. Consequent gel shift analysis demonstrated that these putative regulatory sequences bind Pax-6 and/or Pax-6(5a) in lens nuclear extracts, suggesting that the human alpha 5 and beta 1 integrin promoters contain PAX6/PAX6(5a) binding sites and maybe directly regulated by this transcription factor in the transgenic lens, We conclude that these transgenic mice are good models to study a type of human cataract and for identifying batteries of genes that are directly or indirectly regulated by both forms of Pax-6. C1 Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. Acad Sci Czech Republ, Inst Mol Genet, Lab Transcript Regulat, Prague, Czech Republic. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Ophthalmol, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. RP Duncan, MK (reprint author), Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. RI Cvekl, Ales/B-2427-2013; Kozmik, Zbynek/G-3581-2014; Kozmik, Zbynek/I-8807-2014 FU NEI NIH HHS [EY12200-01, R01 EY12221-01, 1Z01EY00126-17] NR 63 TC 98 Z9 100 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP PY 2000 VL 113 IS 18 BP 3173 EP 3185 PG 13 WC Cell Biology SC Cell Biology GA 362TV UT WOS:000089795100005 PM 10954416 ER PT J AU Sokoloff, L AF Sokoloff, L TI Seymour S. Kety, MD 1915-2000 - In memoriam SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Biographical-Item C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD SEP PY 2000 VL 20 IS 9 BP 1271 EP 1275 PG 5 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 349XA UT WOS:000089069800001 PM 10994848 ER PT J AU Hirshberg, B Livi, A Bartlett, DL Libutti, SK Alexander, HR Doppman, JL Skarulis, MC Gorden, P AF Hirshberg, B Livi, A Bartlett, DL Libutti, SK Alexander, HR Doppman, JL Skarulis, MC Gorden, P TI Forty-eight-hour fast: The diagnostic test for insulinoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROINSULIN-LIKE COMPONENT; HYPOGLYCEMIC DISORDERS; INTRAOPERATIVE ULTRASONOGRAPHY; HYPERINSULINEMIC HYPOGLYCEMIA; SURGICAL ASPECTS; LOCALIZATION; STIMULATION; UNAWARENESS; ENDOCRINE; SYMPTOMS AB Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple's triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970-2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 +/- 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard. C1 NIDDKD, Div Intramural Res, NIH, Bethesda, MD 20892 USA. NCI, Surg Metab Sect, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Hirshberg, B (reprint author), NIDDKD, Div Intramural Res, NIH, Bldg 10,Room 85-235B, Bethesda, MD 20892 USA. NR 26 TC 104 Z9 108 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2000 VL 85 IS 9 BP 3222 EP 3226 DI 10.1210/jc.85.9.3222 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351NZ UT WOS:000089166200038 PM 10999812 ER PT J AU Stratakis, CA Lafferty, A Taymans, SE Gafni, RI Meck, JM Blancato, J AF Stratakis, CA Lafferty, A Taymans, SE Gafni, RI Meck, JM Blancato, J TI Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: Molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503) SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 81st Annual Meeting of the Endocrine-Society CY JUN 12-16, 1999 CL SAN DIEGO, CA SP Endocrine Soc ID ULNAR-MAMMARY SYNDROME; PARTIAL TRISOMY 16Q; MATERNAL TRANSLOCATION; FRAGILE SITE; ARM 16Q; BREAST; REGION; RESOLUTION; MAPS; HETERODISOMY AB Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal land one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized. C1 NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Unit Growth Dev, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Washington, DC 20007 USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. EM stratakc@cc1.nichd.nih.gov NR 50 TC 41 Z9 44 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2000 VL 85 IS 9 BP 3396 EP 3401 DI 10.1210/jc.85.9.3396 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351NZ UT WOS:000089166200066 PM 10999840 ER PT J AU Young, NS Maciejewski, JP AF Young, NS Maciejewski, JP TI Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes "Why? Why? Why?" SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID APLASTIC-ANEMIA; SOMATIC MUTATIONS; ANCHORED PROTEINS; MUTANT-CELLS; DEFICIENT; HEMATOPOIESIS; PROGENITORS; CLONE; MICE C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C-103, Bethesda, MD 20892 USA. NR 29 TC 48 Z9 49 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2000 VL 106 IS 5 BP 637 EP 641 DI 10.1172/JCI11002 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 351VN UT WOS:000089179000007 PM 10974016 ER PT J AU Chen, R Nagarajan, S Prince, GM Maheshwari, U Terstappen, LWMM Kaplan, DR Gerson, SL Albert, JM Dunn, DE Lazarus, HM Medof, ME AF Chen, R Nagarajan, S Prince, GM Maheshwari, U Terstappen, LWMM Kaplan, DR Gerson, SL Albert, JM Dunn, DE Lazarus, HM Medof, ME TI Impaired growth and elevated Fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PIG-A GENE; HEMATOPOIETIC PROGENITOR CELLS; APLASTIC-ANEMIA; NORMAL INDIVIDUALS; PERIPHERAL-BLOOD; APOPTOSIS; RESISTANCE; CD34(+); MICE; BIOSYNTHESIS AB The genetic defect underlying paroxysmal nocturnal hemoglobinuria (PNH) has been shown to reside in PIGA, a gene that encodes an element required for the first step in glycophosphatidylinositol anchor assembly. Why PIGA-mutated cells are able to expand in PNH marrow, however, is as yet unclear. To address this question, we compared the growth of affected CD59(-)CD34(+) and unaffected CD59(+)CD34(+) cells from patients with that of normal CD59(+)CD34(+) cells in liquid culture. One hundred FAGS-sorted cells were added per well into microtiter plates, and after 11 days at 37 degrees C the progeny were counted and were analyzed for their differentiation pattern. We found that CD59-CD34(+) cells from PNH patients proliferated to levels approaching those of normal cells, but that CD59(+)CD34(+) cells from the patients gave rise to 20- to 140-fold fewer cells. Prior to sorting, the patients' CD59(-) and CD59(+)CD34(+) cells were equivalent with respect to early differentiation markers, and following culture, the CD45 differentiation patterns were identical to those of control CD34(+) cells. Further analyses of the unsorted CD59(+)CD34(+) population, however, showed elevated levels of Fas receptor. Addition of agonist anti-Fas mAb to cultures reduced the CD59(+)CD34(+) cell yield by up to 78% but had a minimal effect on the CD59(-)CD34(+) cells, whereas antagonist anti-Fas mAb enhanced the yield by up to 250%. These results suggest that expansion of PIGA-mutated cells in PNH marrow is due to a growth defect in nonmutated cells, and that greater susceptibility to apoptosis is one factor involved in the growth impairment. C1 Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. Immunicon Corp, Huntingdon, PA USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Medof, ME (reprint author), Case Western Reserve Univ, Inst Pathol, 2085 Adelbert Rd, Cleveland, OH 44106 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 FU NIAID NIH HHS [R01 AI-23598, R01 AI023598] NR 42 TC 45 Z9 46 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2000 VL 106 IS 5 BP 689 EP 696 DI 10.1172/JCI8328 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 351VN UT WOS:000089179000013 PM 10974022 ER PT J AU Murphy, WJ AF Murphy, WJ TI Revisiting graft-versus-host disease models of autoimmunity: new insights in immune regulatory processes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID BONE-MARROW TRANSPLANTATION; FAS-LIGAND; GAMMA; THERAPY; MICE C1 NCI, Transplantat Biol Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), NCI, Transplantat Biol Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 17 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2000 VL 106 IS 6 BP 745 EP 747 DI 10.1172/JCI11088 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 355MW UT WOS:000089390300006 PM 10995784 ER PT J AU Fend, F Raffeld, M AF Fend, F Raffeld, M TI Laser capture microdissection in pathology SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE laser capture microdissection; RNA analysis; DNA analysis; gene expression; profiling; immunohistochemistry ID POLYMERASE CHAIN-REACTION; COMPARATIVE GENOMIC HYBRIDIZATION; FROZEN TISSUE-SECTIONS; REED-STERNBERG CELLS; HUMAN BREAST-CANCER; GENE-EXPRESSION; MESSENGER-RNA; SINGLE CELLS; MOLECULAR ANALYSIS; ALLELIC LOSS AB The molecular examination of pathologically altered cells and tissues at the DNA, RNA, and protein level has revolutionised research and diagnostics in pathology. However, the inherent heterogeneity of primary tissues with an admixture of various reactive cell populations can affect the outcome and interpretation of molecular studies. Recently, microdissection of tissue sections and cytological preparations has been used increasingly for the isolation of homogeneous, morphologically identified cell populations, thus overcoming the obstacle of tissue complexity. In conjunction with sensitive analytical techniques, such as the polymerase chain reaction, microdissection allows precise in vivo examination of cell populations, such as carcinoma in situ or the malignant cells of Hodgkin's disease, which are otherwise inaccessible for conventional molecular studies. However, most microdissection techniques are very time consuming and require a high degree of manual dexterity, which limits their practical use. Laser capture microdissection (LCM), a novel technique developed at the National Cancer Institute, is an important advance in terms of speed, ease of use, and versatility of microdissection. LCM is based on the adherence of visually selected cells to a thermoplastic membrane, which overlies the dehydrated tissue section and is focally melted by triggering of a low energy infrared laser pulse. The melted membrane forms a composite with the selected tissue area, which can be removed by simple lifting of the membrane. LCM can be applied to a wide range of cell and tissue preparations including paraffin wax embedded material. The use of immunohistochemical stains allows the selection of cells according to phenotypic and functional characteristics. Depending on the starting material, DNA, good quality mRNA, and proteins can be extracted successfully from captured tissue fragments, down to the single cell level. In combination with techniques Like expression library construction, cDNA array hybridisation and differential display, LCM will allow the establishment of "genetic fingerprints" of specific pathological lesions, especially malignant neoplasms. In addition to the identification of new diagnostic and prognostic markers, this approach could help in establishing individualised treatments tailored to the molecular profile of a tumour. This review provides an overview of the technique of LCM, summarises current applications and new methodical approaches, and tries to give a perspective on future developments. In addition, LCM is compared with other recently developed laser microdissection techniques. C1 Tech Univ Munich, Dept Pathol, Klinikum Rechts Isar, D-81675 Munich, Germany. NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. RP Fend, F (reprint author), Tech Univ Munich, Dept Pathol, Klinikum Rechts Isar, Ismaningerstr 22, D-81675 Munich, Germany. NR 65 TC 143 Z9 152 U1 0 U2 14 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 J9 J CLIN PATHOL JI J. Clin. Pathol. PD SEP PY 2000 VL 53 IS 9 BP 666 EP 672 DI 10.1136/jcp.53.9.666 PG 7 WC Pathology SC Pathology GA 352YV UT WOS:000089247700003 PM 11041055 ER PT J AU Roca, CA Schmidt, PJ Rubinow, DR AF Roca, CA Schmidt, PJ Rubinow, DR TI Association between premenstrual syndrome and depression - Reply SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Roca, CA (reprint author), NIMH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2000 VL 61 IS 9 BP 677 EP 678 PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 359RN UT WOS:000089626000010 ER PT J AU Li, Q Li, T Wu, JG Zhou, NF AF Li, Q Li, T Wu, JG Zhou, NF TI Comparative study on the structure of water in reverse micelles stabilized with sodium bis(2-ethylhexyl) sulfosuccinate or sodium bis(2-ethylhexyl) phosphate in n-heptane SO JOURNAL OF COLLOID AND INTERFACE SCIENCE LA English DT Article DE reverse micelles; water structure; counterion; AOT; NaDEHP ID FT-IR SPECTROSCOPY; AEROSOL-OT; MICROEMULSION; TRANSITION; SYSTEMS AB The microstructure of water solubilized in H2O/surfactant/n-heptane ternary systems has been investigated by employing H-1-NMR and FT-IR spectroscopic techniques. Two reverse micellar systems were prepared and studied, i.e., sodium bis(2-ethylhexyl) sulfosuccinate in n-heptane (H2O/AOT/n-heptane) and sodium bis(2-ethylhexyl) phosphate in n-heptane (H2O/NaDEHP/n-heptane). H-1-NMR data showed that the chemical shift of water protons for the AOT and NaDEHP reverse micelles varied downfield and upheld, respectively, with an increase of the water content. The opposite shift directions with increasing water content are interpreted as due to a composition change of the solubilized water associated with head-groups and sodium counterions in reverse micellar systems. On the basis of deconvolution results of FT-IR spectra, a four-component model is proposed to interpret the FT-IR and H-1-NMR results. (C) 2000 Academic Press. C1 Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. RP Li, T (reprint author), NIH, Bldg 10, Rm 9D50, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 49 Z9 53 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9797 J9 J COLLOID INTERF SCI JI J. Colloid Interface Sci. PD SEP 1 PY 2000 VL 229 IS 1 BP 298 EP 302 DI 10.1006/jcis.2000.7030 PG 5 WC Chemistry, Physical SC Chemistry GA 347LE UT WOS:000088930300036 ER PT J AU Caterina, J Shi, J Sun, X Qian, Q Yamada, S Liu, Y Krakora, S Bartlett, JD Yamada, Y Engler, JA Birkedal-Hansen, H Simmer, JP AF Caterina, J Shi, J Sun, X Qian, Q Yamada, S Liu, Y Krakora, S Bartlett, JD Yamada, Y Engler, JA Birkedal-Hansen, H Simmer, JP TI Cloning, characterization, and expression analysis of mouse enamelysin SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE MMP-20; amelogenin; ameloblast; odontoblast ID MATRIX METALLOPROTEINASES; AMELOGENIN; PROTEINS; TOOTH AB Enamelysin is a recently isolated member of the matrix metalloproteinase (MMP) family of extracellular matrix (ECM)-degrading enzymes. Here we describe the isolation and characterization of the mouse enamelysin cDNA. Expression of mouse enamelysin was detectable only in ameloblasts and odontoblasts of developing teeth. Characterization of mouse enamelysin demonstrated that it is highly conserved in both its sequence content and pattern of expression relative to the porcine, human, and bovine homologues previously described. C1 Natl Inst Dent & Craniofacial Res, Matrix Metalloprot Unit, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat Dent, San Antonio, TX 78284 USA. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. Forsyth Inst, Dept Biomineralizat, Boston, MA 02115 USA. Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. RP Caterina, J (reprint author), Natl Inst Dent & Craniofacial Res, Matrix Metalloprot Unit, 30 Convent Dr,MSC 4380, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA13148]; NIDCR NIH HHS [DE08228, DE10631, R29 DE012098] NR 17 TC 20 Z9 21 U1 0 U2 0 PU AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD SEP PY 2000 VL 79 IS 9 BP 1697 EP 1703 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 359GV UT WOS:000089603900010 PM 11023266 ER PT J AU Wildner, O Morris, JC AF Wildner, O Morris, JC TI Therapy of peritoneal carcinomatosis from colon cancer with oncolytic adenoviruses SO JOURNAL OF GENE MEDICINE LA English DT Article DE cancer gene therapy; adenovirus; HSV-1-tk/GCV system; failsafe gene; viral oncolysis; peritoneal carcinomatosis ID VIRUS THYMIDINE KINASE; GANCICLOVIR-MEDIATED CYTOTOXICITY; GENE-THERAPY; TUMOR-CELLS; P53 STATUS; RECOMBINANT ADENOVIRUS; RETROVIRAL VECTORS; BRAIN-TUMORS; REPLICATION; INFECTION AB Background The major emphasis on the safety of viral vectors for gene delivery has led to the generally accepted approach of disabling their ability to replicate and thus their potential capacity to spread throughout a tumor by consecutive rounds of infection and lysing neighboring cells. Methods In this study we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55-kDa gene, wild-type adenovirus type 5 (Ad5(wt)), and a prototypical replication-deficient adenovirus expressing HSV-tk (Ad. TK) for their cytoreductive effects in a peritoneal carcinomatosis model from human HT-29 colon cancer cells in nude mice. Results The survival of nude mice treated with the replication-defective adenoviral vector Ad.TK was enhanced when followed by GCV. In contrast, administration of GCV diminished the anti-tumor efficacy of the replication-competent HSV-tk expressing vectors. However, the intrinsic oncolytic effect of all replication-competent viruses was superior to that of Ad.TK+GCV. Furthermore, the oncolysis of the E1B 55-kDa-positive viruses was significantly greater than that of the E1B 55-kDa-deleted vector. Conclusions The more efficient diffusion of viral particles in the peritoneal cavity, when compared to the microenvironment of solid tumors and the virostatic effects of GCV, most likely antagonized the anticipated enhanced cytotoxicity of the replication-competent vectors from the use of its gene directed enzyme prodrug system. Nevertheless, in a clinical setting, the HSV-tk/GCV system allows efficient termination of viral replication in the case of a runaway infection. The results of this study warrant further evaluation of controllable viral replication as a treatment modality for cancer, especially in combination with conventional therapies (e.g. chemotherapy). Copyright (C) 2000 John Wiley & Sons, Ltd. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Wildner, O (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, Bldg 10,Rm 10C103, Bethesda, MD 20892 USA. NR 51 TC 27 Z9 28 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD SEP-OCT PY 2000 VL 2 IS 5 BP 353 EP 360 DI 10.1002/1521-2254(200009/10)2:5<353::AID-JGM130>3.0.CO;2-G PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 360KU UT WOS:000089667500007 PM 11045429 ER PT J AU Grehan, JF Hilbert, SL Ferrans, VJ Droel, JS Salerno, CT Bianco, RW AF Grehan, JF Hilbert, SL Ferrans, VJ Droel, JS Salerno, CT Bianco, RW TI Development and evaluation of a swine model to assess the preclinical safety of mechanical heart valves SO JOURNAL OF HEART VALVE DISEASE LA English DT Article; Proceedings Paper CT World Symposium on Heart Valve Disease CY JUN 11-14, 1999 CL LONDON, ENGLAND ID PROSTHESES; THERAPY; THROMBOGENICITY; STENTS; SHEEP; PIGS AB Background ann aim of the study: The current standard of in vitro and in vivo preclinical heart valve testing has recently been questioned because of its failure to reveal the thrombogenic potential of the Medtronic Parallel(TM) prosthetic valve. The aim of this study was to develop a swine model for the in vivo preclinical evaluation of mechanical heart valves, and to assess the ability of this model to identify mechanical heart valve design features that result in valve-related thrombosis. Methods: Twenty-two swine underwent mitral valve replacement (MVR) using three different bileaflet mechanical valve designs (St Jude Medical, CarboMedics, Medtronic Parallel). Each animal was placed in an anticoagulation protocol (group I, INR 3.0-3.5; group II, INR 2.0-2.5; group III, no anticoagulation) and followed for up to 20 weeks. Terminal studies were performed on all animals surviving for more than 30 days. Results: Twenty-one animals survived the immediate postoperative period. Four of six group I animals died from hemorrhagic (large wound hematoma; hemopericardium) complications early in the study. In the two long-term (61 and 89 days) survivors, INRs of 3.0 to 3.5 were never achieved (61-day survivor, mean INR 2.0 +/- 1.03; ranger 0.8-5.4; 89-day survivor, mean INR 1.92 +/- 1.34; range: 1.0-7.9). Pathological analysis of explants from group I survivors revealed minimally obstructive fibrous sheathing on the inflow orifice without restriction of bileaflet motion (61 and 89 days), and two large perivalvular defects (61 days). Six of seven group II animals died from early hemorrhagic complications (hemopericardium) (mean INR 2.32 +/- 1.84; range: 0.8-8.2). Vegetations resulting in obstruction of both sides of the valve orifice and restriction of bileaflet motion were observed in a group II survivor (mean INR 2.33 +/- 1.58; range: 0.9-7.0). Group III animals (n = 8) survived for a mean of 106 +/- 60 days (range: 1-177 days). In group III, fibrous sheathing was present on all explanted valves and organized thrombi in six valves; orifice obstruction (seven valves) and restriction of bileaflet motion (three valves) were also observed. Conclusion: The use of MVR in swine as a preclinical model to evaluate the safety and performance of mechanical heart valves is limited by: (i) difficulty in maintaining safe levels of anticoagulation with warfarin, resulting in a high incidence of hemorrhagic complications; (ii) marked fibrous sheath formation and associated thrombosis; and (iii) an increased incidence of perivalvular defects, believed to result from normal somatic growth occurring in young swine. C1 Univ Minnesota, Dept Surg, Div Expt Surg, Minneapolis, MN 55455 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. NHLBI, NIH, Rockville, MD USA. RP Bianco, RW (reprint author), Univ Minnesota, Dept Surg, Div Expt Surg, Box 220 Mayo,420 Delaware St SE, Minneapolis, MN 55455 USA. NR 37 TC 19 Z9 24 U1 2 U2 2 PU I C R PUBLISHERS PI NORTHWOOD PA CRISPIN HOUSE, 12/A SOUTH APPROACH, MOOR PARK, NORTHWOOD, ENGLAND HA6 2ET SN 0966-8519 J9 J HEART VALVE DIS JI J. Heart Valve Dis. PD SEP PY 2000 VL 9 IS 5 BP 710 EP 719 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 358MB UT WOS:000089560900019 PM 11041189 ER PT J AU Domachowske, JB Bonville, CA Gao, JL Murphy, PM Easton, AJ Rosenberg, HF AF Domachowske, JB Bonville, CA Gao, JL Murphy, PM Easton, AJ Rosenberg, HF TI The chemokine macrophage-inflammatory protein-1 alpha and its receptor CCR1 control pulmonary inflammation and antiviral host defense in paramyxovirus infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; ALLERGIC AIRWAY INFLAMMATION; EOSINOPHIL CATIONIC PROTEIN; PNEUMONIA VIRUS; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; EPITHELIAL-CELLS; MESSENGER-RNA; MICE; GENE AB In this work, we explore the responses of specific gene-deleted mice to infection with the paramyxovirus pneumonia virus of mice (PVM), We have shown previously that infection of wild type mice with PVM results in pulmonary neutrophilia and eosinophilia accompanied by local production of macrophage-inflammatory protein-1 alpha (MIP-1 alpha). Here we examine the role of MIP-1 alpha in the pathogenesis of this disease using mice deficient in MIP-Io or its receptor, CCR1, The inflammatory response to PVM in MIP-1 alpha -deficient mice was minimal, with similar to 10-60 neutrophils/ml and no eosinophils detected in bronchoalveolar lavage fluid, Higher levels of infectious virus were recovered from lung tissue excised from MIP-1 alpha -deficient than from fully competent mice, suggesting that the inflammatory response limits the rate of virus replication in vivo. PVM infection of CCR1-deficient mice was also associated with attenuated Inflammation, with enhanced recovery of infectious virus, and with accelerated mortality, These results suggest that the MIP-1 alpha /CCR1-mediated acute inflammatory response protects mice by delaying the lethal sequelae of infection. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY USA. Univ Warwick, Dept Sci Biol, Coventry CV4 7AL, W Midlands, England. RP Rosenberg, HF (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N104,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 50 TC 120 Z9 122 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2000 VL 165 IS 5 BP 2677 EP 2682 PG 6 WC Immunology SC Immunology GA 390MF UT WOS:000166299300046 PM 10946298 ER PT J AU Yang, D Chen, Q Stoll, S Chen, X Howard, OMZ Oppenheim, JJ AF Yang, D Chen, Q Stoll, S Chen, X Howard, OMZ Oppenheim, JJ TI Differential regulation of responsiveness to fMLP and C5a upon dendritic cell maturation: Correlation with receptor expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID N-FORMYLPEPTIDE RECEPTOR; PLATELET-ACTIVATING-FACTOR; TUMOR-NECROSIS-FACTOR; CHEMOKINE RECEPTOR; CUTTING EDGE; IN-VITRO; TRANSENDOTHELIAL MIGRATION; INFLAMMATORY RESPONSE; DISTINCT CHEMOKINES; DOWN-REGULATION AB The trafficking of immature and mature dendritic cells (DCs) to different anatomical sites in vivo is critical for fulfilling their roles in the induction of Ag-specific immune responses, Although this process is complex and regulated by many. mediators, the capacity of DCs to migrate is predominantly dependent on the expression of particular chemotactic receptors on the surface of DCs that enable them to move along chemotactic gradients formed by the corresponding: chemokines and/or classical chemoattractants. Here we show that immature DCs (iDCs) respond to both fMLP and C5a as determined by chemotaxis and Ca2+ mobilization, whereas mature DCs (mDCs) respond to C5a, but not fMLP, Additionally, iDCs express the receptors for both fMLP and C5a at mRNA and protein levels. Upon maturation of DCs, fMLP receptor expression is almost completely absent, whereas C5a receptor mRNA and protein expression is maintained. Concomitantly, mDCs migrate chemotactically and mobilize intracellular Ca2+ in response to C5a, but not fMLP, Thus the interaction between C5a and its receptor is likely involved in the regulation of trafficking of both iDCs and mDCs, whereas fMLP mobilizes only iDCs. The differential responsiveness to fMLP and C5a of iDCs and mDCs suggests that they play different roles in the initiation of immune responses. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Mol Immunoregulat,NIH, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Oppenheim, JJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Mol Immunoregulat,NIH, Bldg 560,Room 21-89, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU NCI NIH HHS [N01-CO-56000] NR 70 TC 56 Z9 57 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 SEP 1 PY 2000 VL 165 IS 5 BP 2694 EP 2702 PG 9 WC Immunology SC Immunology GA 390MF UT WOS:000166299300048 PM 10946300 ER PT J AU Berger, AC Tang, GQ Alexander, HR Libutti, SK AF Berger, AC Tang, GQ Alexander, HR Libutti, SK TI Endothelial monocyte-activating polypeptide II, a tumor-derived cytokine that plays an important role in inflammation, apoptosis, and angiogenesis SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE tumor-host relationship; angiogenesis; inflammation; apoptosis; EMAP-II ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RECOMBINANT VACCINIA VIRUS; NECROSIS-FACTOR-ALPHA; PROCOAGULANT ACTIVITY; MICROGLIAL CELLS; HUMAN-MELANOMA; EMAP-II; EXPRESSION; INTERLEUKIN-1-BETA; NEURITIS AB The interactions between a tumor and its surrounding environment are complex and characterized by a variety of factors. Tumors produce a number of proteins that enable them to recruit a vascular supply, invade into surrounding tissues, and metastasize to distant sites. The host, in turn, responds to these signals by producing its own repertoire of molecules that may either assist or prevent the actions of the tumor. A thorough understanding of this relationship is critical to the development of novel anti-cancer therapies. The turner-derived cytokine endothelial monocyte-activating polypeptide II (EMAP-II) has profound effects, on the tumor as well as on host response. These effects target the inflammatory cascade as well as the processes involved in angiogenesis, In this review the authors describe the current understanding of the role of EMAP-II in inflammation, apoptosis, and angiogenesis and use this molecule to illustrate the complex interactions that occur in the tumor microenvironment. C1 NCI, Metab Sect, Surg Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), Bldg 10,Room 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 39 Z9 45 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD SEP-OCT PY 2000 VL 23 IS 5 BP 519 EP 527 DI 10.1097/00002371-200009000-00002 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 350NN UT WOS:000089108100002 PM 11001545 ER PT J AU Fritsch, M Rosenberg, SA Duray, PH AF Fritsch, M Rosenberg, SA Duray, PH TI Immunohistologic responses within dermal metastatic melanoma lesions of patients treated with a synthetic peptide vaccine SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE melanoma; synthetic peptide vaccine; CD8(+) T-cell infiltrate ID TUMOR-INFILTRATING LYMPHOCYTES; II ANTIGEN EXPRESSION; MALIGNANT MELANOMAS; GAMMA-INTERFERON; T-LYMPHOCYTES; CELLS; INTERLEUKIN-2; KERATINOCYTES; IMMUNOTHERAPY; MECHANISMS AB Three patients with dermal metastatic melanoma lesions responding to a synthetic peptide vaccine (g209-2M) derived from the sequence of gp100 melanoma associated antigen, along with either IL-2 or granulocyte-monocyte colony-stimulating factor were studied to characterize the immunologic response occurring within and around the lesions during therapy. Standard immunocytochemical techniques were used to study the T-cell response (CD3, CD4, and CD8), the B-cell response (CD20), and the expression of class II major histocompatibility complex (HLA-DR) antigens. Between 40 and 65 days after the initiation of vaccine therapy (more than 3 weeks after the second dose of vaccine), the gross tumor size decreased and the tumors from all three patients showed substantial histologic regression associated with increased number rs of tumor-infiltrating, lymphocytes and melanophages. The increased lesional tumor-infiltrating lymphocytes consisted of CD3(+) T cells and very few CD20(+) B cells. In two of the three patients, the T-cell infiltrate occurring during the initial tumor regression consisted predominantly of CD8(+) cells. The number of perivascular T cells surrounding small vessels adjacent to melanoma lesions also increased during the time of peak histologic tumor regression. Also during the course of vaccine therapy, the expression of HLA-DR by vascular endothelial cells of the small vessels adjacent to lesions increased in all three patients, and elevated endothelial expression of HLA-DR was maintained in two of the three patients. These results show that patients with metastatic melanoma, who responded to melanoma vaccine therapy, had a predominantly CD8(+) T-cell infiltrate associated with a loss of tumor cells. As the tumor cells diminished, they were replaced by heavily pigmented melanophages. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Duray, PH (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N212,10 Ctr Dr, Bethesda, MD 20892 USA. NR 38 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD SEP-OCT PY 2000 VL 23 IS 5 BP 557 EP 569 DI 10.1097/00002371-200009000-00006 PG 13 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 350NN UT WOS:000089108100006 PM 11001549 ER PT J AU Naficy, AB Rao, MR Holmes, JL Abu-Elyazeed, R Savarino, SJ Wierzba, TF Frenck, RW Monroe, SS Glass, RI Clemens, JD AF Naficy, AB Rao, MR Holmes, JL Abu-Elyazeed, R Savarino, SJ Wierzba, TF Frenck, RW Monroe, SS Glass, RI Clemens, JD TI Astrovirus diarrhea in Egyptian children SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID GASTROENTERITIS; PREVALENCE; SEROTYPES; TYPE-1; SEROPREVALENCE; ANTIBODIES; INFECTION; LONDON AB This study describes the epidemiology of astrovirus diarrhea among a population-based cohort of 397 children aged <3 years residing in rural Egypt from 1995 to 1998. The age-specific incidence rates of astrovirus diarrheal episodes per person-year were 0.38 for infants aged <6 months, 0.40 for those aged 6-11 months, 0.16 for those aged 12-23 months, and 0.05 for those aged 24-35 months. The overall incidence rate of astrovirus diarrhea was the same as that of rotavirus diarrhea, 0.19 episodes per person-year. Astrovirus infection was pathogenic and associated with severe dehydration in 17% of the cases. The most frequent serotype was HAstV-1, and, in order of decreasing frequency, HAstV-5, HAstV-8 and HAstV-3, HAstV-6, HAstV-4, and HAstV-2. In determining whether astrovirus diarrhea was associated with a reduced incidence of subsequent disease, there was evidence to suggest HAstV-1 homotypic immunity but not heterotypic immunity. Because we observed 38% of the incidence of astrovirus diarrhea to occur in infants aged <6 months, a candidate astrovirus vaccine would have to confer immunity very early in life. C1 NICHHD, Pediat Infect Dis & Vaccines Sect, Epidemiol Branch, NIH, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, Viral Gastroenteritis Sect, Resp & enter Viruses Branch, Natl Ctr Infect Dis, Atlanta, GA USA. USN, Med Res Unit 3, Cairo, Egypt. Int Vaccine Inst, Seoul, South Korea. RP Naficy, AB (reprint author), NICHHD, Pediat Infect Dis & Vaccines Sect, Epidemiol Branch, NIH, Rm 7B03,6100 Execut Blvd, Rockville, MD 20852 USA. OI Monroe, Stephan/0000-0002-5424-716X FU NICHD NIH HHS [Y1HD0026-01] NR 26 TC 44 Z9 46 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP PY 2000 VL 182 IS 3 BP 685 EP 690 DI 10.1086/315763 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 355LH UT WOS:000089386800006 PM 10950760 ER PT J AU Ray, SC Arthur, RR Carella, A Bukh, J Thomas, DL AF Ray, SC Arthur, RR Carella, A Bukh, J Thomas, DL TI Genetic epidemiology of hepatitis C virus throughout Egypt SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th International Meeting on Hepatitis C Virus and Related Viruses CY JUN 25-28, 1998 CL VENICE, ITALY ID CHRONIC LIVER-DISEASE; ENTIRE NUCLEOTIDE-SEQUENCE; 5' NONCODING REGION; NON-B HEPATITIS; BLOOD-DONORS; PHYLOGENETIC ANALYSIS; PREDOMINANT GENOTYPE; ADDITIONAL SUBTYPES; HIGH SEROPREVALENCE; VIRAL GENOTYPES AB Hepatitis C virus (HCV) infection is a major health problem in Egypt, where the seroprevalence is 10-20-fold higher than that in the United States. To characterize the HCV genotype distribution and concordance of genotype assessments on the basis of multiple genomic regions, specimens were obtained from blood donors in 15 geographically diverse governorates throughout Egypt. The 5' noncoding, core/E1, and NS5B regions were amplified by reverse transcription-polymerase chain reaction and analyzed by both restriction fragment length polymorphism (RFLP) and phylogenetic tree construction. For the 5' noncoding region, 122 (64%) of 190 specimens were amplified and analyzed by RFLP: 111 (91%) were genotype 4, 1 (1%) was genotype 1a, 1 (1%) was genotype 1b, and 9 (7%) could not be typed. Phylogenetic analyses of the core/E1 and NS5B regions confirmed the genotype 4 preponderance and revealed evidence of 3 new subtypes, Analysis of genetic distance between isolates was consistent with the introduction of multiple virus strains 75-140 years ago, and no clustering was detected within geographic regions, suggesting widespread dispersion at some time since then. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. NIAID, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. WHO, CH-1211 Geneva, Switzerland. RP Ray, SC (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, 720 Rutland Ave,Ross 1159, Baltimore, MD 21205 USA. RI Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU NCI NIH HHS [CO56000] NR 75 TC 216 Z9 228 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP PY 2000 VL 182 IS 3 BP 698 EP 707 DI 10.1086/315786 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 355LH UT WOS:000089386800008 PM 10950762 ER PT J AU Marques, AR Weir, SC Fahle, GA Fischer, SH AF Marques, AR Weir, SC Fahle, GA Fischer, SH TI Lack of evidence of Borrelia involvement in Alzheimer's disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Marques, AR (reprint author), Bldg 10,Room 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. NR 8 TC 16 Z9 16 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP PY 2000 VL 182 IS 3 BP 1006 EP 1007 DI 10.1086/315792 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 355LH UT WOS:000089386800056 PM 10950810 ER PT J AU Keusch, GT AF Keusch, GT TI The National Institutes of Health agenda for international research in micronutrient nutrition and infection interactions SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Workshop on Micronutrients and Infectious Diseases CY SEP 16-17, 1999 CL BETHESDA, MARYLAND SP Infectious Dis Soc Amer, Natl Inst Allergy & Infectious Dis, NIH, Off Dietary Supplements AB Nutrition is a central public health concern in the twenty-first century. Previous international research in nutrition was primarily descriptive epidemiology and included large-scale intervention trials. There has been insufficient attention to the mechanisms by which nutrient supplements appear to reduce mortality and little specificity in application and delineation of the forms of a specific nutrient to maximize benefits and minimize adverse affects and on the effect of nutrient combinations. After the dramatic success of the green revolution, agricultural research support was reduced despite an expanding world population and an increasing need for agricultural products. The potential of molecular genetics to improve food quality, specific nutrient content, and yield and disease resistance has just begun to be explored. In addition, the development of edible vaccines as a way to immunize a greater proportion of the world's children is a highly desirable goal and is achievable with sufficient resources. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Keusch, GT (reprint author), NIH, Fogarty Int Ctr, Bldg 31,Rm B2C02, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP PY 2000 VL 182 SU 1 BP S139 EP S142 DI 10.1086/315913 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 356AF UT WOS:000089420200022 PM 10944496 ER PT J AU Taylor, CE Higgs, ES AF Taylor, CE Higgs, ES TI Micronutrients and infectious diseases: Thoughts on integration of mechanistic approaches into micronutrient research SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Workshop on Micronutrients and Infectious Diseases CY SEP 16-17, 1999 CL BETHESDA, MARYLAND SP Infectious Dis Soc Amer, Natl Inst Allergy & Infectious Dis, NIH, Off Dietary Supplements ID VITAMIN-A SUPPLEMENTATION; SUSCEPTIBILITY; RESISTANCE; PATHOGENS; NUTRITION; PNEUMONIA; CHILDREN; MALARIA; PROTEIN AB Results of held and laboratory studies provide convincing evidence that micronutrient deficiencies contribute to the mortality and morbidity of infectious diseases. Despite encouraging results in large trials, understanding the mechanisms by which micronutrients contribute to the outcome of the encounter between an individual and an infectious agent requires additional hypothesis-driven research. Presumably, such understanding should lead to translational studies with targeted nutritional therapy. Although these mechanistic studies are varied and complex, they must be done systematically and should include examination of the mechanisms by which micronutrients affect host-pathogen interactions, development of appropriate animal models and reliable methods for the assessment of micronutrient levels, and translation of the results of basic research findings into clinical studies. Moving the frontiers of micronutrient research from the laboratory to the field will be challenging. However, sound scientific research should lead toward better human health. C1 NIAID, Div Microbiol & Infect Dis, Resp Dis Branch, Bethesda, MD 20892 USA. RP Taylor, CE (reprint author), NIAID, Div Microbiol & Infect Dis, Resp Dis Branch, 6700-B Rockefeller Dr,Room 3128, Bethesda, MD 20892 USA. NR 33 TC 7 Z9 7 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP PY 2000 VL 182 SU 1 BP S1 EP S4 DI 10.1086/315904 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 356AF UT WOS:000089420200002 PM 10944477 ER PT J AU Lenz, P Day, PM Lowy, DR Schiller, JT AF Lenz, P Day, PM Lowy, DR Schiller, JT TI Papillomavirus-like particles induce phenotypic and functional maturation of dendritic cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 NCI, Lab Cellular Oncol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2000 VL 115 IS 3 BP 535 EP 535 PG 1 WC Dermatology SC Dermatology GA 350KR UT WOS:000089100300142 ER PT J AU Pfutzner, W Kolodka, TM Foster, RA Vogel, JC AF Pfutzner, W Kolodka, TM Foster, RA Vogel, JC TI Topical selection of geratinocytes transduced with the MDR gene leads to increased transgene expression in vivo SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2000 VL 115 IS 3 BP 536 EP 536 PG 1 WC Dermatology SC Dermatology GA 350KR UT WOS:000089100300150 ER PT J AU Arseven, A McDermott, MM O'Brien, E Liu, K Guralnik, JM AF Arseven, A McDermott, MM O'Brien, E Liu, K Guralnik, JM TI Does lower extremity peripheral arterial disease (PAD) predict future falling among older adult community dwellers? SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Northwestern Univ, Sch Med, Chicago, IL USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD SEP PY 2000 VL 48 IS 5 MA 201 BP 268A EP 268A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 349GW UT WOS:000089038200213 ER PT J AU McDermott, MM Greenland, P Liu, K Guralnik, J Martin, GJ Criqui, MH Pearce, W Taylor, L Schneider, J Clark, E AF McDermott, MM Greenland, P Liu, K Guralnik, J Martin, GJ Criqui, MH Pearce, W Taylor, L Schneider, J Clark, E TI The ankle brachial index is independently associated with the ability to walk for six minutes without stopping and other objective measures of lower extremity functioning. SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Northwestern Univ, Sch Med, Chicago, IL USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Northwestern Univ, Evanston Hosp, Evanston, IL 60201 USA. Columbus Hosp, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD SEP PY 2000 VL 48 IS 5 MA 200 BP 268A EP 268A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 349GW UT WOS:000089038200212 ER PT J AU Collins, FS Haseltine, WA AF Collins, FS Haseltine, WA TI Of genes and genomes: What lies between the base pairs SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Editorial Material C1 NIH, Natl Genome Res Inst, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Natl Genome Res Inst, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD SEP PY 2000 VL 48 IS 5 BP 295 EP 301 PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 349GW UT WOS:000089038200001 PM 10979234 ER PT J AU Gulson, BL Mizon, KJ Palmer, JM Korsch, MJ Patison, N Jameson, CW Donnelly, JB AF Gulson, BL Mizon, KJ Palmer, JM Korsch, MJ Patison, N Jameson, CW Donnelly, JB TI Urinary lead isotopes during pregnancy and postpartum indicate no preferential partitioning of endogenous lead into plasma SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Article ID BLOOD LEAD; MATERNAL SKELETON; CIRCULATING LEAD; EXTERNAL SOURCES; INORGANIC LEAD; RED-CELLS; BONE LEAD; MOBILIZATION; AIRBORNE; ADULTS AB We have compared lead isotopic ratios and lead concentrations in 51 matched blood and spot urine samples from 13 subjects covering the interval from before pregnancy through 180 days postpartum to evaluate whether mobilization of lead from the maternal skeleton is preferentially partitioned into plasma; we have used urine as an isotopic proxy for plasma. There was no statistically significant difference in the lead 206/lead 204 and lead 207/lead 206 ratios over pregnancy, The urine data for the postpartum period are in the opposite relationships to that predicted for a preferential partitioning hypothesis. These data provide no support for the hypothesis that lead released from the skeleton is preferentially partitioned Into plasma. C1 Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. CSIRO, Sydney, NSW, Australia. NIEHS, Res Triangle Pk, NC 27709 USA. RP Gulson, BL (reprint author), Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. RI Donnelly, John/D-1188-2009 FU NIEHS NIH HHS [N01-ES-05292] NR 26 TC 9 Z9 10 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD SEP PY 2000 VL 136 IS 3 BP 236 EP 242 DI 10.1067/mlc.2000.108751 PG 7 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 350XU UT WOS:000089127600008 PM 10985502 ER PT J AU Wahl, SM Greenwell-Wild, T Hale-Donze, H Moutsopoulos, N Orenstein, JM AF Wahl, SM Greenwell-Wild, T Hale-Donze, H Moutsopoulos, N Orenstein, JM TI Permissive factors for HIV-1 infection of macrophages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on HIV and Cells of Macrophage Lineage and Other Reservoirs CY DEC 01-04, 1999 CL DONNINI, ITALY SP Minist Univ, Inst Super Sanita, Australian Natl Ctr HIV Virol Res, Glaxo Wellcome, Bristol Myers Squibb, Merck & Co, Pharmacia Upjohn, SmithKline Beecham Int, Perkin Elmer Europe, Bechman Coulter DE Mycobacterium avium; nuclear factor kappa beta; viral replication ID IMMUNODEFICIENCY-VIRUS TYPE-1; CC-CHEMOKINE RECEPTOR-5; MONOCYTE-DERIVED MACROPHAGES; LEUKOCYTE PROTEASE INHIBITOR; MULTINUCLEATED GIANT-CELLS; HUMAN LYMPHOID-TISSUE; NECROSIS FACTOR-ALPHA; CD4(+) T-CELLS; IN-VITRO; OPPORTUNISTIC INFECTIONS AB Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. in turn, opportunistic pathogens influence target cell susceptibility to HIV-1 infection and replication. Although the advent of highly active antiretroviral therapy (HAART) has altered these sequelae, co-infections may prevail in some parts of the world and in failed HAART regimens. Moreover, immune activation as occurs in tonsil and non-infections mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between enhancement of HIV-1 infection and activation/inflammation warrant further elucidation of the factors promoting permissiveness to HIV-1 infection. Using the opportunistic pathogen Mycobacterium avium as an in vitro model, we demonstrated that co-infection facilitated HIV-1 infection of monocyte-macrophages by multiple pathways. M. avium activated NF-kappa B, the downstream consequences of which included augmented expression of tumor necrosis factor alpha and CCR5 receptors, both permissive for sustaining HIV-1 infection. Pronounced viral replication in lymph nodes co-infected with M. avium and HIV-1 paralleled these in vitro findings. Furthermore, reduction in viral burden is associated with treatment of infected or inflamed tissues, underscoring the link between immune activation and viral replication. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, 30 Convent Dr,MSC 4352,Bldg 30,Room 332, Bethesda, MD 20892 USA. NR 80 TC 27 Z9 27 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 SEP PY 2000 VL 68 IS 3 BP 303 EP 310 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 352FA UT WOS:000089202800002 PM 10985244 ER PT J AU Lathey, JL Brambilla, D Goodenow, MM Nokta, M Rasheed, S Siwak, EB Bremer, JW Huang, DD Yi, YJ Reichelderfer, PS Collman, RG AF Lathey, JL Brambilla, D Goodenow, MM Nokta, M Rasheed, S Siwak, EB Bremer, JW Huang, DD Yi, YJ Reichelderfer, PS Collman, RG TI Co-receptor usage was more predictive than NSI/SI phenotype for HIV replication in macrophages: is NSI/SI phenotyping sufficient? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on HIV and Cells of Macrophage Lineage and Other Reservoirs CY DEC 01-04, 1999 CL DONNINI, ITALY SP Minist Univ, Inst Super Sanita, Australian Natl Ctr HIV Virol Res, Glaxo Wellcome, Bristol Myers Squibb, Merck & Co, Pharmacia Upjohn, SmithKline Beecham Int, Perkin Elmer Europe, Bechman Coulter DE macrophage tropism; viral phenotype; HIV co-receptors; HIV replication kinetics ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 HIV-1; FUNCTIONAL CORECEPTOR; CHEMOKINE RECEPTORS; DISEASE PROGRESSION; CELL DECLINE; INFECTION; TRANSMISSION; VARIANTS; CXCR4 AB A monocyte-derived macrophage (MDM) culture assay was used to define the replication culture assay was used to define the replication kinetics of HN isolates. Ten-day-old MDMs were infected with HIV, Supernatants were collected and assayed for HIV p24 on days 3, 7, 10, and 14 post-infection (PI). In this assay, SF162 (macrophage tropic, NSI) produced increasing amounts of HIV p24 antigen. with increasing time in culture. BRU (nonmacrophage tropic, SI) infection resulted in low levels of HIV p24 antigen with no increase in production during the culture period. A panel of 12 clinical isolates was evaluated. All isolates produced detectable levels of HIV p24 antigen in MDMs. However, the NSI viruses had significantly higher log(10) HIV p24 antigen values at all times PI (P < 0.01). Co-receptor usage was determined for all 12 isolates (8 NSI and 4 SI). All SI isolates used CXCR4 for entry; two used CXCR4 only, one used CXCR4, CCR5, and CCR3, and one was a mixture of two isolates using CXCR4 and CCR5. None of the NSI viruses used CXCR4 for entry. All used CCR5 as their predominant coreceptor. Of the eight NSI isolates, three used CCR5 only, two used CCR5 and CCR2b, one used CCR5 and CCR3, and one used CCR5, CCR3, and CCR2b, Log(10) HIV p24 antigen production on day 14 PI for viruses that used CCR5+CCR3 (3.19 + 1.40) was greater than for viruses that used CCR5+CCR2b (3.22 + 1.55) or CCR5 (3.32 + 1.49), and all were greater than those that used CXCR4 only (1.69 + 0.28), regardless of SI phenotype (P < 0.05). Thus, in these primary isolates, macrophage tropism and replication kinetics were closely linked to CCR5 utilization, whereas SI capacity was closely linked to CXCR4 utilization, Furthermore, viruses, which could use CCRS and CCR3 for entry, had a replication advantage in macrophages, regardless of SI phenotype. C1 Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Florida, Dept Pathol, Gainesville, FL 32611 USA. Univ Texas, Med Branch, Dept Internal Med, Galveston, TX 77550 USA. Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA. Baylor Coll Med, Dept Otorhinolaryngol & Communicat Sci, Houston, TX 77030 USA. Rush Med Coll, Dept Immunol Microbiol, Chicago, IL 60612 USA. Univ Penn, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Lathey, JL (reprint author), Univ Calif San Diego, Dept Pediat, 9500 Gilman Dr 0672, La Jolla, CA 92093 USA. FU NIAID NIH HHS [N0-AI-35712, N0-AI-85354]; NICHD NIH HHS [HD-32259] NR 26 TC 16 Z9 16 U1 0 U2 2 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 SEP PY 2000 VL 68 IS 3 BP 324 EP 330 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 352FA UT WOS:000089202800005 PM 10985247 ER PT J AU Ribeiro, JMC Charlab, R Rowton, ED Cupp, EW AF Ribeiro, JMC Charlab, R Rowton, ED Cupp, EW TI Simulium vittatum (Diptera : Simuliidae) and Lutzomyia longipalpis (Diptera : Psychodidae) salivary gland hyaluronidase activity SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Simulium vittatum; Phlebotomus papatasi; salivary glands; hyaluronidase; hematophagy; blood feeding ID VESICULAR STOMATITIS; TISSUE INVASION; MACROPHAGES; SPERM AB Hyaluronidase activity in the salivary gland homogenates of Simulium vittatum (Zetterstedt) is described, and its optimal pH determined. Salivary activity was reduced significantly after a blood meal, indicating that it was secreted after blood feeding. Phlebotomus papatasi (Scopoli) also exhibited salivary hyaluronidase activity. These results indicate that hematophagous pool feeding insects may secrete this enzyme to help the spread of salivary antihemostatic agents in the vicinity of the feeding lesion, and perhaps to increase the size of the feeding lesion itself. Additionally this enzyme may affect local host immune reactions and promote arboviral transmission. C1 NIAID, Sect Med Entomol, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. Auburn Univ, Dept Entomol, Auburn, AL 36849 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Med Entomol, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr,MSC-0425, Bethesda, MD 20892 USA. RI Rowton, Edgar/A-4474-2012; Rowton, Edgar/A-1975-2011; OI Rowton, Edgar/0000-0002-1979-1485; Ribeiro, Jose/0000-0002-9107-0818 NR 23 TC 30 Z9 31 U1 0 U2 1 PU ENTOMOL SOC AMER PI LANHAM PA 9301 ANNAPOLIS RD, LANHAM, MD 20706 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD SEP PY 2000 VL 37 IS 5 BP 743 EP 747 DI 10.1603/0022-2585-37.5.743 PG 5 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 359RJ UT WOS:000089625600015 PM 11004788 ER PT J AU Yamamoto, T Ninomiya, H Matsumoto, M Ohta, Y Nanba, E Tsutsumi, Y Yamakawa, K Millat, G Vanier, MT Pentchev, PG Ohno, K AF Yamamoto, T Ninomiya, H Matsumoto, M Ohta, Y Nanba, E Tsutsumi, Y Yamakawa, K Millat, G Vanier, MT Pentchev, PG Ohno, K TI Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts SO JOURNAL OF MEDICAL GENETICS LA English DT Letter ID MUTATIONS; GENE; NIEMANN-PICK-C1-DISEASE; DOMAIN C1 Tottori Univ, Ctr Gene Res, Yonago, Tottori 6838503, Japan. Tottori Univ, Fac Med, Sch Life Sci, Dept Neurobiol, Yonago, Tottori 6838503, Japan. RIKEN, Brain Sci Inst, Neurogenet Lab, Wako, Saitama 3510198, Japan. Lyon Sud Med Sch, INSERM, U189, F-69921 Oullins, France. Lyon Sud Hosp, Fdn Gillet Merieux, F-69921 Oullins, France. NINDS, NIH, Bethesda, MD 20892 USA. RP Yamamoto, T (reprint author), Tottori Univ, Ctr Gene Res, 86 Nishi Machi, Yonago, Tottori 6838503, Japan. RI Yamakawa, Kazuhiro/N-5050-2015 NR 19 TC 41 Z9 45 U1 0 U2 4 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 IS 9 BP 707 EP 711 DI 10.1136/jmg.37.9.707 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 353WQ UT WOS:000089298800015 PM 11182931 ER PT J AU Biesecker, BB McInerney, A Fost, N Green, M AF Biesecker, BB McInerney, A Fost, N Green, M TI Outcomes of a randomised trial on the use of a CD-ROM program on breast cancer genetics: Client knowledge, preferences and intent to undergo BRCA1/2 testing SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIH, NHGRI, Med Genet Branch, Bethesda, MD USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Humanities, Hershey, PA 17033 USA. NR 0 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 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 SU 2 MA P6 BP A2 EP A2 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 355GX UT WOS:000089378900007 ER PT J AU Biesecker, BB Peters, KF Francomano, CA AF Biesecker, BB Peters, KF Francomano, CA TI Living with Marfan syndrome: Perceptions of the condition and its management SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Penn State Univ, Ctr Dev & Hlth Genet, Dept Biobehav Hlth, University Pk, PA 16802 USA. NHGRI, Med Genet Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 SU 2 MA P5 BP A1 EP A2 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 355GX UT WOS:000089378900006 ER PT J AU Collins, F AF Collins, F TI Medical and societal consequences of the human genome project SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NHGRI, NIH, Bethesda, MD USA. NR 0 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 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 SU 1 MA SP62 BP S32 EP S32 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 355GW UT WOS:000089378800061 ER PT J AU Honorio, S Agathanggelou, A Macartney, D Gordon, K Walker, RA Maher, ER Minna, JD Lerman, MI Latif, F AF Honorio, S Agathanggelou, A Macartney, D Gordon, K Walker, RA Maher, ER Minna, JD Lerman, MI Latif, F TI Characterisation of candidate breast tumour suppressor genes located at 3p21.3 SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Univ Birmingham, Sch Med, Sect Med & Mol Genet, Dept Paediat & Child Hlth, Birmingham B15 2TT, W Midlands, England. Univ Leicester, Leicester, Leics, England. Univ Texas, SW Med Ctr, Dallas, TX USA. Natl Canc Inst, Bethesda, MD USA. NR 0 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 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 SU 1 MA 125 BP S41 EP S41 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 355GW UT WOS:000089378800086 ER EF