FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ballantyne, CM Hoogeveen, RC Bang, HJ Coresh, J Folsom, AR Sharrett, AR Wu, KK Myerson, M Chambless, LE Boerwinkle, E AF Ballantyne, CM Hoogeveen, RC Bang, HJ Coresh, J Folsom, AR Sharrett, AR Wu, KK Myerson, M Chambless, LE Boerwinkle, E TI Lipoprotein-associated phospholipase A(2), high-sensitivity C-reactive protein, and risk for ischemic stroke in middle-aged men and women in the atherosclerosis risk in communities study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Baylor Coll Med, Houston, TX 77030 USA. Univ N Carolina, Chapel Hill, NC USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Minnesota, Minneapolis, MN USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. RI Ballantyne, Christie/A-6599-2008 NR 0 TC 5 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 2979 BP 641 EP 641 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503430 ER PT J AU Yanek, LR Becker, DM Moy, TF Faraday, N Reynolds, SS Hasan, AA Becker, LC AF Yanek, LR Becker, DM Moy, TF Faraday, N Reynolds, SS Hasan, AA Becker, LC TI Differences in platelet aggregation using PFA-100 SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3032 BP 653 EP 653 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503481 ER PT J AU Herzog, CA Blaney, M Frederick, P Eggers, P AF Herzog, CA Blaney, M Frederick, P Eggers, P TI Renal failure and acute myocardial infarction: The spectrum of clinical, characteristics in dialysis patients, chronic renal insufficiency, and nonrenal patients: A collaborative project of the United States Renal Data System (USRDS)/NIH and the National Registry of Myocardial Infarction (NRMI) SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 USRDS, Minneapolis Med Fdn, Cardiovasc Special Studies Ctr, Minneapolis, MN USA. Genentech Inc, San Francisco, CA 94080 USA. Ovat Res Grp, Seattle, WA USA. Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3062 BP 660 EP 660 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503511 ER PT J AU Ross, AC Yanek, LR Faraday, N White, LW Moy, TF Hasan, AA Becker, DM AF Ross, AC Yanek, LR Faraday, N White, LW Moy, TF Hasan, AA Becker, DM TI The prevalence of side effects with daily low-dose (81 mg) preventive aspirin use SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3084 BP 665 EP 665 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503533 ER PT J AU Sachdev, V Padmanabhan, S Sidenko, S Aletras, AH Shizukuda, Y Brenneman, CL Lie, GR Vincent, P Arai, AE AF Sachdev, V Padmanabhan, S Sidenko, S Aletras, AH Shizukuda, Y Brenneman, CL Lie, GR Vincent, P Arai, AE TI Myocardial strain decreases with transmurality of infarction: An echo strain and MRI correlation study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Natl Inst Hlth, Bethesda, MD USA. GE Healthcare, Milwaukee, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3130 BP 675 EP 676 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503579 ER PT J AU Najjar, SS Scuteri, A Shetty, V Muller, DC Wright, JG Ferrucci, L Spurgeon, HP Fleg, JL Lakatta, EG AF Najjar, SS Scuteri, A Shetty, V Muller, DC Wright, JG Ferrucci, L Spurgeon, HP Fleg, JL Lakatta, EG TI Arterial stiffness predicts the development of hypertension in younger normotensive adults: The Baltimore Longitudinal Study of Aging SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NIA, Baltimore, MD 21224 USA. Inst Nazl Ricovero & Cura Anziani, Rome, Italy. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3155 BP 681 EP 681 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503604 ER PT J AU Raval, AN Karmarkar, PV Guttman, MA Ozturk, C DeSilva, R Aviles, RJ McVeigh, ER Atalar, E Lederman, RJ AF Raval, AN Karmarkar, PV Guttman, MA Ozturk, C DeSilva, R Aviles, RJ McVeigh, ER Atalar, E Lederman, RJ TI Interactive real-time magnetic resonance-guided atrial septal puncture and atrial balloon septostomy are feasible in swine SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RI Atalar, Ergin/D-3184-2012; Ozturk, Cengizhan/A-6177-2016 OI Atalar, Ergin/0000-0002-6874-6103; Ozturk, Cengizhan/0000-0002-6966-0774 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3199 BP 691 EP 691 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503648 ER PT J AU Faraday, N Becker, DM Herrera-Galeano, JE Fallin, MD Yanek, LR Robarts, P McFillin, A Chen, LP Hasan, AA Becker, LC AF Faraday, N Becker, DM Herrera-Galeano, JE Fallin, MD Yanek, LR Robarts, P McFillin, A Chen, LP Hasan, AA Becker, LC TI High-throughput screening identifies genetic variants associated with variability in platelet function SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3329 BP 719 EP 719 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503777 ER PT J AU Einhorn, PT Davis, BR Piller, LB Simpson, LM Kostis, JB Levy, D Massie, BM Nwachuku, C Black, HR Cushman, WC AF Einhorn, PT Davis, BR Piller, LB Simpson, LM Kostis, JB Levy, D Massie, BM Nwachuku, C Black, HR Cushman, WC TI The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT) heart failure (HF) validation study: Clinical presentation of hospitalized HF events and subsequent mortality rates SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. NHLBI, Framingham, MA USA. VA Med Ctr, San Francisco, CA USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. VA Med Ctr, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3382 BP 731 EP 731 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783503830 ER PT J AU Arant, CB Wessel, TR Johnson, BD Reis, SE Sharaf, BL Kerensky, RA von Mering, G Pauly, DF Handberg, E Sopko, G Merz, CNB Pepine, CJ AF Arant, CB Wessel, TR Johnson, BD Reis, SE Sharaf, BL Kerensky, RA von Mering, G Pauly, DF Handberg, E Sopko, G Merz, CNB Pepine, CJ TI A novel cardiovascular risk score for women with suspected myocardial ischemia: A report from the NHLBI-sponsored WISE study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ Florida, Coll Med, Gainesville, FL USA. Univ Pittsburgh, Data Coordinating Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Rhode Isl Hosp, Providence, RI USA. NHLBI, NIH, Bethesda, MD USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RI Reis, Steven/J-3957-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3441 BP 744 EP 744 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504024 ER PT J AU Fox, CS Parise, H Vasan, RS Larson, MG O'Donnell, CJ D'Agostino, RB Keaney, JF Benjamin, EJ AF Fox, CS Parise, H Vasan, RS Larson, MG O'Donnell, CJ D'Agostino, RB Keaney, JF Benjamin, EJ TI Novel risk factors for valvular calcification: the role of inflammation SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3444 BP 744 EP 744 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504027 ER PT J AU Murabito, JM Nam, BH D'Agostino, RB Lloyd-Jones, DM Wang, TJ Wilson, PW O'Donnell, CJ AF Murabito, JM Nam, BH D'Agostino, RB Lloyd-Jones, DM Wang, TJ Wilson, PW O'Donnell, CJ TI Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: The Framingham Offspring Study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Boston Univ, Sch Med, Boston, MA 02215 USA. Northwestern Univ, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NHLBI, Bethesda, MD 20892 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3527 BP 764 EP 764 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504109 ER PT J AU Butler, J Zhu, YW Vaughan, D Figaro, K Newman, A Goodpaster, B Ding, JZ Bauer, D Holvoet, P Harris, T de Rekeneire, N Rodondi, N Rubin, S Kritchevsky, S AF Butler, J Zhu, YW Vaughan, D Figaro, K Newman, A Goodpaster, B Ding, JZ Bauer, D Holvoet, P Harris, T de Rekeneire, N Rodondi, N Rubin, S Kritchevsky, S CA Hlth ABC Study TI Does metabolic syndrome predict cardiovascular risk in the elderly? SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Vanderbilt Univ, Nashville, TN USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Catholic Univ Louvain, B-3000 Louvain, Belgium. Wake Forest Univ, Winston Salem, NC 27109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3566 BP 772 EP 772 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504143 ER PT J AU Lloyd-Jones, DM Liu, K Colangelo, LA Yan, LL Klein, L Loria, CM Lewis, CE Savage, P AF Lloyd-Jones, DM Liu, K Colangelo, LA Yan, LL Klein, L Loria, CM Lewis, CE Savage, P TI Consistently stable body mass index and changes in risk factors associated with the metabolic syndrome SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Northwestern Univ, Evanston, IL 60208 USA. Univ Alabama, Birmingham, AL USA. NHLBI, Bethesda, MD 20892 USA. RI Lloyd-Jones, Donald/C-5899-2009 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3567 BP 772 EP 772 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504144 ER PT J AU Cooper, LS Appel, LJ Edinger, TP Lin, PH AF Cooper, LS Appel, LJ Edinger, TP Lin, PH TI Lifestyle interventions designed to lower blood pressure also improve serum lipids: The PREMIER trial SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3573 BP 774 EP 774 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504150 ER PT J AU Wessel, TR Arant, CB McClure, CK Johnson, BD Sharaf, BL von Mering, GO Kerensky, RA Pauly, DF Handberg, E Sopko, G Kelsey, SF Merz, NB Pepine, J AF Wessel, TR Arant, CB McClure, CK Johnson, BD Sharaf, BL von Mering, GO Kerensky, RA Pauly, DF Handberg, E Sopko, G Kelsey, SF Merz, NB Pepine, J TI Are traditional cardiovascular risk scores useful for women with suspected myocardial ischemia? A report from the women's ischemia syndrome evaluation SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ Florida, Coll Med, Gainesville, FL 32611 USA. Univ Pittsburgh, Data Coordinatig Ctr, Pittsburgh, PA 15260 USA. Rhode Isl Hosp, Providence, RI USA. NHLBI, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3620 BP 784 EP 785 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504197 ER PT J AU Kathiresan, S Benjamin, EJ Larson, MG Corey, D Keyes, MJ Mitchell, GF Levy, D Vita, JA Vasan, RS AF Kathiresan, S Benjamin, EJ Larson, MG Corey, D Keyes, MJ Mitchell, GF Levy, D Vita, JA Vasan, RS TI Relations of serum aldosterone to measures of endothelial function in the community: The Framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI Framingham Heart Study, Framingham, MA USA. Cardiovasc Engn Inc, Holliston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3659 BP 791 EP 791 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504226 ER PT J AU Bertoni, AG Feeney, P Clark, JM Yanovski, SZ Bantle, J Montgomery, B Safford, MM Haffner, SM AF Bertoni, AG Feeney, P Clark, JM Yanovski, SZ Bantle, J Montgomery, B Safford, MM Haffner, SM CA Look AHEAD Study Grp TI Degree of obesity and control of glycemia, blood pressure, and LDL cholesterol in diabetic subjects: The look AHEAD study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Wake Forest Univ, Winston Salem, NC 27109 USA. Johns Hopkins Univ, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. Univ Washington, Seattle, WA 98195 USA. Univ Alabama, Birmingham, AL USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3678 BP 795 EP 795 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504245 ER PT J AU Wasserman, BA Lai, SH Folsom, AR Cushman, M Bild, DE Sharrett, AR Bluemke, DA AF Wasserman, BA Lai, SH Folsom, AR Cushman, M Bild, DE Sharrett, AR Bluemke, DA TI Risk factor associations for the presence of a lipid core in carotid atheroma of asymptomatic individuals using high-resolution magnetic resonance imaging SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Univ Vermont, Colchester, VT USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3684 BP 797 EP 797 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504251 ER PT J AU Kuller, LH Psaty, B Arnold, A Robbins, J Tracy, R O'Leary, D Burke, G Chaves, P AF Kuller, LH Psaty, B Arnold, A Robbins, J Tracy, R O'Leary, D Burke, G Chaves, P TI Risk of coronary heart disease associated with subelinical disease among older black and white men and women in the cardiovascular health study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ Vermont, Colchester, VT USA. NHLBI, NIH, DECA, Bethesda, MD 20892 USA. Tufts New England Med Ctr, Boston, MA USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3693 BP 799 EP 799 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504260 ER PT J AU Gudnason, V Aspelund, T Thorgeirsson, G Eiriksdottir, G Sigurdsson, S Karlsdottir, G Launer, L Detrano, R Harris, T AF Gudnason, V Aspelund, T Thorgeirsson, G Eiriksdottir, G Sigurdsson, S Karlsdottir, G Launer, L Detrano, R Harris, T TI Midlife cardiovascular risk factors predict coronary calcium in older men and women, whereas concurrently measured risk factors do not: the AGES Reykjavik study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Iceland Heart Assoc, Kopavogur, Iceland. NIA, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Med Ctr, Torrance, CA 90509 USA. RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3711 BP 803 EP 803 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504278 ER PT J AU Pearte, CA Furberg, CD O'Meara, E Psaty, BM Kuller, L Powe, N Manolio, T AF Pearte, CA Furberg, CD O'Meara, E Psaty, BM Kuller, L Powe, N Manolio, T TI Long-term outcomes and their predictors after hospital discharge for MI in the elderly: The cardiovascular health study (CHS) SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Winston Salem, NC USA. Univ Washington, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3722 BP 806 EP 806 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504289 ER PT J AU Fox, CS Yang, Q Guo, CY Atwood, LD Murabito, JM Levy, D Shearman, AM Housman, DE AF Fox, CS Yang, Q Guo, CY Atwood, LD Murabito, JM Levy, D Shearman, AM Housman, DE TI Association between the estrogen receptor alpha gene variation and measures of adiposity: The framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. MIT, Cambridge, MA 02139 USA. RI Yang, Qiong/G-5438-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3726 BP 807 EP 807 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504293 ER PT J AU Fox, CS Coady, S Sorlie, PD Levy, D Meigs, JB Wilson, PW Savage, PJ AF Fox, CS Coady, S Sorlie, PD Levy, D Meigs, JB Wilson, PW Savage, PJ TI Trends in cardiovascular complications of diabetes: the Framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3746 BP 811 EP 811 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504312 ER PT J AU Kon, K Han, SH Quon, MJ Shin, MS Ahn, TH AF Kon, K Han, SH Quon, MJ Shin, MS Ahn, TH TI Additive beneficial effects of ramipril combined with sirinvastatin in the treatment of type II diabetic patients SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Gil Heart Ctr, Gachon Med Sch, Inchon, South Korea. NIH, NCCAM, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3744 BP 811 EP 811 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504310 ER PT J AU Sparks, DL Sabbagh, MN Connor, DJ Launer, LJ Petanceska, S Baxter, L Browne, P Lopez, J Wassar, D Lochhead, J Ziolwolski, C AF Sparks, DL Sabbagh, MN Connor, DJ Launer, LJ Petanceska, S Baxter, L Browne, P Lopez, J Wassar, D Lochhead, J Ziolwolski, C TI Benefits of atorvastatin in subjects with Alzheimer's disease SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Sun Hlth Res Inst, Sun City, AZ USA. NIA, Bethesda, MD 20892 USA. NYU, Nathan Klein Inst, New York, NY USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. Boswell Hosp, Sun City, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3756 BP 813 EP 813 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504322 ER PT J AU Dhingra, R Nam, BH Benjamin, EJ D'Agostino, RB Wilson, PW O'Donnell, CJ AF Dhingra, R Nam, BH Benjamin, EJ D'Agostino, RB Wilson, PW O'Donnell, CJ TI Relations of C-reactive protein to inflammatory conditions in men and women: Implications for cardiovascular disease risk prediction SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Massachusetts Gen Hosp, Framingham Heart Study, NHLBI, Boston, MA 02114 USA. Boston Univ, Med Ctr, Boston, MA USA. Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3761 BP 814 EP 814 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504326 ER PT J AU Wessel, TR Arant, CB Olson, MB Johnson, BD Sharaf, BL Reis, SE Shaw, LJ Handberg, E Sopko, G Merz, NB AF Wessel, TR Arant, CB Olson, MB Johnson, BD Sharaf, BL Reis, SE Shaw, LJ Handberg, E Sopko, G Merz, NB TI Roles of fatness and fitness as cardiovascular risk factors for women: A report from the women's ischemia syndrome evaluation SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ Florida, Coll Med, Gainesville, FL USA. Univ Pittsburgh, Data Coordinating Ctr, Pittsburgh, PA USA. Rhode Isl Hosp, Providence, RI USA. Atlanta Cardiovasc Res Inst, Atlanta, GA USA. NHLBI, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RI Reis, Steven/J-3957-2014 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S BP 821 EP 821 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504357 ER PT J AU North, KE Zeldin, DC Mosher, MJ Avery, CL Coresh, J Boerwinkle, E Lee, CR Couper, D Bray, MS AF North, KE Zeldin, DC Mosher, MJ Avery, CL Coresh, J Boerwinkle, E Lee, CR Couper, D Bray, MS TI Enclothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism association with coronary heart disease risk is modified by smoking: The atherosclerosis risk in communities study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ N Carolina, Chapel Hill, NC USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Texas, Hlth Sci Ctr, Houston, TX 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3800 BP 823 EP 823 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504365 ER PT J AU North, K Almasy, L Fabsitz, RR Goring, HG Cole, S Diego, VP Laston, S Cantu, T Howard, BV Lee, ET Best, LG MacCluer, JW AF North, K Almasy, L Fabsitz, RR Goring, HG Cole, S Diego, VP Laston, S Cantu, T Howard, BV Lee, ET Best, LG MacCluer, JW TI Linkage analysis of LDL cholesterol in American Indian populations: The strong heart family study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ N Carolina, Chapel Hill, NC USA. SW Fdn Biomed Res, San Antonio, TX 78284 USA. NHLBI, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. Missouri Breaks Ind Res Inc, Timber Lake, SD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S BP 827 EP 827 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504382 ER PT J AU Yan, LL Liu, K Matthews, KA Daviglus, ML Iribarren, C Loria, C Kanaya, A Carnethon, MR Kiefe, CI AF Yan, LL Liu, K Matthews, KA Daviglus, ML Iribarren, C Loria, C Kanaya, A Carnethon, MR Kiefe, CI TI Time urgency/impatience and development of metabolic syndrome: The CARDIA study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Northwestern Univ, Chicago, IL 60611 USA. Univ Pittsburgh, Pittsburgh, PA USA. Kaiser Permanente, Oakland, CA USA. NHLBI, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Alabama, Birmingham, AL 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3836 BP 831 EP 831 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504401 ER PT J AU Xu, JQ Lee, ET Best, L Fabsitz, RR Howard, BV AF Xu, JQ Lee, ET Best, L Fabsitz, RR Howard, BV TI Alburninuria and cardiovascular disease mortality in diabetic American indians: The strong heart study SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 Univ Oklahoma, Oklahoma City, OK USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. NHLBI, Bethesda, MD 20892 USA. Medstat Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3840 BP 832 EP 832 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504405 ER PT J AU Miles, RR Detrano, R Reaven, PD Hayden, CT Pring, J Savage, PJ Hanson, RL Knowler, WC Kralkoff, J AF Miles, RR Detrano, R Reaven, PD Hayden, CT Pring, J Savage, PJ Hanson, RL Knowler, WC Kralkoff, J TI Coronary calcium in pima Indians with childhood- and young adult-onset type 2 diabetes SO CIRCULATION LA English DT Meeting Abstract CT 77th Scientific Meeting of the American-Heart-Association CY NOV 07-10, 2004 CL New Orleans, LA SP Amer Heart Assoc C1 NIDDK, Phoenix, AZ USA. Harbor UCLA Med Ctr, Torrance, CA 90509 USA. Inst Educ, Torrance, CA 90509 USA. Carl T Hayden VA Med Ctr, Phoenix, AZ USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2004 VL 110 IS 17 SU S MA 3845 BP 833 EP 833 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866OT UT WOS:000224783504410 ER PT J AU Singleton, A AF Singleton, A TI What does PINK1 mean for Parkinson diseases? SO NEUROLOGY LA English DT Editorial Material ID PARK6-LINKED PARKINSONISM; ALPHA-SYNUCLEIN; MUTATIONS; FAMILIES C1 NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. RP Singleton, A (reprint author), NIA, Mol Genet Sect, NIH, Room 1A1015 MSC 3707,35 Lincoln Dr,Porter Neurosc, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 NR 10 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 26 PY 2004 VL 63 IS 8 BP 1350 EP 1351 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 865VN UT WOS:000224732400003 PM 15505146 ER PT J AU Gaillard, WD Balsamo, L Xu, B McKinney, C Papero, PH Weinstein, S Conry, J Pearl, PL Sachs, B Sato, S Vezina, LG Frattali, C Theodore, WH AF Gaillard, WD Balsamo, L Xu, B McKinney, C Papero, PH Weinstein, S Conry, J Pearl, PL Sachs, B Sato, S Vezina, LG Frattali, C Theodore, WH TI fMRI language task panel improves determination of language dominance SO NEUROLOGY LA English DT Article ID FUNCTIONAL MRI; WADA TEST; AUDITORY COMPREHENSION; ELECTROCORTICAL STIMULATION; INDIVIDUAL SUBJECTS; VERBAL FLUENCY; BRAIN-LESIONS; CHILDREN; LATERALIZATION; LOCALIZATION AB Background: fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). Objective: To determine whether a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance. Methods: Twenty-six patients age 12 to 56 years, predominantly with temporal lobe epilepsy, were studied using whole-brain 1.5 T fMRI (echo planar imaging, blood oxygenation level-dependent) with three task categories using a block design: verbal fluency, reading comprehension, and auditory comprehension. fMRI t maps were visually rated at three thresholds. All patients had assessment of language lateralization by IAT. Results: fMRI showed left dominance in 21 patients, right dominance in 2, and bilateral activation in 2; raters disagreed over a left vs right bilateral rating in 1 patient. There was full agreement between IAT and fMRI in 21 of 25 patients ( IAT failed in 1). In three instances of partial disparity with IAT, the fMRI panel showed consistent findings across raters. Agreement between raters was excellent ( partial disagreement in only one patient); the panel of tasks was superior to any single task for interrater agreement (Cramer V 0.93 [range 0.91 to 1.0] vs 0.72 [range 0.60 to 0.86]). Conclusions: A panel of fMRI language paradigms may be more accurate for evaluating partial epilepsy patients than a single task. A panel of tasks reduces the likelihood of nondiagnostic findings, improves interrater reliability, and helps confirm language laterality. C1 George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Radiol, Washington, DC USA. NINDS, Clin Epilepsy Sect, Bethesda, MD 20892 USA. NIH, Speech Language PAthol Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Gaillard, WD (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM gaillardw@ninds.nih.gov FU NINDS NIH HHS [KO8-NS1663] NR 46 TC 131 Z9 133 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 26 PY 2004 VL 63 IS 8 BP 1403 EP 1408 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 865VN UT WOS:000224732400013 PM 15505156 ER PT J AU Nadareishvili, ZG Li, H Wright, V Maric, D Warach, S Hallenbeck, JM Dambrosia, J Barker, JL Baird, AE AF Nadareishvili, ZG Li, H Wright, V Maric, D Warach, S Hallenbeck, JM Dambrosia, J Barker, JL Baird, AE TI Elevated pro-inflammatory CD4(+)CD28(-) lymphocytes and stroke recurrence and death SO NEUROLOGY LA English DT Article ID NORTHERN MANHATTAN STROKE; ACUTE CORONARY SYNDROMES; C-REACTIVE PROTEIN; ISCHEMIC-STROKE; T-CELLS; CEREBRAL INFARCTION; MULTIPLE-SCLEROSIS; COSTIMULATION; MORTALITY; PREDICTION AB Objective: To determine if the CD4(+) CD28(-) T-cell subset is expanded in patients with recurrent stroke or death after acute ischemic stroke. This subset of the peripheral blood T-cell lymphocyte population has a strong pro-inflammatory and tissue-damaging potential. Methods: Consecutive patients within the first 48 hours of ischemic stroke were prospectively studied. Peripheral blood CD4(+) CD28(-) cells were quantified by flow cytometry. The study endpoint was recurrent stroke or death from any cause during 1 year of follow-up. Results: One hundred six patients (mean age 75.0 +/- 13.5 years; 50 women) were studied. The median CD4(+)CD28(-) cell count was 4.5% (range 0.2 to 72.2%). Twenty-seven endpoints (10 recurrent strokes and 17 deaths) occurred during follow-up. Stroke recurrence/death rates were significantly associated with increasing CD4(+)CD28(-) counts, rising from 14.2% in patients with CD4(+)CD28(-) levels of <1.0 to 48.1% for those with CD4(+)CD28(-) counts of <8.0% (p = 0.003, Cochran linear test of trend). Higher CD4(+)CD28(-) counts were also present in patients with a history of prior stroke (p = 0.03). After adjustment for age, admission NIH Stroke Scale score, prior stroke, and atrial fibrillation, CD4(+)CD28(-) counts of <8.0% were associated with a cumulative hazard ratio of 5.81 (95% CI: 1.58 to 21.32) for stroke recurrence or death. Conclusions: Rising counts of circulating CD4(+)CD28(-) cells are associated with an increasing risk of stroke recurrence and death, in addition to an observed association with prior stroke. Expansion of this T-cell subset presumably represents a biomarker and possibly a contributory pathogenic mechanism of recurrent stroke and death after ischemic stroke. C1 NINDS, Stroke Neurosci Unit, NIH, Bethesda, MD 20892 USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Baird, AE (reprint author), NINDS, Stroke Neurosci Unit, NIH, 10 Ctr Dr,MSC 1294,Rm 3N258, Bethesda, MD 20892 USA. EM bairda@ninds.nih.gov NR 32 TC 41 Z9 46 U1 0 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 OCT 26 PY 2004 VL 63 IS 8 BP 1446 EP 1451 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 865VN UT WOS:000224732400020 PM 15505163 ER PT J AU Goldstein, DS Pechnik, S Moak, J Eldadah, B AF Goldstein, DS Pechnik, S Moak, J Eldadah, B TI Painful sweating SO NEUROLOGY LA English DT Article ID ISOLATED RAT SKIN; TOPICAL GLYCOPYRROLATE; IN-VITRO; SYMPATHECTOMY; RELEASE AB Objective: The authors report a case of spontaneous and gustatory facial pain and sweating. Methods: The patient had frequent episodes of pain, sweating, and flushing bilaterally in the hairless skin of the ophthalmic and maxillary distributions of the trigeminal nerve. Gustatory stimuli ( e. g., orange juice, pickled onions) reliably evoked episodes, but episodes also frequently came on spontaneously. The problem had begun during adolescence, about the time of topical treatment and then electrocauteries for facial warts. The patient reported benefit from tricyclic antidepressants, guanethidine, and trospium chloride (an anti-cholinergic quaternary amine used in Europe for urinary urgency). There was no pain or excessive sweating in other body areas, nor pain with exercise. Results: Administration of edrophonium IV evoked pain and sweating, and ganglion blockade by IV trimethaphan eliminated pain and sweating and markedly attenuated responses to edrophonium. Trospium chloride also prevented edrophonium-induced pain and sweating. Bicycle exercise produced the same increment in forehead humidity as in a spontaneous episode but did not evoke pain. Tyramine infusion did not bring on pain or sweating, whereas iontophoretic acetylcholine administration to one cheek evoked pain and sweating bilaterally. Topical glycopyrrolate cream eliminated spontaneous, gustatory, and edrophonium-induced episodes. Conclusions: The findings indicate that facial pain and sweating can result from occupation of muscarinic cholinergic receptors after acetylcholine release from local nerves. The authors propose that after destruction of cutaneous nerves, aberrant regenerant sprouting innervates sweat glands, producing gustatory sweating as in auriculotemporal syndrome ( Frey syndrome), and innervates nociceptors, producing pain. C1 NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov NR 16 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 26 PY 2004 VL 63 IS 8 BP 1471 EP 1475 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 865VN UT WOS:000224732400024 PM 15505167 ER PT J AU Fritz, TA Hurley, JH Trinh, LB Shiloach, J Tabak, LA AF Fritz, TA Hurley, JH Trinh, LB Shiloach, J Tabak, LA TI The beginnings of mucin biosynthesis: The crystal structure of UDP-GalNAc : polypeptide alpha-N-acetylgalactosaminyltransferase-T1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glycosyltransferase; mucin ID ACETYL-D-GALACTOSAMINE; ALPHA-D-GALACTOSAMINE; N-ACETYLGALACTOSAMINYLTRANSFERASE FAMILY; O-LINKED GLYCOSYLATION; TANDEM REPEAT; SEQUENCE ALIGNMENT; LECTIN DOMAIN; IN-VIVO; GLYCOPEPTIDE; GLYCOSYLTRANSFERASES AB UDP-GaINAc:polypeptide alpha-N-acetylgalactosaminyltransferases (ppGaNTases) initiate the formation of mucin-type, O-linked glycans by catalyzing the transfer of alpha-N-acetylgalactosamine from UDP-GaINAc to Ser or Thr residues of core proteins to form the Tin antigen (GalNAc-alpha-1-O-Ser/Thr). ppGaNTases are unique among glycosyltransferases in containing a C-terminal lectin domain. We present the x-ray crystal structure of a ppGaNTase, murine ppGaNTase-T1, and show that it folds to form distinct catalytic and lectin domains. The association of the two domains forms a large cleft in the surface of the enzyme that contains a Mn2+ ion complexed by invariant D209 and H211 of the "DXH" motif and by invariant H344. Each of the three potential lectin domain carbohydrate-binding sites (alpha, beta, and gamma) is located on the active-site face of the enzyme, suggesting a mechanism by which the transferase may accommodate multiple conformations of glycosylated acceptor substrates. A model of a mucin 1 glycopepticle substrate bound to the enzyme shows that the spatial separation between the lectin alpha site and a modeled active site UDP-GaINAc is consistent with the in vitro pattern of glycosylation observed for this peptide catalyzed by ppGaNTase-T1. The structure also provides a template for the larger ppGaNTase family, and homology models of several ppGaNTase isoforms predict dramatically different surface chemistries consistent with isoform-selective acceptor substrate recognition. C1 NIDDKD, Sect Biol Chem, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Biotechnol Unit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), NIDDKD, Sect Biol Chem, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tabakl@mail.nih.gov NR 51 TC 88 Z9 92 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 OCT 26 PY 2004 VL 101 IS 43 BP 15307 EP 15312 DI 10.1073/pnas.0405657101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866OI UT WOS:000224782400008 PM 15486088 ER PT J AU Hummer, G Schotte, F Anfinrud, PA AF Hummer, G Schotte, F Anfinrud, PA TI Unveiling functional protein motions with picosecond x-ray crystallography and molecular dynamics simulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SPERM-WHALE MYOGLOBIN; CARBON-MONOXIDE; LIGAND-BINDING; CRYSTAL-STRUCTURES; MUTANT MYOGLOBIN; HEME-PROTEINS; B-STATES; CO; PHOTODISSOCIATION; NANOSECOND AB A joint analysis of all-atom molecular dynamics (MID) calculations and picosecond time-resolved x-ray structures was performed to gain single-molecule insights into mechanisms of protein function. Ensemble-averaged MD simulations of the L29F mutant of myoglobin after ligand dissociation reproduce the direction, amplitude, and time scales of crystallographically determined structural changes. This close agreement with experiments at comparable resolution in space and time validates the individual MD trajectories. From 1,700 single-molecule trajectories, we identified and structurally characterized a conformational switch that directs dissociated ligands to one of two nearby protein cavities. Subsequent ligand migration proceeds through a network of transiently interconnected internal cavities, with passage between them involving correlated protein-ligand motions. The simulations also suggest how picosecond protein motions modulate the functional dissociation of oxygen and suppress the geminate recombination of toxic carbon monoxide. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Phys Chem Lab, NIH, 5 Mem Dr, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov; anfinrud@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 43 TC 111 Z9 115 U1 0 U2 32 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 OCT 26 PY 2004 VL 101 IS 43 BP 15330 EP 15334 DI 10.1073/pnas.0405295101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866OI UT WOS:000224782400012 PM 15489270 ER PT J AU Borchers, CH Marquez, VE Schroeder, GK Short, SA Snider, MJ Speir, JP Wolfenden, R AF Borchers, CH Marquez, VE Schroeder, GK Short, SA Snider, MJ Speir, JP Wolfenden, R TI Fourier transform ion cyclotron resonance MS reveals the presence of a water molecule in an enzyme transition-state analogue complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTIDINE DEAMINASE; ESCHERICHIA-COLI; ACTIVE-SITE AB The structures of several powerful inhibitors of hydrolytic enzymes resemble that of the altered substrate in the transition state, except that a hydrogen atom replaces one substituent (typically the leaving group). To test the hypothesis that a water molecule might be present in the gap resulting from this replacement, we examined a transition-state analogue complex formed by Escherichia coli cytidine deaminase by Fourier transform ion cyclotron resonance MS in electrospray mode. Upon nebularization from aqueous solution under conditions (pH 5.6) where the enzyme is active, cytidine deaminase remains dimeric in the vapor phase. In the presence of inhibitor, the enzyme's exact mass can be used to infer the presence at each active site of zinc, 5-fluoro-3,4-dihydrouridine, and a single water molecule. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NCI, Ctr Canc Res, Med Chem Lab, Ft Detrick, MD 21702 USA. GlaxoSmithKline, Dept Gene Express & Prot Biochem, Res Triangle Pk, NC 27709 USA. Bruker Dalton, Billerica, MA 01821 USA. Coll Wooster, Dept Chem, Wooster, OH 44691 USA. RP Wolfenden, R (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM water@med.unc.edu FU NIEHS NIH HHS [ES-11997, R21 ES011997]; NIGMS NIH HHS [R01 GM018325, T32 GM008570, GM-08570, GM-18325, R37 GM018325] NR 12 TC 8 Z9 9 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 OCT 26 PY 2004 VL 101 IS 43 BP 15341 EP 15345 DI 10.1073/pnas.0406781101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866OI UT WOS:000224782400014 PM 15494437 ER PT J AU Finnegan, CM Rawat, SS Puri, A Wang, JM Ruscetti, FW Blumenthal, R AF Finnegan, CM Rawat, SS Puri, A Wang, JM Ruscetti, FW Blumenthal, R TI Ceramide, a target for antiretroviral therapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MEMBRANE CHOLESTEROL; T-LYMPHOCYTES; SERINE PALMITOYLTRANSFERASE; INDUCED APOPTOSIS; MEDIATED FUSION; HIV-1 INFECTION; LIPID RAFTS; CD4; TYPE-1 AB Studies of ceramide metabolism and function in a wide range of biological processes have revealed a role for this lipid in regulating key cellular responses. Our research on the role of sphingolipids in HIV entry has led to the hypothesis that modulation of ceramide levels in target cells affects their susceptibility to HIV infection by rearranging HIV receptors. Cellular ceramide levels were modulated by application of pharmacological agents such as N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide), by treatment with sphingomyelinase (Smase), or by exogenous addition of long-chain ceramide, and determined after metabolic incorporation of [H-3]sphingosine. Infectivity assays were performed by using a HeLa-derived indicator cell line, TZM-bl, CD4(+) lymphocytes, and monocytes. We observed a dose-dependent inhibition by 4-HPR of infection of TZM-bl cells by a broad range of HIV-1 isolates at low micromolar concentrations with an IC50 Of < 1 muM for most isolates tested. Nearly complete inhibition was seen at 5 muM, a dose that enhanced ceramide levels by 50-100%, yet was nontoxic to the cells. Treating cells with other pharmacological agents that enhanced ceramide levels, with Smase, or exogenous addition of long-chain ceramide also resulted in inhibition of HIV-1 infection. Enhancing ceramide levels in CD4(+) lymphocytes and in monocytederived macrophages with 4-HPR or Smase significantly reduced infectivity without toxicity. The minimal toxicity of normal cells exposed to 4-HPR should make the drug exceedingly suitable as an anti-HIV therapeutic. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), POB B,Bldg 469,Room 216A,Miller Dr, Frederick, MD 21702 USA. EM blumen@helix.nih.gov NR 28 TC 57 Z9 61 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 OCT 26 PY 2004 VL 101 IS 43 BP 15452 EP 15457 DI 10.1079/pnas.0402874101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866OI UT WOS:000224782400033 PM 15489273 ER PT J AU Zanuy, D Casanovas, J Aleman, C AF Zanuy, D Casanovas, J Aleman, C TI Structure and dynamics of the surfactant molecules in dodecyltrimethylammonium center dot poly(alpha,L-glutamate) self-assembled complexes SO CHEMICAL PHYSICS LA English DT Article DE molecular dynamics; self-assembled complexes; supramolecular organization; surfactant; polyelectrolyte ID OPPOSITELY CHARGED SURFACTANTS; CHLOROFORM SOLUTION; SOLID-STATE; POLY(ALPHA,L-GLUTAMATE); POLYELECTROLYTE; POLYPEPTIDES; ORGANIZATION; SIMULATIONS; SOLVENTS AB A molecular dynamics study has been carried out to investigate the conformational, structural and dynamical properties of the surfactant molecules in the dodecyltrimethylammonium(.)poly(alpha,L-glutamate) self-assembled complex. Simulations were performed in chloroform solution using eight different temperatures. Results indicate that the strong electrostatic interactions between the carboxylate groups of the polyelectrolyte and the positively charged trimethylammonium moieties, which are retained even at high temperatures, are responsible of the molecular organization and the low mobility of the surfactant molecules. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Politecn Catalunya, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. NCI Frederick, Lab Expt & Computat Biol, Ft Detrick, MD 21702 USA. Univ Lleida, Escola Univ Politecn, Dept Quim, E-25001 Lleida, Spain. RP Aleman, C (reprint author), Univ Politecn Catalunya, ETS Engn Ind Barcelona, Dept Engn Quim, Avda Diagonal 647, E-08028 Barcelona, Spain. EM zanuyd@neiferf.gov; carlos.aleman@upc.es RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178 NR 16 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD OCT 25 PY 2004 VL 305 IS 1-3 BP 85 EP 93 DI 10.1016/j.chemphys.2004.06.034 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 860DY UT WOS:000224321000009 ER PT J AU Frederikse, PH Yun, E Kao, HT Zigler, JS Sun, Q Qazi, AS AF Frederikse, PH Yun, E Kao, HT Zigler, JS Sun, Q Qazi, AS TI Synapsin and synaptic vesicle protein expression during embryonic and post-natal lens fiber cell differentiation SO MOLECULAR VISION LA English DT Article ID AMYLOID PRECURSOR PROTEIN; AXONAL-TRANSPORT; TRANSGENIC MICE; EPITHELIAL-CELLS; GENE-EXPRESSION; BOVINE LENS; RAT LENS; IN-VIVO; BETA; PHOSPHORYLATION AB Purpose: Reorganization of cytoskeleton and membrane biogenesis are dynamically coordinated during lens fiber cell differentiation and development to produce an organ with precise dimensions and optical properties. Cargo vesicle trafficking is fundamental to cell elongation and has also been implicated in degenerative disease mechanisms. Alzheimer precursor protein (AbetaPP) acts with kinesin, synapsin, and synaptic vesicle proteins to mediate cargo vesicle transport and membrane fusion in neurons. In our previous studies we demonstrated that AbetaPP is also a key element in lens fiber cell formation, and in early-onset cataract that occurs along with early-onset Alzheimer disease in Down syndrome. In the present study we examine lens expression and regulation of a complement of genes associated with cargo and synaptic vesicle transport in neurons. Methods: RT-PCR, immunoblot, and immunohistochemical methods were used to characterize expression of AbetaPP and kinesin associated motor proteins, synapsins, and synaptic vesicle proteins in mouse and rat embryonic, post-natal, and adult lenses. Phospho-specific anti-synapsin antibodies were used to determine the distributions of site-1 phosphorylated and dephosphorylated synapsin protein. Results: We demonstrate that a substantial complement of cargo and synaptic vesicle proteins involved in AbetaPP mediated vesicle transport are expressed in lenses along the anterior-posterior axis of fiber cells in embryonic and adult lenses, consistent with vesicles, actin filaments, and neuron-like arrangement of microtubules in lenses shown by others. We identify temporal regulation of synapsins I, II, and III during embryonic and post-natal lens development consistent with their roles in neurons. Regulation of vesicle cytoskeleton attachment, actin polymerization, and the capacity to stimulate cell differentiation by synapsins are governed in large part by phosphorylation at a conserved Ser9 residue (site-1). We demonstrate discrete distributions of Ser9 phospho- and dephospho-synapsins along the axial length of rapidly elongating embryonic lens fiber cells, and decreased levels of site-1 phosphorylated synapsins in adult lenses. Conclusions: The present findings demonstrate several fundamental parallels between lens and neuron vesicle trafficking cell biology and development, and suggest that more extensive AbetaPP related vesicle trafficking disease mechanisms may be shared by lens and brain. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. NYU, Sch Med, Dept Psychiat, Orangeburg, NY USA. NEI, Lab Mech Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Frederikse, PH (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, MSB H-645,185 S Orange Ave, Newark, NJ 07103 USA. EM frederph@umdnj.edu NR 58 TC 19 Z9 21 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 25 PY 2004 VL 10 IS 94 BP 794 EP 804 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 867TA UT WOS:000224863900001 PM 15529118 ER PT J AU Venn, A Bruinsma, F Werther, G Pyett, P Baird, D Jones, P Rayner, P Lumley, J AF Venn, A Bruinsma, F Werther, G Pyett, P Baird, D Jones, P Rayner, P Lumley, J TI Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility SO LANCET LA English DT Article ID SEX STEROID TREATMENT; MANAGEMENT; STATURE AB Background Treatment with oestrogen to reduce the adult height of tall girls has been available since the 1950s. We undertook a retrospective cohort study to assess the long-term effects of this treatment on fertility. Methods Eligible participants were identified from the records of Australian paediatric endocrinologists who assessed tall girls from 1959 to 1993, and from self-referrals. Individuals included girls who had received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) (treated group) and those who were assessed but not treated (untreated group). Information about reproductive history was sought by telephone interview. Findings 1432 eligible individuals were identified, of whom 1243 (87%) could be traced. Of these, 780 (63%) completed interviews: 651 were identified from endocrinologists' records, 129 were self-referred. Treated (n=371) and untreated (n=409) women were similar in socioeconomic and other characteristics. After adjustment for age, treated women were more likely to have ever tried for 12 months or more to become pregnant without success (relative risk [RR] 1.80, 95% CI 1.40-2-30); more likely to have seen a doctor because they were having difficulty becoming pregnant (RR 1.80, 1.39-2.32); and more likely to have ever taken fertility drugs (RR 2.05, 1.39-3.04). Time to first pregnancy analysis showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse (age-adjusted fecundability ratio 0.59, 95% CI 0.46-0.76). These associations persisted when self-referred women were excluded. Interpretation High-dose oestrogen treatment in adolescence seems to reduce female fertility in later life. This finding has implications for current treatment practices and for our understanding of reproductive biology. C1 Univ Tasmania, Menzies Res Inst, Hobart, Tas 7001, Australia. La Trobe Univ, Bundoora, Vic, Australia. Royal Childrens Hosp, Murdoch Childrens Res Inst, Ctr Hormone Res, Melbourne, Vic, Australia. NIEHS, Res Triangle Pk, NC 27709 USA. RP Venn, A (reprint author), Univ Tasmania, Menzies Res Inst, Private Bag 23, Hobart, Tas 7001, Australia. EM Alison.Venn@utas.edu.au RI Werther, George/B-3784-2012; Venn, Alison/J-2803-2013; Rayner, Jo-Anne/B-4934-2016; OI Rayner, Jo-Anne/0000-0001-8622-9997; Baird, Donna/0000-0002-5544-2653 NR 14 TC 44 Z9 44 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 OCT 23 PY 2004 VL 364 IS 9444 BP 1513 EP 1518 DI 10.1016/S0140-6736(04)17274-7 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 864PN UT WOS:000224645500029 PM 15500896 ER PT J AU Jang, MK Kim, JY Jeoung, NH Kang, MA Choi, MS Oh, GT Nam, KT Lee, WH Park, YB AF Jang, MK Kim, JY Jeoung, NH Kang, MA Choi, MS Oh, GT Nam, KT Lee, WH Park, YB TI Oxidized low-density lipoproteins may induce expression of monocyte chemotactic protein-3 in atherosclerotic plaques SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE atherosclerosis; MCP-3; monocyte/macrophage; oxidized LDL; PPAR-gamma ID SMOOTH-MUSCLE-CELLS; MACROPHAGE GENE-EXPRESSION; ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; APOLIPOPROTEIN-B; ADIPOCYTE DIFFERENTIATION; OXIDATIVE MODIFICATION; CYTO-TOXICITY; LDL; LIGAND AB Genes induced or suppressed by oxidized low-density lipoproteins (oxLDL) in human monocytic THP-1 cells were searched using the differential display reverse transcriptase polymerase chain reaction. One of the differentially expressed (up-regulated) cDNA fragments was found to contain sequences corresponding to monocyte chemotactic protein-3 (MCP-3). The stimulatory effect of the oxLDL on the expression of MCP-3 mRNA was both time- and dose-dependent. Treatment with GF109203X and genistein, inhibitors of protein kinase C and tyrosine kinase, respectively, had no effect on the induction of MCP-3 mRNA by oxLDL, while treatment with cycloheximide inhibited the induction. The induction was reproduced by the lipid components in oxLDL such as 9-HODE and 13-HODE, which are known to activate the peroxisome proliferator-activated receptor gamma (PPARgamma). Introduction of an endogenous PPARgamma ligand, 15d-PGJ2, in the culture of THP-1 cells resulted in the induction of MCP-3 gene expression. Furthermore, analyses of human atherosclerotic plaques revealed that the expressional pattern of MCP-3 in the regions of neointimal and necrotic core overlapped with that of PPARgamma. These results suggest that oxLDL delivers its signal for MCP-3 expression via PPARgamma, which may be further related to the atherogenesis. (C) 2004 Elsevier Inc. All rights reserved. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Kyungpook Natl Univ, Dept Food Sci & Nutr, Taegu 702701, South Korea. Ewha Womans Univ, Div Mol Life Sci, Lab Cardiovasc Genom, Seoul 120750, South Korea. Korea FDA, Dept Biol Evaluat, Div Biol Evaluat, Seoul 122704, South Korea. RP Park, YB (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. EM parkyb@knu.ac.kr OI Jeoung, Nam Ho/0000-0002-7584-3761 NR 46 TC 10 Z9 13 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 22 PY 2004 VL 323 IS 3 BP 898 EP 905 DI 10.1016/j.bbrc.2004.08.178 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 858ZT UT WOS:000224232100027 PM 15381085 ER PT J AU Ravindranath, HH Chen, LS Zeichner-David, M Ishima, R Ravindranath, RMH AF Ravindranath, HH Chen, LS Zeichner-David, M Ishima, R Ravindranath, RMH TI Interaction between the enamel matrix proteins amelogenin and ameloblastin SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE enamel; biomineralization; amelogenin; GlcNAc-mimicking peptide; GlcNAc; ameloblastin ID WHEAT-GERM-AGGLUTININ; DEVELOPING DENTAL ENAMEL; ACETYL-D-GLUCOSAMINE; SHEATH PROTEINS; RAT INCISOR; TOOTH; GENE; DEGRADATION; EXPRESSION; IMPERFECTA AB Enamel matrix consists of amelogenin and non-amelogenins. Though antelogenin is not involved in nucleation of minerals, the enamel mineralization is impaired when amelogenin or other matrix protein (ameloblastin/enamelin) genes are mutated. We hypothesize that amelogenin may promote enamel mineralization by interacting with the calcium-binding matrix proteins. Specific binding of amelogenin to N-acetylglucosamine (GlcNAc), GlcNAc-mimicking peptides (GMps), and their carrier proteins and the identification of amelogenin-trityrosyl-motif-peptide (ATMP) as a GlcNAc/GMp-binding domain in amelogenin favor the hypothesis. This study tested the interaction of amelogenin with ameloblastin, a carrier of GMp, sequence at intermittent sites. Neither GlcNAc nor sialic acids were identified in the recombinant-ameloblastin. Amelogenin bound to recombinant-ameloblastin in both Western blots and in ELISA. More specifically, [H-3]ATMP bound to both recombinant and native ameloblastins. Dosimetry and Scatchard analyses showed the specific interaction between ATMP and ameloblastin, suggesting that amelogenin may interact with ameloblastin to form a heteromolecular assembly. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. NIDCR, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. RP Ravindranath, RMH (reprint author), Univ So Calif, Ctr Craniofacial Mol Biol, 2250 Alcazar St, Los Angeles, CA 90033 USA. EM rravindr@usc.edu RI Zeichner-David, Margarita/A-6567-2008 FU NIDCR NIH HHS [R01 DE 013204-05] NR 34 TC 29 Z9 31 U1 4 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 22 PY 2004 VL 323 IS 3 BP 1075 EP 1083 DI 10.1016/j.bbrc.2004.08.207 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 858ZT UT WOS:000224232100051 PM 15381109 ER PT J AU Komisaruk, BR Whipple, B Crawford, A Grimes, S Liu, WC Kalnin, A Mosier, K AF Komisaruk, BR Whipple, B Crawford, A Grimes, S Liu, WC Kalnin, A Mosier, K TI Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the Vagus nerves SO BRAIN RESEARCH LA English DT Article DE human; vagina; cervix; analgesia; solitary nucleus; paraventricular nucleus of hypothalamus ID FEMALE RAT-BRAIN; PELVIC NERVE; VAGINAL STIMULATION; OXYTOCIN INCREASES; ESTROGEN-TREATMENT; NUCLEUS-ACCUMBENS; SEXUAL-RESPONSE; AFFERENT-FIBERS; PAIN; EXPRESSION AB Women diagnosed with complete spinal cord injury (SCI) at T10 or above report vaginal-cervical perceptual awareness. To test whether the Vagus nerves, which bypass the spinal cord, provide the afferent pathway for this response, we hypothesized that the Nucleus Tractus Solitarii (NTS) region of the medulla oblongata, to which the Vagus nerves project, is activated by vaginal-cervical self-stimulation (CSS) in such women, as visualized by functional magnetic resonance imaging (fMRI). Regional blood oxygen level-dependent (BOLD) signal intensity was imaged during CSS and other motor and sensory procedures, using statistical parametric mapping (SPM) analysis with head motion artifact correction. Physiatric examination and MRI established the location and extent of spinal cord injury. In order to demarcate the NTS, a gustatory stimulus and hand movement were used to activate the superior region of the NTS and the Nucleus Cuneatus adjacent to the inferior region of the NTS, respectively. Each of four women with interruption, or "complete" injury, of the spinal cord (ASIA criteria), and one woman with significant, but "incomplete" SCI, all at or above T10, showed activation of the inferior region of the NTS during CSS. Each woman showed analgesia, measured at the fingers, during CSS, confirming previous findings. Three women experienced orgasm during the CSS. The brain regions that showed activation during the orgasms included hypothalamic paraventricular nucleus, medial amygdala, anterior cingulate, frontal, parietal, and insular cortices, and cerebellum. We conclude that the Vagus nerves provide a spinal cord-bypass pathway for vaginal-cervical sensibility in women with complete spinal cord injury above the level of entry into spinal cord of the known genitospinal nerves. (C) 2004 Elsevier B.V. All rights reserved. C1 Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. Rutgers State Univ, Coll Nursing, Newark, NJ 07102 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Radiol, Newark, NJ 07103 USA. RP Komisaruk, BR (reprint author), NIGMS, NIH, Bldg 45 Natcher,Rm 2As37A,45 Ctr Dr, Bethesda, MD 20892 USA. EM komisarb@nigms.nih.gov OI Komisaruk, Barry/0000-0002-3164-9174 FU NIGMS NIH HHS [R25-GM60826] NR 82 TC 130 Z9 132 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 22 PY 2004 VL 1024 IS 1-2 BP 77 EP 88 DI 10.1016/j.brainres.2004.07.029 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 864WX UT WOS:000224664800007 PM 15451368 ER PT J AU Han, C Demetris, AJ Liu, YH Shelhamer, JH Wu, T AF Han, C Demetris, AJ Liu, YH Shelhamer, JH Wu, T TI Transforming growth factor-beta (TGF-beta) activates cytosolic phospholipase A(2)alpha (cPLA(2)alpha)-mediated prostaglandin E-2 (PGE(2))/EP1 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma)/Smad signaling pathways in human liver cancer cells - A novel mechanism for subversion of TGF-beta-induced mitoinhibition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; ARACHIDONIC-ACID RELEASE; PPAR-GAMMA; EPITHELIAL-CELLS; TRANSGENIC MICE; MAMMARY-GLAND; INTESTINAL POLYPOSIS; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; NUCLEAR-ENVELOPE AB Transforming growth factor-beta(TGF-beta) potently inhibits the growth of human epithelial cells. However, neoplastic epithelial cells become resistant to TGF-beta-mediated mitoinhibition, and the mechanisms for this alteration during tumorigenesis are not fully understood. This study was designed to determine whether there is an association between the cytosolic phospholipase A(2)alpha (cPLA(2)alpha)-controlled eicosanoid metabolism and the growth response to TGF-beta in human liver cancer cells. TGF-beta treatment induced simultaneous Smad-mediated gene transcription and phosphorylation of cPLA(2)alpha. Whereas Smad activation inhibited tumor cell growth, phosphorylation of cPLA(2)alpha promoted growth and counteracted Smad-mediated mitoinhibition. TGF-beta1 failed to prevent the growth of cells with high basal expression of cPLA(2)alpha, but inhibition of cPLA(2)alpha, cyclooxygenase-2 (COX-2), or EP1 receptor restored mitoinhibition by TGF-beta1 in these cells. These results suggest that resistance of tumor cells to TGF-beta-mediated mitoinhibition involves activation of cPLA(2)alpha/COX-2/EP1 signaling. Furthermore, the TGF-beta1-induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA(2)alpha or peroxisome proliferator-activated receptor-gamma (PPAR-gamma) but enhanced by depletion of cPLA(2)alpha or PPAR-gamma. These findings, along with the observations that cPLA(2)alpha activates PPAR-gamma and that PPAR-gamma binds Smad3, illustrate novel cPLA(2)alpha/COX-2/EP1 and cPLA(2)alpha/PPAR-gamma/Smad signaling pathways that counteract the mitoinhibition by TGF-beta in human cancer cells. C1 Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wu, T (reprint author), Univ Pittsburgh, Presbyterian Univ Hosp C902, Sch Med, Dept Pathol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM wut@upmc.edu FU NIDDK NIH HHS [DK49615] NR 79 TC 52 Z9 56 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44344 EP 44354 DI 10.1074/jbc.M404852200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600016 PM 15294900 ER PT J AU Lennartsson, J Shivakrupa, R Linnekin, D AF Lennartsson, J Shivakrupa, R Linnekin, D TI Synergistic growth of stem cell factor and granulocyte macrophage colony-stimulating factor involves kinase-dependent and -independent contributions from c-Kit SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EARLY SIGNALING PATHWAYS; GM-CSF; HEMATOPOIETIC PROGENITORS; TYROSINE PHOSPHORYLATION; FACTOR RECEPTORS; PROTEIN-KINASE; ACTIVATION; LINE; ERYTHROPOIETIN; LIGAND AB Stem cell factor (SCF) binds and activates the receptor tyrosine kinase c-Kit, and this interaction is critical for normal hematopoiesis. SCF also synergizes with a variety of growth factors, including those binding members of the cytokine receptor superfamily. The mechanisms mediating this synergy remain to be defined. The present study investigates both structural and biochemical cross-talk between c-Kit and the receptor for granulocyte macrophage colony-stimulating factor (GM-CSF). We have found that c-Kit forms a complex with the beta-chain of the GM-CSF receptor, and this interaction involves the first part of the c-Kit kinase domain. Although inhibition of c-Kit kinase activity completely blocked SCF-induced proliferation, there was still greater than additive growth induced by SCF in combination with GM-CSF. In contrast, an inhibitory antibody against the extracellular domain of c-Kit (K-27) completely inhibited growth in response to SCF alone or in combination with GM-CSF. These results support a kinase-independent component of the synergistic growth induced by SCF and GM-CSF that may relate to interaction of these receptors. It is also clear that a significant part of the synergistic growth is dependent of c-Kit kinase activity. Although synergistic increases in phosphorylation of c-Kit and the beta-chain of the GM-CSF receptor were not observed, SCF and GM-CSF in combination prolonged the duration of Erk1/2 phosphorylation in a phosphatidylinositol 3-kinase-dependent manner. Consistent with these findings, phosphatidylinositol 3-kinase is synergistically activated by SCF and GM-CSF together. Hence, c-Kit makes both kinase-independent and - dependent contributions to the proliferative synergy induced by SCF in combination with GM-CSF. C1 NCI, Basic Res Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Lennartsson, J (reprint author), Biomed Ctr, Ludwig Inst Canc Res, Box 595, SE-75124 Uppsala, Sweden. EM Johan.Lennartsson@LICR.uu.se NR 41 TC 22 Z9 22 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44544 EP 44553 DI 10.1074/jbc.M404085200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600039 PM 15308671 ER PT J AU Djaman, O Outten, FW Imlay, JA AF Djaman, O Outten, FW Imlay, JA TI Repair of oxidized iron-sulfur clusters in Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FE-S CLUSTER; MANGANESE-SUPEROXIDE-DISMUTASE; DIHYDROXY-ACID DEHYDRATASE; SACCHAROMYCES-CEREVISIAE; CYSTEINE DESULFURASE; NITRIC-OXIDE; IN-VIVO; AZOTOBACTER-VINELANDII; ASSEMBLY PROTEINS; HYDROGEN-PEROXIDE AB The [4Fe-4S](2+) clusters of dehydratases are rapidly damaged by univalent oxidants, including hydrogen peroxide, superoxide, and peroxynitrite. The loss of an electron destabilizes the cluster, causing it to release its catalytic iron atom and converting the cluster initially to an inactive [3Fe-4S](1+) form. Continued exposure to oxidants in vitro leads to further iron release. Experiments have shown that these clusters are repaired in vivo. We sought to determine whether repair is mediated by either the Isc or Suf cluster-assembly systems that have been identified in Escherichia coli. We found that all the proteins encoded by the isc operon were critical for de novo assembly, but most of these were unnecessary for cluster repair. IscS, a cysteine desulfurase, appeared to be an exception: although iscS mutants repaired damaged clusters, they did so substantially more slowly than did wild-type cells. Because sulfur mobilization should be required only if clusters degrade beyond the [3Fe-4S](1+) state, we used whole cell EPR to visualize the fate of oxidized enzymes in vivo. Fumarase A was overproduced. Brief exposure of cells to hydrogen peroxide resulted in the appearance of the characteristic [3Fe-4S](1+) signal of the oxidized enzyme. When hydrogen peroxide was then scavenged, the enzyme activity reappeared within minutes, in concert with the disappearance of the EPR signal. Thus it is unclear why IscS is required for efficient repair. The iscS mutants grew poorly, allowing the possibility that metabolic defects indirectly slow the repair process. Our data did indicate that damaged clusters decompose beyond the [3Fe-4S](1+) state in vivo when stress is prolonged. Under the conditions of our experiments, mutants that lacked other repair candidates - Suf proteins, glutathione, and NADPH: ferredoxin reductase - all repaired clusters at normal rates. We conclude that the mechanism of cluster repair is distinct from that of de novo assembly and that this is true because mild oxidative stress does not degrade clusters in vivo to the point of presenting an apoenzyme to the de novo cluster-assembly systems. C1 Univ Illinois, Dept Microbiol, Urbana, IL 61801 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Imlay, JA (reprint author), Univ Illinois, Dept Microbiol, 601 S Goodwin, Urbana, IL 61801 USA. EM jimlay@uiuc.edu OI Outten, Franklin/0000-0002-9095-0194 FU NIGMS NIH HHS [GM49640] NR 82 TC 103 Z9 103 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44590 EP 44599 DI 10.1074/jbc.M406487200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600044 PM 15308657 ER PT J AU Fujii, I Yasuoka, Y Tsai, HF Chang, YC Kwon-Chung, KJ Ebizuka, Y AF Fujii, I Yasuoka, Y Tsai, HF Chang, YC Kwon-Chung, KJ Ebizuka, Y TI Hydrolytic polyketide shortening by Ayg1p, a novel enzyme involved in fungal melanin biosynthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PSEUDOMONAS-FLUORESCENS IP01; ASPERGILLUS-FUMIGATUS; CRYSTAL-STRUCTURE; STRAIN RHA1; HYDROLASE; SYNTHASE; DEGRADATION; GENES; MECHANISM; ACID AB The pentaketide 1,3,6,8-tetrahydroxynaphthalene (T4HN) is a key precursor of 1,8-dihydroxynaphthalenemelanin, an important virulence factor in pathogenic fungi, where T4HN is believed to be the direct product of pentaketide synthases. We showed recently the involvement of a novel protein, Ayg1p, in the formation of T4HN from the heptaketide precursor YWA1 in Aspergillus fumigatus. To investigate the mechanism of its enzymatic function, Ayg1p was purified from an Aspergillus oryzae strain that overexpressed the ayg1 gene. The Ayg1p converted the naphthopyrone YWA1 to T4HN with a release of the acetoacetic acid. Although Ayg1p does not show significant homology with known enzymes, a serine protease-type hydrolytic motif is present in its sequence, and serine-specific inhibitors strongly inhibited the activity. To identify its catalytic residues, site-directed Ayg1p mutants were expressed in Escherichia coli, and their enzyme activities were examined. The single substitution mutations S257A, D352A, and H380A resulted in a complete loss of enzyme activity in Ayg1p. These results indicated that the catalytic triad Asp(352)-His(380)-Ser(257) constituted the active-site of Ayg1p. From a Dixon plot analysis, 2-acetyl-1,3,6,8-tetrahydroxynaphthalene was found to be a strong mixed-type inhibitor, suggesting the involvement of an acyl-enzyme intermediate. These studies support the mechanism in which the Ser(257) at the active site functions as a nucleophile to attack the YWA1 side-chain 1'-carbonyl and cleave the carbon-carbon bond between the naphthalene ring and the side chain. Acetoacetic acid is subsequently released from the Ser(257)-O-acetoacetylated Ayg1p by hydrolysis. An enzyme with activity similar to Ayg1p in melanin biosynthesis has not been reported in any other organism. C1 Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Fujii, I (reprint author), Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM ifujii@mol.f.u-tokyo.ac.jp NR 31 TC 46 Z9 46 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44613 EP 44620 DI 10.1074/jbc.M406758200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600047 PM 15310761 ER PT J AU Inoue, Y Inoue, J Lambert, G Yim, SH Gonzalez, FJ AF Inoue, Y Inoue, J Lambert, G Yim, SH Gonzalez, FJ TI Disruption of hepatic C/EBP alpha results in impaired glucose tolerance and age-dependent hepatosteatosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENHANCER-BINDING-PROTEIN; TRIGLYCERIDE TRANSFER PROTEIN; LIPOPROTEIN-LIPASE; KNOCKOUT MICE; CHOLESTERYL ESTERS; DIABETES-MELLITUS; SELECTIVE UPTAKE; IN-VIVO; LIVER; GENE AB C/EBPalpha is highly expressed in liver and regulates many genes that are preferentially expressed in liver. Because C/EBPalpha-null mice die soon after birth, it is impossible to analyze the function of C/EBPalpha in the adult with this model. To address the function of C/EBPalpha in adult hepatocytes, liver-specific C/EBPalpha-null mice were produced using a floxed C/EBPalpha allele and the albumin-Cre transgene. Unlike whole body C/EBPalpha-null mice, mice lacking hepatic C/EBPalpha expression did not exhibit hypoglycemia, nor did they show reduced hepatic glycogen in adult. Expression of liver glycogen synthase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase remained at normal levels. However, these mice exhibited impaired glucose tolerance due in part to reduced expression of hepatic glucokinase, and hyperammonemia from reduced expression of hepatic carbamoyl phosphate synthase-I. These mice also had reduced serum cholesterol and steatotic livers that was exacerbated with aging. This phenotype could be explained by increased expression of hepatic lipoprotein lipase and reduced expression of microsomal triglyceride transfer protein, apolipoproteins B100, and A-IV. These data demonstrate that hepatic C/EBPalpha is critical for ammonia detoxification and glucose and lipid homeostasis in adult mice. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. INSERM, U539, F-44035 Nantes, France. RP Gonzalez, FJ (reprint author), NIH, Bldg 37,Rm 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov NR 48 TC 47 Z9 48 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44740 EP 44748 DI 10.1074/jbc.M405177200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600062 PM 15292250 ER PT J AU Chi, YL Zhou, B Wang, WQ Chung, SK Kwon, YU Ahn, YH Chang, YT Tsujishita, Y Hurley, JH Zhang, ZY AF Chi, YL Zhou, B Wang, WQ Chung, SK Kwon, YU Ahn, YH Chang, YT Tsujishita, Y Hurley, JH Zhang, ZY TI Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe synaptojanin and SHIP2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POSSIBLE REGIOISOMERS; PHOSPHATASES; PROTEIN; FAMILY; TETRAKISPHOSPHATES; PENTAKISPHOSPHATE; DEPHOSPHORYLATION; MOBILIZATION; MODULATION; SIGNAL AB Inositol-5-phosphatases are important enzymes involved in the regulation of diverse cellular processes from synaptic vesicle recycling to insulin signaling. We describe a comparative study of two representative inositol-5-phosphatases, Schizosaccharomyces pombe synaptojanin (SPsynaptojanin) and human SH2 domain-containing inositol-5-phosphatase SHIP2. We show that in addition to Mg2+, transition metals such as Mn2+, Co2+, and Ni2+ are also effective activators of SPsynaptojanin. In contrast, Ca2+ and Cu2+ are inhibitory. We provide evidence that Mg2+ binds the same site occupied by Ca2+ observed in the crystal structure of SPsynaptojanin complexed with inositol 1,4-bisphosphate (Ins(1,4)P-2). Ionizations important for substrate binding and catalysis are defined for the SPsynaptojanin-catalyzed Ins(1,4,5) P-3 reaction. Kinetic analysis with four phosphatidylinositol lipids bearing a 5-phosphate and 54 water-soluble inositol phosphates reveals that SPsynaptojanin and SHIP2 possess much broader substrate specificity than previously appreciated. The rank order for SPsynaptojanin is Ins(2,4,5) P-3 > phosphatidylinositol-4,5- bisphosphate (PtdIns(4,5) P-2) approximate to Ins(4,5) P-2 approximate to Ins(1,4,5) P-3 approximate to Ins(4,5,6) P-3 > PtdIns(3,5) P-2 approximate to PtdIns(3,4,5) P-3 approximate to Ins(1,2,4,5) P-4 approximate to Ins(1,3,4,5) P-4 approximate to Ins( 2,4,5,6) P-4 approximate to Ins(1,2,4,5,6) P-5. The rank order for SHIP2 is Ins(1,2,3,4,5) P-5 > Ins(1,3,4,5) P-4 > PtdIns(3,4,5) P-4 approximate to PtdIns(3,5) P-2 approximate to Ins(1,4,5,6) P-4 approximate to Ins(2,4,5,6) P-4. Because inositol phosphate isomers elicit different biological activities, the extended substrate specificity for SPsynaptojanin and SHIP2 suggest that these enzymes likely have multiple roles in cell signaling and may regulate distinct pathways. The unique substrate specificity profiles and the importance of 2-position phosphate in binding also have important implications for the design of potent and selective SPsynaptojanin and SHIP2 inhibitors for pharmacological investigation. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. Pohang Univ Sci & Technol, Dept Chem, Pohang 790784, South Korea. NYU, Dept Chem, New York, NY 10003 USA. NIDDK, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Zhang, ZY (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM zyzhang@aecom.yu.edu RI Chang, Young-Tae/B-2780-2010 OI Chang, Young-Tae/0000-0002-1927-3688 FU NCI NIH HHS [CA69202, 5T32-CA09475] NR 33 TC 31 Z9 32 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 44987 EP 44995 DI 10.1074/jbc.M406416200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600090 PM 15316017 ER PT J AU Moon, AF Edavettal, SC Krahn, JM Munoz, EM Negishi, M Linhardt, RJ Liu, J Pedersen, LC AF Moon, AF Edavettal, SC Krahn, JM Munoz, EM Negishi, M Linhardt, RJ Liu, J Pedersen, LC TI Structural analysis of the sulfotransferase (3-O-sulfotransferase isoform 3) involved in the biosynthesis of an entry receptor for herpes simplex virus 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID D-GLUCOSAMINYL 3-O-SULFOTRANSFERASE; HERPES-SIMPLEX-VIRUS; HEPARAN-SULFATE; CRYSTAL-STRUCTURE; CRYSTALLOGRAPHY; ANTITHROMBIN; EXPRESSION; PROGRAM; TYPE-1; SUITE AB Heparan sulfate (HS) plays essential roles in assisting herpes simplex virus infection and other biological processes. The biosynthesis of HS includes numerous specialized sulfotransferases that generate a variety of sulfated saccharide sequences, conferring the selectivity of biological functions of HS. We report a structural study of human HS 3-O-sulfotransferase isoform 3 (3-OST-3), a key sulfotransferase that transfers a sulfuryl group to a specific glucosamine in HS generating an entry receptor for herpes simplex virus 1. We have obtained the crystal structure of 3-OST-3 at 1.95 Angstrom in a ternary complex with 3'-phosphoadenosine 5'-phosphate and a tetrasaccharide substrate. Mutational analyses were also performed on the residues involved in the binding of the substrate. Residues Gln(255) and Lys(368) are essential for the sulfotransferase activity and lie within hydrogen bonding distances to the carboxyl and sulfo groups of the uronic acid unit. These residues participate in the substrate recognition of 3-OST-3. This structure provides atomic level evidence for delineating the substrate recognition and catalytic mechanism for 3-OST-3. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY 12180 USA. RP Liu, J (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Rm 309,Beard Hall, Chapel Hill, NC 27599 USA. EM jian_liu@unc.edu FU NHLBI NIH HHS [R01 HL052622, R01 HL052622-07, R01 HL062244-06, HL52622, R01 HL052622-08, R01 HL062244, R01 HL062244-05A1]; NIAID NIH HHS [AI50050, R01 AI050050]; NIGMS NIH HHS [R01 GM038060-16A2, R01 GM038060-17, R01 GM038060] NR 35 TC 52 Z9 53 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 45185 EP 45193 DI 10.1074/jbc.M405013200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600112 PM 15304505 ER PT J AU Li, YF Prinz, WA AF Li, YF Prinz, WA TI ATP-binding cassette (ABC) transporters mediate nonvesicular, raft-modulated sterol movement from the plasma membrane to the endoplasmic reticulum SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTRACELLULAR CHOLESTEROL TRANSPORT; SACCHAROMYCES-CEREVISIAE; CELL-SURFACE; TANGIER-DISEASE; BREFELDIN-A; GOLGI PROTEINS; DOMAINS RAFTS; LIPID RAFTS; YEAST; MUTATIONS AB Little is known about the mechanisms of intracellular sterol transport or how cells maintain the high sterol concentration of the plasma membrane (PM). Here we demonstrate that two inducible ATP-binding cassette (ABC) transporters (Aus1p and Pdr11p) mediate nonvesicular movement of PM sterol to the endoplasmic reticulum (ER) in Saccharomyces cerevisiae. This transport facilitates exogenous sterol uptake, which we find requires steryl ester synthesis in the ER. Surprisingly, while expression of Aus1p and Pdr11p significantly increases sterol movement from PM to ER, it does not alter intracellular sterol distribution. Thus, ER sterol is likely rapidly returned to the PM when it is not esterified in the ER. We show that the propensity of PM sterols to be moved to the ER is largely determined by their affinity for sterol sphingolipid-enriched microdomains (rafts). Our findings suggest that raft association is a primary determinant of sterol accumulation in the PM and that Aus1p and Pdr11p facilitate sterol uptake by increasing the cycling of sterol between the PM and ER. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM wprinz@helix.nih.gov NR 44 TC 87 Z9 88 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 45226 EP 45234 DI 10.1074/jbc.M407600200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600116 PM 15316012 ER PT J AU DellaVecchia, MJ Croteau, DL Skorvaga, M Dezhurov, SV Lavrik, OI Van Houten, B AF DellaVecchia, MJ Croteau, DL Skorvaga, M Dezhurov, SV Lavrik, OI Van Houten, B TI Analyzing the handoff of DNA from UvrA to UvrB utilizing DNA-protein photoaffinity labeling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; ESCHERICHIA-COLI; DAMAGE RECOGNITION; (A)BC EXCINUCLEASE; CROSS-LINKING; ACTIVE-SITE; 5 INCISION; COMPLEX; NUCLEASE; BINDING AB To better define the molecular architecture of nucleotide excision repair intermediates it is necessary to identify the specific domains of UvrA, UvrB, and UvrC that are in close proximity to DNA damage during the repair process. One key step of nucleotide excision repair that is poorly understood is the transfer of damaged DNA from UvrA to UvrB, prior to incision by UvrC. To study this transfer, we have utilized two types of arylazido-modified photoaffinity reagents that probe residues in the Uvr proteins that are closest to either the damaged or non-damaged strands. The damaged strand probes consisted of dNTP analogs linked to a terminal arylazido moiety. These analogs were incorporated into double-stranded DNA using DNA polymerase beta and functioned as both the damage site and the cross-linking reagent. The non-damaged strand probe contained an arylazido moiety coupled to a phosphorothioate-modified backbone of an oligonucleotide opposite the damaged strand, which contained an internal fluorescein adduct. Six site-directed mutants of Bacillus caldotenax UvrB located in different domains within the protein (Y96A, E99A, R123A, R183E, F249A, and D510A), and two domain deletions (Delta2 and Deltabeta-hairpin), were assayed. Data gleaned from these mutants suggest that the hand-off of damaged DNA from UvrA to UvrB proceeds in a three-step process: 1) UvrA and UvrB bind to the damaged site, with UvrA in direct contact; 2) a transfer reaction with UvrB contacting mostly the non-damaged DNA strand; 3) lesion engagement by the damage recognition pocket of UvrB with concomitant release of UvrA. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Slovak Acad Sci, Canc Res Inst, Dept Mol Genet, Bratislava 83391, Slovakia. Russian Acad Sci, Novosibirsk Inst Chem Biol & Fundamental Med, Siberian Branch, Novosibirsk 630090, Russia. RP Van Houten, B (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM vanhout1@niehs.nih.gov RI Lavrik, Olga /G-4641-2013 NR 44 TC 38 Z9 46 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 22 PY 2004 VL 279 IS 43 BP 45245 EP 45256 DI 10.1074/jbc.M408659200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862QJ UT WOS:000224505600118 PM 15308661 ER PT J AU Vaitheeswaran, S Rasaiah, JC Hummer, G AF Vaitheeswaran, S Rasaiah, JC Hummer, G TI Electric field and temperature effects on water in the narrow nonpolar pores of carbon nanotubes SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID FREE-ENERGY; CYTOCHROME P450CAM; SIMULATION; NANOPORES; CONDUCTION; HYDRATION; MOLECULES; DYNAMICS; MODEL; CHAIN AB Water molecules in the narrow cylindrical pore of a (6,6) carbon nanotube form single-file chains with their dipoles collectively oriented either up or down along the tube axis. We study the interaction of such water chains with homogeneous electric fields for finite closed and infinite periodically replicated tubes. By evaluating the grand-canonical partition function term-by-term, we show that homogeneous electric fields favor the filling of previously empty nanotubes with water from the bulk phase. A two-state description of the collective water dipole orientation in the nanotube provides an excellent approximation for the dependence of the water-chain polarization and the filling equilibrium on the electric field. The energy and entropy contributions to the free energy of filling the nanotube were determined from the temperature dependence of the occupancy probabilities. We find that the energy of transfer depends sensitively on the water-tube interaction potential, and that the entropy of one-dimensionally ordered water chains is comparable to that of bulk water. We also discuss implications for proton transfer reactions in biology. (C) 2004 American Institute of Physics. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Maine, Dept Phys & Astron, Orono, ME 04469 USA. Univ Maine, Dept Chem, Orono, ME 04469 USA. RP Vaitheeswaran, S (reprint author), Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. EM rasaiah@maine.edu; gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 41 TC 137 Z9 137 U1 3 U2 40 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 22 PY 2004 VL 121 IS 16 BP 7955 EP 7965 DI 10.1063/1.1796271 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 861ZF UT WOS:000224456500048 PM 15485258 ER PT J AU Issaq, HJ Janini, GM Chan, KC Veenstra, TD AF Issaq, HJ Janini, GM Chan, KC Veenstra, TD TI Sheathless electrospray ionization interfaces for capillary electrophoresis-mass spectrometric detection - Advantages and limitations SO JOURNAL OF CHROMATOGRAPHY A LA English DT Review DE CE/ESI-MS; CE interface; sheathless CE interfaces; CE/MS ID ZONE-ELECTROPHORESIS; PROTEIN IDENTIFICATION; EMITTERS; PRECONCENTRATION; PERFORMANCE AB A review of sheathless interfaces for capillary electrophoresis (CE)-mass spectrometry (MS) is presented. The review discusses the on-line CE-MS system requirements, advantages and weaknesses of current sheathless interface designs for CE-electrospray ionization MS, and comparison between sheath flow and sheathless interfaces. The advantages and limitations of three sheathless designs are discussed and commented upon, these include single-capillary, two-capillary and three-piece designs. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 20702 USA. RP Issaq, HJ (reprint author), NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, POB B, Frederick, MD 20702 USA. EM issaqh@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 35 TC 49 Z9 50 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD OCT 22 PY 2004 VL 1053 IS 1-2 BP 37 EP 42 DI 10.1016/j.chroma.2004.08.116 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 864XZ UT WOS:000224667900007 PM 15543970 ER PT J AU Zhou, HX Szabo, A AF Zhou, HX Szabo, A TI Enhancement of association rates by nonspecific binding to DNA and cell membranes SO PHYSICAL REVIEW LETTERS LA English DT Article ID DIFFUSION-INFLUENCED REACTIONS; PROTEIN ASSOCIATION; ORIENTATION CONSTRAINTS; KINETICS AB A comprehensive analytic theory is developed for the kinetics of reversible association with specific sites on DNA and receptors on cell membranes in the presence of nonspecific binding to the target surfaces. Nonspecific binding is treated as a short-range attractive potential, which is more fundamental and realistic than the surface sliding model. The presence of a surface potential around the target enhances the rate of specific association and for reversible reactions leads to deviations from single exponential relaxation. C1 Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zhou, HX (reprint author), Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. RI Szabo, Attila/H-3867-2012; Zhou, Huan-Xiang/M-5170-2016 OI Zhou, Huan-Xiang/0000-0001-9020-0302 FU NIGMS NIH HHS [GM 58187] NR 14 TC 49 Z9 49 U1 1 U2 7 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 EI 1079-7114 J9 PHYS REV LETT JI Phys. Rev. Lett. PD OCT 22 PY 2004 VL 93 IS 17 AR 178101 DI 10.1103/PhysRevLett.93.178101 PG 4 WC Physics, Multidisciplinary SC Physics GA 864WC UT WOS:000224662700079 PM 15525128 ER PT J AU Feingold, EA Good, PJ Guyer, MS Kamholz, S Liefer, L Wetterstrand, K Collins, FS Gingeras, TR Kampa, D Sekinger, EA Cheng, J Hirsch, H Ghosh, S Zhu, Z Pate, S Piccolboni, A Yang, A Tammana, H Bekiranov, S Kapranov, P Harrison, R Church, G Struhl, K Ren, B Kim, TH Barrera, LO Qu, C Van Calcar, S Luna, R Glass, CK Rosenfeld, MG Guigo, R Antonarakis, SE Birney, E Brent, M Pachter, L Reymond, A Dermitzakis, ET Dewey, C Keefe, D Denoeud, F Lagarde, J Ashurst, J Hubbard, T Wesselink, JJ Castelo, R Eyras, E Myers, RM Sidow, A Batzoglou, S Trinklein, ND Hartman, SJ Aldred, SF Anton, E Schroeder, DI Marticke, SS Nguyen, L Schmutz, J Grimwood, J Dickson, M Cooper, GM Stone, EA Asimenos, G Brudno, M Dutta, A Karnani, N Taylor, CM Kim, HK Robins, G Stamatoyannopoulos, G Stamatoyannopoulos, JA Dorschner, M Sabo, P Hawrytycz, M Humbert, R Wallace, J Yu, M Navas, PA McArthur, M Noble, WS Dunham, I Koch, CM Andrews, RM Clelland, GK Wilcox, S Fowler, JC James, KD Groth, P Dovey, OM Ellis, PD Wraight, VL Mungall, AJ Dhami, P Fiegler, H Langford, CF Carter, NP Vetrie, D Snyder, M Euskirchen, G Urban, AE Nagalakshmi, U Rinn, J Popescu, G Bertone, P Hartman, S Rozowsky, J Emanuelsson, O Royce, T Chung, S Gerstein, M Lian, Z Lian, J Nakayama, Y Weissman, S Stoic, V Tongprasit, W Sethi, H Jones, S Marra, M Shin, H Schein, J Clamp, M Lindblad-Toh, K Chang, J Jaffe, DB Kamal, ES Lander, ES Mikkelsen, TS Vinson, J Zody, MC de Jong, PJ Osoegawa, K Nefedov, M Zhu, B Baxevanis, AD Wolfsberg, TG Collins, FS Crawford, GE Holt, E Vasicek, TJ Zhou, D Luo, S Green, ED Bouffard, GG Margulies, EH Portnoy, ME Hansen, NF Thomas, PJ Mcdowell, JC Maskeri, B Young, AC Idol, JR Blakesley, RW Schuler, G Miller, W Hardison, R Elnitski, L Shah, P Salzberg, SL Pertea, M Majoros, WH Haussler, D Thomas, D Rosenbloom, KR Clawson, H Siepe, A Kent, WJ Weng, Z Jin, S Halees, A Burden, H Karaoz, U Fu, Y Yu, Y Ding, C Cantor, CR Kingston, RE Dennis, J Green, RD Singer, MA Richmond, TA Norton, JE Farnham, PJ Oberley, MJ Inman, DR McCormick, MR Kim, H Middle, CL Pirrung, MC Fu, XD Kwon, YS Ye, Z Dekker, J Tabuchi, TM Gheldof, N Dostie, J Harvey, SC AF Feingold, EA Good, PJ Guyer, MS Kamholz, S Liefer, L Wetterstrand, K Collins, FS Gingeras, TR Kampa, D Sekinger, EA Cheng, J Hirsch, H Ghosh, S Zhu, Z Pate, S Piccolboni, A Yang, A Tammana, H Bekiranov, S Kapranov, P Harrison, R Church, G Struhl, K Ren, B Kim, TH Barrera, LO Qu, C Van Calcar, S Luna, R Glass, CK Rosenfeld, MG Guigo, R Antonarakis, SE Birney, E Brent, M Pachter, L Reymond, A Dermitzakis, ET Dewey, C Keefe, D Denoeud, F Lagarde, J Ashurst, J Hubbard, T Wesselink, JJ Castelo, R Eyras, E Myers, RM Sidow, A Batzoglou, S Trinklein, ND Hartman, SJ Aldred, SF Anton, E Schroeder, DI Marticke, SS Nguyen, L Schmutz, J Grimwood, J Dickson, M Cooper, GM Stone, EA Asimenos, G Brudno, M Dutta, A Karnani, N Taylor, CM Kim, HK Robins, G Stamatoyannopoulos, G Stamatoyannopoulos, JA Dorschner, M Sabo, P Hawrytycz, M Humbert, R Wallace, J Yu, M Navas, PA McArthur, M Noble, WS Dunham, I Koch, CM Andrews, RM Clelland, GK Wilcox, S Fowler, JC James, KD Groth, P Dovey, OM Ellis, PD Wraight, VL Mungall, AJ Dhami, P Fiegler, H Langford, CF Carter, NP Vetrie, D Snyder, M Euskirchen, G Urban, AE Nagalakshmi, U Rinn, J Popescu, G Bertone, P Hartman, S Rozowsky, J Emanuelsson, O Royce, T Chung, S Gerstein, M Lian, Z Lian, J Nakayama, Y Weissman, S Stoic, V Tongprasit, W Sethi, H Jones, S Marra, M Shin, H Schein, J Clamp, M Lindblad-Toh, K Chang, J Jaffe, DB Kamal, ES Lander, ES Mikkelsen, TS Vinson, J Zody, MC de Jong, PJ Osoegawa, K Nefedov, M Zhu, B Baxevanis, AD Wolfsberg, TG Collins, FS Crawford, GE Holt, E Vasicek, TJ Zhou, D Luo, S Green, ED Bouffard, GG Margulies, EH Portnoy, ME Hansen, NF Thomas, PJ Mcdowell, JC Maskeri, B Young, AC Idol, JR Blakesley, RW Schuler, G Miller, W Hardison, R Elnitski, L Shah, P Salzberg, SL Pertea, M Majoros, WH Haussler, D Thomas, D Rosenbloom, KR Clawson, H Siepe, A Kent, WJ Weng, Z Jin, S Halees, A Burden, H Karaoz, U Fu, Y Yu, Y Ding, C Cantor, CR Kingston, RE Dennis, J Green, RD Singer, MA Richmond, TA Norton, JE Farnham, PJ Oberley, MJ Inman, DR McCormick, MR Kim, H Middle, CL Pirrung, MC Fu, XD Kwon, YS Ye, Z Dekker, J Tabuchi, TM Gheldof, N Dostie, J Harvey, SC CA ENCODE Project Consortium TI The ENCODE (ENCyclopedia of DNA elements) Project SO SCIENCE LA English DT Editorial Material ID INTERNATIONAL HAPMAP PROJECT; HUMAN-GENOME; SEQUENCE; TRANSCRIPTION; ANNOTATION; QUALITY; CDNAS AB The ENCyclopedia Of DNA Elements (ENCODE) Project aims to identify all functional elements in the human genome sequence. The pilot phase of the Project is focused on a specified 30 megabases (similar to1%) of the human genome sequence and is organized as an international consortium of computational and laboratory-based scientists working to develop and apply high-throughput approaches for detecting all sequence elements that confer biological function. The results of this pilot phase will guide future efforts to analyze the entire human genome. C1 NHGRI, Bethesda, MD 20892 USA. RP NHGRI, Bethesda, MD 20892 USA. EM elise_feingold@nih.gov RI Popescu, George/B-7013-2008; Antonarakis, Stylianos/N-8866-2014; Guigo, Roderic/D-1303-2010; Hubbard, Tim/C-2567-2008; Hardison, Ross/G-1142-2010; Castelo, Robert/A-4679-2010; Eyras, Eduardo/A-1560-2010; Cooper, Gregory/D-6914-2011; Mikkelsen, Tarjei/A-1306-2007; Ding, Chunming/B-2593-2008; Dermitzakis, Emmanouil/B-7687-2013; Tang, Macy/B-9798-2014; Eyras, Eduardo/L-1053-2014; Schroeder, Diane/I-2200-2015; Marra, Marco/B-5987-2008; Karnani, Neerja/G-2539-2012; Bertone, Paul/A-6600-2013; Salzberg, Steven/F-6162-2011; Gasull, Martina/A-6630-2013; OI Popescu, George/0000-0002-7580-6792; Antonarakis, Stylianos/0000-0001-8907-5823; Guigo, Roderic/0000-0002-5738-4477; Hubbard, Tim/0000-0002-1767-9318; Hardison, Ross/0000-0003-4084-7516; Castelo, Robert/0000-0003-2229-4508; Cooper, Gregory/0000-0001-5509-9923; Mikkelsen, Tarjei/0000-0002-8133-3135; Ding, Chunming/0000-0002-2063-5594; Eyras, Eduardo/0000-0003-0793-6218; Schroeder, Diane/0000-0003-2282-9912; Bertone, Paul/0000-0001-5059-4829; Salzberg, Steven/0000-0002-8859-7432; Gingeras, Thomas/0000-0001-9106-3573; Siepel, Adam/0000-0002-3557-7219; Dunham, Ian/0000-0003-2525-5598; Koch, Christof/0000-0001-6482-8067; Halees, Anason/0000-0001-5880-7067 NR 28 TC 734 Z9 763 U1 13 U2 104 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 22 PY 2004 VL 306 IS 5696 BP 636 EP 640 DI 10.1126/science.1105136 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866EN UT WOS:000224756700037 ER PT J AU Watson, J Koya, V Leppla, SH Daniell, H AF Watson, J Koya, V Leppla, SH Daniell, H TI Expression of Bacillus anthracis protective antigen in transgenic chloroplasts of tobacco, a non-food/feed crop SO VACCINE LA English DT Article DE bioterrorism; GM crops; anthrax vaccine ID PROTEINS; VACCINE; GENOME; PLANTS; GENE; BIOTECHNOLOGY; CONTAINMENT; STRATEGIES; PEPTIDE; TOXIN AB The Centers for Disease Control (CDC) lists Bacillus anthracis as a category A agent and estimates the cost of an anthrax attack to exceed US$ 26 billion per 100,000 exposed individuals. Concerns regarding anthrax vaccine purity, a requirement for multiple injections, and a limited supply of the protective antigen (PA), underscore the urgent need for an improved vaccine. Therefore, the 83 kDa immunogenic Bacillus anthracis protective antigen was expressed in transgenic tobacco chloroplasts. The PA gene (pag) was cloned into a chloroplast vector along with the psbA regulatory signals to enhance translation. Chloroplast integration of the transgenes was confirmed by PCR and Southern blot analyses. Crude plant extracts contained up to 2.5 mg full length PA/g of fresh leaf tissue and this showed exceptional stability for several months in stored leaves or crude extracts. Maximum levels of expression were observed in mature leaves under continuous illumination. Co-expression of the ORF2 chaperonin from Bacillus thuringiensis did not increase PA accumulation or induce folding into cuboidal crystals in transgenic chloroplasts. Trypsin, chymotrypsin and furin proteolytic cleavage sites present in PA were protected in transgenic chloroplasts because only full length PA 83 was observed without any degradation products. Both CHAPS and SDS detergents extracted PA with equal efficiency and PA was observed in the soluble fraction. Chloroplast-derived PA was functionally active in lysing mouse macrophages when combined with lethal factor (LF). Crude leaf extracts contained up to 25 jig functional PA/ml. With an average yield of 172 mg of PA per plant using an experimental transgenic cultivar grown in a greenhouse, 400 million doses of vaccine (free of contaminants) could be produced per acre, a yield that could be further enhanced 18-fold using a commercial cultivar in the field. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Cent Florida, Dept Mol Biol & Microbiol, Orlando, FL 32816 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Daniell, H (reprint author), Univ Cent Florida, Dept Mol Biol & Microbiol, Biomol Sci Bldg 20,Room 336, Orlando, FL 32816 USA. EM daniell@mail.ucf.edu OI Daniell, Henry/0000-0003-4485-1176 FU NIGMS NIH HHS [R01 GM063879, R01 GM 63879] NR 31 TC 99 Z9 119 U1 0 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 22 PY 2004 VL 22 IS 31-32 BP 4374 EP 4384 DI 10.1016/j.vaccine.2004.01.069 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 866FC UT WOS:000224758200031 PM 15474731 ER PT J AU Costanzi, S Mamedova, L Gao, ZG Jacobson, KA AF Costanzi, S Mamedova, L Gao, ZG Jacobson, KA TI Architecture of P2Y nucleotide receptors: Structural comparison based on sequence analysis, mutagenesis, and homology modeling SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SECONDARY STRUCTURE PREDICTION; ALKYL FUNCTIONAL-GROUP; II FORCE-FIELDS; SIGNAL-TRANSDUCTION; EXTRACELLULAR LOOPS; LIGAND RECOGNITION; ALKANE MOLECULES; P2Y(12) RECEPTOR; UDP-GLUCOSE AB Human P2Y receptors encompass at least eight subtypes of Class A G protein-coupled receptors (GPCRs), responding to adenine and/or uracil nucleotides. Using a BLAST search against the Homo sapiens subset of the SWISS-PROT and TrEMBL databases, we identified 68 proteins showing high similarity to P2Y receptors. To address the problem of low sequence identity between rhodopsin and the P2Y receptors, we performed a multiple-sequence alignment of the retrieved proteins and the template bovine rhodopsin, combining manual identification of the transmembrane domains (TMs) with automatic techniques. The resulting phylogenetic tree delineated two distinct subgroups of P2Y receptors: G(q)-coupled subtypes (e.g., P2Y(1)) and those coupled to G(i) (e.g., P2Y(12)). On the basis of sequence comparison we mutated three Tyr residues of the putative P2Y(1) binding pocket to Ala and Phe and characterized pharmacologically the mutant receptors expressed in COS-7 cells. The mutation of Y306 (7.35, site of a cationic residue in P2Y(12)) or Y203 in the second extracellular loop selectively decreased the affinity of the agonist 2-MeSADP, and the Y306F mutation also reduced antagonist (MRS2179) affinity by 5-fold. The Y273A (6.48) mutation precluded the receptor activation without a major effect on the ligand-binding affinities, but the Y273F mutant receptor still activated G proteins with full agonist affinity. Thus, we have identified new recognition elements to further define the P2Y, binding site and related these to other P2Y receptor subtypes. Following sequence-based secondary-structure prediction, we constructed complete models of all the human P2Y receptors by homology to rhodopsin. Ligand docking on P2Y, and P2Y12 receptor models was guided by mutagenesis results, to identify the residues implicated in the binding process. Different sets of cationic residues in the two subgroups appeared to coordinate phosphate-bearing ligands. Within the P2Y, subgroup these residues are R3.29, K/R6.55, and R7.39. Within the P2Y(12) subgroup, the only residue in common with P2Y(1) is R6.55, and the role of R3.29 in TM3 seems to be fulfilled by a Lys residue in EL2, whereas the R7.39 in TM7 seems to be substituted by K7.35. Thus, we have identified common and distinguishing features of P2Y receptor structure and have proposed modes of ligand binding for the two representative subtypes that already have well-developed ligands. C1 NIDDK, LBC, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, LBC, Mol Recognit Sect, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Costanzi, Stefano/G-8990-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS [Z01 DK031116-20, Z01 DK031126-01] NR 53 TC 102 Z9 104 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 21 PY 2004 VL 47 IS 22 BP 5393 EP 5404 DI 10.1021/jm049914c PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 862MT UT WOS:000224495700008 PM 15481977 ER PT J AU Staudt, LM AF Staudt, LM TI Cancer - Negative feedback for B cells SO NATURE LA English DT Editorial Material ID MULTIPLE-MYELOMA; DIFFERENTIATION; BCL-6; BLIMP-1; TRANSCRIPTION; REPRESSION; EXPRESSION C1 NCI, Lymphoid Malignancies Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov NR 14 TC 7 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 21 PY 2004 VL 431 IS 7011 BP 919 EP 920 DI 10.1038/431919a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863TI UT WOS:000224585600028 PM 15496906 ER PT J AU She, XW Jiang, ZX Clark, RL Liu, G Cheng, Z Tuzun, E Church, DM Sutton, G Halpern, AL Eichler, EE AF She, XW Jiang, ZX Clark, RL Liu, G Cheng, Z Tuzun, E Church, DM Sutton, G Halpern, AL Eichler, EE TI Shotgun sequence assembly and recent segmental duplications within the human genome SO NATURE LA English DT Article ID BROWN-NORWAY RAT; MOUSE; REARRANGEMENTS; EVOLUTION AB Complex eukaryotic genomes are now being sequenced at an accelerated pace primarily using whole-genome shotgun (WGS) sequence assembly approaches. WGS assembly was initially criticized because of its perceived inability to resolve repeat structures within genomes. Here, we quantify the effect of WGS sequence assembly on large, highly similar repeats by comparison Of the segmental duplication content of two different human genome assemblies. Our analysis shows that large (>15 kilobases) and highly identical (>97%) duplications are not adequately resolved by WGS assembly. This leads to significant reduction in genome length and the loss of genes embedded within duplications. Comparable analyses of mouse genome assemblies confirm that strict WGS sequence assembly will oversimplify our understanding of mammalian genome structure and evolution; a hybrid strategy using a targeted clone-by-clone approach to resolve duplications is proposed. C1 Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Appl Biosyst Inc, Rockville, MD 20850 USA. Ctr Advancement Genom, Rockville, MD 20850 USA. RP Eichler, EE (reprint author), Univ Washington, Sch Med, Dept Genome Sci, 1705 NE Pacific St, Seattle, WA 98195 USA. EM eee@gs.washington.edu OI Tuzun, Eray/0000-0002-5550-7816 NR 23 TC 160 Z9 165 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 21 PY 2004 VL 431 IS 7011 BP 927 EP 930 DI 10.1038/nature03062 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863TI UT WOS:000224585600033 PM 15496912 ER PT J AU Ali, K Bilancio, A Thomas, M Pearce, W Gilfillan, AM Tkaczyk, C Kuehn, N Gray, A Giddings, J Peskett, E Fox, R Bruce, I Walker, C Sawyer, C Okkenhaug, K Finan, P Vanhaesebroeck, B AF Ali, K Bilancio, A Thomas, M Pearce, W Gilfillan, AM Tkaczyk, C Kuehn, N Gray, A Giddings, J Peskett, E Fox, R Bruce, I Walker, C Sawyer, C Okkenhaug, K Finan, P Vanhaesebroeck, B TI Essential role for the p110 delta phosphoinositide 3-kinase in the allergic response SO NATURE LA English DT Article ID FC-EPSILON-RI; INCREASED INSULIN SENSITIVITY; MAST-CELL ACTIVATION; MICE LACKING; PHOSPHATIDYLINOSITOL 3-KINASE; P85-ALPHA SUBUNIT; P110 DELTA; KIT; HYPOGLYCEMIA; LEUKOCYTES AB Inflammatory substances released by mast cells induce and maintain the allergic response(1,2). Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE)(2,3). Activated SCF receptors and high-affinity receptors for IgE (FcepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals(2-5). Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3) K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies. C1 Ludwig Inst Canc Res, London W1W 7BS, England. UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England. Novartis Inst Biomed Res, Horsham RH12 5AB, W Sussex, England. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Frimorfo, CH-1705 Fribourg, Switzerland. Univ Dundee, Dept Biochem, Dundee DD1 5EH, Scotland. RP Vanhaesebroeck, B (reprint author), Ludwig Inst Canc Res, 91 Riding House St, London W1W 7BS, England. EM bartvanh@ludwig.ucl.ac.uk RI Okkenhaug, Klaus/D-5149-2012; OI Okkenhaug, Klaus/0000-0002-9432-4051; BILANCIO, Antonio/0000-0002-5118-3359 NR 30 TC 281 Z9 290 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 21 PY 2004 VL 431 IS 7011 BP 1007 EP 1011 DI 10.1038/nature02991 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863TI UT WOS:000224585600049 PM 15496927 ER PT J AU Evans, W Fung, HC Steele, J Eerola, J Tienari, P Pittman, A de Silva, R Myers, A Wavrant-De Vrieze, F Singleton, A Hardy, J AF Evans, W Fung, HC Steele, J Eerola, J Tienari, P Pittman, A de Silva, R Myers, A Wavrant-De Vrieze, F Singleton, A Hardy, J TI The tau H2 haplotype is almost exclusively Caucasian in origin SO NEUROSCIENCE LETTERS LA English DT Article DE tau; neurofibrillary tangles; MAPT gene; populations genetics; FTDP-17; progressive supranuclear palsy; corticobasal degeneration; parkinsonism ID PROGRESSIVE SUPRANUCLEAR PALSY; PARKINSONS-DISEASE; ALLELE AB We, have assessed the distribution of the tau H1/H2 haplotype in the publicly available reference series of samples with representatives of most racial groups. This analysis shows that the H2 haplotype is probably exclusively Caucasian in origin and its marginal occurrence in other racial groups is likely to reflect admixture. We discuss this observation in terms of the origin of the H2 haplotype and the epidemiology of the tauopathies. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Chang Gung Mem Hosp, Dept Neurol 2, Taipei, Taiwan. Micronesian Hlth Study 2, Tamuning 96913, Micronesia. Univ Helsinki, Dept Neurol, Program Neurosci, Biomedicum Helsinki, FIN-02900 Helsinki, Finland. UCL, Ret Lila Weston Inst Neurol Studies, London W1T 4JF, England. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI de Silva, Rohan/C-1734-2008; Myers, Amanda/B-1796-2010; Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012; Hardy, John/C-2451-2009; Pittman, Alan/D-6231-2012 OI de Silva, Rohan/0000-0002-5052-5775; Myers, Amanda/0000-0002-3100-9396; NR 13 TC 61 Z9 61 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 21 PY 2004 VL 369 IS 3 BP 183 EP 185 DI 10.1016/j.neulet.2004.05.119 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 863XL UT WOS:000224596700003 PM 15464261 ER PT J AU Dodd, LE Simon, R AF Dodd, LE Simon, R TI PSA velocity and prostate cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CUTPOINTS C1 NCI, Rockville, MD 20852 USA. RP Dodd, LE (reprint author), NCI, Rockville, MD 20852 USA. EM doddl@mail.nih.gov 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 OCT 21 PY 2004 VL 351 IS 17 BP 1800 EP 1800 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 863TH UT WOS:000224585200027 PM 15496635 ER PT J AU Datta, MW Berman, JJ Dhir, R AF Datta, MW Berman, JJ Dhir, R TI Prostate cancer with low PSA levels SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Datta, MW (reprint author), NCI, Bethesda, MD 20892 USA. EM mdatta@mcw.edu NR 1 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 OCT 21 PY 2004 VL 351 IS 17 BP 1803 EP 1803 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 863TH UT WOS:000224585200033 ER PT J AU Donninger, H Bonome, T Radonovich, M Pise-Masison, CA Brady, J Shih, JH Barrett, JC Birrer, MJ AF Donninger, H Bonome, T Radonovich, M Pise-Masison, CA Brady, J Shih, JH Barrett, JC Birrer, MJ TI Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways SO ONCOGENE LA English DT Article DE ovarian cancer; microarray; signaling pathways ID FOCAL ADHESION KINASE; TUMOR-SUPPRESSOR GENE; TYPE-1 MATRIX-METALLOPROTEINASE; PROTEIN-TYROSINE KINASE; INTEGRIN-ASSOCIATED PROTEIN; SURFACE EPITHELIAL-CELLS; CARCINOMA-CELLS; CYCLIN D1; BREAST-CARCINOMA; CDNA MICROARRAY AB Ovarian cancer is the most lethal type of gynecologic cancer in the Western world. The high case fatality rate is due in part because most ovarian cancer patients present with advanced stage disease which is essentially incurable. In order to obtain a whole genome assessment of aberrant gene expression in advanced ovarian cancer, we used oligonucleotide microarrays comprising over 40000 features to profile 37 advanced stage papillary serous primary carcinomas. We identified 1191 genes that were significantly (P<0.001) differentially regulated between the ovarian cancer specimens and normal ovarian surface epithelium. The microarray data were validated using real time RT-PCR on 14 randomly selected differentially regulated genes. The list of differentially expressed genes includes ones that are involved in cell growth, differentiation, adhesion, apoptosis and migration. In addition, numerous genes whose function remains to be elucidated were also identified. The microarray data were imported into PathwayAssist software to identify signaling pathways involved in ovarian cancer tumorigenesis. Based on our expression results, a signaling pathway associated with tumor cell migration, spread and invasion was identified as being activated in advanced ovarian cancer. The data generated in this study represent a comprehensive list of genes aberrantly expressed in serous papillary ovarian adenocarcinoma and may be useful for the identification of potentially new and novel markers and therapeutic targets for ovarian cancer. C1 NCI, Dept Cell & Canc Biol, Rockville, MD 20850 USA. NCI, Cellular Oncol Lab, Virus Tumor Biol Sect, Rockville, MD 20850 USA. NCI, Biometr Res Branch, Rockville, MD 20852 USA. NCI, Lab Biosyst & Canc, Rockville, MD 20850 USA. RP Birrer, MJ (reprint author), NCI, Dept Cell & Canc Biol, Rockville, MD 20850 USA. EM birrerm@bprb.nci.nih.gov NR 92 TC 84 Z9 89 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 21 PY 2004 VL 23 IS 49 BP 8065 EP 8077 DI 10.1038/sj.onc.1207959 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 865HE UT WOS:000224692500004 PM 15361855 ER PT J AU Kidwell, CS Chalela, JA Saver, JL Starkman, S Hill, MD Demchuk, AM Butman, JA Patronas, N Alger, JR Latour, LL Luby, ML Baird, AE Leary, MC Tremwel, M Ovbiagele, B Fredieu, A Suzuki, S Villablanca, JP Davis, S Dunn, B Todd, JW Ezzeddine, MA Haymore, J Lynch, JK Davis, U Warach, S AF Kidwell, CS Chalela, JA Saver, JL Starkman, S Hill, MD Demchuk, AM Butman, JA Patronas, N Alger, JR Latour, LL Luby, ML Baird, AE Leary, MC Tremwel, M Ovbiagele, B Fredieu, A Suzuki, S Villablanca, JP Davis, S Dunn, B Todd, JW Ezzeddine, MA Haymore, J Lynch, JK Davis, U Warach, S TI Comparison of MRI and CT for detection of acute intracerebral hemorrhage SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE ISCHEMIC-STROKE; SUBARACHNOID HEMORRHAGE; CEREBRAL MICROBLEEDS; RISK-FACTOR; MANAGEMENT; ASSOCIATION; GUIDELINES; STATEMENT; HEMATOMA; COUNCIL AB Context Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. Objective To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. Design, Setting, and Patients A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. Main Outcome Measures Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. Results The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT-each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. Conclusion MRI maybe as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage. C1 Univ Calif Los Angeles, Med Ctr, Stroke Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Med Ctr, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Med Ctr, Dept Emergency Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Med Ctr, Dept Radiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Med Ctr, Ahmanson Lovelace Brain Mapping Ctr, Los Angeles, CA 90024 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. Univ Calgary, Foothills Hosp, Dept Clin Neurosci, Calgary Stroke Program, Calgary, AB, Canada. Univ Calgary, Dept Med, Calgary, AB, Canada. Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Stroke & Vasc Neurol, Boston, MA 02215 USA. Sparks Neurol Ctr, Ft Smith, AR USA. Royal Melbourne Hosp, Parkville, Vic 3050, Australia. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. Washington Adventist Hosp, Ctr Neurosci Serv, Takoma Pk, MD USA. RP Kidwell, CS (reprint author), Washington Hosp Ctr, Stroke Ctr, 100 Irving St NW,East Bldg Room 6126, Washington, DC 20010 USA. EM ckidwell@ucla.edu RI Butman, John/A-2694-2008; Davis, Stephen/L-5260-2013; Demchuk, Andrew/E-1103-2012; Hill, Michael/C-9073-2012; OI Davis, Stephen/0000-0003-0962-2300; Demchuk, Andrew/0000-0002-4930-7789; Hill, Michael/0000-0002-6269-1543; Butman, John/0000-0002-1547-9195; Saver, Jeffrey/0000-0001-9141-2251 FU NIBIB NIH HHS [EB 002087]; NINDS NIH HHS [K23 NS 02088, K24 NS 02092, NS 39498] NR 28 TC 296 Z9 311 U1 0 U2 38 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 OCT 20 PY 2004 VL 292 IS 15 BP 1823 EP 1830 DI 10.1001/jama.292.15.1823 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 862IV UT WOS:000224485100020 PM 15494579 ER PT J AU Fauci, AS AF Fauci, AS TI Emerging infectious diseases - A clear and present danger to humanity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CHALLENGE C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Bldg 31,Room 7A03,MSC 2520, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 12 TC 7 Z9 8 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 20 PY 2004 VL 292 IS 15 BP 1887 EP 1888 DI 10.1001/jama.292.15.1887 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 862IV UT WOS:000224485100030 PM 15494589 ER PT J AU Hutchison, WD Dostrovsky, JO Walters, JR Courtemanche, R Boraud, T Goldberg, J Brown, P AF Hutchison, WD Dostrovsky, JO Walters, JR Courtemanche, R Boraud, T Goldberg, J Brown, P TI Neuronal oscillations in the basal ganglia and movement disorders: Evidence from whole animal and human recordings SO JOURNAL OF NEUROSCIENCE LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the Society-for-Neuroscience CY OCT 23-27, 2004 CL San Diego, CA SP Soc Neurosci DE beta; gamma; globus pallidus; pallidum; oscillator; Parkinson; subcortical ID HUMAN GLOBUS-PALLIDUS; SUBTHALAMIC NUCLEUS; PARKINSONS-DISEASE; MULTISECOND OSCILLATIONS; FIRING RATE; DOPAMINE; MODEL; SYNCHRONIZATION; MODULATION; DISCHARGE C1 Toronto Western Hosp, Div Neurosurg, Toronto, ON M5T 2S8, Canada. Univ Toronto, Dept Physiol, Toronto, ON M5S 1A1, Canada. NIH, Neurophysiol Pharmacol Sect, Bethesda, MD 20892 USA. Concordia Univ, Dept Exercise Sci, Montreal, PQ H3G 1M8, Canada. CNRS, Basal Ganglia Unite Mixte Rech 5543, F-75794 Paris 16, France. Univ Texas, Dept Physiol, San Antonio, TX 78249 USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. Inst Neurol, Sobell Dept Neurophysiol, London WC1N 3BG, England. RP Hutchison, WD (reprint author), Toronto Western Hosp, Div Neurosurg, 399 Bathurst St MP11-308, Toronto, ON M5T 2S8, Canada. EM whutch@uhnres.utoronto.ca RI Boraud, Thomas/A-6260-2008; Brown, Peter/J-4307-2016 OI Brown, Peter/0000-0002-5201-3044 NR 27 TC 141 Z9 143 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 20 PY 2004 VL 24 IS 42 BP 9240 EP 9243 DI 10.1523/JNEUROSCI.366-04.2004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 863TY UT WOS:000224587200007 PM 15496658 ER PT J AU Otmakhov, N Cheng, JHT Carpenter, S Asrican, B Dosemeci, A Reese, TS Lisman, J AF Otmakhov, N Cheng, JHT Carpenter, S Asrican, B Dosemeci, A Reese, TS Lisman, J TI Persistent accumulation of calcium/calmodulin-dependent protein kinase II in dendritic spines after induction of NMDA receptor-dependent chemical long-term potentiation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE protein kinase; postsynaptic density; imaging; synapse; LTP; long-term potentiation; EM; tissue culture; fluorescence ID D-ASPARTATE RECEPTOR; POSTSYNAPTIC DENSITY; IN-VIVO; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; ALPHA-SUBUNIT; NR2B SUBUNIT; CAMKII; AUTOPHOSPHORYLATION AB Calcium/calmodulin-dependent protein kinase II ( CaMKII) is a leading candidate for a synaptic memory molecule because it is persistently activated after long-term potentiation (LTP) induction and because mutations that block this persistent activity prevent LTP and learning. Previous work showed that synaptic stimulation causes a rapidly reversible translocation of CaMKII to the synaptic region. We have now measured green fluorescent protein (GFP)-CaMKIIalpha translocation into synaptic spines during NMDA receptor-dependent chemical LTP (cLTP) and find that under these conditions, translocation is persistent. Using red fluorescent protein as a cell morphology marker, we found that there are two components of the persistent accumulation. cLTP produces a persistent increase in spine volume, and some of the increase in GFP-CaMKIIalpha is secondary to this volume change. In addition, cLTP results in a dramatic increase in the bound fraction of GFP-CaMKIIalpha in spines. To further study the bound pool, immunogold electron microscopy was used to measure CaMKIIalpha in the postsynaptic density (PSD), an important regulator of synaptic function. cLTP produced a persistent increase in the PSD-associated pool of CaMKIIalpha. These results are consistent with the hypothesis that CaMKIIalpha accumulation at synapses is a memory trace of past synaptic activity. C1 Brandeis Univ, Volen Ctr Complex Syst, Waltham, MA 02454 USA. Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. NINDS, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP Brandeis Univ, Volen Ctr Complex Syst, 415 South St, Waltham, MA 02454 USA. EM stephen.carpenter@umassmed.edu; lisman@brandeis.edu FU NINDS NIH HHS [R01 NS-27337] NR 53 TC 153 Z9 160 U1 0 U2 8 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 OCT 20 PY 2004 VL 24 IS 42 BP 9324 EP 9331 DI 10.1523/JNEUROSCI.2350-04.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 863TY UT WOS:000224587200017 PM 15496668 ER PT J AU Taplin, SH Ichikawa, L Yood, MU Manos, MM Geiger, AM Weinmann, S Gilbert, J Mouchawar, J Leyden, WA Altaras, R Beverly, RK Casso, D Westbrook, EO Bischoff, K Zapka, JG Barlow, WE AF Taplin, SH Ichikawa, L Yood, MU Manos, MM Geiger, AM Weinmann, S Gilbert, J Mouchawar, J Leyden, WA Altaras, R Beverly, RK Casso, D Westbrook, EO Bischoff, K Zapka, JG Barlow, WE TI Reason for late-stage breast cancer: Absence of screening or detection, or breakdown in follow-up? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INCREASE MAMMOGRAPHY USE; ABNORMAL MAMMOGRAMS; WOMEN; POPULATION; MORTALITY; QUALITY; CARE; METAANALYSIS; STRATEGIES; DIAGNOSIS AB Background: Mammography screening increases the detection of early-stage breast cancers. Therefore, implementing screening should reduce the percentage of women who are diagnosed with late-stage disease. However, despite high national mammography screening rates, late-stage breast cancers still occur, possibly because of failures in screening implementation. Methods: Using data from seven health care plans that included 1.5 million women aged 50 years or older, we conducted retrospective reviews of chart and automated data for 3 years before 1995-1999 diagnoses of late-stage (metastatic and/or tumor size :3 cm; case subjects, n = 1347) and early-stage breast cancers (control subjects, n = 1347). We categorized the earliest screening mammogram during the period 13-36 months before diagnosis as none (absence of screening), negative (absence of detection), or positive (potential breakdown in follow-up). We compared the proportion of case and control subjects in each category of screening implementation and estimated the likelihood (odds ratio [OR] with 95% confidence intervals [CIs]) of late-stage breast cancer. We also evaluated demographic characteristics associated with absence of screening in women with late-stage disease. All statistical tests were two-sided. Results: Absence of screening, absence of detection, and potential breakdown in follow-up were distributed differently among case (52.1%, 39.5%, and 8.4%, respectively) and control subjects (34.4%, 56.9%, and 8.8%, respectively) (P =.03). Among all women, the odds of having late-stage cancer were higher among women with an absence of screening (OR = 2.17, 95% CI = 1.84 to 2.56; P<.001). Among case patients, women were more likely to be in the absence-of-screening group if they were aged 75 years or older (OR = 2.77,95% CI = 2.10 to 3.65), unmarried (OR = 1.78, 95% CI = 1.41 to 2.24), or without a family history of breast cancer (OR = 1.84, 95% CI = 1.45 to 2.34). A higher proportion of women from census blocks with less education (58.5% versus 49.4%; P =.003) or lower median annual income (54.4% versus 42.9%; P =.004) were in the absence-of-screening category compared with the proportion for the other two categories combined. Conclusions: To reduce late-stage breast cancer occurrence, reaching unscreened women, including elderly, unmarried, low-income, and less educated women, should be made a top priority for screening implementation. C1 Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. Henry Ford Hlth Syst, Detroit, MI USA. Kaiser Permanente No Calif, Oakland, CA USA. Kaiser Permanente So Calif, Pasadena, CA USA. Kaiser Permanente NW, Portland, OR USA. Kaiser Permanente Hawaii, Honolulu, HI USA. Kaiser Permanente Colorade, Denver, CO USA. Univ Massachusetts, Sch Med, Worcester, MA USA. Canc Res & Biostat, Seattle, WA USA. RP Taplin, SH (reprint author), NCI, Appl Res Program, 9000 Rockville Pike,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM taplins@mail.nih.gov FU NCI NIH HHS [CA79689, CA 63731] NR 44 TC 77 Z9 81 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 20 PY 2004 VL 96 IS 20 BP 1518 EP 1527 DI 10.1093/jnci.djh284 PG 10 WC Oncology SC Oncology GA 863PL UT WOS:000224573900011 PM 15494602 ER PT J AU Widemann, BC Balis, FM Shalabi, A Boron, M O'Brien, M Cole, DE Jayaprakash, N Ivy, P Castle, V Muraszko, K Moertel, CL Trueworthy, R Hermann, RC Moussa, A Hinton, S Reaman, G Poplack, D Adamson, PC AF Widemann, BC Balis, FM Shalabi, A Boron, M O'Brien, M Cole, DE Jayaprakash, N Ivy, P Castle, V Muraszko, K Moertel, CL Trueworthy, R Hermann, RC Moussa, A Hinton, S Reaman, G Poplack, D Adamson, PC TI Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G(2) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID VENTRICULOLUMBAR PERFUSION; CEREBROSPINAL-FLUID; RESCUE; PHARMACOKINETICS; LEUCOVORIN AB The bacterial enzyme carboxypeptidase G(2) (CPDG(2)) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG(2) (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG(2) administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Be-fore CPDG(2) administration, the median concentrations of methotrexate in CSF were 264 muM (range = 97-510 muM) among patients who had CSF exchange and 8050 muM (range = 2439-16500 muM) among patients who did not. After intrathecal CTDG(2) administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG(2) were not detected in plasma after treatment with intrathecal CPDG(2). Intrathecal CPDG(2) is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Childrens Hosp & Clin, St Paul, MN USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. NW Georgia Oncol Ctr, PC, Marietta, GA USA. Hillcrest Med Ctr, Tulsa, OK USA. Kansas City Canc Ctr, Kansas City, KS USA. Childrens Oncol Grp, Arcadia, CA USA. Texas Childrens Canc Ctr, Houston, TX USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10,Rm 13C103, Bethesda, MD 20892 USA. EM bw42y@nih.gov NR 14 TC 30 Z9 32 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 20 PY 2004 VL 96 IS 20 BP 1557 EP 1559 DI 10.1093/jnci/djh270 PG 3 WC Oncology SC Oncology GA 863PL UT WOS:000224573900015 PM 15494606 ER PT J AU Alexander, RB Propert, KJ Schaeffer, AJ Landis, JR Nickel, JC O'Leary, MP Pontari, MA McNaughton-Collins, M Shoskes, DA Comiter, CV Datta, NS Fowler, JE Nadler, RB Zeitlin, SI Knauss, JS Wang, YL Kusek, JW Nyberg, LM Litwin, MS AF Alexander, RB Propert, KJ Schaeffer, AJ Landis, JR Nickel, JC O'Leary, MP Pontari, MA McNaughton-Collins, M Shoskes, DA Comiter, CV Datta, NS Fowler, JE Nadler, RB Zeitlin, SI Knauss, JS Wang, YL Kusek, JW Nyberg, LM Litwin, MS CA Chronic Prostatitis Collaborative TI Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome - A randomized, double-blind trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NATIONAL-INSTITUTES; SYMPTOM INDEX; CLINICAL-TRIAL; PREVALENCE; DIAGNOSIS; COHORT; THERAPY AB Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men is principally defined by pain in the pelvic region lasting more than 3 months. No cause of the disease has been established, and therapies are empirical and mostly untested. Antimicrobial agents and alpha-adrenergic receptor blockers are frequently used. Objective: To determine whether 6-week therapy with ciprofloxacin or tamsulosin is more effective than placebo at improving symptoms in men with refractory, long-standing CP/CPPS. Design: Randomized, double-blind trial with a 2 x 2 factorial design comparing 6 weeks of therapy with ciprofloxacin, tamsulosin, both drugs, or placebo. Setting: Urology outpatient clinics at 10 tertiary care medical centers in North America. Patients: Patients were identified from referral-based practices of urologists. One hundred ninety-six men with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score of at least 15 and a mean of 6.2 years of symptoms were enrolled. Patients had received substantial previous treatment. Measurements: The authors evaluated NIH-CPSI total score and subscores, patient-reported global response assessment, a generic measure of quality of life, and adverse events. Interventions: Ciprofloxacin, 500 mg twice daily; tamsulosin, 0.4 mg once daily; a combination of the 2 drugs; or placebo. Results: The NIH-CPSI total score decreased modestly in all treatment groups. No statistically significant difference in the primary outcome was seen for ciprofloxacin versus no ciprofloxacin (P = 0.15) or tamsulosin versus no tamsulosin (P > 0.2). Treatments also did not differ significantly for any of the secondary outcomes. Limitations: Treatment lasting longer than 6 weeks was not tested. Patients who had received less pretreatment may have responded differently. Conclusion: Ciprofloxacin and tamsulosin did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Penn, Philadelphia, PA 19104 USA. Temple Univ, Philadelphia, PA 19104 USA. Northwestern Univ, Chicago, IL 60611 USA. Queens Univ, Kingston, ON, Canada. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Cleveland Clin Florida, Weston, FL USA. Univ Arizona, Tucson, AZ USA. Charles Drew Univ, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Mississippi, Jackson, MS 39216 USA. Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. RP Alexander, RB (reprint author), Vet Affairs Maryland Hlth Care Syst, 10 N Greene St, Baltimore, MD 21201 USA. EM ralexander@smail.umaryland.edu RI Landis, J. Richard/A-9330-2010 FU NIDDK NIH HHS [U01 DK53730, U01 DK53572, U01 DK53732, U01 DK53734, U01 DK53736, U01 DK53738, U01 DK53746] NR 26 TC 119 Z9 131 U1 1 U2 4 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 OCT 19 PY 2004 VL 141 IS 8 BP 581 EP 589 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 864SD UT WOS:000224652300001 PM 15492337 ER PT J AU Kenney, LB Yasui, Y Inskip, PD Hammond, S Neglia, JP Mertens, AC Meadows, AT Friedman, D Robison, LL Diller, L AF Kenney, LB Yasui, Y Inskip, PD Hammond, S Neglia, JP Mertens, AC Meadows, AT Friedman, D Robison, LL Diller, L TI Breast cancer after childhood cancer: A report from the childhood cancer survivor study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; INVOLVED-FIELD RADIATION; HODGKINS-DISEASE; RISK-FACTORS; YOUNG-WOMEN; ADOLESCENCE; CHEMOTHERAPY; COHORT; PROBABILITIES AB Background: Survivors of childhood cancer are at risk for secondary breast cancer. Other than previous chest radiation therapy, risk factors for secondary breast cancer have not been established. Objective: To identify risk factors for breast cancer among female survivors of childhood cancer. Design: Retrospective cohort study. Setting: The Childhood Cancer Survivor Study (CCSS), a multicenter study of persons who survived more than 5 years after childhood cancer diagnosed from 1970 to 1986. Participants: Among 6068 women in the CCSS, 95 women had 111 confirmed cases of breast cancer. Measurements: Standardized incidence ratios for breast cancer were calculated by using age-specific incidence rates in the general population. Breast cancer incidence was evaluated with respect to primary cancer diagnosis and therapy, age at and time since primary diagnosis, menstrual and reproductive history, and family history of cancer. Results: Breast cancer risk was increased in survivors who were treated with chest radiation therapy (standardized incidence ratio, 24.7 [95% CI, 19.3 to 31.0]) and survivors of bone and soft-tissue sarcoma who were not treated with chest radiation therapy (standardized incidence ratios, 6.7 and 7.6, respectively). Family history of breast cancer (relative rate, 2.7 [CI, 1.3 to 5.0]) and history of thyroid disease (relative rate, 1.7 [CI, 1.1 to 2.6]) were independently associated with increased risk, and exposure to pelvic radiation was protective (relative rate, 0.6 [CI, 0.4 to 0.9]). Age at primary cancer diagnosis and menstrual and reproductive histories did not statistically significantly modify risk. Limitations: This cohort has not yet attained an age at which breast cancer risk is greatest. Conclusion: Survivors of childhood sarcomas and those who received chest radiation therapy are at risk for secondary breast cancer. When assessing a survivor's risk, clinicians should consider primary diagnosis, previous radiation therapy, family cancer history, and history of thyroid disease. C1 Dana Farber Canc Inst, Qual Life Clin, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. NCI, Bethesda, MD USA. Ohio State Univ, Coll Med & Publ Hlth, Columbus, OH USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Kenney, LB (reprint author), Dana Farber Canc Inst, Qual Life Clin, 44 Binney St, Boston, MA 02115 USA. EM Lisa_Kenney@DFCI.harvard.edu RI Yasui, Yutaka/E-2564-2015 OI Yasui, Yutaka/0000-0002-7717-8638 FU NCI NIH HHS [CA 55727] NR 37 TC 138 Z9 142 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 19 PY 2004 VL 141 IS 8 BP 590 EP 597 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 864SD UT WOS:000224652300002 PM 15492338 ER PT J AU Islam, A Thompson, KSJ Akhtar, S Handley, SL AF Islam, A Thompson, KSJ Akhtar, S Handley, SL TI Increased 5-HT2A receptor expression and function following central glucocorticoid receptor knockdown in vivo SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE glucocorticoid receptor; serotonin; antisense oligonucleotide; depression ID ANTISENSE OLIGONUCLEOTIDES; TRANSGENIC MICE; RAT-BRAIN; BINDING CHARACTERISTICS; TARGETED DISRUPTION; GENE-EXPRESSION; MESSENGER-RNA; HEAD SHAKES; DEPRESSION; SEROTONIN AB Central glucocorticoid receptor function may be reduced in depression. In vivo modelling of glucocorticoid receptor underfunctionality would assist in understanding its role in depressive illness. The role of glucocorticoid receptors in modulating 5-HT2A receptor expression and function in the central nervous system (CNS) is presently unclear, but 5-HT2A receptor function also appears altered in depression. With the aid of RNAse H accessibility mapping, we have developed a 21-mer antisense oligodeoxynucleotide (5-TAAAAACAGGCTTCTGATCCT-3', termed GRAS-5) that showed 56% reduction in glucocorticoid receptor mRNA and 80% down-regulation in glucocorticoid receptor protein in rat C-6 glioma cells. Sustained delivery to rat cerebral ventricles in slow release biodegradable polymer microspheres produced a marked decrease in glucocorticoid receptor mRNA and protein in hypothalamus (by 39% and 80%, respectively) and frontal cortex (by 26% and 67%, respectively) 5 days after a single injection, with parallel significant up-regulation of 5-HT2A receptor mRNA expression (13%) and binding (21%) in frontal cortex. 5-HT2A receptor function, determined by DOI-head-shakes, showed a 55% increase. These findings suggest that central 5-HT2A receptors are, directly or indirectly, under tonic inhibitory control by glucocorticoid receptor. (C) 2004 Elsevier B.V. All rights reserved. C1 Aston Univ, LHS, Birmingham B4 7ET, W Midlands, England. Knoll Pharmaceut, Nottingham NG1 1GF, England. RP Islam, A (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM islama@nhlbi.nih.gov NR 43 TC 4 Z9 4 U1 1 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 OCT 19 PY 2004 VL 502 IS 3 BP 213 EP 220 DI 10.1016/j.ejphar.2004.09.014 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 864LR UT WOS:000224635500006 PM 15476747 ER PT J AU Takeuchi, S Zhang, WG Wakamatsu, K Ito, S Hearing, VJ Kraemer, KH Brash, DE AF Takeuchi, S Zhang, WG Wakamatsu, K Ito, S Hearing, VJ Kraemer, KH Brash, DE TI Melanin acts as a cause an atypical potent UVB photosensitizer to mode of cell death in murine skin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUNBURN; MICE; CANCER; DAMAGE; PHEOMELANIN; IRRADIATION; APOPTOSIS; EPIDERMIS; TUMORS; BLACK AB Melanin protects the skin against DNA damage induced by direct absorption of sunlight's UV radiation. Yet, irradiating melanin in vitro or in cultured cells also generates active oxygen species such as superoxide, which can indirectly induce oxidative base lesions and DNA strand breaks. This photosensitization is greater for pheomelanin (yellow and red melanin) than for eumelanin (brown and black). The in vivo photosensitizing ability of melanin is unknown. We used congenic mice of black, yellow, and albino coat colors to investigate the induction of DNA lesions and apoptosis after exposure to predominantly UVB (280-320 nm) or UVA (320-400 nm) radiation. Cyclobutane pyrimidine dimers induced by direct UVB absorption were equal in all three strains, as was apoptosis measured as sunburn cells or as keratinocytes containing active caspase-3. However, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL)-positive cells were approximate to 3-fold more frequent in black and yellow mice after UVB or UVA irradiation than in albino. In epidermal sheets, TUNEL-positive cells lined the upper portion of the hair follicle, consistent with UV-induced photosensitization by melanin in the hair shaft. Because the concentration of eumelanin in black mice was three times that of pheomelanin in yellow mice, pheomelanin had 3-fold greater specific activity. We conclude that UV-irradiated melanin, particularly pheomelanin, photosensitizes adjacent cells to caspase-3 independent apoptosis, and this occurs at a frequency greater than the apoptosis induced by direct DNA absorption of UV. Melanin-induced apoptosis may contribute to the increased sensitivity of individuals with blonde and red hair to sunburn and skin cancer. C1 Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT 06520 USA. NCI, Basic Res Lab, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Toyoake, Aichi 4701192, Japan. RP Brash, DE (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, 333 Cedar St, New Haven, CT 06520 USA. EM douglas.brash@yale.edu FU Intramural NIH HHS [Z01 BC004517-31]; NCI NIH HHS [CA55737, CA78735, R01 CA055737] NR 37 TC 103 Z9 107 U1 1 U2 11 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 OCT 19 PY 2004 VL 101 IS 42 BP 15076 EP 15081 DI 10.1073/pnas.0403994101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865FT UT WOS:000224688700020 PM 15477596 ER PT J AU Dubois, M Lizunov, V Meister, A Gulik-Krzywicki, T Verbavatz, JM Perez, E Zimmerberg, J Zemb, T AF Dubois, M Lizunov, V Meister, A Gulik-Krzywicki, T Verbavatz, JM Perez, E Zimmerberg, J Zemb, T TI Shape control through molecular segregation in giant surfactant aggregates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PHASE-EQUILIBRIA; MIXTURES; BEHAVIOR; MODEL; NANODISCS; BILAYERS; SYSTEMS AB Mixtures of cationic and anionic surfactants crystallized at various ratios in the absence of added salt form micrometer-sized colloids. Here, we propose and test a general mechanism explaining how this ratio controls the shape of the resulting colloidal structure, which can vary from nanodiscs to punctured planes; during co-crystallization, excess (nonstoichiometric) surfactant accumulates on edges or pores rather than being incorporated into crystalline bilayers. Molecular segregation then produces a sequence of shapes controlled by the initial mole ratio only. Using freeze-fracture electron microscopy, we identified three of these states and their corresponding coexistence regimes. Fluorescence con-focal microscopy directly showed the segregation of anionic and cationic components within the aggregate. The observed shapes are consistently reproduced upon thermal cycling, demonstrating that the icosahedral shape corresponds to the existence of a local minimum of bending energy for facetted icosahedra when the optimal amount of excess segregated material is present. C1 CEA Saclay, Serv Chim Mol, F-91191 Gif Sur Yvette, France. CNRS, Ctr Genet Mol, F-91191 Gif Sur Yvette, France. NIH, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. Russian Acad Sci, AN Frumkin Electrochem Inst, Moscow 117071, Russia. CNRS, UMR 5623, Lab Interact Mol & Reactiv Chim & Photochim, F-31062 Toulouse, France. CEA Saclay, Serv Biophys Fonct Membranaires, Dept Biol Cellulaire & Morphol, F-91198 Gif Sur Yvette, France. RP Dubois, M (reprint author), CEA Saclay, Serv Chim Mol, F-91191 Gif Sur Yvette, France. EM dubois@drecam.cea.fr RI ZEMB, Thomas/E-5958-2010 NR 37 TC 104 Z9 106 U1 2 U2 21 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 OCT 19 PY 2004 VL 101 IS 42 BP 15082 EP 15087 DI 10.1073/pnas.0400837101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865FT UT WOS:000224688700021 PM 15479765 ER PT J AU Oh, S Perera, LP Burke, DS Waldmann, TA Berzofsky, JA AF Oh, S Perera, LP Burke, DS Waldmann, TA Berzofsky, JA TI IL-15/IL-15R alpha-mediated avidity maturation of memory CD8(+) T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID I TETRAMERIC COMPLEXES; CORECEPTOR FUNCTION; FUNCTIONAL AVIDITY; SELECTIVE EXPANSION; MHC TETRAMERS; CTL; VIRUS; VIVO; EXPRESSION; RESPONSES AB T cell avidity is critical to viral clearance, but mechanisms of CD8(+) T cell avidity maturation are poorly understood. Here, we find that IL-15 mediates two mechanisms of avidity maturation. (i) By selection at the population level, IL-15 promotes greater survival of high- compared with low-avidity cytotoxic T lymphocytes (CTLs). High-avidity CTLs express higher levels of IL-15Ralpha and persist longer by homeostatic proliferation. (ii) At the individual cell level, IL-15 induces higher levels of surface coreceptor CD8alphabeta, increasing functional avidity. IL-15 during priming selects or induces higher-avidity CTLs. Conversely, high-avidity CTLs are diminished in IL15Ralpha knockout mice. These results provide an explanation of CD8+ T cell avidity maturation and may contribute to the design of novel vaccines. C1 NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Publ Hlth, Baltimore, MD 21205 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, NIH, Bldg 10,Room 6B-12,MSC-1578, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 44 TC 94 Z9 99 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 OCT 19 PY 2004 VL 101 IS 42 BP 15154 EP 15159 DI 10.1073/pnas.0406649101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865FT UT WOS:000224688700033 PM 15477598 ER PT J AU Anisimov, SV Sharov, AA AF Anisimov, SV Sharov, AA TI Incidence of "quasi-ditags" in catalogs generated by Serial Analysis of Gene Expression (SAGE) SO BMC BIOINFORMATICS LA English DT Article ID CELLS; IDENTIFICATION; STEP AB Background: Serial Analysis of Gene Expression (SAGE) is a functional genomic technique that quantitatively analyzes the cellular transcriptome. The analysis of SAGE libraries relies on the identification of ditags from sequencing files; however, the software used to examine SAGE libraries cannot distinguish between authentic versus false ditags ("quasi-ditags"). Results: We provide examples of quasi-ditags that originate from cloning and sequencing artifacts (i.e. genomic contamination or random combinations of nucleotides) that are included in SAGE libraries. We have employed a mathematical model to predict the frequency of quasi-ditags in random nucleotide sequences, and our data show that clones containing less than or equal to 2 ditags (which include chromosomal cloning artifacts) should be excluded from the analysis of SAGE catalogs. Conclusions: Cloning and sequencing artifacts contaminating SAGE libraries could be eliminated using simple pre-screening procedure to increase the reliability of the data. C1 Lund Univ, Wallenberg Neurosci Ctr, Sect Neuronal Survival, S-22184 Lund, Sweden. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Anisimov, SV (reprint author), Lund Univ, Wallenberg Neurosci Ctr, Sect Neuronal Survival, S-22184 Lund, Sweden. EM Sergey.Anisimov@mphy.lu.se; sharoval@grc.nia.nih.gov NR 12 TC 5 Z9 5 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 18 PY 2004 VL 5 AR 152 DI 10.1186/1471-2105-5-152 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 880DU UT WOS:000225770000001 PM 15491492 ER PT J AU Gillanders, EM Masiello, A Gildea, D Umayam, L Duggal, P Jones, MP Klein, AP Freas-Lutz, D Ibay, G Trout, K Wolfsberg, TG Trent, JM Bailey-Wilson, JE Baxevanis, AD AF Gillanders, EM Masiello, A Gildea, D Umayam, L Duggal, P Jones, MP Klein, AP Freas-Lutz, D Ibay, G Trout, K Wolfsberg, TG Trent, JM Bailey-Wilson, JE Baxevanis, AD TI GeneLink: a database to facilitate genetic studies of complex traits SO BMC GENOMICS LA English DT Article ID GENOME-WIDE SCAN; HEREDITARY PROSTATE-CANCER; DATA-MANAGEMENT-SYSTEM; CYSTIC-FIBROSIS GENE; SUSCEPTIBILITY GENES; GERMLINE MUTATIONS; FAMILIES; LINKAGE; IDENTIFICATION; PHENOTYPES AB Background: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. Results: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale ( multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses ( e. g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes ( either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. Conclusions: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer ( HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. Translat Gen Res Inst, Phoenix, AZ 85004 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM lgilland@mail.nih.gov; ant@masiello.org; dgildea@mail.nih.gov; umayamla@mail.nih.gov; pduggal@nhgri.nih.gov; mpjones@nhgri.nih.gov; aklein@nhgri.nih.gov; dlutz@nhgri.nih.gov; gibay@nhgri.nih.gov; nezumi@fred.net; tyra@nhgri.nih.gov; jtrent@tgen.org; jebw@mail.nih.gov; andy@nhgri.nih.gov NR 16 TC 6 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 18 PY 2004 VL 5 AR 81 DI 10.1186/1471-2164-5-81 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 869YU UT WOS:000225022000002 PM 15491493 ER PT J AU Hiby, SE Walker, JJ O'Shaughnessy, KM Redman, CWG Carrington, M Trowsdale, J Moffett, A AF Hiby, SE Walker, JJ O'Shaughnessy, KM Redman, CWG Carrington, M Trowsdale, J Moffett, A TI Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE natural killer cells; HLA; placenta killer; immunoglobulin receptors; trophoblast ID NATURAL-KILLER-CELLS; COMPLEX CLASS-I; 3 ETHNIC-GROUPS; INHIBITORY RECEPTOR; DIRECT BINDING; EXPRESSION; TROPHOBLAST; PREGNANCY; REPERTOIRES; DIVERSITY AB Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms. C1 Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. St James Univ Hosp, Dept Obstet & Gynecol, Leeds LS9 7TF, W Yorkshire, England. Univ Cambridge, Addenbrookes Hosp, Sch Clin, Dept Med, Cambridge CB2 2QQ, England. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynecol, Oxford, England. SAIC Frederick Inc, Basic Res Program, NCI, Frederick, MD 21702 USA. RP Moffett, A (reprint author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. EM am485@cam.ac.uk OI Walker, James/0000-0002-8922-083X FU Medical Research Council [G9800943]; NCI NIH HHS [N01CO12400, N01-CO-12400]; NICHD NIH HHS [5R01HD39670-02, R01 HD039670] NR 62 TC 553 Z9 568 U1 3 U2 29 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 OCT 18 PY 2004 VL 200 IS 8 BP 957 EP 965 DI 10.1084/jem.20041214 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 865BQ UT WOS:000224677900002 PM 15477349 ER PT J AU Ruttens, B Kovac, P AF Ruttens, B Kovac, P TI A facile synthesis of armed and disarmed colitose thioglycosides SO SYNTHESIS-STUTTGART LA English DT Article ID VIBRIO-CHOLERAE O139; STRUCTURAL-ANALYSIS; LIPOPOLYSACCHARIDE; DONORS AB Ethyl 2,4-di-O-acetyl-3,6-dideoxy-1-thio-beta-L-xylo-hexopyranoside (10) and ethyl 2,4-di-O-benzyl-3,6-dideoxy-1-thio-beta-L-xylo-hexopyranoside (12) were synthesized in 60% and 55% overall yield, respectively. Starting from alpha-L-fucose, sequential peracetylation, anomeric bromination, nucleophilic substitution of the anomeric bromide with NaSEt and deacetylation gave ethyl 1-thio-beta-L-fucopyranoside (6). Acid catalyzed regioselective cleavage of the orthoester in ethyl 2-O-acetyl-3,4-O-(1-ethoxyethylidene)-1-thio-beta-L-fucopyranoside, prepared from 6, yielded the corresponding 2,4-diacetate, which was deoxygenated at C-3 to provide the disarmed thioglycoside 10. Deacetylation of 10, followed by benzylation, gave armed thioglycoside 12. Several intermediates did not require purification by chromatography. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov NR 23 TC 16 Z9 16 U1 2 U2 6 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD OCT 18 PY 2004 IS 15 BP 2505 EP 2508 DI 10.1055/s-2004-831206 PG 4 WC Chemistry, Organic SC Chemistry GA 864SS UT WOS:000224653800012 ER PT J AU Nicklas, BJ Penninx, BWJH Cesari, M Kritchevsky, SB Newman, AB Kanaya, AM Pahor, M Ding, JZ Harris, TB AF Nicklas, BJ Penninx, BWJH Cesari, M Kritchevsky, SB Newman, AB Kanaya, AM Pahor, M Ding, JZ Harris, TB TI Association of visceral adipose tissue with incident myocardial infarction in older men and women - The health, aging and body composition study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aged; body composition; myocardial infarction; obesity ID CORONARY-HEART-DISEASE; JAPANESE-AMERICAN MEN; ALL-CAUSE MORTALITY; 10-YEAR FOLLOW-UP; FAT DISTRIBUTION; COMPUTED-TOMOGRAPHY; RISK-FACTORS; CARDIOVASCULAR-DISEASE; MASS INDEX; WAIST CIRCUMFERENCE AB Assessment of body fat distribution, particularly visceral adipose tissue, may be important for accurate risk evaluation for cardiovascular disease in the elderly. This 1997-1998 US study examined the association of incident myocardial infarction (MI) with total adiposity (body mass index and fat mass) and body fat distribution (waist-to-thigh ratio, waist circumference, visceral and subcutaneous adipose tissue) in well-functioning men (n = 1,116) and women (n = 1,387) aged 70-79 years enrolled in the Health, Aging and Body Composition Study. There were 116 MI events (71 in men, 45 in women) during an average follow-up time of 4.6 (standard deviation, 0.9) years. No association was found between incident MI and the adiposity or fat distribution variables for men. For women, visceral adipose tissue was an independent predictor of MI (hazard ratio = 1.67, 95% confidence interval: 1.28, 2.17 per standard-deviation increase; p < 0.001). No association was found between body mass index or total fat mass and MI events in women. The association of visceral adipose tissue with MI in women was independent of high density lipoprotein cholesterol, interleukin-6 concentration, hypertension, and diabetes (hazard ratio = 1.79, 95% confidence interval: 1.24, 2.58 per standard-deviation increase; p < 0.01). The amount of adipose tissue stored in the intraabdominal cavity is an important, independent risk factor for MI in well-functioning, elderly women. C1 Wake Forest Univ, Bowman Gray Sch Med, J Paul Sticht Ctr Aging, Ctr Human Genom,Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Nicklas, BJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, J Paul Sticht Ctr Aging, Ctr Human Genom,Sect Gerontol & Geriatr Med, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. EM bnicklas@wfubmc.edu RI Cesari, Matteo/A-4649-2008; Newman, Anne/C-6408-2013; OI Cesari, Matteo/0000-0002-0348-3664; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIA NIH HHS [P30AG 21332, N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106, R01 AG/DK20583] NR 48 TC 137 Z9 151 U1 0 U2 10 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 OCT 15 PY 2004 VL 160 IS 8 BP 741 EP 749 DI 10.1093/aje/kwh281 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860RP UT WOS:000224361000003 PM 15466496 ER PT J AU Zhang, YW Holford, TR Leaderer, B Boyle, P Zahm, SH Zhang, B Zou, KY Morton, LM Owens, PH Flynn, S Tallini, G Zheng, TZ AF Zhang, YW Holford, TR Leaderer, B Boyle, P Zahm, SH Zhang, B Zou, KY Morton, LM Owens, PH Flynn, S Tallini, G Zheng, TZ TI Menstrual and reproductive factors and risk of non-Hodgkin's lymphoma among Connecticut women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; Connecticut; lymphoma, non-Hodgkin; menstruation; reproduction; risk factors; women ID FOOD FREQUENCY QUESTIONNAIRE; HEALTH TRIAL FEASIBILITY; UNITED-STATES; INTERLEUKIN-6 PRODUCTION; MINORITY POPULATIONS; DIETARY INTERVENTION; MEDICAL CONDITIONS; TIME TRENDS; BONE-MARROW; CANCER AB Several recent studies have suggested a potential role of menstrual and reproductive factors in the risk of non-Hodgkin's lymphoma. To further examine the relation, the authors analyzed data from a population-based case-control study of non-Hodgkin's lymphoma in Connecticut women between 1996 and 2000. A total of 601 histologically confirmed cases and 717 randomly selected population-based controls were included in this study. An in-person interview was conducted using a standardized and structured questionnaire to collect information on menstrual and reproductive factors and potential confounding factors. Compared with nulliparous women, women who had four or more pregnancies during their lifetime were found to have a significantly reduced risk of non-Hodgkin's lymphoma (odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.4, 0.9). Risk appeared to decrease with increasing number of pregnancies (p(trend) = 0.03). The authors also observed an increased risk of non-Hodgkin's lymphoma overall (OR = 1.5, 95% CI: 1.0, 2.2) and of diffuse non-Hodgkin's lymphoma (OR = 1.7, 95% CI: 1.1, 2.7) for women who started their first menstrual period at age 15 or more years compared with those who started their first menstrual period before age 12 years. These findings support a reduced risk of non-Hodgkin's lymphoma associated with multiple pregnancies and an increased risk of non-Hodgkin's lymphoma associated with later age at menarche. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. European Inst Oncol, Dept Epidemiol & Biostat, Milan, Italy. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. EM tongzhang.zheng@yale.edu RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; OI Boyle, Peter/0000-0001-6251-0610; Morton, Lindsay/0000-0001-9767-2310; Tallini, Giovanni/0000-0003-0113-6682 NR 37 TC 24 Z9 24 U1 0 U2 2 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 OCT 15 PY 2004 VL 160 IS 8 BP 766 EP 773 DI 10.1093/aje/kwh278 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860RP UT WOS:000224361000006 PM 15466499 ER PT J AU McInerney-Leo, A Biesecker, BB Hadley, DW Kase, RG Giambarresi, TR Johnson, E Lerman, C Struewing, JP AF McInerney-Leo, A Biesecker, BB Hadley, DW Kase, RG Giambarresi, TR Johnson, E Lerman, C Struewing, JP TI BRCA1/2 testing in hereditary breast and ovarian cancer families: Effectiveness of problem-solving training as a counseling intervention SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE genetic counseling; hereditary breast and ovarian cancer; predictive genetic testing; counseling interventions; psychological well-being ID PSYCHOLOGICAL DISTRESS; IMPACT; SUSCEPTIBILITY; RISK; MUTATIONS; RELATIVES; STRESS; WOMEN; GENES AB It remains uncertain whether members of hereditary breast and ovarian cancer (HBOC) families experience psychological distress with genetic testing and whether pre-test counseling can have a moderating effect on client well-being. One purpose of this study was to assess change in psychological well-being from baseline to 6-9 months follow-up and the effect of a problem-solving training (PST) intervention on psychological well-being. Two hundred and twelve members of 13 HBOC families were offered BRCA1/2 testing for a previously identified family mutation. Participants received education and were randomized to one of two counseling interventions; PST or client-centered counseling. Psychological wellbeing was assessed at baseline and again at 69 months following the receipt of test results, or at the equivalent time for those participants who chose not to undergo testing. Well-being was assessed using measures of depressive symptoms (CESD), intrusive thoughts (IES), cancer worries, and self-esteem. Comparisons were made between those who chose testing and those who did not as well as between those who received positive and negative test results. One hundred eighty one participants elected to undergo genetic testing (85%) and 47 of these (26%) were identified as BRCA1/2 mutation carriers. Breast and ovarian cancer worries decreased significantly (p = 0.007 and 0.008, respectively) in those who tested negative while there was no appreciable change in psychological well-being from baseline to follow-up in either those who tested positive or in non-testers. Among all participants, particularly testers, those randomized to PST had a greater reduction in depressive symptoms than those randomized to client-centered counseling (p < 0.05 and p = 0.02, respectively). Regardless of the decision to test, individuals with a personal history of cancer (n = 22) were more likely to have an increase in breast cancer worries compared to those who had never been diagnosed with cancer (p < 0.001). Results suggest that a problem-solving counseling intervention may help to enhance psychological well-being following testing and that a personal history of cancer may increase psychological distress associated with genetic testing. Published 2004 Wiley-Liss, Inc. C1 NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Westat Res, Rockville, MD USA. Johns Hopkins Biostat Ctr, Baltimore, MD USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Biesecker, BB (reprint author), NHGRI, Med Genet Branch, Bldg 10,Room 10C101,10 Ctr Dr,MSC 1852, Bethesda, MD 20892 USA. EM barbarab@nhgri.nih.gov RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 37 TC 19 Z9 19 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 15 PY 2004 VL 130A IS 3 BP 221 EP 227 DI 10.1002/ajmg.a.30265 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 858HA UT WOS:000224181700001 PM 15378542 ER PT J AU Peters, JA Kenen, R Giusti, R Loud, J Weissman, N Greene, MH AF Peters, JA Kenen, R Giusti, R Loud, J Weissman, N Greene, MH TI Exploratory study of the feasibility and utility of the colored eco-genetic relationship map (CEGRM) in women at high genetic risk of developing breast cancer SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE genetic counseling; breast cancer genetics; genetic testing; family; friends; relationships; kin; social network; communications; pedigree; genogram; ecomap; psychosocial; psychological; social; familial cancer; hereditary cancer ID FAMILY RELATIONSHIPS; OVARIAN-CANCER; BRCA1; COMMUNICATION; SPIRITUALITY; PERCEPTIONS; DISCLOSURE; RELATIVES; SPOUSES; CONTEXT AB We report here the results of an exploratory feasibility study of the colored eco-genetic relationship map (CEGRM), a novel, recently-developed psychosocial assessment tool, which incorporates features of the genetic pedigree, family systems genogram, and ecomap. The CEGRM presents a simple, concise, visual representation of the social interaction domains of information, services, and emotional support through the application of color-coded symbols to the genetic pedigree. The interactive process of completing the CEGRM was designed to facilitate contemporary genetic counseling goals oh (a) understanding the client in the context of her/his social milieu; (b) bolstering client self-awareness and insight; (c) fostering active client participation and mutuality in the counseling interaction; (d) eliciting illuminating social narratives; and (e) addressing outstanding emotional issues. Twenty women participating in a breast imaging study of women from families with BRCA1/2 mutations completed and evaluated various aspects of the CEGRM. We found that efficient construction of the CEGRM was feasible, and that compliance was excellent. Participants developed insights into their social milieu through observing the visual pattern of relationships illustrated by the CEGRM. The process of co-constructing the CEGRM fostered the participant's active involvement in the session, marked by mutuality and increased empathy. In this clinical research context, the participants felt free to share poignant stories about their friends and families. Further studies are planned to refine the CEGRM and to examine its utility in cancer genetics research. Published 2004 Wiley-Liss, Inc. C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. New Jersey Med Coll, Dept Sociol & Anthropol, Ewing, NJ USA. US FDA, Rockville, MD 20857 USA. RP Peters, JA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7021, Rockville, MD 20852 USA. EM petersju@mail.nih.gov NR 53 TC 12 Z9 12 U1 2 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 15 PY 2004 VL 130A IS 3 BP 258 EP 264 DI 10.1002/ajmg.a.30271 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 858HA UT WOS:000224181700007 PM 15378540 ER PT J AU Harvey, JJ Lee, SP Chan, EK Kim, JH Hwang, ES Cha, CY Knutson, JR Han, MK AF Harvey, JJ Lee, SP Chan, EK Kim, JH Hwang, ES Cha, CY Knutson, JR Han, MK TI Characterization and applications of CataCleave probe in real-time detection assays SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID ROLLING-CIRCLE AMPLIFICATION; POLYMERASE CHAIN-REACTION; DNA-POLYMERASE; PCR; HYBRIDIZATION; REPLICATION; TECHNOLOGY; INVITRO; SYSTEM; OLIGONUCLEOTIDES AB Cycling probe technology (CPT), which utilizes a chimeric DNA-RNA-DNA probe and RNase H, is a rapid, isothermal probe amplification system for the detection of target DNA. Upon hybridization of the probe to its target DNA, RNase H cleaves the RNA portion of the DNA/RNA hybrid. Utilizing CPT, we designed a catalytically cleavable fluorescence probe (CataCleave probe) containing two internal fluorophores. Fluorescence intensity of the probe itself was weak due to Forster resonance energy transfer. Cleavage of the probe by RNase H in the presence of its target DNA caused enhancement of donor fluorescence, but this was not observed with nonspecific target DNA. Further, RNase H reactions with CataCleave probe exhibit a catalytic dose-dependent response to target DNA. This confirms the capability for the direct detection of specific target DNA through a signal amplification process. Moreover, CataCleave probe is also ideal for detecting DNA amplification processes, such as polymerase chain reaction (PCR) and isothermal rolling circle amplification (RCA). In fact, we observed signal enhancement proportional to the amount of RCA product formed. We were also able to monitor real-time PCR by measuring enhancement of donor fluorescence. Hence, CataCleave probe is useful for real-time monitoring of both isothermal and temperature-cycling nucleic acid amplification methods. (C) 2004 Elsevier Inc. All rights reserved. C1 Excimus Biotech Inc, Baltimore, MD 21202 USA. Seoul Natl Univ, Coll Med, Dept Microbiol, Seoul, South Korea. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Han, MK (reprint author), Excimus Biotech Inc, Baltimore, MD 21202 USA. EM myunhan@yahoo.com RI Hwang, Eung-Soo/J-5731-2012; OI Hwang, Eung Soo/0000-0001-9562-4577 NR 34 TC 25 Z9 27 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 15 PY 2004 VL 333 IS 2 BP 246 EP 255 DI 10.1016/j.ab.2004.05.037 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 862MA UT WOS:000224493800006 PM 15450799 ER PT J AU Insel, TR Fenton, WS AF Insel, TR Fenton, WS TI Ensuring public trust SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, 6001 Executive Blvd,Room 8235,MSC 9669, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2004 VL 56 IS 8 BP 539 EP 539 DI 10.1016/j.biopsych.2004.09.002 PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 863CT UT WOS:000224538800001 PM 15476681 ER PT J AU Schweitzer, JB Lee, DO Hanford, RB Zink, CF Ely, TD Tagamets, MA Hoffman, JM Grafton, ST Kilts, CD AF Schweitzer, JB Lee, DO Hanford, RB Zink, CF Ely, TD Tagamets, MA Hoffman, JM Grafton, ST Kilts, CD TI Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: Normalization of behavior but not related brain activity SO BIOLOGICAL PSYCHIATRY LA English DT Article DE PET; ADHD; methylphenidate; executive function; working memory; PASAT ID DEFICIT HYPERACTIVITY DISORDER; ANTERIOR CINGULATE CORTEX; EVENT-RELATED FMRI; CEREBRAL GLUCOSE-METABOLISM; WORKING-MEMORY; PREFRONTAL CORTEX; MAGNETIC-RESONANCE; STIMULANT MEDICATION; DOPAMINE MODULATION; DECISION-MAKING AB Background: We examined the effect of prolonged methylphenidate (MPH) treatment on the functional neuroanatomy of executive functioning in adult men with attention-deficit/hyperactivity disorder (ADHD). Methods: Positron emission tomography with [O-15] water measured alterations of regional cerebral blood flow (rCBF) during the Paced Auditory Serial Addition Task and a control task in 10 ADHD and 11 normal control men. Attention-deficit/hyperactivity disorder men were imaged unmedicated and after a clinically optimal dose of MPH for 3 weeks. Results: Methylphenidate improved ADHD task performance, reduced rCBF in the prefrontal cortex (PFC), and increased rCBF in the right thalamus and precentral gyrus. Comparisons between the ADHD and normal control groups showed that normal control participants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. Executive functioning was associated with greater subcortical (basal ganglia and cerebellar vermis) activation in the ADHD than normal control group under both conditions. Conclusions: Methylphenidate does not normalize task-related activity in ADHD. Task-related rCBF decreases in the PFC may he due to improved filtering out of task-irrelevant stimuli by way of MPH-mediated dopamine release in the PFC. C1 Univ Maryland, Sch Med, Div Child Psychiat, Catonsville, MD 21228 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. NCI, NIH, Bethesda, MD 20892 USA. Dartmouth Coll, Ctr Cognit Sci, Hanover, NH 03755 USA. RP Schweitzer, JB (reprint author), Univ Maryland, Sch Med, Div Child Psychiat, POB 21247, Catonsville, MD 21228 USA. EM jschweit@mprc.umaryland.edu FU NIMH NIH HHS [K08 MH01053, R03 MH55550] NR 93 TC 80 Z9 82 U1 4 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2004 VL 56 IS 8 BP 597 EP 606 DI 10.1016/j.biopsych.2004.07.011 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 863CT UT WOS:000224538800010 PM 15476690 ER PT J AU Monk, CS Nelson, EE Woldehawariat, G Montgomery, LA Zarahn, E McClure, EB Guyer, AE Leibenluft, E Charney, DS Ernst, M Pine, DS AF Monk, CS Nelson, EE Woldehawariat, G Montgomery, LA Zarahn, E McClure, EB Guyer, AE Leibenluft, E Charney, DS Ernst, M Pine, DS TI Experience-dependent plasticity for attention to threat: Behavioral neurophysiological evidence in humans SO BIOLOGICAL PSYCHIATRY LA English DT Article DE attention; emotion; threat; fMRI; neuroimaging ID GENERALIZED ANXIETY DISORDER; EMOTIONAL FACES; BIAS; SIGNALS; STIMULI; MEMORY; TRAUMA AB Biased attention to threat represents a key feature of anxiety disorders. This bias is altered by therapeutic or stressful experiences, suggesting that the bias is plastic. Charting on-line behavioral and neurophysiological changes in attention bias may generate insights on the nature of such plasticity. We used an attention-orientation task with threat cites to examine bow healthy individuals alter their response over time to such cites. In Experiments 1 through 3, we established that healthy individuals demonstrate an increased attention bias away from threat over time. For Experiment 3, we used functional magnetic resonance imaging to determine the neural bases for this phenomenon. Gradually increasing attention bias away from threat is associated with increased activation in the occipitotemporal cortex. Examination of plasticity of attention bias with individuals at risk for anxiety disorders way reveal how threatening stimuli come to be categorized differently in this population over time. C1 NIMH, Bethesda, MD 20892 USA. US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY USA. RP Monk, CS (reprint author), 15K N Dr,Room 204, Bethesda, MD 20892 USA. EM christopher.monk@nih.gov RI Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014 OI Nelson, Eric/0000-0002-3376-2453; NR 23 TC 25 Z9 26 U1 9 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2004 VL 56 IS 8 BP 607 EP 610 DI 10.1016/j.biopsych.2004.07.012 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 863CT UT WOS:000224538800011 PM 15476691 ER PT J AU Guralnik, JM Eisenstaedt, RS Ferrucci, L Klein, HG Woodman, RC AF Guralnik, JM Eisenstaedt, RS Ferrucci, L Klein, HG Woodman, RC TI Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia SO BLOOD LA English DT Article ID IRON-DEFICIENCY ANEMIA; CHRONIC-RENAL-FAILURE; CHRONIC DISEASE; HEMOGLOBIN CONCENTRATION; ERYTHROPOIETIN THERAPY; INTRAVENOUS IRON; HEPCIDIN; MYELODYSPLASIA; INFLAMMATION; POPULATION AB Clinicians frequently identify anemia in their older patients, but national data on the prevalence and causes of anemia in this population in the United States have been unavailable. Data presented here are from the noninstitutionalized US population assessed in the third National Health and Nutrition Examination Survey (1988-1994). Anemia was defined by World Health Organization criteria; causes of anemia included iron, folate, and B-12 deficiencies, renal insufficiency, anemia of chronic inflammation (ACI), formerly termed anemia of chronic disease, and unexplained anemia (UA). ACI by definition required normal iron stores with low circulating iron (less than 60 mug/dL). After age 50 years, anemia prevalence rates rose rapidly, to a rate greater than 20% at age 85 and older. Overall, 11.0% of men and 10.2% of women 65 years and older were anemic. Of older persons with anemia, evidence of nutrient deficiency was present in one third, ACI or chronic renal disease or both was present in one third, and UA was present in one third. Most occurrences of anemia were mild; 2.8% of women and 1.6% of men had hemoglobin levels lower than 110 g/L (11 g/dL). Therefore, anemia is common, albeit not severe, in the older population, and a substantial proportion of anemia is of indeterminate cause. The impact of anemia on quality of life, recovery from illness, and functional abilities must be further investigated in older persons. (C) 2004 by The American Society of Hematology. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20815 USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20815 USA. Temple Univ, Sch Med, Dept Internal Med, Philadelphia, PA 19122 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Ortho Biotech Prod LP, Bridgewater, NJ USA. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Rm 3C-309, Bethesda, MD 20815 USA. EM jg48s@nih.gov NR 49 TC 534 Z9 558 U1 1 U2 12 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 OCT 15 PY 2004 VL 104 IS 8 BP 2263 EP 2268 DI 10.1182/blood-2004-05-1812 PG 6 WC Hematology SC Hematology GA 860XU UT WOS:000224378300016 PM 15238427 ER PT J AU Hundley, TR Gilfillan, AM Tkaczyk, C Andrade, MV Metcalfe, DD Beaven, MA AF Hundley, TR Gilfillan, AM Tkaczyk, C Andrade, MV Metcalfe, DD Beaven, MA TI Kit and FC epsilon RI mediate unique and convergent signals for release of inflammatory mediators from human mast cells SO BLOOD LA English DT Article ID NF-KAPPA-B; PROTEIN-KINASE-C; ALPHA GENE-EXPRESSION; NECROSIS-FACTOR-ALPHA; TNF-ALPHA; PERIPHERAL-BLOOD; NUCLEAR-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; CYTOKINE PRODUCTION; MAP KINASES AB In human mast cells, derived from CD34(+) peripheral blood cells, we observed that Kit ligand (KL) failed to induce degranulation but acted in synergy with antigen to markedly enhance degranulation, levels of cytokine gene transcripts, and production of cytokines. Further examination revealed that antigen and KL activated common and unique signaling pathways to account for these varied responses. KL, unlike antigen, failed to activate protein kinase C but activated phospholipase Cgamma and calcium mobilization and augmented these signals as well as degranulation when added together with antigen. Both KL and antigen induced signals that are associated with cytokine production, namely phosphorylation of the mitogen-activated protein kinases, phosphatidylinositol 3-kinase-dependent phosphorylation of protein kinase B (also known as Akt), and phosphorylation of nuclear factor kappaB (NFkappaB). However, only KL stimulated phosphorylation of signal transducer and activator of transcription 5 (STAT5) and STAT6, whereas antigen weakly stimulated the protein kinase C-dependent induction and phosphorylation of c-Jun and associated activating protein-1 (AP-1) components, an action that was markedly potentiated by costimulation with KL. Interestingly, most signals were down-regulated on continuous exposure to KL but were reactivated along with cytokine gene transcription on addition of antigen. The findings, in total, indicated that a combination of FcepsilonRI and Kit-mediated signals and transcriptional processes were required for optimal physiologic responses of human mast cells to antigen. (C) 2004 by The American Society of Hematology. C1 NIAID, Lab Mol Immunol, NHLBI, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NHLBI, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), NIAID, Lab Mol Immunol, NHLBI, NIH, Bldg 10,Rm 8N 109, Bethesda, MD 20892 USA. EM beavenm@nhlbi.nih.gov RI ANDRADE, MARCUS/A-4764-2008 OI ANDRADE, MARCUS/0000-0002-3716-0919 NR 67 TC 98 Z9 102 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2004 VL 104 IS 8 BP 2410 EP 2417 DI 10.1182/blood-2004-02-0631 PG 8 WC Hematology SC Hematology GA 860XU UT WOS:000224378300036 PM 15217825 ER PT J AU Sinha-Datta, U Horikawa, I Michishita, E Datta, A Sigler-Nicot, JC Brown, M Kazanji, M Barrett, JC Nicot, C AF Sinha-Datta, U Horikawa, I Michishita, E Datta, A Sigler-Nicot, JC Brown, M Kazanji, M Barrett, JC Nicot, C TI Transcriptional activation of hTERT through the NF-kappa B pathway in HTLV-1-transformed cells SO BLOOD LA English DT Article ID VIRUS TYPE-1 TAX; TELOMERASE CATALYTIC SUBUNIT; MESSENGER-RNA EXPRESSION; BLOOD MONONUCLEAR-CELLS; HTLV-I; C-MYC; GENE-EXPRESSION; LEUKEMIA-CELLS; CONSTITUTIVE ACTIVATION; HISTONE ACETYLATION AB In immortal cells, the existence of a mechanism for the maintenance of telomere length is critical. In most cases this is achieved by the reactivation of telomerase, a cellular reverse transcriptase that prevents telomere shortening. Here we report that the telomerase gene (hTERT) promoter is up-regulated during transmission of human T-cell lymphotropic virus type-I (HTLV-I) to primary T cells in vitro and in ex vivo adult T-cell leukemia/ lymphoma (ATLL) samples, but not asymptomatic carriers. Although Tax impaired induction of human telomerase reverse transcriptase (hTERT) mRNA in response to mitogenic stimulation, transduction of Tax into primary lymphocytes was sufficient to activate and maintain telomerase expression and telomere length when cultured in the absence of any exogenous stimulation. Transient transfection assays revealed that Tax stimulates the hTERT promoter through the nuclear factor kappaB (NF-kappaB) pathway. Consistently, Tax mutants inactive for NF-kappaB activation could not activate the hTERT or sustain telomere length in transduced primary lymphocytes. Analysis of the hTERT promoter occupancy in vivo using chromatin immunoprecipitation assays suggested that an increased binding of c-Myc and Sp1 is involved in the NF-kappaB-mediated activation of the hTERT promoter. This study establishes the role of Tax in regulation of telomerase expression, which may cooperate with other functions of Tax to promote HTLV-I-associated adult T-cell leukemia. C1 Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. Ohio State Univ, Dept Obstet Gynecol, Div Reprod Biol, Columbus, OH 43210 USA. Ohio State Univ, Dept Obstet Gynecol, Vaccine Res Prptide & Prot Engn Lab, Columbus, OH 43210 USA. NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nicot, C (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, 3025 Wahl Hall W,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM cnicot@kumc.edu FU NCI NIH HHS [R01 CA106258] NR 74 TC 84 Z9 91 U1 0 U2 4 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 OCT 15 PY 2004 VL 104 IS 8 BP 2523 EP 2531 DI 10.1182/blood-2003-12-4251 PG 9 WC Hematology SC Hematology GA 860XU UT WOS:000224378300051 PM 15226182 ER PT J AU Yamamoto, Y Moore, R Goldsworthy, TL Negishi, M Maronpot, RR AF Yamamoto, Y Moore, R Goldsworthy, TL Negishi, M Maronpot, RR TI The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice SO CANCER RESEARCH LA English DT Article ID RAT HEPATOCARCINOGENESIS; BETA-CATENIN; CAR; PROLIFERATION; INDUCTION; CYP2B; GENE AB Hepatocellular carcinoma (HCC) is known to progress through a step often called tumor promotion. Phenobarbital (PB) is the prototype of nongenotoxic cacinogens that promote HCC in rodents. The molecular target of PB to elicit the promotion has been the subject of intense investigations over the last 30 years since it was discovered. The nuclear receptor constitutive active/androstane receptor (CAR) is activated by PB as well as by various other xenobiotics such as therapeutic drugs and environmental pollutants. CAR activation results in the transcriptional induction of numerous hepatic genes including those that encode xenobiotic-metabolizing enzymes such as a set of cytochrome P450s. In addition to PB, many CAR activators are nongenotoxic carcinogens, but the role of CAR in liver tumor promotion remains unexplored. Using Car(-/-) mice, we have here examined tumor promotion by chronic treatment with PB in drinking water after tumor initiation with a single dose of the genotoxic carcinogen diethylnitrosamine. None of the Car(-/-) mice developed either eosinophilic foci or advanced liver tumors, whereas all Car(+/+) mice developed HCC and/or adenoma by 39 weeks. The results indicate that CAR is the molecular target of promotion by PB and that activation of this receptor is an essential requirement for liver tumor development. C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Integrated Lab Syst Inc, Res Triangle Pk, NC USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov NR 19 TC 219 Z9 233 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2004 VL 64 IS 20 BP 7197 EP 7200 DI 10.1158/0008-5472.CAN-04-1459 PG 4 WC Oncology SC Oncology GA 862WO UT WOS:000224522200003 PM 15492232 ER PT J AU Wang, E Lichtenfels, R Bukur, J Ngalame, Y Panelli, MC Seliger, B Marincola, FM AF Wang, E Lichtenfels, R Bukur, J Ngalame, Y Panelli, MC Seliger, B Marincola, FM TI Ontogeny and oncogenesis balance the transcriptional profile of renal cell cancer SO CANCER RESEARCH LA English DT Article ID MESSENGER-RNA AMPLIFICATION; EXPRESSION PATTERNS; CARCINOMA; IDENTIFICATION; TUMORS; CLASSIFICATION; MARKERS; GENES; RESPONSES; DISCOVERY AB Global transcript analysis is increasingly used to describe cancer taxonomies beyond the microscopic reach of the eye. Diagnostic and prognostic portraits are formulated by ranking cancers according to transcriptional proximity. However, the role that distinct biological factors play in defining these portraits remains undefined. It is likely that the transcriptional repertoire of cancers depends, on one hand, on the anamnestic retention of their ontogenesis and, on the other, on the emergence of novel expression patterns related to oncogenesis. We compared the transcriptional profile of primary renal cell cancers (RCCs) with that of normal kidney tissue and several epithelial cancers of nonrenal origin to weigh the contribution that ontogeny and oncogenesis make in molding their genetic profile. Unsupervised global transcript analysis demonstrated that RCCs retain transcriptional signatures related to their ontogeny and cluster close to normal renal epithelium. When renal lineage-associated genes are removed from the analysis and cancer-specific genes are analyzed, RCCs segregate with other cancers with limited lineage specificity underlying a predominance of the oncogenic process over lineage specificity. However, a RCC-specific set of oncogenesis-related genes was identified and surprisingly shared by sarcomas. In summary, the transcriptional portrait of primary RCCs is largely dominated by ontogeny. Genes responsible for lineage specificity may represent poor molecular targets for immune or drug therapy. Most genes associated with oncogenesis are shared with other cancers and may represent better therapeutic targets. Finally, a small subset of genes is associated with lineage-specific oncogenesis, and these may provide information regarding the biological behavior of RCCs and facilitate diagnostic classification of RCCs. C1 Ctr Clin, Immunogenet Sect, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. Univ Mainz, Dept Internal Med, D-6500 Mainz, Germany. Univ Halle Wittenberg, Inst Med Immunol, Halle Saale, Germany. RP Marincola, FM (reprint author), Ctr Clin, Immunogenet Sect, Dept Transfus Med, NIH, Bldg 10,Room 1C-711,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. EM FMarincola@mail.ml.nih.gov NR 35 TC 21 Z9 21 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2004 VL 64 IS 20 BP 7279 EP 7287 DI 10.1158/0008-5472.CAN-04-1597 PG 9 WC Oncology SC Oncology GA 862WO UT WOS:000224522200018 PM 15492247 ER PT J AU Kim, IY Lee, DH Lee, DK Kim, WJ Kim, MM Morton, RA Lerner, SP Kim, SJ AF Kim, IY Lee, DH Lee, DK Kim, WJ Kim, MM Morton, RA Lerner, SP Kim, SJ TI Restoration of bone morphogenetic protein receptor type II expression leads to a decreased rate of tumor growth in bladder transitional cell carcinoma cell line TSU-Pr1 SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER CELLS; OSTEOGENIC PROTEIN-1; FACTOR-BETA; IDENTIFICATION; PROLIFERATION; REGULATORS; APOPTOSIS AB Bone morphogenetic proteins (BMPs), potential regulators of cellular growth and metastasis that signal through an interaction with plasma membrane receptors, have been suggested to be important regulators of malignant cells. The present study was carried out to evaluate the potential role of BMP receptor (BMP-R) types IA, IB, and II in bladder transitional cell carcinoma (TCC) cells. Initially, we investigated the expression of these BMP-Rs in 30 archival tissues of human bladder TCC using immunohistochemistry; 10 benign bladder specimens were used for comparison. The results demonstrated that the expression of BMP-Rs is localized preferentially to the transitional epithelium and that there was a significant association between loss of BMP-RII expression and tumor grade. To rind a cell line that can serve as a model system for clinical observation, we subsequently examined sensitivity to BMP-4 and expression of BMP-RII, BMP-RIA, and BMP-RIB in three human bladder cancer cell lines, TCC-Sup, RT4, and TSU-Pr1. Of the three cell lines, TSU-Pr1 exhibited a decreased level of BMP-RII expression and was resistant to the growth-inhibitory effect of BMP-4. Overexpression of BMP-RII in TSU-Pr1 cells not only restored BMP-4 responsiveness but also significantly decreased tumorigenicity in vivo. Taken together, these results demonstrate that human bladder TCC tissues have a frequent loss of BMP-RII expression and that overexpression of BMP-RII leads to restoration of BMP signaling and decreased tumor growth in the human bladder TCC cell line TSU-Pr1. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Chungbuk Natl Univ Hosp, Dept Urol, Cheongju, South Korea. Ewha Womans Univ, Dept Urol, Seoul, South Korea. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. Univ Calif Irvine, Dept Urol, Irvine, CA USA. RP Kim, IY (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kims@dce41.nci.nih.gov NR 22 TC 19 Z9 21 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2004 VL 64 IS 20 BP 7355 EP 7360 DI 10.1158/0008-5472.CAN-04-0154 PG 6 WC Oncology SC Oncology GA 862WO UT WOS:000224522200027 PM 15492256 ER PT J AU Maudsley, S Davidson, L Pawson, AJ Chan, R de Maturana, RL Millar, RP AF Maudsley, S Davidson, L Pawson, AJ Chan, R de Maturana, RL Millar, RP TI Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a G alpha(i)-coupling state of the type I GnRH receptor SO CANCER RESEARCH LA English DT Article ID HUMAN OVARIAN-CANCER; AGONIST-DIRECTED TRAFFICKING; MESSENGER-RIBONUCLEIC-ACID; EPIDERMAL-GROWTH-FACTOR; HIGH-AFFINITY BINDING; PROSTATE-CANCER; PHOSPHOTYROSINE PHOSPHATASE; ENDOMETRIAL CANCER; GENE-EXPRESSION; BREAST-CANCER AB Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the Galpha(1)-type G protein, in contrast to the predominant Galpha(q) coupling in gonadotropes. Unlike Galpha(q) coupling, Galpha(i) coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type 11 GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a Galpha(i)-mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced Galpha(i)-based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the Galpha(i)-coupled form of the type I GnRH receptor. C1 Univ Edinburgh, Med Res Council Human Reprod Sci Unit, Edinburgh EH16 4SB, Midlothian, Scotland. NIA, Gerontol Res Ctr, Johns Hopkins Med Ctr, Natl Inst Hlth, Baltimore, MD 21224 USA. Ardama Biosci, Edinburgh, Midlothian, Scotland. Univ Cape Town, Fac Hlth Sci, Div Med Biochem, ZA-7925 Cape Town, South Africa. RP Millar, RP (reprint author), Univ Edinburgh, Med Res Council Human Reprod Sci Unit, Chancellors Bldg 49,Little France Crescent, Edinburgh EH16 4SB, Midlothian, Scotland. EM r.millar@hrsu.mrc.ac.uk RI Pawson, Adam/Q-5678-2016 OI Pawson, Adam/0000-0003-2280-845X NR 56 TC 101 Z9 105 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2004 VL 64 IS 20 BP 7533 EP 7544 DI 10.1158/0008-5472.CAN-04-1360 PG 12 WC Oncology SC Oncology GA 862WO UT WOS:000224522200051 PM 15492280 ER PT J AU Athar, M Li, CX Tang, XW Chi, SM Zhang, XL Kim, AL Tyring, SK Kopelovich, L Hebert, J Epstein, EH Bickers, DR Xie, JW AF Athar, M Li, CX Tang, XW Chi, SM Zhang, XL Kim, AL Tyring, SK Kopelovich, L Hebert, J Epstein, EH Bickers, DR Xie, JW TI Inhibition of Smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis SO CANCER RESEARCH LA English DT Article ID MEDIATED APOPTOSIS; GENE-EXPRESSION; HUMAN HOMOLOG; TARGET GENES; HEDGEHOG; GROWTH; CANCER; MUTATIONS; PATHWAY; LIGAND AB Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces (similar to66%) UVB-induced basal cell carcinoma formation in Ptch1(-/-) mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1(+/-) mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis. C1 Univ Texas, Dept Pharmacol & Toxicol, Sealy Ctr Canc Cell Biol, Med Branch, Galveston, TX 77555 USA. Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10027 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Univ Texas, Hlth Sci Ctr, Dept Dermatol, Houston, TX USA. RP Xie, JW (reprint author), Univ Texas, Dept Pharmacol & Toxicol, Sealy Ctr Canc Cell Biol, Med Branch, 301 Univ Blvd, Galveston, TX 77555 USA. EM ma493@columbia.edu FU NCI NIH HHS [CA101061, CA 94160, CA81888] NR 31 TC 115 Z9 123 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2004 VL 64 IS 20 BP 7545 EP 7552 DI 10.1158/0008-5472.CAN-04-1393 PG 8 WC Oncology SC Oncology GA 862WO UT WOS:000224522200052 PM 15492281 ER PT J AU Misteli, T AF Misteli, T TI Spatial positioning: A new dimension in genome function SO CELL LA English DT Review ID DOUBLE-STRAND BREAKS; NUCLEAR-ORGANIZATION; GENES; CHROMATIN; DNA; TRANSCRIPTION; LOCALIZATION; DROSOPHILA; INTERPHASE; DOMAINS AB The eukaryotic cell nucleus is a heterogeneous organelle. Chromosomes are nonrandomly positioned within the nuclear space, and individual gene loci experience distinct local environments due to the presence of chromatin domains and subnuclear compartments. Recent observations have highlighted the important yet still largely mysterious role of spatial positioning in genome activity and stability. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov NR 19 TC 119 Z9 128 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD OCT 15 PY 2004 VL 119 IS 2 BP 153 EP 156 DI 10.1016/j.cell.2004.09.035 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 863QQ UT WOS:000224577200004 PM 15479633 ER PT J AU Wang, W Zhu, WZ Wang, SQ Yang, DM Crow, MT Xiao, RP Cheng, HP AF Wang, W Zhu, WZ Wang, SQ Yang, DM Crow, MT Xiao, RP Cheng, HP TI Sustained beta(1)-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway SO CIRCULATION RESEARCH LA English DT Article DE beta(1)-adrenergic receptor; Ca2+/calmodulin-dependent protein kinase II; cAMP-dependent protein kinase; cardiac contractility; phospholamban ID DEPENDENT PROTEIN-KINASE; CHANNEL RYANODINE RECEPTOR; ADRENERGIC-RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; INDEPENDENT PATHWAY; COUPLED RECEPTORS; A PHOSPHORYLATION; CALCIUM-CHANNELS; MYOCYTES; DESENSITIZATION AB A tenet of beta(1)-adrenergic receptor (beta(1)AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in beta(1)AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term beta(1)AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) beta(1)AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site ((16)Ser) to CaMKII site ((17)Thr). Thus, beta(1)AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding beta(1)AR signaling in chronic heart failure. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. RP NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM chengp@grc.nia.nih.gov OI Wang, Wang/0000-0001-9093-412X NR 46 TC 132 Z9 139 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 15 PY 2004 VL 95 IS 8 BP 798 EP 806 DI 10.1161/01.RES.0000145361.50017.aa PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 862CD UT WOS:000224466300008 PM 15375008 ER PT J AU Simon, R Maitournam, A AF Simon, R Maitournam, A TI Evaluating the efficiency of targeted designs for randomized clinical trials SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; SAMPLE SIZES; GEFITINIB; CHEMOTHERAPY; COMBINATION; LYMPHOMA AB Purpose: Genomic technologies make it increasingly possible to identify patients most likely to benefit from a molecularly targeted drug. This creates the opportunity to conduct targeted clinical trials with eligibility restricted to patients predicted to be responsive to the drug. Experimental Design: We evaluated the relative efficiency of a targeted clinical trial design to an untargeted design for a randomized clinical trial comparing a new treatment to a control. Efficiency was evaluated with regard to number of patients required for randomization and number required for screening. Results: The effectiveness of this design, relative to the more traditional design with broader eligibility, depends on multiple factors, including the proportion of responsive patients, the accuracy of the assay for predicting responsiveness, and the degree to which the mechanism of action of the drug is understood. Explicit formulas were derived for computing the relative efficiency of targeted versus untargeted designs. Conclusions: Targeted clinical trials can dramatically reduce the number of patients required for study in cases where the mechanism of action of the drug is understood and an accurate assay for responsiveness is available. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsimon@nih.gov NR 13 TC 163 Z9 166 U1 0 U2 5 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 OCT 15 PY 2004 VL 10 IS 20 BP 6759 EP 6763 DI 10.1158/1078-0432.CCR-04-0496 PG 5 WC Oncology SC Oncology GA 864IO UT WOS:000224627400001 PM 15501951 ER PT J AU Lebowitz, PF Eng-Wong, J Swain, SM Berman, A Merino, MJ Chow, CK Venzon, D Zia, F Danforth, D Liu, E Zujewski, J AF Lebowitz, PF Eng-Wong, J Swain, SM Berman, A Merino, MJ Chow, CK Venzon, D Zia, F Danforth, D Liu, E Zujewski, J TI A phase II trial of Neoadjuvant docetaxel and capecitabine for locally advanced breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SURGICAL ADJUVANT BREAST; PREOPERATIVE CHEMOTHERAPY; THYMIDINE PHOSPHORYLASE; WOMEN; ENHANCEMENT; COMBINATION; INDUCTION; TUMORS; CELLS AB Purpose: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer. Experimental Design: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m(2) i.v. day 1) and capecitabine (1000 mg/m(2) orally twice daily days 2-15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m(2) i.v. day 1) and capecitabine (937.5 mg/m(2) orally twice daily days 2-15). Results: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m(2) at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m(2)/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine. Conclusions: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m(2) docetaxel and 1600 mg/m(2)/day days 2-15 is recommended. C1 NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Zujewski, J (reprint author), NCI, Med Oncol Clin Res Unit, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zujewskj@mail.nih.gov RI Venzon, David/B-3078-2008; Liu, Edison/C-4141-2008 NR 23 TC 28 Z9 30 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2004 VL 10 IS 20 BP 6764 EP 6769 DI 10.1158/1078-0432.CCR-04-0976 PG 6 WC Oncology SC Oncology GA 864IO UT WOS:000224627400002 PM 15501952 ER PT J AU Svingen, PA Loegering, D Rodriquez, J Meng, XW Mesner, PW Holbeck, S Monks, A Krajewski, S Scudiero, DA Sausville, EA Reed, JC Lazebnik, YA Kaufmann, SH AF Svingen, PA Loegering, D Rodriquez, J Meng, XW Mesner, PW Holbeck, S Monks, A Krajewski, S Scudiero, DA Sausville, EA Reed, JC Lazebnik, YA Kaufmann, SH TI Components of the cell death machine and drug sensitivity of the National Cancer Institute cell line panel SO CLINICAL CANCER RESEARCH LA English DT Review ID ETOPOSIDE-INDUCED APOPTOSIS; STRESS-INDUCED APOPTOSIS; TRAIL-INDUCED APOPTOSIS; COLON-CARCINOMA CELLS; CYTOCHROME-C; CASPASE ACTIVATION; IN-VITRO; MYELOGENOUS LEUKEMIA; ANTICANCER AGENTS; ACTIVE CASPASES AB Purpose: According to some studies, susceptibility of cells to anticancer drug-induced apoptosis is markedly inhibited by targeted deletion of genes encoding apoptotic protease activating factor 1 (Apaf-1) or certain caspases. Information about levels of these polypeptides in common cancer cell types and any possible correlation with drug sensitivity in the absence of gene deletion is currently fragmentary. Experimental Design: Immunoblotting was used to estimate levels of Apaf-1 as well as procaspase-2, -3, -6, -7, -8, and -9 in the 60-cell-line panel used for drug screening by the National Cancer Institute. Sensitivity of the same lines to >80,000 compounds was determined with 48-hour sulforhodamine B binding assays. Additional 6-day assays were performed for selected agents. Results: Levels of Apaf-1 and procaspases varied widely. Apaf-1 and procaspase-9, which are implicated in caspase activation after treatment of cells with various anticancer drugs, were detectable in all of the cell lines, with levels of Apaf-1 ranging from similar to1 X 10(5) to 2 X 10(6) molecules per cell and procaspase-9 from similar to5 X 10(3) to similar to1.6 X 10(5) molecules per cell. Procaspase-8 levels ranged from 1.7 X 10(5) to 8 X 10(6) molecules per cell. Procaspase-3, a major effector caspase, varied from undetectable to similar to1.6 X 10(6) molecules per cell. Correlations between levels of these polypeptides and sensitivity to any of a variety of experimental or conventional antineoplastic agents in either 2-day or 6-day cytotoxicity assays were weak at best. Conclusions: With the exception of caspase-3, all of the components of the core cell-death machinery are expressed in all of the cell lines examined. Despite variations in expression, levels of any one component are not a major determinant of drug sensitivity in these cells in vitro. C1 Mayo Clin, Div Oncol Res, Rochester, MN 55901 USA. Mayo Grad Sch, Dept Mol Pharmacol, Rochester, MN USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY USA. SAIC Frederick Inc, NCI, NIH, Frederick, MD USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Kaufmann, SH (reprint author), Mayo Clin, Div Oncol Res, Guggenheim 1342,200 1st St,SW, Rochester, MN 55901 USA. EM Kaufmann.Scott@Mayo.edu FU NCI NIH HHS [CA69008, CA69381] NR 114 TC 40 Z9 45 U1 0 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 OCT 15 PY 2004 VL 10 IS 20 BP 6807 EP 6820 DI 10.1158/1078-0432.CCR-0778-02 PG 14 WC Oncology SC Oncology GA 864IO UT WOS:000224627400007 PM 15501957 ER PT J AU Sparreboom, A Chen, HC Acharya, MR Senderowicz, AM Messmann, RA Kuwabara, T Venzon, DJ Murgo, AJ Headlee, D Sausville, EA Figg, WD AF Sparreboom, A Chen, HC Acharya, MR Senderowicz, AM Messmann, RA Kuwabara, T Venzon, DJ Murgo, AJ Headlee, D Sausville, EA Figg, WD TI Effects of alpha(1)-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine SO CLINICAL CANCER RESEARCH LA English DT Article ID BODY-SURFACE AREA; ALPHA-1-ACID GLYCOPROTEIN; UCN-01 7-HYDROXYSTAUROSPORINE; ALTERED PHARMACOKINETICS; ANTICANCER DRUG; PROTEIN-BINDING; PLASMA; ACID; CANCER; BLOOD AB Objective: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha(1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. Experimental Design: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). Results: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m2/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R-2 = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). Conclusion: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug. C1 NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Invest Drug Branch, Canc Treatment Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Kyowa Hakko Kogyo Co Ltd, Drug Dev Res Labs, Pharmaceut Res Inst, Shizuoka, Japan. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Venzon, David/B-3078-2008; Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 26 TC 19 Z9 19 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2004 VL 10 IS 20 BP 6840 EP 6846 DI 10.1158/1078-0432.CCR-04-0805 PG 7 WC Oncology SC Oncology GA 864IO UT WOS:000224627400010 PM 15501960 ER PT J AU Mocellin, S Provenzano, M Rossi, CR Pilati, P Scalerta, R Lise, M Nitti, D AF Mocellin, S Provenzano, M Rossi, CR Pilati, P Scalerta, R Lise, M Nitti, D TI Induction of endothelial nitric oxide synthase expression by melanoma sensitizes endothelial cells to tumor necrosis factor-driven cytotoxicity SO CLINICAL CANCER RESEARCH LA English DT Article ID ISOLATED LIMB PERFUSION; ALPHA-INDUCED APOPTOSIS; GROWTH-FACTOR PRODUCTION; REAL-TIME PCR; TNF-ALPHA; INDUCED ANGIOGENESIS; MICROVESSEL DENSITY; IN-VITRO; CANCER; INHIBITION AB Purpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF. Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated. Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells' supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells. Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting. C1 Univ Padua, Dipartimento Sci Oncol & Chirurg, Sezione Clin Chirurg, Policlin Univ, I-35128 Padua, Italy. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Mocellin, S (reprint author), Univ Padua, Dipartimento Sci Oncol & Chirurg, Sezione Clin Chirurg, Policlin Univ, Via Giustiniani 2, I-35128 Padua, Italy. EM mocellins@hotmail.com RI Rossi, Carlo Riccardo/A-7685-2010 OI Rossi, Carlo Riccardo/0000-0001-7875-5655 NR 58 TC 13 Z9 14 U1 0 U2 4 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 OCT 15 PY 2004 VL 10 IS 20 BP 6879 EP 6886 DI 10.1158/1078-0432.CCR-04-0791 PG 8 WC Oncology SC Oncology GA 864IO UT WOS:000224627400015 PM 15501965 ER PT J AU Alleman, WG Tabios, RL Chandramouli, GVR Aprelikova, ON Torres-Cabala, C Mendoza, A Rodgers, C Sopko, NA Linehan, WM Vasselli, JR AF Alleman, WG Tabios, RL Chandramouli, GVR Aprelikova, ON Torres-Cabala, C Mendoza, A Rodgers, C Sopko, NA Linehan, WM Vasselli, JR TI The in vitro and in vivo effects of re-expressing methylated von Hippel-Lindau tumor suppressor gene in clear cell renal carcinoma with 5-aza-2 '-deoxycytidine SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; DNA METHYLATION; PROMOTER HYPERMETHYLATION; UBIQUITIN LIGASE; CPG-METHYLATION; SILENCED GENES; FACTOR-ALPHA; CANCER; PROTEIN; BINDING AB Purpose: Clear cell renal carcinoma (ccRCC) is strongly associated with loss of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene is functionally lost through hypermethylation in up to 19% of sporadic ccRCC cases. We theorized that re-expressing VHL silenced by methylation in ccRCC cells, using a hypo-methylating agent, may be an approach to treatment in patients with this type of cancer. We test the ability of two hypo-methylating agents to re-express VHL in cell culture and in mice bearing human ccRCC and evaluate the effects of re-expressed VHL in these models. Experimental Design: Real-time reverse transcription-PCR was used to evaluate the ability of zebularine and 5-aza-2'-deoxycytidine (5-aza-dCyd) to re-express VHL in four ccRCC cell lines with documented VHL gene silencing through hypermethylation. We evaluated if the VHL re-expressed after hypo-methylating agent treatment could recreate similar phenotypic changes in ccRCC cells observed when the VHL gene is re-expressed via transfection in cell culture and in a xenograft mouse model. Finally we evaluate global gene expression changes occurring in our cells, using microarray analysis. Results: 5-Aza-dCyd was able to re-express VHL in our cell lines both in culture and in xenografted murine tumors. Well described phenotypic changes of VHL expression including decreased invasiveness into Matrigel, and decreased vascular endothelial growth factor and glucose transporter-1 expression were observed in the treated lines. VHL methylated ccRCC xenografted tumors were significantly reduced in size in mice treated with 5-aza-dCyd. Mice bearing nonmethylated but VHL-mutated tumors showed no tumor shrinkage with 5-aza-dCyd treatment. Conclusion: Hypo-methylating agents may be useful in the treatment of patients having ccRCC tumors consisting of cells with methylated VHL. C1 NCI, Urol Oncol Branch, CCR, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NCI, Urol Branch, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Chevy Chase, MD USA. Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, CCR, Lab Biosyst & Canc, Bldg 10,Room 2B47, Bethesda, MD 20892 USA. EM UOB@nih.gov NR 56 TC 37 Z9 41 U1 0 U2 1 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 OCT 15 PY 2004 VL 10 IS 20 BP 7011 EP 7021 DI 10.1158/1078-0432.CCR-04-0516 PG 11 WC Oncology SC Oncology GA 864IO UT WOS:000224627400031 PM 15501981 ER PT J AU Thomas, SM Zeng, Q Epperly, MW Gooding, WE Pastan, I Wang, QC Greenberger, J Grandis, JR AF Thomas, SM Zeng, Q Epperly, MW Gooding, WE Pastan, I Wang, QC Greenberger, J Grandis, JR TI Abrogation of head and neck squamous cell carcinoma growth by epidermal growth factor receptor ligand fused to Pseudomonas exotoxin transforming growth factor alpha-PE38 SO CLINICAL CANCER RESEARCH LA English DT Article ID MALIGNANT BRAIN-TUMORS; RECOMBINANT FORM; FUSION PROTEIN; MUTATED FORM; CANCER-CELLS; EXPRESSION; IMMUNOTOXIN; SENSITIVITY; THERAPY AB Purpose: This study was undertaken to determine whether low intratumoral doses of the epidermal growth factor receptor ligand-transforming growth factor alpha (TGF-alpha) fused to Pseudomonas exotoxin (TGF-alpha-PE38)-abrogated head and neck squamous cell carcinoma (HNSCC) tumor growth in vitro and in vivo. Experimental Design: In vitro cytotoxicity assays were carried out to determine the sensitivity of HNSCC cells to TGF-alpha-PE38. TGF-alpha-PE38-treated HNSCC cells were examined by immunoblotting for cleaved poly(ADP-ribose) polymerase to evaluate apoptosis. Nude mice bearing established HNSCC xenografts were treated with several doses of TGF-alpha-PE38 to evaluate the antitumor efficacy in vivo. Tumor sections were stained with terminal deoxynucleotidyl transferase-mediated nick end labeling for apoptosis. To determine the effect of oral administration of TGF-alpha-PE38, gavage injections of TGF-alpha-PE38 were administered, and the esophagus and surrounding soft tissue were then stained for apoptotic cells. Results: HNSCC cell lines examined were sensitive to low doses of TGF-alpha-PE38 (EC50 in the range of 1.6 to 10 ng/mL). HNSCC cells treated with TGF-alpha-PE38 undergo apoptosis. Antitumor effects were observed using 0.1 and 0.03 mug of TGF-alpha-PE38 administered intratumorally. At these doses, the treatment was well tolerated. Tumors treated with the toxin had a higher number of apoptotic cells compared with the control tumors. No apoptotic cells were observed in the pharyngoesophageal tissues of the mice after gavage administration of the toxin suggesting that the toxin could be orally administered without toxicity. Conclusions: These results indicate that topical or intratumoral administration of low doses of TGF-alpha-PE38 may demonstrate antitumor effects in HNSCC without associated systemic toxicity. C1 Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Radiat Oncol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Grandis, JR (reprint author), Eye & Ear Inst Pittsburgh, Dept Otolaryngol, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM jgrandis@pitt.edu OI Thomas, Sufi/0000-0001-5370-0842 FU NCI NIH HHS [R01 CA77308] NR 25 TC 14 Z9 14 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2004 VL 10 IS 20 BP 7079 EP 7087 DI 10.1158/1078-0432.CCR-04-0587 PG 9 WC Oncology SC Oncology GA 864IO UT WOS:000224627400038 PM 15501988 ER PT J AU Shikuma, CM Zackin, R Sattler, F Mildvan, D Nyangweso, P Alston, B Evans, S Mulligan, K AF Shikuma, CM Zackin, R Sattler, F Mildvan, D Nyangweso, P Alston, B Evans, S Mulligan, K CA AIDS Clinical Trial Grp 892 Team TI Changes in weight and lean body mass during highly active antiretroviral therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED PATIENTS; RANDOMIZED-TRIAL; WASTING SYNDROME; MEN; PREDICTORS; INDINAVIR; REGIMENS; ADEFOVIR; FAILURE; ERA AB Background. Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters. Methods. Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects coenrolled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire). Results. Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P = .045) occurred in subjects who achieved virological suppression (HIV- 1 RNA load, <500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight ( median increase in body weight, 2.6 vs. 0.0 kg; P < .001) and LBM (1.0 vs. 0.1 kg; P = .002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (<200 cells/mm(3)) and subjects with higher baseline HIV- 1 RNA loads (greater than or equal to 100,000 copies/mL) were more likely to show increases in LBM of 11.5 kg ( and, respectively). Conclusions. HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immunocompromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study. C1 Univ Hawaii, Dept Med, Hawaii AIDS Clin Res Program, Honolulu, HI 96816 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Beth Israel Med Ctr, New York, NY 10003 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. RP Shikuma, CM (reprint author), Univ Hawaii, Dept Med, Hawaii AIDS Clin Res Program, 3675 Kilauea Ave,Young Bldg,5th Floor, Honolulu, HI 96816 USA. EM shikuma@hawaii.edu FU NCRR NIH HHS [RR-00044]; NIAID NIH HHS [AI-32775, AI-25915, AI-25924, AI-27658, AI-27670, AI-34832, AI-38858, AI-46370, AI-34853, AI-25859, AI-25897, AI-27664, AI-27668, AI-27673, AI-32783, AI-38844, AI-38855, AI-51966] NR 29 TC 36 Z9 36 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2004 VL 39 IS 8 BP 1223 EP 1230 DI 10.1086/424665 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904JF UT WOS:000227491700019 PM 15486848 ER PT J AU Powers, JH AF Powers, JH TI Considerations in clinical trials of combination antifungal therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 2nd John E Bennett Forum on Deep Mycoses Study Design CY FEB, 2003 CL New York, NY ID COMMUNITY-ACQUIRED PNEUMONIA; AMPHOTERICIN-B; INVASIVE ASPERGILLOSIS; LIPOSOMAL AMPHOTERICIN; ANTIBIOTIC-THERAPY; RANDOMIZED-TRIAL; END-POINTS; ENDOCARDITIS; MULTICENTER; FLUCONAZOLE AB The cure rate for serious fungal diseases with currently available agents used as monotherapy is not optimal. The introduction of new classes of antifungal drugs in the last few years naturally leads to the hypothesis that antifungal drugs used in combination may be more effective than the same drugs used alone. The design and interpretation of combination therapy studies raise challenges beyond those encountered when drugs are studied as monotherapy in the treatment of a disease. The definition of combination therapy, the study design, the selection of appropriate patient populations, and the selection of end points, as well as practical considerations, are all important in the design and interpretation of clinical trials of combination therapies. Although combination therapies hold the promise of improved efficacy, it is important to prove this hypothesis, because they also may be associated with increased toxicity and increased drug costs. A careful consideration of study design factors before the initiation of a trial will help obtain the most useful information for patients in this important area. C1 US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20850 USA. NIAID, Dept Infect Dis Attending, NIH, Bethesda, MD USA. RP Powers, JH (reprint author), US FDA, Ctr Drug Evaluat & Res, 9201 Corp Blvd,HFD-104, Rockville, MD 20850 USA. EM powersjoh@cder.fda.gov NR 40 TC 9 Z9 10 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2004 VL 39 SU 4 BP S228 EP S235 DI 10.1086/421962 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904UO UT WOS:000227523400012 PM 15546123 ER PT J AU Powers, JH AF Powers, JH TI Issues in clinical trials of prophylaxis of fungal infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 2nd John E Bennett Forum on Deep Mycoses Study Design CY FEB, 2003 CL New York, NY ID BONE-MARROW TRANSPLANTATION; RANDOMIZED-TRIAL; DOUBLE-BLIND; FLUCONAZOLE; THERAPY; MULTICENTER; RECIPIENTS; CANCER; GUIDELINES AB The validity of the results of a clinical trial is highly dependent upon the design of the trial. The definition of disease, the selection criteria for enrollment in the trial, the selection of the study and control drugs, and the end points all affect whether the information obtained from the trial ultimately is useful in making decisions in clinical practice. These factors all apply to the design of clinical trials of the prophylaxis of infectious diseases. In addition, prophylaxis trials have several important differences from the design of trials of the treatment of those same diseases. The risk-benefit analysis for trials of prophylaxis is different, in that asymptomatic patients are exposed to the drug and more patients will be exposed than will develop the disease under study. Standardization of the design of such clinical trials will allow more efficient development of new drugs and will allow clinicians to compare more accurately the safety and efficacy of prophylactic agents. C1 US FDA, Antimicrobial Drug Dev & Resistance Initiat, Ctr Drug Evaluat & Res, Rockville, MD 20850 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Powers, JH (reprint author), US FDA, Antimicrobial Drug Dev & Resistance Initiat, Ctr Drug Evaluat & Res, 9201 Corp Blvd,HFD-104, Rockville, MD 20850 USA. EM powersjoh@cder.fda.gov NR 22 TC 8 Z9 8 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2004 VL 39 SU 4 BP S211 EP S217 DI 10.1086/421959 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904UO UT WOS:000227523400009 PM 15546120 ER PT J AU Huang, LE AF Huang, LE TI Targeting HIF-alpha: when a magic arrow hits the bull's eye SO DRUG DISCOVERY TODAY LA English DT Editorial Material C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Huang, LE (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. EM huange@mail.nih.gov NR 5 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT 15 PY 2004 VL 9 IS 20 BP 869 EP 869 AR PII S1359-6446(04)03227-1 DI 10.1016/S1359-6446(04)03227-1 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 862JN UT WOS:000224487000005 PM 15493075 ER PT J AU Veenstra, TD Prieto, DA Conrads, TP AF Veenstra, TD Prieto, DA Conrads, TP TI Proteomic patterns for early cancer detection SO DRUG DISCOVERY TODAY LA English DT Review ID HUMAN PLASMA PROTEOME; MASS-SPECTROMETRY; OVARIAN-CANCER; PROSTATE-CANCER; SERUM; IDENTIFICATION; ADENOCARCINOMA; CLASSIFICATION; HAPTOGLOBIN; TECHNOLOGY AB The advent of proteomics has brought with it the hope of discovering novel biomarkers that can be used to diagnose diseases, predict susceptibility, and monitor progression. Much of this effort has focused on the mass spectral identification of the thousands of proteins that populate complex biosystems such as serum and tissues. A revolutionary approach in proteomic pattern analysis has emerged as an effective method for the early diagnosis of diseases such as ovarian, breast, and prostate cancer. This technology is capable of analyzing hundreds of clinical samples per day and has the potential to be a novel, highly sensitive diagnostic tool for the early detection of diseases, or as a predictor of response to therapy. C1 SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Ft Detrick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Ft Detrick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 29 TC 48 Z9 48 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT 15 PY 2004 VL 9 IS 20 BP 889 EP 897 AR PII S1359-6446(04)03246-5 DI 10.1016/S1359-6446(04)03246-5 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 862JN UT WOS:000224487000009 PM 15475322 ER PT J AU Yin, JH Kwon, YT Varshavsky, A Wang, WD AF Yin, JH Kwon, YT Varshavsky, A Wang, WD TI RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME PROTEIN; BLOOM-SYNDROME; WERNER-SYNDROME; MACROMOLECULAR MACHINES; HELICASE MECHANISMS; GENOMIC STRUCTURE; TUMOR-SUPPRESSOR; BETA-CATENIN; DNA HELICASE; MICE LACKING AB The Rothmund-Thomson syndrome (growth retardation, skin and bone defects, predisposition to cancer) and the RAPADILINO syndrome are caused by mutations in the RECQL4 gene. The 133 kDa RECQL4 is a putative DNA helicase, a member of the family that includes the BLM and WRN helicases. The latter are mutated, respectively, in the Bloom and Werner syndromes, whose manifestations include predisposition to cancer. Using antibodies to human RECQL4, we found that the bulk of RECQL4 was present in a cytoplasmic extract of HeLa cells, in contrast to the largely nuclear BLM and WRN helicases. However, in untransformed WI-38 fibroblasts, RECQL4 was found to be largely nuclear, and was present at significantly lower total levels than in transformed HeLa cells. RECQL4 from HeLa cells was isolated as a stable complex with UBR1 and UBR2. These 200 kDa proteins are ubiquitin ligases of the N-end rule pathway, whose substrates include proteins with destabilizing N-terminal residues. The functions of this proteolytic pathway include the regulation of peptide import, chromosome stability, meiosis, apoptosis and cardiovascular development. Although the known role of UBR1 and UBR2 is to mediate polyubiquitylation (and subsequent degradation) of their substrates, the UBR1/2-bound RECQL4 was not ubiquitylated in vivo, and was a long-lived protein in HeLa cells. The isolated RECQL4-UBR1/2 complex had a DNA-stimulated ATPase activity, but was inactive in DNA-based assays for helicases and translocases, the assays in which the BLM helicase was active. We discuss ramifications of these results, possible functions of RECQL4, and the involvement of the N-end rule pathway. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, 333 Cassell Dr,TRIAD Ctr Room 3000, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov FU NIGMS NIH HHS [GM31530, GM69482] NR 62 TC 75 Z9 79 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2004 VL 13 IS 20 BP 2421 EP 2430 DI 10.1093/hmg/ddh269 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 856YA UT WOS:000224080800009 PM 15317757 ER PT J AU Weiland-Fiedler, P Erickson, K Waldeck, T Luckenbaugh, DA Pike, D Bonne, O Charney, DS Neumeister, A AF Weiland-Fiedler, P Erickson, K Waldeck, T Luckenbaugh, DA Pike, D Bonne, O Charney, DS Neumeister, A TI Evidence for continuing neuropsychological impairments in depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE major depressive disorder; cognitive function; Cambridge Automated Neuropsychological Test Battery (CANTAB); California Verbal Learning Test (CVLT) ID SUSTAINED ATTENTION-DEFICIT; UNIPOLAR MAJOR DEPRESSION; COGNITIVE FUNCTION; WORKING-MEMORY; PERFORMANCE; SCHIZOPHRENIA; DYSFUNCTION; MELANCHOLIA; DISORDERS; BIPOLAR AB Background: Neuropsychological deficits have been reported in patients with major depressive disorder (MDD) during an acute episode of MDD. Little is known whether these abnormalities persist when patients are remitted. The purpose of the present study was to describe the neuropsychological functioning of fully remitted, unmedicated patients with a history of MDD by focusing on tasks related to prefrontal cortex functioning. Methods: Twenty-eight young to middle-aged, unmedicated, fully remitted patients with MDD were compared to 23 healthy control subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) and the California Verbal Learning Test (CVLT). Results: Patients with remitted MDD relative to controls were impaired on tasks of rapid visual information processing (RVIP), psychomotor performance and spatial working memory (SWM). After correction for residual depressive symptoms, deficits in sustained attention remained significant. Limitations: CANTAB tasks are not equated for difficulty, and difficulty differences between the CANTAB tasks and the CVLT are not known. Conclusions: These findings suggest deficits in sustained attention as vulnerability marker for MDD. The functional importance of this finding and the neuronal networks involved remain to be elucidated. Published by Elsevier B.V. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Neumeister, A (reprint author), NIMH, Mood & Anxiety Disorders Program, North Dr,Bldg 15K,Room 200, Bethesda, MD 20892 USA. EM neumeisa@intra.nimh.nih.gov NR 36 TC 170 Z9 182 U1 3 U2 24 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 OCT 15 PY 2004 VL 82 IS 2 BP 253 EP 258 DI 10.1016/j.jad.2003.10.009 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 870IQ UT WOS:000225051200010 PM 15488254 ER PT J AU Pesesse, X Choi, K Zhang, T Shears, SB AF Pesesse, X Choi, K Zhang, T Shears, SB TI Signaling by higher inositol Polyphosphates - Synthesis of bisdiphosphoinositol tetrakisphosphate ("InsP(8)") is selectively activated by hyperosmotic stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMALIAN-CELLS; HEXAKISPHOSPHATE; PYROPHOSPHATES; INTEGRITY; PATHWAY; KINASES; MAPK; DICTYOSTELIUM; APOPTOSIS; RESPONSES AB Evidence has accumulated that inositol pyrophosphates ( diphosphoinositol pentakisphosphate (PP-InsP(5)) and bisdiphosphoinositol tetrakisphosphate ([PP](2)-InsP(4))) are intracellular signals that regulate many cellular processes including endocytosis, vesicle trafficking, apoptosis, and DNA repair. Yet, in contrast to the situation with all other second messengers, no one studying multicellular organisms has previously described a stimulus that acutely and specifically elevates cellular levels of PP-InsP(5) or [PP](2)-InsP(4). We now show up to 25-fold elevations in [PP](2)-InsP(4) levels in animal cells. Importantly, this does not involve classical agonists. Instead, we show that this [PP](2)-InsP(4) response is a novel consequence of the activation of ERK1/2 and p38MAPalpha/beta kinases by hyperosmotic stress. JNK did not participate in regulating [PP](2)-InsP(4) levels. Identification of [PP](2)-InsP(4) as a sensor of hyperosmotic stress opens up a new area of research for studies into the cellular activities of higher inositol phosphates. C1 NIEHS, Inositide Signaling Grp, NIH, DHSS, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Grp, NIH, DHSS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov NR 29 TC 39 Z9 41 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2004 VL 279 IS 42 BP 43378 EP 43381 DI 10.1074/jbc.C400286200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860YY UT WOS:000224383100005 PM 15316027 ER PT J AU Utomo, A Jiang, XZ Furuta, S Yun, J Levin, DS Wang, YCJ Desai, KV Green, JE Chen, PL Lee, WH AF Utomo, A Jiang, XZ Furuta, S Yun, J Levin, DS Wang, YCJ Desai, KV Green, JE Chen, PL Lee, WH TI Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION-COUPLED REPAIR; RETINOBLASTOMA GENE-PRODUCT; EICOSAPENTAENOIC ACID; DNA-DAMAGE; THIOREDOXIN PEROXIDASE; ANTIOXIDANT ENZYMES; LIPID-PEROXIDATION; MAMMALIAN-CELLS; FREE-RADICALS; HIGH-TITER AB A dramatic reduction in the expression of a novel phospholipid hydroperoxide glutathione peroxidase ( PHGPx), which incorporates cysteine instead of selenocysteine in the conserved catalytic motif was observed in a microarray analysis using cDNAs amplified from mRNA of Brca1-null mouse embryonic fibroblasts. This non-selenocysteine PHGPx named NPGPx is a cytoplasmic protein with molecular mass of similar to 22 kDa and has little detectable glutathione peroxidase activity in vitro. Ectopic expression of NPGPx in Brca1-null cells that were sensitive to oxidative stress induced by hydrogen peroxide conferred a similar resistance level to that of the wild-type cells, suggesting the importance of this protein in reducing oxidative stress. Expression of NPGPx was found in many tissues, including developing mammary gland. However, the majority of breast cancer cell lines studied ( 11 of 12) expressed very low or undetectable levels of NPGPx irrespective of BRCA1 status. Re-expression of NPGPx in breast cancer lines, MCF-7 and HCC1937, which have very little or no endogenous NPGPx, induced resistance to eicosapentaenoic acid ( an omega-3 type of polyunsaturated fatty acid)-mediated cell death. Conversely, inhibition of the expression of NPGPx by the specific small interfering RNA in HS578T breast cancer cells that originally express substantial amounts of endogenous NPGPx increased their sensitivity to eicosapentaenoic acid-mediated cell death. Thus, NPGPx plays an essential role in breast cancer cells in alleviating oxidative stress generated from polyunsaturated fatty acid metabolism. C1 Univ Calif Irvine, Dept Biol Chem, Sch Med, Irvine, CA 92697 USA. Univ Texas, Hlth Sci Ctr, Dept Mol Med, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Inst Biotechnol, San Antonio, TX 78245 USA. GenTex Inc, San Antonio, TX 78245 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Lee, WH (reprint author), Univ Calif Irvine, Dept Biol Chem, Sch Med, Irvine, CA 92697 USA. EM whlee@uci.edu RI Jiang, Xianzhi/A-5427-2013 OI Jiang, Xianzhi/0000-0002-4645-154X FU NCI NIH HHS [CA81020, CA94170] NR 69 TC 55 Z9 64 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2004 VL 279 IS 42 BP 43522 EP 43529 DI 10.1074/jbc.M407141200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860YY UT WOS:000224383100022 PM 15294905 ER PT J AU Kruman, II Schwartz, E Kruman, Y Cutler, RG Zhu, XX Greig, NH Mattson, MP AF Kruman, II Schwartz, E Kruman, Y Cutler, RG Zhu, XX Greig, NH Mattson, MP TI Suppression of uracil-DNA glycosylase induces neuronal apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; CELL-CYCLE REGULATION; DAMAGE; GENE; P53; TRANSCRIPTION; HOMOCYSTEINE; INHIBITOR; ENZYME; DEATH AB A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6-9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine beta-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression. C1 Sun Hlth Res Inst, Sun City, AZ 85351 USA. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Kruman, II (reprint author), Sun Hlth Res Inst, 10515 Santa Fe Dr, Sun City, AZ 85351 USA. EM inna.kruman@sunhealth.org RI Mattson, Mark/F-6038-2012 NR 58 TC 40 Z9 43 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2004 VL 279 IS 42 BP 43952 EP 43960 DI 10.1074/jbc.M408025200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860YY UT WOS:000224383100073 PM 15297456 ER PT J AU Zhao, L Hart, S Cheng, JG Melenhorst, JJ Bierie, B Ernst, M Stewart, C Schaper, F Heinrich, PC Ullrich, A Robinson, GW Hennighausen, L AF Zhao, L Hart, S Cheng, JG Melenhorst, JJ Bierie, B Ernst, M Stewart, C Schaper, F Heinrich, PC Ullrich, A Robinson, GW Hennighausen, L TI Mammary gland remodeling depends on gp130 signaling through Stat3 and MAPK SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEUKEMIA INHIBITORY FACTOR; GROWTH-FACTOR RECEPTOR; ACTIVATED PROTEIN-KINASE; EGF RECEPTOR; SECRETORY EPITHELIUM; INTERLEUKIN-6 FAMILY; TRANSGENIC MICE; CANCER-CELLS; NECK-CANCER; TRANSDUCER AB The interleukin-6(IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. However, it is not clear whether Stat3 activation is mediated solely through the gp130 pathway or also through other receptors. This question was explored in mice carrying two distinct mutations in the gp130 gene; one that resulted in the complete ablation of gp130 and one that led to the loss of Stat3 binding sites (gp130Delta/Delta). Deletion of gp130 specifically from mammary epithelium resulted in a complete loss of Stat3 activity and resistance to tissue remodeling comparable to that seen in the absence of Stat3. A less profound delay of mammary tissue remodeling was observed in gp130Delta/Delta mice. Stat3 tyrosine and serine phosphorylation was still detected in these mice suggesting that Stat3 activation could be the result of gp130 interfacing with other receptors. Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. Moreover, the gp130-dependent EGFR activation was independent of EGF ligands, suggesting a cytoplasmic interaction and cross-talk between these two receptors. These experiments establish that two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Max Planck Inst Biochem, D-81399 Martinsried, Germany. NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia. Rhein Westfal TH Aachen, Dept Biochem, D-52074 Aachen, Germany. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM hennighausen@nih.gov RI Ernst, Matthias/D-5111-2012; Robinson, Gertraud/I-2136-2012; Schaper, Fred/F-1403-2013 NR 48 TC 32 Z9 34 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2004 VL 279 IS 42 BP 44093 EP 44100 DI 10.1074/jbc.M313131200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860YY UT WOS:000224383100089 PM 15292206 ER PT J AU Heilman-Miller, SL Wu, TY Levin, JG AF Heilman-Miller, SL Wu, TY Levin, JG TI Alteration of nucleic acid structure and stability modulates the efficiency of minus-strand transfer mediated by the HIV-1 nucleocapsid protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRIMER BINDING-SITE; STRONG-STOP DNA; ZINC-FINGER STRUCTURES; RNASE-H ACTIVITY; IMMUNODEFICIENCY-VIRUS; REVERSE TRANSCRIPTION; IN-VITRO; SECONDARY STRUCTURE; CHAPERONE ACTIVITY; GENOMIC RNA AB During human immunodeficiency virus type 1 minus-strand transfer, the nucleocapsid protein (NC) facilitates annealing of the complementary repeat regions at the 3'-ends of acceptor RNA and minus-strand strong-stop DNA ((-) SSDNA). In addition, NC destabilizes the highly structured complementary trans-activation response element (TAR) stem-loop (TAR DNA) at the 3'-end of (-) SSDNA and inhibits TAR-induced self-priming, a dead-end reaction that competes with minus-strand transfer. To investigate the relationship between nucleic acid secondary structure and NC function, a series of truncated (-) SSDNA and acceptor RNA constructs were used to assay minus-strand transfer and self-priming in vitro. The results were correlated with extensive enzymatic probing and mFold analysis. As the length of (-) SSDNA was decreased, self-priming increased and was highest when the DNA contained little more than TAR DNA, even if NC and acceptor were both present; in contrast, truncations within TAR DNA led to a striking reduction or elimination of self-priming. However, destabilization of TAR DNA was not sufficient for successful strand transfer: the stability of acceptor RNA was also crucial, and little or no strand transfer occurred if the RNA was highly stable. Significantly, NC may not be required for in vitro strand transfer if (-) SSDNA and acceptor RNA are small, relatively unstructured molecules with low thermodynamic stabilities. Collectively, these findings demonstrate that for efficient NC-mediated minus-strand transfer, a delicate thermodynamic balance between the RNA and DNA reactants must be maintained. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Rm 216, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov NR 91 TC 46 Z9 48 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2004 VL 279 IS 42 BP 44154 EP 44165 DI 10.1074/jbc.M401646200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860YY UT WOS:000224383100095 PM 15271979 ER PT J AU Heegaard, AM Xie, ZJ Young, MF Nielsen, KL AF Heegaard, AM Xie, ZJ Young, MF Nielsen, KL TI Transforming growth factor beta stimulation of biglycan gene expression is potentially mediated by Sp1 binding factors SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE biglycan; Sp1; Sp3; TGF-beta; transforming growth factor-beta ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; LEUCINE-RICH PROTEOGLYCANS; HUMAN MESANGIAL CELLS; TGF-BETA; SMAD PROTEINS; FUNCTIONAL-CHARACTERIZATION; TRANSCRIPTIONAL REGULATION; DEFICIENT MICE; IN-VIVO; DECORIN AB Biglycan is a small leucine-rich proteoglycan which is localized in the extracellular matrix of bone and other specialized connective tissues. Both biglycan mRNA and protein are up-regulated by transforming growth factor-beta(1) (TGF-beta(1)) and biglycan appears to influence TGF-beta(1) activity. In this study, we have investigated the mechanism by which TGF-beta(1), TGF-beta(2) and TGF-beta(3) stimulate biglycan mRNA expression in the osteoblastic cell line MG-63. The cells were transfected with a series of deletional human biglycan promoter constructs and a region in the biglycan 5' DNA was found to respond to TGF-beta(1) with increased transcriptional activity in a dose-dependent manner. Also TGF-beta(2) and TGF-beta(3), two structurally highly related TGF-beta isoforms stimulated biglycan transcription. A TGF-beta responsive region was identified within the first 218 bp of the human biglycan promoter upstream from the transcriptional start site, which contained several binding sites for the transcription factor Sp1. Electrophoretic mobility shift assays with nuclear extracts from MG-63 cells showed binding of both Sp1 and Sp3 to a site at -216 to -208. When the biglycan promoter construct was cotransfected with Sp1 and Sp3 expression vectors in Sp1-deficient Drosophila Schneider-2 cells, Sp1 induced the transcriptional activity of biglycan. Addition of Sp3 augmented the effect of Sp1 on biglycan gene expression. Induction of biglycan mRNA expression in response to TGF-beta in MG-63 cells was abrogated by mithramycin, an inhibitor of Sp1 binding to GC-rich DNA sequences. A mutation in the Sp1 site at -216 to -208 within the -218 biglycan promoter construct substantially diminished the transcriptional up-regulation by TGF-beta(1). Taken together this data shows for the first time that TGF-beta(1) stimulation of human biglycan mRNA expression relies on increased transcription of the biglycan gene, and is mediated by members of the Sp1 family of transcription factors. C1 Danish Univ Pharmaceut Sci, Dept Pharmacol, DK-2100 Copenhagen, Denmark. Nord Biosci AS, DK-2730 Herlev, Denmark. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Heegaard, AM (reprint author), Danish Univ Pharmaceut Sci, Dept Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark. EM amhe@dfuni.dk NR 69 TC 14 Z9 15 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 15 PY 2004 VL 93 IS 3 BP 463 EP 475 DI 10.1002/jcb.20189 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860AD UT WOS:000224308600004 PM 15372625 ER PT J AU Daumer, KM Tufan, AC Tuan, RS AF Daumer, KM Tufan, AC Tuan, RS TI Long-term in vitro analysis of limb cartilage development: Involvement of Wnt signaling SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE chondrogenesis; chondrocyte hypertrophy and maturation; Wnt signaling; beta-catenin; N-cadherin; Frizzled ID BETA-CATENIN; MESENCHYMAL CELLS; WNT/BETA-CATENIN; N-CADHERIN; PATTERN-FORMATION; X COLLAGEN; CHONDROGENESIS; EXPRESSION; BUD; MECHANISMS AB Endochondral skeletal development involves the condensation of mesenchymal cells, their differentiation into chondrocytes, followed by chondrocyte maturation, hypertrophy, and matrix mineralization, and replacement by osteoblasts. The Wnt family of secreted proteins have been shown to play important roles in vertebrate limb formation. To examine the role(s) of Wnt members and their transmembrane-spanning receptor(s), Frizzled (fz), we retrovirally misexpressed Wnt-5a, Wnt-7a, chicken frizzled-1 (Chfz-1), and frizzled-7 (Chfz-7) in long-term (21 day) high density, micromass cultures of stage 23/24 chick embryonic limb mesenchyme. This culture system recapitulates in vitro the entire differentiation (days 1-10), growth (days 5-12), and maturation and hypertrophy (from day 12 on) program of cartilage development. Wnt-7a misexpression severely inhibited chondrogenesis from day 7 onward. Wnt-5a misexpression resulted in a poor hypertrophic phenotype by day 14. Chfz-7 misexpression caused a slight delay of chondrocyte maturation based on histology, whereas Chfz-1 misexpression did not affect the chondrogenic phenotype. Misexpression of all Wnt members decreased collagen type X expression and alkaline phosphatase activity at day 21. Our findings implicate functional role(s) for Wnt signaling throughout embryonic cartilage development, and show the utility of the long-term in vitro limb mesenchyme culture system for such studies. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, 50 South Dr,Bldg 50,Room 1503, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIAMS NIH HHS [AR Z01-41131]; NIDCR NIH HHS [DE R01-16864]; NIEHS NIH HHS [ES R01-07005] NR 51 TC 39 Z9 41 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 15 PY 2004 VL 93 IS 3 BP 526 EP 541 DI 10.1002/jcb.20190 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860AD UT WOS:000224308600010 PM 15372624 ER PT J AU Podgornik, R Parsegian, VA AF Podgornik, R Parsegian, VA TI Van der Waals interactions in a dielectric with continuously varying dielectric function SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article AB We formulate and evaluate the van der Waals part of the free energy due to a dielectric profile that varies continuously throughout the space between two interacting bodies. Not considering the work needed to create the inhomogeneous dielectric profile, focusing only on that part of the free energy affected by the inhomogeneity, we compare the ensuing interaction free energy with that of the original Lifshitz formulation with its step function changes at material boundaries and uniform dielectric medium. Rather than the monotonically varying attraction between like bodies given by the original formulation, the inhomogeneous continuous dielectric function leads to attractions as well as repulsions. The Lifshitz result emerges naturally in the limit of separations much larger than the thickness of the interfaces. (C) 2004 American Institute of Physics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Dept Phys, Ljubljana 1000, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. RP Podgornik, R (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bldg 9 Room 1E116, Bethesda, MD 20892 USA. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 10 TC 16 Z9 16 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 15 PY 2004 VL 121 IS 15 BP 7467 EP 7473 DI 10.1063/1.1796234 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 859MW UT WOS:000224269300054 PM 15473821 ER PT J AU Parise, RA Sparrow, BR Merrill, JW Grossi, IM Covey, JM Peggins, JO Egorin, MJ AF Parise, RA Sparrow, BR Merrill, JW Grossi, IM Covey, JM Peggins, JO Egorin, MJ TI Liquid chromatography-electrospray tandem mass spectrometric assay suitable for quantitation of halofuginone in plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE halofuginone ID ANTI-COCCIDIAL DRUG; VERSUS-HOST-DISEASE; I SYNTHESIS; CRYPTOSPORIDIUM-PARVUM; INHIBITOR; PERFORMANCE; ANGIOGENESIS; CALVES; EFFICACY; LACTATE AB An LC-MS/MS method was developed to quantitate the potential antitumor agent halofuginone in plasma. The assay uses 0.2 ml of plasma; chlorohalofuginone internal standard; acetonitrile for protein precipitation; a Phenomenex SYNERGI 4mu Polar RP 80A (4 mum, 100 mm x 2 mm) column; an isocratic mobile phase of methanol:water:formic acid (80:20:0.02, v/v/v); and positive-ion electrospray ionization with selective reaction monitoring detection. Halofuginone eluted at approximately 2.4 min, internal standard eluted at approximately 2.9 min, and no endogenous materials interfered with their measurement. The assay was accurate, precise, and linear between 0.1 and 100 ng/ml. Halofuginone could be quantitated in dog plasma for at least 24 h after an i.v. dose of 0.1 mg/kg. The assay is being used in ongoing pharmacokinetic studies of halofuginone. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Pittsburgh, Inst Canc, Mol Therapeut Drug discovery Program, Pittsburgh, PA 15213 USA. Battelle Toxicol, Columbus, OH 43201 USA. NCI, Dev Therapeut Program, Toxicol & Pharmacol Branch, Rockville, MD 20852 USA. Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15213 USA. RP Egorin, MJ (reprint author), Univ Pittsburgh, Inst Canc, Mol Therapeut Drug discovery Program, Room G27E,Hillman Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM egorinmj@msx.upmc.edu FU NCI NIH HHS [2P30 CA47904, N01-CM-07106, N01-CM-87028] NR 34 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD OCT 15 PY 2004 VL 810 IS 1 BP 35 EP 40 DI 10.1016/j.jchromb.2004.07.010 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 855YE UT WOS:000224010000005 PM 15358305 ER PT J AU Maynard, DM Masuda, J Yang, XY Kowalak, JA Markey, SP AF Maynard, DM Masuda, J Yang, XY Kowalak, JA Markey, SP TI Characterizing complex peptide mixtures using a multi-dimensional liquid chromatography-mass spectrometry system: Saccharomyces cerevisiae as a model system SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE multi-dimensional LC-MS; 2D-LC-MS/MS; peptide mixtures; sequence database records (SDRs); S. cerevisiae; DBParser ID PROTEIN IDENTIFICATION; YEAST PROTEOME; EXCHANGE; MS/MS AB A rugged, reproducible, multi-dimensional LC-MS system was developed to identify and characterize proteins involved in protein-protein interactions and/or protein complexes. Our objective was to optimize chromatographic parameters for complex protein mixture analyses using automated peptide sequence recognition as an analytical end-point. The chromatographic system uses orthogonal separation mechanisms by employing strong cation exchange (SCX) in the first dimension and reversed phase (RP) in the second dimension. The system is fully automated and sufficiently robust to handle direct injections of protein digests. This system incorporates a streamlined post analysis results comparison, called DBParser, which permitted comprehensive evaluation of sample loading and chromatographic conditions to optimize the performance and reproducibility. Peptides obtained from trypsin digestion of a yeast soluble extract provided an open-ended model system containing a wide variety and dynamic range of components. Conditions are described that resulted in an average (n = 4) of 1489 unique peptide identifications, corresponding to 459 non-redundant protein sequence database records (SDRs) in the 20 mug soluble fraction digest. (C) 2004 Elsevier B.V. All rights reserved. C1 NHGRI, MGB, SHBG, NIH, Bethesda, MD 20892 USA. NIMH, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. RP Maynard, DM (reprint author), NHGRI, MGB, SHBG, NIH, Bldg 10,Room 10C-107,MSC 1851, Bethesda, MD 20892 USA. EM maynardd@mail.nih.gov NR 14 TC 25 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD OCT 15 PY 2004 VL 810 IS 1 BP 69 EP 76 DI 10.1016/j.jchromb.2004.07.015 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 855YE UT WOS:000224010000009 PM 15358309 ER PT J AU Low, JA Berman, AW Steinberg, SM Danforth, DN Lippman, ME Swain, SM AF Low, JA Berman, AW Steinberg, SM Danforth, DN Lippman, ME Swain, SM TI Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-21, 2002 CL ORLANDO, FL SP Amer Soc Clin Oncol ID COMBINED-MODALITY THERAPY; NEOADJUVANT CHEMOTHERAPY; PROGNOSTIC FACTORS; CARCINOMA; MASTECTOMY; EXPERIENCE; MANAGEMENT; SURVIVAL AB Purpose To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. Patients and Methods Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. Results OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. Conclusion Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook. C1 NCI, NIH, Canc Therapeut Branch, Med Oncol Clin Res Unit,Biostat & Data Management, Bethesda, MD 20892 USA. NCI, NIH, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. RP Swain, SM (reprint author), Natl Canc Inst, Canc Therapeut Branch, Canc Res Ctr, Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM swains@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 NR 30 TC 98 Z9 103 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 15 PY 2004 VL 22 IS 20 BP 4067 EP 4074 DI 10.1200/JCO.2004.04.068 PG 8 WC Oncology SC Oncology GA 863PG UT WOS:000224573400007 PM 15483018 ER PT J AU Nijhara, R van Hennik, PB Gignac, ML Kruhlak, MJ Hordijk, PL Delon, J Shaw, S AF Nijhara, R van Hennik, PB Gignac, ML Kruhlak, MJ Hordijk, PL Delon, J Shaw, S TI Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CORTICAL ACTIN ORGANIZATION; ERM PROTEINS; RHO-GTPASES; IN-VIVO; THREONINE 558; EZRIN/RADIXIN/MOESIN PROTEINS; MOESIN PHOSPHORYLATION; STRESS FIBERS; BINDING; MEMBRANE AB Lymphocytes circulate in the blood and upon chemokine activation rapidly bind, where needed, to microvasculature to mediate immune surveillance. Resorption of microvilli is an early morphological alteration induced by chemokines that facilitates lymphocyte emigration. However, the antecedent molecular mechanisms remain largely undefined. We demonstrate that Rac1 plays a fundamental role in chemokine-induced microvillar breakdown in human T lymphocytes: The supporting evidence includes: first, chemokine induces Rac1 activation within 5 s via a signaling pathway that involves Galpha(i). Second, constitutively active Rac1 mediates microvilli disintegration. Third, blocking Rac1 function by cell permeant C-terminal "Trojan" peptides corresponding to Rac1 (but not Rac2, Rho, or Cde42) blocks microvillar loss induced by the chemokine stromal cell-derived factor 1alpha (SDF-1alpha). Furthermore, we demonstrate that the molecular mechanism of Rac1 action involves dephosphorylation-induced inactivation of the ezrin/radixin/moesin (ERM) family of actin regulators; such inactivation is known to detach the membrane from the underlying actin cytoskeleton, thereby facilitating disassembly of actin-based peripheral processes. Specifically, ERM dephosphorylation is induced by constitutively active Rac1 and stromal cell-derived factor 1alpha-induced ERM dephosphorylation is blocked by either the dominant negative Rac1 construct or by Rac1 C-terminal peptides. Importantly, the basic residues at the C terminus of Rac1 are critical to Rac1's participation in ERM dephosphorylation and in microvillar retraction. Together, these data elucidate new roles for Rac1 in early signal transduction and cytoskeletal rearrangement of T lymphocytes responding to chemokine. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Univ Amsterdam, Netherlands Red Cross, Blood Transfus Serv, Sanquin Res Cent Lab, NL-1012 WX Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1012 WX Amsterdam, Netherlands. SAIC Frederick, Image Anal Lab, Frederick, MD USA. CNRS, INSERM, Inst Cochin Genet Mol, Dept Biol Cellulaire,Unite 567,UMR 8104, Paris, France. RP Shaw, S (reprint author), NIH, Bldg 10,Room 4B36,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. EM shave@nih.gov NR 61 TC 54 Z9 54 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2004 VL 173 IS 8 BP 4985 EP 4993 PG 9 WC Immunology SC Immunology GA 861BX UT WOS:000224392200027 PM 15470041 ER PT J AU Stephens, GL McHugh, RS Whitters, MJ Young, DA Luxenberg, D Carreno, BM Collins, M Shevach, EM AF Stephens, GL McHugh, RS Whitters, MJ Young, DA Luxenberg, D Carreno, BM Collins, M Shevach, EM TI Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4(+) CD25(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOLOGICAL SELF-TOLERANCE; CUTTING EDGE; DENDRITIC CELLS; LEISHMANIA-MAJOR; LYMPH-NODES; IN-VITRO; CD4(+)CD25(+); EXPRESSION; ACTIVATION; GITR AB Nonactivated CD4(+)CD25(+) regulatory T cells constitutively express glucocorticoid-induced TNFR family-related receptor (GITR), a TNFR family member whose engagement was presumed to abrogate regulatory T cell-mediated suppression. Using GITR(-/-)mice, we report that GITR engagement on CD25(-), not CD25(+) T cells abrogates T cell-mediated suppression. Mouse APCs constitutively express GITR ligand (GITR-L), which is down-regulated following TLR signaling in vivo. Although GITR(-/-)CD25(-) T cells were capable of mounting proliferative responses, they were incapable of proliferation in the presence of physiological numbers of CD25+ T cells. Thus, GITR-L provides an important signal for CD25- T cells, rendering them resistant to CD25(+)-mediated regulation at the initiation of the immune response. The down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult. C1 NIAID, Immunol Lab, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. Wyeth Ayerst Res, Cambridge, MA 02140 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, Cellular Immunol Sect, NIH, Bldg 10,Room 11N315, Bethesda, MD 20892 USA. EM EShevach@niaid.nih.gov NR 42 TC 312 Z9 329 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 OCT 15 PY 2004 VL 173 IS 8 BP 5008 EP 5020 PG 13 WC Immunology SC Immunology GA 861BX UT WOS:000224392200030 PM 15470044 ER PT J AU Chen, W Pang, K Masterman, KA Kennedy, G Basta, S Dimopoulos, N Hornung, F Smyth, M Bennink, JR Yewdell, JW AF Chen, W Pang, K Masterman, KA Kennedy, G Basta, S Dimopoulos, N Hornung, F Smyth, M Bennink, JR Yewdell, JW TI Reversal in the immunodominance hierarchy in secondary CD8(+) T cell responses to influenza A virus: Roles for cross-presentation and lysis-independent immunodomination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; ANTIGEN PRESENTATION; DENDRITIC CELLS; HIV-INFECTION; COMPLEX; CTL; LYMPHOCYTES; CD4(+); ESCAPE; MATURATION AB Immunodominance is a central feature of CD8(+) T cell (TCD8+) responses to pathogens, transplants, and tumors. Determinants occupy a stable position in an immunodominance hierarchy (alpha-, beta-, etc.) defined by the frequencies of responding TCD8+. In this paper, we study the mechanistic basis for place-swapping between alpha-(acid polymerase (PA)(224-233)) and beta-determinants (nuclear protein 366-374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA(224-233), and it was proposed that secondary TCD8+ are principally activated by IAV-infected epithelial cells, while primary TCD8+ are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA(224-232) is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA(224-233)-specific TCD8+ by nucleoprotein 366-374-specific TCD8+ plays a critical role in the phenomena, and that this is unlikely to be mediated by TCD8+ lysis of APCs or other cells. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Ludwig Inst Canc Res, Austin & Repatriat Med Ctr, T Cell Lab, Heidelberg, Vic, Australia. Peter MacCallum Canc Inst, Melbourne, Vic, Australia. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Room 211,Bldg 4,4 Ctr Dr, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; Chen, Weisan/E-7828-2012; OI Pang, Ken/0000-0002-6881-775X NR 29 TC 53 Z9 55 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 OCT 15 PY 2004 VL 173 IS 8 BP 5021 EP 5027 PG 7 WC Immunology SC Immunology GA 861BX UT WOS:000224392200031 PM 15470045 ER PT J AU Mbulaiteye, SM Pfeiffer, RM Engels, EA Marshall, V Bakaki, PM Owor, AM Ndugwa, CM Katongole-Mbidde, E Goedert, JJ Biggar, RJ Whitby, D AF Mbulaiteye, SM Pfeiffer, RM Engels, EA Marshall, V Bakaki, PM Owor, AM Ndugwa, CM Katongole-Mbidde, E Goedert, JJ Biggar, RJ Whitby, D TI Detection of Kaposi sarcoma-associated herpesvirus DNA in saliva and buffy-coat samples from children with sickle cell disease in Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 6th International Workshop on Kaposis Sarcoma Associated Herpesvirus (HSHV/HHV8) and Related Agents CY JUL 18-22, 2003 CL Glen Cove, NY ID HUMAN-HERPESVIRUS-8 INFECTION; TRANSMISSION; POPULATION; HISTORY; MEN AB Among 233 children, Kaposi sarcoma-associated herpesvirus ( KSHV) DNA was detected in 43% of children seropositive for both K8.1 and orf73, in 29% of children seropositive for K8.1 only, in 14% of children seropositive for orf73 only, and in 7% of children seronegative for both K8.1 and orf73; among 228 mothers, KSHV DNA was detected in 27%, 25%, 4%, and 1%, respectively. KSHV DNA was detected more frequently and at higher levels in saliva than in buffy-coat samples and in children than in mothers. In both children and mothers, detection in saliva was associated with detection in peripheral blood. Detection was associated with K8.1 seropositivity, younger age, and high household density, indicating the importance of in-household person-to-person transmission, likely via saliva. C1 NCI, Div Canc Epidemiol & Genet, US Dept HHS, Rockville, MD USA. Sci Applicat Corp Frederick, Viral Epidemiol Sect, AIDS Vaccine Program, NCI, Frederick, MD 21701 USA. Makerere Univ, Sch Med, Kampala, Uganda. Mulago Hosp, Kampala, Uganda. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza S,Room 8006, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [N01-CO-12400, N02-CP-91027] NR 15 TC 42 Z9 45 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2004 VL 190 IS 8 BP 1382 EP 1386 DI 10.1086/424489 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 855JF UT WOS:000223968700003 PM 15378429 ER PT J AU Vuong, C Kocianova, S Yao, YF Carmody, AB Otto, M AF Vuong, C Kocianova, S Yao, YF Carmody, AB Otto, M TI Increased colonization of indwelling medical devices by quorum-sensing mutants of Staphylococcus epidermidis in vivo SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Biofilms 2003 Meeting CY NOV 01-06, 2003 CL Victoria, CANADA ID BACTERIAL BIOFILMS; AUREUS; AGR; VIRULENCE; INFECTIONS; PHEROMONE; SYSTEM; IDENTIFICATION; PATHOGENESIS; TRANSDUCTION AB Infections with the leading nosocomial pathogen Staphylococcus epidermidis are characterized by biofilm development on indwelling medical devices. We demonstrate that the quorum-sensing regulator agr affects the biofilm development of S. epidermidis in an unexpected fashion and is likely involved in promoting biofilm detachment. An isogenic agr mutant showed increased biofilm development and colonization in a rabbit model. In addition, nonfunctional agr occurred more frequently among strains isolated from infections of joint prostheses. Lack of functionality was based on mutations, including insertion of an IS256 element. Relative to other bacterial pathogens, quorum sensing in S. epidermidis thus has a different role during biofilm development and biofilm-associated infection. Our results indicate that disabling agr likely enhances the success of S. epidermidis during infection of indwelling medical devices. The permanent elimination of quorum-sensing regulation used by S. epidermidis represents a surprising and unusual means to adapt to a certain environment and type of infection. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Otto, M (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 NR 45 TC 113 Z9 122 U1 0 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2004 VL 190 IS 8 BP 1498 EP 1505 DI 10.1086/424487 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 855JF UT WOS:000223968700018 PM 15378444 ER PT J AU Evans, P Wyatt, K Wistow, GJ Bateman, OA Wallace, BA Slingsby, C AF Evans, P Wyatt, K Wistow, GJ Bateman, OA Wallace, BA Slingsby, C TI The P23T cataract mutation causes loss of solubility of folded gamma D-crystallin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cataract; crystallin; synchrotron radiation; CD spectroscopy; proline; protein solubility ID PROTEIN SECONDARY STRUCTURE; RADIATION CIRCULAR-DICHROISM; LENS; GENE; DISEASE; MUTANT; EYE; IDENTIFICATION; TRANSPARENCY; PREDICTION AB Mutations in the human gammaD-crystallin gene have been linked to several types of congenital cataracts. In particular, the Pro23 to Thr (P23T) mutation of human gammaD crystallin has been linked to cerulean, lamellar, coralliform, and fasciculiform congenital cataracts. We have expressed and purified wild-type human gammaD, P23T, and the Pro23 to Ser23 (P23S) mutant. Our measurements show that P23T is significantly less soluble than wild-type human gammaD, with P23S having an intermediate solubility. Using synchrotron radiation circular dichroism spectroscopy, we have determined that the P23T mutant has a slightly increased content of beta-sheet, which may be attributed to the extension of an edge beta-strand due to the substitution of Pro23 with a residue able to form hydrogen bonds. Neither of the point mutations appears to have reduced the thermal stability of the protein significantly, nor its resistance to guanidine hydrochloride-induced unfolding. These results suggest that insolubility, rather than loss of stability, is the primary basis for P23T congenital cataracts. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ London Birkbeck Coll, Dept Crystallog, London WC1E 7HX, England. NEI, NIH, Bethesda, MD 20892 USA. SERC, Daresbury Lab, Ctr Prot & Membrane Struct & Dynam, Warrington WA4 4AD, Cheshire, England. RP Slingsby, C (reprint author), Univ London Birkbeck Coll, Dept Crystallog, Malet St, London WC1E 7HX, England. EM c.slingsby@mail.cryst.bbk.ac.uk RI Wallace, B. A./C-3753-2008 OI Wallace, B. A./0000-0001-9649-5092 NR 35 TC 74 Z9 76 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 15 PY 2004 VL 343 IS 2 BP 435 EP 444 DI 10.1016/j.jmb.2004.08.050 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860OC UT WOS:000224351900012 PM 15451671 ER PT J AU Nitta, A Nishioka, H Fukumitsu, H Furukawa, Y Sugiura, H Shen, LY Furukawa, S AF Nitta, A Nishioka, H Fukumitsu, H Furukawa, Y Sugiura, H Shen, LY Furukawa, S TI Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE immunophilin; glial cell line-derived neurotrophic factor; brain-derived neurotrophic factor; FK506; Leu-Ile; dopamine; mice ID NERVE GROWTH-FACTOR; MIDBRAIN DOPAMINERGIC-NEURONS; ACTIVITY-DEPENDENT REGULATION; FOREBRAIN-LESIONED RATS; IN-VIVO; FUNCTIONAL RECOVERY; CYCLOSPORINE-A; FACTOR FAMILY; GDNF; CALCINEURIN AB We investigated whether certain hydrophobic dipeptides, Leu-Ile, Leu-Pro, and Pro-Ile, which partially resemble the site on FK506 that binds to immunophilin, could stimulate glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) synthesis in cultured neurons and found only Leu-Ile to be an active dipeptide. Leu-Ile protected against the death of mesencephalic neurons from wild-type mice but not from mice lacking the BDNF or GDNF gene. Next, we examined the effects of i.p. or i.c.v. administration of Leu-Ile on BDNF and GDNF contents. Both types of administration increased the contents of BDNF and GDNF in the striatum of mice. Also, peripheral administration of Leu-Ile inhibited dopaminergic (DA) denervation caused by unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of mice. The number of rotations following a methamphetamine challenge was lower in the Leu-Ile-treated group than in the nontreated group. Next, we compared the calcineurin activity and immunosuppressant activity of Leu-Ile with those of FK506. Leu-Ile was not inhibitory toward calcineurin cellular activity in cultured neuronal cells. Furthermore, Leu-Ile did not suppress concanavalin A (ConA)-induced synthesis/ secretion of interleukin-2 by cultured spleen cells, suggesting that the immunosuppressant activity of Leu-Ile may be negligible when used as a therapeutic tool for neurodegenerative diseases. (C) 2004 Wiley-Liss, Inc. C1 Nagoya Univ, Grad Sch Med, Dept Neuropsychopharmacol, Showa Ku, Nagoya, Aichi 4668560, Japan. Nagoya Univ, Grad Sch Med, Hosp Pharm, Nagoya, Aichi 4668560, Japan. Gifu Pharmaceut Univ, Mol Biol Lab, Gifu, Japan. Gifu Pharmaceut Univ, Lab Exercise Physiol & Hlth Educ, Gifu, Japan. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD USA. RP Nitta, A (reprint author), Nagoya Univ, Grad Sch Med, Dept Neuropsychopharmacol, Showa Ku, Tsuruma Cho, Nagoya, Aichi 4668560, Japan. EM a-nitta@med.nagoya-u.ac.jp NR 49 TC 29 Z9 30 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD OCT 15 PY 2004 VL 78 IS 2 BP 250 EP 258 DI 10.1002/jnr.20258 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 860GE UT WOS:000224329700013 PM 15378610 ER PT J AU Hong, JJ Loiselle, CR Yoon, DY Lee, O Becker, KG Singer, HS AF Hong, JJ Loiselle, CR Yoon, DY Lee, O Becker, KG Singer, HS TI dMicroarray analysis in Tourette syndrome postmortem putamen SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE cDNA microarray; Tourette syndrome; postmortem tissue; putamen; Z test; Z ratio; protein tyrosine phosphatase ID PROTEIN-TYROSINE-PHOSPHATASE; GENE-EXPRESSION; CDNA MICROARRAYS; DOPAMINE D1; PHOSPHORYLATION; SCHIZOPHRENIA; NEUROBIOLOGY; DISORDERS; RECEPTORS; CORTEX AB Gene expression patterns in the postmortem putamen of patients with Tourette syndrome (TS) were investigated using cDNA microarrays. A cDNA neuroarray comprising 1537 genes known to be related to neurological or neuropsychiatric disorders was used to compare patient samples (n=3) with those from control subjects (n=4). Z test and Z ratio were used to analyze results; seven genes were found to be upregulated according to our definition (P<0.1, two-tailed, for Z test; P<0.05 for Z ratio) and three were found to be downregulated. Validation experiments were performed using reverse transcription polymerase chain reaction (RT-PCR) and semiquantitative Western blot analyses. RT-PCR showed concordance with microarray in seven of nine selected genes. In contrast, Western blot analyses performed with five proteins showed that only two of five had similar trends between protein content and level of gene expression. The authors note the inherent difficulty in applying microarray technology to complex neurological disorders such as the TS and conclude that further investigations are required to understand how altered expression of these genes is related to the pathophysiology of the disorder. (C) 2004 Elsevier B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. NIA, DNA Array Unit, Res Resources Branch, NIH, Baltimore, MD 21221 USA. RP Singer, HS (reprint author), Johns Hopkins Univ Hosp, Div Pediat Neurol, Jefferson St Bldg 124,600 N Wolfe St, Baltimore, MD 21287 USA. EM hsinger@jhmi.edu NR 33 TC 19 Z9 19 U1 0 U2 1 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 OCT 15 PY 2004 VL 225 IS 1-2 BP 57 EP 64 DI 10.1016/j.jns.2004.06.019 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 863YL UT WOS:000224599400009 PM 15465086 ER PT J AU Laplante, F Crawley, JN Quirion, R AF Laplante, F Crawley, JN Quirion, R TI Selective reduction in ventral hippocampal acetylcholine release in awake galanin-treated rats and galanin-overexpressing transgenic mice SO REGULATORY PEPTIDES LA English DT Article DE microdialysis; no net flux; transgenic mice; galanin receptor; ventral hippocampus; dorsal hippocampus ID CENTRAL-NERVOUS-SYSTEM; AMYLOID PRECURSOR PROTEIN; NONMATCHING-TO-SAMPLE; ALZHEIMERS-DISEASE; CHOLINERGIC SYSTEMS; MESSENGER-RNA; SPINAL-CORD; PHOSPHOINOSITIDE TURNOVER; RECEPTOR SUBTYPES; NEURONS AB The neuropeptide galanin is an inhibitory modulator of hippocampal acetylcholine (ACh) release and cognitive functions. Anatomical evidence demonstrated some differences between the dorsal and ventral hippocampi notably in the expression of galanin receptor subtypes, and the neuronal population on which galanin-like immunoreactivity is expressed. This is suggestive of a differential role for this peptide in these two areas of the hippocampal formation. Using in vivo microdialysis, we investigated the role of galanin on ACh release in the dorsal and ventral hippocampi. Two models were studied: galanin-administered rats and transgenic mice over-expressing galanin (GAL-tg). In rats, galanin (2.0 and 10.0 muM) infused locally through the dialysis probe induced a significant decrease in ACh release in the ventral hippocampus, confirming previous findings, while no effect was seen in the dorsal hippocampus. Using the no net flux method, a significant reduction in ACh levels was noted only in the ventral hippocampus of GAL-tg compared to wild-type littermates. These results suggest that excess endogenous galanin can suppress basal ACh release, with anatomical specificity, to the ventral hippocampus. These results are of interest in the context of galanin receptor subtypes in the dorsal and ventral hippocampus, and the differential alterations of hippocampal subregions in neurological diseases such as Alzheimer's dementia. (C) 2004 Elsevier B.V. All rights reserved. C1 McGill Univ, Dept Pharmacol Therapeut, Douglas Hosp Res Ctr, Verdun, PQ H4H 1R3, Canada. McGill Univ, Dept Psychiat, Verdun, PQ H4H 1R3, Canada. NIMH, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. RP Quirion, R (reprint author), McGill Univ, Dept Pharmacol Therapeut, Douglas Hosp Res Ctr, 6875 Boul LaSalle Verdun, Verdun, PQ H4H 1R3, Canada. EM quirem@douglas.mcgill.ca NR 68 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD OCT 15 PY 2004 VL 122 IS 2 BP 91 EP 98 DI 10.1016/j.regpep.2004.05.022 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 860HG UT WOS:000224332500006 PM 15380926 ER PT J AU Lederman, MM Veazey, RS Offord, R Mosier, DE Dufour, J Mefford, M Piatak, M Lifson, JD Salkowitz, JR Rodriguez, B Blauvelt, A Hartley, O AF Lederman, MM Veazey, RS Offord, R Mosier, DE Dufour, J Mefford, M Piatak, M Lifson, JD Salkowitz, JR Rodriguez, B Blauvelt, A Hartley, O TI Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5 SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; HIV-1 INFECTION; PRIMATE LENTIVIRUSES; LANGERHANS CELLS; RANTES ANALOGS; DC-SIGN; CORECEPTOR; INTERNALIZATION; RESISTANCE; RECEPTORS AB Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention. C1 Case Western Reserve Univ, Univ Hosp, Dept Med, Cleveland, OH 44106 USA. Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. Univ Geneva, Fac Med, Dept Struct Biol & Bioinformat, CH-1211 Geneva 4, Switzerland. Scripps Res Inst, La Jolla, CA 92037 USA. NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Univ Hosp, Dept Med, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM MXL6@case.edu RI Hartley, Oliver/H-3593-2013; Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU NCI NIH HHS [N01-CO-124000]; NIAID NIH HHS [AI 36219, AI 51649] NR 33 TC 279 Z9 290 U1 0 U2 6 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 OCT 15 PY 2004 VL 306 IS 5695 BP 485 EP 487 DI 10.1126/science.1099288 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 864IF UT WOS:000224626500053 PM 15486300 ER PT J AU Pang, PT Teng, HK Zaitsev, E Woo, NT Sakata, K Zhen, SH Teng, KK Yung, WH Hempstead, BL Lu, B AF Pang, PT Teng, HK Zaitsev, E Woo, NT Sakata, K Zhen, SH Teng, KK Yung, WH Hempstead, BL Lu, B TI Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity SO SCIENCE LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; ACTIVITY-DEPENDENT SECRETION; NEUROTROPHIC FACTOR; LATE-PHASE; LASTING POTENTIATION; EXCITATORY SYNAPSES; BDNF; GROWTH; MEMORY; MICE AB Long-term memory is thought to be mediated by protein synthesis-dependent, late-phase tong-term potentiation (L-LTP). Two secretory proteins, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), have been implicated in this process, but their relationship is unclear. Here we report that tPA, by activating the extracellular protease plasmin, converts the precursor proBDNF to the mature BDNF (mBDNF), and that such conversion is critical for L-LTP expression in mouse hippocampus. Moreover, application of mBDNF is sufficient to rescue L-LTP when protein synthesis is inhibited, which suggests that mBDNF is a key protein synthesis product for L-LTP expression. C1 NICHD, Sect Neural Dev & Plast, Lab Cellular & Synapt Neurophysiol, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Med, Div Hematol, New York, NY 10021 USA. Chinese Univ Hong Kong, Fac Med, Dept Physiol, Shatin, Hong Kong, Peoples R China. RP Lu, B (reprint author), NICHD, Sect Neural Dev & Plast, Lab Cellular & Synapt Neurophysiol, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012; OI Teng, Kenneth/0000-0002-9392-2172 FU NINDS NIH HHS [NS30658] NR 31 TC 607 Z9 632 U1 2 U2 22 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 OCT 15 PY 2004 VL 306 IS 5695 BP 487 EP 491 DI 10.1126/science.1100135 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 864IF UT WOS:000224626500054 PM 15486301 ER PT J AU Ochi, T Suzuki, T Barrett, JC Tsutsui, T AF Ochi, T Suzuki, T Barrett, JC Tsutsui, T TI A trivalent dimethylarsenic compound, dimethylarsine iodide, induces cellular transformation, aneuploidy, centrosome abnormality and multipolar spindle formation in Syrian hamster embryo cells SO TOXICOLOGY LA English DT Article DE trivalent dimethylarsenicals [DMAs (III)]; morphological transformation; aneuploidy; centrosome abnormality; multipolar spindles ID V79 CELLS; NEOPLASTIC TRANSFORMATION; INORGANIC ARSENICS; INDUCTION; ACID; PROGRESSION; CHROMOSOME; DIVISION; CULTURE; CENTERS AB The abilities of dimethylarsine iodide (DMI), a model compound of trivalent dimethylarsenicals, to induce cellular transformation, aneuploidy, centrosome abnormality, and multipolar spindle formations were investigated using the Syrian hamster embryo (SHE) cell model. Cellular growth was decreased in a concentration-dependent manner by treatment with DMI at concentrations over 0.1 muM. Treatment with DMI at concentrations from 0.1 to 1.0 muM induced morphological transformation in SHE cells. The transforming activity of DMI, determined by the frequency of morphologically transformed colonies, was approximately 30 times higher than that induced by treatment with the same concentration of sodium arsenite. Flow cytometry suggested an increase in the aneuploid population caused by DMI, as shown by the appearance of hypo-2N, hypo-4N and hypo-8N. DMI also Caused abnormal staining of gamma-tubulin, indicating loss of centrosome integrity and a resultant induction of multipolar spindles in mitotic cells. Mitotic cells with centrosomes that coalesced partly at the cell periphery, not the cell center, were detected as early changes that resulted in multipolar spindles. These findings indicate that DMI has transforming activity in SHE cells. Moreover, the results suggest the importance of centrosome abnormalities as a causal change of DMI-induced aneuploidy. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Teikyo Univ, Fac Pharmaceut Sci, Toxicol Lab, Kanagawa 1990195, Japan. NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. Nippon Dent Univ Tokyo, Sch Dent, Dept Pharmacol, Chiyoda Ku, Tokyo 1028159, Japan. RP Ochi, T (reprint author), Teikyo Univ, Fac Pharmaceut Sci, Toxicol Lab, Kanagawa 1990195, Japan. EM tkfmochi@pharm.teikyo-u.ac.jp NR 24 TC 12 Z9 12 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD OCT 15 PY 2004 VL 203 IS 1-3 BP 155 EP 163 DI 10.1016/j.tox.2004.06.006 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 860HI UT WOS:000224332700015 PM 15363591 ER PT J AU Shimada, H Takamure, Y Shimada, A Yasutake, A Waalkes, MP Imamura, Y AF Shimada, H Takamure, Y Shimada, A Yasutake, A Waalkes, MP Imamura, Y TI Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation SO TOXICOLOGY LA English DT Article DE cadmium toxicity; strain difference; tissue accumulation; rat ID MAMMALIAN ZINC TRANSPORTER; FUNCTIONAL-CHARACTERIZATION; TOXICITY; METALLOTHIONEIN; RESISTANCE; MICE; EXPOSURE; INDUCTION; CLONING; METALS AB We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Kumamoto Univ, Fac Educ, Kumamoto 8608555, Japan. Tottori Univ, Dept Vet Pathol, Tottori 6800945, Japan. Natl Inst Minamata Dis, Kumamoto 8670008, Japan. NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. Kumamoto Univ, Grad Sch Pharmaceut Sci, Kumamoto 8620973, Japan. RP Shimada, H (reprint author), Kumamoto Univ, Fac Educ, 2-40-1 Kurokami, Kumamoto 8608555, Japan. EM hshimada@gpo.kumamoto-u.ac.jp NR 30 TC 13 Z9 13 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD OCT 15 PY 2004 VL 203 IS 1-3 BP 189 EP 197 DI 10.1016/j.tox.2004.06.012 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 860HI UT WOS:000224332700018 PM 15363594 ER PT J AU Warren, BA Patel, SA Nunn, PB Bridges, RJ AF Warren, BA Patel, SA Nunn, PB Bridges, RJ TI The Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid is a substrate of the L-cystine/L-glutamate exchanger system x(c)(-) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE neurolathyrism; BOAA; transport; excitotoxicity; excitatory amino acid ID OXALYLAMINO-L-ALANINE; BETA-L-ODAP; HIGH-AFFINITY TRANSPORT; CENTRAL-NERVOUS-SYSTEM; AMINO-ACID; SPINAL-CORD; SATIVUS NEUROTOXIN; CORTICAL CULTURES; GLIOMA-CELLS; GLIAL-CELLS AB beta-N-Oxalyl-L-alpha-O-diaminopropionic acid (beta-L-ODAP) is an unusual amino acid present in seeds of plants from the Lathyrus genus that is generally accepted as the causative agent underlying the motor neuron degeneration and spastic paraparesis in human neurolathyrism. Much of the neuropathology produced by beta-L-ODAP appears to be a direct consequence of its structural similarities to the excitatory neurotransmitter L-glutamate and its ability to induce excitotoxicity as an agonist of non-NMDA receptors. Its actions within the CNS are, however, not limited to non-NMDA receptors, raising the likely possibility that the anatomical and cellular specificity of the neuronal damage observed in neurolathyrism may result from the cumulative activity of beta-L-ODAP at multiple sites. Accumulating evidence suggests that system x(c)(-), a transporter that mediates the exchange of L-cystine and L-glutamate, is one such site. In the present work, two distinct approaches were used to define the interactions of beta-L-ODAP with system x(c)(-): Traditional radiolabel-uptake assays were employed to quantify inhibitory activity, while fluorometrically coupled assays that follow the exchange-induced efflux of L-glutamate were used to assess substrate activity. In addition to confirming that beta-L-ODAP is an effective competitive inhibitor of system x(c)(-), we report that the compound exhibits a substrate activity comparable to that of the endogenous substrate L-cystine. The ability of system x(c)(-) to transport and accumulate beta-L-ODAP identifies additional variables that could influence its toxicity within the CNS, including the ability to limit its access to EAA receptors by clearing the excitotoxin from the extracellular synaptic environment, as well as serving as a point of entry through which beta-L-ODAP could have increased access to intracellular targets. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Montana, COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. Univ Portsmouth, Sch Pharm & Biomed Sci, Portsmouth PO1 2DT, Hants, England. RP Bridges, RJ (reprint author), Univ Montana, COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, 32 Campus Dr, Missoula, MT 59812 USA. EM richard.bridges@umontana.edu FU NCRR NIH HHS [RR15583]; NINDS NIH HHS [NS30570] NR 53 TC 27 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 15 PY 2004 VL 200 IS 2 BP 83 EP 92 DI 10.1016/j.taap.2004.04.001 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 865PM UT WOS:000224715000001 PM 15476861 ER PT J AU Morgan, DL Little, PB Herr, DW Moser, VC Collins, B Herbert, R Johnson, GA Maronpot, RR Harry, GJ Sills, RC AF Morgan, DL Little, PB Herr, DW Moser, VC Collins, B Herbert, R Johnson, GA Maronpot, RR Harry, GJ Sills, RC TI Neurotoxicity of carbonyl sulfide in F344 rats following inhalation exposure for up to 12 weeks SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE carbonyl sulfide; neurotoxicity; magnetic resonance microscopy; auditory system; brainstem auditory evoked responses; cytochrome oxidase ID AUDITORY-EVOKED-POTENTIALS; ENERGY DEPRIVATION SYNDROMES; NERVE-CONDUCTION VELOCITY; CYTOCHROME-C OXIDASE; BRAIN-STEM; SELECTIVE VULNERABILITY; INFERIOR COLLICULUS; ALPHA-CHLOROHYDRIN; FLASH; RESPONSES AB Carbonyl sulfide (COS), a high-priority Clean Air Act chemical, was evaluated for neurotoxicity in short-term studies. F344 rats were exposed to 75-600 ppm COS 6 h per day, 5 days per week for up to 12 weeks. In rats exposed to 500 or 600 ppm for up to 4 days, malacia and microgliosis were detected in numerous neuroanatomical regions of the brain by conventional optical microscopy and magnetic resonance microscopy (MRM). After a 2-week exposure to 400 ppm, rats were evaluated using a functional observational battery. Slight gait abnormality was detected in 50% of the rats and hypotonia was present in all rats exposed to COS. Decreases in motor activity, and forelimb and hindlimb grip strength were also detected. In rats exposed to 400 ppm for 12 weeks, predominant lesions were in the parietal cortex area 1 (necrosis) and posterior colliculus (neuronal loss, microgliosis, hemorrhage), and occasional necrosis was present in the putamen, thalamus, and anterior olivary nucleus. Carbonyl sulfide specifically targeted the auditory system including the olivary nucleus, nucleus of the lateral lemniscus, and posterior colliculus. Consistent with these findings were alterations in the amplitude of the brainstem auditory evoked responses (BAER) for peaks N3, P4, N4, and N5 that represented changes in auditory transmission between the anterior olivary nucleus to the medial geniculate nucleus in animals after exposure for 2 weeks to 400 ppm COS. A concentration-related decrease in cytochrome oxidase activity was detected in the posterior colliculus and parietal cortex of exposed rats as early as 3 weeks. Cytochrome oxidase activity was significantly decreased at COS concentrations that did not cause detectable lesions, suggesting that disruption of the mitochondrial respiratory chain may precede these brain lesions. Our studies demonstrate that this environmental air contaminant has the potential to cause a wide spectrum of brain lesions that are dependent on the degree and duration of exposure. (C) 2004 Elsevier Inc. All rights reserved. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Chalk River Labs, Pathol Associates Div, Res Triangle Pk, NC 27713 USA. US EPA, Div Neurotoxicol, Res Triangle Pk, NC 27511 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Sills, RC (reprint author), NIEHS, Lab Expt Pathol, 111 Alexander Dr,South Campus,MD B3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov OI Johnson, G.Allan/0000-0002-7606-5447 NR 58 TC 23 Z9 23 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 15 PY 2004 VL 200 IS 2 BP 131 EP 145 DI 10.1016/j.taap.2004.04.013 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 865PM UT WOS:000224715000006 PM 15476866 ER PT J AU Neeman, Z Hirshberg, B Tal, MG Wood, BJ Harlan, DM AF Neeman, Z Hirshberg, B Tal, MG Wood, BJ Harlan, DM TI Pulmonary angiography for the diagnosis of thromboembolic events in the non-human primate SO TRANSPLANTATION LA English DT Article ID INTRAHEPATIC ISLET ALLOGRAFTS; LONG-TERM SURVIVAL; RHESUS-MONKEYS; HUMANIZED ANTI-CD154; MONOCLONAL-ANTIBODY; PRECLINICAL MODEL; TRANSPLANTATION; REJECTION; LUNG; IMMUNOSUPPRESSION AB Background. Evaluating possible thromboembolic events in the non-human primate has traditionally required euthanasia, significantly limiting the ability to conduct longitudinal studies. We hypothesized that pulmonary angiography could offer a safe, reproducible, and non-lethal means to assess for pulmonary embolus in the non-human primate. Methods. Eleven rhesus primates were studied using standard pulmonary angiography techniques. Five animals studied had previously received humanized anti-CD154 antibodies (associated with thromboembolism risk) in the context of skin transplantation 2 years before the angiography study. Four primates were studied after receiving mouse antihuman CD 154 antibody following allogeneic islet or skin transplantation. Results. Angiography was successful in all primates. We observed no complications, and all animals promptly recovered from the procedure. Angiographic findings consistent with thromboembolism were demonstrated in the three primates actively receiving anti-CD154 antibody and in one primate that last received anti-CD154 nearly 2 years before the study. The study was normal in both the streptozotocin-induced diabetic control animals. Histopathology of the lungs confirmed thrombus in two of the four primates, but no thromboembolus was identified in the other two. The first had limited pathologic evaluation without fine slices, and in the second (treated 2 years before with a humanized anti-CD154), ascariasis was found in the area identified as abnormal by the angiogram. Conclusions. Minimally invasive pulmonary angiography is a safe, reproducible, and inexpensive method to assess possible thromboembolic events in the non-human primate. This method may allow for the longitudinal assessment of non-human primates given novel agents that may promote thromboembolism. C1 Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. NIDDKD, Islet & Autoimmun Branch, NIH, Bethesda, MD USA. Yale Univ, Sch Med, Dept Diagnost Radiol, Div Vasc & Intervent Radiol, New Haven, CT USA. RP Neeman, Z (reprint author), Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, NIH, 10 Ctr Dr,Room 1C 660, Bethesda, MD 20892 USA. EM zneeman@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 26 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD OCT 15 PY 2004 VL 78 IS 7 BP 1025 EP 1029 DI 10.1097/01.TP.0000135462.00668.D7 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 863GJ UT WOS:000224548800012 PM 15480169 ER PT J AU Miller, DS AF Miller, DS TI Confocal imaging of xenobiotic transport across the choroid plexus SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE active transport; cerebrospinal fluid; confocal microscopy; intracellular sequestration; organic anions; organic cations; xenobiotic transport ID ORGANIC ANION TRANSPORT; RENAL PROXIMAL TUBULE; FUNCTIONAL-CHARACTERIZATION; EPITHELIAL-CELLS; APICAL MEMBRANE; EXPRESSION; SECRETION; KIDNEY; IDENTIFICATION; CIMETIDINE AB "You can see a lot by looking."-Yogi Berra Confocal microscopy is a tool by which the distribution of fluorescent compounds within living, complex tissues can be mapped at submicrometer resolution and quantitated. This laboratory has used confocal imaging and quantitative image analysis to visualize transport of xenobiotics across intact rat and mouse choroid plexus. For both organic anions and organic cations, transport from CSF to blood is a three-step process involving: uptake at the apical membrane of the epithelial cells, transcellular transport and efflux at the basolateral membrane. Both transmembrane steps are carrier-mediated and concentrative. In the cytoplasm of the epithelial cells, all fluorescent xenobiotics studied partition between diffuse and punctate compartments, some of which appear to be mobile. Use of confocal imaging in combination with transport inhibitors, treatments that alter metabolism and ion gradients and tissue from genetically altered mice, has allowed us to characterize transport at specific membrane sites and begin to identify the responsible transporters at the molecular level. (C) 2004 Elsevier B.V All rights reserved. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov NR 34 TC 12 Z9 13 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD OCT 14 PY 2004 VL 56 IS 12 BP 1811 EP 1824 DI 10.1016/j.addr.2004.07.010 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 860HT UT WOS:000224333800007 PM 15381335 ER PT J AU Heekeren, HR Marrett, S Bandettini, PA Ungerleider, LG AF Heekeren, HR Marrett, S Bandettini, PA Ungerleider, LG TI A general mechanism for perceptual decision-making in the human brain SO NATURE LA English DT Article ID HUMAN EXTRASTRIATE CORTEX; PREFRONTAL CORTEX; PARIETAL CORTEX; NEURAL BASIS; REPRESENTATION; ATTENTION; OBJECTS; SIGNAL; MICROSTIMULATION; MEMORY AB Findings from single-cell recording studies suggest that a comparison of the outputs of different pools of selectively tuned lower-level sensory neurons may be a general mechanism by which higher-level brain regions compute perceptual decisions. For example, when monkeys must decide whether a noisy field of dots is moving upward or downward, a decision can be formed by computing the difference in responses between lower-level neurons sensitive to upward motion and those sensitive to downward motion(1-4). Here we use functional magnetic resonance imaging and a categorization task in which subjects decide whether an image presented is a face or a house to test whether a similar mechanism is also at work for more complex decisions in the human brain and, if so, where in the brain this computation might be performed. Activity within the left dorsolateral prefrontal cortex is greater during easy decisions than during difficult decisions, covaries with the difference signal between face- and house-selective regions in the ventral temporal cortex, and predicts behavioural performance in the categorization task. These findings show that even for complex object categories, the comparison of the outputs of different pools of selectively tuned neurons could be a general mechanism by which the human brain computes perceptual decisions. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Heekeren, HR (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM hauke@nih.gov RI Heekeren, Hauke/B-7739-2008; Bandettini, Peter/F-5871-2012; OI Heekeren, Hauke/0000-0001-7912-6826; Marrett, Sean/0000-0001-8179-6511 NR 31 TC 320 Z9 323 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 14 PY 2004 VL 431 IS 7010 BP 859 EP 862 DI 10.1038/nature02966 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861RE UT WOS:000224435500050 PM 15483614 ER PT J AU Harvey, BK Shen, H Chen, GJ Yoshida, Y Wang, Y AF Harvey, BK Shen, H Chen, GJ Yoshida, Y Wang, Y TI Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats SO NEUROSCIENCE LETTERS LA English DT Article DE midkine; retinoic acid; neuroprotection; stroke ID TRANSIENT FOREBRAIN ISCHEMIA; MOUSE SPINAL-CORD; NEUROTROPHIC FACTOR; 9-CIS-RETINOIC ACID; NUCLEAR RECEPTOR; GENE-PRODUCT; X-RECEPTOR; EXPRESSION; PROTECTS; BRAIN AB The present study investigates the neuroprotective effects of midkine (MK) and retinoic acid (RA) against ischemia in the CNS. Primary cortical neurons, derived from rat E 15 embryos (DIV9), were treated with 9-cis-RA (9cRA), all-trans-RA (atRA) or vehicle. Using quantitative PCR, the level of MK mRNA was significantly increased at 4 h after 9cRA application. The protective effect of RA and MK was also investigated in adult Sprague-Dawley rats. 9cRA, atRA, MK, or vehicle was injected into the lateral ventricle prior to a 60-min-MCA ligation. Pretreatment with 9cRA or MK attenuated cerebral infarction in stroke animals. Application of a similar dose of atRA did not reduce the size of infarction. In conclusion, our data suggest that 9cRA has neuroprotective effects against ischemia-related brain injury which may involve upregulation of midkine. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIDA, Neural Protect & Regenerat Sect, Mol Neuropsychiat Branch, Baltimore, MD 21124 USA. Kagoshima Univ, Fac Med, Sch Med Sci, Course Phys Therapy, Kagoshima, Japan. RP Wang, Y (reprint author), NIDA, Neural Protect & Regenerat Sect, Mol Neuropsychiat Branch, 5500 Nathan Shock Dr, Baltimore, MD 21124 USA. EM ywang@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010 NR 25 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 14 PY 2004 VL 369 IS 2 BP 138 EP 141 DI 10.1016/j.neulet.2004.07.086 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 861SE UT WOS:000224438100010 PM 15450683 ER PT J AU Kearney, K Chen, DY Taraporewala, ZF Vende, P Hoshino, Y Tortorici, MA Barro, M Patton, JT AF Kearney, K Chen, DY Taraporewala, ZF Vende, P Hoshino, Y Tortorici, MA Barro, M Patton, JT TI Cell-line-induced mutation of the rotavirus genome alters expression of an IRF3-interacting protein SO EMBO JOURNAL LA English DT Article DE gene expression; interferon regulatory factor 3; RNA replication; rotavirus; vaccine production ID MESSENGER-RNA; CONSENSUS SEQUENCE; NSP3; RECOGNITION; REPLICATION; TRANSLATION; INITIATION; VISUALIZATION; COMPLEXES; CHILDREN AB Rotavirus, a cause of severe gastroenteritis, contains a segmented double-stranded (ds) RNA genome that replicates using viral mRNAs as templates. The highly conserved 30-consensus sequence (3'CS), UGUGACC, of the mRNAs promotes dsRNA synthesis and enhances translation. We have found that the 3'CS of the gene (g5) encoding NSP1, an antagonist of interferon signaling, undergoes rapid mutation when rhesus rotavirus (RRV) is serially passaged at high multiplicity of infection (MOI) in cells permitting high titer growth. These mutations increase the promoter activity of the g5 3'-sequence, but decrease its activity as a translation enhancer. The location of the mutations defines the minimal essential promoter for dsRNA synthesis as URN0-5CC. Under passage conditions where cell-to-cell spread of the virus is required to complete infection (low MOI), the 3'CS is retained due to the need for NSP1 to be expressed at levels sufficient to prevent establishment of the antiviral state. These data demonstrate that host cell type and propagation conditions affect the capacity of RRV to produce the virulence gene product NSP1, an important consideration in producing RRV-based vaccines. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr MSC 8026, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 NR 32 TC 11 Z9 16 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 13 PY 2004 VL 23 IS 20 BP 4072 EP 4081 DI 10.1038/sj.emboj.7600408 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 867BG UT WOS:000224816500016 PM 15372078 ER PT J AU Wendler, D Emanuel, E AF Wendler, D Emanuel, E TI Ethics of surrogate consent for living organ donation - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 13 PY 2004 VL 292 IS 14 BP 1685 EP 1685 DI 10.1001/jama.292.14.1685-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 861JS UT WOS:000224413400022 ER PT J AU Cooper, O Isacson, O AF Cooper, O Isacson, O TI Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE TGF alpha; dopaminergic; neural progenitor; Parkinson's disease; subventricular zone; infusion ID MAMMALIAN SUBSTANTIA-NIGRA; STEM-CELLS; SUBVENTRICULAR ZONE; RAT-BRAIN; FACTOR RECEPTOR; NERVOUS-SYSTEM; MOUSE BRAIN; NEUROGENESIS; EXPRESSION; LESIONS AB We examined the cell proliferative, neurogenic, and behavioral effects of transforming growth factor alpha(TGFalpha) in a 6-OHDA Parkinson's disease model when compared with naive rats. Intrastriatal TGFalpha infusion induced significant proliferation, hyperplastic nodules, and substantial migratory waves of nestin-positive progenitor cells from the adult subventricular zone (SVZ) of dopamine-denervated rats. Interestingly, SVZ cells in naive rats displayed proliferation but minimal migration in response to the TGFalpha infusion. The cells in the expanded SVZ accumulated cytoplasmic beta-catenin, indicating activation of classical Wnt signaling. However, no evidence of any neuronal differentiation was found of these recruited progenitor cells anywhere examined in the brain. Consequently, no evidence of dopaminergic (DA) neurogenesis was found in the striatum or substantia nigra in any experimental group, and amphetamine-induced behavioral rotations did not improve. In summary, the cells in the TGFalpha-induced migratory cellular wave remain undifferentiated and do not differentiate into midbrain-like DA neurons. C1 Harvard Univ, Belmont, MA 02478 USA. McLean Hosp, NINDS, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Harvard Ctr Neurodegenerat & Repair, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Ctr Neurodegenerat & Repair, Program Neurosci, Boston, MA 02115 USA. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Sch Med, Neuroregenerat Labs,Mailman Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu FU NINDS NIH HHS [P50 NS039793, P50 NS039793-05] NR 49 TC 116 Z9 130 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 13 PY 2004 VL 24 IS 41 BP 8924 EP 8931 DI 10.1523/JNEUROSCI.2344-04.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 862AR UT WOS:000224461800004 PM 15483111 ER PT J AU Iwahara, J Schwieters, CD Clore, GM AF Iwahara, J Schwieters, CD Clore, GM TI Characterization of nonspecific protein-DNA interactions by H-1 paramagnetic relaxation enhancement SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID GROUP CHROMOSOMAL-PROTEINS; RESONANCE ENERGY-TRANSFER; CISPLATIN-MODIFIED DNA; DIPOLAR COUPLINGS; BINDING PROTEINS; GLOBAL STRUCTURE; STRUCTURAL BASIS; SEX REVERSAL; DUPLEX DNA; NMR AB Nonspecific protein-DNA interactions play an important role in a variety of contexts related to DNA packaging, nucleoprotein complex formation, and gene regulation. Biophysical characterization of nonspecific protein-DNA interactions at the atomic level poses significant challenges owing to the dynamic nature of such complexes. Although NMR spectroscopy represents a powerful tool for the analysis of dynamic systems, conventional NMR techniques have provided little information on nonspecific protein-DNA interactions. We show that intermolecular H-1 paramagnetic relaxation enhancement (PRE) arising from Mn2+ chelated to an EDTA-group covalently attached to a thymine base (dT-EDTA-Mn2+) in DNA provides a unique approach for probing the global dynamics and equilibrium distribution of nonspecific protein-DNA interactions. For nonspecific DNA binding, similar intermolecular H-1-PRE profiles are observed on the H-1 resonances of the bound protein when dT-EDTA-Mn2+ is located at either end of a DNA oligonucleotide duplex. We demonstrate the applicability of this approach to HMG-box proteins and contrast the results obtained for nonspecific DNA binding of the A-box of HMGB-1 (HMGB-1A) with sequence-specific DNA binding of the related SRY protein. Intermolecular 1H-PRE data demonstrate unambiguously that HMGB-1 A binds to multiple sites in multiple orientations even on a DNA fragment as short as 14 base pairs. Combining the 1H-PRE data with the crystal structure of the HMGB-1 A-box/cisplatin-modified DNA complex allows one to obtain a sermiquantitative estimate of the equilibrium populations at the various sites. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 60 TC 50 Z9 51 U1 4 U2 24 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 OCT 13 PY 2004 VL 126 IS 40 BP 12800 EP 12808 DI 10.1021/ja046246b PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 860QI UT WOS:000224357700045 PM 15469275 ER PT J AU Saavedra, JE Bohle, DS Smith, KN George, C Deschamps, JR Parrish, D Ivanic, J Wang, YN Citro, ML Keefer, LK AF Saavedra, JE Bohle, DS Smith, KN George, C Deschamps, JR Parrish, D Ivanic, J Wang, YN Citro, ML Keefer, LK TI Chemistry of the diazeniumdiolates. O- versus N-alkylation of the RNH[N(O)NO](-) ion SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NITRIC-OXIDE DONORS; COMPLEXES; RELEASE; ADDUCTS AB Monomethylation of the potentially ambident RNH[N(O)NO](-) ion (R = isopropyl or cyclohexyl) has been shown to occur at the terminal oxygen to yield the novel diazeniumdiolate structural unit, RNHN-(O)=NOMe. The NH bond of the product proved acidic, with a pK(a) of 12.3 in aqueous solution. The ultraviolet spectrum showed a large bathochromic shift on ionization (lambda(max) 244 --> 284 nm, epsilon(max) 6.9 --> 9.8 mM(-1) cm(-1)). Deprotonation led to a pH-dependent line broadening in the H-1 NMR spectrum of iPrNHN(O)=NOMe, suggesting a complex fluxionality possibly involving isomerizations around the N-N bonds. Consistent with this interpretation, evidence for extensive delocalization and associated changes in bond order on ionizing RNHN(O)=NOR' were found in density functional theory calculations using Gaussian 03 with B3LYP/ 6-311 ++G** basis sets. With MeNHN(O)=NOMe as a model, all N-N and N-O bonds lengthened by 0.04-0.07 A as a result of ionization except for the MeN-N linkage, which shortened by 7%. These anions can be N-alkylated to generate (RRNN)-R-1-N-2(O)=NOR3 derivatives that would otherwise be difficult to access synthetically. Additionally, some RNHN(O)=NOR' species may display unique and beneficial pharmacological properties. As one example, an agent with R = isopropyl and R' = beta-D-glucosyl was prepared and shown to generate nitric oxide in the presence of glucosidase at pH 5. C1 SAIC Frederick, Basic Res Program, NCI, Ft Detrick, MD 21702 USA. McGill Univ, Dept Chem, Montreal, PQ H3A 2K6, Canada. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NCI, SAIC Frederick, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. RP Keefer, LK (reprint author), SAIC Frederick, Basic Res Program, NCI, Ft Detrick, MD 21702 USA. EM keefer@ncifcrf.gov RI Keefer, Larry/N-3247-2014; OI Keefer, Larry/0000-0001-7489-9555; Deschamps, Jeffrey/0000-0001-5845-0010 FU NCI NIH HHS [N01 CO 12400] NR 19 TC 25 Z9 25 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 13 PY 2004 VL 126 IS 40 BP 12880 EP 12887 DI 10.1021/ja0351538i PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 860QI UT WOS:000224357700055 PM 15469285 ER PT J AU O'Donnell, CJ AF O'Donnell, CJ TI Family history, subclinical atherosclerosis, and coronary heart disease risk - Barriers and opportunities for the use of family history information in risk prediction and prevention SO CIRCULATION LA English DT Editorial Material DE editorials; genetics; risk factors; coronary disease; prevention ID INTIMA-MEDIA THICKNESS; PARENTAL CARDIOVASCULAR-DISEASE; BEAM COMPUTED-TOMOGRAPHY; MYOCARDIAL-INFARCTION; WOMEN; HERITABILITY; ACCURACY; EVENTS; ADULTS; DEATH C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM codonnell@nih.gov NR 21 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 12 PY 2004 VL 110 IS 15 BP 2074 EP 2076 DI 10.1161/01.CIR.0000145539.77021.AC PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 861HP UT WOS:000224407000001 PM 15477424 ER PT J AU Spiecker, M Darius, H Hankeln, T Soufi, M Sattler, AM Schaefer, JR Node, K Borgel, J Mugge, A Lindpaintner, K Huesing, A Maisch, B Zeldin, DC Liao, JK AF Spiecker, M Darius, H Hankeln, T Soufi, M Sattler, AM Schaefer, JR Node, K Borgel, J Mugge, A Lindpaintner, K Huesing, A Maisch, B Zeldin, DC Liao, JK TI Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2 SO CIRCULATION LA English DT Article DE atherosclerosis; coronary disease; genetics; inflammation; molecular biology ID EPOXYEICOSATRIENOIC ACIDS; ENDOTHELIAL-CELLS; KAPPA-B; EICOSANOIDS; ACTIVATION; CLONING; GENE AB Background-Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks. Methods and Results-All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism ( SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P = 0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1 +/- 2.4% decrease in CYP2J2 promoter activity (P < 0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP. Conclusions-A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease. C1 Ruhr Univ Bochum, St Josef Hosp, Dept Med 2, D-4630 Bochum, Germany. Ruhr Univ Bochum, Dept Med Stat, D-4630 Bochum, Germany. Univ Mainz, Dept Med 2, D-6500 Mainz, Germany. GENterprise GmbH, Mainz, Germany. Univ Marburg, Dept Med, Marburg, Germany. Saga Med Sch, Dept Cardiol, Saga, Japan. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. F Hoffmann La Roche & Co Ltd, Roche Genet, CH-4002 Basel, Switzerland. F Hoffmann La Roche & Co Ltd, Roche Ctr Med Genom, CH-4002 Basel, Switzerland. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Spiecker, M (reprint author), Ruhr Univ Bochum, St Josef Hosp, Dept Med Cardiol 2, Gudrunstr 56, D-44791 Bochum, Germany. EM martin.spiecker@ruhr-uni-bochum.de FU NHLBI NIH HHS [HL-52233, P01 HL048743, P01 HL048743-120008, R01 HL052233, R01 HL052233-05, R01 HL052233-06, R01 HL052233-07, R01 HL070274, R01 HL070274-01, R01 HL070274-02]; NIDDK NIH HHS [R01 DK062729, R01 DK062729-01A1]; NINDS NIH HHS [P01 NS010828, P01 NS010828-330036, P50 NS010828, P50 NS010828-290036] NR 14 TC 132 Z9 141 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 12 PY 2004 VL 110 IS 15 BP 2132 EP 2136 DI 10.1161/01.CIR.0000143832.91812.60 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 861HP UT WOS:000224407000010 PM 15466638 ER PT J AU Bastepe, M Weinstein, LS Ogata, N Kawaguchi, H Juppner, H Kronenberg, HM Chung, UI AF Bastepe, M Weinstein, LS Ogata, N Kawaguchi, H Juppner, H Kronenberg, HM Chung, UI TI Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-DEVELOPMENT; XL-ALPHA-S; PARATHYROID-HORMONE; MATERNAL TRANSMISSION; PTH/PTHRP RECEPTOR; GENE; EXPRESSION; SUBUNIT; PSEUDOHYPOPARATHYROIDISM AB Stimulatory heterotrimeric G protein (Gs) transduces signals from various cell-surface receptors to adenylyl cyclases, which generate cAMP. The a subunit of Gs (Gsalpha) is encoded by GNAS (Gnas in mice), and heterozygous Gsa inactivating mutations lead to Albright hereditary osteodystrophy. The in vivo role of Gsa in skeletogenesis is largely unknown, because of early embryonic lethality of mice with disruption of Gnas exon 2 (Gnas(E2-)/E2-) and the absence of easily detectable phenotypes in growth plate chondrocytes of heterozygous mutant mice (Gnas(+)/(E2-)). We generated chimeric mice containing wild-type cells and either Gnas(E2-)/(E2-) or Gnas(+/E2-) cells. Gnas(E2-)/(E2-) chondrocytes phenocopied PTH/PTHrP receptor (PPR)(-/-) cells by prematurely undergoing hypertrophy. Introduction of a transgene expressing Gsa, one of several gene products that include Gnas exon 2, into Gnas(E2-)/(E2-) cells prevented premature hypertrophy. Gsa mRNA expression detected by real-time RT-PCR analysis was reduced to approximately half that of the wild-type in both paternal and maternal Gnas(+)/(E2-) growth plate chondrocytes, indicating biallelic expression of Gsa in these cells. Hypertrophy of Gnas(+)/(E2-) chondrocytes was modestly but significantly premature in chimeric growth plates of mice containing wild-type and Gnas(+)/(E2-) cells. These data suggest that Gsa is the primary mediator of the actions of PPR in growth plate chondrocytes and that there is haploinsufficiency of Gsa signaling in Gnas(+)/(E2-) chondrocytes. C1 Tokyo Univ Hosp, Div Tissue Engn, Bunkyo Ku, Tokyo 1138655, Japan. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chung, UI (reprint author), Tokyo Univ Hosp, Div Tissue Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM teiy-ort@h.u-tokyo.ac.jp OI Weinstein, Lee/0000-0002-1899-5152 FU NIAMS NIH HHS [AR47078, R01 AR047078]; NIDDK NIH HHS [R37 DK046718, P01 DK056246, DK46718, R56 DK046718, DK56246, R01 DK046718] NR 29 TC 81 Z9 83 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 OCT 12 PY 2004 VL 101 IS 41 BP 14794 EP 14799 DI 10.1073/pnas.0405091101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 862JX UT WOS:000224488000022 PM 15459318 ER PT J AU Ono, A Ablan, SD Lockett, SJ Nagashima, K Freed, EO AF Ono, A Ablan, SD Lockett, SJ Nagashima, K Freed, EO TI Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 gag targeting to the plasma membrane SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VIRUS TYPE-1 GAG; MATRIX PROTEIN; MULTIVESICULAR BODIES; PARTICLE-PRODUCTION; PRIMARY MACROPHAGES; TERMINAL REGION; LIFE-CYCLE; ARF6; PHOSPHOINOSITIDES; DOMAINS AB A critical early event in the HIV type 1 (HIV-1) particle assembly pathway is the targeting of the Gag protein to the site of virus assembly. In many cell types, assembly takes place predominantly at the plasma membrane. Cellular factors that regulate Gag targeting remain undefined. The phosphoinositide phosphaticlylinositol (4,5) bisphosphate [PI(4,5)P-2] controls the plasma membrane localization of a number of cellular proteins. To explore the possibility that this lipid maybe involved in Gag targeting and virus particle production, we overexpressed phosphoinositicle 5-phos-phatase IV, an enzyme that depletes cellular PI(4,5)P-2, or overexpressed a constitutively active form of Arf6 (Arf6/Q67L), which induces the formation of PI(4,5)P-2-enriched endosomal structures. Both approaches severely reduced virus production. Upon 5-phos-phatase IV overexpression, Gag was no longer localized on the plasma membrane but instead was retargeted to late endosomes. Strikingly, in cells expressing Arf6/Q67L, Gag was redirected to the PI(4,5)P-2-enriched vesicles and HIV-1 virions budded into these vesicles. These results demonstrate that PI(4,5)P-2 plays a key role in Gag targeting to the plasma membrane and thus serves as a cellular determinant of HIV-1 particle production. C1 NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Image Anal Lab, Res Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Ono, A (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM aono@ncifcrf.gov OI Ono, Akira/0000-0001-7841-851X NR 57 TC 281 Z9 287 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2004 VL 101 IS 41 BP 14889 EP 14894 DI 10.1073/pnas.0405596101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 862JX UT WOS:000224488000038 PM 15465916 ER PT J AU Hayashi, T Su, TP AF Hayashi, T Su, TP TI Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID METHYL-D-ASPARTATE; BINDING-SITES; ENDOPLASMIC-RETICULUM; PC12 CELLS; RAT-BRAIN; RAFT; DYNAMICS; LIGANDS; MYELIN; TARGET AB In the brain, myelin is important in regulating nerve conduction and neurotransmitter release by providing insulation at axons. Myelin is a specialized yet continuous sheet structure of differentiated oligodendrocytes (OLs) that is enriched in lipids, specifically galactosylceramides (GalCer) originated at the endoplasmic reticulum (ER). GalCer are known to affect OL differentiation. However, the mechanism whereby GalCer affect OL differentiation is not well understood. Sigma-1 receptors (Sig-1Rs), shown by us to exist in detergent-insoluble lipid microdomains at lipid-enriched loci of ER in NG108 cells, are important in the compartmentalization/ transport of ER-synthesized lipids and in cellular differentiation. In this study, we used rat primary hippocampal cultures and found that Sig-1Rs form GalCer-enriched lipid rafts at ER lipid droplet-like structures in the entire myelin sheet of mature OLs. In rat OL progenitors (CG-4 cells), levels of lipid raft-residing Sig-1Rs and GalCer increase as cells differentiate. Sig-1Rs also increase in OLs and myelin of developing rat brains. Sig-1R, GalCer, and cholesterol are colocalized and are resistant to the Triton X-100 solubilization. Treating cells with a Sig-1R agonist or targeting Sig-1Rs at lipid rafts by overexpression of Sig-1Rs in CG-4 cells enhances differentiation, whereas reducing Sig-1Rs at lipid rafts by transfection of functionally dominant-negative Sig-1Rs attenuates differentiation. Furthermore, Sig-1R siRNA inhibits differentiation. Our findings indicate that, in the brain, Sig-1Rs targeting GalCer-containing lipid microdomains are important for OL differentiation and that Sig-1Rs may play an important role in the pathogenesis of certain demyelinating diseases. C1 NIH, Cellular Pathobiol Unit, Dev & Plascic Sect,Cellular Neurobiol Res Branch, Intramural Res Program,US Dept Hlth& Human Serv, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIH, Cellular Pathobiol Unit, Dev & Plascic Sect,Cellular Neurobiol Res Branch, Intramural Res Program,US Dept Hlth& Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM tsu@intra.nida.nih.gov RI Hayashi, Teruo/A-9690-2008 NR 34 TC 84 Z9 91 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 OCT 12 PY 2004 VL 101 IS 41 BP 14949 EP 14954 DI 10.1073/pnas.0402890101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 862JX UT WOS:000224488000048 PM 15466698 ER PT J AU Emanuel, EJ Fairclough, DL Wolfe, P Emanuel, LL AF Emanuel, EJ Fairclough, DL Wolfe, P Emanuel, LL TI Talking with terminally ill patients and their Caregivers about death, dying, and bereavement - Is it stressful? Is it helpful? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CARE; ADULTS AB Background: Discussing end-of-life issues with terminally ill patients is often considered distressing and harmful. This study was conducted to assess whether interviewing terminally ill patients and their caregivers about death, dying, and bereavement is stressful and/or helpful. Methods: Patients from 6 sites in the United States who were estimated to have 6 months or less to live were interviewed in person and reinterviewed 2 to 6 months later. Their caregivers were interviewed separately. At the end of the interviews, patients and caregivers were asked how stressful and how helpful the interview had been. Of 1131 eligible patients, 988 (87.4%) were interviewed, and of 915 eligible caregivers, 893 (97.6%) were interviewed. Results: At the end of the first interview, 1.9% of the patients reported having experienced a great deal of stress, 7.1% some stress, and 88.7% little or no stress from the interview. Among the caregivers, 1.5% reported a great deal of stress, 8.4% some stress, and 89.7% little or no stress. Slightly more stress was reported to have been caused by the reinterview. Overall, 16.9% of the patients reported the initial interview as very helpful, 29.6% as somewhat helpful, and 49.6% as offering little or no help. Among the caregivers, 19.1% reported the initial interview as very helpful, 34.3% as somewhat helpful, and 44.9% as offering little or no help. The reported helpfulness of the second interview was slightly less. Patients experiencing pain (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.02-1.56), more personal meaning in dying (OR, 3.05; 95% CI, 2.02-4.59), and less ease with talking about the end of life (OR, 1.32; 95% CI, 1.091.60) were significantly more likely to report stress. Patients who were from an ethnic minority (OR, 1.85; 95% CI, 1.31-2.63), anxious about the end of their life (OR, 1.39; 95% CI 1.16-1.67), more spiritual (OR, 1.30; 95% CI, 1.06-1.61), and serene (OR, 1.25; 95% CI, 1.081.45) were significantly more likely to report the interview helpful. There was no relationship between stress and helpfulness. Conclusions: Terminally ill patients and their care-givers can discuss death, dying, and bereavement in a structured interview with minimal stress and report that the interview was helpful. Institutional review boards should not preemptively restrict surveys with terminally ill patients without reliable evidence that they will be stressful or otherwise harmful. C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. Amer Med Ctr, Ctr Res Methodol & Biometr, Ctr Canc Res, Denver, CO USA. Wolf Stat Consulting LLC, Denver, CO USA. Northwestern Univ, Sch Med, Buehler Ctr Aging, Chicago, IL 60611 USA. RP Emanuel, EJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@cc.nih.gov NR 12 TC 71 Z9 73 U1 0 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 11 PY 2004 VL 164 IS 18 BP 1999 EP 2004 DI 10.1001/archinte.164.18.1999 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 862RF UT WOS:000224507900008 PM 15477434 ER PT J AU Hodes, RJ Dutta, C Pocinki, KM AF Hodes, RJ Dutta, C Pocinki, KM TI Don't forget to prescribe exercise for your older patients SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 NIA, Bethesda, MD 20892 USA. RP Pocinki, KM (reprint author), NIA, 31 Ctr Dr,MSC 2292, Bethesda, MD 20892 USA. EM pocinkik@nia.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 11 PY 2004 VL 164 IS 18 BP 2065 EP 2066 DI 10.1001/archinte.164.18.2065-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 862RF UT WOS:000224507900019 PM 15477444 ER PT J AU Pentchev, PG AF Pentchev, PG TI Niemann-Pick C research from mouse to gene SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE cholesterol; cholesteol transport; Niemann-Pick C; positional cloning; sphingomyelinase ID LOW-DENSITY-LIPOPROTEIN; DISEASE TYPE-C; STORAGE DISORDER; CHOLESTEROL ESTERIFICATION; CULTURED FIBROBLASTS; HUMAN CHROMOSOME-18; METABOLISM; LINKAGE; HOMEOSTASIS; DEFICIENCY AB Understanding the molecular basis of Niemann-Pick C (NP-C) disease took decades of struggle. Here I describe our early efforts to unravel the complex lipid storage found in NP-C tissues, and how the mouse model for NP-C pointed us in the right direction. Our success in cloning the NP-Cl gene in 1997 can be attributed to collaboration between an international body of scientists and families coping with NP-C disease. The next challenge is to delineate the biological function of the NP-Cl protein. (C) 2004 Elsevier B.V All rights reserved. C1 NIH, Bethesda, MD 20892 USA. RP Pentchev, PG (reprint author), NIH, Bldg 10,Rm 3D-12 10m Ctr Dr, Bethesda, MD 20892 USA. EM pentchev@codon.nih.gov NR 26 TC 32 Z9 33 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD OCT 11 PY 2004 VL 1685 IS 1-3 BP 3 EP 7 DI 10.1016/j.bbalip.2004.08.005 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 862VG UT WOS:000224518700002 PM 15465420 ER PT J AU Oz, M Tchugunova, Y Dinc, M AF Oz, M Tchugunova, Y Dinc, M TI Differential effects of endogenous and synthetic cannabinoids on voltage-dependent calcium fluxes in rabbit T-tubule membranes: comparison with fatty acids SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE calcium channel; endocannabinoid; cannabinoid; fatty acid; skeletal muscle ID RECEPTOR-MEDIATED RESPONSES; RECTIFYING POTASSIUM CHANNELS; XENOPUS-LAEVIS OOCYTES; SKELETAL-MUSCLE; DIRECT INHIBITION; ARACHIDONIC-ACID; CA2+ FLUXES; VENTRICULAR MYOCYTES; TRANSVERSE TUBULES; ATPASE ACTIVITY AB The effects of cannabinoid receptor ligands including 2-arachidonoylglycerol, R-methanandamide, Delta(9)-THC (Delta(9)-tetrahydrocannabinol), WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], CP 55,940 ([1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol]) and a series of fatty acids on depolarization-induced Ca2+ effluxes mediated by voltage-dependent Ca2+ channels were investigated comparatively in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with Ca-45(2+) and membrane potentials were generated by establishing potassium gradients across the vesicle using the ionophore valinomycin. Endocannabinoids, 2-arachidonoylglycerol and R-methanandamide (all 10 muM), inhibited depolarization-induced Ca2+ effluxes and specific binding of [H-3]PN 200-110 (isradipine) to transverse tubule membranes. On the other hand, synthetic cannabinoids, including CP 55,940, WIN 55,212-2, and Delta(9)-THC (all 10 gm), were ineffective. Additional experiments using endocannabinoid metabolites suggested that whereas ethanolamine and glycerol were ineffective, arachidonic acid inhibited Ca2+ effluxes and specific binding of [H-3]PN 200-110. Further studies indicated that only those fatty acids containing two or more double bonds were effective in inhibiting depolarization-induced Ca2+ effluxes and specific binding of [H-3]PN 200-110. These results indicate that endocannabinoids, but not synthetic cannabinoids, directly inhibit the function of voltage-dependent calcium channels (VDCCs) and modulate the specific binding of calcium channel ligands of the dihydropyridine (DHP) class. (C) 2004 Elsevier B.V. All rights reserved. C1 NIDA, DHHS, Intramural Res Program, Cellular Neurobiol Branch,NIH, Baltimore, MD 21224 USA. Oncol Hosp, Dept Pulm Dis, TR-06947 Ankara, Turkey. RP Oz, M (reprint author), NIDA, DHHS, Intramural Res Program, Cellular Neurobiol Branch,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 NR 57 TC 30 Z9 31 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 OCT 11 PY 2004 VL 502 IS 1-2 BP 47 EP 58 DI 10.1016/j.ejphar.2004.08.052 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 861WI UT WOS:000224448900006 PM 15464089 ER PT J AU Kostich, WA Grzanna, R Lu, NZ Largent, BL AF Kostich, WA Grzanna, R Lu, NZ Largent, BL TI Immunohistochemical visualization of corticotropin-releasing factor type 1 (CRF1) receptors in monkey brain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE neuropeptide; rhesus macaque; urocortin; pituitary; brain stem; cerebellum; cerebral cortex ID CENTRAL-NERVOUS-SYSTEM; FACTOR-LIKE IMMUNOREACTIVITY; MESSENGER-RNA EXPRESSION; NONHUMAN PRIMATE BRAIN; RAT-BRAIN; TONIC INTERNALIZATION; HORMONE-RECEPTOR; HIGH-AFFINITY; AUTORADIOGRAPHIC LOCALIZATION; BIOCHEMICAL-CHARACTERIZATION AB Corticotropin-releasing factor receptor type 1, CRF1, plays a prominent role in the hypothalamic-pituitary-adrenal (HPA) axis and is implicated in the autonomic and behavioral responses to stress. Dysregulation of the CRF system may underlie the pathophysiology of several disorders, including depression and anxiety. The distribution of CRF1 mRNA and CRF1 specific ligand binding has been reported by multiple groups in rodents using in situ hybridization and receptor autoradiography, respectively. More recently, somewhat conflicting rodent anti-CRF1 immunohistochemical studies were reported. In this study we report the generation of an antihuman CRF1 antiserum and provide the first immunohistochemical description of CRF1 distribution in a primate brain, that of the rhesus monkey. The specificity of anti-CRF-R1 antiserum R221 was demonstrated using transfected hCRF(1)-expressing HEK 293 cells and rhesus monkey pituitary. CRF1-immunoreactive neurons were widespread in the rhesus brain. CRF1 staining was associated with neuronal cell bodies and dendrites and was primarily intracellular, suggesting a high rate of receptor turnover or receptor sequestration. Anti-CRF1 immunoreactivity was most abundant in pituitary, cerebellum, and in portions of brain stem associated with sensorimotor function. CRF1 staining was also observed in cerebral cortex, basal forebrain, portions of the basal ganglia, and thalamus. Staining was relatively low in prefrontal cortex and in limbic areas, which may reflect masking of the N-terminal epitope. The distribution of CRF1 immunoreactivity is suggestive of roles in attentional processing as well as the processing of motor and sensory information. (C) 2004 Wiley-Liss, Inc. C1 Bristol Myers Squibb Co, Pharmaceut Res Inst, Neurosci Drug Discovery, Wallingford, CT 06492 USA. Univ Maryland, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Kostich, WA (reprint author), Bristol Myers Squibb Co, Pharmaceut Res Inst, Neurosci Drug Discovery, 5 Res Pkwy, Wallingford, CT 06492 USA. EM Walter.Kostich@bms.com FU NCRR NIH HHS [RR000163]; NICHD NIH HHS [U54 HD 18185]; NIMH NIH HHS [MH62677] NR 77 TC 19 Z9 21 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD OCT 11 PY 2004 VL 478 IS 2 BP 111 EP 125 DI 10.1002/cne.20271 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 851OB UT WOS:000223693300001 PM 15349973 ER PT J AU Kiselyeva, Y Ito, Y Lima, RG Grivel, JC Das, AT Berkhout, B Margolis, LB AF Kiselyeva, Y Ito, Y Lima, RG Grivel, JC Das, AT Berkhout, B Margolis, LB TI Depletion of CD4 T lymphocytes in human lymphoid tissue infected ex vivo with doxycycline-dependent HIV-1 SO VIROLOGY LA English DT Article DE CD4+ T cell; human lymphoid tissue; HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELL DEPLETION; CROSS-LINKING; FAS LIGAND; APOPTOSIS; TYPE-1; REPLICATION; MEMBRANE; DEATH; MACROPHAGES AB We investigated whether CD4(+) T cells that do not produce HIV- 1 are killed in HIV-infected human lymphoid tissue. Tissue blocks were inoculated with high amount of doxycycline-dependent HIV-rtTA. Doxycycline triggered productive infection and loss of CD4(+) T cells in these tissues, whereas without doxycycline, neither productive infection nor CD4(+) T cell depletion was detected in spite of the massive presence of virions in the tissue and of viral DNA in the cells. Thus, HIV- 1 alone is sufficient to deplete productively infected CD4(+) T cells but is not sufficient to cause the death of uninfected or latently infected CD4(+) T cells. Published by Elsevier Inc. C1 Univ Amsterdam, Dept Human Retrovirol, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. RP Berkhout, B (reprint author), Univ Amsterdam, Dept Human Retrovirol, Acad Med Ctr, K3-110,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands. EM b.berkhout@amc.uva.nl; margolis@helix.nih.gov NR 32 TC 12 Z9 13 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2004 VL 328 IS 1 BP 1 EP 6 DI 10.1016/j.virol.2004.07.014 PG 6 WC Virology SC Virology GA 857LE UT WOS:000224117300001 PM 15380352 ER PT J AU Lustig, S Fogg, C Whitbeck, JC Moss, B AF Lustig, S Fogg, C Whitbeck, JC Moss, B TI Synergistic neutralizing activities of antibodies to outer membrane proteins of the two infectious forms of vaccinia virus in the presence of complement SO VIROLOGY LA English DT Article DE synergism; neutralizing activities; complement ID PROTECTS MICE; VACCINATION; CHALLENGE; ENVELOPE; L1R AB The two forms of infectious vaccinia virus particles, known as intracellular mature virions and extracellular enveloped virions, are liberated by cell lysis and exocytosis, respectively. The extracellular enveloped form, which is highly resistant to antibody neutralization, contains an outer membrane surrounding an intracellular mature form. We provide evidence that complement mediates antibody-dependent lysis of the outer membrane of extracellular virus, exposing the inner infectious virus to neutralization by a second antibody. These results can help explain the disparity between the in vitro neutralizing and in vivo protective effects of antibodies to extracellular envelope proteins as well as the enhanced protection afforded by specific combinations of antibodies. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Vet Med, Lab Microbiol & Immunol, Philadelphia, PA 19104 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU NIAID NIH HHS [U54-AI57168, R21-AI053404] NR 19 TC 37 Z9 37 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2004 VL 328 IS 1 BP 30 EP 35 DI 10.1016/j.virol.2004.07.024 PG 6 WC Virology SC Virology GA 857LE UT WOS:000224117300004 PM 15380355 ER PT J AU Kanungo, J Wang, HY Malbon, CC AF Kanungo, J Wang, HY Malbon, CC TI Ku80 is required but not sufficient for G alpha 13-mediated endodermal differentiation in P19 embryonic carcinoma cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID DEPENDENT PROTEIN-KINASE; RIBOSOMAL-RNA SYNTHESIS; RETINOIC ACID; GENE-TRANSCRIPTION; POLYMERASE-I; TERMINAL KINASE; STEM-CELLS; EXPRESSION; SUBUNIT; ANTIGEN AB We have shown that a constitutively active G(alpha13) (G(alpha13Q226L)) induces differentiation in P19 embryonic carcinoma cells to an endodermal phenotype. In this report, we demonstrate that Ku, a heterodimer of p80 (Ku80) and p70 (Ku70), is upregulated ill P19 cells overexpressing G(alpha13Q226L). Ku is the regulatory subunit of the DNA-dependent protein kinase and is primarily involved in DNA repair and recombination. Ku80 also is a somatostatin receptor. We show that while overexpression of Ku80 drastically reduced P19 cell proliferation, it was not sufficient to induce endodermal differentiation. However, coexpression of G(alpha13Q226L) and an antisense Ku8O abrogated the retarded growth rate and endodermal differentiation observed in cells expressing only G(13Q226L). Overexpression of G(13Q226L_) or Ku80 downregulated RNA polymerase 1-mediated transcriptional activity and overexpression of antisense Ku80 restored the activity to control level. These results suggest that Ku80 is required for Galpha13-mediated endodermal differentiation in P19 cells. (C) 2004 Elsevier Inc. All rights reserved. C1 SUNY Stony Brook, Ctr Med, Dept Mol Pharmacol, Stony Brook, NY 11794 USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. SUNY Stony Brook, Hlth Sci Ctr, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. RP Kanungo, J (reprint author), SUNY Stony Brook, Ctr Med, Dept Mol Pharmacol, Stony Brook, NY 11794 USA. EM kanungoj@ninds.nih.gov FU NIDDK NIH HHS [DK30111] NR 34 TC 4 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 8 PY 2004 VL 323 IS 1 BP 293 EP 298 DI 10.1016/j.bbrc.2004.08.092 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 855HY UT WOS:000223965300045 PM 15351736 ER PT J AU Traicoff, JL Galperin, MM Ramesh, A Freebern, WJ Haggerty, CM Gardner, K Knezevic, V AF Traicoff, JL Galperin, MM Ramesh, A Freebern, WJ Haggerty, CM Gardner, K Knezevic, V TI Profiling the expression of mitogen-induced T-cell proteins by using multi-membrane dot-blotting SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cell signaling; multiplex; protein expression; phosphorylation; neoplasia; drug discovery ID STIMULATION; ACTIVATION; PROMOTER; BINDING AB High throughput technologies are standard methods for analysis of the proteome. Multi-layer multi-well plate dot-blotting system (MLDot) technology is a high-throughput dot blotting system that provides a simple, cost-effective approach for protein expression profiling in multiple samples. In contrast to traditional dot blot, MLDot uses a layered stack of thin, sieve-like membranes in place of a single nitrocellulose membrane. Therefore, up to 10 membranes can be prepared from the samples arrayed in a single 96-well plate. We describe the ability of MLDot to detect the predicted changes in protein expression following multiple mitogen treatment of T-cells. We compare the levels of the phopshorylated forms of CREB, Jun, and Akt in Jurkat T-cells as detected by MLDot to those measured by a gel-based assay. We also describe the ability of MLDot to detect differences in the levels of phosphorylated Akt in Jurkat cells as compared to primary lymphocytes. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Knezevic, V (reprint author), 20-20 Gene Syst Inc, Rockville, MD USA. EM vknezevic@2020gene.com FU NCI NIH HHS [N43-CO-31044] NR 11 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 8 PY 2004 VL 323 IS 1 BP 355 EP 360 DI 10.1016/j.bbrc.2004.08.093 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 855HY UT WOS:000223965300053 PM 15351744 ER PT J AU Ohtani, R Tomimoto, H Kondo, T Wakita, H Akiguchi, I Shibasaki, H Okazaki, T AF Ohtani, R Tomimoto, H Kondo, T Wakita, H Akiguchi, I Shibasaki, H Okazaki, T TI Upregulation of ceramide and its regulating mechanism in a rat model of chronic cerebral ischemia SO BRAIN RESEARCH LA English DT Article DE white matter; chionic cerebral hypoperfusion; apoptosis; ceramide; sphingomyelin; astroglia ID TUMOR-NECROSIS-FACTOR; WHITE-MATTER CHANGES; STRESS-INDUCED APOPTOSIS; PROGRAMMED CELL-DEATH; GLUCOSYLCERAMIDE SYNTHASE; FACTOR-ALPHA; HL-60 CELLS; HEAT-SHOCK; NEUTRAL SPHINGOMYELINASE; SIGNAL-TRANSDUCTION AB Ceramide is a key mediator of apoptosis, and is involved in the cellular stress response. We examined the alterations in the ceramide levels and their synthetic/degradative pathway in a rat model of chronic cerebral ischemia, in which ischemic white matter (WM) lesions occur in association with oligodendroglial cell apoptosis. Chronic cerebral ischemia was induced by clipping both common carotid arteries in male Wistar rats. After predetermined periods of 1, 3, 7 and 14 days, the animals were subjected to immunohistochemical and biochemical investigations for ceramide in the region containing the frontal cortex and corpus callosum (region 1), and the region containing the internal capsule and globus pallidus (region 2). After 14 days, the myelin was degraded in the corpus callosum, internal capsule and the optic tract in Kluver-Barrera staining. There was a significant increase in the ceramide level and the activity of its synthetic enzyme, acidic sphingomyelinase (SMase), whereas its degrading enzyme, glucosylceramide synthase (GCS), was downregulated in both regions 1 and 2 as compared to the sham-operated rats. Simultaneously, ceramide immunoreactive glia increased in number in the corpus callosum and the internal capsule after 3, 7 and 14 days. Double labeling for ceramide with glial fibrillary acidic protein but not with leukocyte common antigen indicated the astroglial nature of these glia. These findings indicate that chronic cerebral ischemia induces an increased ceramide level in astroglia as a result of downregulation of GCS and an upregulation of ASMase activity. (C) 2004 Elsevier B.V All rights reserved. C1 Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Sakyo, Kyoto 6068507, Japan. NINDS, NIH, Bethesda, MD 20892 USA. RP Ohtani, R (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo, Kyoto 6068507, Japan. EM ryokyoto@kuhp.kyoto-u.ac.jp NR 66 TC 34 Z9 38 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 OCT 8 PY 2004 VL 1023 IS 1 BP 31 EP 40 DI 10.1016/j.brainres.2004.07.024 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 858CA UT WOS:000224166600004 PM 15364016 ER PT J AU Schmid, AC Wise, HM Mitchell, CA Nussbaum, R Woscholski, R AF Schmid, AC Wise, HM Mitchell, CA Nussbaum, R Woscholski, R TI Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation SO FEBS LETTERS LA English DT Article DE pl-osphatase; phosphatidylinositol; Lowe's oculocerebrorenal syndrome; Synaptojanin; substrate specificity; enzymology ID INOSITOL-POLYPHOSPHATE 5-PHOSPHATASE; TRANS-GOLGI NETWORK; MEMBRANE RUFFLES; SYNAPTOJANIN 2; LOWE-SYNDROME; DOMAINS; OCRL1; IDENTIFICATION; LOCALIZATION; EXPRESSION AB The catalytic properties of the type II phosphoinositide 5-phosphatases of Lowe's oculocercbrorenal syndrome, INPP5B, Synaptojanin1, Synaptojanin2 and SKIP were analysed with respect to their substrate specificity and enzymological properties. Our data reveal that all phosphatases have unique substrate specificities as judged by their corresponding K-M and V-Max values. They also possessed an exclusive sensitivity towards fatty acid composition, head group phosphorylation an micellar presentation. Thus, the biological function of these enzymes will not just be determined by their corresponding regulatory domains, but will be distinctly influenced by their catalytic properties as well. This suggests that the phosphatase domains fulfil a unique catalytic function that cannot be fully compensated by other: phosphatases. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Univ London Imperial Coll Sci Technol & Med, Dept Sci Biol, London SW7 2AZ, England. Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. NHGRI, Bethesda, MD 20892 USA. RP Woscholski, R (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Sci Biol, Exhibit Rd, London SW7 2AZ, England. EM r.woscholski@imperial.ac.uk OI Mitchell, Christina A/0000-0001-9372-3192 NR 23 TC 78 Z9 80 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 8 PY 2004 VL 576 IS 1-2 BP 9 EP 13 DI 10.1016/j.feoslet.2004.08.052 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 864BM UT WOS:000224607800003 PM 15474001 ER PT J AU Meng, QH Zhao, ZG Yan, M Zhou, LX Li, JY Kitt, C Bin, G Fan, SJ AF Meng, QH Zhao, ZG Yan, M Zhou, LX Li, JY Kitt, C Bin, G Fan, SJ TI ERR-10: a new repressor in transcriptional signaling activation of estrogen receptor-alpha SO FEBS LETTERS LA English DT Article DE ERR-10; estrogen receptor; transcription; LXXLL; co-repressor; breast cancer ID STEROID-HORMONE RECEPTORS; BRCA1 INHIBITION; MOLECULAR-CLONING; BINDING PROTEIN; COACTIVATOR; MOTIF; BETA; SUPERFAMILY; MECHANISMS; DISTINCT AB Estrogen receptor-alpha (ER-alpha) is a nuclear transcriptional factor that is part of the nuclear receptor superfamily. In this study, we isolated and identified a new LXXLL-containing protein that interacts with the ER-alpha via a yeast two-hybrid assay. We have termed this protein estrogen receptor repressor-10 (ERR-10). The ERR-10 cDNA is predicted to encode a polypeptide of 94 amino acids, with a molecular mass of about 10 kDa. Although the ERR-10 mRNA transcript is expressed in a wide range of normal human tissues, higher expression levels are found in endocrinal tissues relative to other tissues. We have demonstrated, through immunoprecipitation, Western blot and GST pull-down assays, that ERR-10 associates with ER-alpha. Moreover, ERR-10 decreased 17beta-estrodial-induced activation of ER-alpha transcriptional activity in transient transfection assays of mammalian cells. The ERR-10 N-terminus, which resembles two LXXLL motifs, is essential for ER-alpha binding and repression activity. Estrogen modulation of estrogen-responsive gene expression was markedly blocked by ERR-10. These results suggest that ERR-10 is a novel mediator in ER transcriptional activation. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. Peking Univ, Sch Oncol, Beijing Canc Hosp, Dept Pathol, Beijing 100036, Peoples R China. Soochow Univ, Sch Radiol & Publ Hlth, Suzhou 215007, Peoples R China. NIAAA, Div Liver Biol, NIH, Rockville, MD 20852 USA. RP Fan, SJ (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. EM sf88@georgetown.edu RI Yan, Ming/A-2355-2010; OI Zhao, Zeguo/0000-0002-2901-5033 FU NIAAA NIH HHS [R21AA13122] NR 39 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 8 PY 2004 VL 576 IS 1-2 BP 190 EP 200 DI 10.1016/j.febslet.2004.07.094 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 864BM UT WOS:000224607800038 PM 15474036 ER PT J AU Baucom, J Transue, T Fuentes-Cabrera, M Krahn, JM Darden, TA Sagui, C AF Baucom, J Transue, T Fuentes-Cabrera, M Krahn, JM Darden, TA Sagui, C TI Molecular dynamics simulations of the d(CCAACGTTGG)(2) decamer in crystal environment: Comparison of atomic point-charge, extra-point, and polarizable force fields SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID PARTICLE-MESH-EWALD; NUCLEIC-ACIDS; BIOMOLECULAR SIMULATIONS; POTENTIAL FUNCTIONS; LIQUID WATER; DNA; MECHANICS; MODEL; ELECTROSTATICS; TRANSITIONS AB Molecular dynamics simulations of the DNA duplex d(CCAACGTTGG)(2) were used to study the relationship between DNA sequence and structure in a crystal environment. Three different force fields were used: a traditional description based on atomic point charges, a polarizable force field, and an "extra-point" force field (with additional charges on extranuclear sites). It is found that all the force fields reproduce fairly well the sequence-dependent features of the experimental structure. The polarizable force field, however, provides the most accurate representation of the crystal structure and the sequence-dependent effects observed in the experiment. These results point out to the need of the inclusion of polarization for accurate descriptions of DNA. (C) 2004 American Institute of Physics. C1 N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Baucom, J (reprint author), N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. RI Fuentes-Cabrera, Miguel/Q-2437-2015 OI Fuentes-Cabrera, Miguel/0000-0001-7912-7079 NR 42 TC 29 Z9 29 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 8 PY 2004 VL 121 IS 14 BP 6998 EP 7008 DI 10.1063/1.1788631 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 859MV UT WOS:000224269200050 PM 15473761 ER PT J AU Lelpe, DD Koonin, EV Aravind, L AF Lelpe, DD Koonin, EV Aravind, L TI STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: Multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE molecular evolution; P-loop NTPases; AP-ATPases; signaling; author multidomain proteins ID SOLUBLE ADENYLYL-CYCLASE; FUNGUS PODOSPORA-ANSERINA; NUCLEOTIDE-BINDING SITE; ETHYLMALEIMIDE-SENSITIVE FACTOR; STREPTOMYCES-COELICOLOR A3(2); COLI MALTOSE REGULON; RICH REPEAT DOMAINS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; GTP-BINDING AB Using sequence profile analysis and sequence-based structure predictions, we define a previously unrecognized, widespread class of P-loop NTPases. The signal transduction ATPases with numerous domains (STAND) class includes the AP-ATPases (animal apoptosis regulators CED4/Apaf-1, plant disease resistance proteins, and bacterial AfsR-like transcription regulators) and NACHT NTPases (e.g. NAIP, TLP1, Het-E-1) that have been studied extensively in the context of apoptosis, pathogen response in animals and plants, and transcriptional regulation in bacteria. We show that, in addition to these well-characterized protein families, the STAND class includes several other groups of (predicted) NTPase domains from diverse signaling and transcription regulatory proteins from bacteria and eukaryotes, and three Archaea-specific families. We identified the STAND domain in several biologically well-characterized proteins that have not been suspected to have NTPase activity, including soluble adenylyl cyclases, nephrocystin 3 (implicated in polycystic kidney disease), and Rolling pebble (a regulator of muscle development); these findings are expected to facilitate elucidation of the functions of these proteins. The STAND class belongs to the additional strand, catalytic E division of P-loop NTPases together with the AAA+ ATPases, RecA/helicase-related ATPases, ABC-ATPases, and VirD4/PilT-like ATPases. The STAND proteins are distinguished from other P-loop NTPases by the presence of unique sequence motifs associated with the N-terminal helix and the core strand-4, as well as a C-terminal helical bundle that is fused to the NTPase domain. This helical module contains a signature GxP motif in the loop between the two distal helices. With the exception of the archaeal families, almost all STAND NTPases are multidomain proteins containing three or more domains. In addition to the NTPase domain, these proteins typically contain DNA-binding or protein-binding domains, superstructure-forming repeats, such as WD40 and TPR, and enzymatic domains involved in signal transduction, including adenylate cyclases and kinases. By analogy to the AAA+ ATPases, it can be predicted that STAND NTPases use the C-terminal helical bundle as a "lever" to transmit the conformational changes brought about by NTP hydrolysis to effector domains. STAND NTPases represent a novel paradigm in signal transduction, whereby adaptor, regulatory switch, scaffolding, and, in some cases, signal-generating moieties are combined into a single polypeptide. The STAND class consists of 14 distinct families, and the evolutionary history of most of these families is riddled with dramatic instances of lineage-specific expansion and apparent horizontal gene transfer. The STAND NTPases are most abundant in developmentally and organizationally complex prokaryotes and eukaryotes. Transfer of genes for STAND NTPases from bacteria to eukaryotes on several occasions might have played a significant role in the evolution of eukaryotic signaling systems. Published by Elsevier Ltd. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov NR 133 TC 3 Z9 3 U1 2 U2 19 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 8 PY 2004 VL 343 IS 1 BP 1 EP 28 DI 10.1016/j.jmb.2004.08.023 PG 28 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 858UQ UT WOS:000224217900001 ER PT J AU Viatour, P Dejardin, E Warnier, M Lair, F Claudio, E Bureau, F Marine, JC Merville, MP Maurer, U Green, D Piette, J Siebenlist, U Bours, V Chariot, A AF Viatour, P Dejardin, E Warnier, M Lair, F Claudio, E Bureau, F Marine, JC Merville, MP Maurer, U Green, D Piette, J Siebenlist, U Bours, V Chariot, A TI GSK3-Mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity SO MOLECULAR CELL LA English DT Article ID NF-KAPPA-B; CANDIDATE PROTOONCOGENE BCL-3; GENE-EXPRESSION; PROTEIN-KINASE; CANCER-CELLS; TRANSCRIPTION; TRANSACTIVATION; COACTIVATOR; INHIBITION; ENCODES AB The oncoprotein BCL-3 is a nuclear transcription factor that activates NF-kappaB target genes through formation of heterocomplexes with p50 or p52. BCL-3 is phosphorylated in vivo, but specific BCL-3 kinases have not been identified so far. In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with HDAC1, -3, and -6 and attenuates its oncogenicity by selectively controlling the expression of a subset of newly identified target genes such as SLPI and CxcI1. Our results therefore suggest that constitutive BCL-3 phosphorylation by GSK3 regulates BCL-3 turnover and transcriptional activity. C1 Univ Liege, Lab Med Chem & Human Genet, B-4000 Liege, Belgium. Univ Liege, Dept Physiol, B-4000 Liege, Belgium. Univ Liege, Lab Virol & Immunol, Ctr Biomed Integrated Genoproteom, B-4000 Liege, Belgium. La Jolla Inst Allergy & Immunol, Div Cellular Immunol, San Diego, CA 92121 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Flanders Interuniv Inst BIotechnol, Lab Mol Canc Biol, Ghent, Belgium. RP Chariot, A (reprint author), Univ Liege, Lab Med Chem & Human Genet, B-4000 Liege, Belgium. EM alain.chariot@ulg.ac.bc RI Marine, Jean Christophe/J-2237-2015; Marine, Jean-Christophe/K-3292-2016 OI Marine, Jean-Christophe/0000-0003-2433-9837 NR 32 TC 74 Z9 77 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 8 PY 2004 VL 16 IS 1 BP 35 EP 45 DI 10.1016/j.molcel.2004.09.004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 861NA UT WOS:000224422200004 PM 15469820 ER PT J AU Szabadkai, G Simoni, AM Chami, M Wieckowski, MR Youle, RJ Rizzuto, R AF Szabadkai, G Simoni, AM Chami, M Wieckowski, MR Youle, RJ Rizzuto, R TI Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis SO MOLECULAR CELL LA English DT Article ID CYTOCHROME-C RELEASE; ENDOPLASMIC-RETICULUM; CALCIUM SIGNALS; BCL-2 FAMILY; CELL-DEATH; MEMBRANE; FISSION; BAX; PERMEABILITY; MACHINERY AB By transiently or stably overexpressing the mitochondrial fission factor dynamin-related protein-1 (Drp-1), we evaluated the role of mitochondrial division in organelle Ca2+ homeostasis and apoptotic signaling. Quantitative 3D digital microscopy revealed a split mitochondrial network in Drp-1-overexpressing cells without changes in cell viability. High-speed mitochondrial [Ca2+] ([Ca2+](m)) imaging revealed propagating intramitochondrial Ca2+ waves in intact cells, which were blocked in the Drp-1-fragmented network, leaving a fraction of individual mitochondria without substantial [Ca2+], elevation. Consequently, in Drp-1-expressing cells the apoptotic efficacy of ceramide, which causes a Ca2+-dependent perturbation of mitochondrial structure and function, was drastically reduced. Conversely, the sensitivity to staurosporine-induced apoptosis, previously shown to be directly triggered by Drp-1-dependent recruitment of proapoptotic proteins to mitochondria, was enhanced. These results demonstrate that the regulated process of mitochondrial fusion and fission controls the spatiotemporal properties of mitochondrial Ca2+ responses and, thus, physiological and pathological consequences of cellular Ca2+ signals. C1 Univ Ferrara, Dept Expt & Diagnost Med, Sect Gen Pathol, I-44100 Ferrara, Italy. Univ Ferrara, Interdisciplinary Ctr Study Inflammat, I-44100 Ferrara, Italy. NINDS, Surg Neurol Branch, Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Rizzuto, R (reprint author), Univ Ferrara, Dept Expt & Diagnost Med, Sect Gen Pathol, I-44100 Ferrara, Italy. EM r.rizzuto@unife.it RI Rizzuto, Rosario/B-6312-2008; OI Chami, Mounia/0000-0003-1498-7187 FU Telethon [GTF02013] NR 36 TC 271 Z9 277 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 8 PY 2004 VL 16 IS 1 BP 59 EP 68 DI 10.1016/j.molcel.2004.09.026 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 861NA UT WOS:000224422200006 PM 15469822 ER PT J AU Koehler, NKU Yang, CY Varady, J Lu, YP Wu, XW Liu, M Yin, DX Bartels, M Xu, BY Roller, PP Long, YQ Li, P Kattah, M Cohn, ML Moran, K Tilley, E Richert, JR Wang, SM AF Koehler, NKU Yang, CY Varady, J Lu, YP Wu, XW Liu, M Yin, DX Bartels, M Xu, BY Roller, PP Long, YQ Li, P Kattah, M Cohn, ML Moran, K Tilley, E Richert, JR Wang, SM TI Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MULTIPLE-SCLEROSIS; PEPTIDE BINDING; MOLECULAR DOCKING; CRYSTAL-STRUCTURE; HLA; LIGAND; DATABASE; RECOGNITION; DISEASE; CONTEXT AB We have utilized a computational structure-based approach to identify nonpeptidic small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) structure of DR1301 was derived by homology modeling followed by extensive molecular dynamics simulation for structural refinement. Computational structure-based database searching was performed to identify nonpeptidic small-molecule candidates from the National Cancer Institute (NCI) database containing over 150 000 compounds that can effectively interact with the peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate small molecules, two lead compounds were confirmed to specifically block IL-2 secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. The specificity of blocking DR1301-restricted MBP presentation was further validated in a binding assay using an analogue of the most potent lead compound. Computational docking was performed to predict the three-dimensional binding model of these confirmed small molecule blockers to the DR1301 molecule and to gain structural insight into their interactions. Our results suggest that computational structure-based searching is an effective approach to discover nonpeptidic small organic compounds to block the interaction between DR1301 and T cells. The nonpeptidic small organic compounds identified in this study are useful pharmacological tools to study the interactions between HLA molecules and T cells and a starting point for the development of a novel therapeutic strategy for the treatment of multiple sclerosis (MS) or other immune-related disorders. C1 Georgetown Univ, Ctr Med, Dept Microbiol & Immunol, Washington, DC 20007 USA. Georgetown Univ, Ctr Med, Dept Neurol, Washington, DC 20007 USA. Georgetown Univ, Ctr Med, Dept Pathol, Washington, DC 20007 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. NCI, Med Chem Lab, NIH, Frederick, MD 20892 USA. RP Richert, JR (reprint author), Georgetown Univ, Ctr Med, Dept Microbiol & Immunol, Washington, DC 20007 USA. EM richertj@georgetown.edu; shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010 FU NCI NIH HHS [P30 CA 51008] NR 35 TC 24 Z9 24 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 7 PY 2004 VL 47 IS 21 BP 4989 EP 4997 DI 10.1021/jm030362s PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 858VC UT WOS:000224219200004 PM 15456243 ER PT J AU Siddiqui, MA Hughes, SH Boyer, PL Mitsuya, H Van, QN George, C Sarafinanos, SG Marquez, VE AF Siddiqui, MA Hughes, SH Boyer, PL Mitsuya, H Van, QN George, C Sarafinanos, SG Marquez, VE TI A 4 '-C-ethynyl-2 ',3 '-dideoxynucleoside analogue highlights the role of the 3 '-OH in anti-HIV active 4 '-C-ethynyl-2 '-deoxy nucleosides SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; POTENT INHIBITORS; STERIC HINDRANCE; 3TC RESISTANCE; IN-VITRO; AGENT; 4'-AZIDOTHYMIDINE; TRIPHOSPHATE; NUCLEOTIDES AB 4'-C-Ethynyl-2'-deoxynucleosides belong to a novel class of nucleoside analogues endowed with potent activity against a wide spectrum of HIV viruses, including a variety of resistant clones. Although favorable selectivity indices were reported for several of these analogues, some concern still exists regarding the 3'-OH group and its role in cellular toxicity. To address this problem, we removed the 3'-OH group from 4'-C-ethynyl-2'-deoxycytidine (1a). This compound was chosen because of its combined high potency and low selectivity index. The removal of the 3'-OH was not straightforward; it required a different synthetic approach from the one used to synthesize the parent compound. Starting with glycidyl-4-methoxyphenyl ether, the target 4'-C-ethynyl-2',3'-dideoxycytidine analogue (rac-1h) was obtained after 13 steps. In a cellular assay, rac-1h was completely inactive (0.001-10 muM) against HIVLAI, demonstrating the critical importance of the 3'-OH for antiviral activity. To determine whether the role of the 3'-OH was essential for the phosphorylation of the compound by cellular kinases or for inhibition of DNA polymerization, we synthesized and tested the 5'-triphosphate (rac-1h-TP) for its ability to inhibit HIV reverse transcriptase (RT). rac-lh-TP was slightly more potent than AZT-5'-triphosphate against wild-type HIV RT, suggesting that the role of the 3'-OH is crucial only for the activation of the drug by cellular kinases. The lipase-catalyzed resolution of rac-1h into ent-1h (beta-D-dideoxyribo) and ent-14 (beta-L-dideoxyribo) and the synthesis of the corresponding 5'-triphosphates established the stereochemical assignment based on HIV RT's preference for the beta-D-enantiomer, which was confirmed by assaying against the M184V variant, an RT mutant with a marked preference for incorporating nucleosides in the D-configuration. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Canc Res Ctr, NIH, Frederick, MD 21702 USA. NCI, Expt Retrovirol Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. SAIC Frederick, NMR Grp, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov NR 21 TC 28 Z9 29 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 7 PY 2004 VL 47 IS 21 BP 5041 EP 5048 DI 10.1021/jm049550o PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 858VC UT WOS:000224219200008 PM 15456247 ER PT J AU Edsall, AB Mohanakrishnan, AK Yang, DL Fanwick, PE Hamel, E Hanson, AD Agoston, GE Cushman, M AF Edsall, AB Mohanakrishnan, AK Yang, DL Fanwick, PE Hamel, E Hanson, AD Agoston, GE Cushman, M TI Effects of altering the electronics of 2-methoxyestradiol on cell proliferation, on cytotoxicity in human cancer cell cultures, and on tubulin polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ENDOGENOUS MAMMALIAN METABOLITE; ANTIMITOTIC ACTIVITY; GENERAL-ROUTE; TUMOR-GROWTH; IN-VITRO; ANALOGS; ESTROGENS; ESTRATROPONES; ANGIOGENESIS; MCF-7 AB A series of new analogues of 2-methoxyestradiol (1) were synthesized to further elucidate the relationships between structure and activity. The compounds were designed to diminish the potential for metabolic deactivation at positions 2 and 17 and were analyzed as inhibitors of tubulin polymerization and for cytotoxicity. 17alpha-Methyl-beta-estradiol (30), 2-propynyl-17alpha-methylestradiol (39), 2-ethoxy-17-(1'-methylene)estra-1,3,5(10)-triene-3-ol (50) and 2-ethoxy-17alpha-methylestradiol (51) showed similar or greater tubulin polymerization inhibition than 2-methoxyestradiol (1) and contained moieties that are expected to inhibit deactivating metabolic processes. All of the compounds tested were cytotoxic in the panel of 55 human cancer cell cultures, and generally, the derivatives that displayed the most activity against tubulin were also the most cytotoxic. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. EntreMed Inc, Rockville, MD 20850 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu NR 37 TC 43 Z9 43 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 7 PY 2004 VL 47 IS 21 BP 5126 EP 5139 DI 10.1021/jm049647a PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 858VC UT WOS:000224219200017 PM 15456256 ER PT J AU Chong, HS Torti, SV Ma, R Torti, FM Brechbiel, MW AF Chong, HS Torti, SV Ma, R Torti, FM Brechbiel, MW TI Synthesis and potent antitumor activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PYRIDOXAL ISONICOTINOYL HYDRAZONE; RIBONUCLEOTIDE REDUCTASE; IRON CHELATORS; CELL-LINES; TRANSFERRIN RECEPTOR; MONOCLONAL-ANTIBODY; P53 GENE; AGENTS; CANCER; PROLIFERATION AB The iron chelator N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr) was recently reported to display potent antitumor activity. The present study was focused on identifying an adequate bifunctional version of tachpyr as a lead compound for use in antibody-targeted iron depletion tumor therapy. Preparation of tachpyr derivatives having a side chain is reported, and their cytotoxic activity is evaluated in the HeLa cell line. The observed cytotoxity appears dependent on the functionalization site of the tachpyr employed for introducing the protein conjugation. Tachpyr derivatives 14 and 15 having a side chain introduced into the 5-position of the pyridyl ring display more potent cytotoxicity than tachpyr derivatives 7 and 8 having a side chain introduced onto one of the secondary amines. BOC-protected tachpyr derivative 14 exhibited the most potent cytotoxicity against this cancer cell line, which was reasonably comparable to the parent tachpyr. Tachpyr derivative 14 was further converted into bifunctional tachpyr 17 possessing a maleimide linker for conjugation with thiolated monoclonal antibodies (mAbs). C1 NCI, Chem Sect, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Canc Biol, Winston Salem, NC USA. Wake Forest Univ, Dept Biochem, Winston Salem, NC USA. Wake Forest Univ, Comprehens Canc Ctr, Winston Salem, NC USA. RP Chong, HS (reprint author), NCI, Chem Sect, NIH, Bethesda, MD 20892 USA. EM Chong@iit.edu FU NIDDK NIH HHS [DK 57781] NR 34 TC 23 Z9 24 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 7 PY 2004 VL 47 IS 21 BP 5230 EP 5234 DI 10.1021/jm040076w PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 858VC UT WOS:000224219200027 PM 15456266 ER PT J AU Sechi, M Derudas, M Dallocchio, R Dessi, A Bacchi, A Sannia, L Carta, F Palomba, M Ragab, O Chan, C Shoemaker, R Sei, S Dayam, R Neamati, N AF Sechi, M Derudas, M Dallocchio, R Dessi, A Bacchi, A Sannia, L Carta, F Palomba, M Ragab, O Chan, C Shoemaker, R Sei, S Dayam, R Neamati, N TI Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACTIVE-SITE; MOLECULAR-DYNAMICS; STRAND TRANSFER; CONFORMATIONAL COVERAGE; CATALYTIC DOMAIN; BINDING MODES; MECHANISM; DNA; CHEMOTHERAPY; REPLICATION AB Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a beta-diketo acid moiety, a series of substituted indole-beta-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-beta-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN. C1 Univ Sassari, Dipartimento Farmaco Chim Tossicol, I-07100 Sassari, Italy. CNR Ist Chim Biomol, Sez Sassari, I-07040 Li Punti, Italy. Univ Parma, Dipartimento Chim Gen & Inorgan, I-43100 Parma, Italy. Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA. SAIC Frederick, NCI, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. DCTD, DTP, Screening Technol Branch, Frederick, MD 21702 USA. RP Sechi, M (reprint author), Univ Sassari, Dipartimento Farmaco Chim Tossicol, Via Muroni 23-A, I-07100 Sassari, Italy. EM mario.sechi@uniss.it; neamati@usc.edu RI Dessi, Alessandro/B-8021-2015; Bacchi, Alessia/B-6850-2016; OI Dessi, Alessandro/0000-0001-8258-7332; Bacchi, Alessia/0000-0001-5675-9372; Dallocchio, Roberto Nico/0000-0003-4626-4792 FU NCI NIH HHS [N01 CO 12400] NR 64 TC 87 Z9 90 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 7 PY 2004 VL 47 IS 21 BP 5298 EP 5310 DI 10.1021/jm049944f PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 858VC UT WOS:000224219200035 PM 15456274 ER PT J AU Yeh, IC Hummer, G AF Yeh, IC Hummer, G TI System-size dependence of diffusion coefficients and viscosities from molecular dynamics simulations with periodic boundary conditions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID EFFECTIVE 3-BODY POTENTIALS; PARTICLE MESH EWALD; FREE-ENERGY; COMPUTER-SIMULATIONS; IONIC-SOLVATION; LIQUID WATER; FRICTION; MODEL; TRUNCATION; HYDRATION AB We study the system-size dependence of translational diffusion coefficients and viscosities in molecular dynamics simulations under periodic boundary conditions. Simulations of water under ambient conditions and a Lennard-Jones (LJ) fluid show that the diffusion coefficients increase strongly as the system size increases. We test a simple analytic correction for the system-size effects that is based on hydrodynamic arguments. This correction scales as N-1/3, where N is the number of particles. For a cubic simulation box of length L, the diffusion coefficient corrected for system-size effects is D-0 = D-PBC + 2.837297k(B)T/(6.7pietaL), where D-PBC is the diffusion coefficient calculated in the simulation, k(B) the Boltzmann constant, T the absolute temperature, and eta the shear viscosity of the solvent. For water, LJ fluids, and hard-sphere fluids, this correction quantitatively accounts for the system-size dependence of the calculated self-diffusion coefficients. In contrast to diffusion coefficients, the shear viscosities of water and the LJ fluid show no significant system-size dependences. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 49 TC 356 Z9 359 U1 6 U2 121 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 7 PY 2004 VL 108 IS 40 BP 15873 EP 15879 DI 10.1021/jp0477147 PG 7 WC Chemistry, Physical SC Chemistry GA 858TA UT WOS:000224213500059 ER PT J AU Martin, MJ AF Martin, MJ TI Cetuximab in colon cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Martin, MJ (reprint author), NCI, Bethesda, MD 20892 USA. EM martmich@mail.nih.gov NR 1 TC 1 Z9 1 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 OCT 7 PY 2004 VL 351 IS 15 BP 1575 EP 1575 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 859UP UT WOS:000224293700026 PM 15473023 ER PT J AU Fairhurst, RM Casella, JF AF Fairhurst, RM Casella, JF TI Hemoglobin C disease - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Fairhurst, RM (reprint author), NIAID, Bethesda, MD 20892 USA. NR 1 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 OCT 7 PY 2004 VL 351 IS 15 BP 1577 EP 1577 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 859UP UT WOS:000224293700031 ER PT J AU Kim, IY Lee, DH Lee, DK Ahn, HJ Kim, MM Kim, SJ Morton, RA AF Kim, IY Lee, DH Lee, DK Ahn, HJ Kim, MM Kim, SJ Morton, RA TI Loss of expression of bone morphogenetic protein receptor type II in human prostate cancer cells SO ONCOGENE LA English DT Article DE BMP; BMP receptors; prostate cancer ID OSTEOGENIC PROTEIN-1; GROWTH-FACTOR; IB RECEPTOR; PROLIFERATION; DIFFERENTIATION; INSENSITIVITY; PROGRESSION; TISSUES; MOUSE AB Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily and signal through a number of membrane receptors. We have previously demonstrated that the loss of expression of BMP receptors (BMPRs) type IA, - IB, and - II (BMP-RIA, - RIB, and - RII) correlates with Gleason score in prostate cancer patients. To evaluate the prognostic value of this observation, we used immunohistochemistry to investigate the expression of BMPRs in association with disease progression in 60 patients. The results demonstrated a significant association between the loss of expression of the three BMPRs and Gleason score and clinical stage. However, only the loss of expression of BMP-RII showed a statistically significant association with 5-year survival rate ( P<0.05) and biochemical recurrence-free rate following radical prostatectomy ( P<0.005). To elucidate the effect of an abnormal BMP signaling in prostate cancer cells, we transfected dominant-negative BMP-RII (BMP-RIIDN) into the human prostate cancer cell line, PC3M. When a stable clone overexpressing BMP-RIIDN was inoculated subcutaneously into nude mice, the tumor growth rate was approximately 10 times that of control and parental cell line. These observations, taken together, indicate that the loss of BMP-RII expression as measured by immunohistochemistry may be a prognostic marker in prostate cancer patients, and that the loss of BMP-RII function may result in increased tumorigenicity in human prostate cancer cells. C1 Baylor Coll Med, Dept Urol 2, Houston, TX 77030 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Ewha Womans Univ, Dept Urol, Seoul, South Korea. Asan Med Ctr, Dept Urol, Seoul, South Korea. Univ Calif Irvine, Dept Urol, Orange, CA 92868 USA. RP Morton, RA (reprint author), Baylor Coll Med, Dept Urol 2, Houston, TX 77030 USA. EM mortonra@umdnj.edu NR 33 TC 50 Z9 54 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 7 PY 2004 VL 23 IS 46 BP 7651 EP 7659 DI 10.1038/sj.onc.1207924 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 859ZK UT WOS:000224306700006 PM 15354178 ER PT J AU Usary, J Llaca, V Karaca, G Presswala, S Karaca, M He, XP Langerod, A Karesen, R Oh, DS Dressler, LG Lonning, PE Strausberg, RL Chanock, S Borresen-Dale, AL Perou, CM AF Usary, J Llaca, V Karaca, G Presswala, S Karaca, M He, XP Langerod, A Karesen, R Oh, DS Dressler, LG Lonning, PE Strausberg, RL Chanock, S Borresen-Dale, AL Perou, CM TI Mutation of GATA3 in human breast tumors SO ONCOGENE LA English DT Article DE breast cancer; microarrays; estrogen receptor; transcription factor; GATA3 ID GENE-EXPRESSION PATTERNS; CELL RECEPTOR-ALPHA; TRANSCRIPTION FACTOR; ACQUIRED MUTATIONS; ESTROGEN-RECEPTOR; NERVOUS-SYSTEM; HDR SYNDROME; CANCER; BINDING; BENIGN AB GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast tumors and three breast-tumor-derived cell lines and identified somatic mutations of GATA3 in five tumors and the MCF-7 cell line. These mutations cluster in the vicinity of the highly conserved second zinc-finger that is required for DNA binding. In addition to these five, we identified using cDNA sequencing a unique mis-splicing variant that caused a frameshift mutation. One of the somatic mutations we identified was identical to a germline GATA3 mutation reported in two kindreds with HDR syndrome/OMIM # 146255, which is an autosomal dominant syndrome caused by the haplo-insufficiency of GATA3. The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times. These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Adv Technol, Bethesda, MD 20892 USA. Norwegian Radium Hosp, Dept Genet, N-0310 Oslo, Norway. Ullevaal Univ Hosp, Dept Surg, Oslo, Norway. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Haukeland Univ Hosp, Dept Med, Sect Oncol, N-5021 Bergen, Norway. Inst Genom Res, Rockville, MD 20850 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. RP Perou, CM (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM cperou@med.unc.edu OI Perou, Charles/0000-0001-9827-2247 FU NCI NIH HHS [P50-CA58223-09A1] NR 41 TC 139 Z9 143 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 7 PY 2004 VL 23 IS 46 BP 7669 EP 7678 DI 10.1038/sj.onc.1207966 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 859ZK UT WOS:000224306700008 PM 15361840 ER PT J AU Yao, RS Wang, Y Lemon, WJ Lubet, RA You, M AF Yao, RS Wang, Y Lemon, WJ Lubet, RA You, M TI Budesonide exerts its chemopreventive efficacy during mouse lung tumorigenesis by modulating gene expressions SO ONCOGENE LA English DT Article DE budesonide; lung cancer; chemoprevention; A/J mice; expression profile ID FEMALE A/J MICE; PULMONARY CARCINOGENESIS; APOPTOSIS; MYOINOSITOL; PROGRESSION; CARCINOMAS; RESISTANCE; MECHANISMS; HORMONES; PATHWAYS AB Budesonide, a glucocorticoid, was proven to be a highly effective agent in preventing the development of lung tumors in A/J mice. In a lung tumor bioassay, budesonide produced 70% inhibition of tumor multiplicity and 94% reduction of total tumor load compared to benzopyrene ( B[ a] P) treated mice. Gene expression array analysis was performed on mouse lung tumors from this bioassay using Affymetrix U74Av2 GeneChips to determine gene expression changes associated with budesonide treatment. We found 363 genes that were changed between lung tumors induced by treatment with B[ a] P and similar tumors treated with budesonide. Among them, 243 genes were overexpressed and 120 genes were underexpressed after budesonide treatment. In addition, 108 genes differentially expressed during mouse lung tumorigenesis (50 genes overexpressed and 58 genes underexpressed) were modulated back to normal levels after budesonide treatment when compared with the controls group. These genes are involved in a broad range of different pathways including control of cell cycle, signal transduction, and apoptosis and may play a role in the observed preventive effect. Our results suggest that budesonide exerts its effects of chemoprevention through growth arrest via Mad2/3 and through apoptosis via Bim/Blk and, by inference, caspase-8/9. Using the pathway visualization tool GenMapp, G protein pathway and MAPK cascade were also regulated by budesonide. Thus, we have determined, for the first time, the expression profiles of genes modulated by budesonide during murine lung tumorigenesis. Our results indicate that the chemopreventive effects of budesonide in the mouse lung tumorigenesis assay involved increase and decrease expression of a wide variety of genes in multiple signaling pathways. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Campus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. EM youm@msnotes.wustl.edu NR 25 TC 31 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 7 PY 2004 VL 23 IS 46 BP 7746 EP 7752 DI 10.1038/sj.onc.1207985 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 859ZK UT WOS:000224306700016 PM 15361829 ER PT J AU McCune, AR Houle, D McMillan, K Annable, R Kondrashov, AS AF McCune, AR Houle, D McMillan, K Annable, R Kondrashov, AS TI Two classes of deleterious recessive alleles in a natural population of zebrafish, Danio rerio SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE inbreeding depression; lethal equivalent; variance; mortality; growth rate; zebrafish ID INBREEDING DEPRESSION; CONSANGUINEOUS MARRIAGES; DROSOPHILA-MELANOGASTER; GENETIC LOAD; PREREPRODUCTIVE MORTALITY; MUTATION-RATE; PAKISTAN; FITNESS; NUMBER; VIABILITY AB Natural populations carry deleterious recessive alleles which cause inbreeding depression. We compared mortality and growth of inbred and outbred zebrafish, Danio rerio, between 6 and 48 days of age. Grandparents of the studied fish were caught in the wild. Inbred fish were generated by brother-sister mating. Mortality was 9% in outbred fish, and 42% in inbred fish, which implies at least 3.6 lethal equivalents of deleterious recessive alleles per zygote. There was no significant inbreeding depression in the growth, perhaps because the surviving inbred fish lived under less crowded conditions. In contrast to alleles that cause embryonic and early larval mortality in the same population, alleles responsible for late larval and early juvenile mortality did not result in any gross morphological abnormalities. Thus, deleterious recessive alleles that segregate in a wild zebrafish population belong to two sharply distinct classes: early-acting, morphologically overt, unconditional lethals; and later-acting, morphologically cryptic, and presumably milder alleles. C1 Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP McCune, AR (reprint author), Cornell Univ, Dept Ecol & Evolutionary Biol, Corson Hall, Ithaca, NY 14853 USA. EM arm2@cornell.edu NR 58 TC 9 Z9 11 U1 1 U2 7 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD OCT 7 PY 2004 VL 271 IS 1552 BP 2025 EP 2033 DI 10.1098/rspb.2004.2787 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 860LI UT WOS:000224344700006 PM 15451692 ER PT J AU Castle, P AF Castle, P TI Cervical cancer screening among women without a cervix SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID HUMAN-PAPILLOMAVIRUS C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Castle, P (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 6 PY 2004 VL 292 IS 13 BP 1550 EP 1551 DI 10.1001/jama.292.13.1550-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 859HS UT WOS:000224254600013 PM 15467050 ER PT J AU Flory, J Emanuel, E AF Flory, J Emanuel, E TI Interventions to improve research participants' understanding in informed consent for research - A systematic review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID VACCINE EFFICACY TRIALS; CANCER CLINICAL-TRIALS; INFORMATION; COMPREHENSION; QUALITY; HIV; VIDEO; CAPACITY; STANDARD; LEVEL AB Context Available data suggest that prospective research participants may frequently not understand information disclosed to them in the informed consent process. Little is known about how understanding can be improved. Objective To review research on interventions to improve research participants' understanding of information disclosed in the informed consent process. Data Sources and Study Selection A search of MEDLINE was performed using the terms informed consent and clinical research and informed consent and (comprehension or understanding) from 1966 to March 2004, which included randomized controlled trials, longitudinal trials, and controlled trials with nonrandom allocation that compared the understanding of research participants who had undergone only a standard informed consent process to that of participants who had received an intervention to improve their understanding. A comprehensive bibliography of empirical research on informed consent published in January 1999 was also reviewed, as were personal files and all issues of the journals IRB and Controlled Clinical Trials. Data Extraction Study design, quality criteria, population characteristics, interventions, and outcomes for each trial were extracted. The statistical significance of the interventions' effects on understanding were noted, as were mean scores for understanding for each group of each trial. For those trials that measured the secondary outcomes of satisfaction and willingness to enroll, results were also summarized. Data Synthesis Thirty studies described 42 trials that met inclusion criteria. Of 12 trials of multimedia interventions, 3 showed significant improvement in understanding. Of 15 trials of enhanced consent forms, 6 showed significant improvement in understanding (all P<.05), but 5 of 6 trials were of limited quality, casting doubt on their practical relevance. Of 5 trials of extended discussion, 3 showed significant improvement in understanding (all P<.001) and 2 showed trends toward improvement (P=.054 and P=.08). Of 5 trials of test/feedback, all showed significant improvement in understanding (all P<.05) but were flawed in that they may have mistaken rote memorization for improvement in understanding. Another 5 trials were put into a miscellaneous category and had varying impact on understanding. Some demographic factors, particularly lower education, were associated with less understanding. Satisfaction and willingness to enroll were never significantly diminished by an intervention. Conclusions Efforts to improve understanding through the use of multimedia and enhanced consent forms have had only limited success. Having a study team member or a neutral educator spend more time talking one-on-one to study participants appears to be the most effective available way of improving research participants' understanding; however, further research is needed. C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Emanuel, E (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@cc.nih.gov NR 45 TC 453 Z9 461 U1 5 U2 27 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 OCT 6 PY 2004 VL 292 IS 13 BP 1593 EP 1601 DI 10.1001/jama.292.13.1593 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 859HS UT WOS:000224254600027 PM 15467062 ER PT J AU Hashimoto, I Bhat, AH Li, XK Jones, M Davies, CH Swanson, JC Schindera, ST Sahn, DJ AF Hashimoto, I Bhat, AH Li, XK Jones, M Davies, CH Swanson, JC Schindera, ST Sahn, DJ TI Tissue Doppler-derived myocardial acceleration for evaluation of left ventricular diastolic function SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID WALL-MOTION; HYPERTROPHIC CARDIOMYOPATHY; HEMODYNAMIC DETERMINANTS; FILLING PRESSURES; ANIMAL-MODEL; STRAIN-RATE; VELOCITIES; ECHOCARDIOGRAPHY; CONTRACTILITY; VALIDATION AB OBJECTIVES Our purpose was to evaluate a tissue Doppler-based index-peak myocardial acceleration (pACC)-during isovolumic relaxation and in evaluating left ventricular (LV) diastolic function. BACKGROUND Simple, practical indexes for diastolic function evaluation are lacking, but are much desired for clinical evaluation. METHODS We examined eight sheep by using tissue Doppler ultrasound images obtained in the apical four-chamber views to evaluate mitral valve annular velocity at the septum and LV wall. The pACC thus derived was analyzed during isovolumic relaxation (IVRT) and during the LV filling period (LVFP). We then changed the hemodynamic status of each animal by blood administration, dobutamine, and metoprolol infusion. We compared the pACC values during IVRT and LVFP over the four different hemodynamic conditions with a peak rate of drop in LV pressure (-dP/dt(min)) and the time constant of LV isovolumic pressure decay (tau), as measured with a high-frequency manometer-tipped catheter. RESULTS The pACC of the septal side of the mitral valve annulus during IVRT showed a good correlation with -dP/dt(min) (r = -0.80, p < 0.0001) and tau (r = -0.87, p < 0.0001). The mean left atrial pressure (LAP) correlated well with the septal side pACC during LVFP (r = 0.81, p < 0.0001). There was a weak correlation between the mitral valve annulus pACC at the LV lateral wall and mean LAP. CONCLUSIONS The pACC during IVRT is a sensitive, preload-independent marker for evaluation of LV diastolic function. In addition, pACC during LVFP correlated well with mean LAP. (J Am Coll Cardiol 2004;44:1459-66) (C) 2004 by the American College of Cardiology Foundation. C1 Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97239 USA. NHLBI, Bethesda, MD 20892 USA. RP Sahn, DJ (reprint author), Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 S-W Sam Jackson Pk Rd, Portland, OR 97239 USA. EM sahnd@ohsu.edu NR 27 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 6 PY 2004 VL 44 IS 7 BP 1459 EP 1466 DI 10.1016/j.jacc.2004.06.067 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 858XK UT WOS:000224225600019 PM 15464328 ER PT J AU Buist, DSM Porter, PL Lehman, C Taplin, SH White, E AF Buist, DSM Porter, PL Lehman, C Taplin, SH White, E TI Factors contributing to mammography failure in women aged 40-49 years SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CANCER SCREENING-PROGRAM; BREAST-CANCER; DETECTED CANCERS; HORMONAL FACTORS; UNITED-STATES; SOJOURN TIME; INTERVAL; RISK; DENSITY; SENSITIVITY AB Background: Younger women (40-49 years) have lower mammographic sensitivity (i.e., greater proportion of cancers detected after a negative mammogram) than older women (2:50 years). We explored the effect of tumor growth rate, breast density, mammographic image quality, and breast cancer risk factors on mammographic sensitivity in younger and older women. Methods: We studied 576 women (n = 73 aged 40-49 years and n = 503 aged 50 years or older) who were diagnosed with invasive breast cancer between 1988 and 1993. Interval cancers were defined as those diagnosed within 12 or 24 months after a negative screening mammogram and before a subsequent mammogram. Tumor growth rate was assessed by mitotic figure count and Ki-67 positivity. The main outcome measures were percentage of women with interval cancer (1 - mammographic sensitivity) by age, odds ratio (OR) of interval cancer by age, and excess odds (i.e., the percentage of the odds ratio for age that was explained by individual covariates). Results: Interval cancers occurred in 27.7% of younger women and 13.9% of older women within 12 months (OR = 2.36, 95% confidence interval [CI] = 1.14 to 4.77) and in 52.1% of younger women and 24.7% of older women within 24 months (OR = 3.58, 95% CI = 2.15 to 5.97). Greater breast density explained 67.6% of the decreased mammographic sensitivity in younger women at 12 months, whereas rapid tumor growth explained 30.6% and breast density explained 37.6% of the decreased sensitivity in younger women at 24 months. Conclusions: Breast density largely explained decreased mammographic sensitivity at 12 months, whereas rapid tumor growth contributed to decreased mammographic sensitivity at 24 months. A 12-month versus a 24-month mammography screening interval may therefore reduce the adverse impact of faster growing tumors on mammographic sensitivity in younger women. C1 Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. NCI, Appl Res Program, NIH, Bethesda, MD 20892 USA. RP Buist, DSM (reprint author), Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, 1730 Minor Ave,Ste 1600, Seattle, WA 98101 USA. EM buist.d@ghc.org FU NCI NIH HHS [U01CA63731] NR 40 TC 157 Z9 162 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 6 PY 2004 VL 96 IS 19 BP 1432 EP 1440 DI 10.1093/jnci/djh269 PG 9 WC Oncology SC Oncology GA 859YM UT WOS:000224304300010 PM 15467032 ER PT J AU Habel, LA Dignam, JJ Land, SR Salane, M Capra, AM Julian, TB AF Habel, LA Dignam, JJ Land, SR Salane, M Capra, AM Julian, TB TI Mammographic density and breast cancer after ductal carcinoma in situ SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL ADJUVANT BREAST; HORMONE REPLACEMENT THERAPY; PARENCHYMAL PATTERNS; INTRADUCTAL-CARCINOMA; PATHOLOGICAL FINDINGS; POSTMENOPAUSAL WOMEN; RADIATION-THERAPY; RANDOMIZED-TRIAL; COMPETING RISKS; PROTOCOL B-17 AB Women with ductal carcinoma in situ (DCIS) are at substantially increased risk for a second breast cancer, but few strong predictors for these subsequent tumors have been identified. We used Cox regression modeling to examine the association between mammographic density at diagnosis of DCIS of 504 women from the National Surgical Adjuvant Breast and Bowel Project B-17 trial and risk of subsequent breast cancer events. In this group of patients, mostly 50 years old or older, approximately 6.6% had breasts categorized as highly dense (i.e., greater than or equal to75% of the breast occupied by dense tissue). After adjusting for treatment with radiotherapy, age, and body mass index, women with highly dense breasts had 2.8 (95% confidence interval [CI] = 1.3 to 6.1) times the risk of subsequent breast cancer (DCIS or invasive), 3.2 (95 % CI = 1.2 to 8.5) times the risk of invasive breast cancer, and 3.0 (95% CI = 1.2 to 7.5) times the risk of any ipsilateral breast cancer, compared with women with less than 25% of the breast occupied by dense tissue. Our results provide initial evidence that the risk of second breast cancers may be increased among DCIS patients with highly dense breasts. C1 Kaiser Permanente, Med Care Program, Div Res, Oakland, CA 94612 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ Pittsburgh, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. MSW Consulting, Bloomfield Hills, MI USA. Allegheny Gen Hosp, NSABP Operat Ctr, Pittsburgh, PA 15212 USA. RP Habel, LA (reprint author), Kaiser Permanente, Med Care Program, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM lah@dor.kaiser.org FU NCI NIH HHS [R03-CA83135, R01 CA081302-05, R01 CA081302] NR 42 TC 34 Z9 35 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 6 PY 2004 VL 96 IS 19 BP 1467 EP 1472 DI 10.1093/jnci/djh260 PG 6 WC Oncology SC Oncology GA 859YM UT WOS:000224304300014 PM 15467036 ER PT J AU Kassed, CA Herkenham, M AF Kassed, CA Herkenham, M TI NF-kappa B p50-deficient mice show reduced anxiety-like behaviors in tests of exploratory drive and anxiety SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE anxiety; fear; NF-kappa B; knockout mouse; transcription factor; immune ID NECROSIS-FACTOR-ALPHA; P50 SUBUNIT; TRANSCRIPTION FACTORS; HIPPOCAMPAL-NEURONS; TARGETED DELETION; NUCLEUS-ACCUMBENS; TRANSGENIC MICE; KNOCKOUT MICE; PLUS-MAZE; GENE AB The ubiquitous transcription factor nuclear factor (NF)-kappaB plays a prominent role in regulation of inflammatory immune responses and in cell survival. Recently, it has been found to be active in neurons, and mice lacking NF-kappaB subunits p50 or p65 show deficits in specific cognitive tasks. Here we demonstrate a strikingly low level of anxiety-like behavior in the p50(-/-) mouse. In an open field, the mutant mice showed significantly less defecation, more rearing, and more time spent in the center compartment relative to wild type control mice. The p50(-/-) mice also spent more time investigating a novel object placed in the open field. On the elevated plus maze, p50(-/-) mice spent more time on the open arms and had increased numbers of open arm entries relative to wild type. In group housing conditions, they did not establish dominant-subordinate hierarchies, whereas wild type control animals did so, in part, by whisker barbering and conspecific allogrooming. In tests of general health, sensorimotor function, and daily activity on a circadian rhythm, p50(-/-) mice were normal. Thus, absence of the p50 subunit of the NF-kappaB transcription factor, which results in altered NF-kappaB transcriptional activity in cells throughout the body and brain, alters neuronal circuitry underlying manifestation of emotional behavior. The p50 subunit appears to play a role in normal expression of certain forms of anxiety. (C) 2004 Elsevier B.V. All rights reserved. C1 NIMH, Sect Funct Neuroanat, DHHS, NIH, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Sect Funct Neuroanat, DHHS, NIH, 36,Rm 2D15, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238 NR 53 TC 58 Z9 59 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD OCT 5 PY 2004 VL 154 IS 2 BP 577 EP 584 DI 10.1016/j.bbr.2004.03.026 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 858JQ UT WOS:000224188500031 PM 15313047 ER PT J AU Ramakrishnan, B Boeggeman, E Qasba, PK AF Ramakrishnan, B Boeggeman, E Qasba, PK TI Effect of the Met344His mutation on the conformational dynamics of bovine beta-1,4-galactosyltransferase: Crystal structure of the Met344His mutant in complex with chitobiose SO BIOCHEMISTRY LA English DT Article ID ALPHA-LACTALBUMIN LA; N-ACETYLGLUCOSAMINE; LACTOSE SYNTHETASE; CATALYTIC DOMAIN; GALACTOSYLTRANSFERASE; PROTEIN; BINDING; BETA-4GAL-T1; MECHANISM; ACCEPTOR AB beta-1,4-Galactosyltransferase (beta4Gal-T1) in the presence of manganese ion transfers galactose from UDP-galactose (UDP-Gal) to N-acetylglucosamine (GlcNAc) that is either free or linked to an oligosaccharide. Crystallographic studies on bovine beta4Gal-T1 have shown that the primary metal binding site is located in the hinge region of a long flexible loop, which upon Mn2+ and UDP-Gal binding changes from an open to a closed conformation. This conformational change creates an oligosaccharide binding site in the enzyme. Neither UDP nor UDP analogues efficiently induce these conformational changes in the wild-type enzyme, thereby restricting the structural analysis of the acceptor binding site. The binding of Mn2+ involves an uncommon coordination to the Sdelta atom of Met344; when it is mutated to His, the mutant M344H, in the presence of Mn2+ and UDP-hexanolamine, readily changes to a closed conformation, facilitating the structural analysis of the enzyme bound with an oligosaccharide acceptor. Although the mutant M344H loses 98% of its Mn2+-dependent activity, it exhibits 25% of its activity in the presence of Mg2+. The crystal structures of M344H-Gal-T1 in complex with either UDP-Gal.Mn2+ or UDP-Gal.Mg2+, determined at 2.3 Angstrom resolution, show that the mutant enzyme in these complexes is in a closed conformation, and the coordination stereochemistry of Mg2+ is quite similar to that of Mn2+. Although either Mn2+ or Mg2+, together with UDP-Gal, binds and changes the conformation of the M344H mutant to the closed one, it is the Mg2+ complex that engages efficiently in catalyses. Thus, this property enabled us to crystallize the M344H mutant for the first time with the acceptor substrate chitobiose in the presence of UDP-hexanolamine and Mn2+. The crystal structure determined at 2.3 Angstrom resolution reveals that the GlcNAc residue at the nonreducing end of chitobiose makes extensive hydrophobic interactions with the highly conserved Tyr-286 residue. C1 NCI, LECB, Struct Glycobiol Sect, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, LECB, Struct Glycobiol Sect, Bldg 469,Room 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU PHS HHS [N01-C0-12400] NR 29 TC 24 Z9 24 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 5 PY 2004 VL 43 IS 39 BP 12513 EP 12522 DI 10.1021/bi049007+ PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 858ZN UT WOS:000224231500012 PM 15449940 ER PT J AU McPhie, P AF McPhie, P TI CD studies on films of amyloid proteins and polypeptides: quantitative g-factor analysis indicates a common folding motif SO BIOPOLYMERS LA English DT Article DE amyloid films; beta-helix-like structure; CD; g-factor analysis; protein secondary structure ID SOLID-STATE NMR; CIRCULAR-DICHROISM; SECONDARY STRUCTURE; BETA-SHEETS; FIBRILS; CONFORMATION; CONVERSION; MODEL AB Irrespective of the constituent protein, all amyloid fibrils show similar morphology in the electron microscope and x-ray diffraction patterns characteristic of a "cross-beta" structure, with extended beta-strands perpendicular to the fibril's long axis. Little is known about the amount or type of this structure. I have measured CD spectra of films formed from a number of amyloid proteins and polypeptides, and estimated their contents of extended secondary structure, by analysis of their g-jactor spectra, the ratio of the CD and absorbance signals (P. McPhie, Analytical Biochemistry, 2001, Vol. 293, pp. 109-119). Amyloid films of Abeta-(1-40) peptide, beta-2-microglobulin, insulin, and three homopolypeptides show very intense CD spectra, compatible with the presence of a beta-helixlike structure, arranged in a common framework in the fibrils. The extent of this structure was estimated as 45-80% in the protein fibrils and 30-80% in the polypeptide fibrils. (C) 2004 Wiley Periodicals, Inc. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP McPhie, P (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 215, Bethesda, MD 20892 USA. EM pmcphie@helix.nih.gov NR 24 TC 18 Z9 19 U1 2 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD OCT 5 PY 2004 VL 75 IS 2 BP 140 EP 147 DI 10.1002/bip.20095 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 854ZR UT WOS:000223943100005 PM 15356868 ER PT J AU Tomanee, P Hsu, JT Ito, Y AF Tomanee, P Hsu, JT Ito, Y TI Fractionation of protein, RNA, and plasmid DNA in centrifugal precipitation chromatography using cationic surfactant CTAB containing inorganic salts NaCl and NH4Cl SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE plasmid DNA purification; centrifugal precipitation chromatography ID IONIC-STRENGTH; CETYLTRIMETHYLAMMONIUM BROMIDE; DIELECTRIC-CONSTANT; GENE-THERAPY; MICELLES; COMPLEX; BINDING AB Centrifugal precipitation chromatography (CPC) is a separation system that mainly employs a moving concentration gradient of precipitating agent along a channel and solutes of interest undergo repetitive precipitation-dissolution, fractionate at different locations, and elute out from the channel according to their solubility in the precipitating agent solution. We report here for the first time the use of a CPC system for fractionation of protein, RNA, and plasmid DNA in clarified lysate produced from bacterial culture. The cationic surfactant cetyltrimethylammonium bromide (CTAB) was initially used as a precipitating agent; however, all biomolecules showed no differential solubility in the moving concentration gradient of this surfactant and, as a result, no separation of protein, RNA, and plasmid DNA occurred. To overcome this problem, inorganic salts such as NaCl and NH4Cl were introduced into solution of CTAB. The protein and RNA were found to have higher solubility with the addition of these salts and separated from the plasmid DNA. Decreasing surface charge density of CTAB upon addition of NaCl and NH4Cl was believed to lead to lower surfactant complexation, and therefore caused differential solubility and fractionation of these biomolecules, Addition of CaCl2 did not improve solubility and separation of RNA from plasmid DNA. (C) 2004 Wiley Periodicals, Inc. C1 Lehigh Univ, Dept Chem Engn, Biopharmaceut Technol Inst, Bethlehem, PA 18015 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hsu, JT (reprint author), Lehigh Univ, Dept Chem Engn, Biopharmaceut Technol Inst, Bethlehem, PA 18015 USA. NR 18 TC 11 Z9 11 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD OCT 5 PY 2004 VL 88 IS 1 BP 52 EP 59 DI 10.1002/bit.20203 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 857RP UT WOS:000224136300006 PM 15384057 ER PT J AU Balady, GJ Larson, MG Vasan, RS Leip, EP O'Donnell, CJ Levy, D AF Balady, GJ Larson, MG Vasan, RS Leip, EP O'Donnell, CJ Levy, D TI Usefulness of exercise testing in the prediction of coronary disease risk among asymptomatic persons as a function of the Framingham risk score SO CIRCULATION LA English DT Article DE exercise; risk factors; cardiovascular diseases ID ALL-CAUSE MORTALITY; HEART-DISEASE; CHRONOTROPIC INCOMPETENCE; CARDIOVASCULAR-DISEASE; PRIMARY-PREVENTION; PHYSICAL-ACTIVITY; FOLLOW-UP; MEN; ASSOCIATION; CAPACITY AB Background - The purpose of this study is to determine the usefulness of exercise treadmill testing (ETT) among asymptomatic persons in predicting coronary heart disease (CHD) events over and above the Framingham CHD risk score. Methods and Results - Subjects included 3043 members of the Framingham Heart Study offspring cohort without CHD ( 1431 men and 1612 women; age, 45 +/- 9 years) who underwent ETT and were followed up for 18.2 years. The risk of developing CHD was evaluated relative to 3 exercise test variables: ( 1) ST-segment depression greater than or equal to 1 mm, ( 2) failure to achieve target heart rate (THR) of 85% predicted maximum, and ( 3) exercise capacity. In multivariable analyses that adjusted for age and Framingham CHD risk score, among men, ST-segment depression ( hazard ratio [HR], 1.88; 95% CI, 1.21 to 2.91) and failure to achieve THR (HR, 1.70; 95% CI, 1.18 to 2.45) predicted higher CHD risk, whereas a greater exercise capacity predicted lower CHD risk ( HR per MET, 0.94; 95% CI, 0.89 to 0.99). Although similar HRs were seen in women, those results were not statistically significant. Among men with 10-year predicted risk greater than or equal to20%, failure to reach THR and ST-segment depression both more than doubled the risk of an event ( HR, 2.66 and HR, 2.11, respectively), and each MET increment in exercise capacity reduced risk by 13% ( HR, 0.87). Conclusions - Among asymptomatic men, ST-segment depression, failure to reach THR, and exercise capacity during ETT provided additional prognostic information in age- and Framingham risk score - adjusted models, particularly among those in the highest risk group ( 10-year predicted CHD risk of greater than or equal to 20%). The evaluation of exercise test variables in women is limited, given our sample size and the few CHD events in women. C1 Boston Univ, Sch Med, Boston Med Ctr, Dept Med,Sect Cardiol, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Balady, GJ (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Dept Med,Sect Cardiol, 88 E Newton St, Boston, MA 02118 USA. EM gary.balady@bmc.org OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K-24-HL-04334, N01-HC-25195] NR 33 TC 98 Z9 101 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 5 PY 2004 VL 110 IS 14 BP 1920 EP 1925 DI 10.1161/01.CIR.0000143226.40607.71 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 859KM UT WOS:000224262100009 PM 15451778 ER PT J AU Batkai, S Pacher, P Osei-Hyiaman, D Radaeva, S Liu, J Harvey-White, J Offertaler, L Mackie, K Rudd, MA Bukoski, RD Kunos, G AF Batkai, S Pacher, P Osei-Hyiaman, D Radaeva, S Liu, J Harvey-White, J Offertaler, L Mackie, K Rudd, MA Bukoski, RD Kunos, G TI Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension SO CIRCULATION LA English DT Article DE hypertension; blood pressure; contractility; endocannabinoids; pharmacology ID VASCULAR ENDOTHELIAL-CELLS; CB1 RECEPTORS; BLOOD-PRESSURE; ANANDAMIDE; MICE; RATS; INHIBITION; PROTEIN; HYPOTENSION; DELTA-9-TETRAHYDROCANNABINOL AB Background-Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. Methods and Results-In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. Conclusions-We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension. C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Physiol, Seattle, WA 98195 USA. N Carolina Cent Univ, Cardiovasc Dis Res Program, Durham, NC USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, MSC-8115, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov RI Mackie, Kenneth/B-7358-2011; Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Mackie, Ken/E-3715-2013; Batkai, Sandor/H-7983-2014 OI Pacher, Pal/0000-0001-7036-8108; Mackie, Ken/0000-0001-8501-6199; FU Intramural NIH HHS [Z99 AA999999]; NHLBI NIH HHS [R01 HL064761, UH1 HL059868] NR 40 TC 183 Z9 191 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 5 PY 2004 VL 110 IS 14 BP 1996 EP 2002 DI 10.1161/01.CIR.0000143230.23252.D2 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 859KM UT WOS:000224262100020 PM 15451779 ER PT J AU Buckberg, GD Weisfeldt, ML Ballester, M Beyar, R Burkhoff, D Coghlan, HC Doyle, M Epstein, ND Gharib, M Ideker, RE Ingels, NB LeWinter, MM McCulloch, AD Pohost, GM Reinlib, LJ Sahn, DJ Sopko, G Spinale, FG Spotnitz, HM Torrent-Guasp, F Shapiro, EP AF Buckberg, GD Weisfeldt, ML Ballester, M Beyar, R Burkhoff, D Coghlan, HC Doyle, M Epstein, ND Gharib, M Ideker, RE Ingels, NB LeWinter, MM McCulloch, AD Pohost, GM Reinlib, LJ Sahn, DJ Sopko, G Spinale, FG Spotnitz, HM Torrent-Guasp, F Shapiro, EP TI Left ventricular form and function - Scientific priorities and strategic planning for development of new views of disease SO CIRCULATION LA English DT Article ID MRI C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Div Cardiol, Baltimore, MD 21224 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Lleida, Lleida, Spain. Technion Israel Inst Technol, IL-32000 Haifa, Israel. Columbia Univ, New York, NY USA. Univ Alabama, Birmingham, AL USA. Allegheny Singer Res Inst, Pittsburgh, PA 15212 USA. NHLBI, NIH, Bethesda, MD 20892 USA. CALTECH, Pasadena, CA 91125 USA. Palo Alto Med Fdn, Palo Alto, CA USA. Univ Vermont, Burlington, VT USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ So Calif, Los Angeles, CA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Shapiro, EP (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Div Cardiol, 4940 Eastern Ave, Baltimore, MD 21224 USA. EM eshapiro@jhmi.edu RI Burkhoff, Daniel/D-7674-2011 NR 13 TC 52 Z9 55 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 5 PY 2004 VL 110 IS 14 BP E333 EP E336 DI 10.1161/01.CIR.0000143625.56882.5C PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 859KM UT WOS:000224262100031 PM 15466651 ER PT J AU Shroff, R Arbel-Eden, A Pilch, D Ira, G Bonner, WM Petrini, JH Haber, JE Lichten, M AF Shroff, R Arbel-Eden, A Pilch, D Ira, G Bonner, WM Petrini, JH Haber, JE Lichten, M TI Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break SO CURRENT BIOLOGY LA English DT Article ID HISTONE H2AX PHOSPHORYLATION; DEPENDENT NUCLEAR-DYNAMICS; SACCHAROMYCES-CEREVISIAE; IN-VIVO; MRE11 COMPLEX; DAMAGE CHECKPOINT; ATAXIA-TELANGIECTASIA; REMODELING COMPLEX; CELLULAR-RESPONSE; BUDDING YEAST AB Background: In response to DNA double-strand breaks (DSBs), eukaryotic cells rapidly phosphorylate histone H2A isoform H2AX at a C-terminal serine (to form gamma-H2AX) and accumulate repair proteins at or near DSBs. To date, these events have been defined primarily at the resolution of light microscopes, and the relationship between gamma-H2AX formation and repair protein recruitment remains to be defined. Results: We report here the first molecular-level characterization of regional chromatin changes that accompany a DSB formed by the HO endonuclease in Saccharomyces cerevisiae. Break induction provoked rapid gamma-H2AX formation and equally rapid recruitment of the Mre11 repair protein. gamma-H2AX formation was efficiently promoted by both Tel1p and Mec1p, the yeast ATM and ATR homologs; in G1-arrested cells, most gamma-H2AX formation was dependent on Tell and Mre11. gamma-H2AX formed in a large (ca. 50 kb) region surrounding the DSB. Remarkably, very little gamma-H2AX could be detected in chromatin within 1-2 kb of the break. In contrast, this region contains almost all the Mre11p and other repair proteins that bind as a result of the break. Conclusions: Both Mec1p and Tel1p can respond to a DSB, with distinct roles for these checkpoint kinases at different phases of the cell cycle. Part of this response involves histone phosphorylation over large chromosomal domains; however, the distinct distributions of gamma-H2AX and repair proteins near DSBs indicate that localization of repair proteins to breaks is not likely to be the main function of this histone modification. C1 NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Brandeis Univ, Rosenstiel Ctr, Waltham, MA 02454 USA. Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. RP Lichten, M (reprint author), NCI, Biochem Lab, Ctr Canc Res, Bldg 37,Room 6124, Bethesda, MD 20892 USA. EM lichten@helix.nih.gov RI Ira, Grzegorz/B-7912-2010; Lichten, Michael/C-5795-2013; OI Lichten, Michael/0000-0001-9707-2956; Haber, James/0000-0002-1878-0610 FU NIGMS NIH HHS [R01 GM059413, GM20056, GM59413, GM61766, R01 GM020056, R01 GM061766, R01 GM080600, R37 GM020056, R37 GM059413] NR 74 TC 306 Z9 316 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD OCT 5 PY 2004 VL 14 IS 19 BP 1703 EP 1711 DI 10.1016/j.cub.2004.09.047 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860QM UT WOS:000224358100018 PM 15458641 ER PT J AU Viappiani, C Bettati, S Bruno, S Ronda, L Abbruzzetti, S Mozzarelli, A Eaton, WA AF Viappiani, C Bettati, S Bruno, S Ronda, L Abbruzzetti, S Mozzarelli, A Eaton, WA TI New insights into allosteric mechanisms from trapping unstable protein conformations in silica gels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AFFINITY CONFORMATIONS; QUATERNARY STRUCTURE; ORGANIC-PHOSPHATES; OXYGEN EQUILIBRIUM; LIGAND-BINDING; HEMOGLOBIN; MODEL; KINETICS; COOPERATIVITY; EFFECTORS AB To understand why the classical two-state allosteric model of Monod, Wyman, and Changeux explains cooperative oxygen binding by hemoglobin but does not explain changes in oxygen affinity by allosteric inhibitors, we have investigated the kinetic properties of unstable conformations transiently trapped by encapsulation in silica gels. Conformational trapping reveals that after nanosecond photodissociation of carbon monoxide a large fraction of the subunits of the T quaternary structure has kinetic properties almost identical to those of subunits of the R quaternary structure. Addition of allosteric inhibitors reduces both the fraction of R-like subunits and the oxygen affinity of the T quaternary structure. These kinetic and equilibrium results are readily explained by a recently proposed generalization of the Monod-Wyman-Changeux model in which a preequilibrium between two functionally different tertiary, rather than quaternary, conformations plays the central role. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Parma, Dept Phys, I-43100 Parma, Italy. Univ Parma, Dept Publ Hlth, I-43100 Parma, Italy. Univ Parma, Dept Biochem & Mol Biol, I-43100 Parma, Italy. Univ Parma, Italian Natl Inst Phys Matter, I-43100 Parma, Italy. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 104, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov RI Ronda, Luca/E-5214-2012; Mozzarelli, Andrea/C-3615-2014; abbruzzetti, stefania/M-8640-2015; Bruno, Stefano/A-4582-2011; OI Mozzarelli, Andrea/0000-0003-3762-0062; abbruzzetti, stefania/0000-0001-7685-8554; Ronda, Luca/0000-0002-5389-2669; Bruno, Stefano/0000-0002-7890-2472; Viappiani, Cristiano/0000-0001-7470-4770 FU NIGMS NIH HHS [GM 58890, P01 GM058890] NR 42 TC 82 Z9 83 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 5 PY 2004 VL 101 IS 40 BP 14414 EP 14419 DI 10.1073/pnas.0405987101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 860UR UT WOS:000224369600021 PM 15385676 ER PT J AU Rosenberg, SA Dudley, ME AF Rosenberg, SA Dudley, ME TI Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT Arthur M Sackler Colloquium of the National-Academy-of-Sciences on therapeutic Vaccines CY APR 01-03, 2004 CL Natl Acad Sci, Washington, DC HO Natl Acad Sci ID TUMOR-INFILTRATING LYMPHOCYTES; REACTIVE T-LYMPHOCYTES; ADOPTIVE TRANSFER; TRANSFER THERAPY; EXOGENOUS IL-2; GENE-TRANSFER; IMMUNOTHERAPY; AUTOIMMUNITY; TRANSDUCTION; ANTIGENS AB Our recent clinical trials demonstrate that autologous cell transfer after lymphodepleting chemotherapy can cause the regression of large, vascularized tumors in patients with refractory metastatic melanoma. Eighteen of 35 patients treated with tumor-reactive lymphocyte cultures experienced an objective clinical response (50% reduction in tumor), including four complete responders. In some patients, tumor regression was accompanied by a large in vivo expansion of the administered antitumor lymphocytes, which persisted in peripheral blood at >70% of total lymphocytes for many months after transfer. The cells capable of mediating tumor regression consisted of heterogeneous lymphocyte populations with high avidity for tumor antigens that were derived from tumor-infiltrating lymphocytes cultured for limited times in vitro. The success of thistreatment likely results from the ability to infuse large numbers of activated antitumor lymphocytes into an appropriate host homeostatic environment depleted of regulatory T cells. These studies are elucidating the requirements for successful immunotherapy of patients with advanced metastatic disease and are leading to additional clinical trials with gene-modified lymphocytes. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. EM sar@nih.gov NR 18 TC 256 Z9 264 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 OCT 5 PY 2004 VL 101 SU 2 BP 14639 EP 14645 DI 10.1073/pnas.0405730101 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861NT UT WOS:000224424300014 PM 15381769 ER PT J AU Kipnis, J Avidan, H Caspi, RR Schwartz, M AF Kipnis, J Avidan, H Caspi, RR Schwartz, M TI Dual effect of CD4(+)CD25(+) regulatory T cells in neurodegeneration: A dialogue with microglia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT Arthur M Sackler Colloquium of the National-Academy-of-Sciences on therapeutic Vaccines CY APR 01-03, 2004 CL Natl Acad Sci, Washington, DC HO Natl Acad Sci DE autoimmunity; neuroprotection; neurodegenerative conditions; hippocampai slice cultures; immune regulation ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; PROTECTIVE AUTOIMMUNITY; ORAL TOLERANCE; NEUROPROTECTIVE AUTOIMMUNITY; MEDIATED CONTROL; TH1 CELLS; IN-VITRO; ACTIVATION AB Autoimmune CD4(+) T cells can mediate the ability to withstand neurodegenerative conditions. Here we show that the ability to spontaneously manifest a T cell-dependent protective response is restricted by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg); depletion of Treg was beneficial in two mouse strains (C57BL/6J and BALB/c/OLA) differing in their spontaneous T cell-dependent ability to withstand the consequences of optic nerve injury. Passive transfer of exogenous Treg was destructive in BALB/c/OLA mice (which can spontaneously manifest a T cell-dependent protective anti-self response to injury) but beneficial in C57BL/6J mice (which have only limited ability to manifest such a response). This dichotomy was resolved by the finding that, in severe combined immunodeficient mice, a beneficial effect is obtained by passive transfer of either Treg-free CD4(+) T cells (Teff) or Treg alone, indicating that neuroprotection can be achieved by either Treg or Teff in the absence of the other. We attribute these disparate effects of Treg to their differential interaction (in part via IL-10 and transforming growth factor beta) with local innate immune cells (microglia) in the presence and in the absence of effector T cells. Activation of microglia by pro- and antiinflammatory cytokines in suitably controlled amounts might trigger different signal transduction pathways, each of which induces a neuroprotective microglial phenotype. These results suggest that, under neurodegenerative conditions, the effects of Treg, and possibly also of other regulatory T cells, might not be uniform, and that their expression in different individuals might be genetically determined. Therefore, therapeutic intervention based on induction of regulatory T cells might have limitations. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schwartz, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM michal.schwartz@weizmann.ac.il OI Caspi, Rachel/0000-0002-7140-7671 NR 57 TC 97 Z9 99 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 OCT 5 PY 2004 VL 101 SU 2 BP 14663 EP 14669 DI 10.1073/pnas.0404842101 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861NT UT WOS:000224424300018 PM 15331781 ER PT J AU Jeong, LS Kim, MJ Kim, HO Gao, ZG Kim, SK Jacobson, KA Chun, MW AF Jeong, LS Kim, MJ Kim, HO Gao, ZG Kim, SK Jacobson, KA Chun, MW TI Design and synthesis of 3 '-ureidoadenosine-5 '-uronamides: effects of the 3 '-ureido group on binding to the A(3) adenosine receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE A(3) adenosine receptor; 3 '-ureidoadenosine derivatives; hydrogen bonding donor; binding affinity; steric effects ID IB-MECA; STRUCTURAL DETERMINANTS; LIGANDS; AGONIST; SELECTIVITY; ISCHEMIA; EFFICACY AB On the basis of high binding affinity at the A(3) adenosine receptor of 3'-aminoadenosine derivatives with hydrogen bonding donor ability, novel 3'-ureidoadenosine analogues were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose in order to lead to stronger hydrogen bonding than the corresponding 3'-aminoadeno sine derivatives. However, the synthesized 3'-ureidoadenosine analogues were totally devoid of binding affinity, because 3'-urea moiety caused steric and electrostatic repulsions at the binding site of the A(3) adenosine receptor, leading to conformational distortion. (C) 2004 Elsevier Ltd. All rights reserved. C1 Ewha Womans Univ, Med Chem Lab, Coll Pharm, Seoul 120750, South Korea. Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20982 USA. RP Jeong, LS (reprint author), Ewha Womans Univ, Med Chem Lab, Coll Pharm, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 17 TC 10 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 4 PY 2004 VL 14 IS 19 BP 4851 EP 4854 DI 10.1016/j.bmcl.2004.07.042 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 855ZI UT WOS:000224013000009 PM 15341938 ER PT J AU Blaney, JE Hanson, CT Hanley, KA Murphy, BR Whitehead, SS AF Blaney, JE Hanson, CT Hanley, KA Murphy, BR Whitehead, SS TI Vaccine candidates derived from a novel infectious cDNA clone of an American genotype dengue virus type 2 SO BMC INFECTIOUS DISEASES LA English DT Article ID HUMAN LIVER-CELLS; HEMORRHAGIC-FEVER; CHIMERIC VACCINE; HUMAN VOLUNTEERS; RHESUS-MONKEYS; VERO CELLS; IMMUNOGENICITY; REPLICATION; PATHOGENESIS; ATTENUATION AB Background: A dengue virus type 2 (DEN-2 Tonga/74) isolated from a 1974 epidemic was characterized by mild illness and belongs to the American genotype of DEN-2 viruses. To prepare a vaccine candidate, a previously described 30 nucleotide deletion (Delta30) in the 3' untranslated region of DEN-4 has been engineered into the DEN-2 isolate. Methods: A full-length cDNA clone was generated from the DEN-2 virus and used to produce recombinant DEN-2 (rDEN-2) and rDEN2Delta30. Viruses were evaluated for replication in SCID mice transplanted with human hepatoma cells (SCID-HuH-7 mice), in mosquitoes, and in rhesus monkeys. Neutralizing antibody induction and protective efficacy were also assessed in rhesus monkeys. Results: The rDEN2Delta30 virus was ten-fold reduced in replication in SCID-HuH-7 mice when compared to the parent virus. The rDEN-2 viruses were not infectious for Aedes mosquitoes, but both readily infected Toxorynchites mosquitoes. In rhesus monkeys, rDEN2Delta30 appeared to be slightly attenuated when compared to the parent virus as measured by duration and peak of viremia and neutralizing antibody induction. A derivative of rDEN2Delta30, designated rDEN2Delta30-4995, was generated by incorporation of a point mutation previously identified in the NS3 gene of DEN-4 and was found to be more attenuated than rDEN2Delta30 in SCID-HuH-7 mice. Conclusions: The rDEN2Delta30 and rDEN2Delta30-4995 viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Blaney, JE (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM jblaney@niaid.nih.gov; chanson@niaid.nih.gov; khanley@niaid.nih.gov; bmurphy@niaid.nih.gov; swhitehead@niaid.nih.gov NR 32 TC 54 Z9 58 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD OCT 4 PY 2004 VL 4 AR 39 DI 10.1186/1471-2334-4-39 PG 10 WC Infectious Diseases SC Infectious Diseases GA 866LX UT WOS:000224776100001 PM 15461822 ER PT J AU Wang, SS Schiffman, M Herrero, R Carreon, J Hildesheim, A Rodriguez, AC Bratti, MC Sherman, ME Morales, J Guillen, D Alfaro, M Clayman, B Burk, RD Viscidi, RP AF Wang, SS Schiffman, M Herrero, R Carreon, J Hildesheim, A Rodriguez, AC Bratti, MC Sherman, ME Morales, J Guillen, D Alfaro, M Clayman, B Burk, RD Viscidi, RP TI Determinants of human papillomavirus 16 serological conversion and persistence in a population-based cohort of 10 000 women in Costa Rica SO BRITISH JOURNAL OF CANCER LA English DT Article DE HPV; serology; persistence; conversion; cervix; cancer ID HUMAN-PAPILLOMAVIRUS TYPE-16; VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; SERUM ANTIBODIES; IMMUNOGLOBULIN-A; NATURAL-HISTORY; RISK FACTOR; HPV DNA; CANCER; INFECTION AB Determinants of human papillomavirus (HPV)-16 serological conversion and persistence were assessed in a population-based cohort of 10 049 women in Guanacaste, Costa Rica. Serologic responses to HPV-16 were measured in 7986 women by VLP-based enzyme-linked immunosorbent assay at both study enrolment (1993/94) and at 5-7 years of follow-up. Seropositive women were defined as greater than or equal to5 standard deviations above the mean optical density obtained for studied virgins at enrolment (n=573). Seroconnversion (n=409), persistence (n=675), and clearance (n=541) were defined based on enrolment and follow-up serology measurements. Age-specific distributions revealed that HPV-16 seroconversion was highest among 18- to 24-year-old women, steadily declining with age; HPV-16 seropersistence was lowest in women 65+ years. In age-adjusted multivariate logistic regression models, a 10-fold risk increase for HPV-16 seroconversion was associated with HPV-16 DNA detection at enrolment and follow-up; two-fold risk of seroconversion to HPV-16 was associated with increased numbers of lifetime and recent sexual partners and smoking status. Determinants of HPV-16 seropersistence included a 1.5-fold risk increase associated with having one sexual partner during follow-up, former oral contraceptive use, and a 3-fold risk increase associated with HPV-16 DNA detection at both enrolment and follow-up. Higher HPV-16 viral load at enrolment was associated with seroconversion, and higher antibody titres at enrolment were associated with seropersistence. C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. Albert Einstein Coll Med, Bronx, NY 10461 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Stanley Div Dev Neurovirol, Baltimore, MD 21205 USA. RP Wang, SS (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS MSC 7234, Bethesda, MD 20892 USA. EM wangso@mail.nih.gov FU NCI NIH HHS [R01CA78527, N01CP21081, N01CP31061, R01 CA078527] NR 30 TC 49 Z9 52 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 4 PY 2004 VL 91 IS 7 BP 1269 EP 1274 DI 10.1038/sj.bjc.6602088 PG 6 WC Oncology SC Oncology GA 859GC UT WOS:000224250400008 PM 15292929 ER PT J AU Merkle, TJ O'Brien, K Brooks, PJ Tarone, RE Robbins, JH AF Merkle, TJ O'Brien, K Brooks, PJ Tarone, RE Robbins, JH TI DNA repair in human fibroblasts, as reflected by host-cell reactivation of a transfected UV-irradiated luciferase gene, is not related to donor age SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE host-cell reactivation; luciferase; UV-C; aging and DNA repair; nucleotide excision repair ID HUMAN EPIDERMAL-KERATINOCYTES; XERODERMA PIGMENTOSUM; SKIN-CANCER; EXCISION-REPAIR; LIFE-SPAN; ULTRAVIOLET-IRRADIATION; HUMAN-LYMPHOCYTES; CAPACITY; DAMAGE; REEVALUATION AB The effect of donor age on the ability of mammalian cells to repair ultraviolet (UV)-induced DNA damage has been studied using several approaches, most recently via assays that measure the host-cell reactivation (HCR) of UV-irradiated reporter gene-containing plasmid vectors following their transfection into cells. Plasmid HCR assays indirectly quantify a cell line's ability to perform nucleotide excision repair (NER) by measuring the enzyme activity of the repaired reporter gene, e.g., chloramphenical acetyltransferase (cat) or luciferase (luc), and are useful in studies investigating whether increasing age may be a risk factor for the deficient repair of potentially cancer-causing, sunlight-induced, DNA lesions in skin cells. In our study, we quantified the DNA repair ability of cultured, nontransformed, human skin fibroblast lines through their HCR of a transfected UV-C-irradiated plasmid containing luc. HCR was measured at various times after transfection in five lines from normal donors of ages 21-96 years, and from one donor who had xeroderma pigmentosum (XP). The normal lines displayed increasing HCR at successive post-transfection time points and showed no significant correlation between HCR and donor age. The XP-A line. known to be markedly deficient in NER of UV-induced DNA damage, showed minimal evidence of HCR compared to the normal lines. To further assess potential variation in HCR with donor age, fibroblast lines from five old donors, ages 84-94 years, were compared with lines from five young donors, ages 17-26 years. While significant differences in HCR were found between some lines, no significant difference was found between the young and old age groups (P = 0.44). Our study provides no indication that the higher incidence of skin cancer observed with increasing age is due to an age-related decrease in the ability to repair UV-induced DNA damage. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Alcohol Abuse & Alcoholism, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. Int Epidemiol Inst, Rockville, MD 20850 USA. RP Robbins, JH (reprint author), NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. EM robbinsj@pop.nci.nih.gov NR 52 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD OCT 4 PY 2004 VL 554 IS 1-2 BP 9 EP 17 DI 10.1016/j.mrfmmm.2004.02.013 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 853IY UT WOS:000223821800002 PM 15450399 ER PT J AU Donovan, PJ Smith, GT Nardone, R AF Donovan, PJ Smith, GT Nardone, R TI The mutagenic effects of 7,12-dimethylbenz[a]anthacene, 3-methylcholanthrene and benzo[a]pyrene to the developing Syrian hamster fetus measured by an in vivo/in vitro mutation assay SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE in vivo; diphtheria toxin; mutation; mutagenicity test; somatic cells; 3-methylcholanthrene; 7,12-dimethylbenz[a]anthracene; benzo[a]pyrene; fetus; embryo; transplacental ID POLYCYCLIC AROMATIC-HYDROCARBONS; GENE-TOX PROGRAM; CHILDHOOD BRAIN-TUMORS; CYTOCHROMES P450 1A1; GESTATION DAYS 6-20; TRANSPLACENTAL CARCINOGENESIS; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; PARENTAL SMOKING; MATERNAL SMOKING AB The transplacental mutagenicity of three polycylic aromatic hydrocarbons, 7,12-dimethylbenz[a]anthacene (DMBA), 3-methylcholanthrene (MC) and benzo[a]pyrene (BP), was measured by an in vivo/in vitro mutation assay. Fetal sensitivity and dose-response characteristics with regard to transplacental mutagenesis by these compounds have never been quantified. In the current experiment, pregnant Syrian hamsters were exposed to these compounds at day 12 of gestation. Twenty-four hours later the fetuses were removed and their cells were allowed a 5-day expression time in culture. They were then seeded for colony formation and also for mutation selection by diphtheria toxin. DMBA at 0.2 mmol/kg (51.3 mg/kg) had an induced mutant frequency of 1.56 x 10(-4) Mutants per surviving cell. This was 598 times the historical control. DMBA at 0.2 mmol/kg was 3.6 times more potent than the highly mutagenic positive control, ethylnitrosourea, at 1 mmol/kg. DMBA also caused a dose-dependent increase in cloning efficiency, which was highly correlated with mutation rate. BP and MC were less effective than DMBA, causing increased mutations that were 31.6 and 17.7 times the historical control, respectively, and for neither was there any correlation of mutation rate with cloning efficiency. The special effectiveness of DMBA as a transplacental mutagen may relate to its ability to cause increased cell division and fixation of DNA lesions as mutations. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Lab Comparat Carinogenesis, Ft Detrick, MD 21702 USA. Catholic Univ Amer, Biol Dept, Washington, DC 20064 USA. RP Donovan, PJ (reprint author), NCI, Lab Comparat Carinogenesis, Bldg 538,Room 205E, Ft Detrick, MD 21702 USA. EM donovapa@mail.ncifcrf.gov OI Nardone, Raffaele/0000-0001-5243-6760 NR 66 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD OCT 4 PY 2004 VL 554 IS 1-2 BP 111 EP 120 DI 10.1016/j.mrfmmm.2004.04.003 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 853IY UT WOS:000223821800012 PM 15450409 ER PT J AU Pancioli, AM Barsan, WG Conwit, RA AF Pancioli, AM Barsan, WG Conwit, RA TI Executive summary: The Emergency Neurologic Clinical Trials Network meeting - A National Institute of Neurological Disorders and stroke symposium. SO ACADEMIC EMERGENCY MEDICINE LA English DT Editorial Material C1 Univ Cincinnati, Dept Emergency Med, Cincinnati, OH USA. Univ Michigan, Ann Arbor, MI 48109 USA. NINDS, NIH, Bethesda, MD USA. RP Pancioli, AM (reprint author), Univ Cincinnati, Dept Emergency Med, 231 Albert Sabin Way, Cincinnati, OH USA. EM arthur.pancioli@uc.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2004 VL 11 IS 10 BP 1092 EP 1096 DI 10.1197/j.aem.2004.06.009 PG 5 WC Emergency Medicine SC Emergency Medicine GA 861GW UT WOS:000224405100015 PM 15466154 ER PT J AU Thomasson, DM Gharib, A Li, KCP AF Thomasson, DM Gharib, A Li, KCP TI A primer on molecular biology for imagers: VIII. equipment for imaging molecular processes SO ACADEMIC RADIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; MAGNETIC-RESONANCE; CONTRAST AGENTS; GENE-EXPRESSION; QUANTUM DOTS; MICROSCOPY; PET; ULTRASOUND; FUTURE C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Ctr Clin, Bldg 10,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM kingli@nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X NR 65 TC 2 Z9 2 U1 1 U2 1 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD OCT PY 2004 VL 11 IS 10 BP 1159 EP 1170 DI 10.1016/j.acra.2004.07.008 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 871DS UT WOS:000225110100011 PM 15530810 ER PT J AU Bjork, JM Hommer, DW Grant, SJ Danube, C AF Bjork, JM Hommer, DW Grant, SJ Danube, C TI Impulsivity in abstinent alcohol-dependent patients: relation to control subjects and type 1-/type 2-like traits SO ALCOHOL LA English DT Article DE alcoholism; impulsivity; aggression; behavior; continuous performance test; typology; risk taking ID ANTISOCIAL PERSONALITY-DISORDER; DISRUPTIVE BEHAVIOR DISORDERS; CONTINUOUS PERFORMANCE-TEST; CROSS-FOSTERING ANALYSIS; SUBSTANCE USE DISORDER; CONDUCT DISORDER; ADOLESCENT ALCOHOL; HIGH-RISK; HOSPITALIZED ADOLESCENTS; SENSATION SEEKING AB Extensive literature has linked behavior control problems in childhood to risk for alcoholism, but impulsivity in alcohol-dependent adults has not been well characterized. Using a variety of laboratory measures of impulsivity, we assessed whether detoxified alcohol-dependent patients [(ADP); n = 130] were more impulsive than control subjects [(CS); n = 41]. In comparison with CS, ADP demonstrated (1) increased rates of commission errors, but not omission errors, in a continuous performance test, (2) a more severe devaluation of delayed reward, (3) increased rates of risky responses in a new risk-taking paradigm, and (4) higher psychometric scores of impulsivity and aggression. Across all subjects, aggressiveness correlated significantly with severity of delay discounting. A post hoc analysis of data obtained for male ADP indicated that, in comparison with patients with late onset of problem drinking and no problem-drinking parent, those ADP with earlier age of problem drinking and who reported a problem-drinking father (type 2-like alcohol dependence) demonstrated faster response latencies and more responses to non-target stimuli (commission errors) in the continuous performance test, as well as higher psychometric aggression. In contrast, these subtypes of male ADP did not differ in delay discounting and risk taking. These findings collectively indicate that, in comparison with CS, ADP are more impulsive in several dimensions, with elevated impulsivity in a working memory task as well as aggressivity characteristic of alcohol-dependent men with type 2-like features. (c) 2005 Elsevier Inc. All rights reserved. C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. NIDA, NIH, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIAAA, Clin Studies Lab, NIH, 10 Ctr Dr,Room 3C-103, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 NR 88 TC 166 Z9 169 U1 9 U2 44 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD OCT-NOV PY 2004 VL 34 IS 2-3 BP 133 EP 150 DI 10.1016/j.alcohol.2004.06.012 PG 18 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 908BO UT WOS:000227762400006 PM 15902907 ER PT J AU Pawlosky, RJ Salem, N AF Pawlosky, RJ Salem, N TI Development of alcoholic fatty liver and fibrosis in rhesus monkeys fed a low n-3 fatty acid diet SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE liver fibrosis; rhesus monkeys; alpha-linolenic acid; arachidonic acid; docosahexaenoic acid ID TUMOR-NECROSIS-FACTOR; ETHANOL-FED RATS; ARACHIDONIC-ACID; FISH-OIL; METHIONINE METABOLISM; DOCOSAHEXAENOIC ACID; FOLATE-DEFICIENCY; DISEASE; MITOCHONDRIA; INJURY AB Background: The amount and type of dietary fat seem to be important factors that modulate the development of alcohol-induced liver steatosis and fibrosis. Various alcohol-feeding studies in animals have been used to model some of the symptoms that occur in liver disease in humans. Methods: Rhesus monkeys (Macaca mulatta) were maintained on a diet that had a very low concentration of a-linolenic acid and were given free access to an artificially sweetened 7% ethanol solution. Control and ethanol-consuming animals were maintained on a diet in which the linoleate content was adequate (1.4% of energy); however, alpha-linoleate represented only 0.08% of energy. Liver specimens were obtained, and the fatty acid composition of the liver phospholipids, cholesterol esters, and triglycerides of the two groups were compared at 5 years and histopathology of tissue samples were compared at 3 and 5 years. Results: The mean consumption of ethanol for this group over a 5-year period was 2.4 g . kg(-1) . day(-1). As a consequence of the ethanol-dietary treatment, there were significantly lower concentrations of several polyunsaturated fatty acids in the liver phospholipids of the alcohol-treated group, including arachidonic acid and most of the n-3 fatty acids and particularly docosahexaenoic acid, when compared with dietary controls. Liver specimens from animals in the ethanol group at 5 years showed a marked degree of steatosis, both focal and diffuse cellular necrosis, and an increase in the development of fibrosis compared with specimens obtained at 3 years and with those from dietary controls, in which there was no evidence of fibrotic lesions. Conclusion: These findings suggest that the advancement of ethanol-induced liver disease in rhesus monkeys may be modulated by the amount and type of dietary essential fatty acids and that a marginal intake of n-3 fatty acids may be a permissive factor in the development of liver disease in primates. C1 NIAAA, Lab Membrane Biochem & Biophys, Sect Nutr Neurosci, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. RP Pawlosky, RJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Sect Nutr Neurosci, Div Intramural Clin & Biol Res,NIH, Room 114,12420 Parklawn Dr, Rockville, MD 20852 USA. EM bpawl@mail.nih.gov NR 58 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD OCT PY 2004 VL 28 IS 10 BP 1569 EP 1576 DI 10.1097/01.ALC.0000141810.22855.4E PG 8 WC Substance Abuse SC Substance Abuse GA 865FV UT WOS:000224688900018 PM 15597091 ER PT J AU Sam, C Massaro, JM D'Agostino, RB Levy, D Lambert, JW Wolf, PA Benjamin, EJ AF Sam, C Massaro, JM D'Agostino, RB Levy, D Lambert, JW Wolf, PA Benjamin, EJ TI Warfarin and aspirin use and the predictors of major bleeding complications in atrial fibrillation (the Framingham heart study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RANDOMIZED CONTROLLED TRIALS; RISK-FACTORS; NATIONAL PATTERNS; ANTICOAGULATION; STROKE; OUTPATIENTS; PREVENTION; THERAPY; HEMORRHAGE AB The Framingham Heart Study records of participants with atrial fibrillation (AF) during 1980 and 1994 were retrospectively reviewed to determine the prevalence of warfarin and aspirin use in AF. Anticoagulant use increased significantly in the 393 men and women (mean ages 72.5 and 79.0 years, respectively) who developed AF over the observation period: aspirin use increased from 14% to 39% in men and from 19% to 33% in women, and warfarin use increased from 10% to 39% in men and from 17% to 38% in women. There were no significant gender differences in anticoagulant use (p = 0.61), but participants using warfarin were younger. A total of 65 participants (17%) had major bleeding complications less than or equal to5 years after initial AF. Age was not a significant predictor of bleeding. (C) 2004 by Excerpta Medica, Inc. C1 Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. Emory Univ, Sch Med, Div Gen Med, Atlanta, GA USA. Boston Univ, Sch Med, Dept Cardiol Prevent Med & Neurol, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Beth Israel Deaconess Med Ctr, Div Cardiol & Clin Epidemiol, Boston, MA 02215 USA. Natl Heart Lung & Blood Inst, Bethesda, MD USA. RP Sam, C (reprint author), Emory Univ, Sch Med, 49 Jesse Hill Jr Dr, Atlanta, GA 30303 USA. EM csam@emory.edu OI Massaro, Joseph/0000-0002-2682-4812; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC 25195]; NINDS NIH HHS [5-R01-NS 17950] NR 20 TC 49 Z9 53 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 1 PY 2004 VL 94 IS 7 BP 947 EP + DI 10.1016/j.amjcard.2004.06.038 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 858VO UT WOS:000224220400024 PM 15464686 ER PT J AU Dixon, LB Balder, HF Virtanen, MJ Rashidkhani, B Mannisto, S Krogh, V van Den Brandt, PA Hartman, AM Pietinen, P Tan, F Virtamo, J Wolk, A Goldbohm, RA AF Dixon, LB Balder, HF Virtanen, MJ Rashidkhani, B Mannisto, S Krogh, V van Den Brandt, PA Hartman, AM Pietinen, P Tan, F Virtamo, J Wolk, A Goldbohm, RA TI Dietary patterns associated with colon and rectal cancer: results from the Dietary Patterns and Cancer (DIETSCAN) Project SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE colorectal cancer; dietary pattern; Dietary Patterns and Cancer Project; DIETSCAN; factor analysis; principal components analysis ID SCALE PROSPECTIVE COHORT; COLORECTAL-CANCER; ASSESSMENT INSTRUMENTS; RISK; QUESTIONNAIRE; NETHERLANDS; FRUIT; WOMEN AB Background: An analysis of dietary patterns or combinations of foods may provide insight regarding the influence of diet on the risk of colon and rectal cancer. Objective: A primary aim of the Dietary Patterns and Cancer (DIETSCAN) Project was to develop and apply a common methodologic approach to study dietary patterns and cancer in 4 European cohorts: the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (Finland-ATBC), the Netherlands Cohort Study (NLCS) on Diet and Cancer, the Swedish Mammography Cohort (SMC), and the Ormoni e Dieta nella Eziologia dei Tumori (Italy-ORDET). Three cohorts (ATBC, NLCS, and SMC) provided data on colon and rectal cancer for the present study. Design: The cohorts were established between 1985 and 1992; follow-up data were obtained from national cancer registries. The participants completed validated semiquantitative food-frequency questionnaires at baseline. Results: Exploratory factor analysis, conducted within each cohort, identified 3-5 stable dietary patterns. Two dietary patterns-Vegetables and Pork, Processed Meats, Potatoes (PPP)-were common across all cohorts. After adjustment for potential confounders, PPP was associated with an increased risk of colon cancer in the SMC women (quintile 4(multirelative) risk: 1.62;95%CI: 1.12, 2.34; P for trend = 0.01). PPP was also associated with an increased risk of rectal cancer in the ATBC men (quintile 4(multirelative) risk: 2.21; 95% Cl: 1.07, 4.57; P for trend = 0.05). Neither pattern was associated with the risk of colon or rectal cancer in the NLCS women and men. Conclusion: Although certain dietary patterns may be consistent across European countries, associations between these dietary patterns and the risk of colon and rectal cancer are not conclusive. C1 NYU, Dept Nutr Food Studies & Publ Hlth, New York, NY 10012 USA. TNO, Nutr & Food Res, Dept Nutrit Epidemiol, NL-3700 AJ Zeist, Netherlands. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Karolinska Inst, Inst Environm Epidemiol, Stockholm, Sweden. Ist Nazl Studio & Cura Tumori, Epidemiol Unit, I-20133 Milan, Italy. Univ Limburg, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. Univ Limburg, Dept Methdol & Stat, NL-6200 MD Maastricht, Netherlands. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Dixon, LB (reprint author), NYU, Dept Nutr Food Studies & Publ Hlth, 35 W 4th St,10th Floor, New York, NY 10012 USA. EM beth.dixon@nyu.edu RI Krogh, Vittorio/K-2628-2016 OI Krogh, Vittorio/0000-0003-0122-8624 FU CCR NIH HHS [N01-RC-45035]; NCI NIH HHS [N01-CN-45165] NR 21 TC 54 Z9 54 U1 1 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD OCT PY 2004 VL 80 IS 4 BP 1003 EP 1011 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 856VI UT WOS:000224073000031 PM 15447912 ER PT J AU Brinton, LA Buckley, LM Dvorkina, O Lubin, JH Colton, T Murray, MC Hoover, R AF Brinton, LA Buckley, LM Dvorkina, O Lubin, JH Colton, T Murray, MC Hoover, R TI Risk of connective tissue disorders among breast implant patients SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arthritis, rheumatoid; breast implants; connective tissue diseases; risk; scleroderma, systemic; Sjogren's syndrome ID HUMAN ADJUVANT DISEASE; SYSTEMIC LUPUS-ERYTHEMATOSUS; FEMALE HEALTH-PROFESSIONALS; AUGMENTATION MAMMAPLASTY; RHEUMATOID-ARTHRITIS; RETROSPECTIVE COHORT; AUTOIMMUNE-DISEASE; SILICONE IMPLANTATION; SYMPTOMATIC WOMEN; SJOGRENS-SYNDROME AB In a US retrospective cohort study (1960-1996), 351 (4.8%) of 7,234 patients with breast implants and 62 (2.9%) of 2,138 patients who had undergone other types of plastic surgery reported subsequent rheumatoid arthritis (RA), scleroderma, systemic lupus erythematosus, or Sjogren's syndrome (relative risk = 2.0, 95% confidence interval (CI): 1.5, 2.8). Risks of RA, scleroderma, and Sjogren's syndrome were elevated both before and after 1992, when the Food and Drug Administration changed the status of breast implants to investigational. When records for these diseases were retrieved (35-40% retrieval rate) and blindly reviewed, two expert rheumatologists assessed only a minority of the cases as being "likely" (e.g., regarding RA, 16.5% for implant patients and 23.5% for comparison patients). Recalculation of incidence rates using "likely" diagnoses found relative risks of 2.5 (95% CI: 0.8, 7.8) for RA, scleroderma, and Sjogren's syndrome combined and 1.9 (95% CI: 0.6, 6.2) for RA only. When the proportions deemed "likely" were applied to all self-reports, the estimated relative risks were 2.0 (95% CI: 0.7, 5.4) for the three disorders combined and 1.3 (95% CI: 0.5, 3.8) for RA. These results indicate that self-reports of connective tissue disorders are influenced by reporting and surveillance biases. Given the diagnostic complexities of these diseases, excess risks, if they exist, may be beyond detection even in a study of this size. C1 NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. ABT Associates Inc, Chicago, IL USA. RP Brinton, LA (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 58 TC 19 Z9 20 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2004 VL 160 IS 7 BP 619 EP 627 DI 10.1093/aje/kwh272 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 856ZB UT WOS:000224083700002 PM 15383405 ER PT J AU Schellenbaum, GD Rea, TD Heckbert, SR Smith, NL Lumley, T Roger, VL Kitzman, DW Taylor, HA Levy, D Psaty, BM AF Schellenbaum, GD Rea, TD Heckbert, SR Smith, NL Lumley, T Roger, VL Kitzman, DW Taylor, HA Levy, D Psaty, BM TI Survival associated with two sets of diagnostic criteria for congestive heart failure SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE follow-up studies; heart failure, congestive; prognosis; survival ID CARDIOVASCULAR HEALTH; SYSTOLIC FUNCTION; FRAMINGHAM; COMMUNITY; DYSFUNCTION; EPIDEMIC; MEN; AGE AB Congestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31% fulfilled only the Framingham criteria (Framingham only), and 15% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications. C1 Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. Mayo Clin & Mayo Fdn, Div Cardiovasc Dis & Internal Med, Rochester, MN 55905 USA. Wake Forest Univ, Sch Med, Dept Med, Cardiol Sect, Winston Salem, NC 27109 USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. NHLBI, Framingham, MA USA. Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. RP Schellenbaum, GD (reprint author), 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. EM ginas@u.washington.edu RI Lovasi, Gina/C-2781-2009 OI Lovasi, Gina/0000-0003-2613-9599 FU CCR NIH HHS [RC-HL35129, RC-HL15103]; NHLBI NIH HHS [1-T32-HL07902, HL43201, N01-HC-85079-86]; NIA NIH HHS [AG09556] NR 20 TC 48 Z9 49 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2004 VL 160 IS 7 BP 628 EP 635 DI 10.1093/aje/kwh268 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 856ZB UT WOS:000224083700003 PM 15383406 ER PT J AU Freeman, LEB Dennis, LK Lynch, CF Thorne, PS Just, CL AF Freeman, LEB Dennis, LK Lynch, CF Thorne, PS Just, CL TI Toenail arsenic content and cutaneous melanoma in Iowa SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arsenic; case-control studies; melanoma; skin neoplasms ID MALIGNANT-MELANOMA; SKIN-CANCER; WELL WATER; DRIVERS LICENSE; DRINKING-WATER; SUN EXPOSURE; ENDEMIC AREA; RISK-FACTORS; MORTALITY; NEOPLASMS AB Cutaneous melanoma has the lowest survival rate of all forms of skin cancer. There has been little research investigating the link between arsenic and cutaneous melanoma, although arsenic has been associated with increased risk of nonmelanoma skin cancer. The authors performed a case-control study examining the association between cutaneous melanoma and environmental arsenic exposure among Iowans aged 40 years or older. Participants included 368 cutaneous melanoma cases and 373 colorectal cancer controls diagnosed in 1999 or 2000, frequency matched on gender and age. Participants completed a mailed survey and submitted toenail clippings for analysis of arsenic content by graphite furnace atomic absorption spectrophotometry. The authors found an increased risk of melanoma for participants with elevated toenail arsenic concentrations (odds ratio = 2.1, 95 percent confidence interval: 1.4, 3.3; p-trend = 0.001) and effect modification by prior skin cancer diagnosis (p-interaction = 0.03). The arsenic-melanoma findings in this study are not known to have been previously reported in observational epidemiologic studies involving incident cutaneous melanoma. Therefore, the findings warrant confirmation. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. Univ Iowa, Coll Publ Hlth, Dept Environm & Occupat Hlth, Iowa City, IA USA. Univ Iowa, Dept Civil & Environm Engn, Iowa City, IA 52242 USA. RP Freeman, LEB (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Prevent, 6120 Execut Blvd,EPS 8121,MSC 7240, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov RI Just, Craig/J-4207-2012; Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU NIEHS NIH HHS [P30 ES05605, T32 ES07314] NR 41 TC 40 Z9 41 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2004 VL 160 IS 7 BP 679 EP 687 DI 10.1093/aje/kwh267 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 856ZB UT WOS:000224083700009 PM 15383412 ER PT J AU Laurin, D Masaki, KH White, LR Launer, LJ AF Laurin, D Masaki, KH White, LR Launer, LJ TI Re: "Midlife dietary intake of antioxidants and risk of late-life incident dementia: The Honolulu-Asia Aging Study" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID MEN C1 NIA, Neuroepidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI 96813 USA. RP Laurin, D (reprint author), NIA, Neuroepidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2004 VL 160 IS 7 BP 718 EP 718 DI 10.1093/aje/kwh286 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 856ZB UT WOS:000224083700014 ER PT J AU Jaganmohan, S Duranski, M Dejam, A Gladwin, MT Kevil, CG Langston, W Lefer, DJ AF Jaganmohan, S Duranski, M Dejam, A Gladwin, MT Kevil, CG Langston, W Lefer, DJ TI Cytoprotective effects of nitrite during ischemia-reperfusion of the liver SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 69th Annual Scientific Meeting of the American-College-of-Gastroentrology CY OCT 29-NOV 03, 2004 CL Orlando, FL SP Amer Coll Gastroentrol C1 LSU, Hlth Sci Ctr, Shreveport, LA USA. NIDDK, NIH, Bethesda, MD 20892 USA. RI Kevil, Christopher/G-9318-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2004 VL 99 IS 10 SU S MA 254 BP S83 EP S83 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 862GW UT WOS:000224479700252 ER PT J AU Koff, JM Cash, BD Holtzmuller, KC Bohen, EM Agodoa, LY Abbott, KC AF Koff, JM Cash, BD Holtzmuller, KC Bohen, EM Agodoa, LY Abbott, KC TI Increased risk of colorectal carcinoma in US dialysis patients SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 69th Annual Scientific Meeting of the American-College-of-Gastroentrology CY OCT 29-NOV 03, 2004 CL Orlando, FL SP Amer Coll Gastroentrol C1 Walter Reed Army Med Ctr, Washington, DC 20307 USA. Natl Naval Med Res Inst, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2004 VL 99 IS 10 SU S MA 976 BP S321 EP S321 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 862GW UT WOS:000224479700970 ER PT J AU Ahmad, A Aggarwal, A Sharma, D Dave, HP Kinsella, V Rick, ME Schechter, GP AF Ahmad, A Aggarwal, A Sharma, D Dave, HP Kinsella, V Rick, ME Schechter, GP TI Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP) SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE TTP; rituximab ID VON-WILLEBRAND-FACTOR; FACTOR-CLEAVING PROTEASE; MONOCLONAL-ANTIBODY RITUXIMAB; HEMOLYTIC-UREMIC SYNDROME; IN-VIVO; REMISSION; THERAPY; PATIENT; MUTATIONS AB Plasma exchange is the standard treatment for thrombotic thrombocytopenic purpura (TTP). For patients refractory to plasma exchange, treatment options are limited and often unsuccessful. The platelet thrombi that form in acquired TTP are believed to result from the presence of procoagulant ultralarge multimers of von Willebrand factor (VWF) in the circulation due to autoantibody inhibition of VWF cleaving protease (ADAMTS-13), the enzyme that normally cleaves the ultralarge multimers. Rituximab, a chimeric monoclonal antibody against CD20, has been recognized as a useful therapy for antibody-mediated autoimmune disease. We therefore treated four patients with recurrent TTP with 2 or 4 weekly doses of rituximab in addition to corticosteroids, vincristine, plasma, or continuing plasma exchange. Three patients responded with prompt improvement in microangiopathic hemolytic anemia and thrombocytopenia, which allowed plasma exchange to be discontinued or avoided and prednisone to be rapidly discontinued. Two of the 3 responders have remained in unmaintained complete remission for 13+ months. The third patient relapsed at 13 months; a second course of rituximab and prednisone resulted in an unmaintained remission for 6+ months. All four patients were tested for ADAMTS-13 activity and its inhibitor at a point in their course when samples were available. Low ADAMTS-13 activity was noted in 3 patients tested at relapse, and the inhibitor activity was detectable in 2 patients. ADAMTS-13 activity increased during remission in one of these 2 patients although the patient had a persistence of the inhibitor. One patient tested only during remission had a normal ADAMTS-13 level. We conclude that rituximab may have a role and deserves further study in the treatment of patients with relapsing TTP. (C) 2004 Wiley-Liss, Inc. C1 Washington Hosp Ctr, Inst Canc, Washington, DC 20010 USA. Vet Affairs Med Ctr, Hematol Sect, Washington, DC 20422 USA. George Washington Univ, Med Ctr, Div Hematol Oncol, Washington, DC 20037 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Aggarwal, A (reprint author), Washington Hosp Ctr, Inst Canc, 110 Irving St NW,Suite 2151, Washington, DC 20010 USA. EM anita.aggarwal@medstar.net NR 31 TC 54 Z9 58 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD OCT PY 2004 VL 77 IS 2 BP 171 EP 176 DI 10.1002/ajh.20166 PG 6 WC Hematology SC Hematology GA 857HZ UT WOS:000224108400013 PM 15389904 ER PT J AU Dhingra, R Pencina, MJ Benjamin, EJ Levy, D Larson, MG Meigs, JB Rifai, N D'Agostino, RB Vasan, RS AF Dhingra, R Pencina, MJ Benjamin, EJ Levy, D Larson, MG Meigs, JB Rifai, N D'Agostino, RB Vasan, RS TI Cross-sectional relations of urinary sodium excretion to cardiac structure and hypertrophy - The Framingham Heart Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE sodium; hypertrophy; left ventricle; echocardiography; epidemiology ID LEFT-VENTRICULAR MASS; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; DIETARY-SODIUM; SALT INTAKE; INVOLVEMENT; PREDICTION; DISEASE; RISK AB Background: Increased sodium intake has been positively associated with high blood pressure (BP) and hypertensive target organ damage, but associations with cardiac structure in nonhypertensive individuals have yielded inconsistent results. We tested the hypothesis that sodium intake is associated with left ventricular (LV) mass and left ventricular hypertrophy (LVH), independent of BP, in the community. Methods: We analyzed the cross-sectional relationships between urinary sodium excretion and LV measurements in a community-based sample of 2660 Framingham Offspring Study participants (mean age 58 years, 56% women and 44% men). Participants with known coronary artery disease, congestive heart failure, or renal failure as well as those using diuretics were excluded. Urinary sodium excretion was measured on a spot urine sample and was indexed to urinary creatinine. Results: In sex-specific, multivariable linear regression models adjusting for covariates known to influence LV measurements, log urinary sodium was not associated with LV mass, wall thickness, end-diastolic dimensions, or left atrial size in either sex. Urinary sodium was not related to LVH defined as LV mass sex-specific 80th percentile value. In analyses restricted to hypertensive individuals (n = 983, 470 women), urinary sodium was not associated with LV mass or LVH. Conclusions: In our large community-based sample, urinary sodium excretion was not related to LV mass, function, or hypertrophy. (C) 2004 American Journal of Hypertension, Ltd. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. RP Vasan, RS (reprint author), Boston Univ, Med Ctr, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01HL67288, 2K24HL04334, N01-HC-25195] NR 35 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD OCT PY 2004 VL 17 IS 10 BP 891 EP 896 DI 10.1016/j.amjhyper.2004.06.008 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 862PA UT WOS:000224501900005 PM 15485750 ER PT J AU Ding, JZ Visser, M Kritchevsky, SB Nevitt, M Newman, A Sutton-Tyrrell, K Harris, TB AF Ding, JZ Visser, M Kritchevsky, SB Nevitt, M Newman, A Sutton-Tyrrell, K Harris, TB TI The association of regional fat depots with hypertension in older persons of white and African American ethnicity SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; obesity; epidemiology; aging ID VISCERAL ADIPOSE-TISSUE; BLOOD-PRESSURE; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR RISK; JAPANESE-AMERICANS; INSULIN-RESISTANCE; RENAL-DISEASE; OBESITY; PREVALENCE; WOMEN AB Background: Fat distribution has been shown to be a strong correlate of hypertension, independent of general obesity. However, population-based studies are lacking on the association of regional fat depots with hypertension. Methods: The present study is a cross-sectional analysis of 2969 individuals in the Health, Aging and Body Composition Study (915 men of white ethnicity and 535 of African American; and 833 women of white ethnicity and 686 of African American) who were 70 to 79 years of age. Fat depots were measured by computed tomography. Results: The prevalence of hypertension was 57%. Among those with hypertension, 70% reported antihypertensive treatment. In logistic regression analyses, visceral fat was strongly associated with hypertension (odds ratios for each standard deviation increase in the area of visceral fat: 1.28, P < .0001) after adjustment for age, sex, ethnicity, site, height, smoking status, pack-years of smoking, alcohol consumption status, amount of alcohol consumption, and physical activity. Moreover, the association was the strongest in individuals with the least amount of total body fat. Besides visceral fat, subcutaneous fat and thigh intermuscular fat were also associated with hypertension in African Americans. Conclusions: Larger amounts of visceral fat may indicate a high risk of hypertension in older adults, especially in lean individuals. (C) 2004 American Journal of Hypertension, Ltd. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Vrije Univ Amsterdam, Inst Res Extramural Med, NL-1081 HV Amsterdam, Netherlands. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP Ding, JZ (reprint author), Wake Forest Univ, Baptist Med Ctr, Dept Internal Med Genet, J Paul Sticht Ctr, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jding@wfubmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIA NIH HHS [N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106] NR 25 TC 45 Z9 48 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD OCT PY 2004 VL 17 IS 10 BP 971 EP 976 DI 10.1016/j.amjhyper.2004.05.001 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 862PA UT WOS:000224501900017 PM 15485762 ER PT J AU Turner, JT Cohen, MM Biesecker, LG AF Turner, JT Cohen, MM Biesecker, LG TI Reassessment of the proteus syndrome literature: Application of diagnostic criteria to published cases SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Review DE hemihyperplasia; lipomas; asymmetry; disproportionate overgrowth; hyperostoses; disorganized bone; cerebriform connective tissue nevus ID CONNECTIVE-TISSUE NEVI; OF-THE-MONTH; ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS; HAMARTOMATOUS SYNDROME; SOMATIC MOSAICISM; PTEN MUTATIONS; MUSCULOSKELETAL MANIFESTATIONS; PULMONARY THROMBOEMBOLISM; NEUROCUTANEOUS SYNDROME; DIFFERENTIAL-DIAGNOSIS AB The medical care of patients affected by rare disorders depends heavily on experiences garnered from prior cases, including those patients evaluated by the treating physician and those published in the medical literature. The utility of published cases is wholly dependent upon accurate diagnosis of those patients. In our experience, the rate of misdiagnosis in Proteus syndrome (PS) is high. Diagnostic criteria have been published, but these criteria have not been applied consistently and were published after many case reports appeared in the literature. We reviewed 205 cases of individuals reported to have PS in the literature and three of us independently applied the diagnostic criteria to these case reports. Our initial diagnostic congruence was 97.1% (199/205); the discrepancies in six cases were easily resolved. Only 97 (47.3%) of reported cases met the diagnostic criteria for PS; 80 cases (39%) clearly did not meet the criteria; and although 28 cases (13.7%) had features suggestive of PS, there were insufficient clinical data to make a diagnosis. Reported cases that met the PS criteria had a higher incidence of premature death, and other complications (scoliosis, megaspondyly, central nervous system abnormalities, tumors, otolaryngologic complications, pulmonary cystic malformations, dental and ophthalmogic complications) compared to those in the non-Proteus group. The cases that met the criteria were more often male, which has implications for hypotheses regarding the etiology and pathophysiology of PS. We also studied the attributes that led authors to conclude the reported patients had PS when we concluded they did not. We found that two of the diagnostic criteria (disproportionate overgrowth and connective tissue nevi) were often misinterpreted. In PS, the abnormal growth is asymmetric, distorting, relentless, and occurred at a faster rate compared to the rest of the body. Furthermore, PS was associated with irregular and disorganized bone, including hyperostoses, hyperproliferation of osteoid with variable calcification, calcified connective tissue, and elongation of long bones with abnormal thinning. In contrast, non-Proteus cases displayed overgrowth that was asymmetric but grew at a rate similar to the growth found in unaffected areas of the body. Also, the overgrowth in non-Proteus cases was associated with normal or enlarged bones together with ballooning of the overlying soft tissues. Taken together, these data show that (1) PS diagnostic criteria sort individuals with asymmetric overgrowth into distinct groups; (2) individuals with PS were more likely to have serious complications; (3) PS affects more males than females; and 4) the published diagnostic criteria are useful for clinical care and research. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://ww.interscience.wiley. com/jpages/0148-7299/suppmat/index.html. Published 2004 Wiley-Liss, Inc. C1 NHGRI, GDRB, NIH, Bethesda, MD 20892 USA. Dalhousie Univ, Dept Pediat, Halifax, NS, Canada. RP Biesecker, LG (reprint author), NHGRI, GDRB, NIH, Bldg 49 Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 167 TC 95 Z9 110 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 1 PY 2004 VL 130A IS 2 BP 111 EP 122 DI 10.1002/ajmg.a.30327 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 858HV UT WOS:000224183800001 PM 15372514 ER PT J AU Leung, MYK Al-Muslim, O Wu, SM Aziz, A Inam, S Awadh, M Rennert, OM Chan, WY AF Leung, MYK Al-Muslim, O Wu, SM Aziz, A Inam, S Awadh, M Rennert, OM Chan, WY TI A novel missense homozygous inactivating mutation in the fourth transmembrane helix of the luteinizing hormone receptor in Leydig cell hypoplasia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE luteinizing hormone receptor; Leydig cell hypoplasia; male pseudohermaphroditism; inactivating mutation ID MALE PSEUDOHERMAPHRODITISM; OVARIAN RESISTANCE; GENE; GONADOTROPIN; CHORIOGONADOTROPIN; HYPOGONADISM; PHENOTYPE; BINDS; LH AB Loss-of-function mutations/inactivating mutations of the human chorionic gonadotropin/luteinizing hormone receptor (hCG/LHR), a G-protein coupled receptor, lead to impaired Leydig cell differentiation. Leydig cell hypoplasia/agenesis/ dysplasia (LCH) is one of the causes of male pseudohermaphroditism. (MPH). We studied a 19-year-old MPH patient with female phenotype and 46,XY karyotype. Testicular histology and hormonal profile of the patient is typical of LCH. Nucleotide sequencing of exon 11 of hLHR identified a novel T1505C transversion mutation. The mutation is homozygous in the patient and is heterozygous in both parents. The single base mutation caused the substitution of a conserved leucine at 502 position to proline in transmembrane helix (TM) IV of the hLHR. This is the first LCH causing mutation identified in TM IV of the hLHR. Expression study of the mutated hLHR in human embryonic kidney (HEK)293 cells showed reduced cAMP production and ligand binding. Receptor trafficking was not affected by the mutation when the green fluorescence protein conjugated mutated receptor was expressed in HEK293 cells. The mutation caused inactivation of the hLHR and resulted in LCH in the patient. (C) 2004 Wiley-Liss, Inc. C1 NICHD, Lab Clin Genom, Sect Dev Genom, NIH, Bethesda, MD 20892 USA. Riyadh Armed Forces Hosp, Riyadh, Saudi Arabia. Georgetown Univ, Washington, DC USA. RP Chan, WY (reprint author), NICHD, Lab Clin Genom, Sect Dev Genom, NIH, 49 Convent Dr,MSC 4429, Bethesda, MD 20892 USA. EM chanwy@mail.nih.gov NR 24 TC 10 Z9 12 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 1 PY 2004 VL 130A IS 2 BP 146 EP 153 DI 10.1002/ajmg.a.20681 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 858HV UT WOS:000224183800006 PM 15372531 ER PT J AU Cohen, MM Turner, JT Biesecker, LG AF Cohen, MM Turner, JT Biesecker, LG TI Diagnosis of proteus syndrome was correct - Reply to Kirk et al. SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter C1 Dalhousie Univ, Dept Pediat, Halifax, NS B3H 3J5, Canada. NHGRI, NIH, Bethesda, MD USA. RP Cohen, MM (reprint author), Dalhousie Univ, Dept Pediat, Halifax, NS B3H 3J5, Canada. EM michael.cohen@dal.ca NR 6 TC 5 Z9 6 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 1 PY 2004 VL 130A IS 2 BP 216 EP 217 DI 10.1002/ajmg.a.30328 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 858HV UT WOS:000224183800021 ER PT J AU Promislow, JHE Hertz-Picciotto, I Schramm, M Watt-Morse, M Anderson, JJB AF Promislow, JHE Hertz-Picciotto, I Schramm, M Watt-Morse, M Anderson, JJB TI Bed rest and other determinants of bone loss during pregnancy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE bone loss; pregnancy; bed rest ID RANDOMIZED CONTROLLED TRIAL; CALCIUM HOMEOSTASIS; MINERAL DENSITY; LACTATION; WOMEN; TURNOVER; HYPERTENSION; PAIN; BACK AB Objective: The purpose of this study was to evaluate patterns of bone loss during pregnancy and potential influences. Study design: This was a prospective study of 181 women receiving prenatal care at Magee-Womens Hospital or its auxiliary clinics in Pittsburgh, Pennsylvania, between 1992 and 1995. Bone mineral density was measured at approximately 16 and 36 weeks' gestation. Results: Trabecular, but not cortical, bone loss occurred during pregnancy. Mean ultra-distal bone mineral density loss was 1.9% (95% Cl 1.2-2.5) during the 20-week period. Women prescribed bed rest had an adjusted mean loss of 4.6% compared with 1.5% for women not prescribed bed rest (P = .001) and 6-fold higher odds (P = .001) of bone loss greater than or equal to5% during the 20-week period. Nulliparity, calcium intake < 2000 mg/day, low weight gain, and maternal age < 21 or > 30 years were more modestly associated with greater bone loss. Conclusion: Substantial trabecular bone loss may occur during pregnancy, particularly in women prescribed bed rest. Study of postpartum bone recovery in such women is needed. (C) 2004 Elsevier Inc. All rights reserved. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC USA. Univ Calif Davis, Dept Epidemiol & Prevent Med, Davis, CA 95616 USA. Univ Pittsburgh, Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA USA. RP Promislow, JHE (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Bldg 101,MD A3-05, Res Triangle Pk, NC 27709 USA. EM promisl1@niehs.nih.gov FU NIEHS NIH HHS [1R01 ES 05738, ES 07018] NR 36 TC 20 Z9 20 U1 2 U2 4 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 OCT PY 2004 VL 191 IS 4 BP 1077 EP 1083 DI 10.1016/j.ajog.2004.05.058 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100006 PM 15507924 ER PT J AU Shankaran, S Johnson, Y Langer, JC Vohr, BR Fanaroff, AA Wright, LL Poole, WK AF Shankaran, S Johnson, Y Langer, JC Vohr, BR Fanaroff, AA Wright, LL Poole, WK TI Outcome of extremely-low-birth-weight infants at highest risk: Gestational age <= 24 weeks, birth weight <= 750 g, and 1-minute Apgar <= 3 SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE extremely low birth weight; morbidity and mortality; neurodevelopmental outcome ID NEONATAL RESEARCH NETWORK; EXTREMELY PRETERM BIRTH; DEVELOPMENTAL-DISABILITY; NATIONAL INSTITUTE; CHILD HEALTH; RESOURCE USE; VIABILITY; SURVIVAL; MORBIDITY; ADOLESCENCE AB Objective: The purpose of this study was to evaluate neurodevelopmental outcome in extremely-low-birth-weight (ELBW) infants, all of whom had 3 characteristics: gestational age (GA) less than or equal to24 weeks, birth weight less than or equal to750 g, and 1-minute Apgar score less than or equal to3. Study design: Surviving infants were evaluated at 18 to 22 months' corrected age with a neurologic examination and the Bayley II Mental and Psychomotor Developmental Index (MDI and PDI). Results: Between 1993 and 1999, 1016 infants had GA less than or equal to24 weeks, birth weight less than or equal to750 g, and I-minute Apgar score less than or equal to3. Of 246 survivors, 30% had cerebral palsy (CP), 5% had hearing impairment, and 2% were blind. MDI was greater than or equal to85 in 33% and <70 in 46% of infants, while PDI was greater than or equal to85 in 41% and <70 in 36% infants. Predictors of MDI <70 were grade III-IV ICH, cystic periventricular leukomalacia (PVL), male gender, black race, and Medicaid insurance. Two-parent household was associated with an MDI >70. Predictors of PDI <70 were grade III-IV ICH, PVL, steroids for bronchopulmonary dysplasia (BPD), and Medicaid insurance. CP was associated with grade III-IV ICH and PVL. Conclusion: Perinatologists and neonatologists should be aware of the risk of morbidity and mortality in this high-risk ELBW group. (C) 2004 Elsevier Inc. All rights reserved. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Wayne State Univ, Detroit, MI USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. NICHHD, Bethesda, MD 20892 USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien 4H46, Detroit, MI 48201 USA. EM sshankar@med.wayne.edu FU NCRR NIH HHS [MO1 RR 02172, M01 RR 00070, M01 RR 00750, M01 RR 00997, M01 RR 08084, MO1 RR 01032, MO1 RR 020635, MO1 RR 06022]; NICHD NIH HHS [U10 HD 21364, U10 HD 21385, U10 HD 21397, U10 HD 21415, U10 HD 27851, U10 HD 27853, U10 HD 27856, U10 HD 27871, U10 HD 27880, U10 HD 27881, U10 HD 27904, U10 HD 34167, U10 HD 34216, U10 HD 36790, U10 HD 40689] NR 32 TC 39 Z9 43 U1 2 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 OCT PY 2004 VL 191 IS 4 BP 1084 EP 1091 DI 10.1016/j.ajog.2004.05.032 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100007 PM 15507925 ER PT J AU Dowdy, SC Stefanek, M Hartmann, LC AF Dowdy, SC Stefanek, M Hartmann, LC TI Surgical risk reduction: Prophylactic salpingo-oophorectomy and prophylactic mastectomy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE prophylactic; mastectomy; oophorectomy; breast cancer; ovarian cancer ID BRCA1 MUTATION CARRIERS; BREAST-CANCER RISK; RAPID BONE LOSS; OVARIAN-CANCER; SUBCUTANEOUS MASTECTOMY; POSTMENOPAUSAL WOMEN; PSYCHOLOGICAL IMPACT; PREMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES; REPLACEMENT THERAPY AB Investigators have used retrospective and prospective study designs to provide much needed data on the extent of risk reduction after prophylactic oophorectomy and mastectomy in women at increased risk for breast and ovarian cancer. In this publication we identify those women who may wish to consider prophylactic surgery, review data demonstrating the efficacy of prophylactic surgery, and discuss potential surgical complications. We also present data about the frequency of use and psychosocial impact of prophylactic surgery in this typically young group of women. Finally, we provide general treatment guidelines for the practicing clinician. (C) 2004 Elsevier Inc. All rights reserved. C1 Mayo Clin & Mayo Fdn, Dept Obstet & Gynecol, Div Gynecol Surg, Rochester, MN 55905 USA. NCI, Div Canc Control & Populat Sci, Behav Res Program, Bethesda, MD 20892 USA. Mayo Clin Canc Ctr, Div Med Oncol, Dept Oncol, Rochester, MN USA. RP Dowdy, SC (reprint author), Mayo Clin & Mayo Fdn, Dept Obstet & Gynecol, Div Gynecol Surg, 200 1st St SW, Rochester, MN 55905 USA. EM dowdy.sean@mayo.edu NR 73 TC 26 Z9 26 U1 1 U2 3 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 OCT PY 2004 VL 191 IS 4 BP 1113 EP 1123 DI 10.1016/j.ajog.2004.04.028 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100011 PM 15507929 ER PT J AU Reed, SD Voigt, LF Beresford, SAA Hill, DA Doherty, JA Weiss, NS AF Reed, SD Voigt, LF Beresford, SAA Hill, DA Doherty, JA Weiss, NS TI Dose of progestin in postmenopausal-combined hormone therapy and risk of endometrial cancer SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE endometrial cancer; progestin dose; medroxyprogesterone acetate ID ESTROGEN PLUS PROGESTIN; REPLACEMENT THERAPY; WOMEN; TRIAL; RECALL AB Objective: We studied the impact of progestin dose on this risk. The pattern and number of days per month that progestin is given in postmenopausal combined hormone therapy appears to affect endometrial cancer risk. We assessed the impact of progestin dose on this risk. Study design: A population-based, case-control study included 647 cases with endometrial cancer and 1209 controls. Results: Among users of estrogen with medroxyprogesterone acetate (MPA) 10 to 24 days/month, women who took > 100 mg/month had an endometrial cancer risk that was equal to that of hormone nonusers (95% CI 0.6-1.7). The corresponding relative risk was 0.8 (95% CI 0.5-1.5) in those who used a lower monthly MPA dose for 10 to 24 days/month. Among users of a continuous combined hormone regimen, the risk of endometrial cancer was low relative to hormone nonusers, regardless of MPA dose. Conclusion: Among the combined hormone regimens most commonly used by postmenopausal women today, MPA monthly dose bears little or no relation to endometrial cancer risk. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Washington, Dept Obstet & Gynecol, Dept Epidemiol, Div Publ Hlth Sci,Fred Hutchinson Canc Res Inst, Seattle, WA 98115 USA. NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. RP Reed, SD (reprint author), Univ Washington, Dept Obstet & Gynecol, Dept Epidemiol, Div Publ Hlth Sci,Fred Hutchinson Canc Res Inst, 325 9th Ave,Box 359865, Seattle, WA 98115 USA. EM reeds@u.washington.edu FU NCI NIH HHS [R01 CA 75977, R01 CA 47749, K05 CA 92002]; NICHD NIH HHS [K12 HD 01264] NR 27 TC 14 Z9 14 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 OCT PY 2004 VL 191 IS 4 BP 1146 EP 1151 DI 10.1016/j.ajog.2004.04.041 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100016 PM 15507934 ER PT J AU Luke, B Brown, MB Hediger, ML Nugent, C Misiunas, RB Anderson, E AF Luke, B Brown, MB Hediger, ML Nugent, C Misiunas, RB Anderson, E TI Fetal phenotypes and neonatal and early childhood outcomes in twins SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society of Obstetric Anesthesiology and Perinatology CY MAY, 2002 CL HILTON HEAD ISL, SC SP Soc Obstetr Anesthesiol & Perinatol DE fetal phenotype; intrauterine growth; birth weight; twins ID CORONARY HEART-DISEASE; LATER BLOOD-PRESSURE; GROWTH IN-UTERO; BIRTH-WEIGHT; ADULT LIFE; GLUCOSE-TOLERANCE; CARDIOVASCULAR RISK; INTRAUTERINE GROWTH; PRENATAL EXPOSURE; GESTATIONAL-AGE AB Objectives: The purpose of this study was to evaluate factors associated with, and postnatal consequences of, altered patterns of fetal growth in twins. Study design: Fetal growth was measured at 28 weeks' gestation on 218 twins, including head circumference, abdominal circumference, and femur length, and characterized as > or less than or equal to 10th %ile; children were followed up until the age of three years. Logistic regression was used to generate odds ratios of perinatal factors associated with reduced fetal growth. Results: Maternal height <62 inches was associated with reductions in femur length (adjusted odds ratio [AOR] 3.88, 95% CI 1.42-10.57) and abdominal circumference (AOR 8.63, 95% CI 2.41-30.94), while primiparity had a protective effect on both of these fetal measurements (AOR 0.28, 95% CI 0.13-0.64, and AOR 0.18, 95% CI 0.06-0.60, respectively), as well as head circumference (AOR 0.32, 95% CI 0.15-0.69). Smoking adversely affected femur and head growth (AOR 24.10, 95% CI 3.69-157.57, and AOR 10.82, 95% CI 1.73-67.79, respectively). Fetal reduction adversely affected femur and abdomen growth (AOR 5.85, 95% CI 1.52-22.51 and AOR 4.90, 95% CI 1.01-23.86, respectively), and monochorionicity and maternal weight gain <0.65 1b/wk before 20 weeks adversely affected femur growth (AOR 5.47, 95% CI 1.65-18.10, and AOR 3.39, 95% CI 1.34-8.59, respectively). At age 3 years, all categories of twins with reduced growth by 28 weeks' gestation were significantly shorter in height, and those with reduced abdominal circumference or head circumference at 28 weeks were also significantly lighter in weight compared with twins with adequate fetal growth by 28 weeks' gestation. Conclusion: These data identify short maternal height, smoking, monochorionicity, fetal reduction, and inadequate weight gain before 20 weeks as risk factors associated with reduced twin fetal growth by 28 weeks' gestation and significant residual reductions in height and weight through 3 years of age. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33152 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. RP Luke, B (reprint author), Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33152 USA. NR 44 TC 4 Z9 4 U1 0 U2 2 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 OCT PY 2004 VL 191 IS 4 BP 1270 EP 1276 DI 10.1016/j.ajog.2004.03.006 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100034 PM 15507952 ER PT J AU Tromp, G Kuivaniemi, H Romero, R Chaiworapongsa, T Kim, YM Kim, MR Maymon, E Edwin, S AF Tromp, G Kuivaniemi, H Romero, R Chaiworapongsa, T Kim, YM Kim, MR Maymon, E Edwin, S TI Genome-wide expression profiling of fetal membranes reveals a deficient expression of proteinase inhibitor 3 in premature rupture of membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LA SP Soc Maternal Fetal Med DE prematurity; parturition; genomics; preterm labor; microarray; real-time quantitative RT-PCR; immunohistochemistry; elafin; proteinase inhibitor 3 ID PRETERM PARTURITION; TERM; ELAFIN; LABOR; GENE; ALPHA AB Objective: We used a genome-wide approach to identify differentially expressed genes in patients with preterm, premature rupture of membranes to improve the understanding of underlying molecular mechanisms. Study design: RNA was isolated from the fetal membranes of patients with preterm labor with intact membranes and preterm, premature rupture of membranes and was stratified according to the presence or absence of histologic chorioamnionitis. Microarray experiments were used to identify differentially expressed genes, and real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were used in follow-up experiments. Results: Microarray experiments identified decreased expression of proteinase inhibitor 3 in the preterm premature rupture of membranes cases. Quantitative reverse transcriptase-polymerase chain reaction confirmed these results. Immunohistochemistry demonstrated decreased proteinase inhibitor 3 protein expression in preterm premature rupture of membranes. Conclusion: A genome-wide approach identified deficient expression of proteinase inhibitor 3 in preterm premature rupture of membranes, which demonstrated the usefulness of functional genomics for the dissection of mechanisms of disease and identification of differentially regulated genes that were not suspected previously to play a role in parturition. (C) 2004 Elsevier Inc. All rights reserved. C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Surg, Detroit, MI USA. NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. RP Tromp, G (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RI Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; Kuivaniemi, Helena/0000-0001-5753-8766 NR 20 TC 35 Z9 36 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 OCT PY 2004 VL 191 IS 4 BP 1331 EP 1338 DI 10.1016/j.ajog.2004.07.010 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100044 PM 15507962 ER PT J AU Kim, YM Romero, R Chaiworapongsa, T Kim, GA Kim, MR Kuivaniemi, H Tromp, G Espinoza, J Bujold, E Abrahams, VM Mor, G AF Kim, YM Romero, R Chaiworapongsa, T Kim, GA Kim, MR Kuivaniemi, H Tromp, G Espinoza, J Bujold, E Abrahams, VM Mor, G TI Toll-like receptor-2 and-4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LA SP Soc Maternal Fetal Med DE toll-like receptor; preterm labor; preterm premature rupture of membranes; parturition; chorioamnionitis; NF-kappa B ID EXPRESSION; ACTIVATION; PROTEINS; IMMUNITY; TISSUES; INNATE; CELLS; TLR AB Objective: The Toll-like receptor-2 and -4 recognize microbial products that are associated with gram-positive and gram-negative bacteria, respectively. This study examined Toll-like receptor-2 and -4 expression in fetal membranes in response to labor at term and histologic chorioamnionitis. Study design: Immunohistochemistry and real-time quantitative reverse transcriptase-polymerase chain reaction were used to examine the chorioamnion from patients with (1) preterm labor and intact membranes, (2) preterm premature rupture of membranes who were delivered less than or equal to34 weeks of gestation, and (3) women at term with or without labor. All groups were stratified on the basis of the presence of histologic chorioamnionitis. Results: Toll-like receptor-2 expression was significantly higher in patients with chorioamnionitis than in patients without this condition (all P < .05). The Toll-like receptor-2 and -4 messenger RNA amounts were significantly higher in membranes from women at term with spontaneous labor than women who were not in labor (P = .001 and .002, respectively). Toll-like receptor-2 expression was polarized to the basal surface of amniotic epithelial cells in patients without chorioamnionitis, but this distribution was lost in the presence of inflammation. Conclusion: Spontaneous labor at term and preterm delivery with histologic chorioamnionitis, regardless of the membrane status (intact or ruptured), are associated with an increased expression of Toll-like receptor-2 and -4 in the chorioamniotic membranes. These observations have implications for understanding the biologic nature of innate immunity. (C) 2004 Elsevier Inc. All rights reserved. C1 NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. RP Kim, YM (reprint author), NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RI Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; Kuivaniemi, Helena/0000-0001-5753-8766 NR 15 TC 132 Z9 141 U1 0 U2 5 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 OCT PY 2004 VL 191 IS 4 BP 1346 EP 1355 DI 10.1016/j.ajog.2004.07.009 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100046 PM 15507964 ER PT J AU Bytautiene, E Romero, R Vedernikov, YP El-Zeky, F Saade, GR Garfield, RE AF Bytautiene, E Romero, R Vedernikov, YP El-Zeky, F Saade, GR Garfield, RE TI Induction of premature labor and delivery by allergic reaction and prevention by histamine H-1 receptor antagonist SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LA SP Soc Maternal Fetal Med DE premature labor and delivery; allergy; mast cell; guinea pig; H-1 receptor antagonist; cromolyn sodium ID GUINEA-PIG; MAST-CELLS; MATERNAL ASTHMA; PRETERM LABOR; CONTRACTILITY; RAT; MYOMETRIUM; MEDIATORS; MUSCLE AB Objective: The purpose of this study was to determine whether type I hypersensitivity can induce preterm labor and delivery that may be prevented by the administration of an H-1 receptor antagonist or a mast-cell stabilizer. Study design: At days 40 through 50 of gestation, ovalbumin-sensitized guinea pigs that had not been treated or had been pretreated with an H-1 receptor antagonist (ketotifen) or a mast-cell stabilizer (cromolyn sodium) were challenged with either ovalbumin or saline solution. Nonsensitized guinea pigs were challenged with ovalbumin. Results: The duration of gestation was significantly shorter in sensitized animals that were challenged with ovalbumin than in the other groups. Pretreatment with ketotifen significantly increased the duration of pregnancy in sensitized animals, compared with untreated animals. Cromolyn sodium bad no effect. Conclusion: An allergic reaction can induce premature labor/delivery, and pretreatment with histamine H-1 receptor antagonist can prevent it. These observations provide evidence of a novel mechanism of disease for premature labor and delivery. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Texas, Med Branch, Dept Obstet & Gynecol, Div Reprod Sci, Galveston, TX 77555 USA. NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Garfield, RE (reprint author), Univ Texas, Med Branch, Dept Obstet & Gynecol, Div Reprod Sci, 301 Univ Blvd,Rt J-62, Galveston, TX 77555 USA. EM rgarfiel@utmb.edu NR 25 TC 37 Z9 38 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 OCT PY 2004 VL 191 IS 4 BP 1356 EP 1361 DI 10.1016/j.ajog.2004.06.092 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 866ZO UT WOS:000224812100047 PM 15507965 ER PT J AU Vitale, S AF Vitale, S TI CLEK study reports on the quality of life SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID COLLABORATIVE LONGITUDINAL EVALUATION; VISUAL FUNCTION QUESTIONNAIRE; KERATOCONUS CLEK; REFRACTIVE ERROR; DISEASE; COMFORT; VISION; MYOPIA; LENS C1 NEI, Natl Inst Hlth, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. RP Vitale, S (reprint author), NEI, Natl Inst Hlth, Div Epidemiol & Clin Res, Bldg 31,Room 6A52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM sev@nei.nih.gov NR 15 TC 7 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2004 VL 138 IS 4 BP 637 EP 638 DI 10.1016/j.ajo.2004.06.074 PG 2 WC Ophthalmology SC Ophthalmology GA 864UO UT WOS:000224658600020 PM 15488794 ER PT J AU Griffin, SV Hiromura, K Pippin, J Petermann, AT Blonski, MJ Krofft, R Takahashi, S Kulkarni, AB Shankland, SJ AF Griffin, SV Hiromura, K Pippin, J Petermann, AT Blonski, MJ Krofft, R Takahashi, S Kulkarni, AB Shankland, SJ TI Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HIV-ASSOCIATED NEPHROPATHY; HABU-SNAKE-VENOM; P35/CDK5 KINASE; CELL; EXPRESSION; INHIBITOR; CDK5; GLOMERULONEPHRITIS; P27(KIP1); GLOMERULOSCLEROSIS AB Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in renal physiology, including the prevention of proteinuria. Cyclin-dependent kinase 5 (CDK5) has been shown to influence several cellular processes in other terminally differentiated cells, in particular neurons. in this study, we examined the role of CDK5 in podocyte differentiation, proliferation, and morphology. in conditionally immortalized mouse podocytes in culture, CDK5 increased in association with podocyte differentiation. During mouse glomerulogenesis in vivo, CDK5 expression was predominantly detected in podocytes from the capillary loop stage to maturation and persisted in the podocytes of adult glomeruli. In contrast, CDK5 was markedly decreased in the proliferating and dedifferentiated podocytes of mice with anti-glomerular basement membrane nephritis and in human immunodeficiency virus transgenic mice. p35, the activator of CDK5, was also detected in podocytes and the p35/CDK5 complex was active. Cell fractionation studies showed that active P35/CDK5 was mainly localized to the plasma membrane. Specific inhibition of CDK5 in differentiated cultured podocytes, either pharmacologically or with siRNA, induced shape changes, with cellular elongation and loss of process formation compared to the characteristic arborized phenotype. These data suggest a role for CDK5 as a regulator of podocyte differentiation, proliferation, and morphology. C1 Univ Washington, Sch Med, Div Nephrol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. NIH, Funct Genom Unit, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Shankland, SJ (reprint author), Univ Washington, Sch Med, Div Nephrol, Box 356521, Seattle, WA 98195 USA. EM stuartjs@u.washington.edu FU NIDDK NIH HHS [DK34198, DK47659, DK51096, DK52121, DK56799, R01 DK051096, R01 DK052121, R01 DK056799] NR 35 TC 46 Z9 52 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2004 VL 165 IS 4 BP 1175 EP 1185 DI 10.1016/S0002-9440(10)63378-0 PG 11 WC Pathology SC Pathology GA 857IS UT WOS:000224110400013 PM 15466384 ER PT J AU Jacob, A Smolenski, A Lohmann, SM Begum, N AF Jacob, A Smolenski, A Lohmann, SM Begum, N TI MKP-1 expression and stabilization and cGK I alpha prevent diabetes-associated abnormalities in VSMC migration SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE chemotaxis; proteasome inhibitors; mitogen-activated protein kinases; insulin; cGMP-dependent protein kinase alpha ID ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; SIGNALING PATHWAYS; PHOSPHATASE-1 MKP-1; ALTERED REGULATION; NITRIC-OXIDE; INSULIN; HYPERTENSION; PHOSPHORYLATION; GROWTH AB Diabetes mellitus is a major risk factor in the development of atherosclerosis and cardiovascular disease conditions, involving intimal injury and enhanced vascular smooth muscle cell (VSMC) migration. We report a mechanistic basis for divergences between insulin's inhibitory effects on migration of aortic VSMC from control Wistar Kyoto (WKY) rats versus Goto-Kakizaki (GK) diabetic rats. In normal WKY VSMC, insulin increased MAPK phosphatase-1 (MKP-1) expression as well as MKP-1 phosphorylation, which stabilizes it, and inhibited PDGF-mediated MAPK phosphorylation and cell migration. In contrast, basal migration was elevated in GK diabetic VSMCs, and all of insulin's effects on MKP-1 expression and phosphorylation, MAPK phosphorylation, and PDGF-stimulated migration were markedly inhibited. The critical importance of MKP-1 in insulin inhibition of VSMC migration was evident from several observations. MKP-1 small interfering RNA inhibited MKP-1 expression and abolished insulin inhibition of PDGF-induced VSMC migration. Conversely, adenoviral expression of MKP-1 decreased MAPK phosphorylation and basal migration rate and restored insulin's ability to inhibit PDGF-directed migration in GK diabetic VSMCs. Also, the proteasomal inhibitors lactacystin and MG132 partially restored MKP-1 protein levels in GK diabetic VSMCs and inhibited their migration. Furthermore, GK diabetic aortic VSMCs had reduced cGMP-dependent protein kinase Ialpha (cGK Ialpha) levels as well as insulin-dependent, but not sodium nitroprusside-dependent, stimulation of cGMP. Adenoviral expression of cGK Ialpha enhanced MKP-1 inhibition of MAPK phosphorylation and VSMC migration. We conclude that enhanced VSMC migration in GK diabetic rats is due at least in part to a failure of insulin-stimulated cGMP/cGK Ialpha signaling, MKP-1 expression, and stabilization and thus MAPK inactivation. C1 Winthrop Univ Hosp, Diabet Res Lab, Mineola, NY 11501 USA. SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. Med Univ Klin, Inst Klin Biochem & Pathobiochem, D-97080 Wurzburg, Germany. RP Begum, N (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Smolenski, Albert/0000-0001-9210-9406 NR 34 TC 17 Z9 18 U1 0 U2 1 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 OCT PY 2004 VL 287 IS 4 BP C1077 EP C1086 DI 10.1152/ajpcell.00477.2003 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 852NL UT WOS:000223762000028 PM 15355857 ER PT J AU Smith, CP Potter, EA Fenton, RA Stewart, GS AF Smith, CP Potter, EA Fenton, RA Stewart, GS TI Characterization of a human colonic cDNA encoding a structurally novel urea transporter, hUT-A6 SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE urea; transporter protein; colon; cAMP ID MOLECULAR CHARACTERIZATION; RAT-KIDNEY; VASOPRESSIN; CLONING; LOCALIZATION; PROTEIN; METABOLISM; ISOFORM; SLC14A2; UT-A1 AB Two closely related genes, UT-A (Slc14a2) and UT-B (Slc14a1), encode specialized transporter proteins that modulate the movement of urea across cell membranes. In this article, we report the characterization of a cDNA isolated from human colonic mucosa encoding a novel UT-A urea transporter, hUT-A6. The encoded protein is 235 amino acids (aa) in length, making it the smallest UT-A member characterized. On the basis of previous structural predictions, hUT-A6 is structurally unique in that it consists of a single hydrophobic core flanked by hydrophilic NH2- and COOH-terminal domains. The transcript encoding hUT-A6 contains a novel 129-bp exon, exon 5a, which, as a result of alternative splicing, introduces a unique 19-aa segment and a stop codon. Functionally, the protein transports urea, and this activity is inhibited by phloretin. Interestingly, despite the lack of a protein kinase A (PKA) consensus site {[RK](2)-X-[ST]}, transport of urea by hUT-A6 is stimulated by PKA agonists. Deletion of the two PKA consensus sites from murine UT-A3 (mUT-A3) did not affect the stimulatory response of PKA agonists, which, together with the lack of PKA consensus sites in hUT-A6, indicates that regulation of hUT-A6 and mUT-A3 is not mediated through a classic PKA phosphorylation consensus. C1 Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Smith, CP (reprint author), Univ Manchester, Sch Biol Sci, G-38,Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM cpsmith@man.ac.uk NR 33 TC 44 Z9 44 U1 1 U2 9 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 OCT PY 2004 VL 287 IS 4 BP C1087 EP C1093 DI 10.1152/ajpcell.00363.2003 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 852NL UT WOS:000223762000029 PM 15189812 ER PT J AU Langenickel, TH Pagel, I Buttgereit, J Tenner, K Lindner, M Dietz, R Willenbrock, R Bader, M AF Langenickel, TH Pagel, I Buttgereit, J Tenner, K Lindner, M Dietz, R Willenbrock, R Bader, M TI Rat corin gene: molecular cloning and reduced expression in experimental heart failure SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE gene expression; atrial natiuretic factor ID ATRIAL-NATRIURETIC-FACTOR; SERINE-PROTEASE; DIFFERENTIAL REGULATION; DILATED CARDIOMYOPATHY; CONVERTING ENZYME; CARDIAC MYOCYTES; VOLUME EXPANSION; PEPTIDE; INCREASE; LOCALIZATION AB Stored cardiac pro-atrial natriuretic peptide (pro-ANP) is converted to ANP and released upon stretch from the atria into the circulation. Corin is a serin protease with pro-ANP-converting properties and may be the rate-limiting enzyme in ANP release. This study was aimed to clone and sequence corin in the rat and to analyze corin mRNA expression in heart failure when ANP release upon stretch is blunted. Full-length cDNA of rat corin was obtained from atrial RNA by RT-PCR and sequenced. Tissue distribution as well as regulation of corin mRNA expression in the atria were determined by RT-PCR and RNase protection assay. Heart failure was induced by an infrarenal aortocaval shunt. Stretch was applied to the left atrium in a working heart modus, and ANP was measured in the perfusates. The sequence of rat corin cDNA was found to be 93.6% homologous to mouse corin cDNA. Corin mRNA was expressed almost exclusively in the heart with highest concentrations in both atria. The aortocaval shunt led to cardiac hypertrophy and heart failure. Stretch-induced ANP release was blunted in shunt animals ( control 1,195 +/- 197 fmol . min(-1) . g(-1); shunt: 639 +/- 99 fmol . min(-1) . g(-1), P < 0.05). Corin mRNA expression was decreased in both atria in shunt animals [ right atrium: control 0.638 +/- 0.004 arbitrary units (AU), shunt 0.566 +/- 0.014 AU, P < 0.001; left atrium: control 0.564 +/- 0.009 AU, shunt 0.464 +/- 0.009 AU, P < 0.001]. Downregulation of atrial corin mRNA expression may be a novel mechanism for the blunted ANP release in heart failure. C1 Max Delbrueck Ctr Mol Med, D-13092 Berlin, Germany. Humboldt Univ, Franz Volhard Klin, D-13125 Berlin, Germany. RP Langenickel, TH (reprint author), NHLBI, 50 Ctr Dr,Bldg 50-4529, Bethesda, MD 20892 USA. EM langenit@nhlbi.nih.gov OI Bader, Michael/0000-0003-4780-4164 NR 28 TC 29 Z9 31 U1 0 U2 0 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 OCT PY 2004 VL 287 IS 4 BP H1516 EP H1521 DI 10.1152/ajpheart.00947.2003 PG 6 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 854IH UT WOS:000223895800011 PM 15155264 ER PT J AU Bauer, AK Malkinson, AM Kleeberger, SR AF Bauer, AK Malkinson, AM Kleeberger, SR TI Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Review DE adenocarcinoma; inflammation; loci; quantitative trait locus; pneumotoxicant ID LUNG-TUMOR SUSCEPTIBILITY; QUANTITATIVE TRAIT LOCI; BUTYLATED HYDROXYTOLUENE BHT; ADVANCED INTERCROSS LINES; ADENOMA RESISTANCE LOCUS; EPITHELIAL-CELL LINES; NITRIC-OXIDE SYNTHASE; INBRED MOUSE STRAINS; FEMALE A/J MICE; K-RAS AB Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators ( e. g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL ( quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O-3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O-3-induced inflammation (Inf1, Inf2), O-3-induced acute lung injury (Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided. C1 NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Denver, CO 80262 USA. RP Bauer, AK (reprint author), NIEHS, Lab Resp Biol, NIH, 111 TW Alexander Dr,Bldg 101,Rm E214, Res Triangle Pk, NC 27709 USA. EM bauer1@niehs.nih.gov FU NCI NIH HHS [CA-33497, CA-96133]; NHLBI NIH HHS [HL-66109, HL-57142] NR 258 TC 51 Z9 54 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD OCT PY 2004 VL 287 IS 4 BP L685 EP L703 DI 10.1152/ajplung.00223.2003 PG 19 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 852NM UT WOS:000223762200009 PM 15355860 ER PT J AU McBride, CM Baucom, DH Peterson, BL Pollak, KI Palmer, C Westman, E Lyna, P AF McBride, CM Baucom, DH Peterson, BL Pollak, KI Palmer, C Westman, E Lyna, P TI Prenatal and postpartum smoking abstinence - A partner-assisted approach SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SOCIAL SUPPORT; RELAPSE PREVENTION; CIGARETTE-SMOKING; SELF-HELP; PREGNANCY; CESSATION; WOMEN; TRIAL; INTERVENTIONS; PROGRAM AB Background: A partner's provision of support and smoking status has been consistently associated with women's likelihood of smoking cessation during pregnancy and relapse in postpartum. Design: A three-group randomized controlled intervention trial was conducted in 1996 to 2001, with 583 women and their partners randomized to usual care (UC), woman-only (WO), or partner-assisted (PA) intervention. Follow-ups occurred at 28 weeks of pregnancy, and 2-, 6-, and 12-months postpartum. S etting: Womack Army Medical Center (WAMC) at Fort Bragg in Fayetteville, North Carolina. Intervention: Women in the UC condition received provider advice to quit and a self-help guide. The WO condition received UC components plus a late-pregnancy relapse prevention kit (booklet and gift items) and six counseling calls (three in pregnancy and three postpartum) initiated by a health advisor. Women in the PA condition received the WO intervention, and their partners received telephone counseling and a support guide emphasizing skills to help the woman build and maintain her confidence to quit smoking. Partners who smoked also received cessation aids and related counseling. Main Outcome Measure: Seven-day self-reported abstinence from smoking at each follow-up. Results: Intent-to-treat analyses showed no significant differences by condition in women's reports of abstinence at an), follow-up. In late pregnancy, more partners were abstinent in the PA condition (15%) than in the UC condition (5%), p = 0.02. Conclusions: Partner-assisted smoking-cessation interventions need further refinement. Influencing young couples' support patterns may require more intensive and conjoint intervention. Partners who smoke could benefit from support for their cessation efforts. (C) 2004 American Journal of Preventive Medicine. C1 NHGRI, Social Behav Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Canc Prevent Detect & Control Res Program, Durham, NC 27710 USA. Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. RP McBride, CM (reprint author), NHGRI, Social Behav Res Branch, NIH, Dept Hlth & Human Serv, 50 S Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov RI Sandall, Jane/D-4146-2009 OI Sandall, Jane/0000-0003-2000-743X FU NCI NIH HHS [CA76945] NR 32 TC 64 Z9 64 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2004 VL 27 IS 3 BP 232 EP 238 DI 10.1016/j.amepre.2004.06.005 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 857IM UT WOS:000224109800007 PM 15450636 ER PT J AU Petrakis, IL Limoncelli, D Gueorguieva, R Jatlow, P Boutros, NN Trevisan, L Gelernter, J Krystal, JH AF Petrakis, IL Limoncelli, D Gueorguieva, R Jatlow, P Boutros, NN Trevisan, L Gelernter, J Krystal, JH TI Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RECENTLY DETOXIFIED ALCOHOLICS; HEALTHY-VOLUNTEERS; THOUGHT-DISORDER; KETAMINE; ETHANOL; DISCRIMINATION; ATTENUATION; DEPENDENCE; HISTORY; MK-801 AB Objective: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. Method: Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels. Results: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. Conclusions: These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism. C1 NIAAA, Ctr Translat Neurosci Alcoholism, New Haven, CT USA. VA Connecticut Healthcare Syst, Dept Vet Affairs, Alcohol Res Ctr, New Haven, CT USA. Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, Clin Neurosci Res Unit, New Haven, CT 06519 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Med, Dept Lab Med, New Haven, CT USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Div Biostat, New Haven, CT USA. RP Petrakis, IL (reprint author), W Haven Vet Affairs Med Ctr, 116-A,950 Campbell Ave, West Haven, CT 06516 USA. EM ismene.petrakis@yale.edu OI Gueorguieva, Ralitza/0000-0003-0944-5973 FU NIAAA NIH HHS [P50 AA-12870-01, K02 AA-00261-01, R01 AA-12308-01, 1R01 AA-10121-01] NR 31 TC 80 Z9 82 U1 0 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2004 VL 161 IS 10 BP 1776 EP 1782 DI 10.1176/appi.ajp.161.10.1776 PG 7 WC Psychiatry SC Psychiatry GA 859OY UT WOS:000224279000010 PM 15465973 ER PT J AU Bertolino, A Caforio, G Blasi, G De Candia, M Latorre, V Petruzzella, V Altamura, M Nappi, G Papa, S Callicott, JH Mattay, VS Bellomo, A Scarabino, T Weinberger, DR Nardini, M AF Bertolino, A Caforio, G Blasi, G De Candia, M Latorre, V Petruzzella, V Altamura, M Nappi, G Papa, S Callicott, JH Mattay, VS Bellomo, A Scarabino, T Weinberger, DR Nardini, M TI Interaction of COMT Val(108/158) met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; WORKING-MEMORY TASK; CORTEX DYSFUNCTION; N-ACETYLASPARTATE; PHYSIOLOGICAL DYSFUNCTION; DOPAMINE TRANSPORTER; PARKINSONS-DISEASE; HUMAN BRAIN; PERFORMANCE; ACTIVATION AB Objective: Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val(108/158)Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug. Method: Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks. Results: There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale. Conclusions: These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine. C1 Univ Bari, Dipartimento Sci Neurol & Psychiat, Sect Mental Disorders, Psychiat Neurosci Grp, I-70124 Bari, Italy. Univ Bari, Dept Med Biochem & Med Biol, I-70124 Bari, Italy. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, Giovanni Rotondo, FG, Italy. Univ Foggia, Dept Med Sci, Inst Psychiat & Clin Psychol, Foggia, Italy. RP Bertolino, A (reprint author), Univ Bari, Dipartimento Sci Neurol & Psychiat, Sect Mental Disorders, Psychiat Neurosci Grp, Piazza Giulio Cesare 9, I-70124 Bari, Italy. EM bertolia@psichiat.uniba.it RI Picchioni, Marco/E-3300-2010; Bertolino, Alessandro/O-6352-2016; OI Picchioni, Marco/0000-0001-6681-147X; Bertolino, Alessandro/0000-0002-1251-1380; Papa, Sergio/0000-0002-4417-1763 NR 53 TC 214 Z9 221 U1 1 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2004 VL 161 IS 10 BP 1798 EP 1805 DI 10.1176/appi.ajp.161.10.1798 PG 8 WC Psychiatry SC Psychiatry GA 859OY UT WOS:000224279000013 PM 15465976 ER PT J AU Law, AJ Weickert, CS Hyde, TM Kleinman, JE Harrison, PJ AF Law, AJ Weickert, CS Hyde, TM Kleinman, JE Harrison, PJ TI Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: Molecular evidence for a pathology of dendritic spines SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT Conference of Information Geometry and Its Applications CY JUL, 2002 CL PESCARA, ITALY ID MEDIAL TEMPORAL-LOBE; CORTICAL PYRAMIDAL NEURONS; MESSENGER-RNA; GLUTAMATE RECEPTORS; SYNAPTIC PATHOLOGY; GENE-EXPRESSION; RAT-BRAIN; SYNAPTOPHYSIN; DENSITY; CORTEX AB Objective: Aberrant synaptic connectivity may underlie the involvement of the hippocampus in schizophrenia. There is reasonable neuropathological evidence for a presynaptic pathology but few studies of the postsynaptic component. This study tested the hypothesis that hippocampal dendritic pathology is also present in schizophrenia. Method: Using in situ hybridization in sections of hippocampal formation from 10 patients with schizophrenia, 10 patients with mood disorders (three with bipolar disorder and seven with major depression), and 10 healthy comparison subjects, the authors examined the expression of two important dendritic genes: spinophilin, which serves as a marker of dendritic spines, and microtubule-associated protein 2 (MAP2), an overall dendritic marker. Results: The patients with schizophrenia had lower levels of spinophilin mRNA in CA4 (hilus), CA3, the subiculum, and the entorhinal cortex than did the normal comparison subjects. The mood disorder group showed similar differences from the comparison group, MAP2 and cyclophilin mRNA did not differ between the groups in any subfield. Conclusions: Decreased spinophilin but unchanged MAP2 expression provides molecular evidence for a hippocampal dendritic pathology in schizophrenia that preferentially affects the spines. As spines are the target of most glutamatergic synapses, the data extend the evidence that excitatory synapses are particularly affected. Similar dendritic spine pathology may also occur in mood disorders. C1 Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. Warneford Hosp, Oxford OX3 7JX, England. NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Law, AJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, England. EM amanda.law@psych.ox.ac.uk RI Shannon Weickert, Cynthia/G-3171-2011; Law, Amanda/G-6372-2012 NR 64 TC 87 Z9 91 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2004 VL 161 IS 10 BP 1848 EP 1855 DI 10.1176/appi.ajp.161.10.1848 PG 8 WC Psychiatry SC Psychiatry GA 859OY UT WOS:000224279000019 PM 15465982 ER PT J AU Bonham, VL Sellers, SL Neighbors, HW AF Bonham, VL Sellers, SL Neighbors, HW TI John Henryism - The same old song? Bonham et al. responds SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter ID BLOOD-PRESSURE; BLACK ADULTS; HEALTH; STRESS C1 NHGRI, Bethesda, MD 20892 USA. Univ Wisconsin, Madison, WI USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Bonham, VL (reprint author), NHGRI, Bldg 31,Room 4B25,31 Ctr Dr, Bethesda, MD 20892 USA. EM bonhamv@mail.ih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2004 VL 94 IS 10 BP 1659 EP 1659 DI 10.2105/AJPH.94.10.1659 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860AQ UT WOS:000224309900003 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Depression-era malaria control in the south SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. EM elizabeth_fee@nlm.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2004 VL 94 IS 10 BP 1694 EP 1694 DI 10.2105/AJPH.94.10.1694 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860AQ UT WOS:000224309900014 PM 15451734 ER PT J AU Fitzpatrick, AL Powe, NR Cooper, LS Ives, DG Robbins, JA AF Fitzpatrick, AL Powe, NR Cooper, LS Ives, DG Robbins, JA TI Barriers to health care access among the elderly and who perceives them SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID MEDICARE BENEFICIARIES; RACIAL-DIFFERENCES; INSURANCE; SERVICES; SATISFACTION; ASSOCIATION; RACE; DISPARITIES; ENROLLEES; COVERAGE AB Objectives. We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries. Methods. We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study. Results. The questionnaires were completed by 4889 (91.1%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor's lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors. Conclusions. Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race. C1 Univ Washington, CHS Coordinating Ctr, Seattle, WA 98115 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98115 USA. Johns Hopkins Univ, Dept Epidemiol, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. NHLBI, Prevent Studio Res Grp, Natl Inst Hlth, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. RP Fitzpatrick, AL (reprint author), Univ Washington, CHS Coordinating Ctr, Bldg 29,Suite 310,6200 NE 74th St, Seattle, WA 98115 USA. FU NHLBI NIH HHS [N01-HC-85086, N01-HC-85079, N01 HC035129, N01 HC015103, N01HC85086, N01HC85079] NR 32 TC 53 Z9 56 U1 0 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2004 VL 94 IS 10 BP 1788 EP 1794 DI 10.2105/AJPH.94.10.1788 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860AQ UT WOS:000224309900031 PM 15451751 ER PT J AU Guggino, WB Banks-Schlegel, SP AF Guggino, WB Banks-Schlegel, SP TI Macromolecular interactions and ion transport in cystic fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cystic fibrosis; CFTR; CFTR-macromolecular protein interactions; CFTR processing and degradation ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PROTEIN-KINASE-A; PLASMA-MEMBRANE; EPITHELIAL-CELLS; CFTR; DOMAIN; GENE; MODULATION; EXPRESSION; DIAGNOSIS AB Cystic fibrosis (CF) is a genetic disease caused by autosomal recessive mutations of the CIF transmembrane regulator, CFTR. CFTR functions in the plasma membrane of epithelial cells lining the lung, pancreas, liver, intestines, sweat duct, and the epididymis. The primary problem in CF is that mutations in CFTR affect its ability to be made, processed, and trafficked to the plasma membrane and/or its function as a Cl- channel and conductance regulator. Many proteins and processes normally interact with normal CFTR throughout its life cycle and mutant CFTR during the disease process. Understanding the function of these proteins and processes is expected to provide a clearer understanding of how normal CFTR is involved in salt movement and how mutant CFTR is handled by the cell and leads to the pathophysiology of CF. Recently, efforts to find therapies that correct defective CFTR have been intensifying. To facilitate our understanding of normal and mutant CFTR and the identification of new drug targets for developing novel therapies, a panel of experts was convened by the National Heart, Lung, and Blood Institute to explore the critical questions, challenges, and current opportunities to highlight new areas of research that would facilitate a integrated understanding of the processes and proteins that impact CFTR. The meeting highlighted the multiple pathways and interacting proteins involved in CFTR folding and biosynthesis, processing, and trafficking. A number of critical areas for future study were identified. Although these therapies are promising, a big question remains as to whether simply correcting defective CFTR will lead to significant improvement in patient health or whether the symptoms manifested in CF will require therapies in addition to those that target defective CFTR specifically. C1 NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Physiol & Pediat, Baltimore, MD USA. RP Banks-Schlegel, SP (reprint author), NHLBI, Div Lung Dis, 2 Rockledge Ctr,Room 10018,6701 Rockledge Dr,MSC, Bethesda, MD 20892 USA. EM Schleges@nih.gov NR 46 TC 28 Z9 29 U1 0 U2 3 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 OCT 1 PY 2004 VL 170 IS 7 BP 815 EP 820 DI 10.1164/rccm.200403-381WS PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 857JF UT WOS:000224111800019 PM 15447951 ER PT J AU Haley, M Cui, XH Minneci, PC Deans, KJ Natanson, C Eichacker, PQ AF Haley, M Cui, XH Minneci, PC Deans, KJ Natanson, C Eichacker, PQ TI Recombinant human activated protein C in sepsis: Assessing its clinical use SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE sepsis; activated; protein C; therapy; cost-effectiveness; mortality ID RANDOMIZED CONTROLLED-TRIAL; SEPTIC SHOCK; POSTMARKETING SURVEILLANCE; COST-EFFECTIVENESS; HYDROCORTISONE; EFFICACY; SAFETY; MORTALITY AB Based on the results of the phase III PROWESS trial, recombinant human activated protein C (rhAPC) was approved by the Food and Drug Administration (FDA) for use in severely septic patients. Concerns regarding rhAPC's inconsistent effects, incomplete understanding of its mechanism of action, and its safety in particular subgroups were raised during the FDA's evaluation. This study attempts to assess the cost-effectiveness rhAPC by comparing its effects during recent clinical use to its prior phase III trial testing and by considering other potentially less expensive treatments with effects that may overlap those of rhAPC. In patients with similar numbers of injured organs, mortality rates may be higher with rhAPC during clinical use compared with the phase III trial. There may also be an increased risk of hemorrhage and other adverse events that necessitate early discontinuation of treatment. Many of the patients receiving rhAPC during clinical use may have otherwise been excluded from its phase III trial testing. Data from several recent phase III trials as well as a recent meta-analysis suggest that heparin and physiologic dose steroids offer substantially less expensive alternatives to rhAPC. Further phase IV testing will be required to confirm such possibilities. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Haley, M (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bldg 10,Room 7D43,9000 Rockville Pike, Bethesda, MD 20892 USA. EM michael.haley@nih.hhs.gov NR 23 TC 14 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD OCT PY 2004 VL 328 IS 4 BP 215 EP 219 DI 10.1097/00000441-200410000-00004 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 862SJ UT WOS:000224510900004 PM 15486536 ER PT J AU Xu, X Keefer, LK Waterhouse, DJ Saavedra, JE Veenstra, TD Ziegler, RG AF Xu, X Keefer, LK Waterhouse, DJ Saavedra, JE Veenstra, TD Ziegler, RG TI Measuring seven endogenous ketolic estrogens simultaneously in human urine by high-performance liquid chromatography-mass spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID BREAST-CANCER RISK; CATECHOL ESTROGENS; RADIOIMMUNOASSAY; 2-HYDROXYESTRONE; STEROIDS; 16-ALPHA-HYDROXYESTRONE; IDENTIFICATION; QUANTITATION; METABOLITES; MECHANISMS AB A rapid, sensitive, and specific high-performance liquid chromatography-electrospray ionization-multistage mass spectrometry (MS) method for measuring endogenous ketolic estrogen metabolites in human urine has been developed. The method requires a single hydrolysis/extraction/derivatization step and only 2.5 mL of urine, yet is able to simultaneously quantify estrone and its 2-methoxy and 2-, 4-, and 16alpha-hydroxy derivatives, 16-ketoestradiol, and 2-hydroxyestrone-3-methyl ether metabolites. The combination of a simple hydrazone derivatization step with multistage MS greatly enhances the sensitivity and specificity of the analysis of endogenous estrogen within human urine. Standard curves are linear over a 100-fold concentration range with linear regression correlation coefficients typically greater than 0.99. The lower limit of quantitation for each ketolic estrogen is 0.2 ng/2.5-mL urine sample (10 pg on column), with an accuracy of 93-103% and an overall precision, including the hydrolysis, extraction, and derivatization steps, of 1-13% relative standard derivation (RSD) for samples prepared concurrently and 8-16% RSD for samples prepared in separate batches. This method also allows for the identification of 2-hydroxyestrone-3-methyl ether in urine obtained from both pre- and postmenopausal women. This potentially protective estrogen metabolite has been previously reported only in the urine of pregnant women. Since individual patterns of estrogen metabolism may influence the risk of breast cancer, accurate and specific measurement of estrogen metabolites in biological matrixes will facilitate future research on breast cancer prevention, screening, and treatment. C1 NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Frederick Inc, SAIC, Lab Proteom & Anal Tech, Ft Detrick, MD 21702 USA. NCI, SAIC Frederick Inc, Comparat Carcinogenesis Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. NCI, SAIC, Basic Res Program, Frederick Inc, Ft Detrick, MD 21702 USA. RP Ziegler, RG (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM zieglerr@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01 CO 12400] NR 27 TC 30 Z9 30 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD OCT 1 PY 2004 VL 76 IS 19 BP 5829 EP 5836 DI 10.1021/ac049405i PG 8 WC Chemistry, Analytical SC Chemistry GA 858UL UT WOS:000224217400046 PM 15456304 ER PT J AU Hampton, RR Zivin, A Murray, EA AF Hampton, RR Zivin, A Murray, EA TI Rhesus monkeys (Macaca mulatta) discriminate between knowing and not knowing and collect information as needed before acting SO ANIMAL COGNITION LA English DT Article DE metacognition; metamemory; declarative; introspection; memory; awareness ID BRAIN SYSTEMS; METACOGNITION; MEMORY; RECOGNITION; AWARENESS; CONFLICT; ANIMALS; INTACT; HUMANS AB Humans use memory awareness to determine whether relevant knowledge is available before acting, as when we determine whether we know a phone number before dialing. Such metacognition, or thinking about thinking, can improve selection of appropriate behavior. We investigated whether rhesus monkeys (Macaca mulatta) are capable of a simple form of metacognitive access to the contents of short-term memory. Monkeys chose among four opaque tubes, one of which concealed food. The tube containing the reward varied randomly from trial to trial. On half the trials the monkeys observed the experimenter baiting the tube, whereas on the remaining trials their view of the baiting was blocked. On each trial, monkeys were allowed a single chance to select the tube containing the reward. During the choice period the monkeys had the opportunity to look down the length of each tube, to determine if it contained food. When they knew the location of the reward, most monkeys chose without looking. In contrast, when ignorant, monkeys often made the effort required to look, thereby learning the location of the reward before choosing. Looking improved accuracy on trials on which monkeys had not observed the baiting. The difference in looking behavior between trials on which the monkeys knew, and trials on which they were ignorant, suggests that rhesus monkeys discriminate between knowing and not knowing. This result extends similar observations made of children and apes to a species of Old World monkey, suggesting that the underlying cognitive capacities may be widely distributed among primates. C1 NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Hampton, RR (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. EM robert@ln.nimh.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 NR 29 TC 73 Z9 75 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1435-9448 J9 ANIM COGN JI Anim. Cogn. PD OCT PY 2004 VL 7 IS 4 BP 239 EP 246 DI 10.1007/s10071-004-0215-1 PG 8 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA 868GE UT WOS:000224901300006 PM 15105996 ER PT J AU Latour, LL Kang, DW Ezzeddine, MA Chalela, JA Warach, S AF Latour, LL Kang, DW Ezzeddine, MA Chalela, JA Warach, S TI Early blood-brain barrier disruption in human focal brain ischemia SO ANNALS OF NEUROLOGY LA English DT Article ID CEREBRAL-ARTERY OCCLUSION; TISSUE-PLASMINOGEN ACTIVATOR; HEMORRHAGIC TRANSFORMATION; REPERFUSION INJURY; MATRIX METALLOPROTEINASES; ACUTE STROKE; CONTRAST ENHANCEMENT; THROMBOLYTIC THERAPY; RAT-BRAIN; INFARCTION AB Loss of integrity of the blood-brain barrier (BBB) resulting from ischemia/reperfusion is believed to be a precursor to hemorrhagic transformation (HT) and poor outcome. We used a novel magnetic resonance imaging marker to characterize early BBB disruption in human focal brain ischemia and tested for associations with reperfusion, HT, and poor outcome (modified Rankin score >2). BBB disruption was found in 47 of 144 (33%) patients, having a median time from stroke onset to observation of 10.1 hours. Reperfusion was found to be the most powerful independent predictor of early BBB disruption (p = 0.018; odds ratio, 4.09; 95% confidence interval, 1.28-13.1). HT was observed in 22 patients; 16 (72.7%) of those also had early BBB disruption (p < 0.001; odds ratio, 8.11; 95% confidence interval, 2.85-23.1). In addition to baseline severity (National Institutes of Health Stroke Scale score >6), early BBB disruption was found to be an independent predictor of HT. Because the timing of the disruption was early enough to make it relevant to acute thrombolytic therapy, early BBB disruption as defined by this imaging biomarker may be a promising target for adjunctive therapy to reduce the complications associated with thrombolytic therapy, broaden the therapeutic window, and improve clinical outcome. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20878 USA. RP Latour, LL (reprint author), NINDS, Stroke Branch, NIH, Bldg 10 Room B1D433, Bethesda, MD 20878 USA. EM lawrence_latour@nih.gov NR 50 TC 229 Z9 237 U1 3 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2004 VL 56 IS 4 BP 468 EP 477 DI 10.1002/ana.20199 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 859RG UT WOS:000224285000003 PM 15389899 ER PT J AU Ross, GW Petrovitch, H Abbott, RD Nelson, J Markesbery, W Davis, D Hardman, J Launer, L Masaki, K Tanner, CM White, LR AF Ross, GW Petrovitch, H Abbott, RD Nelson, J Markesbery, W Davis, D Hardman, J Launer, L Masaki, K Tanner, CM White, LR TI Parkinsonian signs and substantia nigra neuron density in decendents elders without PD SO ANNALS OF NEUROLOGY LA English DT Article ID CORONARY HEART-DISEASE; AGE-RELATED DECLINE; EXTRAPYRAMIDAL SIGNS; DOPAMINE TRANSPORTERS; ALZHEIMERS-DISEASE; DISECTOR COUNTS; RHESUS-MONKEYS; HUMAN BRAIN; MEN; PREVALENCE AB Substantia nigra (SN) neurons were counted on single, transverse caudal midbrain sections from 217 male participants in the Honolulu-Asia Aging Study, aged 74-97 years at death. Quadrants areas within the SN were determined with a planimeter and neuronal density was expressed as neurons/mm(2) for 10 Parkinson's disease (PD) cases, 29 incidental Lewy body cases, and 178 controls with neither condition. Mean densities in all quadrants were significantly lower in the PD group compared with the other groups (p = 0.006). This relationship was strongest in the ventrolateral quadrant. In a subgroup of 50 controls who were examined with the Unified Parkinson's Disease Rating Scale an average of 2.1 years prior to death, there was an association of stooped posture (p = 0.009), postural instability (p = 0.013), body bradykinesia (p = 0.048), and gait disturbance (p = 0.05) with neuron density in the dorsolateral quadrant; and impaired speech (p = 0.014), abnormal facial expression (p = 0.022), and difficulty rising from a chair (p = 0.032) with neuron density in the dorsomedial quadrant. There was a significant association of increasing number of signs present with decreasing neuron density in both quadrants (p = 0.001 for trend). Low SN neuron density may be the basis for parkinsonian signs in the elderly without PD. C1 Univ Hawaii, John A Burns Sch Med, Honolulu Dept Vet Affairs, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Pacific Hlth Res Inst, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Honolulu Asia Aging Study, Kuakini Med Ctr,Dept Med, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Honolulu Asia Aging Study, Kuakini Med Ctr,Dept Geriatr, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Honolulu Asia Aging Study, Kuakini Med Ctr,Dept Pathol, Honolulu, HI 96822 USA. Univ Virginia, Sch Med, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. Univ Kentucky, Ctr Med, Sanders Brown Ctr Aging, Lexington, KY USA. Univ Kentucky, Ctr Med, Dept Pathol, Lexington, KY USA. Univ Kentucky, Ctr Med, Dept Neurol, Lexington, KY USA. NIA, Div Epidemiol Demog & Biostat, NIH, Bethesda, MD 20892 USA. Parkinsons Inst, Sunnyvale, CA USA. RP Ross, GW (reprint author), 846 S Hotel St,Suite 307, Honolulu, HI 96813 USA. FU NIA NIH HHS [1 U01 AG19349-01, 5 R01 AG017155-04]; NINDS NIH HHS [5 R01 NS041265-04] NR 36 TC 86 Z9 88 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2004 VL 56 IS 4 BP 532 EP 539 DI 10.1002/ana.20026 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 859RG UT WOS:000224285000010 PM 15389895 ER PT J AU Sohn, YH Hallett, M AF Sohn, YH Hallett, M TI Disturbed surround inhibition in focal hand dystonia SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; MOTOR CORTEX; CORTICAL INHIBITION; SILENT PERIOD; WRITERS CRAMP; LESIONS AB Disturbances in surround inhibition could account for various movement disorders. Here we test the functional operation of surround inhibition in focal hand dystonia. Transcranial magnetic stimulation was set to be triggered by self-initiated voluntary flexion of the index finger. During this movement, motor-evoked potential amplitudes from the little finger muscle were significantly suppressed in healthy subjects but enhanced in dystonia patients. This result supports the idea that disturbed surround inhibition is a principal pathophysiological. mechanism of dystonia. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Dept Neurol, Coll Med, Seoul 120749, South Korea. Yonsei Univ, Brain Res Inst, Korea Project Med Sci 21, Coll Med, Seoul 120749, South Korea. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM hallettm@nind.nih.gov NR 18 TC 107 Z9 107 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2004 VL 56 IS 4 BP 595 EP 599 DI 10.1002/ana.20270 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 859RG UT WOS:000224285000023 PM 15455393 ER PT J AU Hirsch, GA Johnston, PV Conte, JV Achuff, SC AF Hirsch, GA Johnston, PV Conte, JV Achuff, SC TI Mycotic aortocoronary saphenous vein graft aneurysm presenting with unstable angina pectoris SO ANNALS OF THORACIC SURGERY LA English DT Article ID BYPASS GRAFT AB We report the case of a 60-year-old man with a history of coronary bypass surgery 20 years prior who had a fever, chest pain, and a mediastinal mass develop after a complicated postoperative course of abdominal aortic aneurysm resection. A mycotic aneurysm of the saphenous vein graft to his left anterior descending coronary artery was diagnosed based on blood culture results and visualization of the aneurysm before resection. A summary of the saphenous vein graft aneurysm and pseudoaneurysm cause, diagnosis, and management is detailed. (C) 2004 by The Society of Thoracic Surgeons. C1 Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD USA. Johns Hopkins Univ Hosp, Dept Cardiac Surg, Baltimore, MD USA. RP Hirsch, GA (reprint author), NHLBI NIH, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D-416, Bethesda, MD 20892 USA. EM ghirsch@jhmi.edu NR 6 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD OCT PY 2004 VL 78 IS 4 BP 1456 EP 1458 DI 10.1016/S0003-4975(03)01516-9 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 858VZ UT WOS:000224221600056 PM 15464518 ER PT J AU Petraitis, V Petraitiene, R Kelaher, AM Sarafandi, AA Sein, T Mickiene, D Bacher, J Groll, AH Walsh, TJ AF Petraitis, V Petraitiene, R Kelaher, AM Sarafandi, AA Sein, T Mickiene, D Bacher, J Groll, AH Walsh, TJ TI Efficacy of PLD-118, a novel inhibitor of Candida isoleucyl-tRNA synthetase, against experimental oropharyngeal and Esophageal candidiasis caused by fluconazole-resistant C albicans SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; STEROL 14-DEMETHYLASE P450; VIRUS-INFECTED PATIENTS; ACID BAY 10-8888; ANTIFUNGAL ACTIVITY; CROSS-RESISTANCE; DOUBLE-BLIND; IN-VITRO; THERAPY; STRAINS AB PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring beta-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant Candida albicans in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 mug/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P less than or equal to 0.05, P less than or equal to 0.01, P less than or equal to 0.001, respectively), while FLC had no significant activity. PLD-118 demonstrated nonlinear plasma pharmacokinetics across the investigated dosage range, as was evident from a dose-dependent increase in plasma clearance and a dose-dependent decrease in the area under the plasma concentration-time curve. The biochemical safety profile was similar to that of FLC. In summary, PLD-118 demonstrated dosage-dependent antifungal activity and nonlinear plasma pharmacokinetics in treatment of experimental FLC-resistant oropharyngeal and esophageal candidiasis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick, MD USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Univ Munster, Childrens Hosp, Dept Pediat Hematol Oncol, D-4400 Munster, Germany. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 33 TC 19 Z9 23 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2004 VL 48 IS 10 BP 3959 EP 3967 DI 10.1128/AAC.48.10.3959-3967.2004 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 858UH UT WOS:000224217000045 PM 15388459 ER PT J AU Locarnini, S Hatzakis, A Heathcote, J Keeffe, EB Liang, TJ Mutimer, D Pawlotsky, JM Zoulim, F AF Locarnini, S Hatzakis, A Heathcote, J Keeffe, EB Liang, TJ Mutimer, D Pawlotsky, JM Zoulim, F TI Management of antiviral resistance in patients with chronic hepatitis B SO ANTIVIRAL THERAPY LA English DT Review ID LONG-TERM LAMIVUDINE; ADEFOVIR DIPIVOXIL ADV; VIRUS-INFECTION; E-ANTIGEN; LIVER-TRANSPLANTATION; DRUG-RESISTANCE; IN-VITRO; POLYMERASE GENE; SURFACE-ANTIGEN; YMDD MUTATIONS AB A meeting of physicians and scientists involved in the management of chronic hepatitis B (CHB) was held to review current scientific data regarding antiviral resistance in hepatitis B virus (HBV) infection. The goals of the meeting were to describe current treatments for CHB, discuss emerging issues in HBV drug resistance and to delineate patient monitoring, including markers for resistance, during administration of antiviral therapy. The aim of this review article is to provide treating physicians with a framework for the management of CHB in the context of antiviral resistance. Definitions of primary and secondary antiviral treatment failure can be used to aid monitoring and early diagnosis of drug resistance before disease progression occurs as a consequence of viral breakthrough. Primary antiviral treatment failure is defined as failure of a drug to reduce HBV DNA levels by >= 1x(10)g, IU/ml within 3 months following initiation of therapy, and secondary antiviral treatment failure as a rebound of HBV replication of >= 1x(10) IU/ml from nadir in patients with an initial antiviral treatment effect (>= 1xlog(10) IU/ml decrease in serum HBV DNA). Confirmation of antiviral drug failure can be established by sequencing the HBV DNA polymerase and identifying specific genetic markers of antiviral drug resistance. In addition to virological assays, HBV resistance can be assessed from a clinical perspective including increased serum alanine aminotransferase levels and the development of systemic symptoms or signs of liver failure. Potential strategies to prevent the emergence of resistance and how to manage drug-resistant HBV once it emerges are discussed. C1 Victorian Infect Dis Ref Lab, Melbourne, Vic, Australia. Univ Athens, Sch Med, Dept Hyg & Epidemiol, Natl Retrovirus Ref Ctr, GR-11527 Athens, Greece. Univ Hlth Network, Toronto Western Hosp, Dept Med, Toronto, ON, Canada. Stanford Univ, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Queen Elizabeth Hosp, Liver & Hepatobiliary Unit, Birmingham B15 2TH, W Midlands, England. Univ Birmingham, Birmingham B15 2TH, W Midlands, England. Univ Paris 12, Hop Henri Mondor, INSERM, Dept Virol,U635, F-94010 Creteil, France. Hop Hotel Dieu, INSERM, Unit 271, F-69288 Lyon, France. Hop Hotel Dieu, Liver Dept, F-69288 Lyon, France. RP Locarnini, S (reprint author), Victorian Infect Dis Ref Lab, Melbourne, Vic, Australia. EM stephenlocarnini@compuserve.com NR 90 TC 176 Z9 194 U1 3 U2 8 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD OCT PY 2004 VL 9 IS 5 BP 679 EP 693 PG 15 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TJ UT WOS:000231615800006 PM 15535405 ER PT J AU Stewart, PE Hoff, J Fischer, E Krum, JG Rosa, PA AF Stewart, PE Hoff, J Fischer, E Krum, JG Rosa, PA TI Genome-wide transposon mutagenesis of Borrelia burgdorferi for identification of phenotypic mutants SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; CIRCULAR PLASMID; CELL-DIVISION; MARINER; SUFFICIENT; SEQUENCE; GENETICS; BACTERIA; HIMAR1 AB The spirochete Borrelia burgdorferi is the causative agent of Lyme disease, the leading vector-borne illness in the United States. Many of the genetic factors affecting spirochete morphology and physiology are unknown due to the limited genetic tools available and the large number of open reading frames with unknown functions. By adapting a mariner transposon to function in B. burgdorferi, we have developed a random mutagenesis system that tags the mutated locus for rapid identification. Transposition occurs at saturating levels in B. burgdorferi and appears to be random, targeting both linear and circular replicons. By combining the transposon system with a screen for factors affecting growth rate, mutations were readily identified in genes putatively involved in cell division and chemotaxis and a hypothetical open reading frame involved in outer membrane integrity. The successful adaptation of a mariner transposon to function in B. burgdorferi should aid in identifying virulence factors and novel gene products related to spirochete physiology. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Stewart, PE (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov NR 29 TC 50 Z9 53 U1 1 U2 3 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 OCT PY 2004 VL 70 IS 10 BP 5973 EP 5979 DI 10.1128/AEM.70.10.5973-5979.2004 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 860PT UT WOS:000224356200035 PM 15466540 ER PT J AU Schmidt, PJ Berlin, KL Danaceau, MA Neeren, A Haq, NA Roca, CA Rubinow, DR AF Schmidt, PJ Berlin, KL Danaceau, MA Neeren, A Haq, NA Roca, CA Rubinow, DR TI The effects of pharmacologically induced hypogonadism on mood in healthy men SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TESTOSTERONE REPLACEMENT THERAPY; PLACEBO-CONTROLLED TRIAL; CLINICAL RESEARCH-CENTER; PLASMA TESTOSTERONE; DEPRESSION; RADIOIMMUNOASSAY; AGGRESSION; BEHAVIOR; DIHYDROTESTOSTERONE; SUPPLEMENTATION AB Background: The effects of declining androgen secretion on mood regulation and the potential psychotropic efficacy of androgen replacement in men are largely undetermined. Objective: To examine the effects on mood of the acute suppression of testosterone secretion. Design: A double-blind, placebo-controlled, crossover (self-as-own-control) study. Setting: An ambulatory care clinic in a research hospital. Participants: Thirty-one healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse. Interventions: Men received depot leuprolide acetate (Lupron, 7.5 mg intramuscularly) every 4 weeks for 3 months. After the first month of Lupton alone; all men received (in addition to Lupton) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color-matched vehicle) every 2 weeks for I month each in a crossover design. The order of administration of testesterone and placebo was randomly assigned and counterbalanced. Main Outcome Measures: Mood and behavior rating scores (self-report and rater administered). Results: With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus testosterone conditions. Despite the absence of a uniform effect of Lupton plus placebo on mood, 3 men experienced clinically relevant mood symptoms during this induced hypogonadal condition. High baseline levels of sexual functioning predicted the greatest decline in sexual function during Lupron plus placebo. Conclusions: These data, the first to describe the effects on mood of induced hypogonadism in healthy young men, suggest that short-term hypogonadism is sufficient to precipitate depressive symptoms in only a small minority of younger men. The predictors of this susceptibility remain to be determined. C1 NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, NIH, Bldg 10,Room 3N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. EM schmidtp@intra.nimh.nih.gov NR 49 TC 53 Z9 53 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2004 VL 61 IS 10 BP 997 EP 1004 DI 10.1001/archpsyc.61.10.997 PG 8 WC Psychiatry SC Psychiatry GA 860ON UT WOS:000224353000005 PM 15466673 ER PT J AU Schuval, S Van Dyke, RB Lindsey, JC Palumbo, P Mofenson, LM Oleske, JM Cervia, J Kovacs, A Dankner, WN Smith, E Nowak, B Ciupak, G Webb, N Eagle, M Smith, D Hennessey, R Goodman-Kerkau, M Levin, MJ AF Schuval, S Van Dyke, RB Lindsey, JC Palumbo, P Mofenson, LM Oleske, JM Cervia, J Kovacs, A Dankner, WN Smith, E Nowak, B Ciupak, G Webb, N Eagle, M Smith, D Hennessey, R Goodman-Kerkau, M Levin, MJ CA Pediatric AIDS Clinical Trials Grp TI Hepatitis C prevalence in children with perinatal human immunodeficiency virus infection enrolled in a long-term follow-up protocol SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID TO-INFANT TRANSMISSION; HCV VERTICAL TRANSMISSION; INCREASED RISK; MOTHER; COHORT; WOMEN; POPULATION; VIREMIA; DIAGNOSIS; EVOLUTION AB Objective: To evaluate the prevalence of hepatitis C virus (HCV) infection in children with perinatal human immunodeficiency virus (HIV) infection. Design: Cross-sectional substudy. Setting: Multicenter study from 41 sites in the United States. Patients: Children with perinatal HIV infection were randomly selected from a large, long-term, follow-up protocol. Main Outcome Measure: Hepatitis C infection was defined as having positive test results on both HCV antibody and HCV RNA assays. Results: Five hundred thirty children enrolled in the substudy definitive HCV test results were available for 525 children. Eighty-three percent were of a minority race or ethnicity. They were equally distributed by sex, had a median age of 10.7 years, and were relatively healthy, with 75% having CD4(+) lymphocyte counts greater than 500 cells/mm(3). Eight of 525 children (1.5% 95% confidence interval [CI], 0.7%-3.0%) infected with HIV were coinfected with HCV. In contrast, the rate of HCV infection in a serosurvey of more than 2700 children aged 6 to 11 years from the National Health and Nutrition Examination Survey was 0.2% (95% CI, 0.04%-0.6%). In our study, there were no differences between children coinfected with HIV and HCV and those without HCV infection in terms of demographic characteristics, CD4(+) or CD8(+) T-lymphocyte counts, HIV 1 RNA levels, preterm or mode of delivery, or liver disease; however, the number of children coinfected with HIV and HCV was small. Conclusion: While HCV prevalence infection rates are low in children with perinatal HIV infection, they are 8 to 10 times higher than reported in HCV serosurveys of children in the United States. C1 Schneider Childrens Hosp, Div Allergy & Immunol, Long Isl Jewish Med Ctr, New Hyde Pk, NY 11042 USA. Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. NICHHD, Rockville, MD USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. PAREXEL Int, Durham, NC USA. Duke Univ, Med Ctr, Durham, NC USA. NIAID, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Univ Florida, Hlth Sci Ctr, Jacksonville, FL 32209 USA. Univ Massachusetts Mem Hlth Care, Worcester, MA USA. Westat Corp, Rockville, MD USA. Univ N Carolina, Retrovirol Core Lab, Chapel Hill, NC USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Schuval, S (reprint author), Schneider Childrens Hosp, Div Allergy & Immunol, Long Isl Jewish Med Ctr, Suite 108,410 Lakeville Rd, New Hyde Pk, NY 11042 USA. EM schuval@lij.edu RI Oleske, James/C-1951-2016; OI Oleske, James/0000-0003-2305-5605; Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI-41110] NR 44 TC 10 Z9 11 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD OCT PY 2004 VL 158 IS 10 BP 1007 EP 1013 DI 10.1001/archpedi.158.10.1007 PG 7 WC Pediatrics SC Pediatrics GA 859PA UT WOS:000224279200011 PM 15466691 ER PT J AU Santamarina-Fojo, S Gonzalez-Navarro, H Freeman, L Wagner, E Nong, ZX AF Santamarina-Fojo, S Gonzalez-Navarro, H Freeman, L Wagner, E Nong, ZX TI Hepatic lipase, lipoprotein metabolism, and atherogenesis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE transgenic mouse models; lipolytic enzyme; ligand-binding function; macrophages; bone marrow transplantation; aortic atherosclerosis ID LOW-DENSITY-LIPOPROTEIN; CORONARY-ARTERY-DISEASE; IN-VIVO EVIDENCE; RECEPTOR-DEFICIENT MICE; ISCHEMIC-HEART-DISEASE; HUMAN APO-B; TRANSGENIC MICE; APOLIPOPROTEIN-B; SELECTIVE UPTAKE; RAT-LIVER AB The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM silvia@mdb.nhlbi.nih.gov NR 78 TC 95 Z9 100 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2004 VL 24 IS 10 BP 1750 EP 1754 DI 10.1161/01.ATV.0000140818.00570.2d PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 860EV UT WOS:000224326200005 PM 15284087 ER PT J AU Brewer, HB Remaley, AT Neufeld, EB Basso, F Joyce, C AF Brewer, HB Remaley, AT Neufeld, EB Basso, F Joyce, C TI Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE ABCA1 transporter; cholesterol; cholesteryl ester transfer protein; cholesteryl ester transfer protein inhibitor; apoA-I ID ESTER TRANSFER PROTEIN; ATP-BINDING CASSETTE; APOLIPOPROTEIN-A-I; AMINO-ACID-SEQUENCE; CELLULAR CHOLESTEROL EFFLUX; TANGIER-DISEASE; APOA-I; FAMILIAL HYPERALPHALIPOPROTEINEMIA; CORONARY ATHEROSCLEROSIS; TRANSGENIC RABBITS AB High-density lipoproteins (HDL) protect against cardiovascular disease. HDL removes and transports excess cholesterol from peripheral cells to the liver for removal from the body. HDL also protects low-density lipoproteins (LDL) from oxidation and inhibits expression of adhesion molecules in endothelial cells, preventing monocyte movement into the vessel wall. The ABCA1 transporter regulates intracellular cholesterol levels in the liver and in peripheral cells by effluxing excess cholesterol to lipid-poor apoA-I to form nascent HDL, which is converted to mature alpha-HDL by esterification of cholesterol to cholesteryl esters (CE) by lecithin cholesterol acyltransferase. The hepatic ABCA1 transporter and apoA-I are major determinants of levels of plasma alpha-HDL cholesterol as well as poorly lipidated apoA-I, which interact with ABCA1 transporters on peripheral cells in the process of reverse cholesterol transport. Cholesterol in HDL is transported directly back to the liver by HDL or after transfer of CE by the cholesteryl ester transfer protein ( CETP) by the apoB lipoproteins. Current approaches to increasing HDL to determine the efficacy of HDL in reducing atherosclerosis involve acute HDL therapy with infusions of apoA-I or apoA-I mimetic peptides and chronic long-term therapy with selective agents to increase HDL, including CETP inhibitors. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Brewer, HB (reprint author), NHLBI, Mol Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bryan@mdb.nhlbi.nih.gov NR 74 TC 115 Z9 119 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2004 VL 24 IS 10 BP 1755 EP 1760 DI 10.1161/01.ATV.0000142804.27420.5b PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 860EV UT WOS:000224326200006 PM 15319263 ER PT J AU Ward, MM AF Ward, MM TI Outcomes of Hospitalizations for myocardial Infarctions and cerebrovascular accidents in patients with systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CORONARY ATHEROSCLEROSIS; ANGIOGRAPHIC FINDINGS; MORBIDITY; DISEASE; WOMEN; POPULATION; MELLITUS; STROKE AB Objective. Patients with systemic lupus erythematosus (SLE) have increased risks of acute myocardial infarction (AMI) and cerebrovascular accident (CVA), but it is not known whether they have worse outcomes after AMI or CVA compared with patients without SLE. This study compared in-hospital mortality, length of stay, and other measures of severity (congestive heart failure or need for coronary artery bypass grafting after AMI; discharge to a skilled nursing facility after CVA) between patients with SLE and patients without SLE who were hospitalized for AMI or CVA. Methods. Data on all patients hospitalized in California with either AMI or CVA from 1996 to 2000 were abstracted from a state hospitalization database. Outcomes after AMI were compared between 519 patients with SLE and 214,771 patients without SLE, and outcomes after CVA were compared between 905 patients with SLE and 293,326 patients without SLE. Analyses were performed separately for men and women. Results. Among women with AMI, there were no differences in the risk of in-hospital mortality, long length of stay, or congestive heart failure between patients with SLE and those without SLE, but women with SLE were less likely to undergo coronary artery bypass grafting. Outcomes after AMI did not differ between men with SLE and men without SLE. Among women with CVA, there were no differences in outcomes between patients with SLE and patients without SLE. Men with SLE were almost twice as likely to have a long length of stay after CVA than were men without SLE. Conclusion. Outcomes after AMI and CVA are generally similar between patients with SLE and those without SLE. C1 NIAMSD, IRP, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, IRP, NIH, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. EM wardml@mail.nih.gov NR 29 TC 15 Z9 18 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD OCT PY 2004 VL 50 IS 10 BP 3170 EP 3176 DI 10.1002/art.20556 PG 7 WC Rheumatology SC Rheumatology GA 862RK UT WOS:000224508400015 PM 15476215 ER PT J AU Gennari, A van den Berghe, C Casati, S Castell, J Clemedson, C Coecke, S Colombo, A Curren, R Dal Negro, G Goldberg, A Gosmore, C Hartung, T Langezaal, L Lessigiarska, L Maas, W Mangelsdorf, L Parchment, R Prieto, P Sintes, JR Ryan, M Schmuck, G Stitzel, K Stokes, W Vericat, JA Gribaldo, L AF Gennari, A van den Berghe, C Casati, S Castell, J Clemedson, C Coecke, S Colombo, A Curren, R Dal Negro, G Goldberg, A Gosmore, C Hartung, T Langezaal, L Lessigiarska, L Maas, W Mangelsdorf, L Parchment, R Prieto, P Sintes, JR Ryan, M Schmuck, G Stitzel, K Stokes, W Vericat, JA Gribaldo, L CA Report Recommendation ECVAM Work TI Strategies to replace in vivo acute systemic toxicity testing SO ATLA-ALTERNATIVES TO LABORATORY ANIMALS LA English DT Article; Proceedings Paper CT 21st Annual Workshop on In Vito Toxicology CY SEP 19-21, 2003 CL Tampere, FINLAND SP Scandinavian Soc Cell Toxicol ID 30 REFERENCE CHEMICALS; COMPARATIVE CYTOTOXICITY ANALYSIS; TOXICOLOGICAL RISK-EVALUATION; ACUTE LETHAL POTENCY; UP-AND-DOWN; MEIC EVALUATION; INTERNATIONAL VALIDATION; INVITRO CYTOTOXICITY; VITRO METHODS; CELL-LINE AB This is the report of the fiftieth of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importaace to the biosciences and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this priority would be best achieved by the organisation of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (1). This ECVAM workshop on strategies to replace in vivo acute systemic toxicity testing was held at ECVAM on 15-18 September 2003, under the chairmanship of Laura Gribaldo. The participants represented academia, national organisations, international regulatory bodies and industry. The aim of the workshop was to review the state-of-the-art of in vitro methods for estimating acute systemic toxicity, and to develop research, development, and validation strategies necessary for the replacement of in vivo testing, with a focus on oral acute toxicity. The report describes the strategy proposed by the participants for using in vitro methods, and provides recommendations for the test method development and validation activities necessary to support such a strategy that might replace the use of animals for the acute toxicity testing of chemicals. C1 European Commiss, Joint Res Ctr, Inst Hlth & Consumer Protect, ECVAM, I-21020 Ispra, VA, Italy. LOreal Res, Aulnay Sous Bois, France. Hosp Univ La Fe, Ctr Invest, Dept Bioquim, Fac Med, Valencia, Spain. Expertradet AB, Sundbyberg, Sweden. Sicurezza Prod Polimeri Europa, Sicurezza & Ambiente, San Donato Milanese, Italy. Inst Vitro Sci, Gaithersburg, MD USA. GlaxoSmithKline, Med Res Ctr, DVM Med Safety Evaluat, Verona, Italy. Johns Hopkins Univ, Ctr Alternat Anim Testing, Baltimore, MD USA. Hlth & Safety Execut, Bootle, Merseyside, England. European Commiss Joint Res Ctr, Inst Hlth & Consumer Protect, European Chem Bur, Ispra, Italy. TNO Chem, Physiol Sci Dept, Zeist, Netherlands. Inst Toxicol & Expt Med, Dept Chem Risk Assessment, Hannover, Germany. SciTech Dev, Grosse Pointe, MI USA. Univ Coll Dublin, Dept Pharmacol, Conway Inst Biomol & Biomed Res, Dublin 2, Ireland. Natl Inst Environm Hlth Sci, Natl Toxicol Program, Interagcy Ctr Evaluat Alternat Toxicol Methods, Res Triangle Pk, NC USA. NeuroPharma, Madrid, Spain. RP Gribaldo, L (reprint author), European Commiss, Joint Res Ctr, Inst Hlth & Consumer Protect, ECVAM, I-21020 Ispra, VA, Italy. EM laura.gribaldo@jrc.it NR 60 TC 24 Z9 26 U1 0 U2 6 PU FRAME PI NOTTINGHAM PA RUSSELL & BURCH HOUSE 96-98 NORTH SHERWOOD ST, NOTTINGHAM NG1 4EE, NOTTS, ENGLAND SN 0261-1929 J9 ATLA-ALTERN LAB ANIM JI ATLA-Altern. Lab. Anim. PD OCT PY 2004 VL 32 IS 4 BP 437 EP 459 PG 23 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 876OC UT WOS:000225505600018 PM 15651930 ER PT J AU Grillon, C Baas, JP Lissek, S Smith, K Milstein, J AF Grillon, C Baas, JP Lissek, S Smith, K Milstein, J TI Anxious responses to predictable and unpredictable aversive events SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID FEAR-POTENTIATED STARTLE; POSTTRAUMATIC-STRESS-DISORDER; PANIC DISORDER; ANXIETY DISORDERS; ACOUSTIC STARTLE; CONDITIONED FEAR; CARBON-DIOXIDE; BASE-LINE; SHOCK; THREAT AB Anxiety induced by 2 types of predictable and unpredictable aversive stimuli, an unpleasant shock or a less aversive airblast to the larynx, were investigated in a between-group design. Participants anticipated predictable (signaled) or unpredictable (not signaled) aversive events, or no aversive event. Unpredictable, relative to predictable, contexts potentiated the startle reflex in the shock group but not in the airblast group. These data suggest that unpredictability can lead to a sustained level of anxiety only when the pending stimulus is sufficiently aversive. Because predictable and unpredictable danger may induce different types of aversive responses, the proposed design can serve as a useful tool for studying the neurobiology and psychopharmacology of fear and anxiety. C1 NIMH, Mood & Anxiety Disorder Program, NIH, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Mood & Anxiety Disorder Program, NIH, 15k N Dr,Bldg 15K,Room 113,MSC 2670, Bethesda, MD 20892 USA. EM christian.grillon@nih.gov RI Lissek, Shmuel/B-6577-2008; OI Baas, Johanna/0000-0001-6267-8712 NR 57 TC 139 Z9 142 U1 8 U2 28 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD OCT PY 2004 VL 118 IS 5 BP 916 EP 924 DI 10.1037/0735-7044.118.5.916 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 860VN UT WOS:000224371900004 PM 15506874 ER PT J AU LaPlante, JM Ye, CP Quinn, SJ Goldin, E Brown, EM Slaugenhaupt, SA Vassilev, PM AF LaPlante, JM Ye, CP Quinn, SJ Goldin, E Brown, EM Slaugenhaupt, SA Vassilev, PM TI Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE mucolipin-1; mucolipidosis; Ca2+ signaling; membrane trafficking; lysosome; channel; late endosome ID ABNORMAL TRANSPORT; LYSOSOMES; FUSION; CHANNELS; RECEPTOR; GENE; CA2+; IDENTIFICATION; EXOCYTOSIS; MUTATIONS AB Most of the membrane trafficking phenomena including those involving the interactions between endosomes and lysosomes are regulated by changes in intracellular Ca2+ (Ca-i). These processes are disturbed in some types of mucolipidoses and other lysosomal storage disorders, such as mucolipidosis IV (MLIV), a neurological disorder that usually presents during the first year of life with blindness, cognitive impairment, and psychomotor delays. It is caused by mutations in MCOLN1, the gene encoding mucolipin-1 (MLNI), which we have recently established to represent a Ca2+ -permeable cation channel that is transiently modulated by changes in Ca-i. The cells of MLIV patients contain enlarged lysosomes that are likely associated with abnormal sorting and trafficking of these and related organelles. We studied fibroblasts from MLIV patients and found disturbed Ca2+ signaling and large acidic organelles such as late endosomes and lysosomes (LEL) with altered cellular localization in these cells. The fusion between LEL vesicles in these cells was defective. This is a Ca2+-dependent process related to signaling pathways involved in regulation of Ca2+ homeostasis and trafficking. The MLN1 channels could play a key role in Ca2+ release from LEL vesicles, which triggers the fusion and trafficking of these organelles. The characterization of this MLN1-mediated Ca2+-dependent process should provide new insights into the pathophysiological mechanisms that lead to the development of MLIV and other mucolipidoses associated with similar disturbances in membrane trafficking. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens,Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Membrane Biol Program,Dept Med, Boston, MA 02115 USA. NIH, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02115 USA. RP Vassilev, PM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens,Dept Med, Boston, MA 02115 USA. EM pvassilev@rics.bwh.harvard.edu FU NINDS NIH HHS [NS39995] NR 40 TC 61 Z9 62 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 1 PY 2004 VL 322 IS 4 BP 1384 EP 1391 DI 10.1016/j.bbrc.2004.08.045 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 854ZG UT WOS:000223941900033 PM 15336987 ER PT J AU Piek, E Van Dinther, M Parks, WT Sallee, JM Bottinger, EP Roberts, AB Ten Dijke, P AF Piek, E Van Dinther, M Parks, WT Sallee, JM Bottinger, EP Roberts, AB Ten Dijke, P TI RLP, a novel Ras-like protein, is an immediate-early transforming growth factor-beta (TGF-beta) target gene that negatively regulates transcriptional activity induced by TGF-beta SO BIOCHEMICAL JOURNAL LA English DT Article DE GTPase; Ras; sorting nexin; transcriptional regulation; transforming growth factor-beta ID EPITHELIAL-CELL PLASTICITY; RECEPTOR SERINE-THREONINE; SORTING NEXIN-1; FUNCTIONAL-CHARACTERIZATION; NUCLEOTIDE EXCHANGE; TYROSINE KINASES; DOWN-REGULATION; FAMILY; ACTIVATION; EXPRESSION AB We have described previously the use of microarray technology to identify novel target genes of TGF-beta (transforming growth factor-beta) signalling in mouse embryo fibroblasts deficient in Smad2 or Smad3 [Yang, Piek, Zavadil, Liang, Xie, Heyer, Pavlidis, Kucherlapati, Roberts and Bottinger (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 10269-102741. Among the TGF-beta target genes identified, a novel gene with sequence homology to members of the Ras superfamily was identified, which we have designated as RLP (Ras-like protein). RLP is a Smad3-dependent immediate-early TGF-beta target gene, its expression being induced within 45 min. Bone morphogenetic proteins also induce expression of RLP, whereas epidermal growth factor and phorbol ester PMA suppress TGF-beta-indunced expression of RLP. Northern-blot analysis revealed that RLP was strongly expressed in heart, brain and kidney, and below the detection level in spleen and skeletal muscles. At the protein level, RLP is approx. 30 % homologous with members of the Ras superfamily, particularly in domains characteristic for small GTPases. However, compared with prototypic Ras, RLP contains a modified P-loop, lacks the consensus G2 loop and the C-terminal prenylation site and harbours amino acid substitutions at positions that render prototypic Ras oncogenic. However, RLP does not have transforming activity, does not affect phosphorylation of mitogen-activated protein kinase and is unable to bind GTP or GDP. RLP was found to associate with certain subtypes of the TGF-beta receptor family, raising the possibility that RLP plays a role in TGF-beta signal transduction. Although RLP did not interact with Smads and did not affect TGF-beta receptor- induced Smad2 phosphorylation, it inhibited TGF-beta-induced transcriptional reporter activation, suggesting that it is a novel negative regulator of TGF-beta signalling. C1 Netherlands Canc Inst, Div Cellular Biochem, NL-1066 CX Amsterdam, Netherlands. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20814 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. RP Piek, E (reprint author), Netherlands Canc Inst, Div Cellular Biochem, NL-1066 CX Amsterdam, Netherlands. EM e.piek@sci.kun.nl FU NIDDK NIH HHS [R01 DK056077, R01 DK060043, U24 DK058768] NR 48 TC 13 Z9 13 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD OCT 1 PY 2004 VL 383 BP 187 EP 199 DI 10.1042/BJ20040774 PN 1 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863CK UT WOS:000224537800022 PM 15239668 ER PT J AU Sprague, JE Mallett, NM Rusyniak, DE Mills, E AF Sprague, JE Mallett, NM Rusyniak, DE Mills, E TI UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE methamphetamine; hyperthermia; uncoupling proteins; thyroid hormones; 3,4-methylenedioxymethamphetamine; thermogenesis ID UNCOUPLING PROTEIN-3; SKELETAL-MUSCLE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE; THERMOGENESIS; EXPRESSION; ECSTASY AB Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40 mg/kg, s.c.) responded with a hyperthermic response that peaked 1 h post-treatment and was sustained through 2 h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3 h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100 mug/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1 h after METH, remained unchanged. As seen in rats, 1 h post-METH (20 mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2 h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1 h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed. (C) 2004 Elsevier Inc. All rights reserved. C1 Ohio No Univ, Dept Pharmaceut & Biomed Sci, Raabe Coll Pharm, Ada, OH 45810 USA. Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Sprague, JE (reprint author), Ohio No Univ, Dept Pharmaceut & Biomed Sci, Raabe Coll Pharm, Ada, OH 45810 USA. EM j-sprague@onu.edu OI Rusyniak, Daniel/0000-0002-6199-0840 NR 22 TC 24 Z9 26 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD OCT 1 PY 2004 VL 68 IS 7 BP 1339 EP 1343 DI 10.1016/j.bcp.2004.03.049 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 853HR UT WOS:000223818400007 PM 15345323 ER PT J AU Blazar, BR Panoskaltsis-Mortari, A Levine, BL June, CH Lucas, PJ Gress, R Serody, JS Taylor, PA AF Blazar, BR Panoskaltsis-Mortari, A Levine, BL June, CH Lucas, PJ Gress, R Serody, JS Taylor, PA TI The role of CD4(+)CD25(+) T regulatory (TREG) cells in allogeneic bone marrow transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 2nd Annual International Umbilical Cord Blood Symposium CY MAY 14-15, 2004 CL Los Angeles, CA C1 Univ Minnesota, Minneapolis, MN USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. NCI, Bethesda, MD 20892 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RI Levine, Bruce/D-1688-2009 NR 0 TC 1 Z9 1 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2004 VL 10 IS 10 MA 15 BP 737 EP 737 DI 10.1016/j.bbmt.2004.06.025 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 860XS UT WOS:000224378100025 ER PT J AU Goyer, RA Liu, J Waalkes, MP AF Goyer, RA Liu, J Waalkes, MP TI Cadmium and cancer of prostate and testis SO BIOMETALS LA English DT Article DE cadmium; cancer; hormones; prostate; testis ID WISTAR CRL-(WI)BR RATS; DOSE-RESPONSE ANALYSIS; EPITHELIAL-CELLS; TUMOR-INDUCTION; INJECTION SITE; CARCINOGENESIS; TOXICITY; ZINC; METALLOTHIONEIN; TRANSFORMATION AB Cancer of the prostate is an important and potentially fatal disease in humans but the etiology is yet undefined. Cadmium and cadmium compounds are known to be human carcinogens based on findings of increased risk to lung cancer among exposed workers, but a relationship between cancer of the prostate and/or testis in humans is unclear in spite of suggestive results in rats. Parenteral administration or oral exposure to cadmium can result in proliferate lesions and tumors of the prostate in rats. The ability of cadmium to produce neoplasms in the prostate of rats is atypically dose-related and only occurs in rats at doses below the threshold for significant testicular toxicity. Testicular androgen production is essential for the maintenance of the prostate and prostate tumors. The rat testis may also develop tumors if cadmium is given parenterally at high doses. Subsequent to testicular hemorrhagic necrosis, there will be loss of testosterone production and hyperplasia and neoplasia of testicular interstitial cells, thought to be a response to trophic hormone release from the pituitary. The pathogenesis of prostatic cadmium carcinogenesis might include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Activation of transcription factors such as the metallothionein gene and activation of some protooncogenes may enhance cell proliferation with damaged DNA. Suppression of DNA repair would add to the population of cells with damaged DNA. Chemically induced apoptosis can be blocked by cadmium, facilitating aberrant cell accumulation. C1 NIEHS, NCI, Res Triangle Pk, NC 27709 USA. RP Goyer, RA (reprint author), NIEHS, NCI, POB 12233, Res Triangle Pk, NC 27709 USA. NR 26 TC 107 Z9 123 U1 2 U2 13 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0966-0844 J9 BIOMETALS JI Biometals PD OCT PY 2004 VL 17 IS 5 BP 555 EP 558 DI 10.1023/B:BIOM.0000045738.59708.20 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865KM UT WOS:000224701600016 PM 15688863 ER PT J AU Camphausen, K Sproull, M Tantama, S Venditto, V Sankineni, S Scott, T Brechbiel, MW AF Camphausen, K Sproull, M Tantama, S Venditto, V Sankineni, S Scott, T Brechbiel, MW TI Evaluation of chelating agents as anti-angiogenic therapy through copper chelation SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID ANTICANCER IRON CHELATOR; METAL-COMPLEXES; WILSONS-DISEASE; TUMOR-GROWTH; TETRATHIOMOLYBDATE; RADIOPHARMACEUTICALS; TACHPYRIDINE; SUPPRESSION; DERIVATIVES; ANTICOPPER AB The evaluation of several sets of polyamine donor chelating agents including a selection of novel hexadentate 1,3,5-cis,cis-triaminocyclohexane (tach) based derivatives were performed in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity as novel anti-angiogenic agents. The selective nature of the anti-angiogenic agents for human umbilical vein endothelial cells (HUVEC) was compared to a normal fibroblast cell line and a human Glioma cell line to evaluate these compounds. Linear tri- and tetra-polyamines were superior to both macrocyclic and the tach based polyamine chelating agents in terms of selectivity of its inhibitory activity toward the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells. The linear polyamine, triethylenetetramine (22), previously reported to possess anti-angiogenic properties failed to demonstrate any selectivity for inhibiting the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells. (C) Published by Elsevier Ltd. C1 NCI, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, NIH, 10 Ctr Dr,Bldg 10,Rm B3 B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov NR 34 TC 13 Z9 14 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 1 PY 2004 VL 12 IS 19 BP 5133 EP 5140 DI 10.1016/j.bmc.2004.07.034 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 855ZS UT WOS:000224014000011 PM 15351396 ER PT J AU Xiao, XS Antony, S Kohlhagen, G Pommier, Y Cushman, M AF Xiao, XS Antony, S Kohlhagen, G Pommier, Y Cushman, M TI Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID STEREOSELECTIVE-SYNTHESIS; DNA CLEAVAGE; AMINO-ACIDS; CAMPTOTHECIN; INDUCTION; TRANSPORT; CHLORIDE; DERIVATIVES; MECHANISM; OXIDATION AB The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622. Despite an imperfect correlation between cytotoxicities and topoisomerase I inhibition results, the hypothetical structural model of the cleavage complex presented here provides a conceptual framework to explain the structure-activity relationships. (C) 2004 Elsevier Ltd. All rights reserved. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Ctr Canc Res, Lab Mol Pharmacol, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu FU NCI NIH HHS [N01-CO-56000, UO1 CA89566] NR 34 TC 39 Z9 40 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 1 PY 2004 VL 12 IS 19 BP 5147 EP 5160 DI 10.1016/j.bmc.2004.07.027 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 855ZS UT WOS:000224014000013 PM 15351398 ER PT J AU Laco, GS Du, W Kohlhagen, G Sayer, JM Jerina, DM Burke, TG Curran, DP Pommier, Y AF Laco, GS Du, W Kohlhagen, G Sayer, JM Jerina, DM Burke, TG Curran, DP Pommier, Y TI Analysis of human topoisomerase I inhibition and interaction with the cleavage site+1 deoxyguanosine, via in vitro experiments and molecular modeling studies SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID RING-MODIFIED CAMPTOTHECIN; DOUBLE-STRAND BREAKS; HUMAN SERUM-ALBUMIN; DNA TOPOISOMERASES; FORCE-FIELDS; CRYSTAL-STRUCTURES; REPLICATION FORKS; CARBOXYLATE FORMS; CYTO-TOXICITY; CELL-LINE AB Human topoisomerase I (Top1) plays a pivotal role in cell replication and transcription, and therefore is an important anti-cancer target. Homocamptothecin is a lead compound for inhibiting Top1, and is composed of five conjugated planar rings (A-E). The homocamptothecin E-ring beta-hydroxylactone opens slowly to a carboxylate at pH > 7.0. We analyzed, which form of homocamptothecin was biochemically relevant in the following ways: (1) the homocamptothecin carboxylate was tested for activity in vitro and found to be inactive; (2) homocamptothecin was incubated with Top1 and dsDNA, and we found that the homocamptothecin beta-hydroxylactone form was stabilized; (3) the homocamptothecin E-ring beta-hydroxylactone was modified to prevent opening, and the derivatives were either inactive or had low activity. These results indicated that the homocamptothecin beta-hydroxylactone was the active form, and that an E-ring carbonyl oxygen and adjacent unsubstituted/unprotonated ring atom were required for full activity. Homocamptothecin and derivatives were docked into a Top1/DNA active site model, in which the +1 deoxyguanosine was rotated out of the helix, in order to compare the interaction energies between the ligands and the Top1/DNA active site with the in vitro activities of the ligands. It was found that the ligand interaction energies and in vitro activities were correlated, while the orientations of the ligands in the Top1/DNA active site explained the importance of the E-ring beta-hydroxylactone independently of E-ring opening. An essential component of this Top1/DNA active site model is the rotated +1 deoxyguanosine, and in vitro experiments and molecular modeling studies supported rotation of the +1 deoxyguanosine out of the helix. These results allow for the rational design of more potent Top1 inhibitors through engineered interactions with as yet unutilized Top1 active-site residues including: Glu356, Asn430, and Lys751. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Div Basic Sci, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. NIDDKD, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Univ Kentucky, Markey Canc Ctr, Coll Pharm & Expt Therapeut Program, Div Pharmaceut Sci, Lexington, KY 40506 USA. Tigen Pharmaceut Inc, Lexington, KY 40506 USA. RP Pommier, Y (reprint author), NCI, Div Basic Sci, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 61 TC 16 Z9 17 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 1 PY 2004 VL 12 IS 19 BP 5225 EP 5235 DI 10.1016/j.bmc.2004.06.046 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 855ZS UT WOS:000224014000020 PM 15351405 ER PT J AU Durell, SR Shrivastava, IH Guy, HR AF Durell, SR Shrivastava, IH Guy, HR TI Models of the structure and voltage-gating mechanism of the shaker K+ channel SO BIOPHYSICAL JOURNAL LA English DT Article ID GATED POTASSIUM CHANNEL; SENSING DOMAINS; PORE DOMAIN; MOLECULAR-MOVEMENT; HELICAL STRUCTURE; CRYSTAL-STRUCTURE; CHARGE MOVEMENT; ION CHANNELS; SENSOR; S4 AB In the preceding, accompanying article, we present models of the structure and voltage-dependent gating mechanism of the KvAP bacterial K+ channel that are based on three types of evidence: crystal structures of portions of the KvAP protein, theoretical modeling criteria for membrane proteins, and biophysical studies of the properties of native and mutated voltage-gated channels. Most of the latter experiments were performed on the Shaker K+ channel. Some of these data are difficult to relate directly to models of the KvAP channel's structure due to differences in the Shaker and KvAP sequences. We have dealt with this problem by developing new models of the structure and gating mechanism of the transmembrane and extracellular portions of the Shaker channel. These models are consistent with almost all of the biophysical data. In contrast, much of the experimental data are incompatible with the "paddle'' model of gating that was proposed when the KvAP crystal structures were first published. The general folding pattern and gating mechanisms of our current models are similar to some of our earlier models of the Shaker channel. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, 12 S Dr, Bethesda, MD 20892 USA. EM bg4y@nih.gov NR 52 TC 43 Z9 47 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 OCT PY 2004 VL 87 IS 4 BP 2116 EP 2130 DI 10.1529/biophysj.104.040618 PG 15 WC Biophysics SC Biophysics GA 857OY UT WOS:000224129200003 PM 15454416 ER PT J AU Shrivastava, IH Durell, SR Guy, HR AF Shrivastava, IH Durell, SR Guy, HR TI A model of voltage gating developed using the KvAP channel crystal structure SO BIOPHYSICAL JOURNAL LA English DT Article ID SHAKER K+ CHANNEL; MOLECULAR-DYNAMICS SIMULATIONS; POTASSIUM CHANNEL; PORE DOMAIN; ION-CHANNEL; MEMBRANE-PROTEINS; SENSING DOMAINS; CHARGE MOVEMENT; SODIUM-CHANNEL; S4 SEGMENT AB Having inspected the crystal structure of the complete KvAP channel protein, we suspect that the voltage-sensing domain is too distorted to provide reliable information about its native tertiary structure or its interactions with the central pore-forming domain. On the other hand, a second crystal structure of the isolated voltage-sensing domain may well correspond to a native open conformation. We also observe that the paddle model of gating developed from these two structures is inconsistent with many experimental results, and suspect it to be energetically unrealistic. Here we show that the isolated voltage-sensing domain crystal structure can be docked onto the pore domain portion of the full-length KvAP crystal structure in an energetically favorable way to create a model of the open conformation. Using this as a starting point, we have developed rather conventional models of resting and transition conformations based on the helical screw mechanism for the transition from the open to the resting conformation. Our models are consistent with both theoretical considerations and experimental results. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, 12 S Dr, Bethesda, MD 20892 USA. EM bg4y@nih.gov NR 62 TC 27 Z9 28 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 OCT PY 2004 VL 87 IS 4 BP 2255 EP 2270 DI 10.1529/biophysj.104.040592 PG 16 WC Biophysics SC Biophysics GA 857OY UT WOS:000224129200015 PM 15454428 ER PT J AU Sidorova, NY Rau, DC AF Sidorova, NY Rau, DC TI Differences between EcoRI nonspecific and "star'' sequence complexes revealed by osmotic stress SO BIOPHYSICAL JOURNAL LA English DT Article ID RESTRICTION-ENDONUCLEASE ECORI; PROTEIN-DNA INTERACTIONS; RI ENDONUCLEASE; WATER RELEASE; CRYSTAL-STRUCTURE; LAC REPRESSOR; MACROMOLECULAR HYDRATION; GEL-ELECTROPHORESIS; LINEAR DIFFUSION; BINDING AB The binding of the restriction endonuclease EcoRI to DNA is exceptionally specific. Even a single basepair change ("star'' sequence) from the recognition sequence, GAATTC, decreases the binding free energy of EcoRI to values nearly indistinguishable from nonspecific binding. The difference in the number of waters sequestered by the protein-DNA complexes of the "star'' sequences TAATTC and CAATTC and by the specific sequence complex determined from the dependence of binding free energy on water activity is also practically indistinguishable at low osmotic pressures from the 110 water molecules sequestered by nonspecific sequence complexes. Novel measurements of the dissociation rates of noncognate sequence complexes and competition equilibrium show that sequestered water can be removed from "star'' sequence complexes by high osmotic pressure, but not from a nonspecific complex. By 5 Osm, the TAATTC "star'' sequence complex has lost almost 90 of the similar to110 waters initially present. It is more difficult to remove water from the CAATTC "star'' sequence complex. The sequence dependence of water loss correlates with the known sequence dependence of "star'' cleavage activity. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Rau, DC (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bldg 9,Room 1E114, Bethesda, MD 20892 USA. EM raud@mail.nih.gov NR 54 TC 18 Z9 19 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 OCT PY 2004 VL 87 IS 4 BP 2564 EP 2576 DI 10.1529/biophysj.104.042390 PG 13 WC Biophysics SC Biophysics GA 857OY UT WOS:000224129200039 PM 15454451 ER PT J AU Shoelson, B Dimitriadis, EK Cai, HX Kachar, B Chadwick, RS AF Shoelson, B Dimitriadis, EK Cai, HX Kachar, B Chadwick, RS TI Evidence and implications of inhomogeneity in tectorial membrane elasticity SO BIOPHYSICAL JOURNAL LA English DT Article ID ATOMIC-FORCE MICROSCOPE; ULTRASTRUCTURAL ORGANIZATION; GUINEA-PIG; INNER-EAR; MATRIX; INDENTATION; STIFFNESS; HEARING; COCHLEA; SAMPLES AB The motion of the tectorial membrane (TM) with respect to the reticular lamina subserves auditory function by bending the outer hair cell bundles and inducing fluid flows that shear the inner hair bundles in response to sound energy. Little is currently known about its intrinsic elasticity or about the relation between the mechanical properties and function of the membrane. Here we subdivide the TM into three longitudinal regions and five radial zones and map the shear modulus of the TM using atomic force microscopy, and present evidence that the TM elasticity varies radially, after the distribution of type A collagen fibrils. This is seen most dramatically as a decrease in shear modulus in the neighborhood of the sensory hair cells; we argue that this inhomogeneity of properties not only protects the hair bundles but also increases the energy efficiency of the vibrational shearing during sound transduction. C1 NIDDK, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. NIDDK, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. NIDDK, Sect Struct Biol, NIH, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), NIDDK, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov NR 36 TC 44 Z9 44 U1 0 U2 8 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2004 VL 87 IS 4 BP 2768 EP 2777 DI 10.1529/biophysj.104.040774 PG 10 WC Biophysics SC Biophysics GA 857OY UT WOS:000224129200059 PM 15454468 ER PT J AU Morfin, I Horkay, F Basser, PJ Bley, F Hecht, AM Rochas, C Geissler, E AF Morfin, I Horkay, F Basser, PJ Bley, F Hecht, AM Rochas, C Geissler, E TI Adsorption of divalent cations on DNA SO BIOPHYSICAL JOURNAL LA English DT Article ID ANGLE X-RAY; NEUTRON-SCATTERING; POLYELECTROLYTE SOLUTIONS; CONDENSATION; FRAGMENTS; GELS AB The distribution of divalent ions in semidilute solutions of high-molecular-mass DNA containing both sodium chloride and strontium chloride in near-physiological conditions is studied by small-angle x-ray scattering and by small-angle neutron scattering. Both small-angle neutron scattering and small-angle x-ray scattering reveal a continuous increase in the scattering intensity at low q with increasing divalent ion concentration, while at high q the scattering curves converge. The best fit to the data is found for a configuration in which DNA strands of cross-sectional radius 10 Angstrom are surrounded by a counterion sheath of outer radius similar to 13.8 Angstrom, independent of the strontium chloride concentration. When the strontium chloride is replaced by calcium chloride, similar results are obtained, but the thickness of the sheath increases when the divalent salt concentration decreases. These results correspond in both cases to partial localization of the counterions within a layer that is thinner than the effective Debye screening length. C1 Univ Grenoble 1, Spectrometrie Phys Lab, CNRS, Unite Mixte Rech 5588, F-38402 St Martin Dheres, France. NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Inst Natl Polytech Grenoble, CNRS, Unite Mixte Rech 5614, Thermodynam & Physicochim Met Lab, F-38402 St Martin Dheres, France. RP Geissler, E (reprint author), Univ Grenoble 1, Spectrometrie Phys Lab, CNRS, Unite Mixte Rech 5588, F-38402 St Martin Dheres, France. EM erik.geissler@ujf-grenoble.fr RI Basser, Peter/H-5477-2011; d2am, beamline/I-6445-2015 NR 28 TC 20 Z9 21 U1 0 U2 7 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2004 VL 87 IS 4 BP 2897 EP 2904 DI 10.1529/biophysj.104.045542 PG 8 WC Biophysics SC Biophysics GA 857OY UT WOS:000224129200070 PM 15454479 ER PT J AU Albert, PS Hunsberger, SA Hu, N Taylor, PR AF Albert, PS Hunsberger, SA Hu, N Taylor, PR TI Identifying multiple changepoints in heterogeneous binary data with an application to molecular genetics SO BIOSTATISTICS LA English DT Article DE change point detection; correlated binary data; heterogeneity; loss of heterozygosity; repeated binary data; spectral correlation ID DNA-SEQUENCE SEGMENTATION; SQUAMOUS-CELL CARCINOMA; ALLELIC-LOSS; IDENTIFICATION AB Identifying changepoints is an important problem in molecular genetics. Our motivating example is from cancer genetics where interest focuses on identifying areas of a chromosome with an increased likelihood of a tumor suppressor gene. Loss of heterozygosity (LOH) is a binary measure of allelic loss in which abrupt changes in LOH frequency along the chromosome may identify boundaries indicative of a region containing a tumor suppressor gene. Our interest was on testing for the presence of multiple changepoints in order to identify regions of increased LOH frequency. A complicating factor is the substantial heterogeneity in LOH frequency across patients, where some patients have a very high LOH frequency while others have a low frequency. We develop a procedure for identifying multiple changepoints in heterogeneous binary data. We propose both approximate and full maximum-likelihood approaches and compare these two approaches with a naive approach in which we ignore the heterogeneity in the binary data. The methodology is used to estimate the pattern in LOH frequency on chromosome 13 in esophageal cancer patients and to isolate an area of inflated LOH frequency on chromosome 13 which may contain a tumor suppressor gene. Using simulations, we show that our approach works well and that it is robust to departures from some key modeling assumptions. C1 NCI, Biomet Res Branch, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biomet Res Branch, 6130 Execut Blvd,Room 8136, Bethesda, MD 20892 USA. NR 22 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2004 VL 5 IS 4 BP 515 EP 529 DI 10.1093/biostatics/kxh005 PG 15 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 865GD UT WOS:000224689700002 PM 15475416 ER PT J AU Kaposi-Novak, P Lee, JS Mikaelyan, A Patel, V Thorgeirsson, SS AF Kaposi-Novak, P Lee, JS Mikaelyan, A Patel, V Thorgeirsson, SS TI Oligonucleotide microarray analysis of aminoallyl-labeled cDNA targets from linear RNA amplification SO BIOTECHNIQUES LA English DT Article ID LASER-CAPTURE MICRODISSECTION; GENE-EXPRESSION PROFILES; GROWTH-FACTOR-ALPHA; MESSENGER-RNA; C-MYC; TRANSGENIC MICE; QUANTITIES; ARRAYS; MODEL AB Single-stranded long oligonucleotide-based (50- to 70-mer) Microarrays offer several advantages over conventional cDNA microarrays. These include the easy preparation of the probes, low cost of array production, and low cross-contamination during probe handling. However the application of oligonucleotide microarrays for the analysis of global gene expression with small amounts of total RNA using the conventional oligo(dT)-T7 promoter-based amplification is hampered by the single-stranded nature (sense strand) of oligonucleotide probes in microarrays. In this report, we describe modified RNA amplification methods generating antisense-labeled cDNA targets and a successful application for oligonucleotiole microarray gene expression analysis. In the first round, mRNA was amplified linearly with oligo(dT)(24)T7-primed reverse transcription and in vitro transcription by T7 RNA polymerase. In the second round, random 9-mer T3 primers and T3 RNA polymerase were used to generate sense-strand amplified RNA (aRNA). Fluorescently labeled cDAA targets were generated front the aRNA and hybridized to the oligonucleotide microarrays. Our data show that the amplification provides highly reproducible results, as evidenced by a significant correlation between the amplified and nonamplified samples. We also demonstrate that amplification of RNA derived from laser-microdissected tumor samples reproduced the gene expression profiles that were obtained from total RNA isolated from the same samples. C1 NCI, Lab Experimental Carcinogeneseis, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethlehem, MD USA. RP Thorgeirsson, SS (reprint author), NCI, Lab Experimental Carcinogeneseis, NIH, Bldg 37,Room 4146A1,37 Convent Dr, Bethesda, MD 20892 USA. EM thorgeirsson@nih.gov NR 26 TC 5 Z9 7 U1 1 U2 3 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD OCT PY 2004 VL 37 IS 4 BP 580 EP + PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863CY UT WOS:000224539400014 PM 15517970 ER PT J AU Biragyn, A Ruffini, PA Coscia, M Harvey, LK Neelapu, SS Baskar, S Wang, JM Kwak, LW AF Biragyn, A Ruffini, PA Coscia, M Harvey, LK Neelapu, SS Baskar, S Wang, JM Kwak, LW TI Chemokine receptor-mediated delivery directs self-tumor antigen efficiently into the class II processing pathway in vitro and induces protective immunity in vivo SO BLOOD LA English DT Article ID T-CELL RESPONSES; DENDRITIC CELLS; ANTITUMOR IMMUNITY; ENDOCYTOSIS; INTERNALIZATION; DEGRADATION; CHEMOTAXIS; SEQUESTRATION; HERPESVIRUS; GENERATION AB Nonimmunogenic antigens can be efficiently rendered immunogenic by targeting them to antigen-presenting cells via differentially expressed chemokine receptors. For example, self-tumor or HIV antigens genetically fused with proinflammatory chemoattractants elicit potent immune responses and protective antitumor immunity in mice. Herein we demonstrate that the mechanism by which chemokine fusions elicit responses is efficient uptake, processing, and presen tation of antigens via the major histocompatibility complex class II pathway. Experiments with inhibitors of intracellular trafficking suggest that chemoattractant fusion proteins, but not antigen alone, were processed and presented through early/late endosomal and Golgi compartments and stimulated antigen-specific CD4(+) T cells both in vitro and in vivo. Chemokine fusion also facilitated the presentation of antigen by dendritic cells to an autologous human tumor-specific CD4(+) T-cell line. Taking advantage of chemokine redundancy, viral chemokine fusions were equally potent in inducing protective immunity in vivo, providing a possible strategy to circumvent hypothetical, vaccine-induced antihost chemokine autoimmunity, for example, by use of viral chemoattractants in humans. (C) 2004 by The American Society of Hematology. C1 NIA, Gerontol Res Ctr, Lab Immunol, NIH, Baltimore, MD 21224 USA. NCI, Immunoregulat Lab, Expt Transplantat & Immunol Branch, Frederick, MD USA. MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX USA. IRSP SAIC, Frederick, MD USA. Osped Niguarda Ca Granda, Div Oncol Med Falck, Milan, Italy. RP Biragyn, A (reprint author), NIA, Gerontol Res Ctr, Lab Immunol, NIH, 5600 Nathan Shock,Dr,Box 21, Baltimore, MD 21224 USA. EM biragyna@grc.nia.nih.gov RI coscia, marta/K-4832-2016 OI coscia, marta/0000-0003-2123-7675 FU NCI NIH HHS [N01-CO-12400] NR 44 TC 40 Z9 45 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2004 VL 104 IS 7 BP 1961 EP 1969 DI 10.1182/blood-2004-02-0637 PG 9 WC Hematology SC Hematology GA 857JP UT WOS:000224112800016 PM 15191951 ER PT J AU Monsurro, V Wang, E Yamano, Y Migueles, SA Panelli, MC Smith, K Nagorsen, D Connors, M Jacobson, S Marincola, FM AF Monsurro, V Wang, E Yamano, Y Migueles, SA Panelli, MC Smith, K Nagorsen, D Connors, M Jacobson, S Marincola, FM TI Quiescent phenotype of tumor-specific CD8+ T cells following immunization SO BLOOD LA English DT Article ID MESSENGER-RNA AMPLIFICATION; METASTATIC MELANOMA; IN-VIVO; NK-CELLS; MEMORY; PEPTIDE; EXPRESSION; ACTIVATION; ANTIGEN; VACCINE AB In a human melanoma model of tumor antigen (TA)-based immunization, we tested the functional status of TA-specific CD8(+) cytotoxic T lymphocytes. A "quiescent" phenotype lacking direct ex vivo cytotoxic and proliferative potential was identified that was further characterized by comparing its transcriptional profile to that of TA-specific T cells sensitized in vitro by exposure to the same TA and the T-cell growth factor interleukin 2 (IL-2). Quiescent circulating tumor-specific CD8(+) T cells were deficient in expression of genes associated with T-cell activation, proliferation, and effector function. This quiescent status may explain the observed lack of correlation between the presence of circulating immunization-induced lymphocytes and tumor regression. In addition, the activation of TA-specific T cells by in vitro antigen recall and IL-2 suggests that a complete effector phenotype might be reinstated in vivo to fulfill the potential of anticancer vaccine protocols. (C) 2004 by The American Society of Hematology. C1 NIH, Dept Transfus Med, Clin Ctr, Immunogenet Sect, Bethesda, MD 20892 USA. NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD USA. NIAID, Lab Immunoregulat, NIH, Bethesda, MD USA. RP Marincola, FM (reprint author), NIH, Dept Transfus Med, Clin Ctr, Immunogenet Sect, Bldg 10,R-1C711, Bethesda, MD 20892 USA. EM fmarincola@cc.nih.gov NR 58 TC 57 Z9 61 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2004 VL 104 IS 7 BP 1970 EP 1978 DI 10.1182/blood-2004-02-0525 PG 9 WC Hematology SC Hematology GA 857JP UT WOS:000224112800017 PM 15187028 ER PT J AU Karandikar, NJ Kroft, SH Yegappan, S Rogers, BB Aquino, VM Lee, KM Kumar, V Guenaga, FJ Jaffe, ES Douelk, DC McKenna, RW AF Karandikar, NJ Kroft, SH Yegappan, S Rogers, BB Aquino, VM Lee, KM Kumar, V Guenaga, FJ Jaffe, ES Douelk, DC McKenna, RW TI Unusual immunophenotype of CD8+ T cells in familial hemophagocytic lymphohistiocytosis SO BLOOD LA English DT Article ID PERFORIN; MUTATIONS AB Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, fatal disorder of infancy. We report here a 17-day-old female infant who presented with high fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, thrombocytopenia, and liver failure. Leukocytosis was detected with circulating "atypical" lymphoid cells. Flow cytometric studies revealed expanded subpopulations of CD8(+) T cells with unusual immunophenotypic features, including a subset that lacked CD5 expression. A liver biopsy showed hemophagocytic lymphohistiocytosis with exuberant infiltrates of CD8(+) T cells that lacked perforin. Mutational studies revealed a 666C -->A (H222Q) missense mutation in the perform gene. T-cell receptor studies on flow-sorted T-cell subpopulations revealed no evidence of monoclonality. Analysis of T-cell receptor excision circle levels indicated long proliferative history in the aberrant CD8(+) T-cell subsets. This case provides an instructive example of uncontrolled reactive proliferation of CD8(+) T cells in FHL, resulting in atypical morphology and unusual immunophenotypic features that might suggest malignancy in other clinical settings. (C) 2004 by The American Society of Hematology. C1 Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX 75390 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Korea Univ, Coll Med, Dept Biochem, Seoul, South Korea. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Karandikar, NJ (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM nitin@pathology.swmed.edu FU NIAID NIH HHS [AI49990] NR 17 TC 9 Z9 9 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 OCT 1 PY 2004 VL 104 IS 7 BP 2007 EP 2009 DI 10.1182/blood-2004-04-1431 PG 3 WC Hematology SC Hematology GA 857JP UT WOS:000224112800023 PM 15205266 ER PT J AU Beleslin-Cokic, BB Cokic, VP Yu, XB Weksler, BB Schechter, AN Noguchi, CT AF Beleslin-Cokic, BB Cokic, VP Yu, XB Weksler, BB Schechter, AN Noguchi, CT TI Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells SO BLOOD LA English DT Article ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; SYNTHASE EXPRESSION; INDUCED HYPERTENSION; BLOOD-VISCOSITY; RENAL-FAILURE; MESSENGER-RNA; KINASE-I; DISEASE; MICE; RATS AB Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell mass. (C) 2004 by The American Society of Hematology. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Div Hematol Oncol, New York, NY USA. RP Noguchi, CT (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9N307,10 Ctr Dr MSC 1822, Bethesda, MD 20892 USA. EM cnoguchi@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 55 TC 176 Z9 191 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2004 VL 104 IS 7 BP 2073 EP 2080 DI 10.1182/blood-2004-02-0744 PG 8 WC Hematology SC Hematology GA 857JP UT WOS:000224112800032 PM 15205261 ER PT J AU Fieschi, C Bosticardo, M de Beaucoudrey, L Boisson-Dupuis, S Feinberg, J Santos, OF Bustamante, J Levy, J Candotti, F Casanova, JL AF Fieschi, C Bosticardo, M de Beaucoudrey, L Boisson-Dupuis, S Feinberg, J Santos, OF Bustamante, J Levy, J Candotti, F Casanova, JL TI A novel form of complete IL-12/IL-23 receptor beta 1 deficiency with cell surface-expressed nonfunctional receptors SO BLOOD LA English DT Article ID INTERFERON-GAMMA-RECEPTOR; BACILLE CALMETTE-GUERIN; INHERITED INTERLEUKIN-12 DEFICIENCY; BETA-1 DEFICIENCY; MYCOBACTERIAL INFECTION; T-CELLS; CLINICAL TUBERCULOSIS; IFN-GAMMA; IL-12; IMMUNITY AB Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rbeta1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL12Rbeta1. These 6 exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Five of 6 monoclonal anti-IL-12Rbeta1 antibodies tested recognized the internally truncated chain on the cell surface. However, IL-12 and IL-23 did not bind normally to the patient's IL-12Rbeta1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon-gamma (IFN-gamma) production was not induced in the patient's cells upon stimulation with even high doses of IL-12 or IL-23. The functional defect was completely rescued by retrovirus-mediated IL-12Rbeta1 gene transfer. Thus, the detection of IL-12Rbeta1 on the cell surface does not exclude the possibility of complete IL-12Rbeta1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12RP1,defining a novel genetic form of IL-12Rbeta1 deficiency. (C) 2004 by The American Society of Hematology. C1 Univ Paris 05, INSERM U550, Fac Med Necker, Lab Genet Humaine Malad Infect, F-75015 Paris, France. Necker Med Sch, Paris, France. NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Fac Hlth Sci, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Soroka Med Ctr, Div Pediat, IL-84105 Beer Sheva, Israel. Hop Necker Enfants Malad, Pediat Immunol & Hematol Unit, Paris, France. RP Casanova, JL (reprint author), Univ Paris 05, INSERM U550, Fac Med Necker, Lab Genet Humaine Malad Infect, 156 Rue Vaugirard, F-75015 Paris, France. EM casanova@necker.fr NR 44 TC 51 Z9 54 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2004 VL 104 IS 7 BP 2095 EP 2101 DI 10.1182/blood-2004-02-0584 PG 7 WC Hematology SC Hematology GA 857JP UT WOS:000224112800036 PM 15178580 ER PT J AU Abi-Habib, RJ Liu, SH Bugge, TH Leppla, SH Frankel, AE AF Abi-Habib, RJ Liu, SH Bugge, TH Leppla, SH Frankel, AE TI A urokinase-activated recombinant diphtheria toxin targeting the granulocyt-emacrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts SO BLOOD LA English DT Article ID FACTOR FUSION PROTEIN; I CLINICAL-TRIALS; BLOOD CELLS; EXPRESSION; PURIFICATION; INVASION; SURFACE; GROWTH; MODEL; UPAR AB Novel agents to treat acute myeloid leukemia (AML) are needed with increased efficacy and specificity. We have synthesized a dual-specificity fusion toxin DTU2GMCSF composed of the catalytic and translocation domains of diphtheria toxin (DT) fused to the granulocyte-macrophage colony-stimulating factor (GM-CSF) in which the DT furin cleavage site 163RVRRSV170 is modified to a urokinase plasminogen activator (uPA) cleavage site (163)GSGRSA(170), termed U2. DTU2GMCSF was highly toxic to the TF1-vRaf AML cell line (proliferation inhibition assay; IC50 := 3.14 pM), and this toxicity was greatly inhibited following pretreatment with anti-uPA and anti-GM-CSF antibodies. The activity of this toxin was then tested on a larger group of 13 human AML cell lines; 5 of the 13 cell lines were sensitive to DTU2GMCSF. An additional 5 of the 13 cell lines became sensitive when exogenous pro-uPA was added. Sensitivity to DTU2GMCSF strongly correlated with the expression levels of uPA receptors (uPARs) and GM-CSF receptors (GM-CSFRs) as well as with total uPA levels. DTU2GMCSF was less toxic to normal cells expressing uPAR or GMCSFR alone, that is, human umbilical vein endothelial cells and peripheral macrophages, respectively. These results indicate that DTU2GMCSF may be a selective and potent agent for the treatment of patients with AML. (C) 2004 by The American Society of Hematology. C1 Wake Forest Univ, Sch Med, Dept Biochem & Mol Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Natl Inst Dent & Craniofacial Res, Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD USA. RP Frankel, AE (reprint author), Wake Forest Univ, Sch Med, Dept Biochem & Mol Biol, Hanes 4046,Med Ctr Blvd, Winston Salem, NC 27157 USA. EM afrankel@wfubmc.edu NR 20 TC 24 Z9 27 U1 1 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 OCT 1 PY 2004 VL 104 IS 7 BP 2143 EP 2148 DI 10.1182/blood-2004-01-0339 PG 6 WC Hematology SC Hematology GA 857JP UT WOS:000224112800042 PM 15161668 ER PT J AU Haldeman, RJ Cooper, LF Hart, TC Phillips, C Boyd, C Wright, JT Lester, GE AF Haldeman, RJ Cooper, LF Hart, TC Phillips, C Boyd, C Wright, JT Lester, GE TI Increased bone density associated with DLX3 mutation in the tricho-dento-osseous syndrome SO BONE LA English DT Article DE bone; density; osteogenesis; transcription factor; distal-less gene ID DENTO-OSSEOUS SYNDROME; X-RAY ABSORPTIOMETRY; DISTAL-LESS; HOMEOBOX GENES; DISTINCT ROLES; MICE LACKING; TDO SYNDROME; DIFFERENTIATION; HETEROGENEITY; OSTEOPOROSIS AB Tricho-dento-osseous syndrome (TDO) (OMIM #190320) is an autosomal dominant disorder characterized and named for the three most commonly affected tissues hair, teeth, and bones. Common to all individuals with TDO studied to date is a four base-pair deletion in the DLX3 gene on chromosome 17q21. This mutation is associated with a variable bone phenotype that includes alteration in intramembranous bone formation in the skull. The purpose of this study was to characterize and compare endochondral bone phenotypes and variability at central and peripheral locations of the skeleton by evaluating bone density in individuals having the same DLX3, 4 bp DEL,NT3 198 mutation (OMIM 600525) and non-affected family members using dual-energy x-ray absorptiometry (DEXA). Thirty-four individuals (20 TDO-affected and 14 non-affected) participated in this prospective study. All participants were evaluated for the DLX3 mutation associated with TDO. All subjects received DEXA scans at common, literature-supported osteoporotic test regions including: (1) non-dominant distal radius/ulna, (2) femoral neck, and (3) lumbar spine L2-4. There was a significant increase (P < 0.05) in bone mineral density in TDO-affected individuals compared with control individuals at each test region. The markedly increased bone density in individuals having the DLX3, 4 bp DEL, NT3198 mutation shows that this alteration affects both endochondral and intramembranous bone formation and suggests that the DLX3 gene is important in bone formation and/or homeostasis of the appendicular skeleton. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Dent, Dept Prosthodont, Chapel Hill, NC 27599 USA. NIDCR, Human Craniofacial Genet Sect, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Dent, Dept Orthodont, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Orthopaed & Pharmacol, Chapel Hill, NC 27599 USA. RP Wright, JT (reprint author), Univ N Carolina, Sch Dent, Dept Pediat Dent, Brauer Hall CB, Chapel Hill, NC 27599 USA. EM tim_wright@dentistry.unc.edu FU NCRR NIH HHS [RR00046]; NIDCR NIH HHS [DE12202] NR 38 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD OCT PY 2004 VL 35 IS 4 BP 988 EP 997 DI 10.1016/j.bone.2004.06.003 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 862WY UT WOS:000224523300020 PM 15454107 ER PT J AU Sidtis, DV Postman, WA Glosser, G AF Sidtis, DV Postman, WA Glosser, G TI Feast or famine: Fixed expressions in the spontaneous speech of left hemisphere- and right hemisphere-damaged subjects SO BRAIN AND LANGUAGE LA English DT Meeting Abstract ID LANGUAGE C1 NYU, NKI, New York, NY USA. NIDCD, NIH, Bethesda, MD USA. EM drv1@nyu.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD OCT PY 2004 VL 91 IS 1 BP 47 EP 48 DI 10.1016/j.bandl.2004.06.026 PG 2 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 861TZ UT WOS:000224442800021 ER PT J AU Luo, Q Weekes, BS AF Luo, Q Weekes, BS TI Tonal dyslexia in Chinese SO BRAIN AND LANGUAGE LA English DT Meeting Abstract ID MANDARIN CHINESE; SPEECH C1 NIMH, Bethesda, MD 20892 USA. Univ Sussex, Brighton BN1 9QG, E Sussex, England. EM B.S.Weekes@sussex.ac.uk RI Weekes, Brendan/E-9897-2010 NR 6 TC 4 Z9 4 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD OCT PY 2004 VL 91 IS 1 BP 102 EP 103 DI 10.1016/j.bandl.2004.06.053 PG 2 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 861TZ UT WOS:000224442800049 ER PT J AU Frattali, C Kang, YK AF Frattali, C Kang, YK TI An errorless learning approach to treating dysnomia SO BRAIN AND LANGUAGE LA English DT Meeting Abstract AB Few errorless learning approaches to dysnomia treatment are found in the aphasia literature; none are found when paired with effortful rather than effortless learning (Fillingham, Hodgson, Sage, & Lambon Ralph, 2003). Grounded in Hebbian plasticity (Hebb, 1961), errorless learning occurs with increases in synaptic strength. Therefore, if a stimulus elicits an errorless response, Hebbian learning will strengthen the tendency to activate the same pattern of response on subsequent occasions. Our interest was in developing and piloting a treatment method of errorless and effortful learning cast in an ecologically valid framework of interactive discourse. (C) 2004 Published by Elsevier Inc. C1 NIH, Speech Language Pathol Sect, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. EM carol_frattali@nih.gov NR 5 TC 2 Z9 2 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD OCT PY 2004 VL 91 IS 1 BP 177 EP 178 DI 10.1016/j.bandl.2004.06.091 PG 2 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 861TZ UT WOS:000224442800087 ER PT J AU Harvey, BK Mark, A Chou, J Chen, GJ Hoffer, BJ Wang, Y AF Harvey, BK Mark, A Chou, J Chen, GJ Hoffer, BJ Wang, Y TI Neurotrophic effects of bone morphogenetic protein-7 in a rat model of Parkinson's disease SO BRAIN RESEARCH LA English DT Article DE bone morphogenetic protein-7; Parkinson's disease; neuroprotection ID MIDBRAIN DOPAMINERGIC-NEURONS; SUBSTANTIA-NIGRA; 6-HYDROXYDOPAMINE LESION; OSTEOGENIC PROTEIN-1; STROKE RATS; TIME-COURSE; IN-VIVO; BRAIN; ISCHEMIA; TRANSPLANTATION AB Previous studies have demonstrated that pretreatment with bone morphogenetic protein-7 (BMP7) reduces ischemic neuronal injury in vivo. Moreover, exogenous application of BMP7 increases both the number of tyrosine hydroxylase (+) cells and dopamine (DA) uptake in rat mesencephalic cell cultures. The purpose of this study was to investigate the in vivo effects of BMP7 on 6-hydroxydopamine (6-OHDA) induced lesioning of midbrain DA neurons. Adult Fischer 344 rats were anesthetized and injected with BMP7 or vehicle into the left substantia nigra, followed by local administration of 9 mug of 6-OHDA into the left medial forebrain bundle. The lesioned animals that received BMP7 pretreatment, as compared to vehicle/6-OHDA controls, had a significant reduction in methamphetamine-induced rotation 1 month after the surgery. BMP7-pretreatment partially preserved KCl-induced dopamine release in the lesioned striatum and significantly increased TH immunoreactivity in the lesioned nigra and striatum. In summary, our data suggest that BMP7 has neuroprotective and/or neuroreparative effects against 6-OHDA lesioning of the nigrostriatal DA pathway in an animal model of Parkinson's disease (PD). Published by Elsevier B.V. C1 Natl Inst Drug Abuse, Neural Protect & Regenerat Sect, NIH, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Drug Abuse, Neural Protect & Regenerat Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov NR 34 TC 22 Z9 23 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 OCT 1 PY 2004 VL 1022 IS 1-2 BP 88 EP 95 DI 10.1016/j.brainres.2004.06.072 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 856GL UT WOS:000224033600011 PM 15353217 ER PT J AU Cairo, MS Bishop, M AF Cairo, MS Bishop, M TI Tumour lysis syndrome: new therapeutic strategies and classification SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE tumour lysis syndrome; allopurinol; rasburicase ID RECOMBINANT URATE OXIDASE; METABOLIC COMPLICATIONS; LYMPHOID MALIGNANCIES; RECEIVING ALLOPURINOL; NEOPLASTIC DISEASE; PURINE EXCRETION; ACUTE-LEUKEMIA; HYPERURICEMIA; PREVENTION; HYPERPHOSPHATEMIA AB Tumour lysis syndrome (TLS) describes the metabolic derangements that occur with tumour breakdown following the initiation of cytotoxic therapy. TLS results from the rapid destruction of malignant cells and the abrupt release of intracellular ions, nucleic acids, proteins and their metabolites into the extracellular space. These metabolites can overwhelm the body's normal homeostatic mechanisms and cause hyperuricaemia, hyperkalaemia, hyperphosphaetemia, hypocalcaemia and uraemia. TLS can lead to acute renal failure and can be life-threatening. Early recognition of patients at risk and initiation of therapy for TLS is essential. There is a high incidence of TLS in tumours with high proliferative rates and tumour burden such as acute lymphoblastic leukaemia and Burkitt's lymphoma. The mainstays of TLS prophylaxis and treatment include aggressive hydration and diuresis, control of hyperuricaemia with allopurinol prophylaxis and rasburicase treatment, and vigilant monitoring of electrolyte abnormalities. Urine alkalinization remains controversial. Unfortunately, there have been few comprehensive reviews on this important subject. In this review, we describe the incidence, pathophysiological mechanisms of TLS and risk factors for its development. We summarise recent advances in the management of TLS and provide a new classification system and recommendations for prophylaxis and/or treatment based on this classification scheme. C1 Columbia Univ, Childrens Hosp New York Presbyterian, Dept Pediat, New York, NY USA. NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Cairo, MS (reprint author), Columbia Univ, Div Pediat Hematol & Blood & Marrow Transplantat, 180 Ft Washington Ave,HP 506, New York, NY 10032 USA. EM mc1310@columbia.edu FU NCI NIH HHS [P30 CA13696, U01 CA97452] NR 41 TC 260 Z9 279 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2004 VL 127 IS 1 BP 3 EP 11 DI 10.1111/j.1365-2141.2004.05094.x PG 9 WC Hematology SC Hematology GA 856FE UT WOS:000224030300001 PM 15384972 ER PT J AU Maslov, LN Lasukova, TV Bespalova, ZD Oldgen, P Rice, KK Nagase, H AF Maslov, LN Lasukova, TV Bespalova, ZD Oldgen, P Rice, KK Nagase, H TI delta-opioid receptor antagonists exhibit properties of partial delta-receptor agonists in isolated perfused heart SO BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE opioid receptor ligands; isolated perfused heart AB Perfusion of the isolated intact rat heart with Krebs-Henseleit solution containing agonists ((-)-TAN-67, DPDPE, and dalargin) or antagonists of delta-opioid receptors (naltrindole, TIPP[psi], and ICI 174,864) in a final concentration of 0.1 mg/liter was followed by a decrease in the heart rate, end-diastolic pressure, contraction rate, relaxation rate, and left ventricular developed pressure. Perfusion with a solution containing the delta-opioid receptor agonist DPDPE or delta-antagonists naltrindole, TIPP[psi], and ICI 174,864 before modeling of global ischemia increased the severity of reperfusion-induced contractile dysfunction in the myocardium. Our results suggest that delta-opioid receptor antagonists in vitro exhibit properties of partial delta-receptor agonists. C1 Russian Acad Med Sci, Inst Cardiol, Tomsk Res Ctr, Siberian Div, Moscow 109801, Russia. Tomsk State Pedag Univ, Moscow, Russia. Russian Minist Hlth, Russian Cardiol Res & Prod Ctr, Lab Peptide Synthesis, Moscow, Russia. Univ Kentucky, Dept Pathol, Lexington, KY USA. NIDDKD, NIH, Med Chem Lab, Bethesda, MD 20892 USA. Toray Ind Co, Fundamental Res Labs, Kamakura, Kanagawa, Japan. RP Maslov, LN (reprint author), Russian Acad Med Sci, Inst Cardiol, Tomsk Res Ctr, Siberian Div, Moscow 109801, Russia. EM maslov@cardio.tsu.ru NR 13 TC 0 Z9 0 U1 0 U2 2 PU CONSULTANTS BUREAU PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0007-4888 J9 B EXP BIOL MED+ JI Bull. Exp. Biol. Med. PD OCT PY 2004 VL 138 IS 4 BP 376 EP 379 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 909ED UT WOS:000227842100016 PM 15665949 ER PT J AU Yonehara, S Brenner, AV Kishikawa, M Inskip, PD Preston, DL Ron, E Mabuchi, K Tokuoka, S AF Yonehara, S Brenner, AV Kishikawa, M Inskip, PD Preston, DL Ron, E Mabuchi, K Tokuoka, S TI Clinical and epidemiologic characteristics of first primary tumors of the central nervous system and related organs among atomic bomb survivors in Hiroshima and Nagasaki, 1958-1995 SO CANCER LA English DT Article DE Japan; epidemiology; atomic warfare; longitudinal study; central nervous system neoplasms; pituitary neoplasms; trends ID PRIMARY BRAIN-TUMORS; VESTIBULAR SCHWANNOMA; CANCER INCIDENCE; UNITED-STATES; RADIATION; TRENDS; CHILDHOOD; MENINGIOMAS; IRRADIATION; HEAD AB BACKGROUND. Analysis conducted in the Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki found a significant dose-related excess of tumors of the central nervous system (CNS) and the pituitary gland. The objective of the current study was to evaluate clinical and epidemiologic characteristics of first primary tumors of the CNS and the pituitary gland in this cohort and to compare them with characteristics among other populations. METHODS. CNS and pituitary gland tumors that were diagnosed between 1958 and 1995 among 80,160 LSS cohort members were ascertained through Hiroshima and Nagasaki tumor registries, autopsy reports, and other sources. Pathologists reviewed all available records and slides to verify histologic diagnoses. Poisson regression analysis was used to model background incidence rates allowing for radiation effects. RESULTS. Meningioma was the most common tumor among clinically diagnosed tumors, followed by neuroepithelial tumor, schwannoma, and pituitary tumor. The overall incidence of these tumors increased initially with age but declined among the elderly. For all age groups and for both genders, incidence increased over time. By contrast, when tumors diagnosed at autopsy were included, incidence rose continuously with age and was stable over time. CONCLUSIONS. The main characteristics of CNS and pituitary gland tumors diagnosed in the LSS cohort were consistent with the characteristics of "spontaneous" tumors observed in other population-based studies. The predominance of meningiomas over neuroepithelial tumors in the Japanese population was noteworthy and warrants further investigation. The secular rise in incidence of all clinically diagnosed CNS and pituitary gland tumors is most likely to be attributable to the increased use of new imaging techniques. Published 2004 by the American Cancer Society.*. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Nagasaki Univ, Sch Med, Sci Data Ctr Atom Bomb Disaster, Nagasaki 852, Japan. Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. RP Brenner, AV (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd,MSC 7362, Bethesda, MD 20892 USA. FU NCPDCID CDC HHS [NCI-4893-8-001] NR 40 TC 32 Z9 33 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2004 VL 101 IS 7 BP 1644 EP 1654 DI 10.1002/cncr.20543 PG 11 WC Oncology SC Oncology GA 855RV UT WOS:000223992300023 PM 15378499 ER PT J AU Xiao, WH Hodge, DR Wang, LH Yang, XY Zhang, XH Farrar, WL AF Xiao, WH Hodge, DR Wang, LH Yang, XY Zhang, XH Farrar, WL TI NF-kappa B activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, but is independent of its IL6-NF kappa B regulatory site in autocrine human multiple myeloma cells SO CANCER BIOLOGY & THERAPY LA English DT Article DE IL-6; multiple myeloma; autocrine; NF-kappa B; c-Jun; IL-6 promoter ID INFLAMMATORY RESPONSE; GENE-TRANSCRIPTION; INDUCED APOPTOSIS; BINDING; PROTEIN; CANCER; P50; PHOSPHORYLATION; ACETYLATION; PROMOTER AB IL-6 stimulates the growth and survival of a variety of tumors. In multiple myeloma (MM), IL-6 prevents spontaneous, drug-induced, and Fas-induced apoptosis. The sources of IL-6 in multiple myeloma appear to be both autocrine and paracrine in nature, with autocrine MM cells exhibiting a constitutively activated expression of the cytokine. Here we present a systematic analysis of the functional roles of the four major transcriptional regulatory sites present in the IL-6 promoter region, IL6-NFkappaB, IL6-C/EBP, IL6-CREB and IL6-AP1. Among these regulatory sites, IL6-AP1 is the most important cis-regulatory site, and plays a vital role in the constitutive expression of IL-6 in IM9 cells. Conversely, the IL6-CREB site, when bound by the transcription factor CREB, exhibits a repression of IL-6 autocrine expression, a result of possible steric hinderence of C/EBP-P, due to the close proximity and site overlap between the IL6-C/EBP and IL6-CREB sites. Uniquely, although the presence of NF-kappaB protein is fundamental for constitutive expression of IL-6, a functional NF-kappaB site on the IL-6 promoter region is not required. The mechanism of NF-kappaB activation of IL-6 appears to occur through the cooperation with c-Jun protein, that constitutively occupies the IL6-AP1 site, and this indicates a novel transcriptional mechanism for NF-kappaB in the activation of NF-kappaB-driven genes. C1 NCI, Frederick Canc Res & Dev Ctr, Cytokine Mol Mech Sect, Lab Mol Immunoregulat,NIH, Frederick, MD 21702 USA. SAIC, Basic Res Program, Frederick, MD USA. RP Farrar, WL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Cytokine Mol Mech Sect, Lab Mol Immunoregulat,NIH, POB B,Bldg 560,Rm 31-76, Frederick, MD 21702 USA. EM farrar@ncifcrf.gov RI Xiao, Weihua/N-2775-2013 OI Xiao, Weihua/0000-0001-9102-6326 FU NCI NIH HHS [N01-CO-12400] NR 28 TC 56 Z9 62 U1 0 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD OCT PY 2004 VL 3 IS 10 BP 1007 EP 1017 PG 11 WC Oncology SC Oncology GA 903QI UT WOS:000227440300025 PM 15467434 ER PT J AU Rangel, LBA Agarwal, R Sherman-Baust, CA de Mello-Coelho, V Pizer, ES Ji, HX Taub, DD Morin, PJ AF Rangel, LBA Agarwal, R Sherman-Baust, CA de Mello-Coelho, V Pizer, ES Ji, HX Taub, DD Morin, PJ TI Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers SO CANCER BIOLOGY & THERAPY LA English DT Article DE ovarian cancer; HLA-DR; Ii; CD74; immunoediting; biomarker; Class II MHC ID CLASS-II TRANSACTIVATOR; BARE LYMPHOCYTE SYNDROME; GENE-EXPRESSION; GASTRIC-CANCER; PROGNOSTIC-SIGNIFICANCE; ANTIGEN EXPRESSION; THYROID-CARCINOMA; INTERFERON-GAMMA; TUMOR ESCAPE; T-CELLS AB Tumor formation in immunocompetent hosts is believed to be dependent on the ability of tumor cells to evade the immune system, as suggested by the alterations of expression of the major histocompatibility complex (MHC) and related molecules in a number of cancers. Our previous serial analysis of gene expression (SAGE) study revealed that HLA-DRA (encoding the alpha chain of HLA-DR) is one of the most highly overexpressed genes in ovarian cancer. This finding was unanticipated, as overexpression of MHC molecules would be expected to increase tumor immunogenicity, therefore compromising tumor growth. We have now examined the expression of HLA-DR alpha chain in ovarian and a variety of other cancers using tissue arrays and found it overexpressed in a majority of the cancer tissues investigated. In contrast, the HLA-DR beta chain, which together with the a chain forms the functional HLA-DR complex, was not frequently found expressed in cancer, resulting to a lack of mature HLA-DR in these tissues. Interestingly, HLADRA and HLADRB transcripts were both found expressed in many other cancer types, including ovarian cancer, suggesting that the downregulation of HLADR beta chain is a post-transcriptional or post-translational mechanism. In addition, we observed high levels of the invariant chain (li/CD74) expression in both the cytoplasm and plasma membrane of ovarian tumor cells, possibly contributing to the lack of mature HLA-DR protein expression. Interestingly, we found that IFN-gamma could induce mature HLA-DR at the surface of normal ovarian cells, while this ability was reduced in tumor cells. Together, these data suggest that, while ovarian tumors overexpress HLA-DR alpha, perhaps as a result of inflammatory events in the tumor microenvironment, the tumor cells may have compensatory mechanisms to reduce the production of functional MHC class II molecules, thus reducing immunogenicity and favoring tumor growth. In addition, because of its ubiquitous expression in ovarian and other cancers, HLA-DR alpha may represent a novel biomarker for malignancy. C1 NIA, Gerontol Res Ctr, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Immunol Lab, NIH, Baltimore, MD 21224 USA. Fed Univ Rio De Janeiro, Dept Basic & Clin Pharmacol, Rio De Janeiro, Brazil. Swedish Med Ctr, Seattle, WA USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), NIA, Gerontol Res Ctr, Lab Cellular & Mol Biol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM morinp@grc.nia.nih.gov NR 56 TC 20 Z9 26 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD OCT PY 2004 VL 3 IS 10 BP 1021 EP 1027 PG 7 WC Oncology SC Oncology GA 903QI UT WOS:000227440300027 PM 15467430 ER PT J AU Colt, JS Baris, D Stewart, P Schned, AR Heaney, JA Mott, LA Silverman, D Karagas, M AF Colt, JS Baris, D Stewart, P Schned, AR Heaney, JA Mott, LA Silverman, D Karagas, M TI Occupation and bladder cancer risk in a population-based case-control study in New Hampshire SO CANCER CAUSES & CONTROL LA English DT Article DE bladder cancer; occupation; case-control study; epidemiology ID LOWER URINARY-TRACT; NON-HODGKINS LYMPHOMA; RURAL NEW-ENGLAND; UNITED-STATES; MORTALITY; MEN; EXPOSURE; CYCLOPHOSPHAMIDE; CARCINOMA; INDUSTRY AB Objective: To identify occupations with excess bladder cancer risk in New Hampshire, where bladder cancer mortality rates have been elevated for decades. Methods: Lifetime occupational histories were obtained from interviews with 424 cases and 645 controls in a population-based case-control study. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for each occupation, adjusted for age and smoking. Analyses by duration of employment were carried out and interactions with smoking were examined. Results: Male tractor-trailer truck drivers had an elevated risk for bladder cancer ( OR = 2.4, CI = 1.4 - 4.1), with a significant positive trend in risk with increasing duration of employment (P-trend = 0.0003). Male metal/plastic processing machine operators also had a significant excess ( OR = 4.9, CI = 1.6 - 15.1), attributable mainly to molding/casting machine operators ( OR = 16.6, CI = 2.1 - 131). Elevated risk was also observed for male fabricators, assemblers, and hand workers ( OR = 1.8, CI = 1.0 - 3.4). Women in certain sales occupations ( sales clerks, counter clerks, and cashiers) had a significant excess risk ( OR = 2.2, CI = 1.3 - 3.9) and a significant trend with duration of employment (P-trend = 0.016), as did female health service workers (OR = 4.1, CI = 1.6 - 10.7; P-trend = 0.014). There was a positive interaction between smoking and employment as a health service worker ( p = 0.036). Conclusions: These findings are generally consistent with previous studies. Elevated risks for male molding/casting machine operators, female salesworkers, and female health service workers, especially those with a history of smoking, require further investigation. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Dartmouth Coll, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03755 USA. RP Colt, JS (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Room 8112, Bethesda, MD 20892 USA. EM coltj@mail.nih.gov NR 42 TC 41 Z9 41 U1 3 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2004 VL 15 IS 8 BP 759 EP 769 DI 10.1023/B:CACO.0000043426.28741.a2 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 857YZ UT WOS:000224158300002 PM 15456989 ER PT J AU Spiegel, AM AF Spiegel, AM TI Focus on hereditary endocrine neoplasia SO CANCER CELL LA English DT Review ID PARATHYROID CARCINOMA; THYROID-CANCER; MUTATIONS; HRPT2; GENE; MANAGEMENT; DISEASE C1 Natl Inst Deafness & Commun Disorders, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. RP Spiegel, AM (reprint author), Natl Inst Deafness & Commun Disorders, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. EM spiegela@extra.niddk.nih.gov NR 25 TC 3 Z9 3 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT PY 2004 VL 6 IS 4 BP 327 EP 332 DI 10.1016/j.ccr.2004.09.023 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 865HO UT WOS:000224693500005 PM 15488756 ER PT J AU Gius, D Cui, HM Bradbury, CM Cook, J Smart, DDK Zhao, SP Young, L Brandenburg, SA Hu, YL Bisht, KS Ho, AS Mattson, D Sun, LC Munson, PJ Chuang, EY Mitchell, JB Feinberg, AP AF Gius, D Cui, HM Bradbury, CM Cook, J Smart, DDK Zhao, SP Young, L Brandenburg, SA Hu, YL Bisht, KS Ho, AS Mattson, D Sun, LC Munson, PJ Chuang, EY Mitchell, JB Feinberg, AP TI Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach SO CANCER CELL LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; TUMOR-SUPPRESSOR GENE; GROWTH-FACTOR-II; DNA METHYLATION; CPG METHYLATION; COLORECTAL-CANCER; RAT HEPATOMA; PROMOTER; CELLS; CTCF AB We tested the hypothesis that the effects on gene expression of altered DNA methylation by 5-aza-2'-deoxycytidine (5-aza-CdR) and genetic (DNMT knockout) manipulation of DNA are similar, and distinct from Trichostatin A (TSA)-induced chromatin decondensation. Surprisingly, the effects of 5-aza-CdR were more similar to those of TSA than to DNMT1, DNMT3B, or double DNMT somatic cell knockout. Furthermore, the effects of 5-aza-CdR were similar at one and five days exposure, suggesting active demethylation or direct influence of both drugs on the stability of methylation and/or chromatin marks. Agents that induce gene activation through hypomethylation may have unintended consequences, since nearly as many genes were downregulated as upregulated after demethylation. In addition, a 75 kb cluster of metallothionein genes was coordinately regulated. C1 Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Biol Mol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. NCI, Radiat Oncol Branch, Radiat Oncol Sci Program,Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Feinberg, AP (reprint author), Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. EM afeinberg@jhu.edu RI Cui, Hengmi/A-2598-2008 FU NCI NIH HHS [CA65145, CA72602, CA75556, R37 CA054358, R37 CA054358-14] NR 42 TC 132 Z9 134 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT PY 2004 VL 6 IS 4 BP 361 EP 371 DI 10.1016/j.ccr.2004.08.029 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 865HO UT WOS:000224693500008 PM 15488759 ER PT J AU Morgan, RJ Synold, TW Gandara, D Muggia, F Scudder, S Reed, E Margolin, K Raschko, J Leong, L Shibata, S Tetef, M Vasilev, S McGonigle, K Longmate, J Yen, Y Chow, W Somlo, G Carroll, M Doroshow, JH AF Morgan, RJ Synold, TW Gandara, D Muggia, F Scudder, S Reed, E Margolin, K Raschko, J Leong, L Shibata, S Tetef, M Vasilev, S McGonigle, K Longmate, J Yen, Y Chow, W Somlo, G Carroll, M Doroshow, JH TI Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE chemomodulation; chemotherapy; phase II ID REFRACTORY GYNECOLOGIC CANCER; MULTIDRUG-RESISTANCE; WHOLE-BLOOD; DRUG-RESISTANCE; CARCINOMA CELLS; ONCOLOGY-GROUP; MODULATION; EXPRESSION; ASSAY; METABOLITES AB Purpose. To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA. Experimental design. To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Results. Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean+/-SD end-of-infusion CSA level (HPLC assay) was 1253+/-400 mug/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC. Conclusions. Steady-state levels of >1 mug/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics. C1 City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. Univ So Calif, Dept Med Oncol, Los Angeles, CA USA. Univ Calif Davis, Dept Med Oncol, Davis, CA 95616 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Morgan, RJ (reprint author), City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM rmorgan@coh.org OI Muggia, Franco/0000-0003-0703-9146 FU NCI NIH HHS [CA 33572, CA 62505, CA 63265] NR 27 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2004 VL 54 IS 4 BP 283 EP 289 DI 10.1007/s00280-004-0818-x PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 849RG UT WOS:000223557700001 PM 15184995 ER PT J AU Althuis, MD Fergenbaum, JH Garcia-Closas, M Brinton, LA Madigan, MP Sherman, ME AF Althuis, MD Fergenbaum, JH Garcia-Closas, M Brinton, LA Madigan, MP Sherman, ME TI Etiology of hormone receptor-defined breast cancer: A systematic review of'the literature SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID ESTROGEN REPLACEMENT THERAPY; WOMEN UNITED-STATES; PROGESTERONE-RECEPTOR; RISK-FACTORS; POSTMENOPAUSAL WOMEN; FAMILY-HISTORY; EPIDEMIOLOGIC CHARACTERISTICS; COLLABORATIVE REANALYSIS; ALCOHOL-CONSUMPTION; MENSTRUAL FACTORS AB Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite.. limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor-defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor-positive than hormone receptor-negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor-defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology. C1 NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. RP Althuis, MD (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Room 7084,6120 Execut Blvd, Rockville, MD 20852 USA. EM mda27@georgetown.edu RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562 NR 92 TC 361 Z9 369 U1 8 U2 25 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2004 VL 13 IS 10 BP 1558 EP 1568 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 861YE UT WOS:000224453700004 PM 15466970 ER PT J AU Shields, TS Brinton, LA Burk, RD Wang, SS Weinstein, SJ Ziegler, RG Studentsov, YY McAdams, M Schiffman, M AF Shields, TS Brinton, LA Burk, RD Wang, SS Weinstein, SJ Ziegler, RG Studentsov, YY McAdams, M Schiffman, M TI A case-control study of risk factors for invasive cervical cancer among US women exposed to oncogenic types of human papillomavirus SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VIRUS-LIKE PARTICLES; LINKED-IMMUNOSORBENT-ASSAY; MULTICENTRIC CASE-CONTROL; CHLAMYDIA-TRACHOMATIS; SEXUAL-BEHAVIOR; INTRAEPITHELIAL NEOPLASIA; YOUNG-WOMEN; COSTA-RICA; HIGH-GRADE; INFECTION AB Oncogenic human papillomavirus (HPV) infections, the necessary cause of most cervical cancers, are common and usually clear within 1 to 2 years. Identifying cofactors that lead to cancer among HPV-infected women has depended mainly on case-control studies defining HPV by DNA testing. DNA testing assesses only current infection; thus, concerns about residual confounding remain. To assess cofactors, we used seropositivity to five oncogenic HPV types as a marker of past exposure and confined our analysis to seropositive controls compared with cancer cases. Study subjects had participated in a multicenter U.S. case-control study conducted in the early 1980s. The detailed questionnaire and stored sera for 235 cases of squamous carcinoma and 486 controls motivated the reanalysis. We measured antibodies to HPV types 16, 18, 31, 45, and 52. Independent, significant predictors of seropositivity among controls included numbers of sexual partners, Black race, and oral contraceptive use. Condom use was protective. Among HPV-exposed women, Papanicolaou screening, Black race, and yeast infection were significantly associated with reduced cancer risk. Current smoking was associated with a 2-fold increase in risk; there were independent, significant trends of increased risk with numbers of cigarettes smoked.(P for trend = 0.003) and years of smoking (P for trend = 0.01). Other significant predictors of increased risk included low education and income and history of nonspecific genital infection. Unlike recent HPV DNA-based investigations, based on the use of HPV-seropositive controls in this study, oral contraceptive use was unrelated to the risk of cervical cancer and multiparity was only weakly related to risk. It is particularly worth considering further why studies of different designs are inconsistent regarding the effect of oral contraceptive use. C1 NCI, Div Canc Epidemiol & Genet, NIH,Hormonal & Reprod Epidemiol Branch, Dept HHS, Rockville, MD 20852 USA. Informat Management Serv Inc, Silver Spring, MD USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Shields, TS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH,Hormonal & Reprod Epidemiol Branch, Dept HHS, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM shieldst@mail.nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 30 TC 43 Z9 49 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2004 VL 13 IS 10 BP 1574 EP 1582 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 861YE UT WOS:000224453700006 PM 15466972 ER PT J AU Huang, K Whelan, EA Ruder, AM Ward, EM Deddens, JA Davis-King, KE Carreon, T Waters, MA Butler, MA Calvert, GM Schulte, PA Zivkovich, Z Heineman, EF Mandel, JS Morton, RF Reding, DJ Rosenman, KD AF Huang, K Whelan, EA Ruder, AM Ward, EM Deddens, JA Davis-King, KE Carreon, T Waters, MA Butler, MA Calvert, GM Schulte, PA Zivkovich, Z Heineman, EF Mandel, JS Morton, RF Reding, DJ Rosenman, KD CA Brain Canc Collaborative Study Gr TI Reproductive factors and risk of glioma in women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER RISK; BRAIN-TUMORS; UNITED-STATES; ASSOCIATION; HISTORY; EPIDEMIOLOGY; PREGNANCY; PARITY; AGE AB Objective: Glioma is the most common primary malignant brain tumor in adults, responsible for 75% of adult primary malignant brain tumors, yet aside from its association with ionizing radiation, its etiology is poorly understood. Sex differences in brain tumor incidence suggest that hormonal factors may play a role in the etiology of these tumors, but few studies have examined this association in detail. The objective of this study was to explore the role of reproductive factors in the etiology of glioma in women. Method: As part of a population-based case-control study, histologically confirmed primary glioma cases (n = 341 women) diagnosed between January 1, 1995 and January 31, 1997 were identified through clinics and hospitals in four Midwest U.S. states. Controls (n = 527 women) were randomly selected from lists of licensed drivers and Health Care Finance Administration enrollees. In-person interviews with subjects (81%) or their proxies (19%) collected reproductive history and other exposure information. Results: Glioma risk increased with older age at menarche (P for trend = 0.009) but only among postmenopausal women. Compared with women who never breast-fed, women who breast-fed >18 months over their lifetime were at increased risk of glioma (odds ratio, 1.8; 95% confidence interval, 1.1-2.9). Women who reported using hormones for symptoms of menopause had a decreased risk of glioma compared with women who never used such hormones (odds ratio, 0.7; 95% confidence interval, 0.5-1.1). Conclusion: These results support the hypothesis that reproductive hormones play a role in the etiology of glioma among women. C1 NIOSH, Div Surveillance Hazard Evaluat & Field Studi, Industrywide Studies Branch, Cincinnati, OH 45226 USA. Univ Cincinnati, Dept Math Sci, Cincinnati, OH 45221 USA. Natl Canc Inst, Rockville, MD USA. Univ Minnesota, Minneapolis, MN 55455 USA. St Johns Mercy Med Ctr, Des Moines, IA USA. Marshfield Med Res Fdn, Marshfield, WI 54449 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Whelan, EA (reprint author), NIOSH, Div Surveillance Hazard Evaluat & Field Studi, Industrywide Studies Branch, 4676 Columbia Pkwy,R-15, Cincinnati, OH 45226 USA. EM EWhelan@cdc.gov RI Carreon, Tania/A-6548-2008; Waters, Martha/B-7441-2011; Ruder, Avima/I-4155-2012 OI Ruder, Avima/0000-0003-0419-6664 NR 24 TC 38 Z9 40 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2004 VL 13 IS 10 BP 1583 EP 1588 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 861YE UT WOS:000224453700007 PM 15466973 ER PT J AU Purdue, MP Bassani, DG Klar, NS Sloan, M Kreiger, N AF Purdue, MP Bassani, DG Klar, NS Sloan, M Kreiger, N CA Canadian Canc Registries Epid TI Dietary factors and risk of non-Hodgkin lymphoma by histologic subtype: A case-control analysis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID WORKING FORMULATION; DRINKING-WATER; AGRICULTURAL PRACTICES; UNITED-STATES; OLDER WOMEN; CANCER-RISK; CONSUMPTION; NITRATE; TISSUE; VIRUS AB There is speculation that etiologic heterogeneity exists among tumors classified as non-Hodgkin lymphoma (NHL), although it is not known whether diet-related associations vary between tumor subgroups. We analyzed data on 1,642 NHL cases and 5,039 controls aged 20 to 74 years from a population-based case-control study conducted in eight Canadian provinces to explore associations between dietary factors and NHL by histologic subtype. Dietary information was collected using a 69-item food frequency questionnaire. Tumors were categorized into histologic subtypes using the contents of pathology reports from the original histopathologic review of diagnostic material. Odds ratios (OR) relating consumption of dietary factors (divided into three categories) to each NHL subtype (diffuse, follicular, small lymphocytic, high grade, peripheral T cell, and unspecified lymphomas) were calculated using polytomous logistic regression. We found an increased risk of NHL with high (versus low) intake of processed meat (OR, 1.49), cheese (OR, 1.38), eggs (OR, 1.49), and dessert foods (OR, 1.24). Positive associations with NHL were also found for high consumption of total fat (OR, 1.28), saturated fat (OR, 1.29), and monounsaturated fat (OR, 1.27). Associations for consumption of some vegetables and fats were found to differ between lymphoma subtypes. Given the large number of diet/subtype comparisons done, however, the possibility that this heterogeneity arose by chance cannot be ruled out. In conclusion, these findings generally do not support the existence of etiologic heterogeneity between histologic subtypes of NHL in their associations with components of dietary intake. C1 Canc Care Ontario, Div Prevent Oncol, Toronto, ON, Canada. Univ Toronto, Fac Med, Dept Publ Hlth Sci, Toronto, ON, Canada. Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON, Canada. Fed Univ Pelotas, Postgrad Program Epidemiol, Pelotas, Brazil. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8121,MSC 7240, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 NR 59 TC 52 Z9 52 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2004 VL 13 IS 10 BP 1665 EP 1676 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 861YE UT WOS:000224453700019 PM 15466985 ER PT J AU Slavin-Chiorini, DC Catalfamo, M Kudo-Saito, C Hodge, JW Schlom, J Sabzevari, H AF Slavin-Chiorini, DC Catalfamo, M Kudo-Saito, C Hodge, JW Schlom, J Sabzevari, H TI Amplification of the lytic potential of effector/memory CD8(+) cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy SO CANCER GENE THERAPY LA English DT Article DE CTL; costimulation; T lymphocytes; tumor immunity; vaccination ID INTERCELLULAR-ADHESION MOLECULE-1; CYTOTOXIC T-LYMPHOCYTES; SUPRAMOLECULAR ACTIVATION CLUSTERS; CARCINOEMBRYONIC ANTIGEN GENE; COSTIMULATORY MOLECULES; IMMUNOLOGICAL SYNAPSE; CO-STIMULATION; MELANOMA-CELLS; IN-VITRO; INDUCTION AB We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 ( designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8(+) T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8(+) T cells is mediated mainly through CD54. Intracellular staining of CD8(+) cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules ( specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8(+) T cells and heightened lytic activity of CD8(+) cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen ( CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 45 TC 27 Z9 28 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD OCT PY 2004 VL 11 IS 10 BP 665 EP 680 DI 10.1038/sj.cgt.7700741 PG 16 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 857CA UT WOS:000224091900002 PM 15354200 ER PT J AU Rapisarda, A Zalek, J Hollingshead, M Braunschweig, T Uranchimeg, B Bonomi, CA Borgel, SD Carter, JP Hewitt, SM Shoemaker, RH Melillo, G AF Rapisarda, A Zalek, J Hollingshead, M Braunschweig, T Uranchimeg, B Bonomi, CA Borgel, SD Carter, JP Hewitt, SM Shoemaker, RH Melillo, G TI Schedule-dependent inhibition of hypoxia-inducible factor-1 alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts SO CANCER RESEARCH LA English DT Article ID TOPOISOMERASE-I INHIBITORS; SOLID TUMORS; FACTOR 1-ALPHA; PHASE-I; CANCER; OVEREXPRESSION; CAMPTOTHECIN; HIF-1 AB We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1alpha protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1alpha protein expression in U251-HRE glioblastoma xenografts. Concomitant with HIF-1alpha inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissue. These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients. C1 NCI, DTP Tumor Hypoxia Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp Frederick Inc, NCI, Frederick, MD USA. NCI, Dev Therapeut Program, Frederick, MD USA. Adv Technol Ctr, Ctr Canc Res, Lab Pathol, NCI, Bethesda, MD USA. RP Melillo, G (reprint author), NCI, DTP Tumor Hypoxia Lab, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillog@ncifcrf.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU NCI NIH HHS [N01-CO-12400] NR 16 TC 136 Z9 144 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 6845 EP 6848 DI 10.1158/0008-5472.CAN-04-2116 PG 4 WC Oncology SC Oncology GA 859UC UT WOS:000224292400003 PM 15466170 ER PT J AU Hussain, SP Trivers, GE Hofseth, LJ He, PJ Shaikh, I Mechanic, LE Doja, S Jiang, WD Subleski, J Shorts, L Haines, D Laubach, VE Wiltrout, RH Djurickovic, D Harris, CC AF Hussain, SP Trivers, GE Hofseth, LJ He, PJ Shaikh, I Mechanic, LE Doja, S Jiang, WD Subleski, J Shorts, L Haines, D Laubach, VE Wiltrout, RH Djurickovic, D Harris, CC TI Nitric oxide, a mediator of inflammation, suppresses tumorigenesis SO CANCER RESEARCH LA English DT Article ID SYNTHASE EXPRESSION; P53-DEFICIENT MICE; APOPTOSIS; CELL; P53; NECROSIS; INTERLEUKIN-10; CANCER; SURVEILLANCE; ACTIVATION AB Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor alpha and interleukin 1beta, and produces nitric oxide (NO.), a critical mediator of the inflammatory response. Because p53 governs NO. production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO. and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53-/-NOS2-/- or p53-/-NOS2 +/- mice than in p53-/-NOS2+/+ mice that were crossbred into a >95% C57BL6 background and maintained in a pathogen-free condition. Likewise, sarcomas and lymphomas developed faster in p53+/-NOS2-/- or p53+/-NOS2+/- than in p53+/-NOS2+/+ mice. When compared with the double knockout mice, p53-/-NOS2+/+ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21(waf1), in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO. can suppress. tumorigenesis. C1 NCI, Lab Human Carcinogenet, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Univ S Carolina, Coll Pharm, Dept Basic Pharmaceut Sci, Columbia, SC USA. NCI, Lab Expt Immunol, Frederick, MD USA. Sci Applicat Int Corp, Lab Anim Sci Program, NCI, Frederick, MD USA. Univ Virginia, Hlth Sci Ctr, Dept Surg, Charlottesville, VA USA. Dev Ctr, Frederick, MD USA. RP Harris, CC (reprint author), NCI, Lab Human Carcinogenet, NIH, Ctr Canc Res, Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Laubach, Victor/E-8818-2015 OI Laubach, Victor/0000-0001-9673-5383 FU NCI NIH HHS [N01-CO-12400] NR 34 TC 77 Z9 82 U1 3 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 6849 EP 6853 DI 10.1158/0008-5472.CAN-04-2201 PG 5 WC Oncology SC Oncology GA 859UC UT WOS:000224292400004 PM 15466171 ER PT J AU Wei, JS Greer, BT Westermann, F Steinberg, SM Son, CG Chen, QR Whiteford, CC Bilke, S Krasnoselsky, AL Cenacchi, N Catchpoole, D Berthold, F Schwab, M Khan, J AF Wei, JS Greer, BT Westermann, F Steinberg, SM Son, CG Chen, QR Whiteford, CC Bilke, S Krasnoselsky, AL Cenacchi, N Catchpoole, D Berthold, F Schwab, M Khan, J TI Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; N-MYC; DROSOPHILA-DELTA; NERVOUS-SYSTEM; GROWTH-FACTOR; CELL FATE; AMPLIFICATION; DIFFERENTIATION; CANCER; CLASSIFICATION AB Currently, patients with neuroblastoma are classified into risk groups (e.g., according to the Children's Oncology Group risk-stratification) to guide physicians in the choice of the most appropriate therapy. Despite this careful stratification, the survival rate for patients with high-risk neuroblastoma remains <30%, and it is not possible to predict which of these high-risk patients will survive or succumb to the disease. Therefore, we have performed gene expression profiling using cDNA microarrays containing 42,578 clones and used artificial neural networks to develop an accurate predictor of survival for each individual patient with neuroblastoma. Using principal component analysis we found that neuroblastoma tumors exhibited inherent prognostic specific gene expression profiles. Subsequent artificial neural network-based prognosis prediction using expression levels of all 37,920 good-quality clones achieved 88% accuracy. Moreover, using an artificial neural network-based gene minimization strategy in a separate analysis we identified 19 genes, including 2 prognostic markers reported previously, MYCN and CD44, which correctly predicted outcome for 98% of these patients. In addition, these 19 predictor genes were able to additionally partition Children's Oncology Group-stratified high-risk patients into two subgroups according to their survival status (P = 0.0005). Our findings provide evidence of a gene expression signature that can predict prognosis independent of currently known risk factors and could assist physicians in the individual management of patients with high-risk neuroblastoma. C1 NCI, Oncogenet Sect, Pediat Oncol Branch, Adv Technol Ctr,NIH, Gaithersburg, MD 20877 USA. German Canc Res Ctr, Dept Tumour Genet B030, Heidelberg, Germany. NCI, Ctr Canc Res, Biostat & Data Management Sect, NIH, Bethesda, MD USA. Daejeon Univ, Coll Oriental Med, Dept Internal Med, Taejon, South Korea. Childrens Hosp, Tumour Bank, Westmead, NSW, Australia. Univ Cologne, Klin Kinderheilkunde, Dept Pediat, Cologne, Germany. RP Khan, J (reprint author), NCI, Oncogenet Sect, Pediat Oncol Branch, Adv Technol Ctr,NIH, 8717 Govt Circle, Gaithersburg, MD 20877 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NCI NIH HHS [Z01 SC010366-05] NR 44 TC 123 Z9 128 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 6883 EP 6891 DI 10.1158/0008-5472.CAN-04-0695 PG 9 WC Oncology SC Oncology GA 859UC UT WOS:000224292400010 PM 15466177 ER PT J AU Upender, MB Habermann, JK McShane, LM Korn, EL Barrett, JC Difilippantonio, MJ Ried, T AF Upender, MB Habermann, JK McShane, LM Korn, EL Barrett, JC Difilippantonio, MJ Ried, T TI Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells SO CANCER RESEARCH LA English DT Article ID COMPARATIVE-GENOMIC-HYBRIDIZATION; GENE-EXPRESSION; BREAST-CANCER; COPY NUMBER; INSITU HYBRIDIZATION; MICROARRAY ANALYSIS; MYELOID-LEUKEMIA; INSTABILITY; TUMORS; CARCINOMA AB Chromosomal aneuploidies are observed in essentially all sporadic carcinomas. These aneuploidies result in tumor-specific patterns of genomic imbalances that are acquired early during tumorigenesis, continuously selected for and faithfully maintained in cancer cells. Although the paradigm of translocation induced oncogene activation in hematologic malignancies is firmly established, it is not known how genomic imbalances affect chromosome-specific gene expression patterns in particular and how chromosomal aneuploidy dysregulates the genetic equilibrium of cells in general. To model specific chromosomal aneuploidies in cancer cells and dissect the immediate consequences of genomic imbalances on the transcriptome, we generated artificial trisomies in a karyotypically stable diploid yet mismatch repair-deficient, colorectal cancer cell line and in telomerase immortalized, cytogenetically normal human breast epithelial cells using microcell-mediated chromosome transfer. The global consequences on gene expression levels were analyzed using cDNA arrays. Our results show that regardless of chromosome or cell type, chromosomal trisomies result in a significant increase in the average transcriptional activity of the trisomic chromosome. This increase affects the expression of numerous genes on other chromosomes as well. We therefore postulate that the genomic imbalances observed in cancer cells exert their effect through a complex pattern of transcriptional dysregulation. C1 NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Biomet Res Branch, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Canc Ctr Karolinska, Dept Oncol & Pathol, Stockholm, Sweden. RP Ried, T (reprint author), NCI, Ctr Canc Res, Genet Branch, NIH, Bldg 50,Room 1408,50 S Dr, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov RI Habermann, Jens/E-2968-2010 FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 99 Z9 101 U1 3 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 6941 EP 6949 DI 10.1158/0008-5472.CAN-04-0474 PG 9 WC Oncology SC Oncology GA 859UC UT WOS:000224292400018 PM 15466185 ER PT J AU Cavin, LG Venkatraman, M Factor, VM Kaur, S Schroeder, I Mercurio, F Beg, AA Thorgeirsson, SS Arsura, M AF Cavin, LG Venkatraman, M Factor, VM Kaur, S Schroeder, I Mercurio, F Beg, AA Thorgeirsson, SS Arsura, M TI Regulation of a-fetoprotein by nuclear factor-kappa B protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis SO CANCER RESEARCH LA English DT Article ID TRANSGENIC MOUSE MODEL; GROWTH-FACTOR-ALPHA; EMBRYONIC LETHALITY; C-MYC; DEFICIENT MICE; HEPATOCELLULAR CARCINOMAS; BREAST-CANCER; ACTIVATION; APOPTOSIS; DEGENERATION AB Nuclear factor-kappaB (NF-kappaB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-kappaB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-kappaB kinase-beta (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-alpha/c-myc bitransgenic mice leads to inhibition of NF-kappaB and promotes tumor necrosis factor (TNF)-alpha-mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bel-X-L and XIAP, two pro-survival NF-kappaB target genes. In addition, we have identified the alpha-fetoprotein (AFP) as a novel downstream target of NF-kappaB. We show that repression of IKK-2 activity in hepatocellular carcinomas promotes down-regulation of AFP gene expression. Likewise, genetic disruption of the ReIA subunit results in reduced AFP gene expression during embryonic liver development, at a time in which fetal hepatocytes are sensitized to TNF-alpha-mediated cell killing. In this regard, we show that AFP inhibits TNF-alpha-induced cell death of murine hepatocellular carcinomas through association with TNF-alpha and inhibition of TNFRI signaling. Thus, NF-kappaB-mediated regulation of AFP gene expression during liver tumor formation and embryonic development of the liver constitutes a potential novel mechanism used by malignant and fetal hepatocytes to evade immune surveillance. C1 Univ Tennessee, Coll Med, Dept Pharmacol, Canc Inst,Ctr Anticanc Drug Res, Memphis, TN 38163 USA. NCI, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD USA. Columbia Univ, Dept Biosci, New York, NY USA. Celgene Signal Res Div, San Diego, CA USA. RP Arsura, M (reprint author), Univ Tennessee, Coll Med, Dept Pharmacol, Canc Inst,Ctr Anticanc Drug Res, 874 Union Ave, Memphis, TN 38163 USA. EM marsura@utmem.edu FU NCI NIH HHS [CA074892, CA78616, CA78616-S1] NR 37 TC 31 Z9 36 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 7030 EP 7038 DI 10.1158/0008-5472.CAN-04-1647 PG 9 WC Oncology SC Oncology GA 859UC UT WOS:000224292400029 PM 15466196 ER PT J AU Scacheri, PC Kennedy, AL Chin, K Miller, MT Hodgson, JG Gray, JW Marx, SJ Spiegel, AM Collins, FS AF Scacheri, PC Kennedy, AL Chin, K Miller, MT Hodgson, JG Gray, JW Marx, SJ Spiegel, AM Collins, FS TI Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; MEN1 GENE; PARATHYROID TUMORS; DNA-DAMAGE; MUTATIONS; INTERACTS; PROTEIN; EXPRESSION; RETINOBLASTOMA; HYBRIDIZATION AB Multiple endocrine neoplasia, type I (MEN1) is an inherited cancer syndrome characterized by tumors arising primarily in endocrine tissues. The responsible gene acts as a tumor suppressor, and tumors in affected heterozygous individuals occur after inactivation of the wild-type allele. Previous studies have shown that Men1 knockout mice develop multiple pancreatic insulinomas, but this occurs many months after loss of both copies of the Men1 gene. These studies imply that loss of Men1 is not alone sufficient for tumor formation and that additional somatic genetic changes are most likely essential for tumorigenesis. The usual expectation is that such mutations would arise either by a chromosomal instability or microsatellite instability mechanism. In a study of more then a dozen such tumors, using the techniques of array-based comparative genomic hybridization, fluorescent in situ hybridization, loss of heterozygosity analysis using multiple microsatellite markers across the genome, and real time PCR to assess DNA copy number, it appears that many of these full-blown clonal adenomas remain remarkably euploid. Furthermore, the loss of the wild-type Men1 allele in heterozygous Men1 mice occurs by loss and reduplication of the entire mutant-bearing chromosome. Thus, the somatic genetic changes that are postulated to lead to tumorigenesis in a mouse model of MEN1 must be unusually subtle, occurring at either the nucleotide level or through epigenetic mechanisms. C1 NIDDKD, Bethesda, MD 20892 USA. Natl Inst Deafness & Commun Disorders, Bethesda, MD 20892 USA. Univ Calif San Francisco Comprehens Canc Ctr, San Francisco, CA USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, NIH, Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. EM fc23a@nih.gov NR 42 TC 17 Z9 17 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2004 VL 64 IS 19 BP 7039 EP 7044 DI 10.1158/0008-5472.CAN-04-1648 PG 6 WC Oncology SC Oncology GA 859UC UT WOS:000224292400030 PM 15466197 ER PT J AU DeCicco, KL Tanaka, T Andreola, F De Luca, LM AF DeCicco, KL Tanaka, T Andreola, F De Luca, LM TI The effect of thalidomide on non-small cell lung cancer (NSCLC) cell lines: possible involvement in the PPAR gamma pathway SO CARCINOGENESIS LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; GENE-EXPRESSION; INDUCTION; INFLAMMATION; ANGIOGENESIS; INHIBITION; APOPTOSIS; PROGNOSIS; ANALOGS AB Lung cancer is the leading cause of cancer-related death in developed countries. Non-small cell lung cancer (NSCLC) represents 80% of the total lung cancer cases and is comprised of adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma and large cell carcinoma (LCC) subtypes. The ability of LCC to metastasize earlier than the other forms of lung cancer suggests anti-angiogenic drugs as effective agents to combat this cancer. Thalidomide is an anti-angiogenic drug that has shown promise in multiple hematological diseases, and myeloma and other cancers. However, the molecular mechanism by which thalidomide exerts its effects is poorly understood. Therefore, we evaluated the effectiveness of thalidomide on NSCLC cell growth, and found that LCC cells were growth inhibited by 40-60%. This effect seemed specific to LCC cancer cells, since other forms of NSCLC were only mildly affected by thalidomide. At the molecular level, thalidomide increased peroxisome proliferator-activated receptor gamma (PPARgamma) protein dose-dependently, and peroxisome proliferator response element activity. Further, thalidomide treatment of LCC cells decreased nuclear factor kappa B activity in a dose-dependent fashion, increased apoptosis and decreased the expression of angiogenic proteins. In our mouse xenograft model of lung cancer, we found that intratumoral thalidomide caused a 64% decrease in tumor growth; moreover, tumors from the thalidomide-treated mice expressed higher PPARgamma, than tumors from control mice. This study shows the antitumor activity of thalidomide against LCC tumors and suggests a model in which thalidomide exerts its antitumor effects on LCC cells through the induction of PPARgamma and subsequent downstream signaling. To our knowledge, this is the first study to show a link between thalidomide and PPARgamma. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP De Luca, LM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM delucal@dc37a.nci.nih.gov NR 30 TC 14 Z9 14 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 OCT PY 2004 VL 25 IS 10 BP 1805 EP 1812 DI 10.1093/carcin/bgh210 PG 8 WC Oncology SC Oncology GA 856YM UT WOS:000224082000003 PM 15205358 ER PT J AU Pereira, MA Tao, L Wang, W Li, Y Umar, A Steele, VE Lubet, RA AF Pereira, MA Tao, L Wang, W Li, Y Umar, A Steele, VE Lubet, RA TI Modulation by celecoxib and difluoromethylornithine of the methylation of DNA and the estrogen receptor-alpha gene in rat colon tumors SO CARCINOGENESIS LA English DT Article ID SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; MALIGNANT HUMAN-COLON; ABERRANT CRYPT FOCI; COLORECTAL-CANCER; C-MYC; CARCINOGENESIS; CHEMOPREVENTION; EXPRESSION; HYPOMETHYLATION; COMBINATION AB The ability of celecoxib and alpha-difluoromethylornithine (DFMO) to modulate the DNA hypomethylation and the hypermethylation of the estrogen receptor (ER)-alpha gene in colon tumors was evaluated as potential biomarkers for chemoprevention. Colon tumors were induced in rats by azoxymethane. Celecoxib (500 mg/kg), DFMO (100, 1000 and 3000 mg/kg) or celecoxib + 1000 mg/kg DFMO were administered in the diet for 7 or 28 days prior to death at week 37. Relative to the normal colon mucosa, colon tumors contained global hypomethylated DNA but simultaneous hypermethylation of the promoter plus exon-1 region of the ER-alpha gene. Limited treatment with celecoxib (500 p.p.m. in diet) or DFMO (1000 or 3000 p.p.m. in diet) reversed the DNA hypomethylation. Administering 1000 and 3000 p.p.m. DFMO for 7-days decreased the number of methylated CpG sites in the ER-alpha gene from 5.00 +/- 0.95 to 3.83 +/- 0.75 and 1.75 +/- 0.49 these levels were further reduced to 0.50 +/- 0.26 following administration of 1000 mg/kg for 28 days. Celecoxib administered for 7 and 28 days reduced the number of methylated sites to 4.25 +/- 0.48 and 1.5 +/- 0.50. The combination containing celecoxib and DFMO reduced the number of methylated sites to 0.20 +/- 0.20 at both 7 and 28 days. In parallel with the hypermethylation of the ER-alpha gene, the mRNA expression of the gene was decreased in colon tumors and was increased by celecoxib, DFMO or the combination. Celecoxib and DFMO reversed DNA hypomethylation and the hypermethylation of the ER-alpha gene in colon tumors supporting the hypothesis that modulation of methylation is a biomarker of chemoprevention. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Pereira, MA (reprint author), Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. EM pereira-l@medctr.osu.edu FU NCI NIH HHS [N01-CN-05123, N01-CN-15121] NR 34 TC 23 Z9 23 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 OCT PY 2004 VL 25 IS 10 BP 1917 EP 1923 DI 10.1093/carcin/bgh209 PG 7 WC Oncology SC Oncology GA 856YM UT WOS:000224082000016 PM 15205357 ER PT J AU Hu, J Nakano, H Sakurai, H Colburn, NH AF Hu, J Nakano, H Sakurai, H Colburn, NH TI Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-kappa B activation and transformation in resistant JB6 cells SO CARCINOGENESIS LA English DT Article ID TUMOR-NECROSIS-FACTOR; RIBOSOMAL S6 KINASE; PROTEIN-KINASE; FACTOR-ALPHA; TRANSCRIPTIONAL ACTIVITY; HISTONE H3; DEPENDENT TRANSCRIPTION; P65/RELA SUBUNIT; IN-VIVO; ACETYLATION AB NF-kappaB activation is required for TNF-alpha-induced transformation of JB6 mouse epidermal cells. Deficient activation of p65 contributes to the lack of NF-kappaB activation in transformation-resistant (P-) cells. We hypothesized that the differential NF-kappaB activation involves differential p65 phosphorylation arising from enzyme activity differences. Here we show that TNF-alpha induces greater ERK-dependent p65 phosphorylation at S536 in transformation sensitive (P+) cells than in P- cells. Our results establish that limited ERK content contributes to a low IkappaB kinase (IKKbeta) level, in turn resulting in insufficient p65 phosphorylation at S536 upon TNF-alpha stimulation in P- cells. Phosphorylation of p65 at S536 appears to play a role in TNF-alpha-induced p65 DNA binding and recruitment of p300 to the p65 complex as well as in release of p65 bound to HDAC1 and 3. Blocking p65 phosphorylation at S536, but not at S276 or S529, abolishes p65 transactivational activity. Over-expression of p65 but not p65 phosphorylation mutant (S536A) in transformation-resistant P- cells renders these cells sensitive to TNF-alpha-induced transformation. Over-expression of p65 phosphorylation mimics p65-S536D or p65-S536E in P- cells and also rescues the transformation response. These findings provide direct evidence that phosphorylation of p65 at S536 is required for TNF-alpha-induced NF-kappaB activation in the JB6 transformation model. The lack of NF-kappaB activation seen in P- cells can be attributed to an insufficient level of p65 phosphorylation on S536 that arises from insufficient IKKbeta that in turn arises from insufficient ERK. Thus, p65 phosphorylation at S536 offers a potential molecular target for cancer prevention. C1 NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. Juntendo Univ, Sch Med, Dept Immunol, Bunkyo Ku, Tokyo 1138421, Japan. Toyama Med & Pharmaceut Univ, Inst Nat Med, Dept Pathogen Biochem, Toyama 9300194, Japan. RP Hu, J (reprint author), NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. EM huji@ncifcrf.gov RI Hu, Jing/M-3130-2014; OI Sakurai, Hiroaki/0000-0003-0657-9570 NR 41 TC 83 Z9 86 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2004 VL 25 IS 10 BP 1991 EP 2003 DI 10.1093/carcin/bgh198 PG 13 WC Oncology SC Oncology GA 856YM UT WOS:000224082000025 PM 15192014 ER PT J AU Buxton, DB AF Buxton, DB TI Cytokines and Late Preconditioning SO CARDIOVASCULAR RESEARCH LA English DT Editorial Material ID MYOCARDIAL-INFARCTION; BRIEF ISCHEMIA; INTERLEUKIN-6; INJURY C1 NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Buxton, DB (reprint author), NHLBI, Div Heart & Vasc Dis, 6701 Rockledge Rd, Bethesda, MD 20892 USA. EM db225a@nih.gov OI Buxton, Denis/0000-0003-3077-6435 NR 17 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD OCT 1 PY 2004 VL 64 IS 1 BP 6 EP 8 DI 10.1016/j.cardiores.2004.07.019 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 859DF UT WOS:000224241900003 PM 15364607 ER PT J AU Xiao, X Dimitrov, DS AF Xiao, X Dimitrov, DS TI The SARS-CoV S glycoprotein SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE SARS; S glycoprotein; S protein; virus; fusion; entry; ACE2 ID ACUTE RESPIRATORY SYNDROME; CORONAVIRUS SPIKE PROTEIN; ANGIOTENSIN-CONVERTING ENZYME-2; FUNCTIONAL-CHARACTERIZATION; FUSION PROTEIN; RECEPTOR; VIRUS; ENTRY; ACE2; NEUTRALIZATION AB The severe acute respiratory syndrome-coronavirus (SARS-CoV) spike ( S) glycoprotein alone can mediate the membrane fusion required for virus entry and cell fusion. It is also a major immunogen and a target for entry inhibitors. Recent rapid advances in our knowledge of the structure and function of this protein have lead to the development of a number of candidate vaccine immunogens and SARS-CoV entry inhibitors. C1 NCI, Prot Interact Grp, LECB, CCR,NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, LECB, CCR,NIH, Bldg 469,Room 105, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov NR 27 TC 15 Z9 21 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD OCT PY 2004 VL 61 IS 19-20 BP 2428 EP 2430 DI 10.1007/s00018-004-4257-y PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 868BX UT WOS:000224888600002 PM 15526150 ER PT J AU Wiese, C Rolletschek, A Kania, G Blyszczuk, P Tarasov, KV Tarasova, Y Wersto, RP Boheler, KR Wobus, AM AF Wiese, C Rolletschek, A Kania, G Blyszczuk, P Tarasov, KV Tarasova, Y Wersto, RP Boheler, KR Wobus, AM TI Nestin expression - a property of multi-lineage progenitor cells? SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE nestin; embryonic stem cells; progenitor cells; differentiation; regeneration ID EMBRYONIC STEM-CELLS; INTERMEDIATE-FILAMENT PROTEIN; INSULIN-PRODUCING CELLS; CENTRAL-NERVOUS-SYSTEM; DEVELOPING MOUSE PANCREAS; IN-VITRO DIFFERENTIATION; HEPATOCYTE-LIKE CELLS; BONE-MARROW; GROWTH-FACTOR; ENDOTHELIAL-CELLS AB Tissue-specific progenitor cells are characterized by proliferation and differentiation, but, in contrast to embryonic stem (ES) cells, have limited capacities for self-renewal and no tumourigenic potential. These latter traits make progenitor cells an ideal source for regenerative cell therapies. In this review, we describe what is currently known about nestin, an intermediate filament first identified in neuroepithelial stem cells. During embryogenesis, nestin is expressed in migrating and proliferating cells, whereas in adult tissues, nestin is mainly restricted to areas of regeneration. We show that nestin is abundant in ES-derived progenitor cells that have the potential to develop into neuroectodermal, endodermal and mesodermal lineages. Although it remains unclear what factors regulate in vitro and in vivo expression of nestin, we conclude that nestin represents a characteristic marker of multi-lineage progenitor cells and suggest that its presence in cells may indicate multi-potentiality and regenerative potential. C1 Inst Plant Genet & Crop Plant Res IPK, In Vitro Differentiat Grp, D-06466 Gatersleben, Germany. NIA, NIH, Baltimore, MD 21224 USA. RP Inst Plant Genet & Crop Plant Res IPK, In Vitro Differentiat Grp, Corrensstr 3, D-06466 Gatersleben, Germany. EM wobusam@ipk-gatersleben.de NR 137 TC 381 Z9 403 U1 1 U2 15 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD OCT PY 2004 VL 61 IS 19-20 BP 2510 EP 2522 DI 10.1007/s00018-004-4144-6 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 868BX UT WOS:000224888600010 PM 15526158 ER PT J AU Wu, X Burgess, SM AF Wu, X Burgess, SM TI Integration target site selection for retroviruses and transposable elements SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE MLV; HIV-1; insertion; transposable element; co-factors; genomic bias ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNA-POLYMERASE-III; I-HYPERSENSITIVE SITES; ADENOASSOCIATED VIRUS; DNA INTEGRATION; YEAST RETROTRANSPOSON; HIV-1 INTEGRASE; HUMAN GENOME; VIRAL-DNA; DROSOPHILA-MELANOGASTER AB When a retrovirus infects a cell, its RNA genome is reverse transcribed into a double-stranded DNA, which is then permanently integrated into the host chromosome. Integration is one of the essential steps in the retroviral life cycle. Many transposable elements also move around and integrate into the host genome as part of their life cycle, some through RNA intermediates and some through 'cut-and-paste' mechanisms. Integration of retroviruses and transposable elements into 'sensitive areas' of the genome can cause irreparable damage. On the other hand, because of their ability to integrate permanently, and the relatively efficient rates of transgenesis, retroviruses and transposable elements are widely used as gene delivery tools in basic research and gene therapy trials. Recent events in gene therapy treatments for X-linked severe combined immunity deficiencies (X-SCID) have highlighted both the promise and some of the risks involved with utilizing retroviruses. Nine of 11 children were successfully treated for X-SCID using a retrovirus carrying the gene mutated in this disease. However, later two of these children developed leukemias because of retroviral integrations in the putative oncogene LMO2 [ 1]. A third child has also been demonstrated to have an integration in LMO2, but is as of yet nonsymptomatic [ 2]. It is a bit difficult to explain the high frequency of integrations into the same gene using a random model of retroviral integration, and there has been evidence for decades that retroviral integrations may not be random. But the data were somewhat limited in their power to determine the precise nature of the integration biases. The completion of the human genome sequence coupled with sensitive polymerase chain reaction techniques and an ever-decreasing cost of sequencing has given a powerful new tool to the study of integration site selection. In this review, we describe the findings from several recent global surveys of target site selection by retroviruses and transposable elements, and discuss the possible ramifications of these findings to both mechanisms of action and to the use of these elements as gene therapy vectors. C1 NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. NCI, Lab Mol Technol, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP NHGRI, Genome Technol Branch, 50 South Dr,Room 5537, Bethesda, MD 20892 USA. OI Burgess, Shawn/0000-0003-1147-0596 NR 66 TC 47 Z9 53 U1 1 U2 5 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD OCT PY 2004 VL 61 IS 19-20 BP 2588 EP 2596 DI 10.1007/s00018-004-4206-9 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 868BX UT WOS:000224888600016 PM 15526164 ER PT J AU Chen, X Oppenheim, JJ Howard, OMZ AF Chen, Xin Oppenheim, Joost J. Howard, O. M. Zack TI Chemokines and Chemokine Receptors as Novel Therapeutic Targets in Rheumatoid Arthritis (RA): Inhibitory Effects of Traditional Chinese Medicinal Components SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE chemokine; receptor; rheumatoid arthritis; traditional Chinese medicine AB Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory sites. Over the past decade, accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by leukocytes. Chemokines play an important role in the infiltration, localization, retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed synovium. Recent evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in RA. Traditional Chinese medicinals (TCMs) have a long history in the treatment of inflammatory joint disease. The basis for the clinical benefits of TCM remains largely unclear. Our studies have led to the identification of numerous novel chemokine/ chemokine receptor inhibitors present in anti-inflammatory TCMs. All of these inhibitors were previously reported by other researchers to have anti-arthritic effect, which may be attributable, at least in part, to their inhibitory effect on chemokine and/or chemokine receptor. Therefore, identification of agents capable of targeting chemokine/ chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA TCM. Thus, this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory reactions. C1 [Chen, Xin] SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. [Chen, Xin; Oppenheim, Joost J.; Howard, O. M. Zack] Natl Canc Inst Frederick, NIH, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Chen, X (reprint author), Natl Canc Inst Frederick, NIH, Mol Immunoregulat Lab, POB B,Bldg 560,Rm 31-19, Frederick, MD 21702 USA. EM xinc@ncifcrf.gov 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 National Cancer Institute; National Cancer Institute, and Alternative Medicine Program, National Institutes of Health [U01 CA91269-01, NO1-CO-12400] FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, and Alternative Medicine Program, National Institutes of Health, under Contract No. U01 CA91269-01 and NO1-CO-12400. NR 68 TC 24 Z9 25 U1 0 U2 1 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD OCT PY 2004 VL 1 IS 5 BP 336 EP 342 PG 7 WC Immunology SC Immunology GA V32AN UT WOS:000208924200003 PM 16285892 ER PT J AU Song, X Tao, YG Deng, XY Jin, X Tan, YN Tang, M Wu, Q Lee, LM Cao, Y AF Song, X Tao, YG Deng, XY Jin, X Tan, YN Tang, M Wu, Q Lee, LM Cao, Y TI Heterodimer formation between c-Jun and Jun B proteins mediated by Epstein-Barr virus encoded latent membrane protein 1 SO CELLULAR SIGNALLING LA English DT Article DE Epstein-Barr virus; latent membrane protein 1; Jun B; c-Jun; heterodimer; DNA binding; JNK; JIP ID NF-KAPPA-B; CARCINOMA-CELL LINE; TRANSCRIPTION FACTOR; AP-1 ACTIVITY; DNA-BINDING; EXPRESSION; PHOSPHORYLATION; DIFFERENTIATION; ACTIVATION; KINASE AB Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is essential for the immortalization of human B cells and is linked etiologically to several human tumors. LMP1 is an integral membrane protein which acts like a constitutively active receptor. It binds tumor necrosis factor (TNF)-receptor-associated factors (TRAFs), activates NFkappaB and triggers the transcription factor activating protein-1 (AP-1) via the c-Jun N-terminal kinase (JNK) cascade, but its specific contribution to AP-1 has not been elucidated fully. Members of AP-1 family, the Jun and fos related protein, have been shown to directly interact and form heterodimeric complexes. In this report, using a Tet-on LMP1 HNE2 cell line which is a dual-stable LMP1 integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 in which could be regulated by Tet-on system, we show that Jun B can efficiently form a new heterodimeric complex with the c-Jun protein under the regulation of LMP1, phosphorylation of c-Jun (ser63, ser73) and Jun B involved in the process of the new heterodimeric form. We also find that this heterodimeric form can bind to the AP-1 consensus sequence. Transfection studies suggest that JNK interaction protein (JIP) could inhibit the heterodimer form of c-Jun and Jun B through blocking the AP-1 signaling pathway triggered by LMP1. The interaction and function between c-Jun protein and Jun B protein increase the repertoire of possible regulatory complexes by LMP1 that could play an important role in the regulation of transcription of specific cellular genes in the process of genesis of nasopharyngeal carcinoma. (C) 2004 Elsevier Inc. All rights reserved. C1 Cent S Univ, Xiangya Sch Med, Canc Res Inst, Changsha 410078, Peoples R China. Xiamen Univ, Sch Life Sci, Key Lab Minist Educ Cell Biol & Tumor Cell Engn, Xiamen 361005, Peoples R China. NCI, Lab Mol Technol, SAIC Frederick, Frederick, MD 21702 USA. RP Cao, Y (reprint author), Cent S Univ, Xiangya Sch Med, Canc Res Inst, 88 Xiangya Rd, Changsha 410078, Peoples R China. EM ycao98@public.cs.hn.cn RI Cao, Ya/C-6801-2008; Wu, Q/G-4646-2010 NR 55 TC 22 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2004 VL 16 IS 10 BP 1153 EP 1162 DI 10.1016/j.cellsig.2004.03.014 PG 10 WC Cell Biology SC Cell Biology GA 840GP UT WOS:000222845600007 PM 15240010 ER PT J AU Prodi, DA Drayna, D Forabosco, P Palmas, MA Maestrale, GB Piras, D Pirastu, M Angius, A AF Prodi, DA Drayna, D Forabosco, P Palmas, MA Maestrale, GB Piras, D Pirastu, M Angius, A TI Bitter taste study in a sardinian genetic isolate supports the association of phenylthiocarbamide sensitivity to the TAS2R38 bitter receptor gene SO CHEMICAL SENSES LA English DT Article DE genetic isolates; genomewide search; haplotypes; 7q35 ID THRESHOLD DISTRIBUTIONS; LINKAGE ANALYSIS; FOOD PREFERENCE; PTC; TRAIT; MICE; 6-N-PROPYLTHIOURACIL; LOCALIZATION; PERCEPTION; LOCATION AB Recently, a major locus on chromosome 7qwas found in association with the taste sensitivity to phenylthiocarbamide (PTC) inhumans. This region contains the TAS2R38 gene that encodes a member of the TAS2R bittertaste receptor family. Three SNPs within this gene demonstrated a strong association withtaster status in Utah families and in an additional sample of 85 unrelated individuals.We studied a small isolated village in eastern Sardinia and carried out a genome-widescan to map the genetic basis of PTC perception in this population. We performed bothqualitative and quantitative PTC-taste linkage analysis. Qualitative analysis was carriedout by defining a cut-off from the bimodal distribution of the trait and classifyingsubjects as tasters and non-tasters (75 and 25%, respectively). Linkage analysison 131 subjects belonging to a unique large multi-generation pedigree comprising 239subjects confirmed significant evidence for linkage at 7q35 also in our population.Haplotype analyses of the three SNPs inside the PTC gene allowed us to identify only twohaplotypes that were associated with the non-taster phenotype (80% AVI homozygous)and to taster phenotype (40% PAV homozygous and 56% PAV/AVI heterozygous).Sex, age and haplotype effect explained 77.2 % of the total variance in PTCsensitivity. C1 Shardna Life Sci, I-09125 Cagliari, Italy. Natl Inst Deafness & Other Commun Disorders, Rockville, MD USA. CNR, Inst Populat Genet, Alghero, Italy. RP Angius, A (reprint author), Shardna Life Sci, Piazza Deffenu 4, I-09125 Cagliari, Italy. EM angius@shardna.it RI Angius, Andrea/B-8966-2015; Angius, Andrea/P-9549-2015 OI Angius, Andrea/0000-0003-2596-6461 NR 33 TC 40 Z9 40 U1 4 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD OCT PY 2004 VL 29 IS 8 BP 697 EP 702 DI 10.1093/chemse/bjh074 PG 6 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 860RB UT WOS:000224359600006 PM 15466815 ER PT J AU Imahashi, K Schneider, MD Steenbergen, C Murphy, E AF Imahashi, K Schneider, MD Steenbergen, C Murphy, E TI Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury SO CIRCULATION RESEARCH LA English DT Article DE transgenic models; magnetic resonance spectroscopy; mitochondria; reperfusion injury ID MITOCHONDRIAL-MEMBRANE PERMEABILITY; CYTOCHROME-C; RAT CARDIOMYOCYTES; TRANSITION PORE; APOPTOSIS; FAMILY; BAX; RELEASE; DEATH; VDAC AB The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH(i) and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P < 0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin ( Oligo), an F1F0-ATPase inhibitor, the decrease in pHi was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pHi during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Baylor Coll Med, Dept Med Mol & Cellular Biol, Houston, TX USA. Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM murphy1@niehs.nih.gov OI Schneider, Michael/0000-0001-9645-1938 FU NHLBI NIH HHS [R01 HL039752] NR 34 TC 129 Z9 137 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD OCT 1 PY 2004 VL 95 IS 7 BP 734 EP 741 DI 10.1161/01.RES.0000143898.67182.4c PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 858MR UT WOS:000224196400011 PM 15345651 ER PT J AU Metz, JM Smith, D Mick, R Lustig, R Mitchell, J Cherakuri, M Glatstein, E Hahn, SM AF Metz, JM Smith, D Mick, R Lustig, R Mitchell, J Cherakuri, M Glatstein, E Hahn, SM TI A phase I study of topical tempol for the prevention of alopecia induced by whole brain radiotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID ANDROGENETIC ALOPECIA; MINOXIDIL; DAMAGE; WOMEN AB Purpose: Complete alopecia is a universal complication of whole brain radiation therapy which contributes to patient anxiety over treatment. Tempol, a nitroxide radioprotector, has been shown to protect against radiation-induced alopecia in an animal model. This phase Ib study was designed to evaluate the safety and side effect profile of topical Tempol in patients with brain metastases being treated with whole brain radiotherapy. Experimental Design: Twelve patients with metastatic cancer to the brain were enrolled in the study between October 2000 and February 2003. Tempol (70 mg/ml concentration solution) was applied topically to the scalp 15 minutes before and washed off immediately after the completion of each of 10 fractions of whole brain radiation. Pharmacokinetic studies to evaluate the systemic absorption of Tempol were performed. Patients were assessed for toxicity before, during, and after Tempol administration. A secondary end point of the study, hair retention, was also scored. Results: Eleven patients were treated with topical Tempol. Adverse events that were considered possibly, probably, or definitely related to Tempol, included asymptomatic grade 2 (two patients) and grade 1 (one patient) hypoglycemia, grade I forehead skin redness (one patient), grade I dry scalp (one patient), and grade 1 tingling sensation on the scalp (one patient). Tempol was not detected in blood samples from more than 50% of the patients. Mean maximum Tempol levels for individual patients at any time point varied from 0.4 to 3.1 mumol/L. Hair retention was localized to the base of the scalp where the Tempol solution pooled after application in the first four patients on the study. Subsequently, full scalp hair retention was seen in three of final five evaluable patients after gauze had been wrapped around the head to hold the solution against the scalp. Conclusions: This study demonstrates that topical application of Tempol to the scalp before whole brain radiation is safe and well tolerated. Evidence of protection against radiation-induced alopecia was observed. A phase H study that uses a gel formulation to increase the exposure of scalp to Tempol has been initiated. C1 Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD USA. RP Metz, JM (reprint author), Univ Penn, Dept Radiat Oncol, 3400 Spruce St,2 Donner, Philadelphia, PA 19104 USA. EM metz@xrt.upenn.edu NR 16 TC 81 Z9 85 U1 0 U2 6 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 OCT 1 PY 2004 VL 10 IS 19 BP 6411 EP 6417 DI 10.1158/1078-0432.CCR-04-0658 PG 7 WC Oncology SC Oncology GA 862WF UT WOS:000224521300002 PM 15475427 ER PT J AU van Kouwen, MCA Drenth, JPH Oyen, WJG de Bruin, JHFM Ligtenberg, MJ Bonenkamp, JJ van Krieken, JHJM Nagengast, FM AF van Kouwen, MCA Drenth, JPH Oyen, WJG de Bruin, JHFM Ligtenberg, MJ Bonenkamp, JJ van Krieken, JHJM Nagengast, FM TI [F-18]fluoro-2-deoxy-d-glucose positron emission tomography detects gastric carcinoma in an early stage in an asymptomatic e-cadherin mutation carrier SO CLINICAL CANCER RESEARCH LA English DT Article ID PROPHYLACTIC TOTAL GASTRECTOMY; GERMLINE MUTATIONS; CANCER; PET; DIAGNOSIS; TUMOR; CDH1; FDG; HEXOKINASE; REGISTRY AB Purpose: Autosomal dominant hereditary diffuse gastric cancer (HDGC) is caused by germ-line E-cadherin (CDH1) gene mutations. Early detection of cancer in carriers is difficult because HDGC escapes endoscopic detection. We hypothesized that the glucose metabolism is enhanced in HDGC and that this can be detected with [F-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Experimental Design and Results: An asymptomatic twenty-eight year-old female was seen at our outpatient clinic because of a request for screening on HDGC. Her father and younger sister died of diffuse gastric cancer, at the ages of 52 and 27, respectively. Mutational analysis of the CDH1 gene in this patient demonstrated a novel heterozygous splice-site mutation in exon 8 (1135delACGGTA-ATinsTTAGA). Upper gastrointestinal endoscopies revealed no macroscopic abnormalities, but one of the 40 random biopsy specimens showed well-differentiated signet-cell carcinoma. A FDG-PET scan demonstrated two spots of FDG accumulation, one located in the proximal part of the stomach and the second in the region of the pylorus. A total gastrectomy was performed and microscopic examination showed focal localization of intramucosal adenocarcinoma of the signet-cell type in the cardiac and antrum area. Most notably, the localization of the FDG accumulation matched the localization of the carcinoma. Conclusions: We present an asymptomatic patient from a HDGC family carrying a novel CDH1 mutation in whom FDG-PET scanning facilitated early detection of HDGC. This calls for further investigation of the role of FDG-PET scan as a screening modality in HDGC. C1 Univ Med Ctr St Radboud, Dept Gastroenterol, Nijmegen, Netherlands. Univ Med Ctr St Radboud, Dept Nucl Med, Nijmegen, Netherlands. Univ Med Ctr St Radboud, Dept Human Genet, Nijmegen, Netherlands. Univ Med Ctr St Radboud, Dept Surg, Nijmegen, Netherlands. Univ Med Ctr St Radboud, Dept Pathol, Nijmegen, Netherlands. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD USA. RP Drenth, JPH (reprint author), Univ Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM JoostPHDrenth@CS.com RI Oyen, Wim/D-4178-2009; Drenth, J.P.H./H-8025-2014; van Krieken, Joannes/D-4138-2009; Bonenkamp, J.J./L-4213-2015; Kouwen, M.C.A./L-4453-2015; Ligtenberg, Marjolijn/N-9666-2013 OI Oyen, Wim/0000-0001-8235-7078; van Krieken, Joannes/0000-0001-6544-1040; Ligtenberg, Marjolijn/0000-0003-1290-1474 NR 29 TC 28 Z9 28 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2004 VL 10 IS 19 BP 6456 EP 6459 DI 10.1158/1078-0432.CCR-04-0599 PG 4 WC Oncology SC Oncology GA 862WF UT WOS:000224521300007 PM 15475432 ER PT J AU Lam, S leRiche, JC McWilliams, A MacAulay, C Dyachkova, Y Szabo, E Mayo, J Schellenberg, R Coldman, A Hawk, E Gazdar, A AF Lam, S leRiche, JC McWilliams, A MacAulay, C Dyachkova, Y Szabo, E Mayo, J Schellenberg, R Coldman, A Hawk, E Gazdar, A TI A randomized phase IIb trial of Pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium SO CLINICAL CANCER RESEARCH LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; FEMALE A/J MICE; LUNG-CANCER; FORMER SMOKERS; AEROSOLIZED BUDESONIDE; AIRWAY INFLAMMATION; ANTIGEN RETRIEVAL; SMOKING-CESSATION; CHEMOPREVENTION; GLUCOCORTICOIDS AB Purpose: Preclinical studies suggest that inhaled budesonide may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of inhaled budesonide in smokers with bronchial dysplasia. Experimental Design: A total of 112 smokers with more than or equal to one site of bronchial dysplasia > 1.2 mm in size identified by autofluorescence bronchoscopy-directed biopsy was randomly assigned to receive placebo or budesonide (Pulmicort Turbuhaler) 800 jig twice daily inhalation for 6 months. The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months. Results: There were no significant differences in the regression or progression rates of bronchial dysplasia between the two groups. There was a statistically significant but modest decrease in p53 and BclII expression in the bronchial biopsies after 6 months of Pulmicort Turbuhaler versus placebo (P = 0.01 and P = 0.001, respectively). There was a small but statistically significant decrease in the proportion of computed tomography-detected lung nodules after Pulmicort Turbuhaler compared with placebo (P = 0.024). Conclusions: Our results suggest that in smokers, inhaled budesonide in the dose of 1600 mug daily for 6 months had no effect in regression of bronchial dysplastic lesions or prevention of new lesions. Budesonide treatment resulted in a modest decrease in p53 and BclII protein expression in bronchial biopsies and a slightly higher rate of resolution of computed tomography-detected lung nodules. Whether budesonide truly has an effect in preneoplastic lesions in the peripheral airways and alveoli requires additional investigation. C1 British Columbia Canc Agcy, Canc Imaging Dept, Vancouver, BC V5Z 4E6, Canada. British Columbia Canc Agcy, Dept Resp Med, Vancouver, BC, Canada. British Columbia Canc Agcy, Dept Pathol, Vancouver, BC, Canada. British Columbia Canc Agcy, Dept Populat & Prevent Oncol, Vancouver, BC, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NCI, DCP, Lung & Upper Aerodigest Canc Res Grp, Bethesda, MD USA. Vancouver Gen Hosp, Dept Radiol, Vancouver, BC V5Z 1M9, Canada. St Pauls Hosp, Pulm Res Lab, Vancouver, BC, Canada. NCI, Div Canc Prevent, Gastrointestinal Canc Res Grp, Bethesda, MD USA. UT Southwestern Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX USA. UT Southwestern Med Ctr, Dept Pathol, Dallas, TX USA. RP Lam, S (reprint author), British Columbia Canc Agcy, Canc Imaging Dept, 600 W 10th Ave, Vancouver, BC V5Z 4E6, Canada. EM slam@bccancer.bc.ca RI MacAulay, Calum/K-1795-2016 FU NCI NIH HHS [N01-CN85188] NR 43 TC 86 Z9 87 U1 0 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 OCT 1 PY 2004 VL 10 IS 19 BP 6502 EP 6511 DI 10.1158/1078-0432.CCR-04-0686 PG 10 WC Oncology SC Oncology GA 862WF UT WOS:000224521300012 PM 15475437 ER PT J AU Chen, XX Wang, S Wu, N Sood, S Wang, P Jin, Z Beer, DG Giordano, TJ Lin, Y Shih, WCJ Lubet, RA Yang, CS AF Chen, XX Wang, S Wu, N Sood, S Wang, P Jin, Z Beer, DG Giordano, TJ Lin, Y Shih, WCJ Lubet, RA Yang, CS TI Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis SO CLINICAL CANCER RESEARCH LA English DT Article ID BARRETTS-ESOPHAGUS; ESOPHAGOGASTRODUODENAL ANASTOMOSIS; GROWTH-INHIBITION; PANCREATIC-CANCER; SYRIAN-HAMSTERS; DEFICIENT MICE; LIPOXYGENASE; CYCLOOXYGENASE-2; EXPRESSION; MODEL AB Purpose: Aberrant arachidonic acid (AA) metabolism, especially through the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, has been suggested to play an important role in the development of esophageal adenocarcinoma (EAC). The purpose of this study was to investigate the expression of 5-Lox in EAC of a rat model and in human samples as well as the chemopreventive effects of Menton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor) in the rat EAC model. Experimental Design: 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis. Results: With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P > 0.05) and 31.3% (5 of 16; P < 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P < 0.05) and 20% (3 of 15; P < 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P < 0.01). Leukotriene B-4 and prostaglandin E-2 levels in the esophageal tissues were also significantly reduced by Menton and celecoxib. Conclusions: This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism. C1 Rutgers State Univ, Ernst Mario Sch Pharm, Dept Biol Chem, Susan Lehman Cullman Lab Canc Res, Piscataway, NJ 08854 USA. Univ Michigan, Dept Surg, Sect Gen Thorac Surg, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. Univ Med & Dent New Jersey, Sch Publ Hlth, Div Biometr, New Brunswick, NJ USA. Natl Canc Inst, Div Canc Prevent, Chemoprevent Branch, Bethesda, MD USA. RP Chen, XX (reprint author), Rutgers State Univ, Ernst Mario Sch Pharm, Dept Biol Chem, Susan Lehman Cullman Lab Canc Res, 164 Frelinghyusen Rd, Piscataway, NJ 08854 USA. EM xiaochen@rci.rutgers.edu OI Giordano, Thomas/0000-0003-0641-8873 FU NCI NIH HHS [CA75683, N01-CN15117]; NIDDK NIH HHS [DK63650] NR 42 TC 62 Z9 65 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2004 VL 10 IS 19 BP 6703 EP 6709 DI 10.1158/1078-0432.CCR-04-0838 PG 7 WC Oncology SC Oncology GA 862WF UT WOS:000224521300036 PM 15475461 ER PT J AU Nolte, G Bai, O Wheaton, L Mari, Z Vorbach, S Hallett, M AF Nolte, G Bai, O Wheaton, L Mari, Z Vorbach, S Hallett, M TI Identifying true brain interaction from EEG data using the imaginary part of coherency SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE coherence; EEG; connectivity; motor control; volume conduction; time-lag ID FALSE DISCOVERY RATE; DIRECTED TRANSFER-FUNCTION; HUMAN ELECTROENCEPHALOGRAM; STATISTICAL ASSESSMENT; GRANGER CAUSALITY; INFORMATION-FLOW; PHASE; AREAS; POWER; SYNCHRONY AB Objective: The main obstacle in interpreting EEG/MEG data in terms of brain connectivity is the fact that because of volume conduction, the activity of a single brain source can be observed in many channels. Here, we present an approach which is insensitive to false connectivity arising from volume conduction. Methods: We show that the (complex) coherency of non-interacting sources is necessarily real and, hence, the imaginary part of coherency provides an excellent candidate to study brain interactions. Although the usual magnitude and phase of coherency contain the same information as the real and imaginary parts, we argue that the Cartesian representation is far superior for studying brain interactions. The method is demonstrated for EEG measurements of voluntary finger movement. Results: We found: (a) from 5 s before to movement onset a relatively weak interaction around 20 Hz between left and right motor areas where the contralateral side leads the ipsilateral side; and (b) approximately 2-4 s after movement, a stronger interaction also at 20 Hz in the opposite direction. Conclusions: It is possible to reliably detect brain interaction during movement from EEG data. Significance: The method allows unambiguous detection of brain interaction from rhythmic EEG/MEG data. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Nolte, G (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 5N226, Bethesda, MD 20892 USA. EM nolteg@ninds.nih.gov RI Wheaton, Lewis /B-4482-2009 OI Wheaton, Lewis /0000-0003-0771-0294 NR 34 TC 452 Z9 460 U1 5 U2 43 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD OCT PY 2004 VL 115 IS 10 BP 2292 EP 2307 DI 10.1016/j.clinph.2004.04.029 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 856KV UT WOS:000224045000011 PM 15351371 ER PT J AU Slobounov, S Hallett, M Newell, KM AF Slobounov, S Hallett, M Newell, KM TI Perceived effort in force production as reflected in motor-related cortical potentials SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE EEG; MRCP; control-signal gain; perceived effort; force production ID MOVEMENT-RELATED POTENTIALS; FINGER MOVEMENTS; EEG; EXERTION; TASKS; SINGLE; SCALE; BLOOD; LOAD AB Objective: The perceived effort in force production was investigated in a series of experiments where subjects performed isometric force tasks with the index finger while the nominal force, the rate of force development and signal gain were controlled and rating of effort for each task was obtained. The hypotheses tested were that: (1) force-related perceived effort may selectively influence the amplitude of motor-related cortical potentials (MRCP); and (2) the MRCP may directly reflect the intensity of perceived effort associated with force production. Methods: The force trace was displayed on a computer monitor using various control-gains so that the perceived effort matched or was at odds with actual muscular effort applied to the load cell to accomplish the task. The MRCP were extracted from continuous EEG records using averaging techniques. Results: The findings showed that: (1) perceived effort proportionally increased with the increment of rate of force development and force error, but not with the actual force level; (2) the amplitude of the MRCP increased when a large amount of force was accompanied by an increased rate of force development; (3) the amplitude of early components of MRCP preceding the force initiation (MP-100 to 0) increased as a function of anticipated effort, whereas, the amplitude movement-monitoring potentials (MNIP) accompanying the force production increased as a function of actual force level. Conclusions: The findings from this study provide additional insight clarifying the distinct patterns of EEG activity exhibited under various degrees of perceived effort associated with force output. The findings support the hypothesis that the early components of MRCP may reflect the perceived effort associated with achieving the required force level. Significance: The results from this study may be considered in the larger context of physical activity in terms of importance of perceived effort during prescribed exercise in rehabilitation programs. (C) 2004 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 NINDS, Motor Control Sect, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. RP Slobounov, S (reprint author), NINDS, Motor Control Sect, NIH, Bldg 10,Room 5N240,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM sms18@psu.edu NR 44 TC 37 Z9 38 U1 1 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD OCT PY 2004 VL 115 IS 10 BP 2391 EP 2402 DI 10.1016/j.clinph.2004.05.021 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 856KV UT WOS:000224045000022 PM 15351382 ER PT J AU El-Amin, SF Kofron, MD Attawia, MA Lu, HH Tuan, RS Laurencin, CT AF El-Amin, SF Kofron, MD Attawia, MA Lu, HH Tuan, RS Laurencin, CT TI Molecular regulation of osteoblasts for tissue engineered bone repair SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID INTEGRIN EXPRESSION; BIOERODIBLE POLYMERS; DYNAMIC REGULATION; IMPLANT MATERIALS; RECOGNITION SITE; CELL-ADHESION; MATRICES; BINDING; CULTURE; GROWTH AB The use of biodegradable polymers in medicine and biomedical research is increasing. A key growth area has been the use of these materials in tissue engineering, especially for guided regeneration of bone and cartilage. Our interest has been in determining the mechanisms by which cellular attachment and growth occurs on these materials. In the current study, we examined human osteoblast cell adhesion, growth, and morphologic changes on polymeric scaffolds composed of polylactic-co-glycolic acid and polylactic acid materials. We examined these characteristics in association with measurements of levels of key adhesion integrin receptors in the presence and absence of antibodies against alpha(2), alpha(3), alpha(4), alpha(5), alpha(6), and beta(1) subunits, and the adhesion ligand peptides RGD (Arg-Gly-Asp) and RGE (Arg-Gly-Ser). At 2 hours, results showed initial cell adhesion was considerably decreased on polylactic-co-glycolic acid and polylactic acid in the presence of the alpha(2) and beta(1) antibodies with a 70% adhesion rate difference observed among the groups evaluated. Higher levels of inhibition were observed on polylactic-co-glycolic acid relative to polylactic acid, which may be correlated to a higher number of cells being able to interact with the surface initially. The presence of known competitive peptide (RGD) at 2 hours, revealed its ability to block cellular adhesion to these matrices relative to the control and noncompetitive peptide RGE on polylactic-co-glycolic acid matrices. Overall adhesion rate was affected by the presence of the integrin antibodies to the alpha(2), alpha(3), alpha(4), alpha(5), alpha(6), and beta(1) subunits with highest differences among polylactic-co-glycolic acid relative to its control, therefore suggesting that initial osteoblastic cell adhesion to commonly used biomaterials is regulated through integrin binding. C1 Univ Virginia, Dept Orthopaed Surg, Charlottesville, VA 22903 USA. Univ Virginia, Dept Chem Engn, Charlottesville, VA 22903 USA. Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22903 USA. Depuy Johnson & Johnson, Raymond, MA USA. Natl Inst Musculoskeletal Res, NIH, Bethesda, MD USA. Columbia Univ, Dept Chem Engn, New York, NY 10027 USA. RP Laurencin, CT (reprint author), Univ Virginia, Dept Orthopaed Surg, 400 Ray C Hunt Dr,Suite 330, Charlottesville, VA 22903 USA. EM ctlf3f@virginia.edu FU NIAMS NIH HHS [AR44051, AR08562-01, AR39740]; NIDCR NIH HHS [DE12864] NR 31 TC 14 Z9 14 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2004 IS 427 BP 220 EP 225 DI 10.1097/01.blo.0000137556.51604.0c PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 861NC UT WOS:000224422500035 PM 15552161 ER PT J AU Tuan, RS AF Tuan, RS TI Biology of developmental and regenerative skeletogenesis SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article; Proceedings Paper CT Carl T Brighton Annual Workshop CY NOV 14, 2004 CL Tampa Bay, FL ID MESENCHYMAL PROGENITOR CELLS; VERTEBRATE LIMB DEVELOPMENT; APICAL ECTODERMAL RIDGE; HUMAN TRABECULAR BONE; AGGLUTININ AFFINITY-CHROMATOGRAPHY; GAP JUNCTIONAL COMMUNICATION; IN-VITRO CHARACTERIZATION; HEPARIN-BINDING DOMAIN; N-CADHERIN EXPRESSION; DEVELOPING CHICK LIMB AB Embryonic skeletal development involves the recruitment, commitment, differentiation, and maturation of mesenchymal cells into those in the skeletal tissue lineage, specifically cartilage and bone along the intramembranous and endochondral ossification pathways. The exquisite control of skeletal development is regulated at the level of gene transcription, cellular signaling, cell-cell and cell-matrix interactions, as well as systemic modulation. Mediators include transcription factors, growth factors, cytokines, metabolites, hormones, and environmentally derived influences. Understanding the mechanisms underlying developmental skeletogenesis is crucial to harnessing the inherent regenerative potential of skeletal tissues for wound healing and repair, as well as for functional skeletal tissue engineering. In this review, a number of key issues are discussed concerning the current and future challenges of the scientific investigation of developmental skeletogenesis in the embryo, specifically limb cartilage development, and how these challenges relate to regenerative or reparative skeletogenesis in the adult. Specifically, a more complete understanding the biology of skeletogenic progenitor cells and the cellular and molecular mechanisms governing tissue patterning and morphogenesis should greatly facilitate the development of regenerative approaches to cartilage repair. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bldg 50,Room 1523,MSC 8022, Bethesda, MD 20892 USA. EM Tuanr@mail.nih.gov NR 122 TC 67 Z9 69 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2004 IS 427 SU S BP S105 EP S117 DI 10.1097/01.blo.0000143560.41767.ee PG 13 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 862XI UT WOS:000224524400019 PM 15480052 ER PT J AU Reid, BC Hyman, JJ Macek, MD AF Reid, BC Hyman, JJ Macek, MD TI Race/ethnicity and untreated dental caries: the impact of material and behavioral factors SO COMMUNITY DENTISTRY AND ORAL EPIDEMIOLOGY LA English DT Article DE dental caries; ethnicity; NHANES III; race ID AFRICAN-AMERICAN WOMEN; UNITED-STATES; ORAL-HEALTH; EDUCATIONAL-DIFFERENCES; NORTH-CAROLINA; ATTITUDES; CHILDREN; DENTITION; KNOWLEDGE; MORTALITY AB Objective: To use nationally representative data, group variables into categories of material and behavioral factors, and assess their relative contribution to racial/ethnic variation in untreated caries. Methods: Participants were from the Third National Health and Nutrition Examination Survey (NHANES III), aged 20-50 years. Material factors were income, education, employment status, dental insurance status, and urban residence. Behavioral factors were marital status, tobacco use, alcohol use, obesity, and social support. All models were additionally adjusted for age, gender, and quartile of missing teeth. The outcome was three or more carious teeth. Results: Non-Hispanic blacks and Mexican-Americans displayed excess risk of untreated caries compared with non-Hispanic whites when adjusted for age, sex, and missing teeth (adjusted odds ratios 1.73 and 1.69, respectively). The addition of behavioral factors to this model resulted in virtually no changes in the adjusted odds ratios for race/ethnicity and untreated caries. When material factors were added to the basic model the excess risk for untreated caries among non-Hispanic blacks was reduced by approximately 21% and that of Mexican-Americans was no longer statistically significant compared with non-Hispanic whites (adjusted odds ratios 1.36 and 0.83, respectively). Conclusions: Much of the excess risk for untreated dental caries among non-Hispanic blacks and Mexican-Americans compared with non-Hispanic whites was eliminated when material factors were controlled, while no risk reductions were observed when behavioral factors were controlled. Addressing material factors may provide greater reductions in untreated caries disparities than behavioral interventions, and these risk reductions may vary with racial/ethnic group. C1 Univ Maryland, Sch Dent, Dept Hlth Promot & Policy, Baltimore, MD 21201 USA. Natl Inst Dent & Craniofacial Res, Hlth Policy & Anal Branch, NIH, Bethesda, MD USA. RP Reid, BC (reprint author), Univ Maryland, Sch Dent, Dept Hlth Promot & Policy, 666 W Baltimore St, Baltimore, MD 21201 USA. EM BCR001@dental.umaryland.edu NR 32 TC 26 Z9 26 U1 6 U2 9 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0301-5661 J9 COMMUNITY DENT ORAL JI Community Dentist. Oral Epidemiol. PD OCT PY 2004 VL 32 IS 5 BP 329 EP 336 DI 10.1111/j.1600-0528.2004.00165.x PG 8 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 851CL UT WOS:000223662900003 PM 15341617 ER PT J AU Smedley, JV Lomax, LG Williams, JF Barras, PW Hasselschwert, DL AF Smedley, JV Lomax, LG Williams, JF Barras, PW Hasselschwert, DL TI Legg-Calve-Perthes disease in a rhesus macaque (Macaca mulatta) SO COMPARATIVE MEDICINE LA English DT Article ID FEMORAL-HEAD; AVASCULAR NECROSIS; TREATED RABBITS; HIP-JOINT; OSTEONECROSIS; PATHOGENESIS; SYNOVITIS; PRESSURE; VESSELS; RATS AB Ajuvenile rhesus macaque presented with atrophy of the musculature of its left leg. Physical examination localized the problem to the coxofemoral joint. Radiography revealed changes consistent with Legg-Calve-Perthes (LCP) disease. Femoral head ostectomy was performed, and the femoral head was submitted for histologic examination, results of which confirmed a diagnosis of LCP. C1 NCI, Bethesda, MD 20892 USA. Louisiana State Univ, Sch Vet Med, Baton Rouge, LA 70803 USA. New Iberia Res Ctr, New Iberia, LA 70560 USA. RP Smedley, JV (reprint author), NCI, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Smedley, Jeremy/0000-0003-3369-4662 NR 31 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD OCT PY 2004 VL 54 IS 5 BP 585 EP 588 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 874NN UT WOS:000225357200016 PM 15575374 ER PT J AU Przytycka, TM Yu, YK AF Przytycka, TM Yu, YK TI Scale-free networks versus evolutionary drift SO COMPUTATIONAL BIOLOGY AND CHEMISTRY LA English DT Article DE biological networks; evolutionary drift; domain evolution; scale-free models; yule distribution ID METABOLIC NETWORKS; CLASSIFICATION; ORGANIZATION; FREQUENCIES; BEHAVIOR; BIOLOGY; GENOMES; BIRTH; MODEL; DNA AB Recent studies of properties of various biological networks revealed that many of them display scale-free characteristics. Since the theory of scale-free networks is applicable to evolving networks, one can hope that it provides not only a model of a biological network in its current state but also sheds some insight into the evolution of the network. In this work, we investigate the probability distributions and scaling properties underlying some models for biological networks and protein domain evolution. The analysis of evolutionary models for domain similarity networks indicates that models which include evolutionary drift are typically not scale free. Instead they adhere quite closely to the Yule distribution. This finding indicates that the direct applicability of scale-free models in understanding the evolution of biological network may not be as wide as it has been hoped for. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIH, NCBI, Natl Lib Med, Bethesda, MD 20894 USA. Florida Atlantic Univ, Dept Phys, Boca Raton, FL 33431 USA. RP Przytycka, TM (reprint author), NIH, NCBI, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov NR 27 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1476-9271 J9 COMPUT BIOL CHEM JI Comput. Biol. Chem. PD OCT PY 2004 VL 28 IS 4 BP 257 EP 264 DI 10.1016/j.compbiochem.2004.07.001 PG 8 WC Biology; Computer Science, Interdisciplinary Applications SC Life Sciences & Biomedicine - Other Topics; Computer Science GA 888NZ UT WOS:000226382800002 PM 15548452 ER PT J AU Pettitt, DJ Bell, R Dabelea, D Dolan, L Imperatore, G Lawrence, JM Liese, AD Liu, LL Waitzfelder, B Rodriguez, BL Hillier, T Pihoker, C Hirsch, I Greenbaum, C Petitti, DB Kershnar, A Hamman, RF Klingensmith, GJ Rewers, M Krakoff, J Nash, PV Smith, CM Standiford, DA Daniels, SR Mayer-Davis, EJ Oeltmann, J Marcovina, S Aldrich, A Morgan, T Hardy, L Vestal, S Linder, B Engelgau, M Kahn, H Narayan, V Saaddine, J Valdez, R Williams, D AF Pettitt, DJ Bell, R Dabelea, D Dolan, L Imperatore, G Lawrence, JM Liese, AD Liu, LL Waitzfelder, B Rodriguez, BL Hillier, T Pihoker, C Hirsch, I Greenbaum, C Petitti, DB Kershnar, A Hamman, RF Klingensmith, GJ Rewers, M Krakoff, J Nash, PV Smith, CM Standiford, DA Daniels, SR Mayer-Davis, EJ Oeltmann, J Marcovina, S Aldrich, A Morgan, T Hardy, L Vestal, S Linder, B Engelgau, M Kahn, H Narayan, V Saaddine, J Valdez, R Williams, D CA SEARCH Study Grp TI SEARCH for Diabetes in Youth: a multicenter study of the prevalence, incidence and classification of diabetes mellitus in youth SO CONTROLLED CLINICAL TRIALS LA English DT Article DE type 1 diabetes; type 2 diabetes; children; adolescents; ethnic groups ID ACID DECARBOXYLASE GAD65; CAPTURE-RECAPTURE; CHILDREN; AUTOANTIBODIES; ADOLESCENTS; DIAGNOSIS; MINORITY; AMERICAN; TRENDS AB SEARCH for Diabetes in Youth is an observational, multicenter study focusing on physician-diagnosed diabetes in individuals <20 years old. The study will estimate the population prevalence and incidence of diabetes by type, age, gender, and ethnicity and develop practical approaches to diabetes classification in 5 million children (similar to6% of the <20 U.S. population) with wide ethnic and socioeconomic representation from four geographically defined populations and two health plans. An estimated 6000 prevalent and 800 incident diabetes cases per year will be identified with annual follow-up. Cases will be ascertained through clinical and nonclinical resources or partnerships at each site. Data collection involves patient interviews, physical examinations, laboratory measurements (diabetes autoantibodies, fasting/stimulating C-peptide, hemoglobin A1c, blood glucose, lipids, urine albumin, creatinine), medical records reviews, and documentation of risk factors for complications and processes of care. (C) 2004 Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Sansum Med Res Inst, Santa Barbara, CA USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. Cincinnati Childrens Hosp, Cincinnati, OH USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Kaiser Permanente, Pasadena, CA USA. Univ S Carolina, Sch Publ Hlth, Columbia, SC 29208 USA. Childrens Hosp & Reg Med Ctr, Seattle, WA USA. Pacific Hlth Res Inst, Honolulu, HI USA. Childrens Hosp Med Ctr, Cincinnati, OH USA. NW Lipid Res Labs, Seattle, WA USA. NIDDK, Bethesda, MD 20892 USA. RP Bell, R (reprint author), Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM rbell@wfubmc.edu NR 24 TC 114 Z9 115 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD OCT PY 2004 VL 25 IS 5 BP 458 EP 471 DI 10.1016/j.cct.2004.08.002 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 863YS UT WOS:000224600100004 ER PT J AU Berger, VW Weinstein, S AF Berger, VW Weinstein, S TI Ensuring the comparability of comparison groups: is randomization enough? SO CONTROLLED CLINICAL TRIALS LA English DT Editorial Material DE allocation concealment; broken experiment; confounding; selection bias ID NONRANDOMIZED CLINICAL-TRIALS; SELECTION BIAS; BREAST-CANCER; SUBVERTING RANDOMIZATION; HEALTH INTERVENTIONS; IMMUNE GLOBULIN; YOUNG-CHILDREN; PRIMARY-CARE; QUALITY; MAMMOGRAPHY AB Background: It is widely believed that baseline imbalances in randomized trials must necessarily be random. In fact, there is a type of selection bias that can cause substantial, systematic and reproducible baseline imbalances of prognostic covariates even in properly randomized trials. It is possible, given complete data, to quantify both the susceptibility of a given trial to this type of selection bias and the extent to which selection bias appears to have caused either observable or unobservable baseline imbalances. Yet, in articles reporting on randomized trials, it is uncommon to find either these assessments or the information that would enable a reader to conduct them. Nevertheless, there have been a few published reports that contain descriptions of either this type of selection bias or indicators that it may have occurred. Objective: To document that the same type of selection bias has been described in numerous randomized trials and therefore that it represents a problem deserving of greater attention. Study selection: Computerized searches were not useful in locating trials with one or more elements that contribute to or are indicative of selection bias in randomized trials. We limit our treatment to trials that were previously questioned for susceptibility to selection bias or for large baseline imbalances. Results: We found 14 randomized trials that appear to be suspicious for selection bias. This may represent only the tip of the iceberg, because the status of other trials is inconclusive. Conclusions: Authors of clinical trial reports should be required to disclose sufficient details to allow for an assessment of both allocation concealment and selection bias. The extent to which a randomized study was susceptible to selection bias should be considered in determining the relative contribution it makes to any subsequent meta-analysis, policy or decision. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, EPN, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. George Washington Univ, Washington, DC 20052 USA. RP Berger, VW (reprint author), NCI, EPN, Suite 3131,6130 Executive Bldg,MSC 7354, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 65 TC 31 Z9 31 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD OCT PY 2004 VL 25 IS 5 BP 515 EP 524 DI 10.1016/j.cct.2004.04.001 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 863YS UT WOS:000224600100008 PM 15465620 ER PT J AU Berra, L De Marchi, L Panigada, M Yu, ZX Baccarelli, A Kolobow, T AF Berra, L De Marchi, L Panigada, M Yu, ZX Baccarelli, A Kolobow, T TI Evaluation of continuous aspiration of subglottic secretion in an in vivo study SO CRITICAL CARE MEDICINE LA English DT Article DE mechanical ventilation; aspiration; ventilator-associated pneumonia; endotracheal tube; continuous aspiration of subglottic secretions ID VENTILATOR-ASSOCIATED PNEUMONIA; RECEIVING MECHANICAL VENTILATION; RANDOMIZED CLINICAL-TRIAL; BACTERIAL-COLONIZATION; NOSOCOMIAL PNEUMONIA; BODY POSITION; PREVENTION; INTUBATION; MANAGEMENT; DRAINAGE AB Objective: Continuous aspiration of subglottic secretions (CASS) is believed to lower the incidence of ventilator-associated pneumonia. Animal studies to establish safety and efficacy of CASS have not been conducted. Design: Prospective randomized animal study. Setting: Animal-research facility at the U.S. National Institutes of Health. Subjects: Twenty-two sheep. Interventions: Sheep were randomized into three groups. In group C (control), eight sheep were kept prone, intubated with a standard endotracheal tube (ETT), and mechanically ventilated for 72 hrs with head and ETT elevated at an angle of 30degrees. In group CASS-HU (CASS, head up), seven sheep were managed as group G and intubated with a Hi-Lo Evac, Mallinckrodt ETT (CASS suction kept at less than or equal to20 mm Hg). In group CASS-HD (CASS, head down), seven sheep were kept prone with CASS, and the ETT and trachea were horizontal to promote spontaneous drainage of mucus from the ETT. Measurements and results: The lower respiratory tract in the CASS-HU group was heavily colonized in all seven sheep (median 4.6 x 10(9), range, 1.5 x 10(8) to 7.9 x 10(9) colony-forming units/g), with a reduction of lung bacterial colonization compared with the C group (p = .05). In group CASS-HD, the lower respiratory tract was not colonized in six of seven sheep. One sheep showed low levels of bacterial growth (median, 0; range, 0-2.2 x 10(5)). At autopsy, in all 14 sheep with CASS, we found tracheal mucosal injury of different degrees of severity at the level of the suction port of the ETT. Conclusions: In group CASS-HU, regardless of finding a marginal decrease of the bacterial colonization of the lower airways, there was pervasive trachea-bronchial-lung bacterial colonization. Second, there was minimal, or absent, bacterial colonization when the orientation of the CASS ETT was at, or just below, horizontal. Third, there was widespread injury to tracheal mucosa/submucosa from the use of CASS. Note that results of studies conducted in an animal model are always difficult to extrapolate to the clinical practice due to anatomical and functional differences. C1 NHLBI, NIH, PCCMB, Sect Pulm & Cardiac Assist Devices, Bethesda, MD 20892 USA. NHLBI, NIH, Pathol Core, Bethesda, MD 20892 USA. NCI, NIH, Dept Hlth & Human Serv, Genet Epidemiol Branch,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kolobow, T (reprint author), NHLBI, NIH, PCCMB, Sect Pulm & Cardiac Assist Devices, Bldg 10,9000 Rockville Pike,Rm 5D-07, Bethesda, MD 20892 USA. EM kolobowt@nhlbi.nih.gov RI Panigada, Mauro/K-4650-2014 OI Panigada, Mauro/0000-0003-4841-9794 NR 27 TC 68 Z9 74 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD OCT PY 2004 VL 32 IS 10 BP 2071 EP 2078 DI 10.1097/01.CCM.0000142575.86468.98 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 865HH UT WOS:000224692800013 PM 15483416 ER PT J AU Horne, MK AF Horne, MK TI Thrombolytics for occluded catheters SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE recombinant urokinase; catheters; alteplase; venous access ID CENTRAL VENOUS CATHETERS; TISSUE-PLASMINOGEN ACTIVATOR; OCCLUSION; ALTEPLASE; EFFICACY; TRIAL; RESTORATION; THERAPY C1 WG Magnuson Clin Ctr, Serv Hematol, Dept Lab Med, NIH, Bethesda, MD USA. RP Horne, MK (reprint author), WG Magnuson Clin Ctr, Serv Hematol, Dept Lab Med, NIH, Bethesda, MD USA. NR 13 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD OCT PY 2004 VL 32 IS 10 BP 2146 EP 2147 DI 10.1097/01.CCM.0000142905.76171.B6 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 865HH UT WOS:000224692800024 PM 15483427 ER PT J AU Aoki, Y Tosato, G AF Aoki, Y Tosato, G TI Neoplastic conditions in the context of HIV-1 infection SO CURRENT HIV RESEARCH LA English DT Article DE HIV; EBV; KSHV; HPV; Tat; KS; PEL; MCD; cervical cancer ID SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; EPSTEIN-BARR-VIRUS; PRIMARY EFFUSION LYMPHOMA; ACTIVE ANTIRETROVIRAL THERAPY; NON-HODGKIN-LYMPHOMA; HUMAN-PAPILLOMAVIRUS INFECTION; MULTICENTRIC CASTLEMANS-DISEASE; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; FACTOR/VASCULAR PERMEABILITY FACTOR AB HIV-1 infection predisposes to the development of specific types of cancer. Most cancers seen in the AIDS setting are related to oneogenic virus infections, such as Epstein-Barr virus (EBV), Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) and human papillomavirus (HPV). It is generally assumed that HIV-1 infection play a passive role in cancer development by impairing the host immune surveillance and increasing the risk of oncogenic virus infection. Recent insights, however, indicate that HIV-1 infection more actively promotes cancer growth. Experimental evidence has shown that HIV-1-encoded proteins can directly induce tumor angiogenesis and enhance KSHV transmission to target cells. Clinical evidence suggests that the oncogenicity of HPV is altered by the presence of HIV-1 infection irrespective of host immune status. The introduction of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS whereas the impact of HAART is variable in EBV-related lymphoma and HPV-related cervical cancer, suggesting that additional factors are involved in the pathogenesis of these cancers. Understanding the direct and indirect roles of HIV-1 in the pathogenesis of neoplastic conditions could provide the rationale for prevention and development of new treatments for AIDS-associated malignancies. C1 NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Aoki, Y (reprint author), NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, 10 Ctr Dr 12N226, Bethesda, MD 20892 USA. EM aokiy@mail.nih.gov NR 95 TC 28 Z9 30 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1570-162X J9 CURR HIV RES JI Curr. HIV Res. PD OCT PY 2004 VL 2 IS 4 BP 343 EP 349 DI 10.2174/1570162043351002 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 853UK UT WOS:000223854200006 PM 15544455 ER PT J AU Dai, X Segre, JA AF Dai, X Segre, JA TI Transcriptional control of epidermal specification and differentiation SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID NF-KAPPA-B; STEM-CELLS; C-MYC; MICE LACKING; HAIR FOLLICLE; IKK-ALPHA; HYPERSENSITIVE SITES; INDUCED APOPTOSIS; SKIN; KERATINOCYTES AB Recent experiments reveal the role of transcription factors in integrating upstream signals to execute specification and differentiation of epidermal cells. Based on the skin phenotype observed with misregulation of transcription factors such as p63, c-Myc, RelA, pRb, Klf4 and others, their function in controlling proliferation and differentiation is dissected. Understanding the pathways regulated by these factors and their coordinate interactions remains a challenge for the future. C1 Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Dai, X (reprint author), Univ Calif Irvine, Dept Biol Chem, 234D Med Sci 1, Irvine, CA 92697 USA. EM xdai@uci.edu; jsegre@nhgri.nih.gov FU NIAMS NIH HHS [R01 AR047320, R01 AR047320-02, R01 AR047320-03, R01 AR47320] NR 56 TC 66 Z9 67 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD OCT PY 2004 VL 14 IS 5 BP 485 EP 491 DI 10.1016/j.gde.2004.07.002 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 860JE UT WOS:000224337700005 PM 15380238 ER PT J AU Kimmel, AR Firtel, RA AF Kimmel, AR Firtel, RA TI Breaking symmetries: regulation of Dictyostelium development through chemoattractant and morphogen signal-response SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID STALK CELL-DIFFERENTIATION; PLECKSTRIN HOMOLOGY DOMAIN; BETA-CATENIN; NONAUTONOMOUS REGULATION; NEUTROPHIL CHEMOTAXIS; EFFICIENT CHEMOTAXIS; MEDIATED ACTIVATION; SERPENTINE RECEPTOR; ADENYLYL-CYCLASE; LIVING CELLS AB Dictyostelium discoideum grow unicellularly, but develop as multicellular organisms. At two stages of development, their underlying symmetrical pattern of cellular organization becomes disrupted. During the formation of the multicellular aggregate, individual non-polarized cells re-organize their cytoskeletal structures to sequester specific intracellular signaling elements for activation by and directed movement within chemoattractant gradients. Subsequently, response to secreted morphogens directs undifferentiated populations to adopt different cell fates. Using a combination of cellular, biochemical and molecular approaches, workers have now begun to understand the mechanisms that permit Dictyostelium (and other chemotactic cells) to move directionally in shallow chemoattractant gradients and the transcriptional regulatory pathways that polarize cell-fate choice and initiate pattern formation. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Genet Mol, La Jolla, CA 92093 USA. RP Kimmel, AR (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov NR 65 TC 49 Z9 51 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD OCT PY 2004 VL 14 IS 5 BP 540 EP 549 DI 10.1016/j.gde.2004.08.001 PG 10 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 860JE UT WOS:000224337700013 PM 15380246 ER PT J AU Kirk, AD AF Kirk, AD TI Transplantation - Integrating the concepts of innate and acquired immunity with translational trials - Editorial overiew SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 NIDDKD, Transplantat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kirk, AD (reprint author), NIDDKD, Transplantat Branch, NIH, Dept Hlth & Human Serv, Room 11S219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM allank@intra.niddk.nih.gov RI Kirk, Allan/B-6905-2012 NR 9 TC 1 Z9 1 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2004 VL 16 IS 5 BP 535 EP 537 DI 10.1016/j.coi.2004.07.020 PG 3 WC Immunology SC Immunology GA 854NS UT WOS:000223911200001 ER PT J AU Hale, DA AF Hale, DA TI Biological effects of induction immunosuppression SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID RENAL-TRANSPLANT RECIPIENTS; DOSE INTRAVENOUS IMMUNOGLOBULIN; T-CELL DEPLETION; ANTITHYMOCYTE GLOBULINS; HOMEOSTATIC PROLIFERATION; LYMPHOCYTE SUBPOPULATIONS; KIDNEY-TRANSPLANTATION; MONOCLONAL-ANTIBODIES; ANTIGENIC MODULATION; ALLOGRAFT RECIPIENTS AB The concept of induction immunosuppression is evolving. Once used to buttress the inadequacies of past maintenance immunosuppressive regimens, it is now being used to permit effective maintenance immunosuppression using ever decreasing amounts of modern agents. In addition to lymphocyte depletion, with which it was once synonymous, it is now recognized that induction immunosuppression is associated with a host of non-depletional effects such as receptor modulation and blockade, which profoundly alter the lymphocyte's capacity to mount an effective response. Additionally, the recent focus on the effect of induction agents on antigen presenting cells and on regulatory factors controlling homeostatic repopulation may ultimately permit a safer, more refined and more effective approach to induction immunosuppression. C1 NIDDKD, Bethesda, MD 20892 USA. RP Hale, DA (reprint author), NIDDKD, Room 11S219,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM douglash@intra.niddk.nih.gov NR 58 TC 9 Z9 10 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2004 VL 16 IS 5 BP 565 EP 570 DI 10.1016/j.coi.2004.07.005 PG 6 WC Immunology SC Immunology GA 854NS UT WOS:000223911200006 PM 15342000 ER PT J AU Duncan, K Barry, CE AF Duncan, K Barry, CE TI Prospects for new antitubercular drugs SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID EARLY BACTERICIDAL ACTIVITY; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; STERILIZING ACTIVITIES; MURINE TUBERCULOSIS; GENOME SEQUENCE; IN-VIVO; MOXIFLOXACIN; MICROPARTICLES; COMBINATION AB The inexorable rise in cases of tuberculosis worldwide, fuelled by the HIV epidemic, highlights the need for new drugs and particularly those that can shorten the duration of treatment. Clinical trials of existing broad-spectrum agents such as the fluoroquinolone moxifloxacin are proceeding, on the basis of efficacy in models of infection and preliminary clinical data. These may provide a stopgap, but the real breakthrough will come when novel agents with potent sterilising activity are discovered. Few such novel pre-clinical drug candidates exist and therefore considerable effort is being exerted to employ new tools to identify drug targets essential for survival of Mycobacterium tuberculosis. C1 GlaxoSmithKline, Stevenage SG1 2NY, Herts, England. NIH, TB Res Stn, Rockville, MD 20852 USA. RP Duncan, K (reprint author), GlaxoSmithKline, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England. EM ken.5.duncan@gsk.com RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000693-15] NR 58 TC 89 Z9 90 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD OCT PY 2004 VL 7 IS 5 BP 460 EP 465 DI 10.1016/j.mib.2004.08.011 PG 6 WC Microbiology SC Microbiology GA 863QC UT WOS:000224575700005 PM 15451500 ER PT J AU Leapman, RD AF Leapman, RD TI Novel techniques in electron microscopy SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID CRYOELECTRON TOMOGRAPHY; ENERGY-LOSS; MACROMOLECULAR COMPLEXES; ENDOPLASMIC-RETICULUM; CORRELATIVE LIGHT; RESOLUTION; CALCIUM; CELLS; ARCHITECTURE; JUNCTION AB Emerging techniques in electron microscopy promise to yield a wide range of new information about the nervous system. Aided by the development of detectors, electron optics, energy filters, computer automation and preparative methods, electron tomography now provides three-dimensional structures over a scale ranging from single receptor molecules to synapses and neurons. To relate structure to function, a variety of correlative methods are being developed, including protein tags observable both by light microscopy of living cells and, subsequently, by electron microscopy. It is also becoming possible to measure functionally important ions like Ca2+ in cellular compartments at a scale of about 10 nm by exploiting new advances in electron energy loss and X-ray spectroscopic imaging. C1 ORS, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20982 USA. RP Leapman, RD (reprint author), ORS, Div Bioengn & Phys Sci, NIH, Bldg 13,Room 3N17,9000 Rockville Pike, Bethesda, MD 20982 USA. EM leapman@helix.nih.gov NR 38 TC 25 Z9 27 U1 2 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD OCT PY 2004 VL 14 IS 5 BP 591 EP 598 DI 10.1016/j.conb.2004.08.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 865RU UT WOS:000224721200011 PM 15464893 ER PT J AU Dalakas, MC AF Dalakas, MC TI Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE beta-amyloid; cytotoxic T cells; dermatomyositis; inclusion body myositis; polymyositis ID CELL-RECEPTOR REPERTOIRE; INFILTRATING T-CELLS; COSTIMULATORY MOLECULE; MACROPHAGIC MYOFASCIITIS; ADHESION MOLECULES; MYOPATHIES; EXPRESSION; LYMPHOCYTES; CHEMOKINES; DISEASES AB Purpose of review To provide an update on the major advances in inflammatory myopathies. Recent findings Polymyositis is an uncommon disorder that can be misdiagnosed when the old, and never validated, criteria of Bohan and Peter are used. New diagnostic criteria were recently introduced, in which the MHC/CD8 complex is considered a specific immunopathological marker because it distinguishes the antigen-driven inflammatory cells that characterize polymyositis and sporadic inclusion-body myositis from the non-specific, secondary inflammation seen in other disorders, such as dystrophies. In sporadic inclusion-body myositis the inflammatory cells invade non-vacuolated fibers, whereas the vacuolated fibers are not invaded by T cells, implying two independent processes, a primary immune process with antigen-driven T cells identical to polymyositis, and a degenerative process in which beta-amyloid and amyloid-related proteins participate in vacuolar degeneration. In polymyositis and sporadic inclusion-body myositis, antigen-specific and clonally expanded autoinvasive T cells persist for years, even in different muscles, as reconfirmed by proof-of-principle techniques involving CDR3 spectratyping combined with laser microdissected single-cell polymerase chain reaction of the T-cell receptor genes. The formation of immunological synapse between autoinvasive T cells and muscle fibers was recently strengthened by the upregulation of co-stimulatory molecules ICOS/ICOS-L and PD-L1. A new, distinct myopathy characterized by T-cell-triggered macrophage hyperactivation has now been recognized in patients with dermatomyositis-like disease. Summary Despite recent progress, the antigen(s) responsible for T-cell activation in polymyositis and sporadic inclusion-body myositis and the cause of vacuolar degeneration in sporadic inclusion-body myositis remain unclear. Newer, more aggressive immunotherapies may be encouraging, but control trials are needed to prove efficacy. C1 NINDS, Neuromuscular Dis Sec, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sec, NIH, Bldg 10,Room 4N248,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov NR 58 TC 63 Z9 70 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD OCT PY 2004 VL 17 IS 5 BP 561 EP 567 DI 10.1097/00019052-200410000-00006 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 865HT UT WOS:000224694000005 PM 15367860 ER PT J AU Maeda, K Nakata, H Ogata, H Koh, Y Miyakawa, T Mitsuya, H AF Maeda, K Nakata, H Ogata, H Koh, Y Miyakawa, T Mitsuya, H TI The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection SO CURRENT OPINION IN PHARMACOLOGY LA English DT Review ID ANTIRETROVIRAL-DRUG-RESISTANCE; SCH-C SCH-351125; SMALL-MOLECULE; CHEMOKINE RECEPTORS; ENVELOPE GLYCOPROTEIN; FUSION COFACTORS; HIGHLY POTENT; IN-VITRO; ENTRY; ANTAGONISTS AB The discovery of CCR5 as a HIV-1 co-receptor unfolded the cryptic and complicated process of HIV-1 cellular entry and has provided more than a few entry steps as possible modalities for effective viral intervention. The proof-of-principle has already been established for the use of entry inhibitors against HIV-1 and there is a cautious optimism that several CCR5 inhibitors might soon be added to our armamentarium for therapy of HIV-1 infection. C1 Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. EM hmitsuya@helix.nih.gov NR 66 TC 39 Z9 41 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD OCT PY 2004 VL 4 IS 5 BP 447 EP 452 DI 10.1016/j.coph.2004.07.004 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 859KN UT WOS:000224262200004 PM 15351348 ER PT J AU Altieri, AS Byrd, RA AF Altieri, AS Byrd, RA TI Automation of NMR structure determination of proteins SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID CHEMICAL-SHIFT ASSIGNMENT; NOESY SPECTRA; RESONANCE ASSIGNMENTS; PROJECTION-RECONSTRUCTION; MACROMOLECULAR STRUCTURE; POLYPEPTIDE BACKBONE; MULTIDIMENSIONAL NMR; BAYESIAN PROTOCOL; PLANE PROJECTIONS; WEAK ALIGNMENT AB The automation of protein structure determination using NMR is coming of age. The tedious processes of resonance assignment, followed by assignment of NOE (nuclear Overhauser enhancement) interactions (now intertwined with structure calculation), assembly of input files for structure calculation, intermediate analyses of incorrect assignments and bad input data, and finally structure validation are all being automated with sophisticated software tools. The robustness of the different approaches continues to deal with problems of completeness and uniqueness; nevertheless, the future is very bright for automation of NMR structure generation to approach the levels found in X-ray crystallography. Currently, near completely automated structure determination is possible for small proteins, and the prospect for medium-sized and large proteins is good. C1 NCI, Canc Res Ctr, Struct Biophys Lab, Frederick, MD 21702 USA. RP Altieri, AS (reprint author), NCI, Canc Res Ctr, Struct Biophys Lab, Frederick, MD 21702 USA. EM altieri@ncifcrf.gov; rabyrd@ncifcrf.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 NR 47 TC 45 Z9 46 U1 0 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD OCT PY 2004 VL 14 IS 5 BP 547 EP 553 DI 10.1016/j.sbi.2004.09.003 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 865QX UT WOS:000224718800005 PM 15465314 ER PT J AU Ramakrishnan, B Boeggeman, E Ramasamy, V Qasba, PK AF Ramakrishnan, B Boeggeman, E Ramasamy, V Qasba, PK TI Structure and catalytic cycle of beta-1,4-galactosyltransferase SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID ALPHA-LACTALBUMIN LA; LACTOSE SYNTHETASE; CRYSTAL-STRUCTURE; N-ACETYLGLUCOSAMINE; MOLECULAR-CLONING; GALACTOSYLTRANSFERASE; BINDING; SPECIFICITY; SYNTHASE; PROTEIN AB beta-1,4-galactosyltransferase-1, a housekeeping enzyme that functions in the synthesis of glycoconjugates, has two flexible loops, one short and one long. Upon binding a metal ion and UDP-galactose, the loops change from an open to a closed conformation, repositioning residues to lock the ligands in place. Residues at the N-terminal region of the long loop form the metal-binding site and those at the C-terminal region form a helix, which becomes part of the binding site for the oligosaccharide acceptor; the remaining residues cover the bound sugar-nucleotide. After binding of the oligosaccharide acceptor and transfer of the galactose moiety, the product disaccharide unit is ejected and the enzyme returns to the open conformation, repeating the catalytic cycle. C1 NCI, Struct Glycobiol Sect, Frederick, MD 21702 USA. NCI, Intramural Res Support Program SAIC, Lab Expt & Computat Biol, Canc Res Ctr, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, Frederick, MD 21702 USA. EM qasba@helix.nih.gov NR 36 TC 56 Z9 57 U1 1 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD OCT PY 2004 VL 14 IS 5 BP 593 EP 600 DI 10.1016/j.sbi.2004.09.006 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 865QX UT WOS:000224718800012 PM 15465321 ER PT J AU Seidman, MM AF Seidman, MM TI Oligonucleotide mediated gene targeting in mammalian cells SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Review ID TRIPLE-HELIX FORMATION; PEPTIDE NUCLEIC-ACID; DOUBLE-STRANDED DNA; FRAGMENT HOMOLOGOUS REPLACEMENT; SEQUENCE-SPECIFIC RECOGNITION; IN-VITRO TRANSCRIPTION; PHOTO-CROSS-LINKING; FORMING-OLIGONUCLEOTIDES; 3RD STRAND; SYNTHETIC OLIGONUCLEOTIDES AB Gene targeting can be loosely defined as a process through which a specific chromosomal sequence is recognized and bound by a reagent designed for the purpose. The endpoint may be modulation of events at the target, such as transcription, or a permanent change in sequence at the site. A facile strategy for mammalian cells would have broad applications in basic and applied research, including gene therapy. Although approaches based on homologous recombination are routinely employed for transgenic animal construction, they are too laborious and inefficient for broader use. Consequently there has been a longstanding interest in developing effective synthetic reagents. Sequence recognition can be either at the level of a single strand or via the major or minor grooves, and specific approaches for each route are under development. In this review several oligonucleotide-based strategies will be discussed. These include single and double strand oligonucleotides designed to attack single strand targets, and triple helix forming olgonucleotides and peptide nucleic acids, intended for double stranded targets. C1 NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Seidman, MM (reprint author), NIA, Lab Mol Gerontol, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov NR 183 TC 11 Z9 12 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD OCT PY 2004 VL 5 IS 5 BP 421 EP 430 DI 10.2174/1389201043376625 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 859XY UT WOS:000224302900004 PM 15544490 ER PT J AU Kimchi-Sarfaty, C Gottesman, MM AF Kimchi-Sarfaty, C Gottesman, MM TI SV40 pseudovirions as highly efficient vectors for gene transfer and their potential application in cancer therapy SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Review DE SV40 vectors; SV40 in vitro packaging; high efficiency; chemoprotection; anti-HIV gene therapy; Pseudomonas exotoxin; pigment epithelium derived factor ID EPITHELIUM-DERIVED FACTOR; HEMATOPOIETIC PROGENITOR CELLS; CLASS-I MOLECULES; SV40-DERIVED VECTORS; CAVEOLAR ENDOCYTOSIS; SIMIAN VIRUS-40; DRUG-RESISTANCE; INSECT CELLS; SIMIAN-VIRUS-40; DNA AB Among viral and non-viral gene delivery systems, SV40-based vectors show great promise in the cancer gene therapy field. SV40 vectors very efficiently deliver genes such as anti-viral agents, DNA vaccine, genes for chemoprotection (such as ABC transporters genes), suicide genes and antiangiogenic genes. The recombinant SV40 vectors can infect a wide variety of cells-dividing cells as well as non-cycling ones. Most of the SV40-based vectors can incorporate larger transgenes than the capacity of the SV40 wild-type, which is 5.2 kb; Moreover, in vitro packaged vectors demonstrate efficient delivery of plasmids with a molecular weight of up to 17.7 kb. SV40-based vectors carry some SV40 viral sequences, but the SV40 in vitro-packaged vectors are free of any SV40 wild-type viral DNA sequences. These vectors are prepared with nuclear extracts of SF9 insect cells containing the main viral capsid protein of the SV40 wild-type virus, VP1. This review summarizes different strategies in which SV40 vectors are used to deliver genes in vitro, to living mice, and to tumors growing in nude mice. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1A09,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 64 TC 21 Z9 23 U1 0 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD OCT PY 2004 VL 5 IS 5 BP 451 EP 458 DI 10.2174/1389201043376670 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 859XY UT WOS:000224302900007 PM 15544493 ER PT J AU Gustafson, KR McKee, TC Bokesch, HR AF Gustafson, KR McKee, TC Bokesch, HR TI Anti-HIV cyclotides SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review DE cyclotide; HIV; macrocyclic peptide; circulin; cycloviolin; palicourein; cyclic cystine knot ID INHIBITORY NATURAL-PRODUCTS; POLYPEPTIDE KALATA B1; PLANT DEFENSIVE GENES; CYSTINE KNOT MOTIF; MACROCYCLIC PEPTIDES; STRUCTURAL MOTIF; MOMORDICA-COCHINCHINENSIS; CALOPHYLLUM-LANIGERUM; CHASSALIA-PARVIFOLIA; CYCLIC DEPSIPEPTIDE AB The cyclotides are a recently discovered, structurally unique family of bioactive plant peptides. Their discovery spawned a series of structural analyses, synthetic efforts, and studies to define the biosynthesis and biological properties of these novel peptide metabolites. Cyclotides have a head-to-tail cyclized amino acid backbone and a conserved cystine knot motif that provides an extremely stable structural framework. They all share a common global fold and are highly resistant to denaturation and to cleavage by proteolytic enzymes. However, these macrocyclic peptides are quite permissive to amino acid substitutions or additions in several peripheral loop regions, since changes in these loops do not alter the core cyclotide structure. These features make cyclotides attractive templates for incorporating desired amino acid sequences and then delivering these peptide sequences in a well defined, highly stable framework. Cyclotides likely function in a defensive role in the source plants since they exhibit a broad spectrum of antimicrobial activity and are detrimental to the growth and survival of herbivorous insects. Cyclotides are gene-encoded polypeptides that are cleaved from larger precursor proteins and then cyclized. This review summarizes research done on a subset of cyclotides that were discovered due to their HIV inhibitory properties. It details the isolation and characterization of these compounds and describes this work in the context of our current state of knowledge of the entire cyclotide family. C1 NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Dev Program, Ctr Canc Res, Bldg 1052,Room 121, Frederick, MD 21702 USA. EM manuscripts@mail.ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 64 TC 105 Z9 107 U1 3 U2 19 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD OCT PY 2004 VL 5 IS 5 BP 331 EP 340 DI 10.2174/1389203043379468 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852KH UT WOS:000223753700004 PM 15544529 ER PT J AU Grube, M Melenhorst, JJ Barrett, AJ AF Grube, M Melenhorst, JJ Barrett, AJ TI An APC for every occasion: induction and expansion of human Ag-specific CD4 and CD8 T cells using cellular and non-cellular APC SO CYTOTHERAPY LA English DT Review DE APC; artificial APC; DC; immunotherapy ID ANTIGEN-PRESENTING CELLS; CHRONIC MYELOGENOUS LEUKEMIA; COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; HUMAN DENDRITIC CELLS; LYMPHOCYTES IN-VITRO; CLASS-II COMPLEXES; EX-VIVO INDUCTION; HUMAN B-CELLS; METASTATIC MELANOMA AB APC are used extensively to induce and expand Ag-specific T cells as well as to test their specificity and function. In the treatment of malignant and infectious diseases, APC are used to stimulate and expand Ag-specific T cells for adoptive transfer, or used directly in vivo to present Ag. The choice of APC to use depends on the particular application and on practical considerations, which include ease of production, availability, reproducibility and ( for clinical use) established safety. The diversity of APC in use partly reflects the fact that no single technique of Ag presentation is ideal. For the clinician and laboratory worker alike the field can seem illogical and confusing. In this review we outline the functional requirements of APC for the induction of T cells, classify the APC in common use and describe their laboratory and clinical applications. C1 NHLBI, Stem Cell Allogen Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Grube, M (reprint author), NHLBI, Stem Cell Allogen Transplantat Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 97 TC 5 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD OCT PY 2004 VL 6 IS 5 BP 440 EP 449 DI 10.1080/14653240410005230 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 859LQ UT WOS:000224265500002 PM 15512910 ER PT J AU Chu, EY Hens, J Andl, T Kairo, A Yamaguchi, TP Brisken, C Glick, A Wysolmerski, JJ Millar, SE AF Chu, EY Hens, J Andl, T Kairo, A Yamaguchi, TP Brisken, C Glick, A Wysolmerski, JJ Millar, SE TI Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis SO DEVELOPMENT LA English DT Article DE mammary gland; placode; mammary bud; WNT; TOPGAL; Dkk1; mouse ID HAIR FOLLICLE MORPHOGENESIS; HORMONE-RELATED PROTEIN; BETA-CATENIN; GENE-EXPRESSION; TRANSGENIC MICE; MOUSE DEVELOPMENT; CELL FATE; DIFFERENTIATION; SKIN; MULTIPLE AB Mammary glands, like other skin appendages such as hair follicles and teeth, develop from the surface epithelium and underlying mesenchyme; however, the molecular controls of embryonic mammary development are largely unknown. We find that activation of the canonical WNT/beta-catenin signaling pathway in the embryonic mouse mammary region coincides with initiation of mammary morphogenesis, and that WNT pathway activity subsequently localizes to mammary placodes and buds. Several Wnt genes are broadly expressed in the surface epithelium at the time of mammary initiation, and expression of additional Wnt and WNT pathway genes localizes to the mammary lines and placodes as they develop. Embryos cultured in medium containing WNT3A or the WNT pathway activator lithium chloride (LiCI) display accelerated formation of expanded placodes, and LiCl induces the formation of ectopic placode-like structures that show elevated expression of the placode marker Wnt10b. Conversely, expression of the secreted WNT inhibitor Dickkopf 1 in transgenic embryo surface epithelium in vivo completely blocks mammary placode formation and prevents localized expression of all mammary placode markers tested. These data indicate that WNT signaling promotes placode development and is required for initiation of mammary gland morphogenesis. WNT signals play similar roles in hair follicle formation and thus may be broadly required for induction of skin appendage morphogenesis. C1 Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA. Yale Univ, Sect Endocrinol & Metab, Dept Internal Med, New Haven, CT 06520 USA. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Swiss Inst Expt Canc Res, NCCR Mol Oncol, CH-1066 Epalinges, Switzerland. NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. RP Millar, SE (reprint author), Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. EM millars@mail.med.upenn.edu FU NCI NIH HHS [CA94175]; NIAMS NIH HHS [AR47709, T32-AR07465, T32 AR007465]; NIDDK NIH HHS [DK55501] NR 50 TC 161 Z9 165 U1 1 U2 9 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 OCT PY 2004 VL 131 IS 19 BP 4819 EP 4829 DI 10.1242/dev.01347 PG 11 WC Developmental Biology SC Developmental Biology GA 865SP UT WOS:000224723400017 PM 15342465 ER PT J AU Ramos, SBV Stumpo, DJ Kennington, EA Phillips, RS Bock, CB Ribeiro-Neto, F Blackshear, PJ AF Ramos, SBV Stumpo, DJ Kennington, EA Phillips, RS Bock, CB Ribeiro-Neto, F Blackshear, PJ TI The CCCH tandem zinc-finger protein Zfp36I2 is crucial for female fertility and early embryonic development SO DEVELOPMENT LA English DT Article DE female fertility; early embryonic development; CCCH tandem zinc-finger proteins ID EARLY MOUSE EMBRYOS; C-ELEGANS EMBRYOS; AU-RICH ELEMENTS; MESSENGER-RNA; TRISTETRAPROLIN FAMILY; GERMLINE SPECIFICATION; OOCYTE MATURATION; ZONA-PELLUCIDA; STEM-CELLS; TNF-ALPHA AB The CCCH tandem zinc finger protein, Zfp3612, like its better-known relative tristetraprolin (TTP), can decrease the stability of AU-rich element-containing transcripts in cell transfection studies; however, its physiological importance is unknown. We disrupted Zfp3612 in mice, resulting in decreased expression of a truncated protein in which the N-terminal 29 amino acids had been deleted (DeltaN-Zfp3612). Mice derived from different clones of ES cells exhibited complete female infertility, despite evidence from embryo and ovary transplantation experiments that they could gestate and rear wild-type young. DeltaN-Zfp3612 females apparently cycled and ovulated normally, and their ova could be fertilized; however, the embryos did not progress beyond the two-cell stage of development. These mice represent a specific model of disruption of the earliest stages of embryogenesis, implicating Zfp3612, a probable mRNA-binding and destabilizing protein, in the physiological control of female fertility at the level of early embryonic development. This newly identified biological role for Zfp3612 may have implications for maternal mRNA turnover in normal embryogenesis, and conceivably could be involved in some cases of unexplained human female infertility. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Durham, NC 27710 USA. NIEHS, Off Clin Res, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU NICHD NIH HHS [K08 HD069597] NR 39 TC 69 Z9 72 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2004 VL 131 IS 19 BP 4883 EP 4893 DI 10.1242/dev.01336 PG 11 WC Developmental Biology SC Developmental Biology GA 865SP UT WOS:000224723400022 PM 15342461 ER PT J AU Coppola, V Barrick, CA Southon, EA Celeste, A Wang, K Chen, B Haddad, EB Yin, J Nussenzweig, A Subramaniaml, A Tessarollo, L AF Coppola, V Barrick, CA Southon, EA Celeste, A Wang, K Chen, B Haddad, EB Yin, J Nussenzweig, A Subramaniaml, A Tessarollo, L TI Ablation of TrkA function in the immune system causes B cell abnormalities SO DEVELOPMENT LA English DT Article DE TrkA; NGF; immune system; mouse ID NERVE GROWTH-FACTOR; FOREBRAIN CHOLINERGIC NEURONS; MAST-CELLS; TRANSGENIC MICE; IMMUNOGLOBULIN PRODUCTION; NEUROTROPHIC FACTOR; SURVIVAL FACTOR; GENE; LYMPHOCYTES; EXPRESSION AB The nerve growth factor (NGF) receptor TrkA is widely expressed in non-neural tissues suggesting pleiotropic functions outside the nervous system. Based on pharmacological and immuno-depletion experiments, it has been hypothesized that NGF plays an important role in the normal development and function of the immune system. However, attempts to unravel these functions by conventional gene targeting in mice have been hampered by the early postnatal lethality caused by null mutations. We have developed a novel 'reverse conditional' gene targeting strategy by which TrkA function is restored specifically in the nervous system. Mice lacking TrkA in non-neuronal tissues are viable and appear grossly normal. All major immune system cell populations are present in normal numbers and distributions. However, mutant mice have elevated serum levels of certain immunoglobulin classes and accumulate B1 cells with aging. These data, confirmed in a classical reconstitution model using embryonic fetal liver from TrkA-mill mice, demonstrate that endogenous NGF modulates B cell development through TrkA in vivo. Furthermore, they demonstrate that many of the dramatic effects previously reported by pharmacological or immuno-depletion approaches do not reflect physiological developmental roles of TrkA in the immune system. C1 NCI, Neural Dev Grp, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Aventis Pharmaceut, Bridgewater, NJ 08807 USA. RP Tessarollo, L (reprint author), NCI, Neural Dev Grp, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. EM tessarol@ncifcrf.gov RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 NR 57 TC 32 Z9 33 U1 1 U2 6 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 OCT PY 2004 VL 131 IS 20 BP 5185 EP 5195 DI 10.1242/dev.01383 PG 11 WC Developmental Biology SC Developmental Biology GA 870YE UT WOS:000225094000025 PM 15459109 ER PT J AU Hoeppner, DJ Spector, MS Ratliff, TM Kinchen, JM Granat, S Lin, SC Bhusri, SS Conradt, B Herman, MA Hengartner, MO AF Hoeppner, DJ Spector, MS Ratliff, TM Kinchen, JM Granat, S Lin, SC Bhusri, SS Conradt, B Herman, MA Hengartner, MO TI eor-1 and eor-2 are required for cell-specific apoptotic death in C-elegans SO DEVELOPMENTAL BIOLOGY LA English DT Article DE apoptosis; hermaphrodite-specific neuron (HSN); egl-1 suppressor; eor; differentiation; BTB/POZ; kruppel ID NEMATODE CAENORHABDITIS-ELEGANS; ACUTE PROMYELOCYTIC LEUKEMIA; FINGER TRANSCRIPTION FACTOR; GENETIC-CONTROL; POLYMORPHISM MAP; ACTIVATOR GENE; MOTOR NEURONS; HIGH-DENSITY; DNA-BINDING; POZ DOMAIN AB Programmed cell death occurs in every multicellular organism and in diverse cell types yet the genetic controls that define which cells will live and which will die remain poorly understood. During development of the nematode Caenorhabditis elegalls, the coordinated activity of four gene products, EGL-1, CED-9, CED-4 and CED-3, results in the death of essentially all cells fated to die. To identify novel upstream components of the cell death pathway, we performed a genetic screen for mutations that abolish the death of the hermaphrodite-specific neurons (HSNs), a homologous pair of cells required for egg-laying in the hermaphrodite. We identified and cloned the genes, eor-1 and eor-2, which are required to specify the fate of cell death in male HSNs. In addition to defects in HSN death, mutation of either gene leads to defects in coordinated movement, neuronal migration, male tail development, and viability; all consistent with abnormal neuronal differentiation. eor-1 encodes a putative transcription factor related to the human oncogene PLZF. eor-2 encodes a novel but conserved protein. We propose that eor-1 and eor-2 function together throughout the nervous system to promote terminal differentiation of neurons and function specifically in male HSNs to promote apoptotic death of the HSNs. (C) 2004 Elsevier Inc. All rights reserved. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. SUNY Stony Brook, Genet Program, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. Kansas State Univ, Div Biol, Program Mol Cellular & Dev Biol, Manhattan, KS 66506 USA. SUNY Stony Brook, Program Mol Microbiol, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. Univ Zurich, Inst Mol Biol, CH-8057 Zurich, Switzerland. Dartmouth Coll Sch Med, Dept Genet, Hanover, NH 03755 USA. RP Hoeppner, DJ (reprint author), NINDS, NIH, LMB, 36 Convent Dr, Bethesda, MD 20892 USA. EM hoeppner@ninds.nih.gov; michael.hengartner@molbio.unizh.ch RI Hengartner, Michael/A-7058-2008; Hengartner, Michael/E-6235-2011; Conradt, Barbara/K-2665-2014; OI Hengartner, Michael/0000-0002-7584-596X FU NIGMS NIH HHS [GM52540, GM56339] NR 64 TC 21 Z9 31 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2004 VL 274 IS 1 BP 125 EP 138 DI 10.1016/j.ydbio.2004.06.022 PG 14 WC Developmental Biology SC Developmental Biology GA 855JD UT WOS:000223968500011 PM 15355793 ER PT J AU Lefrancois, S Janvier, K Boehm, M Ooi, CE Bonifacino, JS AF Lefrancois, S Janvier, K Boehm, M Ooi, CE Bonifacino, JS TI An ear-core interaction regulates the recruitment of the AP-3 complex to membranes SO DEVELOPMENTAL CELL LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; ADP-RIBOSYLATION FACTORS; ADAPTER COMPLEX; PROTEIN COMPLEX; BETA-3A SUBUNIT; CLATHRIN; AP2; TRAFFICKING; TRANSPORT; BINDING AB AP-3 is a heterotetrameric adaptor involved in the biogenesis of lysosome-related organelles. The function of AP-3 as an adaptor relies on its ability to bind to membranes in an Art-dependent fashion and to recognize sorting signals in the cytosolic tails of the transmembrane cargo. Here, we report an interdomain interaction involving the ear domain of the delta subunit and the sigma3 subunit of AP-3. This interaction interferes with the binding of AP-3 to Art but not to dileucine-based sorting signals. As a consequence, the delta-ear inhibits the recruitment of AP-3 to membranes both in vitro and in vivo and impairs the sorting of lysosomal membrane proteins. These observations suggest a new regulatory mechanism for the recruitment of AP-3 to membranes involving delta-ear-sigma3 interactions. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 26 TC 11 Z9 13 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT PY 2004 VL 7 IS 4 BP 619 EP 625 DI 10.1016/j.devcel.2004.08.009 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 864ZG UT WOS:000224671300019 PM 15469849 ER PT J AU Ma, L Tataranni, PA Bogardus, C Baier, LJ AF Ma, L Tataranni, PA Bogardus, C Baier, LJ TI Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians SO DIABETES LA English DT Article ID CHILDHOOD OBESITY; MUTATIONS; INHERITANCE; DOMINANT; MC4R AB Heterozygous coding mutations in the melanocortin 4 receptor gene (MC4R) are the most common genetic causes of severe human obesity identified to date. To determine whether MC4R has a role in causing severe obesity in Pima Indians, we sequenced the coding region of this gene in 426 full-heritage, non-first-degree related, adult Pima Indians (300 severely obese and 126 nondiabetic nonobese control subjects). Three coding variations were detected as heterozygotes only in severely obese subjects. One variation, detected in three obese subjects, was a novel single-base insertion (A) at nucleotide 100, and it predicted a frameshift and premature STOP at codon 37. The second variant, detected in 10 obese subjects, predicted a previously identified arginine-to-glutamine substitution at codon 165, and the third variant, detected in one obese subject, predicted a novel glycine-to-serine substitution at codon 231. Three polymorphisms were also identified in the 5 untranslated region, but these variants were detected in both obese and lean subjects and had similar allele frequencies. We conclude that variations in MC4R may account for a small portion of obesity in Pima Indians, but they do not explain the overall high prevalence of obesity in this Native American population. C1 NIDDKD, Clin Diabet & Nutr Sect, Dept Hlth & Human Serv, NIH, Phoenix, AZ 85016 USA. RP Baier, LJ (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Dept Hlth & Human Serv, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. EM lbaier@phx.niddk.nih.gov NR 17 TC 31 Z9 37 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD OCT PY 2004 VL 53 IS 10 BP 2696 EP 2699 DI 10.2337/diabetes.53.10.2696 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857KU UT WOS:000224116100025 PM 15448103 ER PT J AU Fong, DS Aiello, LP Ferris, FL Klein, R AF Fong, DS Aiello, LP Ferris, FL Klein, R TI Diabetic retinopathy SO DIABETES CARE LA English DT Review ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; BLOOD-PRESSURE CONTROL; OPTICAL COHERENCE TOMOGRAPHY; POSTERIOR HYALOIDAL TRACTION; EPITHELIUM-DERIVED FACTOR; DIFFUSE MACULAR EDEMA; VITAMIN-E; MICROVASCULAR COMPLICATIONS; INTRAVITREAL TRIAMCINOLONE C1 So Calif Permanente Med Grp, Dept Res & Evaluat, Pasadena, CA 91101 USA. So Calif Permanente Med Grp, Dept Ophthalmol, Baldwin Pk, CA USA. So Calif Permanente Med Grp, Dept Res & Evaluat, Pasadena, CA USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. NEI, Dept Clin Res, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. RP Fong, DS (reprint author), So Calif Permanente Med Grp, Dept Res & Evaluat, 100 S Los Robles, Pasadena, CA 91101 USA. NR 131 TC 268 Z9 280 U1 0 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2004 VL 27 IS 10 BP 2540 EP 2553 DI 10.2337/diacare.27.10.2540 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857KQ UT WOS:000224115700045 PM 15451934 ER PT J AU Stefan, N Stumvoll, M Weyer, C Bogardus, C Tataranni, PA Pratley, RE AF Stefan, N Stumvoll, M Weyer, C Bogardus, C Tataranni, PA Pratley, RE TI Exaggerated insulin secretion in Pima Indians and African-Americans but higher insulin resistance in Pima Indians compared to African-Americans and Caucasians SO DIABETIC MEDICINE LA English DT Article DE ethnicity; insulin action; insulin secretion; glucose clamp; Type 2 diabetes ID IMPAIRED GLUCOSE-TOLERANCE; DIABETES-MELLITUS; RISK-FACTORS; PREPUBERTAL CHILDREN; MEXICAN-AMERICANS; FAT DISTRIBUTION; NATURAL-HISTORY; WHITE AMERICANS; SENSITIVITY; POPULATIONS AB Aims African-Americans have a higher prevalence of Type 2 diabetes than Caucasians, but a lower prevalence than Pima Indians. Studies suggest that both African-Americans and Pima Indians are more insulin resistant and have higher acute insulin secretory responses to glucose than Caucasians; however, a direct comparison between these three populations is lacking. Methods We measured insulin secretory responses to intravenous glucose (acute insulin response, AIR, 25 g ivGTT); insulin action at physiological (M-low) and supra-physiological (M-high) levels of hyperinsulinaemia (2-step hyperinsulinaemic clamp); basal and insulin-suppressed endogenous glucose production in 30 African-Americans, 30 Pima Indians and 30 Caucasians with normal glucose tolerance who were carefully matched for age, sex, and body fat (hydrodensitometry or DEXA). A subgroup of 24 subjects from each group additionally underwent a standardized mixed meal test. Results M-low was lower in Pima Indians (0.50 +/- 0.03) compared to Caucasians (0.59 +/- 0.02, P = 0.02) and African-Americans [0.58 +/- 0.03 mg/kgEMBS/min, log(10) (means +/- SE), P = 0.03] but was not different between African-Americans and Caucasians. Basal endogenous glucose production was lower in Pima Indians (2.43 +/- 0.06) compared to African-Americans (2.70 +/- 0.06, P = 0.02) and was not different between Pima Indians and Caucasians (2.59 +/- 0.09 mg/kgEMBS/min) or African-Americans and Caucasians (all P > 0.18). Insulin-suppressed endogenous glucose production during the clamp was not different among the groups (all P > 0.40). AIR was higher in both African-Americans (13.51 +/- 0.26) and Pima Indians (13.72 +/- 0.27) compared to Caucasians (12.33 +/- 0.25 pM, log(10), both P < 0.01). The areas under the curve for glucose in response to the oral glucose tolerance test and mixed meal test were higher in Pima Indians compared to African-Americans (P = 0.03 and P = 0.03, respectively) and Caucasians (P = 0.01, mixed meal test), but not different between African-Americans and Caucasians. Conclusions Exaggerated glucose-stimulated insulin secretion, manifested initially as an increased response to an intravenous glucose challenge, appears to be a characteristic in people with normal glucose tolerance at higher risk for diabetes. Lower whole-body insulin sensitivity in Pima Indians compared to African-Americans, however, may contribute to the higher risk for Type 2 diabetes in Pima Indians compared to African-Americans. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Stefan, N (reprint author), Univ Tubingen, Dept Internal Med, Otfried Muller Str 10, D-72076 Tubingen, Germany. EM norbert.stefan@med.uni-tuebingen.de OI Stefan, Norbert/0000-0002-2186-9595 NR 25 TC 19 Z9 19 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD OCT PY 2004 VL 21 IS 10 BP 1090 EP 1095 DI 10.1111/j.1464-5491.2004.01290.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 856FH UT WOS:000224030600006 PM 15384955 ER PT J AU Conneely, KN Silander, K Scott, LJ Mohlke, KL Lazaridis, KN Valle, TT Tuomilehto, J Bergman, RN Watanabe, RM Buchanan, TA Collins, FS Boehnke, M AF Conneely, KN Silander, K Scott, LJ Mohlke, KL Lazaridis, KN Valle, TT Tuomilehto, J Bergman, RN Watanabe, RM Buchanan, TA Collins, FS Boehnke, M TI Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects SO DIABETOLOGIA LA English DT Article DE genetics of Type 2 diabetes; genetic susceptibility; human genetics; non-insulin-dependent diabetes mellitus ID SINGLE NUCLEOTIDE POLYMORPHISMS; EXPRESSION; SUSCEPTIBILITY; CAUCASIANS; POPULATION; PROMOTER; VARIANTS; HISTORY; ABSENCE; GLUCOSE AB Aims/hypothesis. Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and Type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with Type 2 diabetes and related traits in a Finnish sample. Methods. In 781 cases with Type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with Type 2 diabetes and related traits. Results. The SNPs were not significantly associated with Type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls. Conclusions. Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance. C1 Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. Natl Inst Publ Hlth, Dept Mol Med, Helsinki, Finland. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Diabet & Genet Epidemiol Unit, Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. Univ So Calif, Dept Physiol & Biophys, Keck Sch Med, Los Angeles, CA 90089 USA. Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. Univ So Calif, Dept Med, Keck Sch Med, Los Angeles, CA 90089 USA. RP Boehnke, M (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, 1420 Washington Hts, Ann Arbor, MI 48109 USA. EM boehnke@umich.edu FU NHGRI NIH HHS [HG00376, R01 HG000376, T32 HG000040, Z01 HG000040]; NIDDK NIH HHS [U01 DK062370, DK27619, DK29867, DK62370, R01 DK027619, R01 DK029867, R01 DK062370, R37 DK027619, R56 DK062370] NR 28 TC 61 Z9 64 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2004 VL 47 IS 10 BP 1782 EP 1788 DI 10.1007/s00125-004-1537-x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 870HJ UT WOS:000225047900020 PM 15517149 ER PT J AU Bertario, L Russo, A Sala, P Varesco, L Crucianelli, R Frattini, M Pierotti, MA Radice, P AF Bertario, L Russo, A Sala, P Varesco, L Crucianelli, R Frattini, M Pierotti, MA Radice, P CA Hereditary Colorectal Tumors TI APC genotype is not a prognostic factor in familial adenomatous polyposis patients with colorectal cancer SO DISEASES OF THE COLON & RECTUM LA English DT Article; Proceedings Paper CT 3rd Joint Meeting of the International-Collaborative-Group-for-Hereditary-Non-Polyposis-Colorecta l-Cancer CY APR 26-28, 2001 CL VENICE, ITALY SP Int Colloraborat Grp Hereditary Non Polyposis Colorectal Canc DE familial adenomatous polyposis; survival; APC ID SOMATIC MUTATIONS; COLON-CANCER; SURVIVAL; GENE; PHENOTYPE; IDENTIFICATION; INSTABILITY; EXPRESSION; FREQUENCY; REGISTER AB PURPOSE: Several studies have shown that the clinical phenotype of patients with familial adenomatous polyposis is influenced by the position of the associated germline mutation in the APC gene. The aim of this work was to assess whether the site of the APC mutation may also predict the survival of familial adenomatous polyposis patients with a confirmed diagnosis of colorectal cancer. METHODS: A total of 387 familial adenomatous polyposis patients with colorectal cancer were examined. Of these, 287 (74 percent) belonged to families with an identified mutation, whereas 100 (26 percent) were from families in which no detectable APC mutation had been found by standard screening methods. The subjects were subdivided into four groups, according to the presence and localization of the identified mutation: with mutation before (a), at (b), or beyond codon 1309 (c), and without identified mutation (d). RESULTS: The cumulative five-year survival estimate of all cases included in the study was 0.56 (95 percent confidence interval, 0.51-0.61). No difference was observed in survival probability among patients from families with mutations before (0.56; 95 percent confidence interval, 0.49-0.63), at (0.58; 95 percent confidence interval, 0.43-0.72), or beyond (0-52; 95 percent confidence interval, 0.31-0.73) codon 1309 or those from families that were mutation negative (0.58; 95 percent confidence interval, 0.48-0.68) (log-rank test, P = 0.9). Survival analysis did not reveal any significant advantage for patients carrying a mutation in a specific region of the APC gene, after adjustment for age, gender, site, and stage. CONCLUSION: These data do not support the hypothesis that APC mutation may influence the outcome of familial adenomatous polyposis cases affected by colorectal cancer. C1 Ist Nazl Tumori, Dept Predict & Prevent Med, I-20133 Milan, Italy. Natl Canc Inst, Hereditary Colorectal Tumors Registry, I-20133 Milan, Italy. Local Hlth Author Milan, Epidemiol Unit, Milan, Italy. Natl Canc Inst, Hereditary Canc Unit, Genoa, Italy. Natl Canc Inst, Dept Expt Oncol, I-20133 Milan, Italy. Italian Fdn Canc Res, Inst Mol Oncol, Milan, Italy. Natl Canc Inst, Dept Pathol, I-20133 Milan, Italy. RP Bertario, L (reprint author), Ist Nazl Tumori, Dept Predict & Prevent Med, Via Venezian 1, I-20133 Milan, Italy. EM lucio.bertario@istitutotumori.mi.it RI Radice, Paolo/O-3119-2013; OI Pierotti, Marco Alessandro/0000-0002-7431-8332; Russo, Antonio Giampiero/0000-0002-5681-5861 NR 34 TC 4 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD OCT PY 2004 VL 47 IS 10 BP 1662 EP 1669 DI 10.1007/s10350-004-0652-6 PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 860JD UT WOS:000224337600016 PM 15540296 ER PT J AU Puertollano, R AF Puertollano, R TI Clathrin-mediated transport: assembly required - Workshop on Molecular Mechanisms of Vesicle Selectivity SO EMBO REPORTS LA English DT Article; Proceedings Paper CT Workshop on Molecular Mechanisms of Vesicle Selectivity CY MAR 29-31, 2004 CL Madrid, SPAIN DE clathrin; endocytosis; adaptors ID BETA-PROPELLER; ENDOCYTOSIS; MEMBRANE; COMPLEX; CARGO C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 10, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov NR 19 TC 13 Z9 14 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD OCT PY 2004 VL 5 IS 10 BP 942 EP 946 DI 10.1038/sj.embor.7400249 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859GH UT WOS:000224250900007 PM 15448637 ER PT J AU Morris, A Lundgren, JD Masur, H Walzer, PD Hanson, DL Frederick, T Huang, L Beard, CB Kaplan, JE AF Morris, A Lundgren, JD Masur, H Walzer, PD Hanson, DL Frederick, T Huang, L Beard, CB Kaplan, JE TI Current epidemiology of Pneumocystis pneumonia SO EMERGING INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HIV-POSITIVE PATIENTS; CARINII-PNEUMONIA; OPPORTUNISTIC INFECTIONS; UNITED-STATES; AFRICAN CHILDREN; RISK-FACTORS; AIDS; DEATH AB Pneumocystis pneumonia (PCP) has historically been one of the leading causes of disease among persons with AIDS. The introduction of highly active antiretroviral therapy in industrialized nations has brought about dramatic declines in the incidence of AIDS-associated complications, including PCP. In the adult population, the incidence of PCP has significantly decreased, but it remains among the most common AIDS-defining infections. Similar declines have been documented in the pediatric population. In much of the developing world, PCP remains a significant health problem, although its incidence among adults in sub-Saharan Africa has been debated. This review discusses the epidemiology of PCP during the current era of the AIDS epidemic. Although fewer cases of PCP occur in industrialized countries, increasing drug-resistant HIV infections, possible drug-resistant PCP, and the tremendous number of AIDS cases in developing countries make this disease of continued public health importance. C1 Univ So Calif, Los Angeles, CA USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Univ Copenhagen, DK-2650 Hvidovre, Denmark. NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Ctr Dis Control & Prevent, Ft Collins, CO USA. RP Morris, A (reprint author), 2011 Zonal Ave,HMR 911, Los Angeles, CA 90033 USA. EM alison.morris@usc.edu OI Lundgren, Jens/0000-0001-8901-7850 FU NHLBI NIH HHS [K23 HL072117, K23 HL072117-01A1] NR 45 TC 196 Z9 207 U1 0 U2 2 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD OCT PY 2004 VL 10 IS 10 BP 1713 EP 1720 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 860XB UT WOS:000224376200001 PM 15504255 ER PT J AU Ben Beard, C Roux, P Nevez, G Hauser, PM Kovacs, JA Unnasch, TR Lundgren, B AF Ben Beard, C Roux, P Nevez, G Hauser, PM Kovacs, JA Unnasch, TR Lundgren, B TI Strain typing methods and molecular epidemiology of Pneumocystis pneumonia SO EMERGING INFECTIOUS DISEASES LA English DT Article ID MAJOR SURFACE GLYCOPROTEIN; RIBOSOMAL-RNA GENES; DIHYDROPTEROATE SYNTHASE GENE; INTERNAL TRANSCRIBED SPACERS; F-SP HOMINIS; NUCLEOTIDE-SEQUENCE VARIATIONS; CARINII-PNEUMONIA; SP. HOMINIS; SULFONE PROPHYLAXIS; EXPRESSION SITE AB Pneumocystis pneumonia (PCP) caused by the opportunistic fungal agent Pneumocystis jirovecii (formerly P. carinii) continues to cause illness and death in HIV-infected patients. In the absence of a culture system to isolate and maintain live organisms, efforts to type and characterize the organism have relied on polymerase chain reaction-based approaches. Studies using these methods have improved understanding of PCP epidemiology, shedding light on sources of infection, transmission patterns, and potential emergence of antimicrobial resistance. One concern, however, is the lack of guidance regarding the appropriateness of different methods and standardization of these methods, which would facilitate comparing results reported by different laboratories. C1 NCID, CDC, Div Vector Borne Infect Dis, Ft Collins, CO 80521 USA. St Antoine Univ Hosp, Paris, France. Univ Picardie, Amiens, France. Univ Lausanne Hosp, Lausanne, Switzerland. NIH, Bethesda, MD 20892 USA. Univ Alabama, Birmingham, AL USA. Hvidovre Univ Hosp, Hvidovre, Denmark. RP Ben Beard, C (reprint author), NCID, CDC, Div Vector Borne Infect Dis, Rampart Rd,Foothills Campus, Ft Collins, CO 80521 USA. EM cbeard@cdc.gov NR 40 TC 0 Z9 0 U1 3 U2 5 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD OCT PY 2004 VL 10 IS 10 BP 1729 EP 1735 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 860XB UT WOS:000224376200003 ER PT J AU Kato, Y Ying, H Willingham, MC Cheng, SY AF Kato, Y Ying, H Willingham, MC Cheng, SY TI A tumor suppressor role for thyroid hormone beta receptor in a mouse model of thyroid carcinogenesis SO ENDOCRINOLOGY LA English DT Article ID DOMINANT-NEGATIVE ACTIVITY; SECRETING PITUITARY-TUMOR; CLEAR-CELL CARCINOMA; GROWTH-FACTOR-BETA; TRANSCRIPTIONAL ACTIVITY; GENERALIZED RESISTANCE; NUCLEAR RECEPTORS; TRANSGENIC MICE; GENE-EXPRESSION; MOLECULAR-BASIS AB We have created a knockin mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse). TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice, spontaneously develop follicular thyroid carcinoma. To identify other genetic changes in the TRbeta gene that could also induce thyroid carcinoma, we crossed TRbetaPV mice with TRbeta(-/-) mice. As TRbeta(PV/-) mice (mutation of one TRbeta allele in the absence of the other wild-type allele) aged, they also spontaneously developed follicular thyroid carcinoma through the pathological progression of hyperplasia, capsular and vascular invasion, anaplasia, and eventually metastasis to the lung, but not to the lymph nodes. The pathological progression of thyroid carcinoma in TRbeta(PV/-) mice was indistinguishable from that in TRbeta(PV/PV) mice. Analyses of the expression patterns of critical genes indicated activation of the signaling pathways mediated by TSH, peptide growth factors ( epidermal growth factor and fibroblast growth factor), TGF-beta, TNF-alpha, and nuclear factor-kappaB, and also suggested progressive repression of the pathways mediated by the peroxisome proliferator-activated receptor gamma. The patterns in the alteration of these signaling pathways are similar to those observed in TRbeta(PV/PV) mice during thyroid carcinogenesis. These results indicate that in the absence of a wild-type allele, the mutation of one TRbeta allele is sufficient for the mutant mice to spontaneously develop follicular thyroid carcinoma. These results provide, for the first time, in vivo evidence to suggest that the TRbeta gene could function as a tumor suppressor gene. Importantly, these findings present the possibility that TRbeta could serve as a novel therapeutic target in thyroid cancer. C1 NCI, Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM sycheng@helix.nih.gov NR 44 TC 32 Z9 33 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4430 EP 4438 DI 10.1210/en.2004-0162 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600002 PM 15231697 ER PT J AU Zhou, H Ko, WKW Ho, WKK Stojilkovic, SS Wong, AOL AF Zhou, H Ko, WKW Ho, WKK Stojilkovic, SS Wong, AOL TI Novel aspects of growth hormone (GH) autoregulation: GH-induced GH gene expression in grass carp pituitary cells through autocrine/paracrine mechanisms SO ENDOCRINOLOGY LA English DT Article ID CYCLASE-ACTIVATING POLYPEPTIDE; GONADOTROPIN-RELEASING-HORMONE; MESSENGER-RNA LEVELS; ANTERIOR-PITUITARY; TRANSGENIC MICE; SIGNAL-TRANSDUCTION; RECEPTOR/BINDING PROTEIN; MOLECULAR-CLONING; NEGATIVE FEEDBACK; FACTOR-I AB GH feedback on its own secretion at the pituitary level has been previously reported, but the mechanisms involved have not been elucidated. Here we examined the autocrine/paracrine effects of GH on GH synthesis using grass carp pituitary cells as a cell model. GH receptors were identified in carp somatotrophs, and their activation by exogenous GH increased steady-state GH mRNA levels and GH production. Removal of endogenous GH by immunoneutralization using GH antiserum inhibited basal as well as stimulated GH mRNA expression induced by GH-releasing factors in fish, including GnRH, apomorphine, and pituitary adenylate cyclase-activating polypeptide-38. Cytosolic mature GH mRNA levels were elevated by GH treatment and reduced by GH antiserum, whereas nuclear GH primary transcripts were almost undetectable after GH immunoneutralization. Inhibition of Janus kinase-2 (JAK2), phosphoinositide 3-kinase, and MAPK also abolished GH-induced steady-state GH mRNA expression. GH immunoneutralization in pituitary cells pretreated with actinomycin D induced a marked decrease in the half-life of GH mRNA, indicating that the clearance of GH transcripts could be enhanced by removing endogenous GH. These results provide evidence that GH can serve as a novel intrapituitary autocrine/paracrine factor maintaining GH gene expression in somatotrophs, and this action is mediated by JAK(2)/MAPK and JAK(2)/phosphoinositide 3-kinase cascades coupled to GH receptors. C1 Univ Hong Kong, Dept Zool, Hong Kong, Hong Kong, Peoples R China. Chinese Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Wong, AOL (reprint author), Univ Hong Kong, Dept Zool, Room 4S-12,Kadoorie Biol Sci Bldg,Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. EM olwong@hkucc.hku.hk RI Wong, Anderson/A-2735-2010 NR 52 TC 18 Z9 20 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4615 EP 4628 DI 10.1210/en.2004-0163 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600024 PM 15231712 ER PT J AU Heron-Milhavet, L Haluzik, M Yakar, S Gavrilova, O Pack, S Jou, WC Ibrahimi, A Kim, H Hunt, D Yau, D Asghar, Z Joseph, J Wheeler, MB Abumrad, NA LeRoith, D AF Heron-Milhavet, L Haluzik, M Yakar, S Gavrilova, O Pack, S Jou, WC Ibrahimi, A Kim, H Hunt, D Yau, D Asghar, Z Joseph, J Wheeler, MB Abumrad, NA LeRoith, D TI Muscle-specific overexpression of CD36 reverses the insulin resistance and diabetes of MKR mice SO ENDOCRINOLOGY LA English DT Article ID HEPATIC GLYCOGEN-SYNTHESIS; FREE FATTY-ACIDS; SKELETAL-MUSCLE; GLUCOSE-TOLERANCE; TARGETED DISRUPTION; ADIPOSE-TISSUE; RECEPTOR GENE; IGF-I; SENSITIVITY; TRIGLYCERIDE AB Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5-6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, beta-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. Univ Sidi Mohammed Ben Abdellah, Ctr Etud Univ Taza, Mouse Metab Core Facil, Taza 1223, Morocco. Univ Toronto, Dept Physiol, Endocrine & Diabet Res Grp, Toronto, ON M5S 1AB, Canada. SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. RP LeRoith, D (reprint author), NIDDK, Diabet Branch, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. EM Derek@helix.nih.gov OI Wheeler, Michael/0000-0002-7480-7267; Shyr, Zeenat/0000-0001-8710-9938 NR 43 TC 35 Z9 37 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4667 EP 4676 DI 10.1210/en.2003-1543 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600030 PM 15231693 ER PT J AU Couse, JF Yates, MM Sanford, R Nyska, A Nilson, JH Korach, KS AF Couse, JF Yates, MM Sanford, R Nyska, A Nilson, JH Korach, KS TI Formation of cystic ovarian follicles associated with elevated luteinizing hormone requires estrogen receptor-beta SO ENDOCRINOLOGY LA English DT Article ID 17-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; MESSENGER-RIBONUCLEIC-ACID; ALPHA-KNOCKOUT MOUSE; STIMULATING-HORMONE; TARGETED DISRUPTION; ER-BETA; MOLECULAR-CLONING; GRANULOSA-CELLS; SEX REVERSAL; NULL MICE AB Stringent regulation of LH secretion from the pituitary is vital to ovarian function in mammals. Two rodent models of LH hypersecretion are the transgenic LHbeta-C-terminal peptide (LHbetaCTP) and estrogen receptor-alpha( ERalpha)-null (alphaERKO) mice. Both exhibit ovarian phenotypes of chronic anovulation, cystic and hemorrhagic follicles, lack of corpora lutea, interstitial/stromal hyperplasia, and elevated plasma estradiol and testosterone. Because ERbeta is highly expressed in granulosa cells of the ovary, we hypothesized the intraovarian actions of ERbeta may be necessary for full manifestation of phenotypes associated with LH hyperstimulation. To address this question, we generated female mice that possess elevated LH, but lack ERbeta, by breeding the LHbetaCTP and ERbeta-null (betaERKO) mice. A comparison of LHbetaCTP, alphaERKO, and betaERKO(LHCTP) females has allowed us to elucidate the contribution of each ER form to the pathologies and endocrinopathies that occur during chronic LH stimulation of the ovary. alphaERKO ovaries respond to elevated LH by exhibiting an amplified steroidogenic pathway characteristic of the follicular stage of the ovarian cycle, whereas wild-type(LHCTP) and betaERKO(LHCTP) females exhibit a steroidogenic profile more characteristic of the luteal stage. In addition, the hemorrhagic and cystic follicles of the LHbetaCTP and alphaERKO ovaries require the intraovarian actions of ERbeta for manifestation, because they were lacking in the betaERKO(LHCTP) ovary. In turn, ectopic expression of the Leydig cell-specific enzyme, Hsd17b3, and male-like testosterone synthesis in the alphaERKO ovary are unique to this genotype and are therefore the culmination of elevated LH and the loss of functional ERalpha within the ovary. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233,MD B3-02, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 44 TC 24 Z9 24 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4693 EP 4702 DI 10.1210/en.2004-0548 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600033 PM 15231698 ER PT J AU Grassadonia, A Tinari, N Fiorentino, B Suzuki, K Nakazato, M De Tursi, M Giuliani, C Napolitano, G Singer, DS Iacobelli, S Kohn, LD AF Grassadonia, A Tinari, N Fiorentino, B Suzuki, K Nakazato, M De Tursi, M Giuliani, C Napolitano, G Singer, DS Iacobelli, S Kohn, LD TI The 90K protein increases major histocompatibility complex class I expression and is regulated by hormones, gamma-interferon, and double-strand polynucleotides SO ENDOCRINOLOGY LA English DT Article ID TUMOR-ASSOCIATED ANTIGEN; CYSTEINE-RICH DOMAIN; RAT-THYROID CELLS; GROWTH FACTOR-I; BREAST-CANCER; MONOCLONAL-ANTIBODY; GENE-EXPRESSION; SERUM MARKER; CLONING; RECEPTOR AB Here we report the cloning of the rat 90K, a homolog of the mouse cyclophilin C-associated protein/mouse adherent macrophage and human 90K. The protein is constitutively expressed by FRTL-5 thyrocytes, and its levels are modulated by TSH, insulin/IGF-I, and gamma-interferon. Transfection of the cells with 90K cDNA or exposure to purified 90K resulted in a significant increase of the expression of major histocompatibility complex class I but not class II antigens. An increased expression of 90K was obtained after viral infection or introduction into the cells of fragments of viral, bacterial, or mammalian double-strand polynucleotides. The increase was sequence independent, not CpG mediated, and associated with the expression of molecules characterizing antigen-presenting cell phenotype. The present data along with results from previous studies suggest that 90K plays an important role in the maintenance of an appropriate level of immune response. C1 Univ G DAnnunzio, SEBI, Fac Med & Surg, Dept Oncol & Neurosci,Sect Med Oncol, I-66100 Chieti, Italy. NIDDKD, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Univ G DAnnunzio, Fac Med & Surg, Dept Med & Sci Aging, Endocrinol Sect, I-66100 Chieti, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Edison Biotechnol Inst, Athens, OH 45701 USA. RP Iacobelli, S (reprint author), Univ G DAnnunzio, SEBI, Fac Med & Surg, Dept Oncol & Neurosci,Sect Med Oncol, Via Vestini, I-66100 Chieti, Italy. EM iacobell@unich.it RI DE TURSI, MICHELE/L-3427-2016 OI DE TURSI, MICHELE/0000-0002-1411-1946 NR 48 TC 9 Z9 10 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4728 EP 4736 DI 10.1210/en.2004-0506 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600037 PM 15231701 ER PT J AU Pennisi, PA Kopchick, JJ Thorgeirsson, S LeRoith, D Yakar, S AF Pennisi, PA Kopchick, JJ Thorgeirsson, S LeRoith, D Yakar, S TI Role of growth hormone (GH) in liver regeneration SO ENDOCRINOLOGY LA English DT Article ID CYCLIN D1 EXPRESSION; FACTOR-I; TRANSGENIC MICE; HEPATOCYTE PROLIFERATION; TYROSINE PHOSPHORYLATION; GENE-EXPRESSION; EGF RECEPTOR; C-JUN; INSULIN; CELLS AB Liver regeneration is a fundamental mechanism by which the liver responds to injury. This process is regulated by endogenous growth factors and cytokines, and it involves proliferation of all mature cells that exist within the intact organ. To understand the role of the GH/IGF-I axis in liver regeneration, we performed partial hepatectomies in three groups of mice: GH antagonist (GHa) transgenic mice, in which the action of GH is blocked; liver IGF-I-deficient mice that lack IGF-I specifically in the liver and also lack the acid-labile subunit (ALS; LID + ALSKO mice), in which IGF-I levels are very low and GH secretion is increased; and control mice. Interestingly, the survival rate of GHa transgenic mice was dramatically reduced after partial hepatectomy (57%) compared with the survival rate of controls (100%) or LID + ALSKO mice (88%). In control mice, the liver was completely regenerated after 4 d, whereas liver regeneration required 7 d in LID + ALSKO mice. In contrast, in GHa mice, liver regeneration reached only 70% of the original liver mass after 4 d and did not improve thereafter. Strikingly, 36 and 48 h after hepatectomy, the livers of control and LID + ALSKO mice, respectively, exhibited intense 5-bromo-2'-deoxyuridine (BrdU) staining, whereas BrdU staining was dramatically decreased in the livers of GHa-treated mice. These results suggest that GH plays a critical role in liver regeneration, although whether it acts directly or indirectly remains to be determined. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Ohio Univ, Coll Osteopath Med, Edison Biotechnol Inst, Athens, OH 45701 USA. RP Yakar, S (reprint author), NIDDKD, Diabet Branch, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. EM shoshanay@intra.niddk.nih.gov NR 45 TC 39 Z9 42 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 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2004 VL 145 IS 10 BP 4748 EP 4755 DI 10.1210/en.2004-0655 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 854FB UT WOS:000223885600039 PM 15242989 ER PT J AU Galperin, MY AF Galperin, MY TI The bugs that came in from the cold SO ENVIRONMENTAL MICROBIOLOGY LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE GENOME; BARTONELLA-HENSELAE; XYLELLA-FASTIDIOSA; ASHBYA-GOSSYPII; SEQUENCE; GROWTH; CHAPERONINS; VIRULENCE; EVOLUTION; STRAINS C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 19 TC 1 Z9 1 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD OCT PY 2004 VL 6 IS 10 BP 1001 EP 1004 DI 10.1111/j.1462-2920.2004.00707.x PG 4 WC Microbiology SC Microbiology GA 851UJ UT WOS:000223710900001 PM 15344925 ER PT J AU Howden, R Lightfoot, JT Turner, MJ Brown, SJ Swaine, IL AF Howden, R Lightfoot, JT Turner, MJ Brown, SJ Swaine, IL TI A wide range of baroreflex stimulation does not alter forearm blood flow SO EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE carotid sinus baroreflex; neck chamber; venous occlusion plethysmography ID BODY NEGATIVE-PRESSURE; PERIPHERAL VASCULAR-RESISTANCE; BARORECEPTOR-CARDIAC REFLEX; CENTRAL VENOUS-PRESSURE; CAROTID-SINUS NERVE; RESPONSES; HUMANS; CARDIOPULMONARY; EXERCISE; MUSCLE AB The contribution to the regulation of forearm blood flow (FBF) by different baroreceptor populations has previously only been studied over a limited range of stimuli. Therefore, FBF and R-R interval were recorded during neck suctions and neck pressures ranging from -60 to +40 mmHg. The change in R-R interval (DeltaR-R) during neck suction was significantly increased at each stage when compared to the control (P<0.05). DeltaR-R did not show any significant change during any of the neck pressure stages (P>0.05). Suction or pressure applied to the neck did not elicit any significant changes in FBF when compared to the control (P>0.05). These data show that widening the range of applied stimuli to carotid sinus baroreceptors does not induce a change in FBF. However, the small transient changes reported previously cannot be discounted. C1 De Montfort Univ, Bedford, England. Univ N Carolina, Dept Hlth Promot & Kinesiol, Charlotte, NC 28223 USA. Canterbury Christ Church Univ Coll, Canterbury, Kent, England. RP Howden, R (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,MD D2-01, Res Triangle Pk, NC 27709 USA. EM howden@niehs.nih.gov NR 39 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1439-6319 J9 EUR J APPL PHYSIOL JI Eur. J. Appl. Physiol. PD OCT PY 2004 VL 93 IS 1-2 BP 124 EP 129 DI 10.1007/s00421-004-1181-7 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 869AQ UT WOS:000224955000016 PM 15278354 ER PT J AU Chen, J Vistica, BP Takase, H Ham, DI Fariss, RN Wawrousek, EF Chan, CC DeMartino, JA Farber, JM Gery, I AF Chen, J Vistica, BP Takase, H Ham, DI Fariss, RN Wawrousek, EF Chan, CC DeMartino, JA Farber, JM Gery, I TI A unique pattern of up- and down-regulation of chemokine receptor CXCR3 on inflammation-inducing Th1 cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE chemokine; chemokine receptor; T cell trafficking; T cell activation; inflammation ID CD4(+) T-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; OCULAR INFLAMMATION; LYMPHOCYTES; EXPRESSION; ACTIVATION; SUBSETS; DIFFERENTIATION; INDUCTION; MIGRATION AB Chemokine receptor CXCR3 and its CXC ligands play major roles in Th1 cell-induced inflammatory processes. Here, we examined the expression of CXCR3 by TCR-transgenic Th1 lymphocytes that induce ocular inflammation in mice expressing the target antigen in their lenses. The essential role of CXCR3 in this model was indicated by the observation that the ocular inflammation was significantly blocked by an antibody against this receptor. CXCR3 expression by Th1 cells was elevated during their initial activation in culture and further increased during the consecutive incubation with IL-2. However, CXCR3 expression declined dramatically during the ensuing antigenic reactivation, in parallel with down-regulation of its mRNA. Yet, reactivated Th1 cells exhibited the highest degree of pathogenicity when adoptively transferred into recipients. Transferred reactivated Th1 cells proliferated vigorously and re-expressed CXCR3 while residing in the spleen of recipient mice, reaching similar to85% positivity 4 days post cell transfer when their massive migration to the target eyes began. Importantly, infiltrating Th1 cells underwent profound phenotypic changes in the eye that closely resembled those seen during reactivation of Th1 cells in vitro and included down-regulation of CXCR3. These observations thus show that expression of CXCR3, a major participant in Th1-induced inflammation, fluctuates profoundly during cell activation and migration and is down-regulated upon re-exposure of these cells to the antigen, in vitro or in the target organ. C1 NEI, NIH, Bethesda, MD 20892 USA. Merck Res Labs, Rahway, NJ USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Gery, I (reprint author), NEI, NIH, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov RI Wawrousek, Eric/A-4547-2008 NR 32 TC 33 Z9 33 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD OCT PY 2004 VL 34 IS 10 BP 2885 EP 2894 DI 10.1002/eji.200425318 PG 10 WC Immunology SC Immunology GA 862UX UT WOS:000224517800027 PM 15368305 ER PT J AU Wittenberg, GF Werhahn, KJ Wassermann, EM Herscovitch, P Cohen, LG AF Wittenberg, GF Werhahn, KJ Wassermann, EM Herscovitch, P Cohen, LG TI Functional connectivity between somatosensory and visual cortex in early blind humans SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE critical period; PET; somatosensory cortex; transcranial magnetic stimulation; visual cortex ID TRANSCRANIAL MAGNETIC STIMULATION; CROSS-MODAL PLASTICITY; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; CONGENITALLY BLIND; MOTOR CORTEX; EARLY-ONSET; ACTIVATION; BRAIN; DISCRIMINATION AB Crossmodal plasticity occurs when loss of input in one sensory modality leads to reorganization in brain representations of other sensory modalities. In congenital blindness the visual cortex becomes responsive to somatosensory input such as occurs during Braille reading. The route by which somatosensory information reaches the visual cortex is not known. Here, we used repetitive transcranial magnetic stimulation (rTMS) to probe the connection between primary somatosensory cortex (S1) and early visual cortex (V1 and neighboring areas), combining rTMS with positron emission tomography (PET). We applied stimulation over S1 in sighted, early blind and late blind individuals. Baseline regional cerebral blood flow in occipital cortex was highest in early blind and lowest in late blind individuals. Only the early blind group showed significant activation of early visual areas when rTMS was delivered over S1. This activation was significantly higher in early than in late blind, but not relative to sighted controls. These results are consistent with the hypothesis that tactile information may reach early visual areas in early blind humans through cortico-cortical pathways, possibly supporting enhanced tactile information processing. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov NR 33 TC 84 Z9 85 U1 2 U2 11 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD OCT PY 2004 VL 20 IS 7 BP 1923 EP 1927 DI 10.1111/j.1460-9568.2004.03630.x PG 5 WC Neurosciences SC Neurosciences & Neurology GA 855TJ UT WOS:000223996900025 PM 15380014 ER PT J AU Goldberg, TE Egan, MF Straub, RE Weinberger, DR AF Goldberg, TE Egan, MF Straub, RE Weinberger, DR TI Cognitive genomics and schizophrenia: Implications for drug targets SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 17th Congress of the European-College-of-Neuropsychopharmacology CY OCT 09-13, 2004 CL Stockholm, SWEDEN SP European Coll Neuropsychopharmacol C1 NIMH, Clin Brain Disorders Branch, GCAP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2004 VL 14 SU 3 BP S148 EP S148 DI 10.1016/S0924-977X(04)80058-0 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 875YX UT WOS:000225460400059 ER PT J AU Ling, W Shoptaw, S Rawson, R Vocci, F AF Ling, W Shoptaw, S Rawson, R Vocci, F TI Medication development for cocaine dependence SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 17th Congress of the European-College-of-Neuropsychopharmacology CY OCT 09-13, 2004 CL Stockholm, SWEDEN SP European Coll Neuropsychopharmacol ID TRIAL C1 Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NIDA, Washington, DC USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2004 VL 14 SU 3 BP S163 EP S164 DI 10.1016/S0924-977X(04)80079-8 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 875YX UT WOS:000225460400080 ER PT J AU Sunderland, T AF Sunderland, T TI Alzheimer's disease: The search for surrogate biomarkers SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 17th Congress of the European-College-of-Neuropsychopharmacology CY OCT 09-13, 2004 CL Stockholm, SWEDEN SP European Coll Neuropsychopharmacol C1 NIMH, Gen Psychiat Branch, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2004 VL 14 SU 3 BP S147 EP S148 DI 10.1016/S0924-977X(04)80057-9 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 875YX UT WOS:000225460400058 ER PT J AU Sohn, YH Hallett, M AF Sohn, YH Hallett, M TI Surround inhibition in human motor system SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE motor cortex; surround inhibition; transcranial magnetic stimulation; voluntary movements ID TRANSCRANIAL MAGNETIC STIMULATION; PARKINSONS-DISEASE; SILENT PERIOD; INTRACORTICAL FACILITATION; CORTICAL EXCITABILITY; VOLUNTARY CONTRACTION; EVOKED-RESPONSES; CONSCIOUS HUMANS; STRIATE CORTEX; NEURONS AB In sensory systems, a neural mechanism called surround inhibition (SI) sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, the functional operation of SI remains to be demonstrated, although it has been hypothesized to contribute to the selection of voluntary movements. Here we test this hypothesis by using transcranial magnetic stimulation of the human motor cortex. The motor evoked potential of the little finger muscle is suppressed or unchanged during self-paced, voluntary movements of the index finger, mouth or leg, despite an increase in spinal excitability. This result indicates that motor excitability related to little finger movement is suppressed at the supraspinal level during these movements, and supports the idea that SI is an organizational principle of the motor system. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Dept Neurol, Coll Med, Seoul, South Korea. Yonsei Univ, Brain Res Inst, Brain Korea Project Med Sci 21, Seoul, South Korea. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10-5N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 50 TC 91 Z9 91 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD OCT PY 2004 VL 158 IS 4 BP 397 EP 404 DI 10.1007/s00221-004-1909-y PG 8 WC Neurosciences SC Neurosciences & Neurology GA 863IR UT WOS:000224555400001 PM 15146307 ER PT J AU Portero-Otin, M Requena, JR Bellmunt, MJ Ayala, V Pamplona, R AF Portero-Otin, M Requena, JR Bellmunt, MJ Ayala, V Pamplona, R TI Protein nonenzymatic modifications and proteasome activity in skeletal muscle from the short-lived rat and long-lived pigeon SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE aminoadipic semialdehyde; N-epsilon-(carboxyethyl)lysine; N-epsilon-(carboxymethyl)lysine; glutamic semialdehyde; Maillard reaction; N-epsilon-(malondialdehyde)lysine; maximum life span; peroxidizability index; proteasome; protein oxidation ID FATTY-ACID UNSATURATION; MAXIMUM LIFE-SPAN; LIPID-PEROXIDATION; OXIDIZED PROTEINS; OXIDATIVE STRESS; CALORIC RESTRICTION; TISSUE PROTEINS; MITOCHONDRIA; DEGRADATION; LONGEVITY AB What are the mechanisms determining the rate of animal aging? Of the two major classes of endothermic animals, bird species are strikingly long-lived compared to similar size mammalian counterparts. Since oxidative stress is causally related to the basic aging process, markers of different kinds of oxidative damage to proteins (glutamic semialdehyde, aminoadipic semialdehyde, N-epsilon-(carboxyethyl)lysine; N-epsilon-(carboxymethyl)lysine, N-epsilon-(malondialdehyde)lysine and dinitrophenylhydrazyne-reactive protein carbonyls), peptidase activities of the proteasome. and amino acid and membrane fatty acyl composition were identified and measured in skeletal muscle from the short-lived rat (maximum life span, 4 years) and compared with the Iona-lived pigeon (maximum life span, 35 years). Skeletal muscle from pigeon showed significantly higher levels of glutamic semialdehyde, protein carbonyls (by western blot), N-epsilon-(carboxyethyl)lysine and N-epsilon-(carboxymethyl)lysine. No differences were observed for aminoadipic semialdehyde, whereas the lipoxidation marker N-epsilon-(malondialdehyde)lysine displayed a significant low steady-state level, probably related with their significantly lower membrane unsaturation. The amino acid compositional analysis revealed that arginine, serine, threonine and methionine showed significantly lower levels in pigeon. Finally, pigeon samples showed also significantly lower levels of the peptidase activities of the proteasome. These results reinforces the role of structural components such as membrane unsaturation and protein composition in determining the longer maximum life span showed by birds compared with mammals of similar body size. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Lleida, Dept Basic Med Sci, Lleida 25198, Spain. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Pamplona, R (reprint author), Univ Lleida, Dept Basic Med Sci, Avinguda Rovira Roure 44, Lleida 25198, Spain. EM reinald.pamplona@cmb.udi.es RI Portero-Otin, Manuel/B-7122-2009; Bellmunt Curco, Maria Josep/C-3784-2011; Ayala, Maria Victoria/A-7391-2010; Pamplona, Reinald/A-7359-2010 OI Portero-Otin, Manuel/0000-0002-1823-0299; Bellmunt Curco, Maria Josep/0000-0002-3187-1576; Ayala, Maria Victoria/0000-0002-1496-966X; Pamplona, Reinald/0000-0003-4337-6107 NR 39 TC 24 Z9 24 U1 3 U2 7 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 OCT PY 2004 VL 39 IS 10 BP 1527 EP 1535 DI 10.1016/j.exger.2004.08.001 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 871IZ UT WOS:000225125700012 PM 15501023 ER PT J AU Zheng, M Reynolds, C Jo, SH Wersto, R Han, QD Xiao, RP AF Zheng, M Reynolds, C Jo, SH Wersto, R Han, QD Xiao, RP TI Intracellular acidosis-activated p38 MAPK signaling and its essential role in cardiomyocyte hypoxic injury SO FASEB JOURNAL LA English DT Article DE hypoxia; ischemia; hypoxic cell death; cardiac myocytes ID N-TERMINAL KINASES; VACUOLAR PROTON ATPASE; PROTEIN-KINASE; CARDIAC MYOCYTES; MYOCARDIAL-ISCHEMIA; INDUCED APOPTOSIS; REGULATED KINASE; HEART-FAILURE; CYTOSOLIC PH; ACIDIFICATION AB Activation of p38 mitogen-activated protein kinase (MAPK) plays a central role in cellular responses to a multitude of stress signals. In the heart, enhanced p38 MAPK signaling has been implicated in cardiac hypoxic and ischemic injury. However, the mechanism underlying hypoxia-induced p38 MAPK activation remains elusive. We investigated p38 MAPK activation during hypoxia in adult rat cardiomyocytes. Here, we reported that hypoxia leads to concurrent intracellular acidosis and activation of p38 MAPK and that the hypoxia-induced p38 MAPK signaling can be fully abolished by neutralizing intracellular pH, whereas intracellular acidosis (intracellular pH<7.0) per se overtly augments activation of p38 MAPK but not ERK1/2 and JNK. Furthermore, inhibition of p38 MAPK protects myocytes against hypoxic cell death, suggesting that acidosis-evoked p38 MAPK signaling plays an important role in hypoxic cell injury and cell death. These results demonstrate, for the first time, that intracellular acidosis constitutes a necessary and sufficient link responsible for hypoxia-activated p38 MAPK signaling and the subsequent hypoxic cardiomyocyte injury and death. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Flow Cytometry Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Peking Univ, Chinese Minist Educ, Key Lab Mol Cardiovasc Biol, Beijing 100871, Peoples R China. Peking Univ, Chinese Minist Educ, Inst Mol Med, Inst Cardiovasc Sci, Beijing 100871, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. EM xiaor@grc.nia.nih.gov NR 43 TC 0 Z9 0 U1 1 U2 14 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 OCT PY 2004 VL 18 IS 13 BP 109 EP + DI 10.1096/fj.04-2604fje PG 20 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 867NS UT WOS:000224849900018 ER PT J AU Suganami, T Mukoyama, M Mori, K Yokoi, H Koshikawa, M Sawai, K Hidaka, S Ebihara, K Tanaka, T Sugawara, A Kawachi, H Vinson, C Ogawa, Y Nakao, K AF Suganami, T Mukoyama, M Mori, K Yokoi, H Koshikawa, M Sawai, K Hidaka, S Ebihara, K Tanaka, T Sugawara, A Kawachi, H Vinson, C Ogawa, Y Nakao, K TI Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy SO FASEB JOURNAL LA English DT Article DE lipoatrophic diabetes; TGF-beta 1; podocytes; proteinuria; transgenic mice ID MICE OVEREXPRESSING LEPTIN; MATRIX GENE-EXPRESSION; GROWTH-FACTOR-BETA; TGF-BETA; PANCREAS TRANSPLANTATION; EXTRACELLULAR-MATRIX; INSULIN SENSITIVITY; GLUCOSE-METABOLISM; HYPERTENSIVE-RATS; TRANSGENIC MICE AB Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy. C1 Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Sakyo Ku, Kyoto 6068507, Japan. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Niigata Univ, Dept Cell Biol, Inst Nephrol, Grad Sch Med & Dent Sci, Niigata, Japan. RP Mukoyama, M (reprint author), Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Sakyo Ku, 54 Shogoin Kawahara Cho, Kyoto 6068507, Japan. EM muko@kuhp.kyoto-u.ac.jp RI SUGANAMI, Takayoshi/A-9475-2016; Yokoi, Hideki/R-1289-2016; OI Yokoi, Hideki/0000-0001-8343-9737; Mori, Kiyoshi/0000-0002-7285-8351 NR 39 TC 2 Z9 2 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD OCT PY 2004 VL 18 IS 13 BP 127 EP + DI 10.1096/fj.04-2183fje PG 23 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 867NS UT WOS:000224849900014 ER PT J AU Romero, R Espinoza, J Mazor, M AF Romero, R Espinoza, J Mazor, M TI Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization? SO FERTILITY AND STERILITY LA English DT Editorial Material ID TUMOR-NECROSIS-FACTOR; EARLY-PREGNANCY DECIDUA; NATURAL-KILLER-CELLS; HUMAN INVITRO FERTILIZATION; COLONY-STIMULATING FACTOR; NON-SPECIFIC VAGINITIS; BACTERIAL VAGINOSIS; AMNIOTIC-FLUID; CONTROLLED-TRIAL; GENITAL-TRACT AB The endometrial cavity is frequently invaded by microorganisms, and subclinical endometrial infection or inflammation may play a role in implantation failure after IVF, spontaneous abortion, and preterm birth. Microbial products and host-inflammatory mediators such as cytokines and chemokines can cause trophoblast apoptosis and the cascade of events leading to expulsion of the embryo or fetus. (C)2004 by American Society for Reproductive Medicine. C1 NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI 48201 USA. RP Romero, R (reprint author), NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, 4707 St Antoine Blvd, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov NR 143 TC 83 Z9 95 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD OCT PY 2004 VL 82 IS 4 BP 799 EP 804 DI 10.1016/j.fertnstert.2004.05.076 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UO UT WOS:000224516800008 PM 15482749 ER PT J AU Frattarelli, JL Levi, AJ Miller, BT Segars, JH AF Frattarelli, JL Levi, AJ Miller, BT Segars, JH TI Prognostic use of mean ovarian volume in in vitro fertilization cycles: a prospective assessment SO FERTILITY AND STERILITY LA English DT Article DE in vitro fertilization; mean ovarian volume; basal antral follicle count; pregnancy; cancellation rate; ovarian response; ovarian reserve; predictive value; clinical outcome; review ID REPRODUCTIVE TECHNOLOGY CYCLES; STIMULATING-HORMONE LEVELS; CITRATE CHALLENGE TEST; DAY 3 ESTRADIOL; TRANSVAGINAL SONOGRAPHY; INVITRO FERTILIZATION AB Objective: To determine the predictive value and to define prognostic threshold measurements for mean ovarian volume (MOV) in patients undergoing IVF. Design: Prospective cohort analysis. Setting: Tertiary care center. Patient(s): Two hundred sixty-seven patients. Intervention(s): Transvaginal ultrasound before starting gonadotropins. Main Outcome Measure(s): Number of oocytes retrieved, basal hormone levels, and cycle outcomes. Result(s): The MOV for the population was 4.78 +/- 2.6 cm(3) (range 0.9-21.1 cm(3)). The MOV significantly correlated with the majority of prestimulation and poststimulation IVF parameters. Threshold analysis demonstrated a lower pregnancy rate associated with a MOV of <2 cm(3) (31.6% vs. 55.6%). Threshold analysis revealed a trend toward higher cancellation rate associated with a MOV of <2 cm(3) (21.1% vs. 7.3%). Conclusion(s): Although MOV correlated with IVF stimulation parameters, its use as an adjunct in counseling patients during IVF appears to be of limited value. A MOV <2 cm(3) was associated clinically with a higher cancellation rate (21.1%) and a lower pregnancy rate (31.6%) in those cycles not cancelled. However, these values do not deviate far from the mean national IVF outcome rates. There was no absolute MOV that was predictive of pregnancy outcome or cycle cancellation. (C)2004 by American Society for Reproductive Medicine. C1 Tripler Army Med Ctr, Dept Obstet & Gynecol, Honolulu, HI 96859 USA. Connecticut Fertil Associates, Bridgeport, CT USA. Reprod Med Associates New Jersey, Morristown, NJ USA. Uniformed Serv Univ Hlth Sci, USN, Natl Med Ctr, Combined Fed Program Reprod Endocrinol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, USN, Natl Med Ctr, Walter Reed Army Med Ctr,Pediat & Reprod Endocrin, Bethesda, MD 20814 USA. NIH, Bethesda, MD 20892 USA. RP Frattarelli, JL (reprint author), Tripler Army Med Ctr, Dept Obstet & Gynecol, 1 Jarrett White Rd, Honolulu, HI 96859 USA. EM john.frattarelli@amedd.army.mil NR 17 TC 15 Z9 19 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD OCT PY 2004 VL 82 IS 4 BP 811 EP 815 DI 10.1016/j.fertnstert.2004.02.143 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UO UT WOS:000224516800011 PM 15482752 ER PT J AU Whitcomb, BW Schisterman, EF AF Whitcomb, BW Schisterman, EF TI Units of analysis - matched pairs, single patient, or cycles? SO FERTILITY AND STERILITY LA English DT Letter ID SELECTION; OUTCOMES C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Whitcomb, BW (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD OCT PY 2004 VL 82 IS 4 BP 987 EP 988 DI 10.1016/j.fertnstert.2004.07.004 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UO UT WOS:000224516800052 PM 15482793 ER PT J AU Leppert, PC Baginski, T Prupas, C Catherino, WH Pletcher, S Segars, JH AF Leppert, PC Baginski, T Prupas, C Catherino, WH Pletcher, S Segars, JH TI Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium SO FERTILITY AND STERILITY LA English DT Article DE leiomyomas; collagen; collagen fibrillogenesis; electron microscopy ID GENE-EXPRESSION; PROLIFERATIVE PHASE; THERAPY; GROWTH; ACIDS; IX AB Objective: To examine the ultrastructural characteristics of extracellular matrix and mature Collagen fibrils in uterine leiomyomas and compare them with those in adjacent normal myometrium. Design: Analysis of paired leiomyoma-myometrium in surgical specimens. Setting: Research center and tertiary care center. Subject(s): Women undergoing medically indicated hysterectomy for symptomatic uterine leiomyomas. Intervention(s): None. Main Outcome Measure(s): Appearance and spatial orientation of the collagen fibrils in leiomyomas compared with myometrium. Result(s): Observation of specimens at X12,500 magnification indicated that Collagen fibrils were more abundant, loosely packed, and arrayed in a nonparallel manner in leiomyomas compared with myometrium. Random areas were examined at X6,500 to X64,000 magnification and revealed collagen fibrils of equal diameter in both leiomyomas and myometrium. However, an ordered and regular barbed appearance was present in collagen fibrils from myometrium but was lacking in leiomyomas. Conclusion(s): Leiomyomas contain an abnormal collagen fibril structure and orientation, which suggests that the well-regulated fibril formation in myometrium is altered in leiomyomas. Alterations in collagen genes may play a role in the pathogenesis of leiomyomas. (C) 2004 by American Society for Reproductive Medicine. C1 NICHD, Pediat & Reprod Endocrinol Branch, Rockville, MD 20852 USA. NICHD, Dept Obstet & Gynecol, Rockville, MD 20852 USA. NICHD, Biomed Imaging Ctr, Rockville, MD 20852 USA. NIH, Program Reprod Endocrinol, Bethesda, MD USA. RP Leppert, PC (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, 6100 Execut Blvd, Rockville, MD 20852 USA. EM leppertp@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999]; PHS HHS [Z01-008737-02] NR 28 TC 68 Z9 68 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD OCT PY 2004 VL 82 SU 3 BP 1182 EP 1187 DI 10.1016/j.fertnstert.2004.04.030 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 863RV UT WOS:000224580500030 PM 15474093 ER PT J AU Wang, AG Xia, T Yuan, J Yu, RA Yang, KD Chen, XM Qu, W Waalkes, MP AF Wang, AG Xia, T Yuan, J Yu, RA Yang, KD Chen, XM Qu, W Waalkes, MP TI Effects of phenobarbital on metabolism and toxicity of diclofenac sodium in rat hepatocytes in vitro SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE diclofenac sodium; phenobarbital; sandwich culture; enzyme leakage; cytochrome P450 3A ID LIVER; 7-ETHOXYCOUMARIN; CULTURES; HUMANS; DRUG; PHARMACOKINETICS; HEPATOTOXICITY; IDENTIFICATION; BIOACTIVATION; CELLS AB Diclofenac sodium (DF-Na) was a nonsteroidal anti-inflammatory drug used in various aspects of inflammatory disease. The purpose of this study was to examine the effects of phenobarbital (PB) on metabolism and toxicity of DF-Na in vitro and explore the potential mechanism of DF-Na induced hepatotoxicity. Rat hepatocytes were isolated by a modification of the two-step in situ collagenase perfusion technique and the harvested rat hepatocytes were cultured with sandwich method. Control or PB (2 mM) pre-treated hepatocytes were incubated with DF-Na (0.1, 0.05 or 0.01 mM) in vitro and cytosolic enzyme leakage levels, cytochrome P450 (CYP) 3A activity, and metabolite content of DF-Na in cell culture medium were measured. The results showed that without any treatment hepatocyte CYP 3A activity gradually decreased with culture time. On day four, CYP 3A activity was 53% of the initial value. The decline of CYP 3A was partially reversed by CYP inducer PB, and the maximum induction of CYP 3A was 2.2-fold over control after continuous exposure of hepatocytes to 2 mM PB for 48 h. Lactic dehydrogenase (LDH), aspartate transaminase (AST), and alanine transamine (ALT) activity and the contents of the DF-Na metabolites 4'-hydroxydiclofenac (4'-OH-DF) and 5-hydroxydiclofenac (5-OH-DF) in media appeared to increase with increasing DF-Na concentrations, though there were no significant differences between DF-Na exposed and control hepatocytes. However, if the hepatocytes first were pre-treated with 2 mM PB for 2 days and then exposed to DF-Na, the concentrations of DF-Na metabolites and the activity of LDH in the media were significantly higher than that of control group. These findings suggest that the hepatotoxicity and metabolism of DF-Na in rat hepatocytes are increased when hepatic CYP 3A activity is increased. (C) 2004 Elsevier Ltd. All rights reserved. C1 Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Environm Hlth, Wuhan 430034, Peoples R China. NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Wang, AG (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Environm Hlth, Wuhan 430034, Peoples R China. EM wangaiguo@mails.tjmu.edu.cn NR 26 TC 15 Z9 15 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD OCT PY 2004 VL 42 IS 10 BP 1647 EP 1653 DI 10.1016/j.fct.2004.05.010 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 850WA UT WOS:000223643900011 PM 15304311 ER PT J AU Bartoshuk, LM Duffy, VB Chapo, AK Fast, K Yiee, JH Hoffman, HJ Ko, CW Snyder, DJ AF Bartoshuk, LM Duffy, VB Chapo, AK Fast, K Yiee, JH Hoffman, HJ Ko, CW Snyder, DJ TI From psychophysics to the clinic: missteps and advances SO FOOD QUALITY AND PREFERENCE LA English DT Article; Proceedings Paper CT 5th Pangborn Sensory Science Symposium CY JUL 20-24, 2003 CL Boston, MA DE across-group comparisons; category scales; general labeled magnitude scale; magnitude estimation; oral pathology; PROP (6-n-propylthiouracil); pain; supertasters; taste ID GUSTATORY CROSS-ADAPTATION; BURNING MOUTH SYNDROME; CHORDA TYMPANI NERVE; GRAPHIC RATING-SCALE; PROP TASTER STATUS; FAT PERCEPTION; 6-N-PROPYLTHIOURACIL PROP; FUNGIFORM PAPILLAE; GENETIC ABILITY; WATER TASTE AB People live in different oral sensory worlds. This variation affects health and quality of life. The need to make valid comparisons across individuals/groups to reveal this variation highlighted invalid use of conventional labeled scales (e.g., visual analogue, category scales). Valid comparisons can be made with magnitude matching and the general Labeled Magnitude Scale (gLMS) employing multiple standards (real and remembered), thus permitting associations between oral sensation, preferences, intake (e.g., fats, vegetables), and health outcomes (e.g., cancer, phantoms, burning mouth syndrome). These measurement insights broadly apply to sensory/hedonic assessment of differences across groups in many different fields. As an illustration, we assess differences across groups experiencing different types of pain. (C) 2004 Elsevier Ltd. All rights reserved. C1 Yale Univ, Sch Med, Dept Surg Otolarngol, New Haven, CT 06520 USA. Univ Connecticut, Sch Allied Hlth, Dept Appl Hlth Sci, Storrs, CT 06269 USA. Natl Inst Deafness & Other Commun Disorders, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Bartoshuk, LM (reprint author), Yale Univ, Sch Med, Dept Surg Otolarngol, POB 208041, New Haven, CT 06520 USA. EM linda.bartoshuk@yale.edu NR 161 TC 40 Z9 40 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0950-3293 J9 FOOD QUAL PREFER JI Food. Qual. Prefer. PD OCT-DEC PY 2004 VL 15 IS 7-8 BP 617 EP 632 DI 10.1016/j.foodqual.2004.05.007 PG 16 WC Food Science & Technology SC Food Science & Technology GA 868WZ UT WOS:000224945100002 ER PT J AU Manal, K Stanhope, SJ AF Manal, K Stanhope, SJ TI A novel method for displaying gait and clinical movement analysis data SO GAIT & POSTURE LA English DT Article DE color; graph; deviation; communication ID REPEATABILITY AB Plotting kinematic and kinetic data of a patient's movement patterns relative to normative values (i.e., mean and +/- 1 S.D.) is a common method used by clinicians to visually assess deviations and interpret the patient's gait analysis data. This method of data interpretation is often time consuming and complex, especially when the process requires the inspection of a plethora of line graphs for numerous variables that are displayed across several report pages. In this paper we propose an alternate method for displaying movement pattern deviations relative to normative data by color-coding the magnitude and the direction of the deviation. An advantage of this approach is that a single page summary of all the deviation magnitudes can be displayed simultaneously, in a manner that is concise, visually effective and reduces complexity. The purpose of this paper is to describe the algorithmic development of the color-coding method. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Delaware, Ctr Biomed Engn Res, Spencer Lab 126, Newark, DE 19716 USA. NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. RP Manal, K (reprint author), Univ Delaware, Ctr Biomed Engn Res, Spencer Lab 126, Newark, DE 19716 USA. EM manal@udel.edu FU NCRR NIH HHS [RR16458-01] NR 4 TC 20 Z9 21 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD OCT PY 2004 VL 20 IS 2 BP 222 EP 226 DI 10.1016/j.gaitpost.2003.09.009 PG 5 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 856IY UT WOS:000224040100015 PM 15336294 ER PT J AU Takehara, T Tatsumi, T Suzuki, T Rucker, EB Hennighausen, L Jinushi, M Miyagi, T Kanazawa, Y Hayashi, N AF Takehara, T Tatsumi, T Suzuki, T Rucker, EB Hennighausen, L Jinushi, M Miyagi, T Kanazawa, Y Hayashi, N TI Hepatocyte-specific disruption of Bcl-x(L) leads to continuous hepatocyte apoptosis and liver fibrotic responses SO GASTROENTEROLOGY LA English DT Article ID HUMAN HEPATOCELLULAR CARCINOMAS; PULMONARY-FIBROSIS; CELL-SURVIVAL; BCL-2 FAMILY; CRE RECOMBINASE; EXPRESSION; MOUSE; GENE; MICE; PATHWAY AB Background & Aims: Recent research has suggested that apoptosis could be involved in the development of fibrosis, although it is generally considered to be a mechanism of cell removal without consequences to the tissue. Bcl-x(L), an antiapoptotic member of the Bcl-2 family, is expressed in hepatocytes and up-modulated during various pathologic conditions. The aim of this study was to explore the function of Bcl-x(L) in hepatocytes using the Cre-loxP system and to analyze the consequences of long-term apoptosis in hepatocytes. Methods: Hepatocytes isolated from mice homozygous for a floxed bcl-x allele (bcl-x fl/fl) were infected with recombinant adenovirus expressing the Cre recombinase gene (AdexCre). Bcl-x fl/fl mice were crossed with Alb-Cre transgenic mice, which express Cre under regulation of the albumin gene promoter to generate hepatocyte-specific Bcl-x(L)-deficient mice. Results: On AdexCre infection, primary cultured bcl-x fl/fl hepatocytes reduced their expression of Bcl-x(L) and rapidly underwent apoptosis associated with mitochondrial damage. In vivo hepatocyte-specific disruption of Bcl-x(L) resulted in spontaneous apoptosis of hepatocytes for more than 6 months. The Bcl-x(L-) deficient mice showed liver fibrosis with advanced age that was preceded by an increase in hepatic transforming growth factor beta production. In vitro, macrophages and hepatocytes produced transforming growth factor beta on exposure to apoptotic hepatocytes. Conclusions: The present study identified Bcl-x(L) as a critical apoptosis antagonist in hepatocytes. Furthermore, it offers proof that persistent apoptosis of parenchymal cells is sufficient to induce fibrotic responses and suggests a mechanistic link between apoptosis and fibrosis. C1 Osaka Univ, Grad Sch Med, Dept Mol Therapeut, Suita, Osaka 5650871, Japan. Univ Missouri, Anim Sci Unit, Columbia, MO USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hayashi, N (reprint author), Osaka Univ, Grad Sch Med, Dept Mol Therapeut, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM hayashin@moltx.med.osaka-u.ac.jp RI Jinushi, Masahisa/A-4311-2012 NR 32 TC 125 Z9 136 U1 1 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2004 VL 127 IS 4 BP 1189 EP 1197 DI 10.1053/j.gastro.2004.07.019 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 864AG UT WOS:000224604400023 PM 15480996 ER PT J AU Song, L Wang, J Wang, R Yu, M Sun, Y Han, G Li, Y Qian, J Scott, DW Kang, Y Soukhareva, N Shen, B AF Song, L Wang, J Wang, R Yu, M Sun, Y Han, G Li, Y Qian, J Scott, DW Kang, Y Soukhareva, N Shen, B TI Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4(+) regulatory T cells and TGF-beta? SO GENE THERAPY LA English DT Article DE immune tolerance; GAD-IgG fusion construct; diabetes; CD4(+) regulatory T cells; TGF-beta ID GLUTAMIC-ACID DECARBOXYLASE; INDUCTION; MICE; PEPTIDE; IMMUNOGLOBULIN; AUTOIMMUNITY; MECHANISMS; PROTEIN AB Previous studies have demonstrated that antigen-specific tolerance could be induced by lipopolysaccharide (LPS)stimulated B cells retrovirally transduced with an immunoglobulin-antigen ( or epitope-containing peptide) fusion construct. To investigate the mechanism of this gene therapy system, we now adapted this approach to immunotherapy of spontaneous diabetes in nonobese diabetic ( NOD) mice, a T-cell-mediated autoimmune disease triggered, in part, by a pathogenic response to glutamate decarboxylase ( GAD) 65. We demonstrate that LPS-stimulated splenocytes, retrovirally transfected with GAD-IgG fusion construct, induce a significant antigen-specific hyporesponsiveness at both cellular and humoral levels and reduce the incidence of diabetes in female NOD mice. Parallel with disease protection, we observed a prolonged increase of the numbers of CD4(+)CD25(+) T cells in the periphery of GAD-IgG-treated mice, compared to those treated with a control IgG vector, both in the prediabetic period and persisting even 8 months after gene therapy. This increase appeared to be induced by the repeated stimulation of the antigen in the periphery instead of a result of differentiation of T-cell precursor in the thymus. Moreover, CD4(+)CD25(+) T cells induced by GAD-IgG fusion construct were capable of suppressing the proliferative response of CD4(+)CD25(+) T cells in vitro; and ablation of the activity of CD4(+) CD25(+) T cells by blocking antibody against CD25 could reverse GAD-specific T-cell hyporesponsiveness. These results suggested that CD4(+) CD25(+) T-cell subset induced in GAD-IgG-treated NOD mice represented the regulatory or suppressive CD4(+)CD25(+) T cells (Treg) and might play an important role in the induction and maintenance of tolerance in NOD mice. Furthermore, the numbers of splenic CD4(+)CD62L(+) regulatory T cells in GAD-IgG-treated mice during the prediabetic period and serum TGF-beta levels in 34-38-week-old GAD-IgG-protected mice were also increased, compared to control IgG-treated ones. Therefore, we propose that the induction of tolerance and the prevention of diabetes incidence in NOD female mice induced by the GAD-IgG fusion construct may require CD4(+) regulatory T cells, and the possible mediation of TGF-beta. C1 Inst Basic Med Sci, Dept Mol Immunol, Beijing 100850, Peoples R China. NCI, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Dept Immunol, Rockville, MD USA. RP Shen, B (reprint author), Inst Basic Med Sci, Dept Mol Immunol, 27 Taiping Rd, Beijing 100850, Peoples R China. NR 25 TC 50 Z9 55 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD OCT PY 2004 VL 11 IS 20 BP 1487 EP 1496 DI 10.1038/sj.gt.3302327 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 857YL UT WOS:000224156300001 PM 15343360 ER PT J AU Moy, SS Nadler, JJ Perez, A Barbaro, RP Johns, JM Magnuson, TR Piven, J Crawley, JN AF Moy, SS Nadler, JJ Perez, A Barbaro, RP Johns, JM Magnuson, TR Piven, J Crawley, JN TI Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice SO GENES BRAIN AND BEHAVIOR LA English DT Article DE autism; exploration; inbred strains; locomotion; mice; olfaction; rotarod; sociability; social interaction; social preference ID FRAGILE-X-SYNDROME; EARLY INFANTILE-AUTISM; FMR1 KNOCKOUT MOUSE; GENOMIC SCREEN; MENTAL-RETARDATION; SPECTRUM DISORDERS; ASPERGER-SYNDROME; RECOGNITION; ANXIETY; MEMORY AB Deficits in social interaction are important early markers for autism and related neurodevelopmental disorders with strong genetic components. Standardized behavioral assays that measure the preference of mice for initiating social interactions with novel conspecifics would be of great value for mutant mouse models of autism. We developed a new procedure to assess sociability and the preference for social novelty in mice. To quantitate sociability, each mouse was scored on measures of exploration in a central habituated area, a side chamber containing an unfamiliar conspecific (stranger 1) in a wire cage, or an empty side chamber. In a secondary test, preference for social novelty was quantitated by presenting the test mouse with a choice between the first, now-familiar, conspecific (stranger 1) in one side chamber, and a second unfamiliar mouse (stranger 2) in the other side chamber. Parameters scored included time spent in each chamber and number of entries into the chambers. Five inbred strains of mice were tested, C57BL/6J, DBA/2J, FVB/NJ, A/J and B6129PF2/J hybrids. Four strains showed significant levels of sociability (spending more time in the chamber containing stranger 1 than in the empty chamber) and a preference for social novelty (spending more time in the chamber containing stranger 2 than in the chamber containing the now-familiar stranger 1). These social preferences were observed in both male and female mice, and in juveniles and adults. The exception was A/J, a strain that demonstrated a preference for the central chamber. Results are discussed in terms of potential applications of the new methods, and the proper controls for the interpretation of social behavior data, including assays for health, relevant sensory abilities and motor functions. This new standardized procedure to quantitate sociability and preference for social novelty in mice provides a method to assess tendencies for social avoidance in mouse models of autism. C1 Univ N Carolina, Neurdev Disorders Res Ctr, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Psychiat, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, N Carolina STAART Ctr Autism Res, Sch Med, Chapel Hill, NC 27599 USA. NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Moy, SS (reprint author), Univ N Carolina, Neurdev Disorders Res Ctr, Sch Med, CB 7146, Chapel Hill, NC 27599 USA. EM ssmoy@med.unc.edu FU NICHD NIH HHS [P30 HD03110]; NIMH NIH HHS [U54 MH66418] NR 73 TC 422 Z9 427 U1 9 U2 48 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD OCT PY 2004 VL 3 IS 5 BP 287 EP 302 DI 10.1111/j.1601-183X.2004.00076.x PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 855QK UT WOS:000223988600004 PM 15344922 ER PT J AU Nadler, JJ Moy, SS Dold, G Trang, D Simmons, N Perez, A Young, NB Barbaro, RP Piven, J Magnuson, TR Crawley, JN AF Nadler, JJ Moy, SS Dold, G Trang, D Simmons, N Perez, A Young, NB Barbaro, RP Piven, J Magnuson, TR Crawley, JN TI Automated apparatus for quantitation of social approach behaviors in mice SO GENES BRAIN AND BEHAVIOR LA English DT Article DE autism; automated equipment; C57BL/6J; DBA/2J; exploratory activity; FVB/ NJ; inbred strains; mice; scoring methods; sociability; social behavior; social preference ID INBRED MOUSE STRAINS; WILLIAMS-SYNDROME; SCHIZOPHRENIA; AUTISM; DEFICITS; PHOBIA; NEUROBIOLOGY; RECOGNITION; PREFERENCES; GENETICS AB Mouse models of social dysfunction, designed to investigate the complex genetics of social behaviors, require an objective methodology for scoring social interactions relevant to human disease symptoms. Here we describe an automated, three chambered apparatus designed to monitor social interaction in the mouse. Time spent in each chamber and the number of entries are scored automatically by a system detecting photocell beam breaks. When tested with the automated equipment, juvenile male C57BL/6J mice spent more time in a chamber containing a stranger mouse than in an empty chamber (sociability), similar to results obtained by the observer scored method. In addition, automated scoring detected a preference to spend more time with an unfamiliar stranger than a more familiar conspecific (preference for social novelty), similar to results obtained by the observer scored method. Sniffing directed at the wire cage containing the stranger mouse correlated significantly with time spent in that chamber, indicating that duration in a chamber represents true social approach behavior. Number of entries between chambers did not correlate with duration of time spent in the chambers; entries instead proved a useful control measure of general activity. The most significant social approach behavior took place in the first five minutes of both the sociability and preference for social novelty tests. Application of these methods to C57BL/6J, DBA/2J and FVB/NJ adult males revealed that all three strains displayed tendencies for sociability and preference for social novelty. To evaluate the importance of the strain of the stranger mouse on sociability and preference for social novelty, C57BL/6J subject mice were tested either with A/J strangers or with C57BL/6J strangers. Sociability and preference for social novelty were similar with both stranger strains. The automated equipment provides an accurate and objective approach to measuring social tendencies in mice. Its use may allow higher-throughput scoring of mouse social behaviors in mouse models of social dysfunction. C1 Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Neurodev Disorders Res Ctr, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, N Carolina STAART Ctr Autism Res, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Psychiat, Sch Med, Chapel Hill, NC 27599 USA. NIMH, Res Serv Branch, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Nadler, JJ (reprint author), Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA. EM jjnadler@med.unc.edu FU NICHD NIH HHS [P30 HD03110, T32-HD40127]; NIMH NIH HHS [U54 MH66418] NR 40 TC 310 Z9 316 U1 4 U2 18 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD OCT PY 2004 VL 3 IS 5 BP 303 EP 314 DI 10.1111/j.1601-183X.2004.00071.x PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 855QK UT WOS:000223988600005 PM 15344923 ER PT J AU Clark, AM Reynolds, SH Anderson, M Wiest, JS AF Clark, AM Reynolds, SH Anderson, M Wiest, JS TI Mutational activation of the MAP3K8 protooncogene in lung cancer SO GENES CHROMOSOMES & CANCER LA English DT Article ID NF-KAPPA-B; T-CELL LYMPHOMAS; PROTEIN-KINASE; SIGNALING PATHWAYS; NF-KAPPA-B1 P105; ONCOGENIC KINASE; COT ONCOGENE; TPL-2; INDUCTION; EXPRESSION AB The MAP3K8 protooncogene (Cot/Tpl-2) activates the MAP kinase, SAP kinase, and NF-kappaB signaling pathways. MAP3K8 mutations occur in the rat homologue, but activating mutations have yet to be identified in primary human tumors. We have identified MAP3K8 as a transforming gene from a human lung adenocarcinoma and characterized a 3' end mutation in the cDNA. In addition, we confirmed that the mutation occurs in the original lung tumor, and we screened a series of lung cancer cell lines to determine whether the MAP3K8 mutation is a common occurrence in lung tumorigenesis. The oncogene was isolated and identified with the NH3T3 nude mouse turnorigenicity assay and cDNA library screening. The gene was analyzed by polymerase chain reaction (PCR), single-strand conformational polymorphism (SSCP), and 3'RACE for mutations. The mutation was localized to MAP3K8 exon 8 and confirmed in the primary tumor DNA. Both wild-type and mutant MAP3K8 cDNAs transformed NIH3T3 cells, but the transforming activity of the mutant was much greater than that of the wild type. PCR-SSCP screening of cell line cDNAs identified one silent polymorphism in cell line SK-LU-1. Although we were unable to find additional activating mutations, these data support a role for MAP3K8 activity in cellular transformation, but suggest that mutational activation of the gene is a rare event in lung cancer. (C) 2004 Wiley-Liss, Inc. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. NIOSH, Morgantown, WV 26505 USA. RP Wiest, JS (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, 31 Ctr Dr,Bldg 31A-Rm 3A11, Bethesda, MD 20892 USA. EM wiestj@mail.nih.gov FU Intramural NIH HHS [ZIA BC010448-09]; NIEHS NIH HHS [5 T32 ES07250, T32 ES007250] NR 33 TC 21 Z9 24 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD OCT PY 2004 VL 41 IS 2 BP 99 EP 108 DI 10.1002/gcc.20069 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 847CR UT WOS:000223367100002 PM 15287022 ER PT J AU Paik, JH Skoura, A Chae, SS Cowan, AE Han, DK Proia, RL Hla, T AF Paik, JH Skoura, A Chae, SS Cowan, AE Han, DK Proia, RL Hla, T TI Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization SO GENES & DEVELOPMENT LA English DT Article DE sphingosine 1-phosphate; cadherin; angiogenesis; vascular stabilization; endothelial cells; pericytes ID PROTEIN-COUPLED RECEPTOR; BLOOD-VESSEL FORMATION; ENDOTHELIAL-CELLS; TYROSINE PHOSPHORYLATION; DIABETIC-RETINOPATHY; BARRIER INTEGRITY; PDGF-B; ADHESION; GROWTH; ANGIOGENESIS AB Vascular stabilization, a process by which nascent vessels are invested with mural cells, is important in angiogenesis. Here we describe the molecular basis of vascular stabilization regulated by sphingosine 1-phosphate (SIP), a platelet-derived lipid mediator. S1P(1) receptor-dependent cell-surface trafficking and activation of the cell-cell adhesion molecule N-cadherin is essential for interactions between endothelial and mural cells. Endothelial cell S1P(1)/G(i)/Rac pathway induces microtubule polymerization, resulting in trafficking of N-cadherin to polarized plasma membrane domains. S1P treatment modulated the phosphorylation of N-cadherin as well as p120-catenin and induced the formation of cadherin/catenin/actin complexes containing novel regulatory and trafficking factors. The net result of endothelial cell S1P, receptor activation is the proper trafficking and strengthening of N-cadherin-dependent cell-cell adhesion with mural cells. Perturbation of N-cadherin expression with small interfering RNA profoundly attenuated vascular stabilization in vitro and in vivo. S1P-induced trafficking and activation of N-cadherin provides a novel mechanism for the stabilization of nascent blood vessels by mural cells and may be exploited to control angiogenesis and vascular diseases. C1 Univ Connecticut, Ctr Hlth, Dept Cell Biol, Ctr Vasc Biol, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Ctr Biomed Imaging Technol, Farmington, CT 06030 USA. NIDDK, Genet Dis & Dev Branch, NIH, Bethesda, MD 20892 USA. RP Hla, T (reprint author), Univ Connecticut, Ctr Hlth, Dept Cell Biol, Ctr Vasc Biol, Farmington, CT 06030 USA. EM hla@nso2.uchc.edu RI Proia, Richard/A-7908-2012; Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 FU NHLBI NIH HHS [HL70694, HL67330, P01 HL070694, R01 HL067330, R37 HL067330] NR 59 TC 147 Z9 151 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 1 PY 2004 VL 18 IS 19 BP 2392 EP 2403 DI 10.1101/gad.1227804 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 858MT UT WOS:000224196600009 PM 15371328 ER PT J AU Guo, XZ Day, TF Jiang, XY Garrett-Beal, L Topol, L Yang, YZ AF Guo, XZ Day, TF Jiang, XY Garrett-Beal, L Topol, L Yang, YZ TI Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation SO GENES & DEVELOPMENT LA English DT Article DE Wnt; beta-catenin; joint formation; skeletal development ID PRO-ALPHA-1(II) COLLAGEN GENE; BETA-CATENIN; CHONDROCYTE DIFFERENTIATION; DOUBLE MUTATIONS; TRANSGENIC MICE; DIGIT IDENTITY; EXPRESSION; MOUSE; CARTILAGE; CELL AB A critical step in skeletal morphogenesis is the formation of synovial joints, which define the relative size of discrete skeletal elements and are required for the mobility of vertebrates. We have found that several Wnt genes, including Wnt4, Wnt14, and Wnt16, were expressed in overlapping and complementary patterns in the developing synovial joints, where beta-catenin protein levels and transcription activity were up-regulated. Removal of p-catenin early in mesenchymal progenitor cells promoted chondrocyte differentiation and blocked the activity of Wnt14 in joint formation. Ectopic expression of an activated form of beta-catenin or Wnt14 in early differentiating chondrocytes induced ectopic joint formation both morphologically and molecularly. In contrast, genetic removal of p-catenin in chondrocytes led to joint fusion. These results demonstrate that the Wnt/beta-catenin signaling pathway is necessary and sufficient to induce early steps of synovial joint formation. Wnt4, Wnt14, and Wnt16 may play redundant roles in synovial joint induction by signaling through the beta-catenin-mediated canonical Wnt pathway. C1 Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Yang, YZ (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. EM yyang@nhgri.nih.gov NR 58 TC 226 Z9 234 U1 2 U2 20 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 1 PY 2004 VL 18 IS 19 BP 2404 EP 2417 DI 10.1101/gad.1230704 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 858MT UT WOS:000224196600010 PM 15371327 ER PT J AU Brasch, MA Hartley, JL Vidal, M AF Brasch, MA Hartley, JL Vidal, M TI ORFeome cloning and systems biology: Standardized mass production of the parts from the parts-list SO GENOME RESEARCH LA English DT Editorial Material ID GREEN FLUORESCENT PROTEIN; SACCHAROMYCES-CEREVISIAE GENOME; SITE-SPECIFIC RECOMBINATION; DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; C-ELEGANS; ESCHERICHIA-COLI; INTERACTION MAP; FUNCTIONAL-ORGANIZATION; DROSOPHILA-MELANOGASTER C1 Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Atto Biosci, Rockville, MD 20850 USA. NCI, SAIC, Frederick, MD 21702 USA. RP Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu NR 85 TC 49 Z9 54 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD OCT PY 2004 VL 14 IS 10B BP 2001 EP 2009 DI 10.1101/gr.2769804 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 862TM UT WOS:000224514000001 PM 15489318 ER PT J AU Hill, DE Brasch, MA del Campo, AA Doucette-Stamm, L Garrels, JI Glaven, J Hartley, JL Hudson, JR Moore, T Vidal, M AF Hill, DE Brasch, MA del Campo, AA Doucette-Stamm, L Garrels, JI Glaven, J Hartley, JL Hudson, JR Moore, T Vidal, M TI Academia-industry collaboration: An integral element for building "omic" resources SO GENOME RESEARCH LA English DT Editorial Material ID HUMAN-GENOME-PROJECT; DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; GENETIC INTERFERENCE; SACCHAROMYCES-CEREVISIAE; BETA-GLOBIN; C-ELEGANS; DNA; EXPRESSION; MICROARRAY C1 Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Atto Biosci, Rockville, MD 20850 USA. Dana Farber Canc Inst, Off Res & Technol Ventures, Boston, MA 02115 USA. Agencourt BIosci Corp, Beverly, MA 01915 USA. NCI, SAIC, Frederick, MD 21702 USA. CityScapes, Huntsville, AL 35801 USA. Open Biosyst, Huntsville, AL 35806 USA. RP Hill, DE (reprint author), Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM david_hill@dfci.harvard.edu RI Hill, David/B-6617-2011 NR 57 TC 0 Z9 0 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD OCT PY 2004 VL 14 IS 10B BP 2010 EP 2014 DI 10.1101/gr.2771404 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 862TM UT WOS:000224514000002 PM 15489319 ER PT J AU Rual, JF Hirozane-Kishikawa, T Hao, T Bertin, N Li, SM Dricot, A Li, N Rosenberg, J Lamesch, P Vidalain, PO Clingingsmith, TR Hartley, JL Esposito, D Cheo, D Moore, T Simmons, B Sequerra, R Bosak, S Doucette-Stamm, L Le Peuch, C Vandenhaute, J Cusick, ME Albala, JS Hill, DE Vidal, M AF Rual, JF Hirozane-Kishikawa, T Hao, T Bertin, N Li, SM Dricot, A Li, N Rosenberg, J Lamesch, P Vidalain, PO Clingingsmith, TR Hartley, JL Esposito, D Cheo, D Moore, T Simmons, B Sequerra, R Bosak, S Doucette-Stamm, L Le Peuch, C Vandenhaute, J Cusick, ME Albala, JS Hill, DE Vidal, M TI Human ORFeome version 1.1: A platform for reverse proteomics SO GENOME RESEARCH LA English DT Article ID SITE-SPECIFIC RECOMBINATION; CAENORHABDITIS-ELEGANS; PROTEIN COMPLEXES; SYSTEMS BIOLOGY; GENOME SEQUENCE; GENES; PROJECTS; DATABASE; GATEWAY; CLONING AB The advent of systems biology necessitates the cloning of nearly entire sets of protein-encoding open reading frames (ORFs), or ORFeomes, to allow functional studies of the corresponding proteomes. Here, we describe the generation of a first version of the human ORFeome using a newly improved Gateway recombinational cloning approach. Using the Mammalian Gene Collection (MGC) resource as a starting point, we report the successful cloning of 8076 human ORFs, representing at least 7263 human genes, as mini-pools of PCR-amplified products. These were assembled into the human ORFeome version 1.1 (hORFeome v1.1) collection. After assessing the overall quality of this version, we describe the use of hORFeome v1.1 for heterologous protein expression in two different expression systems at proteome scale. The hORFeome v1.1 represents a central resource for the cloning of large sets of human ORFs in various settings for functional proteomics of many types, and will serve as the foundation for subsequent improved versions of the human ORFeome. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Fac Univ Notre Dame Paix, B-5000 Namur, Belgium. CNRS, FRE 2593, Ctr Rech Biochim Macromol, F-34293 Montpellier 5, France. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. Atto Biosci, Rockville, MD 20850 USA. Open Biosyst Inc, Huntsville, AL 35806 USA. Agencourt Biosci Corp, Beverly, MA 01905 USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. RP Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM david_hill@dfci.harvard.edu; marc_vidal@dfci.harvard.edu RI Bertin, Nicolas/C-3025-2008; Hill, David/B-6617-2011 OI Bertin, Nicolas/0000-0002-9835-9606; FU NCI NIH HHS [U01 CA105423, U01 CA105423-01] NR 39 TC 135 Z9 142 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD OCT PY 2004 VL 14 IS 10B BP 2128 EP 2135 DI 10.1101/gr.2973604 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 862TM UT WOS:000224514000018 PM 15489335 ER PT J AU Pfeifer, HR Gueye-Girardet, A Reymond, D Schlegel, C Temgoua, E Hesterberg, DL Chou, JWQ AF Pfeifer, HR Gueye-Girardet, A Reymond, D Schlegel, C Temgoua, E Hesterberg, DL Chou, JWQ TI Dispersion of natural arsenic in the Malcantone watershed, Southern Switzerland: field evidence for repeated sorption-desorption and oxidation-reduction processes SO GEODERMA LA English DT Article DE arsenic; groundwater; soil; sorption; weathering; X-ray absorption spectroscopy ID DISSOLVED ORGANIC-CARBON; CLAY-MINERALS; ADSORBED ARSENATE; ADSORPTION; SOILS; SPECIATION; FERRIHYDRITE; MOBILIZATION; GROUNDWATER; ENVIRONMENT AB In recent years, elevated arsenic concentrations have been found in waters and soils of many, countries, often resulting in a health threat for the local population. Switzerland is not an exception and this paper deals with the release and subsequent fate of arsenic in a 200-km(2) mountainous watershed, characterized by crystalline silicate rocks (gneisses, schists, amphibolites) that contain abundant As-bearing sulfide ore deposits, some of which have been mined for iron and gold in the past. Using analytical methods common for mineralogical, ground water and soil studies (XRD, XRF, XAS-XANES and -EXAFS, electron microprobe, extraction, ICP, AAS with hydride generator, ion chromatography), seven different field situations and related dispersion processes of natural arsenic have been studied: (1) release by rock weathering, (2) transport and deposition by water and ice; (3) release of As to the ground and surface water due to increasing pH; (4) accumulation in humic soil horizons; (5) remobilization by reduction in water-saturated soils and stagnant ground waters; (6) remobilization by using P-rich fertilizers or dung and (7) oxidation, precipitation and dilution in surface waters. Comparison of the results with experimental adsorption studies and speciation diagrams from the literature allows us to reconstruct and identify the typical behavior of arsenic in a natural environment under temperate climatic conditions. The main parameters identified are: (a) once liberated from the primary minerals, sorption processes on Fe-oxy-hydroxides dominate over Al-phases, such as Al-hydroxides or clay minerals and limit the As concentrations in the spring and well waters between 20 and 300 mug/l. (b) Precipitation as secondary minerals is limited to the weathering domain, where the As concentrations are still high and not yet too diluted by rain and soils waters. (c) Although neutral and alkaline pH conditions clearly increase the mobility of As, the main factor to mobilize As is a low redox potential (Eh close or below 0 mV), which favors the dissolution of the Fe-oxy-hydroxides on which the As is sorbed. (d) X-ray absorption spectroscopy (XAS) of As in water-logged humic forest soils indicates that the reduction to As III only occurs at the solid-water interface and that the solid contains As as As V (e) A and Bh horizons of humic cambisols can effectively capture As when As-rich waters flow through them. Complex spatial and temporal variation of the various parameters in a watershed results in repeated mobilization and immobilization of As, which continuously transports As from the upper to the lower part of a watershed and ultimately to the ocean. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Lausanne, Ctr Anal Minerale, CH-1015 Lausanne, Switzerland. N Carolina State Univ, Dept Soil Sci, Raleigh, NC 27695 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Pfeifer, HR (reprint author), Univ Lausanne, Ctr Anal Minerale, BFSH 2, CH-1015 Lausanne, Switzerland. EM Hans-Rudolf.Pfeifer@cam.unil.ch NR 102 TC 35 Z9 39 U1 2 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0016-7061 J9 GEODERMA JI Geoderma PD OCT PY 2004 VL 122 IS 2-4 BP 205 EP 234 DI 10.1016/j.geoderma.2004.01.009 PG 30 WC Soil Science SC Agriculture GA 855ZL UT WOS:000224013300009 ER PT J AU Hodes, R Hodes, R Warner, H Hadley, E Suzman, R Morrison-Bogoard, M Barr, R Harden, J AF Hodes, R Hodes, R Warner, H Hadley, E Suzman, R Morrison-Bogoard, M Barr, R Harden, J TI Nia symposium: Research initiatives, funding and training opportunities at the national institute on aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, NIH, Bethesda, MD 20892 USA. EM hodesr@nia.nih.gov NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 1 EP 2 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800004 ER PT J AU Walsh, S Hurley, B Ferrucci, L Metter, J Roth, S Roth, S AF Walsh, S Hurley, B Ferrucci, L Metter, J Roth, S Roth, S TI ACTN3 genotype is associated with muscle strength in women but not men across the adult age span SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Maryland, College Pk, MD 20742 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 2 EP 2 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800005 ER PT J AU Batra, A Kagaruki, E Fishbein, K Spencer, R Ling, S AF Batra, A Kagaruki, E Fishbein, K Spencer, R Ling, S TI Effects of erythropoietin on skeletal muscle bioenergetics SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, NIH, IRP, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 5 EP 5 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800016 ER PT J AU Wu, J Mattison, J Ottinger, M Zelinski-Wooten, M Handy, A Roth, G Ingram, D Tilmont, E Lane, M AF Wu, J Mattison, J Ottinger, M Zelinski-Wooten, M Handy, A Roth, G Ingram, D Tilmont, E Lane, M TI Ovarian function and incidence of endometriosis in monkeys on long-term calorie restriction SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. Univ Maryland, College Pk, MD 20742 USA. ONPRC, Portland, OR USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 10 EP 10 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800031 ER PT J AU Cassol, M Bos, A Gerling, G AF Cassol, M Bos, A Gerling, G TI Singing improves vocal health and performance in elderly SO GERONTOLOGIST LA English DT Meeting Abstract C1 Pontif Catholic Univ Rio Grande Sul, Inst Gerontol & Geriatr, Porto Alegre, RS, Brazil. NIA, MRI, Baltimore, MD 21224 USA. PUCRS, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 15 EP 16 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800048 ER PT J AU Shoji, J Ling, S Leonessa, F AF Shoji, J Ling, S Leonessa, F TI Serum biomarkers in animal models of arthritis and physical inactivity: A proteomic approach SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, IRP, Clin Res Branch, Baltimore, MD 21224 USA. NIA, IRP, Clin Invest Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 15 EP 15 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800047 ER PT J AU Ferrucci, L Tinetti, M AF Ferrucci, L Tinetti, M TI Multiple biological pathways explaining loss of mobility in late life SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, ASTRA Unit, Baltimore Longtudinal Study Aging, Harbor Hosp Ctr, Baltimore, MD 21225 USA. Yale Univ, Dept Internal Med, Sect Geriatr, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 35 EP 36 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800114 ER PT J AU Warner, H Helfand, S Driscoll, M Bartke, A AF Warner, H Helfand, S Driscoll, M Bartke, A TI Biology for non-biologists: Use of model organisms to study aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Biol Aging Program, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Rutgers State Univ, Piscataway, NJ USA. So Illinois Univ, Springfield, IL USA. RI Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 35 EP 35 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800113 ER PT J AU Vitiello, M Stratton, K Foley, D White, E AF Vitiello, M Stratton, K Foley, D White, E TI Relationships of sleep complaints, insomnia and medical conditions in the vital study cohort of 77,000 older men and women. SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Washington, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 38 EP 38 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800116 ER PT J AU Vitiello, M Walsh, J Foley, D Ancoli-Israel, S Bliwise, D AF Vitiello, M Walsh, J Foley, D Ancoli-Israel, S Bliwise, D TI Relationship of napping, health and subjective sleep quality in older adults: Results from the 2003 NSF sleep in America poll SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Washington, Seattle, WA 98195 USA. St Lukes Hosp, Sleep Med Res Ctr, Chesterfield, MO USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. Univ Calif San Diego, San Diego, CA 92103 USA. Emory Univ, Atlanta, GA 30322 USA. NIA, Neurobiol Aging Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 39 EP 39 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800119 ER PT J AU Teresi, J Calkins, M Stahl, S AF Teresi, J Calkins, M Stahl, S TI Cultural diversity, cultural competence and quality of care SO GERONTOLOGIST LA English DT Meeting Abstract C1 Columbia Univ, HHAR Res Div, Riverdale, NY 10471 USA. IDEAS Inc, Kirkland, OH 44094 USA. NIA, Behav & Social Res Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 43 EP 43 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800129 ER PT J AU Gonzalgo, S Ostir, G Ko, C Markides, K Simonsick, E AF Gonzalgo, S Ostir, G Ko, C Markides, K Simonsick, E TI Acculturation and active life expectancy in Mexican American older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 Johns Hopkins Sch Med, Baltimore, MD USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 52 EP 53 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800159 ER PT J AU Harris, T Bailey-Wilson, J Rothschild, H Craglow, C AF Harris, T Bailey-Wilson, J Rothschild, H Craglow, C TI Reasons for participation in a familial lung cancer study during a 20-week period among patients 65 and older SO GERONTOLOGIST LA English DT Meeting Abstract C1 LSU, Hlth Sci Ctr, New Orleans, LA USA. NHGRI, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 67 EP 67 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800198 ER PT J AU Lee, J Harris, T Newman, A AF Lee, J Harris, T Newman, A TI Implications of weight loss and protein intake for function and for body composition in older adults-the health ABC study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Natl Inst Aging, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 116 EP 118 PG 3 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800337 ER PT J AU Schrager, M Metter, E Ferrucci, L Simonsick, E AF Schrager, M Metter, E Ferrucci, L Simonsick, E TI Development of sarcopenic obesity in participants of the Baltimore Longitudinal Study of Aging (BLSA) SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 120 EP 121 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800345 ER PT J AU Cesari, M Brach, L Harris, T Pahor, M Simonsick, E Penninx, B Rubin, S Satterfield, S Newman, A Nicklas, B Tylavsky, F Visser, M Bauer, D Kritchevsky, S AF Cesari, M Brach, L Harris, T Pahor, M Simonsick, E Penninx, B Rubin, S Satterfield, S Newman, A Nicklas, B Tylavsky, F Visser, M Bauer, D Kritchevsky, S TI Additive value of physical performance measures in the prediction of adverse health events: Results from the health ABC study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Pittsburgh, Pittsburgh, PA USA. NIA, Bethesda, MD USA. Wake Forest Univ, Sch Med, Winston Salem, NC USA. Vrije Univ Amsterdam, Amsterdam, Netherlands. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Memphis, TN USA. RI Cesari, Matteo/A-4649-2008 OI Cesari, Matteo/0000-0002-0348-3664 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 128 EP 129 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800366 ER PT J AU Butler, R Carnes, B Austad, S Finch, C Warner, H Hayflick, L AF Butler, R Carnes, B Austad, S Finch, C Warner, H Hayflick, L TI Are there life forms that age negligibly or not at all? SO GERONTOLOGIST LA English DT Meeting Abstract C1 Int Longev Ctr, New York, NY 10028 USA. Univ Oklahoma, Ctr Hlth Sci, Dept Geriatr Med, Oklahoma City, OK 73104 USA. Univ Idaho, Moscow, ID 83844 USA. Univ So Calif, Los Angeles, CA 90089 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. Univ Calif San Francisco, Sea Ranch, CA 95497 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 130 EP 130 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800370 ER PT J AU Clark, P Stahl, S AF Clark, P Stahl, S TI Senior project: Stage-based intervention on exercise and diet in a large community sample of older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Rhode Isl, Program Gerontol & RI Geriatr Educ Ctr, Kingston, RI 02881 USA. NIA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 132 EP 132 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800373 ER PT J AU De Rekeneire, N Harris, T Crepaldi, G AF De Rekeneire, N Harris, T Crepaldi, G TI Diabetes outcomes in aging: From international studies SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. CNR, Ctr Aging, Padua, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 162 EP 163 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800463 ER PT J AU Bernard, M Burris, J Chernoff, R Yoshikawa, T Salerno, J Wetle, T Fulmer, T Barry, P Barr, R Rieder, C Saunders, M AF Bernard, M Burris, J Chernoff, R Yoshikawa, T Salerno, J Wetle, T Fulmer, T Barry, P Barr, R Rieder, C Saunders, M TI Marsha Goodwin-Beck Memorial Symposium: gaps in the geriatrics workforce - Present and future SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Oklahoma, Coll Med, Reynolds Dept Geriatr, Oklahoma City, OK 73104 USA. Dept Vet Affairs, Washington, DC USA. Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. Charles R Drew Univ Med & Sci, Los Angeles, CA 90059 USA. NIA, Bethesda, MD 20892 USA. Brown Univ, Providence, RI 02912 USA. NYU, New York, NY USA. Merck Inst Aging & Hlth, Washington, DC 20005 USA. John A Hartford Fdn, New York, NY USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 171 EP 171 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800484 ER PT J AU Suthers, K Jagger, C Simonsick, E AF Suthers, K Jagger, C Simonsick, E TI The relationship between cognitive function and physical activity in late life: A synthesis and overview SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21225 USA. Univ Leicester, Leicester LE1 6TP, Leics, England. NR 0 TC 1 Z9 1 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 195 EP 195 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800549 ER PT J AU Faulkner, J Warner, H AF Faulkner, J Warner, H TI Nathan shock center symposium on microarrays in aging research: Current status and future directions SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Michigan, Inst Gerontol, Nathan Shock Ctr Excellence Basic Biol Aging, Ann Arbor, MI 48109 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 213 EP 213 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800600 ER PT J AU Pope, S Kritchevsky, S Ambrosone, C Harris, T Rosano, C Yaffe, K Stewart, S Simonsick, E Tylaysky, F AF Pope, S Kritchevsky, S Ambrosone, C Harris, T Rosano, C Yaffe, K Stewart, S Simonsick, E Tylaysky, F CA Health ABC Study TI Myeloperoxidase g463 genotype and cognitive decline in older adults in the health, aging, and body composition study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NIA, Bethesda, MD 20892 USA. Hlth ABC, San Francisco, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 219 EP 219 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800606 ER PT J AU Simonsick, E Guralnik, J Ferrucci, L AF Simonsick, E Guralnik, J Ferrucci, L TI The baltimore longitudinal study of aging (BLSA): Promise and potential for understanding the aging process SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21225 USA. NIA, NIH, Bethesda, MD 20895 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 223 EP 224 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458800616 ER PT J AU Chang, M Ferrucci, L Phillips, C Guralnik, J AF Chang, M Ferrucci, L Phillips, C Guralnik, J TI Effect of incident disability on depressive symptoms over 3 years of follow-up among disabled older women SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 261 EP 261 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801066 ER PT J AU Hicks, G Simonsick, E Weiner, D Nevitt, M Harris, T Newman, A Tylavsky, F AF Hicks, G Simonsick, E Weiner, D Nevitt, M Harris, T Newman, A Tylavsky, F TI Trunk muscle composition as a predictor of reduced functional capacity in health ABC: The moderating role of back pain SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Tennessee, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 265 EP 265 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801076 ER PT J AU Guilley, E Ghisletta, P Guralnik, J d'Epinay, CL AF Guilley, E Ghisletta, P Guralnik, J d'Epinay, CL TI Multidisciplinary outlook on the frailty process: Theoretical issues, individual trajectories and consequences for life SO GERONTOLOGIST LA English DT Meeting Abstract C1 Ctr Interdisciplinary Gerontol, Geneva, Switzerland. NIA, NIH, Bethesda, MD 20895 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 279 EP 279 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801117 ER PT J AU Resnick, B Remsburg, R Zimmerman, S Gruber-Baldini, A Berkovitz, A AF Resnick, B Remsburg, R Zimmerman, S Gruber-Baldini, A Berkovitz, A TI Restorative care in nursing homes: Where we are and where we need to go SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Maryland, Baltimore, MD 21201 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 287 EP 287 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801141 ER PT J AU Muehrer, P AF Muehrer, P TI NIMH funding opportunties for health and behavior research in older populations SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 304 EP 304 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801193 ER PT J AU Brenes, G Fried, L Simonsick, E Williamson, J Penninx, B Guralnik, J Simpson, C AF Brenes, G Fried, L Simonsick, E Williamson, J Penninx, B Guralnik, J Simpson, C TI The influence of anxiety on the development of disability SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Johns Hopkins Sch Med, Baltimore, MD USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 324 EP 324 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801249 ER PT J AU Brenes, G Penninx, B Fried, L Guralnik, J Williamson, J AF Brenes, G Penninx, B Fried, L Guralnik, J Williamson, J TI Predictors of anxiety in older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Johns Hopkins Sch Med, Baltimore, MD USA. NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 324 EP 325 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801250 ER PT J AU Angleman, S Harris, T Melzer, D AF Angleman, S Harris, T Melzer, D TI Obesity more than doubles mobility disability in peri-retirement age British men and women SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Bethesda, MD USA. Lab Epidemiol Demography Biometry, Bethesda, MD USA. Dept Publ Hlth & Primary Care, Cambridge, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 352 EP 353 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801328 ER PT J AU Cherubini, A Pahor, M Ferrucci, L AF Cherubini, A Pahor, M Ferrucci, L TI Biological markers of physical and cognitive frailty in late life SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Perugia, Inst Gerontol & Geriatr, Monteluce Policlin, I-06100 Perugia, Italy. Wake Forest Univ Hlth Sci, Sticht Ctr Aging, Winston Salem, NC USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 355 EP 356 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801336 ER PT J AU Skaff, M Abeles, R Pearlin, L AF Skaff, M Abeles, R Pearlin, L TI A life span perspective on sense of control: Antecedents, consequences, and mechanisms SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIH, OBSSR, OD, Bethesda, MD 20814 USA. Univ Maryland, Dept Sociol, College Pk, MD 20742 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 379 EP 379 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801404 ER PT J AU Crandall, J Andres, R AF Crandall, J Andres, R TI Causes and consequences of the metabolic syndrome of aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 Albert Einstein Coll Med, Bronx, NY 10461 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 395 EP 396 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801448 ER PT J AU Kritchevsky, S Pahor, M Ferrucci, L AF Kritchevsky, S Pahor, M Ferrucci, L TI The role of the renin-angiotensin system in the age-related functional decline: A multidisciplinary approach SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 397 EP 398 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801450 ER PT J AU Harris, T Rooks, R AF Harris, T Rooks, R TI Race and socioeconomic status: The health, aging and body composition study (Health ABC) SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, LEDB, IRP, Bethesda, MD 20892 USA. Kent State Univ, Dept Sociol, Kent, OH 44242 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 404 EP 405 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801462 ER PT J AU Carlson, M Frick, K Zeger, S Tielsch, J Saczynski, J McGill, S Fried, L Rebok, G Glass, T Hill, J Seeman, T AF Carlson, M Frick, K Zeger, S Tielsch, J Saczynski, J McGill, S Fried, L Rebok, G Glass, T Hill, J Seeman, T TI Experience corps: Results of a modified, randomized controlled trial of a senior service program on cognitive functions SO GERONTOLOGIST LA English DT Meeting Abstract C1 Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Natl Inst Aging Intramural Program, Bethesda, MD USA. Greater Homewood Community Corp, Baltimore, MD USA. Johns Hopkins Sch Med, Baltimore, MD USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 434 EP 435 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458801552 ER PT J AU Goodpaster, B Harris, T AF Goodpaster, B Harris, T TI The loss of muscle mass and alterations in muscle quality in older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 438 EP 439 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802006 ER PT J AU Curb, J Hadley, E Willcox, B AF Curb, J Hadley, E Willcox, B TI The genetics of exceptional survival: The pacific genetic epidemiologic study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Pacific Hlth Res Inst, Honolulu, HI 96813 USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 439 EP 440 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802007 ER PT J AU Niederehe, G Lebowitz, B AF Niederehe, G Lebowitz, B TI Update on NIMH programs in mental health and aging research SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, Aging Treatment & Prev Intervent Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 452 EP 453 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802037 ER PT J AU Telonidis, J Lund, D Caserta, M Guralnik, J Pennington, J AF Telonidis, J Lund, D Caserta, M Guralnik, J Pennington, J TI The effects of widowhood on moderately to severely disabled older women SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Utah, Salt Lake City, UT USA. NIA, NIH, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 571 EP 571 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802389 ER PT J AU Caplan, L Schooler, C AF Caplan, L Schooler, C TI The effects of retirement on anxiety and self-deprecation in men and women SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, SSES, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 612 EP 613 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802511 ER PT J AU Wild-Wesley, R Marottoli, R Foley, D AF Wild-Wesley, R Marottoli, R Foley, D TI Driving while demented: How well can we determine who's safe and help retire those who are unsafe? SO GERONTOLOGIST LA English DT Meeting Abstract C1 Hartford Hosp, Inst Living, Braceland Ctr Mental Hlth & Aging, Hartford, CT 06106 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. NIA, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2004 VL 44 SI 1 BP 633 EP 634 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 875YJ UT WOS:000225458802571 ER PT J AU Goedert, JJ Brown, DL Hoots, K Sherman, KE AF Goedert, JJ Brown, DL Hoots, K Sherman, KE TI Human immunodeficiency and hepatitis virus infections and their associated conditions and treatments among people with haemophilia SO HAEMOPHILIA LA English DT Article; Proceedings Paper CT 26th International Congress of the World-Federation-of-Hemophilia CY OCT 17-21, 2004 CL Bangkok, THAILAND SP World Federat Hemophilia DE haemophilia; HCV; HIV; virus treatment ID C VIRUS; NATURAL-HISTORY; VIRAL-HEPATITIS; UNITED-STATES; BLEEDING DISORDERS; LIVER-DISEASE; COHORT; HIV; AIDS; PREVALENCE AB Treatment with contaminated plasma products before 1990 resulted in extraordinary prevalence rates of human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV, HCV). In the Second Multicentre Haemophilia Cohort Study (MHCS-II) during 2001-03, 30% of HCV-seropositive survivors had HIV and 4.6% were HBV carriers. Highly active antiretroviral therapy (HAART) radically altered the consequences of HIV/HCV coinfection. Whereas opportunistic infections predominated previously, current major complications are liver failure and bleeding (exacerbated by decreased clotting factor synthesis, hypersplenic thrombocytopenia, and oesophageal varices). Most HIV-positives in MHCS-II were HIV RNA-negative and had > 200 CD4(+) cells muL(-1), but only 59% were on HAART. With HIV, especially after 41 years of age, liver disease was apparent (jaundice in 5%, ascites 7%, hepatomegaly 9%, splenomegaly 19%). HAART increases survival but may contribute to various comorbidities. Without HIV, sustained HCV clearance is obtained in > 50% with combined pegylated interferons plus ribavirin, but data in haemophilic populations, especially with HIV, are limited. In MHCS-II, HCV RNA negativity was 41% following standard interferon plus ribavirin; among interferon-naive participants (implying spontaneous HCV clearance), HCV RNA negativity was 12% with and 25% without HIV. Without HIV, spontaneous HCV clearance was much more likely with early age at infection and particularly with recent birth (late 1970s or early 1980s) but not with bleeding propensity or its treatment. Most (72%) participants had received no anti-HCV therapy. Hepatic and haematological conditions are likely to increase during the coming years unless most adult haemophiliacs are successfully treated for HIV, HCV or both. C1 NCI, Viral Epidemiol Branch, Rockville, MD USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Goedert, JJ (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Blvd,Room 8012, Rockville, MD USA. EM goedertj@mail.nih.gov FU NCI NIH HHS [N01-CP-01004, N01-CO-12400] NR 38 TC 26 Z9 27 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD OCT PY 2004 VL 10 SU 4 BP 205 EP 210 DI 10.1111/j.1365-2516.2004.00997.x PG 6 WC Hematology SC Hematology GA 885FV UT WOS:000226143400036 PM 15479399 ER PT J AU Simons-Morton, BG AF Simons-Morton, BG TI The protective effect of parental expectations against early adolescent smoking initiation SO HEALTH EDUCATION RESEARCH LA English DT Article ID CIGARETTE-SMOKING; SUBSTANCE USE; START SMOKING; PREDICTORS; SCHOOL; BEHAVIORS; CHILDREN; ALCOHOL; MODEL; RISK AB Substantial research and theory suggests that smoking initiation is socially mediated, with both peers and parents playing important roles. To learn more about how parenting behaviors influence smoking initiation, students (n = 1002) from four middle schools were surveyed at the beginning of the sixth grade (T1), and the end of the sixth (T2) and seventh (T3) grades. T1 and T2 - T1 predictors were regressed on smoking initiation at the end of seventh grade. In bivariate logistic regression analyses, association with friends who smoke, attitudes toward deviance, outcome expectations for smoking, perceived school climate, parental expectations, parental involvement at T1 and increases in these variables (T2 - T1) were associated with smoking initiation at T3, but only the T1 measures of social competence, academic engagement, school adjustment, perceived prevalence, parental monitoring and parental involvement were associated with smoking initiation at T3. In multivariate logistic regression analyses, parental expectations were negatively associated, and increases in attitudes accepting of deviance and affiliation with friends who smoke were positively associated with smoking initiation. Analysis of interactions indicated that parental expectations and monitoring did not mediate the effect on smoking initiation of attitudes toward deviance or the number of friends who smoke. These findings provide evidence that parental expectations may protect early adolescents against smoking even in the context of increases in favorable attitudes and friends who smoking. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, NIH, Rockville, MD 20852 USA. RP Simons-Morton, BG (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, NIH, Rockville, MD 20852 USA. EM MORTONB@exchange.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU NICHD NIH HHS [N01-HD-4-3207] NR 32 TC 59 Z9 61 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD OCT PY 2004 VL 19 IS 5 BP 561 EP 569 DI 10.1093/her/cyg071 PG 9 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 854YU UT WOS:000223940700008 PM 15150137 ER PT J AU Gornick, ME Eggers, PW Riley, GF AF Gornick, ME Eggers, PW Riley, GF TI Associations of race, education, and patterns of preventive service use with stage of cancer at time of diagnosis SO HEALTH SERVICES RESEARCH LA English DT Article DE health behaviors; race; socioeconomic status; disparities; preventive service use; stage of cancer ID HEALTH BEHAVIORS; RACIAL VARIATION; BREAST-CANCER; UNITED-STATES; WOMEN; CARE; MAMMOGRAPHY; VALIDATION; EXERCISE; WORKING AB Objective. To go beyond the documentation of disparities by race and SES by analyzing health behaviors regarding preventive and cancer screening services and determining if these behaviors are associated with stage of cancer when first diagnosed. Data. Stage of cancer for Medicare patients diagnosed in 1995 with breast, colorectal, uterine, ovarian, prostate, bladder, or stomach cancer; and use of influenza and pneumonia immunization, mammography, pap smear, colon cancer screening, and the prostate specific antigen test during the two years preceding diagnosis of cancer. Study Design. Hypothesis tested: health behaviors regarding use of preventive and cancer screening services are associated with stage of cancer when first diagnosed. Data Collection/Extraction Methods. Information was extracted from the database formed by the linkage of Surveillance, Epidemiology, and End Results (SEER) cancer registries with Medicare files. Principal Findings. Black and white patients (of higher and lower SES) who used more of the preventive and cancer screening services were at a lower risk of having late stage cancer for six cancers studied (breast, colorectal [male and female], prostate, uterine, and male bladder cancer) than their counterparts who used fewer of these services. Conclusions. The use of preventive and cancer screening services is a health behavior associated with better health outcomes for the elderly diagnosed with cancer. The lack of preventive service use can serve as a marker for identifying persons at risk of late stage cancer when first diagnosed. Strategies that encourage the use of preventive services by low users of these services are likely to reinforce a range of healthy behaviors that help to ameliorate disparities in health outcomes. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Ctr Medicare & Medicaid Serv, Off Res Dev & Informat, Baltimore, MD USA. RP Gornick, ME (reprint author), 3704 N Charles St, Baltimore, MD 21218 USA. NR 32 TC 56 Z9 56 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD OCT PY 2004 VL 39 IS 5 BP 1403 EP 1427 DI 10.1111/j.1475-6773.2004.00296.x PG 25 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 893TQ UT WOS:000226742600011 PM 15333115 ER PT J AU Purow, B Fine, HA AF Purow, B Fine, HA TI Antiangiogenic therapy for primary and metastatic brain tumors SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; MALIGNANT GLIOMA GROWTH; HIGH-GRADE GLIOMAS; VASCULAR-PERMEABILITY FACTOR; RECOMBINANT HUMAN ENDOSTATIN; COMBRETASTATIN A4 PHOSPHATE; ANTI-ANGIOGENIC THERAPY; IN-VIVO; SOLID TUMORS AB We first provide the theoretic foundation of antiangiogenic therapy by describing the biology of angiogenesis as it applies to brain tumors. We then outline experimental antiangiogenic therapies that are being applied preclinically to brain tumors, as well as published clinical trial data and ongoing clinical trials in patients. Primary and metastatic brain tumors are covered, although there is far less exploration in the literature of brain metastases. C1 NINDS, Neuro Oncol Branch, NCI, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NINDS, Neuro Oncol Branch, NCI, NIH, Room 235,Bloch Bldg,Bldg 82,9030 Old Georgetown R, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov NR 139 TC 14 Z9 15 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD OCT PY 2004 VL 18 IS 5 BP 1161 EP + DI 10.1016/j.hoc.2004.05.003 PG 22 WC Oncology; Hematology SC Oncology; Hematology GA 866ZA UT WOS:000224810700013 PM 15474340 ER PT J AU Katuri, V Tang, Y Cui, CL Jogunoori, W Deng, CX Sidawy, AN Mishra, B Reddy, EP Mishra, L AF Katuri, V Tang, Y Cui, CL Jogunoori, W Deng, CX Sidawy, AN Mishra, B Reddy, EP Mishra, L TI Critical role of ELF/TGF-beta signaling in hepatocellular cancer suppression SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. DVAMC, Washington, DC USA. NIDDK, NIH, Bethesda, MD USA. Temple Univ, Philadelphia, PA 19122 USA. RI deng, chuxia/N-6713-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 187A EP 187A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100058 ER PT J AU Calvisi, DF Gorden, A Thorgeirsson, SS AF Calvisi, DF Gorden, A Thorgeirsson, SS TI Nonrandom methylation of tumor suppressor gene promoters defines major molecular pathways in human hepatocarcinogenesis. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 188A EP 188A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100061 ER PT J AU Manigold, T Piccirillo, CA Shin, EC Mihalik, K Rice, CM Rehermann, B AF Manigold, T Piccirillo, CA Shin, EC Mihalik, K Rice, CM Rehermann, B TI CD4+CD25+T cells regulate hepatitis C virus-specific T cell memory SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIDDK, NIH, Bethesda, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Rockefeller Univ, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 198A EP 198A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100083 ER PT J AU Shneider, B Brown, M Sokol, R Whitington, P Schwarz, K Squires, R Bucuvalas, J Haber, B Shepherd, R Rosenthal, P Robuck, P AF Shneider, B Brown, M Sokol, R Whitington, P Schwarz, K Squires, R Bucuvalas, J Haber, B Shepherd, R Rosenthal, P Robuck, P TI A multi-center analysis of outcome at 24 months of age in children with biliary atresia in the United States. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Mt Sinai Sch Med, New York, NY USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Colorado, Denver, CO 80202 USA. Northwestern Univ, Chicago, IL 60611 USA. Johns Hopkins, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Cincinnati, Cincinnati, OH USA. Univ Penn, Philadelphia, PA 19104 USA. Washington Univ, St Louis, MO USA. UCSF, San Francisco, CA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 201A EP 201A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100091 ER PT J AU Berg, CL Abecassis, M Brown, RS Everhart, JE Gillespie, BW Hulbert-Shearon, TE Merion, RM AF Berg, CL Abecassis, M Brown, RS Everhart, JE Gillespie, BW Hulbert-Shearon, TE Merion, RM CA A2ALL Study Grp TI Living donor liver transplantation reduces the risk of death of transplant candidates SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ Virginia, Charlottesville, VA USA. Northwestern Univ, Chicago, IL 60611 USA. Columbia Univ, New York, NY USA. NIDDK, NIH, Bethesda, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. RI Abecassis, Michael/F-7977-2011 NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 209A EP 209A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100109 ER PT J AU Kagawa, T Mochizuki, K Numari, A Watanabe, N Mine, T Matsuzaki, S Arias, IM AF Kagawa, T Mochizuki, K Numari, A Watanabe, N Mine, T Matsuzaki, S Arias, IM TI Role of N-linked glycosylation in function and subcellular localization of bile acid export pump SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Tokai Univ, Isehara, Kanagawa, Japan. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 210A EP 210A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100112 ER PT J AU Saito, S Heller, T Williams, T Luo, GX Moreen, TR Cruz, B Jazwinski, A Jeurkar, N Auerbach, J Liang, TJ AF Saito, S Heller, T Williams, T Luo, GX Moreen, TR Cruz, B Jazwinski, A Jeurkar, N Auerbach, J Liang, TJ TI An in vitro model of hepatitis C virion production SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIDDK, NIH, Bethesda, MD USA. Univ Kentucky, Coll Med, Lexington, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 214A EP 214A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100121 ER PT J AU Adams, PC Zaccaro, D Reboussin, D Moses, G Eckfeldt, J Leiendecker-Foster, C McLaren, C McLaren, G Dawkins, F Gordeuk, V Acton, R Barton, J Harris, E Press, R Chang, H AF Adams, PC Zaccaro, D Reboussin, D Moses, G Eckfeldt, J Leiendecker-Foster, C McLaren, C McLaren, G Dawkins, F Gordeuk, V Acton, R Barton, J Harris, E Press, R Chang, H TI A comparison of the unsaturated iron binding capacity to transferrin saturation to detect C282Y homozygotes for hemochromatosis in 101,168 participants in the HEIRS study SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 London Hlth Sci Ctr, London, ON, Canada. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. MDS Labs, Toronto, ON, Canada. Univ Minnesota, Minneapolis, MN USA. Univ Calif Irvine, Irvine, CA USA. Howard Univ, Washington, DC 20059 USA. Univ Alabama, Birmingham, AL USA. So Iron Disorders Ctr, Birmingham, AL USA. Kaiser Permanente, Portland, OR USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 232A EP 233A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100160 ER PT J AU Lutchman, A Promrat, K Kleiner, DE Ghany, M Heller, T Bozorg, B Park, Y Freedman, R Yanovski, J Liang, TJ Hoofnagle, JH AF Lutchman, A Promrat, K Kleiner, DE Ghany, M Heller, T Bozorg, B Park, Y Freedman, R Yanovski, J Liang, TJ Hoofnagle, JH TI Changes in serum adiponectin, leptin and cytokine levels during pioglitazone therapy for nonalcoholic steatohepatitis (NASH)-relationship to histological improvement SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 235A EP 235A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100166 ER PT J AU Lee, JS Chu, IS Mikaelyan, A Calvisi, DF Heo, JH Reddy, JK Thorgeirsson, SS AF Lee, JS Chu, IS Mikaelyan, A Calvisi, DF Heo, JH Reddy, JK Thorgeirsson, SS TI Application of comparative functional genomics to identify best-fit mouse models to study human liver cancer. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NCI, Bethesda, MD 20892 USA. Northwestern Univ, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 257A EP 257A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100213 ER PT J AU Meunier, JC Bartosch, B Engle, RE Faulk, K Alter, HJ Emerson, SU Cosset, FL Purcell, RH Bukh, J AF Meunier, JC Bartosch, B Engle, RE Faulk, K Alter, HJ Emerson, SU Cosset, FL Purcell, RH Bukh, J TI Neutralizing antibodies against hepatitis C virus (HCV) genotype 1A cross-neutralize genotypes 1B, 2A, 4A and 5A, but not genotype 3A. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. Ecole Normale Super Lyon, F-69364 Lyon, France. NR 0 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 278A EP 278A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100262 ER PT J AU Lok, AS Everhart, JE Chung, RT Padmanabhan, L Shiffman, ML Everson, GT Lindsay, KL Bonkovsky, HL di Bisceglie, AM Lee, WM Ghany, MG Morishima, C AF Lok, AS Everhart, JE Chung, RT Padmanabhan, L Shiffman, ML Everson, GT Lindsay, KL Bonkovsky, HL di Bisceglie, AM Lee, WM Ghany, MG Morishima, C CA Halt-C Trial Investigators TI Prevalence of insulin resistance (IR) and impact on treatment in chronic hepatitis C (CHC). SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIDDK, NIH, Bethesda, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. New England Res Inst, Watertown, MA 02172 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Colorado, Denver, CO 80202 USA. Univ So Calif, Los Angeles, CA USA. Univ Connecticut, Farmington, CT USA. St Louis Univ, St Louis, MO 63103 USA. Univ Texas SW, Dallas, TX USA. Univ Calif Irvine, Irvine, CA USA. Univ Washington, Seattle, WA 98195 USA. RI Lok, Anna /B-8292-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 314A EP 315A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100352 ER PT J AU Shiffman, ML Morgan, TR Ghany, MG Wright, EC AF Shiffman, ML Morgan, TR Ghany, MG Wright, EC CA HALT-C Trial Grp TI The impact of peginterferon (PEGIFN) and ribavirin (RBV) dosing on sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) undergoing retreatment in the HALT-C trial. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Virginia Commonwealth Univ, Richmond, VA USA. Univ Calif Irvine, Irvine, CA USA. NIDDK, Bethesda, MD USA. New England Res Inst, Watertown, MA 02172 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 314A EP 314A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100351 ER PT J AU Bozorg, B Neumann, AU Heller, T Ghany, M Kleiner, DE Pawlotsky, JM Zeuzem, S Schalm, SW Lutchman, G Park, Y Rymer, C Liang, TJ Hoofnagle, JH AF Bozorg, B Neumann, AU Heller, T Ghany, M Kleiner, DE Pawlotsky, JM Zeuzem, S Schalm, SW Lutchman, G Park, Y Rymer, C Liang, TJ Hoofnagle, JH TI Early viral kinetics during treatment with low doses of peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C infected with genotypes 2 and 3 SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Hop Henri Mondor, F-94010 Creteil, France. Saarland Univ Hosp, Homburg, Germany. Eramus Med Ctr, Rotterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 340A EP 340A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100406 ER PT J AU Zhong, Z Conner, HD Sun, JJ Waldmeier, PC Mason, RP Lemasters, JJ AF Zhong, Z Conner, HD Sun, JJ Waldmeier, PC Mason, RP Lemasters, JJ TI NIM811, a non-immunosuppressive cyclosporin A analog, attenuates injury and stimulates regeneration of small-for-size liver grafts. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ N Carolina, Chapel Hill, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. Novartis Pharma Ltd, Basel, Switzerland. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 376A EP 377A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100493 ER PT J AU Lutchman, A Danehower, S Park, Y Ward, C Liang, TJ Hoofnagle, JH Thomson, MZ Ghany, MG AF Lutchman, A Danehower, S Park, Y Ward, C Liang, TJ Hoofnagle, JH Thomson, MZ Ghany, MG TI Mutation rate of hepatitis C virus in patients during ribavirin monotherapy. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. GlaxoSmithKline, Raleigh Durham, NC USA. GlaxoSmithKline, Stevenage, Herts, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 385A EP 385A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100514 ER PT J AU Conjeevaram, HS Kleiner, DE Everhart, JE Afdhal, N Brown, RS Fried, MW Howell, CD Jeffers, LJ Terrault, N Wiley, TE Cherry, CR Wahed, AS AF Conjeevaram, HS Kleiner, DE Everhart, JE Afdhal, N Brown, RS Fried, MW Howell, CD Jeffers, LJ Terrault, N Wiley, TE Cherry, CR Wahed, AS CA Virahep-C Grp TI Race, insulin resistance, visceral adiposity and hepatic steatosis in patients with chronic hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIH, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. New York Presbyterian Med Ctr, New York, NY USA. Univ N Carolina, Chapel Hill, NC USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Miami, Miami, FL 33152 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. Univ Pittsburgh, Pittsburgh, PA USA. RI Wahed, Abdus/A-6441-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 443A EP 443A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100645 ER PT J AU Barth, H Ulsenheimer, A Pape, GR Diepolder, HM Paranhos-Baccala, G Depla, E Liang, TJ Blum, HE Baumert, TF AF Barth, H Ulsenheimer, A Pape, GR Diepolder, HM Paranhos-Baccala, G Depla, E Liang, TJ Blum, HE Baumert, TF TI Uptake and presentation of hepatitis C virus-like particles by human dendritic cells - A novel model for the study of hepatitis C virus-dendritic cell interaction. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ Freiburg, Dept Med 2, Freiburg, Germany. Univ Munich, Klinikum Grosshadern, Dept Med 2, D-8000 Munich, Germany. CNRS BioMerieux CERVI IFR 128, UMR2142, Lyon, France. Innogenet NV, Ghent, Belgium. NIDDK, Liver Dis Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 454A EP 454A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100671 ER PT J AU Haber, BA Brown, M Shneider, B Sokol, R Whitington, P Derusso, P Squires, R Bezerra, J Shepherd, R Rosenthal, P Robuck, P AF Haber, BA Brown, M Shneider, B Sokol, R Whitington, P Derusso, P Squires, R Bezerra, J Shepherd, R Rosenthal, P Robuck, P TI Patient demographics and clinical practices in a us multi-center study of Biliary Atresia. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Childrens Hosp, Denver, CO 80218 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Johns Hopkins Sch Med, Baltimore, MD USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 472A EP 472A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100712 ER PT J AU Neumann, AU Mohan, P Lutchman, G Narkewicz, M Molleston, JP Lopez-Talavera, JC Liang, TJ Schwarz, KB AF Neumann, AU Mohan, P Lutchman, G Narkewicz, M Molleston, JP Lopez-Talavera, JC Liang, TJ Schwarz, KB TI Hepatitis C viral kinetics in children treated with pegIFN alfa-2a. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIDDK, NIH, Bethesda, MD USA. George Washington Univ Hosp, Washington, DC USA. Univ Colorado, Denver, CO 80202 USA. James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. Roche Labs, Nutley, NJ USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 473A EP 473A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100714 ER PT J AU Wakabayashi, Y Veilluex, M Arias, LM AF Wakabayashi, Y Veilluex, M Arias, LM TI The role of rab11a and myosin Vb in BSEP targeting to the canalicular membrane. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NICHD, NIH, Bethesda, MD USA. Tufts Univ, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 492A EP 493A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100758 ER PT J AU Kremer-Tal, S Narla, G Banck, M Difeo, AV Lee, JS Thorgeirsson, SS Martignetti, JA Friedman, SL AF Kremer-Tal, S Narla, G Banck, M Difeo, AV Lee, JS Thorgeirsson, SS Martignetti, JA Friedman, SL TI Significantly decreased expression of the tumor suppressor KLF6 in 85% of HCCS contributes to enhanced growth and reduced differentiation. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Mt Sinai Sch Med, New York, NY USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 520A EP 520A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100819 ER PT J AU Oe, S Conner, EA Uchida, K Factor, VM Thorgeirsson, SS AF Oe, S Conner, EA Uchida, K Factor, VM Thorgeirsson, SS TI Hepatocyte-specific disruption of TGF beta signaling protects against experimental liver fibrosis in mice. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 537A EP 537A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100863 ER PT J AU Jin, B Cheng, LF Shih, JW Alter, HJ AF Jin, B Cheng, LF Shih, JW Alter, HJ TI Delayed development and regression of experimental rabbit liver cirrhosis by portal administration of collagenase. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. Mil Med Grad Sch, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 544A EP 544A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100878 ER PT J AU Zhou, ZX Liu, J Wang, LP Jiang, YC Song, ZY McClain, CJ Kang, YJ AF Zhou, ZX Liu, J Wang, LP Jiang, YC Song, ZY McClain, CJ Kang, YJ TI Zinc supplementation corrects the imbalance between hepatocyte death and proliferation in mice chronically fed alcohol. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Univ Louisville, Louisville, KY 40292 USA. NIEHS, NCI, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 573A EP 573A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100948 ER PT J AU Thio, CL Mosbruger, T Astemborski, J Greer, S Vlahov, D O'Brien, S Thomas, D AF Thio, CL Mosbruger, T Astemborski, J Greer, S Vlahov, D O'Brien, S Thomas, D TI MBL2 genotypes are important determinants of HBV clearance or persistence. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Johns Hopkins, Baltimore, MD USA. New York Acad Med, New York, NY USA. NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 594A EP 595A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102100999 ER PT J AU Schroeder, IS Factor, VM Sanchez, A Thorgeirsson, SS AF Schroeder, IS Factor, VM Sanchez, A Thorgeirsson, SS TI Differentiation and engraftment potential of oval cell subpopulations from rat liver. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 619A EP 619A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102101059 ER PT J AU Heo, J Takahama, Y Factor, V Schroeder, I Thorgeirsson, SS AF Heo, J Takahama, Y Factor, V Schroeder, I Thorgeirsson, SS TI In vitro generation of mature hepatocytes from mouse embryonic stem cells. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 621A EP 621A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102101064 ER PT J AU Bourdi, M Holt, M Daniel, E Reilly, T Welch, K Pohl, L AF Bourdi, M Holt, M Daniel, E Reilly, T Welch, K Pohl, L TI High susceptibility of interleukin (IL)-10 and IL-4 double knockout mice to acetaminophen-induced liver injury: Role of IL-6. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 700A EP 700A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102101233 ER PT J AU Kulkarni, BR Brancati, FL Seeff, LB Clark, JM AF Kulkarni, BR Brancati, FL Seeff, LB Clark, JM TI A systematic review of the stability of serum alanine aminotransferase and aspartate aminotransferase in storage conditions. SO HEPATOLOGY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis C1 Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIDDK, NIH, Bethesda, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 SU 1 BP 715A EP 715A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857FR UT WOS:000224102101269 ER PT J AU Hong, F Radaeva, S Pan, HN Tian, ZG Veech, R Gao, B AF Hong, F Radaeva, S Pan, HN Tian, ZG Veech, R Gao, B TI Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease SO HEPATOLOGY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; ACTIVATED RECEPTOR-ALPHA; NECROSIS-FACTOR-ALPHA; PPAR-ALPHA; PRECONDITIONING PROTECTS; NONALCOHOLIC STEATOSIS; ALCOHOLIC HEPATITIS; BETA-OXIDATION; MOUSE-LIVER; RAT-LIVER AB Fatty liver, formerly associated predominantly with excessive alcohol intake, is now also recognized as a complication of obesity and an important precursor state to more severe forms of liver pathology including ischemia/reperfusion injury. No standard protocol for treating fatty liver exists at this time. We therefore examined the effects of 10 days of interleukin 6 (IL-6) injection in 3 murine models of fatty liver: leptin deficient ob/ob mice, ethanol-fed mice, and mice fed a high-fat diet. In all 3 models, IL-6 injection decreased steatosis and normalized serum aminotransferase. The beneficial effects of IL-6 treatment in vivo resulted in part from an increase in mitochondrial beta oxidation of fatty acid and an increase in hepatic export of triglyceride and cholesterol. However, administration of IL-6 to isolated cultured steatotic hepatocytes failed to decrease lipid contents, suggesting that the beneficial effects of IL-6 in vivo do not result from its effects on hepatocytes alone. IL-6 treatment increased hepatic peroxisome proliferator-activated receptor (PPAR) alpha and decreased liver and serum tumor necrosis factor (TNF) alpha. Finally, 10 days of treatment with IL-6 prevented the susceptibility of fatty livers to warm ischemia/reperfusion injury. In conclusion, long-term IL-6 administration ameliorates fatty livers and protects against warm ischemia/reperfusion fatty liver injury, suggesting the therapeutic potential of IL-6 in treating human fatty liver disease. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Univ Sci & Technol China, Sch Life Sci, Inst Immunol, Hefei, Anhui, Peoples R China. NIAAA, Metab & Mol Biol Lab, NIH, Bethesda, MD USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg,Rm 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Tian, Zhigang/J-3512-2013 NR 50 TC 116 Z9 118 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 BP 933 EP 941 DI 10.1002/hep.20400 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857AX UT WOS:000224088800021 PM 15382116 ER PT J AU Nakajima, T Kamijo, Y Tanaka, N Sugiyama, E Tanaka, E Kiyosawa, K Fukushima, Y Peters, JM Gonzalez, FJ Aoyama, T AF Nakajima, T Kamijo, Y Tanaka, N Sugiyama, E Tanaka, E Kiyosawa, K Fukushima, Y Peters, JM Gonzalez, FJ Aoyama, T TI Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage SO HEPATOLOGY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; PPAR-ALPHA; FUNCTIONAL-CHARACTERIZATION; CONSTITUTIVE EXPRESSION; SUPEROXIDE-DISMUTASE; CHRONIC HEPATITIS; LIPID-METABOLISM; ANIMAL-MODELS; GENE; MICE AB The mechanisms underlying alcoholic liver disease are not completely understood, but lipid accumulation seems to be central to the cause of this disease. The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the control of lipid homeostasis, metabolism of bioactive molecules, and modulation of inflammatory responses. To investigate the roles of PPARaalpha in alcoholic liver injury, wild-type and PPARalpha-null mice were continuously fed a diet containing 4% ethanol, and liver injury was analyzed. PPARalpha-null mice fed ethanol exhibited marked hepatomegaly, hepatic inflammation, cell toxicity, fibrosis, apoptosis, and mitochondrial swelling. Some of these hepatic abnormalities were consistent with those of patients with alcoholic liver injury and were not found in wild-type mice. Next, the molecular mechanisms of ethanol-induced liver injury in PPARalpha-null mice were investigated, and changes related to ethanol and acetaldehyde metabolism, oxidative stress, inflammation, hepatocyte proliferation, fibrosis, and mitochondrial permeability transition activation occurred specifically in PPARalpha-null mice as compared with wild-type mice. In conclusion, these studies suggest a protective role for PPARalpha in alcoholic liver disease. Humans may be more susceptible to liver toxicity induced by ethanol as PPARalpha expression in human liver is considerably lower compared to that of rodents. C1 Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. Shinshu Univ, Sch Med, Dept Hyg & Med Genet, Matsumoto, Nagano 3908621, Japan. Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Nagoya, Aichi, Japan. Shinshu Univ, Sch Med, Dept Internal Med, Matsumoto, Nagano 3908621, Japan. Nagano Prefectural Coll, Course Sci Living, Nagano, Japan. Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet Sci, University Pk, PA 16802 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. EM tanaka@showa-inan-hp.komagane.nagano.jp RI Peters, Jeffrey/D-8847-2011 NR 53 TC 126 Z9 133 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 BP 972 EP 980 DI 10.1002/hep.20399 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857AX UT WOS:000224088800025 PM 15382117 ER PT J AU Gujral, JS Liu, J Farhood, A Jaeschke, H AF Gujral, JS Liu, J Farhood, A Jaeschke, H TI Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation SO HEPATOLOGY LA English DT Article ID INDUCED LIVER-INJURY; HEPATIC ISCHEMIA-REPERFUSION; PARENCHYMAL-CELL APOPTOSIS; MURINE ENDOTOXIN-SHOCK; IN-VIVO; NEUTROPHIL ACTIVATION; URSODEOXYCHOLIC ACID; RAT HEPATOCYTES; OXIDANT STRESS; UP-REGULATION AB Neutrophils aggravate cholestatic liver injury after bile duct ligation (BDL). Recently, it was suggested that hepatocellular apoptosis might be critical for liver injury in this model. To test the hypothesis that apoptosis could be a signal for neutrophil extravasation and injury, we assessed parameters of apoptosis and inflammation after BDL using 2 different approaches: (1) wild-type and Fas receptor-deficient lpr mice of the C57BL/6J or C3H/HeJ strains, and (2) treatment with the pancaspase inhibitor z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk)in C3HeB/FeJ mice. After BDL for 3 days, total cell death was estimated to be between 10% and 50% of all cells evaluated. However, less than 0.1% of hepatocytes showed apoptotic morphology in all 3 strains. Processing of procaspase-3, caspase-3 enzyme activities, and immunohistochemical staining for cytokeratin 18 cleavage products indicated no activation of caspases. Real-time reverse-transcriptase polymerase chain reaction analysis revealed increased expression of many inflammatory mediators but no effect on proapoptotic genes. More than 50% of all accumulated neutrophils were extravasated and colocalized with foci of oncotic hepatocytes and chlorotyrosine adducts. z-VAD-fmk treatment had no effect on apoptosis or liver injury after BDL but eliminated apoptosis after galactosamine/endotoxin in C3HeB/FeJ mice. In Fas receptor-deficient lpr mice (C57BL/6J), expression of inflammatory mediators, neutrophil accumulation and extravasation, chlorotyrosine adduct formation, and liver injury were reduced. This protection was not observed in lpr mice of the endotoxin-resistant C3H/HeJ strain. In conclusion, liver injury (oncotic necrosis) after BDL correlated with the severity of the inflammatory response. The minimal amount of apoptosis had no effect on inflammation or on the overall injury. C1 Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. NIEHS, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, Houston, TX USA. RP Jaeschke, H (reprint author), Univ Arizona, Coll Med, Liver Res Inst, 1501 N Campbell Ave,Room 6309, Tucson, AZ 85724 USA. EM Jaeschke@email.arizona.edu FU NIAAA NIH HHS [AA12916] NR 50 TC 67 Z9 69 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2004 VL 40 IS 4 BP 998 EP 1007 DI 10.1002/hep.20380 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857AX UT WOS:000224088800028 PM 15382126 ER PT J AU Chan, CC Smith, JA Shen, DF Ursea, R LeHoang, P Grossniklaus, HE AF Chan, CC Smith, JA Shen, DF Ursea, R LeHoang, P Grossniklaus, HE TI Helicobacter pylori (H-pylori) molecular signature in conjunctival mucosa-associated lymphold tissue (MALT) lymphoma SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE mucosa-associated lymphoid tissue (MALT) lymphoma; Helicobacter pylori (H. pylori); conjunctiva; microdissection; PCR ID B-CELL LYMPHOMA; POLYMERASE-CHAIN-REACTION; GASTRIC LYMPHOMA; NATURAL TRANSFORMATION; T-CELLS; INFECTION; ERADICATION; CURE; DNA; SITES AB Conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal marginal zone B-cell lymphoma that is characterized by an exaggerated clonal expansion of B cells, which implicate a pathological proliferative response to antigen(s) including bacteria. Helicobacter pylori (H. pylori) infection is recognized as one of the causative agents of gastric MALT lymphoma; however, it has not been reported in extra gastric MALT lymphoma. We studied 5 patients (4 adults and 1 child) with salmon-colored conjunctival lesions. One patient also had a history of abnormal bone marrow biopsy a year earlier with lymphoid aggregates involving 5% of the overall bone marrow. The conjunctival lesions of the 5 patients were biopsied. Histopathological diagnoses were consistent with conjunctival MALT lymphoma. Lymphoma and normal conjunctival cells were microdissected using laser capture microscopy or manual techniques. DNA was extracted and subjected to PCR amplification using H. pylori gene-specific primers from the urease B and vac/m2 gene. Cells from chronic conjunctivitis (normal lymphocytes), conjunctival human T-cell lymphotropic virus type-1/adult T-cell leukemia/lymphoma (HTLV-1/ATL), and orbital B-cell lymphoma were also microdissected, processed and analyzed. PCR amplification and Southern blot hybridization demonstrated H. pylori DNA in the conjunctival MALT lymphoma cells of 4/5 cases. The negative case was the one with a history of abnormal bone marrow. In contrast, H. pylori gene was not detected in normal conjunctival cells from the cases of MALT lymphoma or the lymphocytes, ATL and orbital B-lymphoma cells from the controls. These data suggest that H. pylori may play a role in conjunctival MALT lymphoma. C1 NEI, NIH, Bethesda, MD 20892 USA. Hop La Pitie Salpetriere, Dept Ophthalmol, Paris, France. Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA. RP Chan, CC (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000222-22] NR 42 TC 27 Z9 28 U1 0 U2 0 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD OCT PY 2004 VL 19 IS 4 BP 1219 EP 1226 PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 864NF UT WOS:000224639500022 PM 15375765 ER PT J AU Gray, GM Cohen, JT Cunha, G Hughes, C McConnell, EE Rhomberg, L Sipes, IG Mattison, D AF Gray, GM Cohen, JT Cunha, G Hughes, C McConnell, EE Rhomberg, L Sipes, IG Mattison, D TI Weight of the evidence evaluation of low-dose reproductive and developmental effects of bisphenol A SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE bisphenol A; endocrine disruption; reproductive toxicity; developmental toxicity; weight of evidence ID ESTROGEN-RECEPTOR-ALPHA; DAILY SPERM PRODUCTION; EXPOSED IN-UTERO; FEMALE C3H MICE; PRENATAL EXPOSURE; PERINATAL-DEVELOPMENT; UTEROTROPHIC ACTIVITY; ENDOCRINE DISRUPTION; PATHOLOGICAL-CHANGES; ANOGENITAL DISTANCE AB A panel convened by the Harvard Center for Risk Analysis (HCRA) evaluated the weight of evidence for potential developmental and reproductive toxicity of bisphenol A (BPA, CASRN 80-05-7) in animals at doses well below the Lowest Observed Adverse Effect Level (LOAEL) of 50 mg/kg-day previously identified by the U.S. Environmental Protection Agency (US EPA) and even US EPA's reference dose (RfD) of 0.05 mg/kg-day. The effects are hypothesized to occur through an endocrine-modulating mode of action, specifically through estrogen receptors. The panel focused on potential male reproductive effects but also examined other endpoints possibly associated with hormone-like effects. The review considered studies published through April 2002. A formal deliberation framework focused on consistency, generalizability, and biological plausibility. The panel found no consistent affirmative evidence of low-dose BPA effects for any endpoint. Inconsistent responses across rodent species and strains made generalizability of low-dose BPA effects questionable. Lack of adverse effects in two multiple-generation reproductive and developmental studies casts doubt on suggestions of significant physiological or functional impairment. The panel was concerned about generalization of non-oral administration results to oral exposures. Differences in the pattern of BPA responses compared to estradiol or diethylstilbestrol (DES) cast doubt on estrogenicity as a low-dose mechanism of action for BPA. Finally, there is indirect evidence that humans may be less sensitive to possible estrogenic effects from BPA exposure due to pharmacodynamic factors. The panel recommended replication of existing studies under carefully controlled conditions and further study of BPA's pharmacokinetics and pharmacodynamics. The study was funded by a grant from the American Plastics Council. C1 Harvard Univ, Sch Publ Hlth, Harvard Ctr Risk Anal, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. ToxPath Inc, Raleigh, NC USA. Univ Arizona, Dept Pharmacol Toxicol, Tucson, AZ 85721 USA. NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. RP Gray, GM (reprint author), Harvard Univ, Sch Publ Hlth, Harvard Ctr Risk Anal, 718 Huntington Ave, Boston, MA 02115 USA. EM ggray@hsph.harvard.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Cohen, Joshua/0000-0003-1737-0991 NR 90 TC 60 Z9 62 U1 4 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1080-7039 J9 HUM ECOL RISK ASSESS JI Hum. Ecol. Risk Assess. PD OCT PY 2004 VL 10 IS 5 BP 875 EP 921 DI 10.1080/10807030490513883 PG 47 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 870EX UT WOS:000225041500010 ER PT J AU Sharma, S Sommers, JA Brosh, RM AF Sharma, S Sommers, JA Brosh, RM TI In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication SO HUMAN MOLECULAR GENETICS LA English DT Article ID OKAZAKI FRAGMENT MATURATION; DEPENDENT PROTEIN-KINASE; BLOOMS-SYNDROME PROTEIN; S-PHASE; FLAP ENDONUCLEASE-1; SACCHAROMYCES-CEREVISIAE; SYNDROME CELLS; SYNDROME GENE; GENOMIC INSTABILITY; POLYMERASE DELTA AB Werner syndrome is a genetic disorder characterized by genomic instability, elevated recombination and replication defects. The WRN gene encodes a RecQ helicase whose function(s) in cellular DNA metabolism is not well understood. To investigate the role of WRN in replication, we examined its ability to rescue cellular phenotypes of a yeast dna2 mutant defective in a helicase-endonuclease that participates with flap endonuclease 1 (FEN-1) in Okazaki fragment processing. Genetic complementation studies indicate that human WRN rescues dna2-1 mutant phenotypes of growth, cell cycle arrest and sensitivity to the replication inhibitor hydroxyurea or DNA damaging agent methylmethane sulfonate. A conserved non-catalytic C-terminal domain of WRN was sufficient for genetic rescue of dna2-1 mutant phenotypes. WRN and yeast FEN-1 were reciprocally co-immunoprecipitated from extracts of transformed dna2-1 cells. A physical interaction between yeast FEN-1 and WRN is demonstrated by yeast FEN-1 affinity pull-down experiments using transformed dna2-1 cells extracts and by ELISA assays with purified recombinant proteins. Biochemical analyses demonstrate that the C-terminal domain of WRN or BLM stimulates FEN-1 cleavage of its proposed physiological substrates during replication. Collectively, the results suggest that the WRN-FEN-1 interaction is biologically important in DNA metabolism and are consistent with a role of the conserved non-catalytic domain of a human RecQ helicase in DNA replication intermediate processing. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Hyderabad, Sch Life Sci, Dept Biochem, Hyderabad 500046, Andhra Pradesh, India. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM broshr@grc.nia.nih.gov OI Sharma, Sudha/0000-0003-2765-2482 FU NIGMS NIH HHS [GM24441] NR 64 TC 38 Z9 38 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 OCT 1 PY 2004 VL 13 IS 19 BP 2247 EP 2261 DI 10.1093/hmg/ddh234 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 854ZC UT WOS:000223941500008 PM 15282207 ER PT J AU Hamatani, T Falco, G Akutsu, H Stagg, CA Sharov, AA Dudekula, DB VanBuren, V Ko, MSH AF Hamatani, T Falco, G Akutsu, H Stagg, CA Sharov, AA Dudekula, DB VanBuren, V Ko, MSH TI Age-associated alteration of gene expression patterns in mouse oocytes SO HUMAN MOLECULAR GENETICS LA English DT Review ID DNA MISMATCH REPAIR; MITOCHONDRIAL DEOXYRIBONUCLEIC-ACID; EARLY EMBRYONIC-DEVELOPMENT; STEM-CELLS; OXIDATIVE STRESS; OOPLASMIC TRANSPLANTATION; TARGETED DISRUPTION; CALORIC RESTRICTION; ENERGY-METABOLISM; ZONAE-PELLUCIDAE AB Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, we compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using the NIA 22K 60-mer oligo microarray. Among approximately 11 000 genes whose transcripts were detected in oocytes, about 5% (530) showed statistically significant expression changes, excluding the possibility of global decline in transcript abundance. Consistent with the generally accepted view of aging, the differentially expressed genes included ones involved in mitochondrial function and oxidative stress. However, the expression of other genes involved in chromatin structure, DNA methylation, genome stability and RNA helicases was also altered, suggesting the existence of additional mechanisms for aging. Among the transcripts decreased with aging, we identified and characterized a group of new oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family. These results have implications for aging research as well as for clinical ooplasmic donation to rejuvenate aging oocytes. C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM kom@grc.nia.nih.gov RI Carter, Mark/B-5089-2010; Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Dudekula, Dawood/0000-0002-4054-1827 NR 101 TC 239 Z9 261 U1 1 U2 9 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 OCT 1 PY 2004 VL 13 IS 19 BP 2263 EP 2278 DI 10.1093/hmg/ddh241 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 854ZC UT WOS:000223941500009 PM 15317747 ER PT J AU Koivukoski, L Fisher, SA Kanninen, T Lewis, CM von Wowern, F Hunt, S Kardia, SLR Levy, D Perola, M Rankinen, T Rao, DC Rice, T Thiel, BA Melander, O AF Koivukoski, L Fisher, SA Kanninen, T Lewis, CM von Wowern, F Hunt, S Kardia, SLR Levy, D Perola, M Rankinen, T Rao, DC Rice, T Thiel, BA Melander, O TI Meta-analysis of genome-wide scans for hypertension and blood pressure in Caucasians shows evidence of susceptibility regions on chromosomes 2 and 3 SO HUMAN MOLECULAR GENETICS LA English DT Article ID LINKAGE ANALYSIS; BIPOLAR DISORDER; FAMILY; SCHIZOPHRENIA; LOCUS; GENE; AMERICANS; DISEASE AB Individual genome-wide scans of blood pressure (BP) and hypertension (HT) have shown inconsistent results. The aim of this study was to investigate whether there was any consistent evidence of linkage across multiple studies with similar ethnicity. We applied the genome-search meta-analysis method (GSMA) to nine published genome-wide scans of BP (n=5) and HT (n=4) from Caucasian populations. For each study, the genome was divided into 120 bins and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies and significance levels were estimated, on the basis of a distribution function of summed ranks or permutation tests without (P-U) or with (P-W) a study sample size weighting factor. Chromosome 3p14.1-q12.3 showed consistent evidence of linkage to HT (P-U=0.0001 and P-W=0.0001), diastolic BP (DBP) (P-U=0.007 and P-W=0.02), HT and DBP pooled (P-U=0.00002 and P-W=0.0001) and HT and systolic BP (SBP) pooled (P-U=0.0003 and P-W=0.0005). Chromosome 2p12-q22.1 showed evidence of linkage to HT (P-U=0.003 and P-W=0.009), DBP (P-U=0.05 and P-W=NS), HT and DBP pooled (P-U=0.001 and P-W=0.004) and HT and SBP pooled (P-U=0.001 and P-W=0.005). The summed ranks of the HT analysis correlated significantly with those of the DBP (r=0.20, P=0.03) but not with those of the SBP. Both loci showed clustering of significant bins in the analysis of HT and DBP. We conclude that modest or non-significant linkage on chromosomes 3p14.1-q12.3 and 2p12-q22.1 in each individual study translates into genome-wide significant or highly suggestive linkages to HT and DBP in our GSMA analysis. C1 Lund Univ, Dept Endocrinol, Malmo Univ Hosp, SE-20502 Malmo, Sweden. Univ London Kings Coll, Guys Kings & St Thomas Sch Med, Div Genet & Dev, London WC2R 2LS, England. Biocomp Platforms Ltd, Espoo, Finland. Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. MOLS, KTL, Dept Mol Med, Helsinki, Finland. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. Washington Univ, Div Biostat, St Louis, MO USA. Washington Univ, Dept Genet, St Louis, MO 63110 USA. Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Dept Math, St Louis, MO 63130 USA. Washington Univ, Sch Med, Div Biostat, St Louis, MO 63130 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. RP Melander, O (reprint author), Lund Univ, Dept Endocrinol, Malmo Univ Hosp, SE-20502 Malmo, Sweden. EM olle.melander@endo.mas.lu.se RI Lewis, Cathryn/A-5225-2010; Rice, Treva/D-1385-2009 OI Lewis, Cathryn/0000-0002-8249-8476; FU NHLBI NIH HHS [HL45508, HL47910] NR 27 TC 43 Z9 45 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2004 VL 13 IS 19 BP 2325 EP 2332 DI 10.1093/hmg/ddh237 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 854ZC UT WOS:000223941500014 PM 15294874 ER PT J AU Scherer, SW Green, ED AF Scherer, SW Green, ED TI Human chromosome 7 circa 2004: a model for structural and functional studies of the human genome SO HUMAN MOLECULAR GENETICS LA English DT Review ID CYSTIC-FIBROSIS GENE; HUMAN-CHROMOSOME 7; YEAST ARTIFICIAL CHROMOSOMES; COMMON FRAGILE SITE; QUANTITATIVE TRAIT LOCUS; WILLIAMS-SYNDROME; DNA MARKERS; HOMEOBOX GENE; PHYSICAL MAP; DEVELOPMENTAL DISORDER AB Human chromosome 7 is arguably amongst the most comprehensively characterized segments of the human genome. By microscopic examination, it belongs to the medium-sized group C submetacentric class, and historical studies involving chromosome-length measurements estimated that it accounts for similar to5.3% of the human genome (or 160 Mb). Early successes in molecular genetics led to the identification of some of its biomedically important genes, including the T-cell receptor and homeobox families as well as the erythropoietin and cystic fibrosis genes. The Human Genome Project brought chromosome 7-specific and genome-wide initiatives, generating a wealth of genomic resources that have revealed the presence of over 350 disease-associated genes. Two distinct assemblies of the chromosome 7 sequence have been generated-one based largely on mapped large-insert clones and the other based on an integrated whole-genome shotgun sequencing strategy. These two sequences are mainly identical (<1% difference), and both estimate the unit length of chromosome 7 to be just over 158 Mb, remarkably similar to the originally predicted size. Systematic annotation efforts have anchored to the sequence, amongst many features, over 900 known genes and some 1000 other gene structures, as well as over 650 chromosomal breakpoints identified in patients with characterized phenotypic differences. Chromosome 7 has also been shown to contain the highest content of intra-autosomal segmental duplications in the human genome. The orthologous regions of roughly 22 Mb of chromosome 7 are currently being sequenced in multiple other vertebrate species. Examining these comparative sequence data, in conjunction with the other accumulating genomic information about these regions and the rest of the chromosome, should provide a model for the next generation of structural and functional analyses of the human genome. C1 Hosp Sick Children, Dept Genet & Genom Biol, Program Genet & Genom Biol, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5G 1X8, Canada. NHGRI, NIH, Bethesda, MD 20892 USA. RP Scherer, SW (reprint author), Hosp Sick Children, Dept Genet & Genom Biol, Program Genet & Genom Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM steve@genet.sickkids.on.ca RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 NR 118 TC 8 Z9 9 U1 0 U2 3 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 OCT 1 PY 2004 VL 13 SI 2 BP R303 EP R313 DI 10.1093/hmg/ddh231 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 854ZK UT WOS:000223942400016 PM 15358738 ER PT J AU He, P Varticovski, L Bowman, ED Fukuoka, J Welsh, JA Miura, K Jen, J Gabrielson, E Brambilla, E Travis, WD Harris, CC AF He, P Varticovski, L Bowman, ED Fukuoka, J Welsh, JA Miura, K Jen, J Gabrielson, E Brambilla, E Travis, WD Harris, CC TI Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray SO HUMAN PATHOLOGY LA English DT Article DE atypical carcinoid; biomarkers; carboxypeptidase E; gamma-glutamyl hydrolase; gene pulmonary neuroendocrine tumors ID LASER CAPTURE MICRODISSECTION; GENE-EXPRESSION PROFILES; CELL LUNG-CANCER; FOLYLPOLYGLUTAMATE SYNTHETASE; DNA MICROARRAY; CARCINOMAS; PATTERNS; ADENOCARCINOMA; POLYGLUTAMYLATION; CLASSIFICATION AB Pulmonary neuroendocrine tumors vary dramatically in their malignant behavior. Their classification, based on histological examination, is often difficult. In search of molecular and prognostic markers for these tumors, we used cDNA microarray analysis of human transcripts against reference RNA from a well-characterized immortalized bronchial epithelial cell line, BEAS-2B. Tumor cells were isolated by laser-capture microdissection from primary tumors of 17 typical carcinoids, small cell lung cancers, and large cell neuroendocrine carcinomas. An unsupervised, hierarchical clustering algorithm resulted in a precise classification of each tumor subtype according to the proposed histological classification. Selection of genes, using supervised analysis, resulted in the identification of 198 statistically significant genes (P <.004) that also accurately discriminated between 3 predefined tumor subtypes. Two-by-two comparisons of these genes identified classifier genes that distinguished each tumor subtype from the others. Changes in expression of selected differentially expressed genes for each tumor subtype were internally validated by real-time reverse-transcription polymerase chain reaction. Expression of 2 potential classifier gene products, carboxypeptidase E (CPE) and gamma-glutamyl hydrolase (GGH), was validated by immunohistochemistry and cross-validated on additional archival samples of pulmonary neuroendocrine tumors. Kaplan-Meier survival analysis revealed that immunostaining for CPE was a statistically significant predictor of good prognosis, whereas GGH expression correlated with poor prognosis. Thus, cDNA microarray analysis led to the identification of 2 novel biomarkers that should facilitate molecular diagnosis and further study of pulmonary neuroendocrine tumors. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Human Carcinogenesis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol, Bethesda, MD 20014 USA. Tohoku Univ, Postgrad Med Sch, Dept Surg, Sendai, Miyagi 980, Japan. NCI, Lab Populat Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Lab Cellular Pathol, Grenoble, France. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Natl Inst Hlth, 37 Convent Dr,Bldg 37,Rm 3068, Bethesda, MD 20892 USA. RI Brambilla, Elisabeth/L-8796-2013; OI Miura, Koh/0000-0001-7303-9430 NR 34 TC 46 Z9 49 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD OCT PY 2004 VL 35 IS 10 BP 1196 EP 1209 DI 10.1016/j.humpath.2004.06.014 PG 14 WC Pathology SC Pathology GA 864AJ UT WOS:000224604700005 PM 15492986 ER PT J AU Basso, O Christensen, K Olsen, J AF Basso, O Christensen, K Olsen, J TI Fecundity and twinning. A study within the Danish National Birth Cohort SO HUMAN REPRODUCTION LA English DT Article DE fecundity; time to pregnancy; twinning ID SECULAR TRENDS; RATES; FERTILITY; DENMARK AB BACKGROUND. Decreased fecundity has been hypothesized as one of the causes of the widespread decline in twin rates in the 1960s and 1970s. The association between high fecundity and twinning is not, however, well documented. METHODS. In the Danish National Birth Cohort, we identified 56 295 births (including 729 twin deliveries) with data on pregnancy planning and time to pregnancy (TTP) and no report of infertility treatment. We estimated the odds ratio (OR) of twinning as a function of TTP and having planned a pregnancy. RESULTS. Increasing TTP correlated with decreased twinning rates. Compared with women who conceived within 2 months of trying, women who took longer than 1 year had an OR of 0.55 (95% confidence interval 0.39-0.77) of giving birth to twins. The association was slightly stronger for opposite sex twins. Women not planning a pregnancy had a lower rate of opposite sex twins than planners, but a comparable rate of same sex twins. We saw an excess of same sex pairs in women conceiving despite contraception. CONCLUSIONS. A long TTP is associated with a reduced risk of twinning. The marked decline observed in the 1960s and 1970s may derive from a widespread decrease in fecundity. C1 Aarhus Univ, Danish Epidemiol Sci Ctr, Dept Epidemiol & Social Med, DK-8000 Aarhus, Denmark. Univ So Denmark, Inst Publ Hlth, Odense, Denmark. Univ So Denmark, Danish Twin Registry, Odense, Denmark. RP Basso, O (reprint author), NIEMS, Epidemiol Branch, NIH, MD A3-05,POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM bassoo2@niehs.nih.gov RI Christensen, Kaare/C-2360-2009; Basso, Olga/E-5384-2010 OI Christensen, Kaare/0000-0002-5429-5292; Basso, Olga/0000-0001-9298-4921 NR 21 TC 16 Z9 16 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD OCT PY 2004 VL 19 IS 10 BP 2222 EP 2226 DI 10.1093/humrep/deh437 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 854ZV UT WOS:000223943500008 PM 15298973 ER PT J AU Fields, LE Burt, VL Cutler, JA Hughes, J Roccella, EJ Sorlie, P AF Fields, LE Burt, VL Cutler, JA Hughes, J Roccella, EJ Sorlie, P TI The burden of adult hypertension in the United States 1999 to 2000 - A rising tide SO HYPERTENSION LA English DT Article DE hypertension, detection and control; blood pressure ID HIGH BLOOD-PRESSURE; EDUCATION-PROGRAM; SODIUM; HEALTH; PREVALENCE; TRIAL; COMPLICATIONS; PREVENTION; JAPAN; COST AB This study aims to estimate the absolute number of persons with hypertension (the hypertension burden) and time trends using data from the National Health and Nutrition Examination Survey of United States resident adults who had hypertension in 1999 to 2000. This information is vitally important for health policy, medical care, and public health strategy and resource allocation. At least 65 million adults had hypertension in 1999 to 2000. The total hypertension prevalence rate was 31.3%. This value represents adults with elevated systolic or diastolic blood pressure, or using antihypertensive medications (rate of 28.4%; standard error [SE], 1.1), and adults who otherwise by medical history were told at least twice by a physician or other health professional that they had high blood pressure (rate of 2.9%; SE, 0.4). The number of adults with hypertension increased by approximate to30% for 1999 to 2000 compared with at least 50 million for 1988 to 1994. The 50 million value was based on a rate of 23.4% for adults with elevated blood pressure or using antihypertensive medications and 5.5% for adults classified as hypertensive by medical history alone (28.9% total; P < 0.001). The &AP;30% increase in the total number of adults with hypertension was almost 4-times greater than the 8.3% increase in total prevalence rate. These trends were associated with increased obesity and an aging and growing population. Approximately 35 million women and 30 million men had hypertension. At least 48 million non-Hispanic white adults, &AP;9 million non-Hispanic black adults, 3 million Mexican American, and 5 million other adults had hypertension in 1999 to 2000. C1 US Dept HHS, Off Secretarys Off Publ Hlth & Sci, Washington, DC 20201 USA. Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63110 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, US Dept HHS, Hyattsville, MD 20782 USA. NHLBI, NIH, US Dept HHS, Bethesda, MD 20892 USA. Orkand Corp, Falls Church, VA USA. RP Fields, LE (reprint author), US Dept HHS, Off Secretarys Off Publ Hlth & Sci, 200 Independence Ave, Washington, DC 20201 USA. EM lefields@osophs.dhhs.gov NR 32 TC 566 Z9 582 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2004 VL 44 IS 4 BP 398 EP 404 DI 10.1161/01.HYP.0000142248.54761.56 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856PB UT WOS:000224056000009 PM 15326093 ER PT J AU Zhao, XY Bradbury, JA Graves, J Miller, L Athirakul, K Coffman, T Zeldin, DC Imig, JD AF Zhao, XY Bradbury, JA Graves, J Miller, L Athirakul, K Coffman, T Zeldin, DC Imig, JD TI Estrogen replacement therapy decreases blood pressure and renal vascular reactivity to angiotensin II in CYP2J5 null female mice SO HYPERTENSION LA English DT Meeting Abstract CT 9th Annual Meeting of the European-Council-for-Cardiovascular-Research CY OCT 01-04, 2004 CL Nice, FRANCE SP European Council Cardiovasc Res C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Durham, NC USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Med Coll Georgia, Augusta, GA 30912 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 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2004 VL 44 IS 4 MA 72 BP 512 EP 512 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856PB UT WOS:000224056000097 ER PT J AU Randall, OS Kwagyan, J Greene, T Pogue, V Jamison, K Norris, K Xu, SC Wang, XL Agodoa, L AF Randall, OS Kwagyan, J Greene, T Pogue, V Jamison, K Norris, K Xu, SC Wang, XL Agodoa, L TI The impact of pulse pressure on target organ function in African-Americans with nondiabetic kidney disease SO HYPERTENSION LA English DT Meeting Abstract CT 9th Annual Meeting of the European Council for Cardiovascular Research CY OCT 01-03, 2004 CL Nice, FRANCE C1 Howard Univ, Washington, DC 20059 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Columbia Univ Coll Phys & Surg, Harlem Hosp Ctr, New York, NY 10032 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Martin Luther King Charles R Drew Univ Med, Los Angeles, CA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2004 VL 44 IS 4 MA P115 BP 537 EP 537 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856PB UT WOS:000224056000225 ER PT J AU Batkai, S Kunos, G Pacher, P AF Batkai, S Kunos, G Pacher, P TI The role of the vanilloid receptor in hypertension SO HYPERTENSION LA English DT Meeting Abstract CT 9th Annual Meeting of the European Council for Cardiovascular Research CY OCT 01-03, 2004 CL Nice, FRANCE C1 NIAAA, NIH, Bethesda, MD USA. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014 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 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2004 VL 44 IS 4 BP 562 EP 562 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856PB UT WOS:000224056000349 ER PT J AU Schroeder, C Birkenfeld, AL Goldstein, DS Haertter, S Luft, FC Jordan, J AF Schroeder, C Birkenfeld, AL Goldstein, DS Haertter, S Luft, FC Jordan, J TI Lack of influence of St. John's Wort on norepinephrine turnover and monoamine oxidase in humans SO HYPERTENSION LA English DT Meeting Abstract CT 9th Annual Meeting of the European Council for Cardiovascular Research CY OCT 01-03, 2004 CL Nice, FRANCE C1 Med Univ Charite, Franz Volhard Clin Res Ctr, Berlin, Germany. NIH, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. Univ Mainz, Dept Psychiat, Neurochem Lab, D-6500 Mainz, Germany. Helios Klinikum Berlin, Berlin, Germany. 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 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2004 VL 44 IS 4 BP 575 EP 575 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856PB UT WOS:000224056000417 ER PT J AU Vaska, P Woody, CL Schlyer, DJ Shokouhi, S Stoll, SP Pratte, JF O'Connor, P Junnarkar, SS Rescia, S Yu, B Purschke, M Kandasamy, A Villanueva, A Kriplani, A Radeka, V Volkow, N Lecomte, R Fontaine, R AF Vaska, P Woody, CL Schlyer, DJ Shokouhi, S Stoll, SP Pratte, JF O'Connor, P Junnarkar, SS Rescia, S Yu, B Purschke, M Kandasamy, A Villanueva, A Kriplani, A Radeka, V Volkow, N Lecomte, R Fontaine, R TI RatCAP: Miniaturized head-mounted PET for conscious rodent brain imaging SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article DE biomedical applications of nuclear radiation; biomedical nuclear imaging; gamma-ray detectors; motion compensation; nervous system; positron emission tomography (PET) ID PERFORMANCE EVALUATION; MICROPET; SCANNER; ANESTHESIA AB Anesthesia is currently required for positron emission tomography (PET) studies of the animal brain in order to eliminate motion artifacts. However, anesthesia profoundly affects the neurological state of the animal, complicating the interpretation of PET data. Furthermore, it precludes the use of PET to study the brain during normal behavior. The rat conscious animal PET tomograph (RatCAP) is designed to eliminate the need for anesthesia in rat brain studies. It is a miniaturized full-ring PET scanner that is attached directly to the head, imaging nearly the entire brain. RatCAP utilizes arrays of 2 mm x 2 mm LSO crystals coupled to matching avalanche photodiode arrays, which are in turn read out by full custom integrated circuits. Principal challenges have been addressed considering the physical constraints on size, weight, and heat generation in addition to the usual requirements of small-animal PET, such as high spatial resolution in the presence of parallax error. A partial prototype has been constructed and preliminary measurements and optimization completed. Realistic Monte Carlo simulations have also been carried out to optimize system performance, which is predicted to be competitive with existing microPET systems. C1 Brookhaven Natl Lab, Upton, NY 11973 USA. NIDA, Bethesda, MD 20892 USA. Univ Sherbrooke, Sherbrooke, PQ J1K 2R1, Canada. RP Vaska, P (reprint author), Brookhaven Natl Lab, Upton, NY 11973 USA. EM vaska@bnl.gov RI Rescia, Sergio/D-8604-2011; OI Rescia, Sergio/0000-0003-2411-8903; LECOMTE, Roger/0000-0002-8541-0783 NR 15 TC 65 Z9 65 U1 3 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD OCT PY 2004 VL 51 IS 5 BP 2718 EP 2722 DI 10.1109/TNS.2004.835740 PN 2 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 862LB UT WOS:000224491100032 ER PT J AU Muppidi, JR Tschopp, J Siegel, RM AF Muppidi, JR Tschopp, J Siegel, RM TI Life and death decisions: Secondary complexes and lipid rafts in TNF receptor family signal transduction SO IMMUNITY LA English DT Review ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; CELL-DEATH; MEDIATED APOPTOSIS; T-LYMPHOCYTES; INDUCTION; ACTIVATION; CD95; INHIBITION; RECRUITMENT AB Signaling by receptors in the TNF receptor (TNFR) superfamily mediate biological outcomes ranging from inflammation to apoptosis and other forms of programmed cell death. How receptor signaling mediates these divergent responses is just beginning to be understood. Here, we discuss how receptor submembrane localization and the formation of alternate signaling complexes can alter the fate of cells stimulated through TNFRs with a death domain, also known as "death receptors." C1 NIAMSD, Autoimmun Branch, Immunoregulat Unit, Bethesda, MD 20892 USA. Univ Lausanne, Inst Biochem, BIL Biomed Res Ctr, CH-1066 Epalinges, Switzerland. Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. RP Siegel, RM (reprint author), NIAMSD, Autoimmun Branch, Immunoregulat Unit, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 33 TC 229 Z9 235 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2004 VL 21 IS 4 BP 461 EP 465 DI 10.1016/j.immuni.2004.10.001 PG 5 WC Immunology SC Immunology GA 866AD UT WOS:000224744400003 PM 15485624 ER PT J AU Flornes, LM Bryceson, YT Spurkland, A Lorentzen, JC Dissen, E Fossum, S AF Flornes, LM Bryceson, YT Spurkland, A Lorentzen, JC Dissen, E Fossum, S TI Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex SO IMMUNOGENETICS LA English DT Article DE antigen presenting cells; lectin-like receptors ID BETA-GLUCAN RECEPTOR; DENDRITIC CELLS; MOLECULAR CHARACTERIZATION; INHIBITORY RECEPTORS; MONOCYTE/MACROPHAGE; IMMUNORECEPTOR; MACROPHAGES; RECOGNITION; EVOLUTION; DECTIN-1 AB In an experimental rat model, we recently mapped an arthritis susceptibility locus to the distal part of Chromosome 4 containing genes predicted to encode C-type lectin superfamily (CLSF) receptors. Here we report the cDNA cloning and positional arrangement of these receptor genes, which represent rat orthologues to human Mincle and DCIR and to mouse MCL and Dectin-2, as well as four novel receptors DCIR2, DCIR3, DCIR4 and DCAR1, not previously reported in other species. We furthermore report the cDNA cloning of human Dectin-2 and MCL, and of the mouse orthologues to the novel rat receptors. Similar to the killer-cell lectin-like receptors (KLR) some of these receptors exhibit structural features suggesting that they regulate leukocyte reactivity; e.g., human DCIR and rodent DCIR1 and DCIR2 carry an immunoreceptor tyrosine-based inhibitory motif (ITIM), predicting inhibitory function, and conversely, in all three species Mincle has a positively charged amino acid in the transmembrane region, suggesting activating function. Sequence comparisons show that the receptors form a discrete family, more closely related to group II CLSF receptors than to the group V KLR. Their distance to the KLR is underscored by their preservation of evolutionary conserved calcium/saccharide binding residues, present in group II and lacking in group V CLSF and their cellular expression patterns, with most of the genes preferentially expressed by professional antigen-presenting cells (dendritic cells, macrophages and B cells) and neutrophils. In all three species, the genes map together, forming an evolutionary conserved gene complex, which we call the antigen presenting lectin-like receptor complex (APLEC). C1 Univ Oslo, Dept Anat, N-0317 Oslo, Norway. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. RP Fossum, S (reprint author), Univ Oslo, Dept Anat, N-0317 Oslo, Norway. EM sigbjorn.fossum@basalmed.uio.no OI Spurkland, Anne/0000-0003-4421-0766; Bryceson, Yenan/0000-0002-7783-9934 NR 35 TC 59 Z9 66 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD OCT PY 2004 VL 56 IS 7 BP 506 EP 517 DI 10.1007/s00251-004-0714-x PG 12 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 864AK UT WOS:000224604800005 PM 15368084 ER PT J AU Aliberti, J Jankovic, D Sher, A AF Aliberti, J Jankovic, D Sher, A TI Turning it on and off: regulation of dendritic cell function in Toxoplasma gondii infection SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CD4(+) T-CELLS; IL-12 PRODUCTION; IFN-GAMMA; INTRACELLULAR PATHOGEN; MICROBIAL INFECTION; LIPOXIN A(4); CUTTING EDGE; PARASITE; RESISTANCE; IMMUNITY AB Because of its intrinsic virulence, Toxoplasma gondii induces a potent interleukin-12 (IL-12)-dependent cell-mediated immune response that shuts down the growth of the replicative tachyzoite stage, thus promoting host survival and successful transmission through predation. At the same time, this response must be tightly controlled to prevent lethality due to cytokine-mediated immunopathology. Evidence accumulated in recent years suggests that dendritic cells (DCs) play a major role in the initiation of IL-12-driven host resistance and that IL-12 synthesis by DCs is carefully regulated to avoid overproduction. In addition, this work has revealed a critical role for DCs in determining the highly polarized T-helper 1 (Th1)-type response triggered by the parasite. In this review, we summarize our current understanding of how DC function is initiated by Toxoplasma and how parasite-primed DCs drive Th1 effector choice. In addition, we discuss recent findings concerning the pathways responsible for endogenous regulation of DC IL-12 production during T. gondii infection. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Dept Immunol, Durham, NC USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, Bldg 50,Room 6140,MSC 8003, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 40 TC 33 Z9 36 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2004 VL 201 BP 26 EP 34 DI 10.1111/j.0105-2896.2004.00179.x PG 9 WC Immunology SC Immunology GA 853ID UT WOS:000223819600003 PM 15361230 ER PT J AU Semnani, RT Nutman, TB AF Semnani, RT Nutman, TB TI Toward an understanding of the interaction between filarial parasites and host antigen-presenting cells SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CD4(+) T-CELLS; MIGRATION INHIBITORY FACTOR; PAHANGI-INFECTED JIRDS; EPIDERMAL LANGERHANS CELLS; HUMAN LYMPHATIC FILARIASIS; NEMATODE-SECRETED PRODUCT; HUMAN DENDRITIC CELLS; BRUGIA-MALAYI; NITRIC-OXIDE; ACTIVATED MACROPHAGES AB Lymphatic filarial infection, from an immunologic point of view, is one of the most complex parasite infections. Not only are there different clinical manifestations that reflect differing immune responses, but the parasite's multiple stages, each with distinct anatomic tropism, add a compartmental layer of complexity to an already complicated process. Moreover, these parasites have finely tuned immune evasion strategies that enable escape from the innate immune system. As different stages of the parasite interact with different types of antigen-presenting cells that, in turn, may play a significant role in shaping the subsequent adaptive immune response, the focus of this review is to provide insight into the interaction between filarial parasites and antigen-presenting cells with an eye toward understanding how they influence parasite antigen-driven T-cell responses. C1 NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Semnani, RT (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-B1-05, Bethesda, MD 20892 USA. EM rsemnani@niaid.nih.gov NR 99 TC 31 Z9 31 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2004 VL 201 BP 127 EP 138 DI 10.1111/j.0105-2896.2004.00196.x PG 12 WC Immunology SC Immunology GA 853ID UT WOS:000223819600010 PM 15361237 ER PT J AU Wynn, TA Thompson, RW Cheever, AW Mentink-Kane, MM AF Wynn, TA Thompson, RW Cheever, AW Mentink-Kane, MM TI Immunopathogenesis of schistosomiasis SO IMMUNOLOGICAL REVIEWS LA English DT Review ID SEVERE HEPATIC-FIBROSIS; MOUSE BONE-MARROW; MANSONI INFECTION; MURINE SCHISTOSOMIASIS; GRANULOMA-FORMATION; TH2 RESPONSES; IFN-GAMMA; T-CELLS; IN-VIVO; IMMUNE-RESPONSES AB In schistosomiasis mansoni, the chronic egg-induced granulomatous response in the liver and intestines may eventually cause extensive tissue scarring and development of portal hypertension. Indeed, much of the morbidity and mortality associated with this disease is directly attributable to the deposition of connective tissue elements in affected tissues. Elucidating the mechanisms that regulate the severity of schistosomiasis has been a major research objective over the past several years. Research conducted with DNA microarrays as well as investigations with a variety of gene knock-out mice have been particularly helpful in achieving this goal. A notable accomplishment in the past few years was the identification of interleukin-13 (IL-13) and the IL-13 receptor complex as central regulators of disease progression in schistosomiasis. Liver fibrogenesis is severely decreased in infected IL-13-deficient mice as well as in wildtype animals treated with IL-13 antagonists. In contrast, IL-13 effector function increases dramatically in IL-13 receptor alpha2 (IL-13Ralpha2)-deficient mice. These mice develop severe hepatic fibrosis, fail to downregulate granuloma formation in the chronic phase of S. mansoni infection, and succumb to the disease at an accelerated rate; thus, identifying the 'decoy' IL-13 receptor as a critical life sustaining 'off' switch for tissue damaging egg-induced inflammation. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, NIH, 50 South Dr,Room 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 NR 123 TC 170 Z9 181 U1 2 U2 21 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2004 VL 201 BP 156 EP 167 DI 10.1111/j.0105-2896.2004.00176.x PG 12 WC Immunology SC Immunology GA 853ID UT WOS:000223819600012 PM 15361239 ER PT J AU Sacks, D Anderson, C AF Sacks, D Anderson, C TI Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CD4(+) T-CELLS; AZAR DERMAL LEISHMANIASIS; SUSCEPTIBLE BALB/C MICE; INHIBITS DISEASE PROGRESSION; CELLULAR IMMUNE-RESPONSE; RESISTANT C57BL/6 MICE; MAJOR INFECTION; CUTANEOUS LEISHMANIASIS; DENDRITIC CELLS; KALA-AZAR AB The interleukin (IL)-4 driven, polarized T-helper 2 cell (Th2) response that controls non-healing infection with Leishmania major in BALB/c mice has long been embraced as the underlying principle with which to consider the pathogenesis of non-healing and systemic forms of leishmaniasis in humans. The inability, however, to reveal a Th2 polarity associated with non-curing clinical disease has suggested that alternative cells and cytokines are involved in susceptibility. In this review, various mouse models of non-curing infection with L. major and other Leishmania species are re-examined in the context of the suppression mediated by IL-10 and regulatory T (Treg) cells. These activities are revealed in L. major-infected BALB/c IL-4 knockout (KO) and IL-4Ralpha KO mice and especially in non-cure resistant mice that do not default to a Th2 pathway as a result of inherent defects in Th1 differentiation. In contrast to the extreme BALB/c susceptibility arising from an aberrant Th2 response, non-cure in resistant mice arises from an imbalance in Treg cells that are activated in the context of an ongoing Th1 response and whose primary function may be to suppress the immunopathology associated with persistent antiparasite responses in infected tissues. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov NR 126 TC 85 Z9 89 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2004 VL 201 BP 225 EP 238 DI 10.1111/j.0105-2896.2004.00185.x PG 14 WC Immunology SC Immunology GA 853ID UT WOS:000223819600017 PM 15361244 ER PT J AU Pomerantsev, AP Pomerantseva, OM Leppla, SH AF Pomerantsev, AP Pomerantseva, OM Leppla, SH TI A spontaneous translational fusion of Bacillus cereus PlcR and PapR activates transcription of PlcR-dependent genes in Bacillus anthracis via binding with a specific palindromic sequence SO INFECTION AND IMMUNITY LA English DT Article ID GENOME SEQUENCE; PHOSPHOLIPASE-C; THURINGIENSIS; VIRULENCE; BACTERIA; PHOSPHATASES; EXPRESSION; PROTEIN; CIRCUIT; REGULON AB Transformation of Bacillus anthracis with plasmid pUTE29-plcR-papR carrying the native Bacillus cereus plcR-papR gene cluster did not activate expression of B. anthracis hemolysin genes, even though these are expected to be responsive to activation by the global regulator PlcR. To further characterize the action of PlcR, we examined approximately 3,000 B. anthracis transformants containing pUTE29-plcR-papR and found a single hemolytic colony. The hemolytic strain contained a plasmid having a spontaneous plcR-papR intergenic region deletion. Transformation of the resulting plasmid pFP12, encoding a fused PlcR-PapR protein, into the nonhemolytic B. anthracis parental strain produced strong activation of B. anthracis hemolysins, including phosphatidylcholine-specific phospholipase C and sphingomyelinase. The fused PlcR-PapR protein present in a lysate of B. anthracis containing pFP12 bound strongly and specifically to the double-stranded palindrome 5'-TATGCATTATTTCATA-3' that matches the consensus PlcR-binding site. In contrast, native PlcR protein in a lysate from a B. anthracis strain expressing large amounts of this protein did not demonstrate binding with the palindrome. The results suggest that the activation of PlcR by binding of a PapR pentapeptide as normally occurs in Bacillus thuringiensis and B. cereus can be mimicked by tethering the peptide to PlcR in a translational fusion, thereby obviating the need for PapR secretion, extracellular processing, retrieval into the bacterium, and binding with PlcR. C1 NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. USN, Res Ctr, Biol Def Res Directorate, Rockville, MD USA. RP Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov NR 20 TC 14 Z9 15 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 OCT PY 2004 VL 72 IS 10 BP 5814 EP 5823 DI 10.1128/IAI.72.10.5814-5823.2004 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 857QS UT WOS:000224134000033 PM 15385482 ER EF