FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Zlotnik, J Morrow-Howell, N Burnette, D Takamura, J Niederehe, G Manske, J AF Zlotnik, J Morrow-Howell, N Burnette, D Takamura, J Niederehe, G Manske, J TI Building and sustaining practice, policy, research relationships: Emerging strategies for gerontological social work SO GERONTOLOGIST LA English DT Meeting Abstract C1 Inst Advanecement SW Res, Washington, DC 20002 USA. George Warren Sch Social Work, St Louis, MO USA. Columbia Univ, Sch Social Work, New York, NY USA. NIMH, Bethesda, MD USA. Dept Vet Affairs, 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 2002 VL 42 SI 1 BP 124 EP 124 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400429 ER PT J AU Yie, S Merritt, M Sollers, J Nie, Z Zonderman, A Evans, M Abernethy, D Thayer, J AF Yie, S Merritt, M Sollers, J Nie, Z Zonderman, A Evans, M Abernethy, D Thayer, J TI Effect of angiotensin converting enzyme I/D polymorphisms on heart rate variability in a community based African-American sample SO GERONTOLOGIST LA Rumanian DT Meeting Abstract C1 Johns Hopkins Geriatr Ctr, Baltimore, MD USA. NIA, Baltimore, MD USA. 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 2002 VL 42 SI 1 BP 132 EP 132 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400456 ER PT J AU Talbot, L Gaines, J Ling, S Metter, E AF Talbot, L Gaines, J Ling, S Metter, E TI Electromyostimulation improves quadriceps muscle strength in older adults with knee osteoarthritis SO GERONTOLOGIST LA English DT Meeting Abstract C1 Erickson Fdn, Catonsville, MD USA. GRC, NIA, Baltimore, MD 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 2002 VL 42 SI 1 BP 153 EP 153 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400539 ER PT J AU Clark, P Stahl, S Greene, G Riebe, D Greaney, M Nigg, C Rossi, J Lees, F Burbank, P Garber, C Fey-Yensan, N Padula, C Ruggiero, L Edwards, G Saunders, S AF Clark, P Stahl, S Greene, G Riebe, D Greaney, M Nigg, C Rossi, J Lees, F Burbank, P Garber, C Fey-Yensan, N Padula, C Ruggiero, L Edwards, G Saunders, S TI The senior project: Stage-based intervention on diet and exercise in a large community sample SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Rhode Isl, Prog Gerontol & RI Geriatr Educ Ctr, Kingston, RI 02881 USA. NIA, Bethesda, MD 20892 USA. Univ Hawaii, Honolulu, HI USA. Northeastern Univ, Boston, MA 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 2002 VL 42 SI 1 BP 157 EP 157 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400554 ER PT J AU Bean, J Leveille, S Kiely, D Ferrurcci, L AF Bean, J Leveille, S Kiely, D Ferrurcci, L TI Power, strength and performance-based function in mobility limited elders: The InCHIANTI study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD USA. RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 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 2002 VL 42 SI 1 BP 172 EP 173 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400612 ER PT J AU Penninx, B Kritchevsky, S Yaffe, K Simonsick, E Ferrucci, L Harris, T Pahor, M AF Penninx, B Kritchevsky, S Yaffe, K Simonsick, E Ferrucci, L Harris, T Pahor, M TI Depressed mood and inflammation: Data from the health ABC study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Univ Tennessee, Memphis, TN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. INRCA, Inst Res, Florence, 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 2002 VL 42 SI 1 BP 211 EP 212 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400748 ER PT J AU Niederehe, G AF Niederehe, G TI NIMH update: Opportunities in mental health and aging research SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, Adult & Geriatr 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 2002 VL 42 SI 1 BP 227 EP 227 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541400803 ER PT J AU Jylha, M Volpato, S Guralnik, J AF Jylha, M Volpato, S Guralnik, J TI Self-rated health is associated with biomarkers, but predicts mortality independently of them SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Tampere, Sch Publ Hlth, FIN-33101 Tampere, Finland. Natl Inst Aging, Bethesda, MD USA. 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 2002 VL 42 SI 1 BP 284 EP 284 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401012 ER PT J AU Lunney, J Lynn, J Guralnik, J AF Lunney, J Lynn, J Guralnik, J TI Trajectories of functional decline in the year before death SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, LEDB, NIH, Bethesda, MD 20892 USA. Ctr Improve Care Dying, Arlington, VA 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 2002 VL 42 SI 1 BP 284 EP 285 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401014 ER PT J AU Fiske, A Baker, T Gatz, M Barr, R McCarter, R Fiske, A AF Fiske, A Baker, T Gatz, M Barr, R McCarter, R Fiske, A TI Post-docs: Choosing a career path in a changing world SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. Univ Michigan, Ann Arbor, MI USA. Off Extramural Natl Inst Aging, Bethesda, MD USA. Univ Texas San Antonio, San Antonio, TX USA. EM fiske@rcf.usc.edu 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 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2002 VL 42 SI 1 BP 295 EP 295 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401053 ER PT J AU Dominick, K Bosworth, H Jeffreys, A Grambrow, S Oddone, E Horner, R AF Dominick, K Bosworth, H Jeffreys, A Grambrow, S Oddone, E Horner, R TI Racial/ethnic variations in NSAID use among patients with osteoathritis SO GERONTOLOGIST LA English DT Meeting Abstract C1 VAMC, Durham, NC USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 2002 VL 42 SI 1 BP 301 EP 301 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401074 ER PT J AU McCarter, R Lakoski, J Fernandes, G McGowan, J AF McCarter, R Lakoski, J Fernandes, G McGowan, J TI The diversity of aging in tissues from rodents to humans SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX 78284 USA. Penn State Univ, Coll Med, Hershey, PA USA. NIAMS, NIH, 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 2002 VL 42 SI 1 BP 313 EP 313 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401122 ER PT J AU Roubenoff, R Sacheck, J Janssen, I Harris, T AF Roubenoff, R Sacheck, J Janssen, I Harris, T TI Sarcopenia in the 21st century SO GERONTOLOGIST LA English DT Meeting Abstract C1 Tufts Univ, USDA, Jean Mayer HNRCA, Boston, MA 02111 USA. Harvard Univ, Sch Med, Boston, MA USA. Tufts Univ, HNRCA, Boston, MA USA. NIH, Natl Inst Aging, 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 2002 VL 42 SI 1 BP 317 EP 317 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401126 ER PT J AU Bowman, K Deimling, G Blank, T Bellizzi, K Pinquart, M Nixdorf, J Silbereisen, K Given, C Rahbar, M Jeon, S Given, B O'Toole, E Rose, J Dawson, N Thomas, C Kahana, B Kahana, E Yancik, R AF Bowman, K Deimling, G Blank, T Bellizzi, K Pinquart, M Nixdorf, J Silbereisen, K Given, C Rahbar, M Jeon, S Given, B O'Toole, E Rose, J Dawson, N Thomas, C Kahana, B Kahana, E Yancik, R TI Research on cancer and aging informal interest groups symposium: The dual challenges of cancer and aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 Case Western Reserve Univ, Dept Sociol, Cleveland, OH 44106 USA. Dept Family Studies, Storrs, CT USA. Dept Dev Psychol, Jena, Germany. Dept Family Practice, E Lansing, MI USA. Sch Med, Cleveland, OH USA. Dept Psychol, Cleveland, OH USA. Dept Sociol, Cleveland, OH USA. Natl Inst Hlth, NIA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 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 2002 VL 42 SI 1 BP 327 EP 327 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401158 ER PT J AU Simonsick, E Kritchevsky, S Bennett, J Stewart, A Danielson, M Newman, A Rubin, S Rosano, C Harris, T Brach, J Rubin, S Visser, M Yaffe, A Penninx, B Tracy, R Pahor, M Goodpaster, B Nevitt, M AF Simonsick, E Kritchevsky, S Bennett, J Stewart, A Danielson, M Newman, A Rubin, S Rosano, C Harris, T Brach, J Rubin, S Visser, M Yaffe, A Penninx, B Tracy, R Pahor, M Goodpaster, B Nevitt, M TI Hidden risks in self-described well-functioning 70 year-olds: Insights from health SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, GRC, Intramural Res Program, Baltimore, MD 21224 USA. Univ Tennessee, Memphis, TN 38105 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. NIA, IRP, 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 2002 VL 42 SI 1 BP 332 EP 333 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401163 ER PT J AU Lichtenstein, A Rasmussen, H Russell, R Simonsick, E Newman, A Visser, M Goodpaster, B Kritchevsky, S Rubin, S Nevitt, M Harris, T AF Lichtenstein, A Rasmussen, H Russell, R Simonsick, E Newman, A Visser, M Goodpaster, B Kritchevsky, S Rubin, S Nevitt, M Harris, T TI Modified food pyramid for older adults: Guidance to meet their unique nutrient requirements SO GERONTOLOGIST LA English DT Meeting Abstract C1 Tufts Univ, USDA, HNRCA, Boston, MA 02111 USA. NIA, IRP, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. 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 2002 VL 42 SI 1 BP 333 EP 333 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401165 ER PT J AU Zimmerman, S Sloane, P Gruber-Baldini, A Watson, L Boustani, M Magaziner, J Hebel, J Roth, M Mitchell, C Reed, P Morgan, L Eckert, J Stahl, S AF Zimmerman, S Sloane, P Gruber-Baldini, A Watson, L Boustani, M Magaziner, J Hebel, J Roth, M Mitchell, C Reed, P Morgan, L Eckert, J Stahl, S TI Promising directions in assisted living research SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ N Carolina, Cecil G Sheps Ctr Heal, Chapel Hill, NC 27599 USA. Univ Maryland, Sch Med, Baltimore, MD 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 2002 VL 42 SI 1 BP 342 EP 342 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401195 ER PT J AU Barron, J Simonsick, E Fleg, J Metter, E AF Barron, J Simonsick, E Fleg, J Metter, E TI Fitness and strength among older American workers SO GERONTOLOGIST LA English DT Meeting Abstract C1 Johns Hopkins Univ, Div Geriatr, Baltimore, MD USA. Natl Heart Lung Blood Inst, Bethesda, MD 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 2002 VL 42 SI 1 BP 353 EP 353 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401240 ER PT J AU Chang, M Corti, C Fried, L Gularnik, J AF Chang, M Corti, C Fried, L Gularnik, J TI Resting heart rate and mortality in older women: Evidence from the women's health and aging study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. Univ Padua, Inst Internal Med, Padua, Italy. JH Sch Med, Baltimore, MD 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 2002 VL 42 SI 1 BP 354 EP 354 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401243 ER PT J AU Boyd, C Xue, Q Guralnik, J Fried, L AF Boyd, C Xue, Q Guralnik, J Fried, L TI Predictors of functional decline among hospitalized, community-dwelling older, disabled women SO GERONTOLOGIST LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD 21218 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 2002 VL 42 SI 1 BP 367 EP 367 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401296 ER PT J AU Rabinovitch, P Warner, H Maguire-Zeiss, K Short, D Luo, A Federoff, H Csete, M Faulkner, J Richardson, A Walter, C Manguino, D Zhou, Z McMahan, C Herbert, D Reddick, R Ikeno, Y Nelson, J Rabinovitch, P Schriner, S Wallace, D Marin, G AF Rabinovitch, P Warner, H Maguire-Zeiss, K Short, D Luo, A Federoff, H Csete, M Faulkner, J Richardson, A Walter, C Manguino, D Zhou, Z McMahan, C Herbert, D Reddick, R Ikeno, Y Nelson, J Rabinovitch, P Schriner, S Wallace, D Marin, G TI Nathan shock center symposium on transgenic/knockout mice and aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Washington, Dept Pathol, Nathan Shock Ctr Excellence Basic Biol Aging, Seattle, WA 98195 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. Univ Rochester, Rochester, NY 14627 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. EM petersr@u.washington.edu 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 2002 VL 42 SI 1 BP 367 EP 368 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401298 ER PT J AU Rossi, W Mayeux, R Lee, J Flaquer, A Estrada-Nadal, L Munger, R Cawthon, R Corcoran, C Smith, K Kerber, R Pahor, M Nicklas, B Mychaleckyj, J Ambrosius, W Kritchevsky, S Newman, A Bleecker, E Messier, S Harris, T Terry, D McCormick, M Lawler, E Perls, T Hadley, E AF Rossi, W Mayeux, R Lee, J Flaquer, A Estrada-Nadal, L Munger, R Cawthon, R Corcoran, C Smith, K Kerber, R Pahor, M Nicklas, B Mychaleckyj, J Ambrosius, W Kritchevsky, S Newman, A Bleecker, E Messier, S Harris, T Terry, D McCormick, M Lawler, E Perls, T Hadley, E TI Genetic epidemiology of aging and survival outcomes SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, NIH, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. Utah State Univ, Logan, UT USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Boston Univ, Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA USA. RI Corcoran, Chris/F-2155-2010; Kerber, Richard/B-8038-2009; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 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 2002 VL 42 SI 1 BP 405 EP 405 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 620PH UT WOS:000179541401430 ER PT J AU Liu, Y Wu, YY Lee, JC Xue, HP Pevny, LH Kaprielian, Z Rao, MS AF Liu, Y Wu, YY Lee, JC Xue, HP Pevny, LH Kaprielian, Z Rao, MS TI Oligodendrocyte and astrocyte development in rodents: An in situ and immunohistological analysis during embryonic development SO GLIA LA English DT Article DE NEP; E-NCAM; self-renewal; neuroblast; glioblast; development; astrocyte; oligodendrocyte ID CENTRAL-NERVOUS-SYSTEM; FIBRILLARY ACIDIC PROTEIN; PDGF ALPHA-RECEPTOR; RADIAL GLIAL-CELLS; NEUROEPITHELIAL STEM-CELLS; O2A PROGENITOR CELLS; SPINAL-CORD; PRECURSOR CELLS; RESTRICTED PRECURSORS; REMYELINATING CELLS AB Lineally related multipotent neuroepithelial cells (NEP), neuronal restricted precursors (NRP), and glial restricted precursors (GRP) have been identified in the spinal cord. To determine the sequence of differentiation and identify lineage and stage-specific markers, we have examined the spatiotemporal expression of established glial markers during rodent embryonic development and within fetal cell culture. In this report, we show that proliferating stem cells in the developing neural tube do not express any glial markers at E10.5. By E11, however, glial precursors have begun to differentiate and at least two regions of the ventral neural tube containing glial precursor cells can be distinguished, an Nkx2.2/Neurogenin 3 (Ngn3) domain and a platelet-derived growth factor receptor alpha (PDGFRalpha)/Olig2/Sox10 domain. Radial glia, as identified by RC1 immunoreactivity, develop in concert with other glial precursors and can be distinguished by their morphology, spatial distribution, and antigen expression. Astrocytes as assessed by glial fibrillary acidic protein (GFAP) immunoreactivity are first detected at E16. A novel dorsal domain of CD44 immunoreactivity that can be distinguished from the more ventral glial precursor domains can be detected as early as E13.5. Published 2002 Wiley-Liss, Inc.(dagger). C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. Univ N Carolina, Ctr Neurosci, Chapel Hill, NC USA. Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. RP Rao, MS (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 73 TC 123 Z9 127 U1 1 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2002 VL 40 IS 1 BP 25 EP 43 DI 10.1002/glia.10111 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 599ZC UT WOS:000178364300003 PM 12237841 ER PT J AU Yu, C Hang, HC Winans, KA Ten Hagen, KG Tabak, LA Bertozzi, CR AF Yu, C Hang, HC Winans, KA Ten Hagen, KG Tabak, LA Bertozzi, CR TI Identification of polypeptidyl-N-acetyl-galactosaminyltransferase (ppGalNAcT) inhibitors from a uridine-based library SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. NIDDK, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. 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 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 67 BP 664 EP 664 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200072 ER PT J AU Saksena, R Chernyak, A Karavanov, A Kovac, P AF Saksena, R Chernyak, A Karavanov, A Kovac, P TI Development of a conjugate vaccine for cholera from synthetic carbohydrate antigens: Chemistry, monitoring of the conjugation, and recovery of the excess hapten SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Ciphergen Biosyst Inc, Fremont, CA 94555 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 83 BP 670 EP 671 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200088 ER PT J AU Sheeley, DM AF Sheeley, DM TI MS/MS of glycoconjugates using Qq-TOF and TOF/TOF instruments SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. 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 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 101 BP 676 EP 677 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200106 ER PT J AU Ramakrishnan, B Qasba, PK AF Ramakrishnan, B Qasba, PK TI Mutation of Arg228 residue to lysine enhances the glucosyltransferase activity of beta 1,4-galactosyltransferase-I SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 NCI, Struct Glycobiol Sect, LECB, CCR, Frederick, MD 21701 USA. SAIC Frederick Inc, IRSP, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 147 BP 691 EP 691 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200152 ER PT J AU Boeggeman, EE Ramakrishnan, R Qasba, PK AF Boeggeman, EE Ramakrishnan, R Qasba, PK TI Effect of the extended N-terminal stem region on the stability and folding of bovine and human beta 1,4-galactosyltransferase SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 NCI, Struct Glycobiol Sect, LECB, CCR, Frederick, MD 21702 USA. NCI, IRSP, SAIC Frederick Inc, Frederick, MD 21702 USA. 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 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 152 BP 692 EP 692 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200157 ER PT J AU Guo, HB Lee, I Akiyama, SK Pierce, MJ AF Guo, HB Lee, I Akiyama, SK Pierce, MJ TI Over-expression of GnT-V reduces cell-cell adhesion mediated by N-cadherin in HT1080 cells SO GLYCOBIOLOGY LA English DT Meeting Abstract CT 7th Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2002 CL BOSTON, MASSACHUSETTS SP Soc Glycobiol C1 Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD OCT PY 2002 VL 12 IS 10 MA 162 BP 695 EP 696 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601LT UT WOS:000178448200167 ER PT J AU Solomon, S Kington, R AF Solomon, S Kington, R TI National efforts to promote behavior-change research: views from the Office of Behavioral and Social Sciences Research SO HEALTH EDUCATION RESEARCH LA English DT Editorial Material C1 NIH, Off Beh & Social Sci Res, Bethesda, MD 20897 USA. RP Solomon, S (reprint author), NIH, Off Beh & Social Sci Res, 1 Ctr Dr,Room 256, Bethesda, MD 20897 USA. NR 11 TC 21 Z9 21 U1 0 U2 0 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 2002 VL 17 IS 5 BP 495 EP 499 DI 10.1093/her/17.5.495 PG 5 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 603KC UT WOS:000178557500002 PM 12408194 ER PT J AU Ory, MG Jordan, PJ Bazzarre, T AF Ory, MG Jordan, PJ Bazzarre, T TI The Behavior Change Consortium: setting the stage for a new century of health behavior-change research SO HEALTH EDUCATION RESEARCH LA English DT Article ID UNITED-STATES; PROMOTION; POPULATION; PROGRAMS AB The Behavior Change Consortium (BCC), a collective of 15 National Institutes of Health-funded behavior-change projects, was conceived with the goal of evaluating the efficacy and effectiveness of novel ways of intervening in diverse populations to reduce tobacco dependence, and improve physical activity, nutrition and other health behaviors. The purpose of this article is to provide a general introduction and context to this theme issue by: (1) reviewing the promises and challenges of past efforts related to promoting change for three key health behaviors; (2) reviewing successful intervention strategies and principles of health behavior change; (3) discussing major theoretical approaches for obtaining successful behavior change; (4) setting BCC activities within the context of recent recommendations for the behavioral and social sciences; and (5) providing an organizational framework for describing each of the projects within this consortium. In addition to the rich database on behavioral outcomes for tobacco dependence, physical activity and diet, the BCC represents a unique opportunity to share data and address cross-cutting intervention research issues critical for strengthening the field of behavior change research. C1 Texas A&M Univ Syst, Sch Rural Publ Hlth, College Stn, TX 77840 USA. Behav Change Consortium, Honolulu, HI 96816 USA. Robert Wood Johnson Fdn, Princeton, NJ 08543 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Ory, MG (reprint author), Texas A&M Univ Syst, Sch Rural Publ Hlth, College Stn, TX 77840 USA. NR 55 TC 121 Z9 121 U1 0 U2 10 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 2002 VL 17 IS 5 BP 500 EP 511 DI 10.1093/her/17.5.500 PG 12 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 603KC UT WOS:000178557500003 PM 12408195 ER PT J AU Nigg, CR Allegrante, JP Ory, M AF Nigg, CR Allegrante, JP Ory, M TI Theory-comparison and multiple-behavior research: common themes advancing health behavior research SO HEALTH EDUCATION RESEARCH LA English DT Article ID SMOKING CESSATION; PHYSICAL-ACTIVITY; AEROBIC EXERCISE; CLINICAL-TRIALS; PUBLIC-HEALTH; DISEASE RISK; PROMOTION; IMPACT; INTERVENTIONS; PERSPECTIVE AB Research that seeks to compare and contrast theories of behavior change and assess the utility of a particular theoretical model for changing two or more health-related behaviors is critical to advancing health behavior research. Theory-comparison can help us learn more about the processes by which people change and maintain health behaviors than does study of any single theory alone and thus has the potential to better guide the development of intervention. Multiple-behavior interventions promise to have much greater impact on public health than single-behavior interventions. However, theory-comparison and multiple-behavior research presents several emerging challenges. These include finding new ways to enhance recruitment and retention, especially among diverse populations; improving treatment fidelity; developing common metrics across behaviors that can be used to advance the measurement and assessment of behavioral change; and expanding the reach and translation of intervention approaches that have demonstrated efficacy. This paper discusses the rationale for conducting theory-comparison and multiple-behavior research and presents several common themes that have emerged from the work of the National Institutes of Health Behavior Change Consortium (BCC). The activities of each BCC workgroup and the potential contribution of each to these common themes to advance health behavior research are also described. C1 Univ Hawaii Manoa, John A Burns Sch Med, Dept Publ Hlth Sci & Epidemiol, Honolulu, HI 96822 USA. Columbia Univ, Teachers Coll, Natl Ctr Hlth Educ, New York, NY 10027 USA. Columbia Univ, Teachers Coll, Dept Hlth & Behav Studies, New York, NY 10027 USA. Texas A&M Univ Syst, Sch Rural Publ Hlth, College Stn, TX 77840 USA. NIH, Bethesda, MD 20892 USA. RP Nigg, CR (reprint author), Univ Hawaii Manoa, John A Burns Sch Med, Dept Publ Hlth Sci & Epidemiol, Honolulu, HI 96822 USA. NR 56 TC 137 Z9 139 U1 0 U2 5 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 2002 VL 17 IS 5 BP 670 EP 679 DI 10.1093/her/17.5.670 PG 10 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 603KC UT WOS:000178557500019 PM 12408211 ER PT J AU Dancey, JE AF Dancey, JE TI Clinical development of mammalian target of rapamycin inhibitors SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID LYMPHOCYTE-PROLIFERATION ASSAYS; PROTEIN-KINASE-B; CELL-GROWTH; CANCER-CELLS; CYCLIN D1; CYCLOSPORINE/PREDNISOLONE/SIROLIMUS INTERACTIONS; DRUG DEVELOPMENT; MESSENGER-RNA; IN-VITRO; PHASE-I AB Rapamycin and CCI-779 have significant in vitro and in vivo antiproliferative activity against a broad range of human tumor cell lines, justifying the clinical evaluation of this class of agent in cancer patients. Preliminary results from phase I studies of CCI-779 suggest that the agent is well tolerated and has anti-tumor activity The challenge to investigators is to efficiently determine what role this class of agent will play in the treatment of cancer patients. This article focuses on recent advances in the understanding of the mechanisms of cell growth inhibition by rapamycin and the issues surrounding the development of this class of agent as a potential cancer therapy. C1 NCI, DCTD, CTEP,Canc Treatment Evaluat Program, Div Canc Treatment & Diag,Invest Drug Branch, Rockville, MD 20854 USA. RP Dancey, JE (reprint author), NCI, DCTD, CTEP,Canc Treatment Evaluat Program, Div Canc Treatment & Diag,Invest Drug Branch, 6130 Execut Blvd,EPN 7131, Rockville, MD 20854 USA. NR 69 TC 55 Z9 65 U1 1 U2 2 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 2002 VL 16 IS 5 BP 1101 EP + AR PII S0889-8588(02)00051-5 DI 10.1016/S0889-8588(02)00051-5 PG 15 WC Oncology; Hematology SC Oncology; Hematology GA 656HU UT WOS:000181603200005 PM 12512385 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Cyclin-dependent kinases as new targets for the prevention and treatment of cancer SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID BREAST-CARCINOMA CELLS; FLAVOPIRIDOL INDUCES APOPTOSIS; HUMAN EPIDERMOID CARCINOMA; SMALL-MOLECULE INHIBITORS; CDK-ACTIVATING KINASE; RNA-POLYMERASE-II; PROTEIN-KINASE; SELECTIVE INHIBITOR; LUNG-CANCER; RETINOBLASTOMA PROTEIN AB Based on the frequent aberration in cell cycle regulatory pathways in human cancer by cyclin-dependent kinase (cdk) hyperactivation, novel ATP competitive cdk inhibitors are being developed. The first two tested in clinical trials, flavopiridol and UCN-01, showed promising results with evidence of antitumor activity and plasma concentrations sufficient to inhibit cdk-related functions. Best schedule to be administered, combination with standard chemotherapeutic agents, best tumor types to be targeted, and demonstration of cdk modulation from tumor samples from patients in these trials are important questions that need to be answered to advance this class of agents to the prevention and treatment of human cancer. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Mol Therapeut Univ, NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Mol Therapeut Univ, NIH, Bldg 30,Room 211, Bethesda, MD 20892 USA. NR 148 TC 16 Z9 16 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 2002 VL 16 IS 5 BP 1229 EP + AR PII S0889-8588(02)00049-7 DI 10.1016/S0889-8588(02)00049-7 PG 26 WC Oncology; Hematology SC Oncology; Hematology GA 656HU UT WOS:000181603200010 PM 12512390 ER PT J AU Charlton, MR Ruppert, K Belle, SH Nathan, BM Schafer, D Wiesner, RH Detre, KM Wei, Y Everhart, JE AF Charlton, MR Ruppert, K Belle, SH Nathan, BM Schafer, D Wiesner, RH Detre, KM Wei, Y Everhart, JE TI Predicting early and long term patient and graft survival for liver transplant recipients with HCV infection - Results of the NIDDK liver transplant database. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Mayo Clin, Rochester, MN USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Nebraska, Med Ctr, Omaha, NE 68182 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 42 BP 177A EP 177A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700044 ER PT J AU Belle, SH Ruppert, K Bass, NM Detre, K Wei, Y Everhart, JE Schafer, D Wiesner, R AF Belle, SH Ruppert, K Bass, NM Detre, K Wei, Y Everhart, JE Schafer, D Wiesner, R TI Long term quality of life following liver transplantation in recipients with hepatitis C virus (HCV): Results from the NIDDK liver transplantation database (LTD). SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Omaha, NE 68182 USA. Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 52 BP 179A EP 179A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700053 ER PT J AU Weston, SR Ruppert, K Bell, SH Everhart, JF Charlton, MR Weisner, RH Schafer, D Detre, K Roberts, JP Bass, NM Terrault, NA AF Weston, SR Ruppert, K Bell, SH Everhart, JF Charlton, MR Weisner, RH Schafer, D Detre, K Roberts, JP Bass, NM Terrault, NA TI Are risk factors for non-alcoholic fatty liver disease (NAFLD) important in determining hepatitis C virus (HCV) recurrence and severity in patients undergoing liver transplantation (LT)? SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. NIDDK, Bethesda, MD USA. Mayo Clin, Rochester, MN USA. Univ Nebraska, Omaha, NE 68182 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 61 BP 182A EP 182A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700062 ER PT J AU Balan, V Ruppert, K Ledneva, T Belle, SH Charlton, M Demetris, J Bass, N Detre, K Everhart, J Schafer, D Wiesner, R AF Balan, V Ruppert, K Ledneva, T Belle, SH Charlton, M Demetris, J Bass, N Detre, K Everhart, J Schafer, D Wiesner, R TI HLA mismatching is predictive of rejection, recurrent hepatitis C and recurrent autoimmune liver disease afetr liver transplantation SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Mayo Clin Arizona, Phoenix, AZ USA. Univ Pittsburgh, Pittsburgh, PA USA. Mayo Clin, Rochester, MN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Omaha, NE 68182 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 77 BP 186A EP 186A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700078 ER PT J AU Omori, K Terai, S Yamamoto, N Kawaguchi, K Takami, T Tuchiya, M Miyamoto, K Uchida, K Sakida, I Ohata, S Watanabe, T Nishina, H Thorgeirsson, SS Okita, K AF Omori, K Terai, S Yamamoto, N Kawaguchi, K Takami, T Tuchiya, M Miyamoto, K Uchida, K Sakida, I Ohata, S Watanabe, T Nishina, H Thorgeirsson, SS Okita, K TI Gene expression profile which regulates the differentiation of bone marrow cell into hepatocyte in GFP/CCL4 model. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Yamaguchi Univ, Sch Med, Ube, Yamaguchi 755, Japan. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 129 BP 199A EP 199A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700130 ER PT J AU Terat, S Yamamoto, N Omori, K Miyamoto, K Sakaida, I Watanabe, T Ohata, S Nishina, H Katada, T Thorgeirsson, SS Okita, K AF Terat, S Yamamoto, N Omori, K Miyamoto, K Sakaida, I Watanabe, T Ohata, S Nishina, H Katada, T Thorgeirsson, SS Okita, K TI The strategy for development of cell therapy using bone marrow cell to repair damaged liver. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Yamaguchi Univ, Sch Med, Yamaguchi, Japan. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 135 BP 200A EP 200A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700135 ER PT J AU Yamamoto, N Terai, S Omori, K Kawaguchi, K Takami, T Tsuchiya, M Uchida, K Miyamoto, K Sakaida, I Thorgeirsson, S Nishina, H Okita, K AF Yamamoto, N Terai, S Omori, K Kawaguchi, K Takami, T Tsuchiya, M Uchida, K Miyamoto, K Sakaida, I Thorgeirsson, S Nishina, H Okita, K TI LIV8 MAB: A new murine monoclonal antibody separate hepatic stem cell population in bone marrow. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Yamaguchi Univ, Sch Med, Ube, Yamaguchi 755, Japan. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 136 BP 200A EP 200A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700137 ER PT J AU Bukh, J Pietschmann, T Lohmann, V Krieger, N Faulk, K Engle, R Emerson, S Purcell, R Bartenschlager, R AF Bukh, J Pietschmann, T Lohmann, V Krieger, N Faulk, K Engle, R Emerson, S Purcell, R Bartenschlager, R TI Hepatitis C virus full-length genomes with cell culture adaptive mutations in NS3 and NS5A (replicon-derived) replicate efficiently in HUH-7 cells but are highly attenuated in vivo. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ Mainz, D-6500 Mainz, Germany. NIAID, Hepatitis Viruses Sect, LID, NIH, Bethesda, MD 20892 USA. RI Pietschmann, Thomas/E-9241-2015; Bartenschlager, Ralf/L-2582-2015 OI Pietschmann, Thomas/0000-0001-5138-6239; NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 153 BP 205A EP 205A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700154 ER PT J AU Bukh, J Thimme, R Satterfield, W Spangenberg, HC Forns, X Chang, KM Yanagi, M Emerson, S Chisari, F Purcell, R AF Bukh, J Thimme, R Satterfield, W Spangenberg, HC Forns, X Chang, KM Yanagi, M Emerson, S Chisari, F Purcell, R TI Immunity against Hepatitis C virus following resolved infection does not prevent viral persistence after homologous monoclonal re-challenge SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAID, LID, Viruses Sect, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA USA. Univ Texas, MD Anderson Canc Ctr, Bastrop, TX USA. RI Chisari, Francis/A-3086-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 240 BP 226A EP 226A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700241 ER PT J AU Nascimbeni, M Mizukoshi, E Bosmann, M Major, M Mihalik, M Rice, C Feinstone, S Rehermann, B AF Nascimbeni, M Mizukoshi, E Bosmann, M Major, M Mihalik, M Rice, C Feinstone, S Rehermann, B TI Differential regulation of CD4+ and CD8+ memory T cells during HCV rechallenge of chimpanzees. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Rockefeller Univ, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 237 BP 226A EP 226A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700238 ER PT J AU Wilkinson, J Laskus, T Groninger, H Radkowski, M Adair, D Vargas, HE Buskell, Z Seeff, L Rakela, J AF Wilkinson, J Laskus, T Groninger, H Radkowski, M Adair, D Vargas, HE Buskell, Z Seeff, L Rakela, J TI Analysis of Hepatitis C virus (HCV) quasispecies transmission and evolution in patients infected through blood transfusion: Differences associated with outcome. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Mayo Clin Scottsdale, Scottsdale, AZ USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 238 BP 226A EP 226A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700240 ER PT J AU Radaeva, S Jaruga, B Feng, H Kim, WH Fan, SJ Cai, HB Strom, S Liu, YH El-Assal, O Bin, G AF Radaeva, S Jaruga, B Feng, H Kim, WH Fan, SJ Cai, HB Strom, S Liu, YH El-Assal, O Bin, G TI Interferon-A activates multiple STAT signals and down-regulates C-met in primary human hepatocytes. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. Albert Einstein Coll Med, New Hyde Pk, NY USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 300 BP 238A EP 238A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700284 ER PT J AU Sakai, A Thimme, R Spangenberg, C Govindarajan, S Engle, R Emerson, S Purcell, R Chisari, F Bukh, J AF Sakai, A Thimme, R Spangenberg, C Govindarajan, S Engle, R Emerson, S Purcell, R Chisari, F Bukh, J TI Vigorous cellular immune response and accumulation of mutations in known T-cell epitopes may not predict the outcome of acute HCV infection. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAID, Hepatitis Viruses Sect, LID, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA USA. Univ So Calif, Rancho Los Amigos Med Ctr, Downey, CA 90242 USA. RI Chisari, Francis/A-3086-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 404 BP 264A EP 264A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700388 ER PT J AU Kim, WH Feng, H Radaeva, S Jaruga, B Bin, G AF Kim, WH Feng, H Radaeva, S Jaruga, B Bin, G TI Hyperexpression of STAT1 correlates with liver damage in chronic hepatitis C infection: Essential role of STAT1 in hepatitis. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 463 BP 279A EP 279A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700446 ER PT J AU Promrat, K Tang, G Dai, W Gonzalez, C Tong, XM Lan, Z Ghany, M Alter, HJ Rotter, JI Hoofnagle, JH Yang, H Liang, TJ AF Promrat, K Tang, G Dai, W Gonzalez, C Tong, XM Lan, Z Ghany, M Alter, HJ Rotter, JI Hoofnagle, JH Yang, H Liang, TJ TI The association of interferon regulatory factor-1 (IRF-1) promoter polymorphism with HCV infection and interferon treatment response. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MA SP Amer Assoc Study Liver Dis C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Div Med Genet, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Div Med Genet, Los Angeles, CA 90048 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 475 BP 282A EP 282A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700458 ER PT J AU Wakabayashi, Y Lippincott-Schwartz, J Arias, IM AF Wakabayashi, Y Lippincott-Schwartz, J Arias, IM TI Dynamics and kinetics of BSEP constitutive cycling between the bile canalicular membrane and RAB11-associated endosomes as determined by confocal fluorescence imaging in WIF-B9 cells. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis ID GOLGI C1 Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. NICHD, Cell Biol & Metab Branch, Bethesda, MD USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 526 BP 294A EP 294A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700509 ER PT J AU Spangenberg, HC Wieland, S Thimme, R Purcell, RH Chisari, F AF Spangenberg, HC Wieland, S Thimme, R Purcell, RH Chisari, F TI Distinct kinetics of elimination of hbv replicative forms and cccDNA from the liver of acutely infected chimpanzees. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Scripps Res Inst, La Jolla, CA USA. NIH, Bethesda, MD 20892 USA. RI Chisari, Francis/A-3086-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 602 BP 313A EP 313A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700585 ER PT J AU Lok, AS Everhart, JE Everson, G Wright, EC Sterling, R Ghany, M Goodman, Z AF Lok, AS Everhart, JE Everson, G Wright, EC Sterling, R Ghany, M Goodman, Z TI Clinical model to predict cirrhosis in patients in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIDDKD, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. New England Res Inst, Watertown, MA 02172 USA. Virginia Commonwealth Univ, Richmond, VA USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. RI Lok, Anna /B-8292-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 608 BP 315A EP 315A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700592 ER PT J AU Hong, F Kim, WH Jaruga, B Gao, B AF Hong, F Kim, WH Jaruga, B Gao, B TI Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: Involvement of induction of multiple anti-apoptotic proteins. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 646 BP 324A EP 324A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700629 ER PT J AU Liu, J Li, CX Waalkes, MP Clark, J Myers, PH Saavedra, JE Keefer, LK AF Liu, J Li, CX Waalkes, MP Clark, J Myers, PH Saavedra, JE Keefer, LK TI The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIEHS, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. SAIC, Frederick, MD USA. NCI, Carcinogenesis Lab, Frederick, MD 21701 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 655 BP 327A EP 327A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700638 ER PT J AU Hong, F Van, N Gao, B AF Hong, F Van, N Gao, B TI Tumor necrosis factor a attenuates interferon alpha/beta signaling in the liver: Involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 674 BP 331A EP 331A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700657 ER PT J AU Tanaka, Y Alter, HJ Hanada, K Yeo, AE Shih, JW Mizokami, M Gojobori, T AF Tanaka, Y Alter, HJ Hanada, K Yeo, AE Shih, JW Mizokami, M Gojobori, T TI A comparison of the evolutionary clock of hepatitis C virus infection in the United States and Japan predicts that hepatocellular carcinoma incidence in the us will increase over the next two decades. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi, Japan. NIH, Bethesda, MD 20892 USA. Natl Inst Genet, Mishima, Shizuoka 411, Japan. Jacobus Pharmaceut Co INC, Princeton, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 727 BP 345A EP 345A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700710 ER PT J AU Theodore, D Bassett, R Coel, M Sherman, KE Glesby, MJ Chow, D Brobst, SW Alston, B Colquhoun, D Shiramizu, B AF Theodore, D Bassett, R Coel, M Sherman, KE Glesby, MJ Chow, D Brobst, SW Alston, B Colquhoun, D Shiramizu, B TI Correlation of single photon emission computed tomography (SPECT) parameters with liver biopsies in the setting of HIV and HCV co-infection: A multicenter trial of the adult aids clinical trials group, ACTG 5096. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ N Carolina, Chapel Hill, NC 27515 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Hawaii, Honolulu, HI 96822 USA. Univ Cincinnati, Med Ctr, Cincinnati, OH 45221 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Social & Sci Syst Inc, Silver Spring, MD USA. NIH, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 732 BP 346A EP 346A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700716 ER PT J AU Thio, CL Carrington, M Kaslow, R Goedert, J Hilgartner, M O'Brien, S Gao, XJ Karacki, P Marti, D Thomas, D AF Thio, CL Carrington, M Kaslow, R Goedert, J Hilgartner, M O'Brien, S Gao, XJ Karacki, P Marti, D Thomas, D TI The human leukocyte antigen complex contains candidate genes important for determining the outcome of a hepatitis B virus infection. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MA SP Amer Assoc Study Liver Dis C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NCI, Frederick, MD 21701 USA. Univ Alabama, Birmingham, AL USA. New York Acad Med, New York, NY USA. NCI, Rockville, MD USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Cornell Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 811 BP 366A EP 366A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700794 ER PT J AU Farci, P Quinti, I Strazzera, R Cao, D Farci, S Casadei, AM Iorio, R Coiana, A Balestrieri, A Vegnente, A Purcell, RH AF Farci, P Quinti, I Strazzera, R Cao, D Farci, S Casadei, AM Iorio, R Coiana, A Balestrieri, A Vegnente, A Purcell, RH TI Evolution of the HCV quasispecies in perinatally infected children with chronic hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Univ Cagliari, Cagliari, Italy. Univ Roma La Sapienza, Rome, Italy. Univ Naples Federico II, Naples, Italy. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 886 BP 384A EP 384A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700868 ER PT J AU Promrat, K McDermott, D Gonzalez, C Lessie, M Merrell, M Kleiner, DE Koziol, D Soza, A Ghany, M Alter, H Hoofnagle, J Murphy, P Liang, TJ AF Promrat, K McDermott, D Gonzalez, C Lessie, M Merrell, M Kleiner, DE Koziol, D Soza, A Ghany, M Alter, H Hoofnagle, J Murphy, P Liang, TJ TI Chemokine and chemokine receptor polymorphisms and clinical outcomes of HCV infection. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 890 BP 385A EP 385A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700872 ER PT J AU Kleiner, DE Ghany, MG Doo, E Theo, H Soza, A Park, Y Liang, TJ Hoofnagle, JH AF Kleiner, DE Ghany, MG Doo, E Theo, H Soza, A Park, Y Liang, TJ Hoofnagle, JH TI Steatosis and steatohepatitis in patients with chronic hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 991 BP 411A EP 411A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301700973 ER PT J AU Allina, J Sullivan, D Hu, B Bai, JX Cederbaum, A Finkel, T Odin, JA AF Allina, J Sullivan, D Hu, B Bai, JX Cederbaum, A Finkel, T Odin, JA TI Glutathiolation during apoptosis is a common feature of PBC autoantigens and is inhibited by estradiol. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Mt Sinai Sch Med, New York, NY USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1019 BP 418A EP 418A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701001 ER PT J AU Li, CX Liu, J Waalkes, MP Jaeschke, HW AF Li, CX Liu, J Waalkes, MP Jaeschke, HW TI Genomic analysis of the response to endotoxin in glutathione peroxidase-deficient mice SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIEHS, Natl Canc Inst, Res Triangle Pk, NC 27709 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1088 BP 435A EP 435A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701071 ER PT J AU Kawaguchi, K Sakaida, I Terai, S Tsuchiya, M Omori, K Takami, T Yamamoto, N Okamoto, M Uchida, K Thorgeirsson, SS Okita, K AF Kawaguchi, K Sakaida, I Terai, S Tsuchiya, M Omori, K Takami, T Yamamoto, N Okamoto, M Uchida, K Thorgeirsson, SS Okita, K TI Expression of helix-loop-helix transcription factor in rat hepatic stellate cell. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Yamaguchi Univ, Sch Med, Ube, Yamaguchi 755, Japan. NCI, Expt Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Yamaguchi Univ, Sch Med, Ube, Yamaguchi 755, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1103 BP 439A EP 439A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701085 ER PT J AU Takami, T Terai, S Kawaguchi, K Tamimoto, H Tsuchiya, M Omori, K Yamamoto, N Miyamoto, K Uchida, K Yamasaki, T Kurokawa, F Sakaida, I Nishina, H Thorgeirsson, SS Okita, K AF Takami, T Terai, S Kawaguchi, K Tamimoto, H Tsuchiya, M Omori, K Yamamoto, N Miyamoto, K Uchida, K Yamasaki, T Kurokawa, F Sakaida, I Nishina, H Thorgeirsson, SS Okita, K TI HHM : A dominant inhibitory HLH protein, which regulates liver carcinogenesis. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Yamaguchi Univ, Sch Med, Ube, Yamaguchi 755, Japan. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1141 BP 448A EP 448A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701122 ER PT J AU Fickert, P Zollner, G Silbert, D Fuchsbichler, A Arbeiter, S Gonzalez, F Denk, H Trauner, M AF Fickert, P Zollner, G Silbert, D Fuchsbichler, A Arbeiter, S Gonzalez, F Denk, H Trauner, M TI Adaptive hepatic and renal transporter regulation in cholic acid (CA)-fed mice: Role of nuclear bile acid receptor (FXR). SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Karl Franzens Univ Graz, Graz, Austria. Karl Franzens Univ Graz, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1164 BP 454A EP 454A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701147 ER PT J AU Zollner, G Fickert, P Arbeiter, S Silbert, D Fuchsbichler, A Gonzalez, F Zatloukal, K Denk, H Trauner, M AF Zollner, G Fickert, P Arbeiter, S Silbert, D Fuchsbichler, A Gonzalez, F Zatloukal, K Denk, H Trauner, M TI Ursodeoxycholic acid (UDCA) feeding induces adaptive hepatic and renal ABC-transporter expression in mice. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 Karl Franzens Univ Graz, Graz, Austria. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1166 BP 454A EP 454A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701148 ER PT J AU Gao, B Hong, F Jaruga, B Radaeva, S Tian, ZG Nguyen, VA AF Gao, B Hong, F Jaruga, B Radaeva, S Tian, ZG Nguyen, VA TI Mutual antagonism of STAT1 and STAT3 controls T cell-mediated hepatitis: Regulation by SOCS. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1251 BP 476A EP 476A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701233 ER PT J AU Jaruga, B Kim, VH Al-Assai, O Hong, F Radaeva, S Gao, B AF Jaruga, B Kim, VH Al-Assai, O Hong, F Radaeva, S Gao, B TI Activation of STAT6 is essential for T cell-mediated hepatitis: Involvement of interleukin-4 and upregulation of JNK. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1252 BP 476A EP 476A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701235 ER PT J AU Fan, XF Xu, YJ Lang, D Detre, KM Belle, SH Wei, YL Wiesner, RH Charlton, MR Schafer, D Bass, N Roberts, J Korber, BTM Everhart, JE Di Bisceglie, AM AF Fan, XF Xu, YJ Lang, D Detre, KM Belle, SH Wei, YL Wiesner, RH Charlton, MR Schafer, D Bass, N Roberts, J Korber, BTM Everhart, JE Di Bisceglie, AM TI Clonal nature of hepatitis C virus: Full length sequencing shows lack of recombination of HCV isolates from heterologous HCV positive recipient/donor pairs in liver transplantation. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 St Louis Univ, Ctr Liver, St Louis, MO 63103 USA. St Louis Univ, HSC, St Louis, MO 63103 USA. Los Alamos Natl Lab, Los Alamos, NM USA. Univ Pittsburgh, Pittsburgh, PA USA. Mayo Clin, Rochester, MN USA. Univ Nebraska, Omaha, NE 68182 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1535 BP 547A EP 547A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701517 ER PT J AU Umemura, T Tanaka, E Lee, WM Ostapowicz, G Heringlake, S Manns, MP Tasopoulos, NC Hatzakis, A Brown, KE Young, NS Wang, R Yeo, A Shih, J Orii, K Kiyosawa, K Alter, HJ AF Umemura, T Tanaka, E Lee, WM Ostapowicz, G Heringlake, S Manns, MP Tasopoulos, NC Hatzakis, A Brown, KE Young, NS Wang, R Yeo, A Shih, J Orii, K Kiyosawa, K Alter, HJ TI The role of SEN virus infection in various liver diseases from different geographical regions. SO HEPATOLOGY LA English DT Meeting Abstract CT 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 01-05, 2002 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Dis C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. Shinshu Univ, Sch Med, Matsumoto, Nagano 390, Japan. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Hannover Med Sch, D-3000 Hannover, Germany. Univ Athens, Sch Med, GR-11527 Athens, Greece. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2002 VL 36 IS 4 SU S MA 1934 BP 646A EP 646A PN 2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 598XK UT WOS:000178301701916 ER PT J AU Mobasheri, A Vannucci, SJ Bondy, CA Carter, SD Innes, JF Arteaga, MF Trujillo, E Ferraz, I Shakibaei, M Martin-Vasallo, P AF Mobasheri, A Vannucci, SJ Bondy, CA Carter, SD Innes, JF Arteaga, MF Trujillo, E Ferraz, I Shakibaei, M Martin-Vasallo, P TI Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE cartilage; chondrocyte; chondrogenesis; osteoarthritis; osteochondritis dissecans; glucose; GLUT/SLC2A family; glucosamine sulfate; IGF-1; vitamin C; nutraceutrical; glucose transporter ID GROWTH-FACTOR-I; INTESTINAL NUTRIENT TRANSPORT; HUMAN ARTICULAR CHONDROCYTES; INSULIN SIGNAL-TRANSDUCTION; EPITHELIAL SODIUM-CHANNELS; DEVELOPING MOUSE EPIPHYSIS; SWARM RAT CHONDROSARCOMA; LONGITUDINAL BONE-GROWTH; BLOOD-BRAIN-BARRIER; ASCORBIC-ACID AB Despite the recognition that degenerative cartilage disorders like osteoarthritis (OA) and osteochondritis dissecans (OCD) may have nutritional abnormalities at the root of their pathogenesis, balanced dietary supplementation programs have played a secondary role in their management. This review emphasizes the importance and role of nutritional factors such as glucose and glucose-derived sugars (i.e. glucosamine sulfate and vitamin C) in the development, maintenance, repair, and remodeling of cartilage. Chondrocytes, the cells of cartilage, consume glucose as a primary substrate for ATP production in glycolysis and utilize glucosamine sulfate and other sulfated sugars as structural components for extracellular matrix synthesis and are dependant on hexose uptake and delivery to metabolic and biosynthetic pools. Data from several laboratories suggests that chondrocytes express multiple isoforms of the GLUT/SLC2A family of glucose/polyol transporters. These facilitative glucose transporter proteins are expressed in a tissue and cell-specific manner, exhibit distinct kinetic properties, and are developmentally regulated. They may also be regulated by endocrine factors like insulin and insulin-like growth factor I (IGF-I) and cytokines such as interleukin 1 beta (IL-1beta) and tumour necrosis factor alpha (TNF-alpha). Recent studies suggest that degeneration of cartilage may be triggered by metabolic disorders of glucose balance and that OA occurs coincident with metabolic disease, endocrine dysfunction and diabetes mellitus. Based on these metabolic, endocrine and developmental considerations we present a novel hypothesis regarding the role of glucose transport and metabolism in cartilage physiology and pathophysiology and speculate that supplementation with sugar-derived vitamins and nutraceuticals may benefit patients with degenerative joint disorders. C1 Univ Liverpool, Fac Vet Sci, Connect Tissue Res Grp, Liverpool L69 7ZJ, Merseyside, England. Univ Liverpool, Fac Vet Sci, Musculoskeletal Physiol Lab, Liverpool L69 7ZJ, Merseyside, England. Columbia Univ, Coll Phys & Surg, Morgan Stanley Childrens Hosp New York, New York, NY USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. Univ La Laguna, Dept Biochem & Mol Biol, Dev Biol Lab, Tenerife, Spain. Free Univ Berlin, Inst Anat, D-1000 Berlin, Germany. RP Mobasheri, A (reprint author), Univ Liverpool, Fac Vet Sci, Dept Preclin Vet Sci, Liverpool L69 7ZJ, Merseyside, England. RI Carter, Stuart/D-9374-2013; OI Carter, Stuart/0000-0002-3585-9400 FU NICHD NIH HHS [P01 HD-30704] NR 220 TC 64 Z9 68 U1 3 U2 11 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 2002 VL 17 IS 4 BP 1239 EP 1267 PG 29 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 597RG UT WOS:000178234100025 PM 12371151 ER PT J AU Toraason, M Andersen, M Bogdanffy, MS Dankovic, D Faustman, E Foster, P Frederick, C Haber, L Kimmel, CA Lewis, S McClellan, R Melnick, R Mirer, F Morgan, K Schaeffer, V Silbergeld, E Slikker, W Swenberg, J Vainio, H AF Toraason, M Andersen, M Bogdanffy, MS Dankovic, D Faustman, E Foster, P Frederick, C Haber, L Kimmel, CA Lewis, S McClellan, R Melnick, R Mirer, F Morgan, K Schaeffer, V Silbergeld, E Slikker, W Swenberg, J Vainio, H TI Improving risk assessment: Toxicological research needs SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE susceptibility; life stages; pharmacokinetics; dose response; exposure assessment; genomics ID GLUTATHIONE-S-TRANSFERASE; DEVELOPMENTAL TOXICITY; BREAST-MILK; LUNG-CANCER; EXPOSURE; SUSCEPTIBILITY; EXPRESSION; HEALTH; CYP1A1; POLYMORPHISMS AB A workshop convened to define research needs in toxicology identified several deficiencies in data and methods currently applied in risk assessment. The workshop panel noted that improving the link between chemical exposure and toxicological response requires a better understanding of the biological basis for inter- and intra-human variability and susceptibility. This understanding will not be complete unless all life stages are taken into consideration. Because animal studies serve as a foundation for toxicological assessment, proper accounting for cross-species extrapolation is essential. To achieve this, adjustments for dose-rate effects must be improved, which will aid in extrapolating toxicological responses to low doses and from short-term exposures. Success depends on greater use of validated biologically based dose-response models that include pharmacokinetic and pharmacodynamic data. Research in these areas will help define uncertainty factors and reduce reliance on underlying default assumptions. Throughout the workshop the panel recognized that biomedical science and toxicology in particular is on the verge of a revolution because of advances in genomics and proteomics. Data from these high-output technologies are anticipated to greatly improve risk assessment by enabling scientists to better define and model the elements of the relationship between exposure to biological hazards and health risks in populations with differing susceptibilities. C1 NIOSH, Cincinnati, OH 45226 USA. DuPont Co Inc, Newark, DE 19714 USA. NIOSH, Cincinnati, OH 45226 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Rohm & Haas Co, Spring House, PA 19477 USA. Toxicol Excellence Risk Assessment, Cincinnati, OH USA. US EPA, Washington, DC 20460 USA. Exxon Mobile, Annandale, NJ USA. NIEHS, Res Triangle Pk, NC 27709 USA. UAW, Int Union, Detroit, MI USA. Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA. US Occupat Safety & Hlth Adm, Washington, DC USA. Univ Maryland, Baltimore, MD 21201 USA. US FDA, Jefferson, AR USA. Univ N Carolina, Chapel Hill, NC USA. Int Agcy Res Canc, F-69372 Lyon, France. RP Toraason, M (reprint author), NIOSH, MSc23,C23,4676 Columbia Pkwy, Cincinnati, OH 45226 USA. EM mtoraason@cdc.gov OI Andersen, Melvin/0000-0002-3894-4811 NR 47 TC 2 Z9 2 U1 0 U2 3 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 2002 VL 8 IS 6 BP 1405 EP 1419 DI 10.1080/20028091057439 PG 15 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 612VB UT WOS:000179095200016 ER PT J AU Zeise, L Hattis, D Andersen, M Bailer, AJ Bayard, S Chen, C Clewell, H Conolly, R Crump, K Dunson, D Finkel, A Haber, L Jarabek, AM Kodell, R Krewski, D Thomas, D Thorslund, T Wassell, JT AF Zeise, L Hattis, D Andersen, M Bailer, AJ Bayard, S Chen, C Clewell, H Conolly, R Crump, K Dunson, D Finkel, A Haber, L Jarabek, AM Kodell, R Krewski, D Thomas, D Thorslund, T Wassell, JT TI Improving risk assessment: Research opportunities in dose response modeling to improve risk assessment SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE interindividual variability; injury risk; Bayesian analysis; latent variables; Markov Chain Monte Carlo analysis ID HUMAN INTERINDIVIDUAL VARIABILITY; OCCUPATIONAL FATAL INJURY; MULTISTEP CARCINOGENESIS; PHARMACOKINETIC MODEL; GENETIC ALTERATIONS; TUMOR PROMOTION; LIFETIME RISK; UNITED-STATES; CANCER RISKS; UNCERTAINTY AB Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates. C1 Calif Environm Protect Agcy, Off Environm Hlth Hazard Assessment, Oakland, CA USA. Clark Univ, Marsh Inst, Worcester, MA 01610 USA. Colorado State Univ, Ft Collins, CO 80523 USA. Miami Univ, Oxford, OH 45056 USA. US Occupat Safety & Hlth Adm, Washington, DC USA. US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Washington, DC 20460 USA. ICF Consulting, KS Crump Grp, Ruston, LA USA. CIIT Ctr Hlth Res, Res Triangle Pk, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. US Occupat Safety & Hlth Adm, Washington, DC USA. Toxicol Excellence Risk Assessment, Cincinnati, OH USA. US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Univ Ottawa, Ottawa, ON, Canada. Univ So Calif, Los Angeles, CA USA. NIOSH, Morgantown, WV USA. RP Zeise, L (reprint author), Calif Environm Protect Agcy, Off Environm Hlth Hazard Assessment, Oakland, CA USA. EM dhattis@aol.com OI Andersen, Melvin/0000-0002-3894-4811 NR 90 TC 7 Z9 7 U1 0 U2 1 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 2002 VL 8 IS 6 BP 1421 EP 1444 DI 10.1080/20028091057448 PG 24 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 612VB UT WOS:000179095200017 ER PT J AU Modregger, J DiProspero, NA Charles, V Tagle, DA Plomann, M AF Modregger, J DiProspero, NA Charles, V Tagle, DA Plomann, M TI PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECEPTOR-MEDIATED ENDOCYTOSIS; SUBCELLULAR-LOCALIZATION; INTRANUCLEAR INCLUSIONS; TRANSGENIC MICE; BINDING-PROTEIN; CELL-LINES; RAT-BRAIN; CLATHRIN; HIP1; DYSFUNCTION AB Huntington's disease (HD) is caused by a pathological expansion of a CAG repeat in the first exon of the gene coding for huntingtin, resulting in an abnormally long polyglutamine stretch. Despite its widespread expression, mutant huntingtin leads to selective neuronal loss in the striatum and cortex. Here we report that the neurospecific phosphoprotein PACSIN 1, which has been implicated as playing a central role in synaptic vesicle recycling, interacts with huntingtin via its C-terminal SH3 domain. Moreover, two other isoforms, PACSIN 2 and 3, which show a wider tissue distribution including the brain, do not interact with huntingtin despite a highly conserved SH3 domain. Furthermore, this interaction is repeat-length-dependent and is enhanced with mutant huntingtin, possibly causing the sequestration of PACSIN 1. Normally, PACSIN 1 is located along neurites and within synaptic boutons, but in HD patient neurons, there is a progressive loss of PACSIN 1 immunostaining in synaptic varicosities, beginning in presymptomatic and early-stage HD. Further, PACSIN 1 immunostaining of HD patient tissue reveals a more cytoplasmic distribution of the protein, with particular concentration in the perinuclear region coincident with mutant huntingtin. Thus, the specific interaction of huntingtin with the neuronal PACSIN isoform, PACSIN 1, and its altered intracellular distribution in pathological tissue, together with the observed differences in the binding behavior, suggest a role for PACSIN 1 during early stages of the selective neuropathology of HD. C1 Univ Cologne, Inst Biol 2, D-50931 Cologne, Germany. NHGRI, NIH, Bethesda, MD 20892 USA. RP Plomann, M (reprint author), Univ Cologne, Inst Biol 2, D-50931 Cologne, Germany. FU NIMH NIH HHS [MH/NS 31862] NR 44 TC 75 Z9 76 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2002 VL 11 IS 21 BP 2547 EP 2558 DI 10.1093/hmg/11.21.2547 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 602QM UT WOS:000178516000002 PM 12354780 ER PT J AU Rotman-Pikielny, P Hirschberg, K Maruvada, P Suzuki, K Royaux, IE Green, ED Kohn, LD Lippincott-Schwartz, J Yen, PM AF Rotman-Pikielny, P Hirschberg, K Maruvada, P Suzuki, K Royaux, IE Green, ED Kohn, LD Lippincott-Schwartz, J Yen, PM TI Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME GENE; LIVING CELLS; INNER-EAR; PDS; CHAPERONES; TRANSPORT; MUTATIONS; GOLGI; CFTR; TRAFFICKING AB Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and 6384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP-WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and. defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred syndrome. C1 NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Infect Dis, Tokyo, Japan. Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Athens, OH 45701 USA. Ohio Univ, Coll Osteopath Med, Edison Biotechnol Inst, Athens, OH 45701 USA. Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Tel Aviv, Israel. RP Yen, PM (reprint author), NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bldg 10,Room 8D12, Bethesda, MD 20892 USA. NR 27 TC 60 Z9 65 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 2002 VL 11 IS 21 BP 2625 EP 2633 DI 10.1093/hmg/11.21.2625 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 602QM UT WOS:000178516000010 PM 12354788 ER PT J AU Sinaii, N Cleary, SD Ballweg, ML Nieman, LK Stratton, P AF Sinaii, N Cleary, SD Ballweg, ML Nieman, LK Stratton, P TI High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis SO HUMAN REPRODUCTION LA English DT Article DE autoimmune; chronic fatigue syndrome; endocrine; endometriosis; fibromyalgia ID UNITED-STATES; PREMENSTRUAL SYMPTOMS; PELVIC ENDOMETRIOSIS; PREVALENCE; EPIDEMIOLOGY; INFERTILITY; DIAGNOSIS; HEALTH; PAIN AB BACKGROUND: Women with endometriosis may also have associated disorders related to autoimmune dysregulation or pain. This study examined whether the prevalence of autoimmune, chronic pain and fatigue and atopic disorders is higher in women with endometriosis than in the general female population. METHODS AND RESULTS: A cross-sectional survey was conducted in 1998 by the Endometriosis Association of 3680 USA members with surgically diagnosed endometriosis. Almost all responders had pain (99%), and many reported infertility (41%). Compared with published rates in the general USA female population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%, P < 0.0001), fibromyalgia (5.9 versus 3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P < 0.0001), rheumatoid arthritis (1.8 versus 1.2%, P = 0.001), systemic lupus erythematosus (0.8 versus 0.04%, P < 0.0001), Sjogren's syndrome (0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P < 0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among women with endometriosis alone (61%, P < 0.001 and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA female population (18%, P < 0.001 and 5%, P < 0.001 respectively). CONCLUSIONS: Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma are all significantly more common in women with endometriosis than in women in the general USA population. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC 20037 USA. Endometriosis Assoc, Int Headquarters, Milwaukee, WI 53233 USA. RP Sinaii, N (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9D42,MSC 1583, Bethesda, MD 20892 USA. NR 42 TC 218 Z9 230 U1 1 U2 20 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 2002 VL 17 IS 10 BP 2715 EP 2724 DI 10.1093/humrep/17.10.2715 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 623WQ UT WOS:000179726200037 PM 12351553 ER PT J AU Landmesser, U Cai, H Dikalov, S McCann, L Hwang, J Jo, H Holland, SM Harrison, DG AF Landmesser, U Cai, H Dikalov, S McCann, L Hwang, J Jo, H Holland, SM Harrison, DG TI Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II SO HYPERTENSION LA English DT Article DE oxidative stress; endothelium; angiotensin II; hypertension, experimental ID NADPH OXIDASE ACTIVITY; SMOOTH-MUSCLE CELLS; SUPEROXIDE PRODUCTION; NAD(P)H OXIDASE; ENDOTHELIAL-CELLS; BLOOD-PRESSURE; MICE; PEROXYNITRITE; VALIDATION; LUCIGENIN AB Hypertension caused by angiotensin II is dependent on vascular superoxide (O-2(.-)) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O-2(.-) and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47(phox), a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105+/-2 to 151+/-6 min Hg and increased vascular O-2(.-) formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47(phox-/-) mice the hypertensive response to angiotensin II infusion (122 +/- 4 mm Hg; P<0.05) was markedly blunted, and there was no increase of vascular O-2(.-) production. In situ staining for O-2(.-) using dihydroethidium revealed a marked increase of O(2)(.-)production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47(phox-/-) mice. To directly examine the role of the NAD(P)H oxidase in endothelial production Of O-2(.-), endothelial cells from WT and p47(phox-/-) mice were cultured. Western blotting confirmed the absence of p47(phox) in p47(phox-/-) mice. Angiotensin II increased O-2(.-) production in endothelial cells from WT mice, but not in those from p47(phox-/-) mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47(phox) in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo. C1 Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. Atlanta Vet Adm Hosp, Atlanta, GA USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Harrison, DG (reprint author), Emory Univ, Sch Med, Div Cardiol, 1639 Pierce Dr,319 WMB, Atlanta, GA 30322 USA. EM dharr02@emory.edu FU NHLBI NIH HHS [P01 HL058000, HL390006, HL58000, HL59248, R01 HL071014] NR 27 TC 361 Z9 374 U1 0 U2 4 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 2002 VL 40 IS 4 BP 511 EP 515 DI 10.1161/01.HYP.0000032100.23772.98 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 604MW UT WOS:000178626200012 PM 12364355 ER PT J AU Poletto, CJ Van Doren, CL AF Poletto, CJ Van Doren, CL TI Elevating pain thresholds in humans using depolarizing prepulses SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE depolarizing prepulse; electrocutaneous; electrotactile; pain ID HUMAN PERIPHERAL-NERVE; ELECTROCUTANEOUS STIMULATION; DELAYED DEPOLARIZATION; LATENT ADDITION; MOTOR; FIBERS; AXONS AB Electrocutaneous stimulation is a potentially useful communication tool for applications in virtual reality, sensory substitution, an sensory augmentation. Many of these applications require the use of arrays of small electrodes. Stimulation through small electrodes is often painful, however, limiting the practicality of such arrays. The purpose of this study was to test a method for elevating the pain threshold to electrocutaneous stimulation through small (1-mm diameter) electrodes on the fingertip. We hypothesized that long, subthreshold, depolarizing prepulses (PP) would elevate the pain threshold so that a subsequent stimulus pulse (SP) would be less likely to be painful. We used psychophysical methods to measure the probability that an SP would be perceived as painful both by itself and when preceded by a PP that was 2, 4, 6, 8, or 10 dB lower in amplitude than the SP. We found that the PPs significantly increased the pain threshold, reducing the likelihood that the SP was painful (p <.6001). The dose effect of PP amplitude was also highly significant (p <.0001), with larger PPs elevating pain thresholds more. To our knowledge, this is the first report of PPs being used to elevate electrical stimulation thresholds in humans. PPs may be useful for selective inactivation of neural subpopulations in many human neuroprosthetic applications. C1 Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44109 USA. Case Western Reserve Univ, Dept Orthopaed & Biomed Engn, Cleveland, OH 44109 USA. RP Poletto, CJ (reprint author), NINDS, Bethesda, MD 20892 USA. NR 23 TC 6 Z9 6 U1 1 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD OCT PY 2002 VL 49 IS 10 BP 1221 EP 1224 DI 10.1109/TBME.2002.803563 PG 4 WC Engineering, Biomedical SC Engineering GA 599KL UT WOS:000178333700020 PM 12374350 ER PT J AU Bhandoola, A Tai, XG Eckhaus, M Auchincloss, H Mason, K Rubin, SA Carbone, KM Grossman, Z Rosenberg, AS Singer, A AF Bhandoola, A Tai, XG Eckhaus, M Auchincloss, H Mason, K Rubin, SA Carbone, KM Grossman, Z Rosenberg, AS Singer, A TI Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4(+) T cells: Evidence from a lymphopenic T cell model SO IMMUNITY LA English DT Article ID POSITIVE SELECTION; HOMEOSTATIC PROLIFERATION; ACTIVATION THRESHOLD; PEPTIDE LIGANDS; SURVIVAL; THYMUS; COMPLEX; MOLECULES; ANTIGENS; MOUSE AB While intrathymic MHC expression influences the specificity of developing thymocytes, we considered that peripheral MHC expression might influence the reactivity of postthymic T cells. We now report for CD4(+) T cells that peripheral MHC-II expression does influence their reactivity and self-tolerance. Upon transfer into MHC-II-deficient lymphopenic hosts, mature CD4(+) T cells were found to acquire an activated memory phenotype and to become: (1) autoreactive against syngeneic MHC-II+ skin grafts, (2) hyperreactive against third-party MHC-II+ skin grafts, and (3) functionally dysregulated, resulting in a lymphoproliferative disorder characterized by intraepithelial infiltrations. Peripheral MHC-II expression appeared to influence CD4+ T cell reactivity by two complementary mechanisms: maintenance of CD4(+)CD25(+) regulatory T cells ("suppression") and direct dampening of CD4(+) T cell reactivity ("tuning"). C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. US FDA, Div Therapeut Prot, Bethesda, MD 20892 USA. US FDA, Lab Pediat & Resp Viral Dis, Bethesda, MD 20892 USA. Tel Aviv Univ, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. RI Grossman, Zvi/A-9643-2008 NR 40 TC 68 Z9 68 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2002 VL 17 IS 4 BP 425 EP 436 DI 10.1016/S1074-7613(02)00417-X PG 12 WC Immunology SC Immunology GA 605FQ UT WOS:000178667100004 PM 12387737 ER PT J AU Stoddart, A Dykstra, ML Brown, BK Song, WX Pierce, SK Brodsky, FM AF Stoddart, A Dykstra, ML Brown, BK Song, WX Pierce, SK Brodsky, FM TI Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization SO IMMUNITY LA English DT Article ID CELL ANTIGEN RECEPTOR; IMMATURE B-CELLS; ENDOCYTIC PATHWAY; COATED VESICLES; CUTTING EDGE; MEMBRANE; PROTEIN; ACTIVATION; COMPLEX; PHOSPHORYLATION AB A major function of the B cell is the internalization of antigen through the BCR for processing and presentation to T cells. While there is evidence suggesting that lipid raft signaling may regulate internalization, the molecular machinery coordinating these two processes remains to be defined. Here we present a link between the B cell signaling and internalization machinery and show that Src-family kinase activity is required for inducible clathrin heavy chain phosphorylation, BCR colocalization with clathrin, and regulated internalization. An analysis of different B cell lines shows that BCR uptake occurs only when clathrin is associated with rafts and is tyrosine phosphorylated following BCR crosslinking. We therefore propose that lipid rafts spatially organize signaling cascades with clathrin to regulate BCR internalization. C1 Univ Calif San Francisco, George Williams Hooper Fdn, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. RP Brodsky, FM (reprint author), Univ Calif San Francisco, George Williams Hooper Fdn, San Francisco, CA 94143 USA. FU NIAID NIH HHS [AI42093, AI45865]; NIGMS NIH HHS [GM38093] NR 49 TC 155 Z9 156 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2002 VL 17 IS 4 BP 451 EP 462 DI 10.1016/S1074-7613(02)00416-8 PG 12 WC Immunology SC Immunology GA 605FQ UT WOS:000178667100006 PM 12387739 ER PT J AU Cravens, PD Lipsky, PE AF Cravens, PD Lipsky, PE TI Dendritic cells, chemokine receptors and autoimmune inflammatory diseases SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article DE autoimmune inflammatory lesions; chemokines; chemokine receptors; dendritic cells ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TUMOR-NECROSIS-FACTOR; REGIONAL LYMPH-NODES; MULTIPLE-SCLEROSIS; CUTTING EDGE; TNF-ALPHA; RHEUMATOID-ARTHRITIS; SJOGRENS-SYNDROME; LANGERHANS CELLS; T-LYMPHOCYTES AB Dendritic cells (DC) have been implicated in the induction of autoimmune diseases and have been identified in lesions associated with several autoimmune inflammatory diseases. Since DC are regarded as the professional antigen-presenting cell (APC) of the immune system and the only APC capable of activating naive T cells, they are likely to play a significant role in breaking tolerance of self-reactive lymphocytes and in supporting autoimmune responses in these diseases. A number of studies have revealed that small molecular weight chemotactic proteins known as chemokines are present within the autoimmune lesions and may contribute to the recruitment not only of DC populations, but also of immune cells such as T cells, B cells, neutrophils and monocytes into the site, and to the formation of organized lymphoid tissue structures within the target organ. The focus of this review will be a discussion of the role of chemokines in the recruitment of DC in human autoimmune inflammatory disorders, specifically the trafficking of DC into the inflammatory sites and the subsequent migration of differentiated DC from the inflammatory sites into the draining lymph nodes. Once DC are properly positioned within the lymph nodes, circulating antigen specific naive T cells can interact with DC and become activated, clonally expanded and stimulated to undergo differentiation into antigen-experienced memory T cells. Subsequent reactivation of memory T cells that enter the autoimmune lesions by DC present in the inflammatory lesion is thought to play a central role in tissue inflammation. C1 NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Div Infect Dis, Dallas, TX USA. RP Lipsky, PE (reprint author), NIAMSD, Autoimmun Branch, NIH, Bldg 10,Room 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 62 TC 73 Z9 81 U1 0 U2 2 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD OCT PY 2002 VL 80 IS 5 BP 497 EP 505 DI 10.1046/j.1440-1711.2002.01118.x PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 592YM UT WOS:000177964500012 PM 12225387 ER PT J AU Lehrnbecher, T Marshall, D Gao, C Chanock, SJ AF Lehrnbecher, T Marshall, D Gao, C Chanock, SJ TI A second look at anorectal infections in cancer patients in a large Cancer Institute: The success of early intervention with antibiotics and surgery SO INFECTION LA English DT Article ID MALIGNANT DISEASES; HOST-DEFENSE; COMPLICATIONS; NEUTROPENIA; MANAGEMENT; LEUKEMIA; THERAPY; CHILDREN; FEVER; RISK AB Background: Infection of anorectal region represents a significant compilication of anti-cancer therapy. Anorectal infection occurs in patients receiving aggressive chemotherapy. Untreated infection leads to substantial morbidity and in the past, mortality. Methods: 82 episodes of anorectal infection in 64 patients with malignant diseases occurring over 12 years at the National Cancer Institute (NCI) were retrospectively reviewed. Results: The overall incidence is comparable to the prior NCI experience despite a shift in patient population to a lower percentage of lymphoid/leukemic diagnoses (34% vs 77%). There were no deaths associated with anorectal infection in the 12 years reviewed compared to seven of 44 in the previous decade (p = 0.003). Antibiotic therapy alone was successful in managing 52/82 episodes, whereas surgery and antibiotics were required in 25/82. Only five episodes were treated with surgery alone compared to nearly 45% in the previous decade. There were no major surgical complications. Neutropenia was present in 43/82 episodes. 11 episodes were complicated by bacteremia, predominately with Staphylococcus non-aureus (n = 8). Wound cultures were performed in 36 episodes from 23 patients yielding 99 separate isolates. Gram-negative isolates were most common overall. Modification of antibiotic therapy with further anaerobic coverage was administered successfully in 39/77 episodes. Conclusion: This study illustrates that anorectal infections in cancer patients can be successfully managed with antibiotic therapy and Local care; surgery can be withheld unless there is evidence of progressive infect ion or substantial fluctuance and necrosis. C1 NCI, Ctr Adv Technol, Pediat Oncol Branch, Immmunocompromisd Host Sect, Gaithersburg, MD 20877 USA. RP Chanock, SJ (reprint author), NCI, Ctr Adv Technol, Pediat Oncol Branch, Immmunocompromisd Host Sect, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. NR 25 TC 15 Z9 15 U1 0 U2 0 PU MMV MEDIEN & MEDIZIN VERLAGSGESELLSCHAFT MBH PI MUNICH PA NEUMARKTER STR 18, D-81673 MUNICH, GERMANY SN 0300-8126 J9 INFECTION JI Infection PD OCT PY 2002 VL 30 IS 5 BP 272 EP 276 DI 10.1007/s15010-002-2197-8 PG 5 WC Infectious Diseases SC Infectious Diseases GA 605XN UT WOS:000178702500004 PM 12382085 ER PT J AU Lyons, MJ Yoshimura, T McMurray, DN AF Lyons, MJ Yoshimura, T McMurray, DN TI Mycobacterium bovis BCG vaccination augments interleukin-8 mRNA expression and protein production in guinea pig alveolar macrophages infected with Mycobacterium tuberculosis SO INFECTION AND IMMUNITY LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; PULMONARY TUBERCULOSIS; HOST-DEFENSE; CDNA CLONING; NEUTROPHILS; MICE; CHEMOKINES; LIPOARABINOMANNAN; CYTOKINES; VIRULENT AB Alveolar macrophages are likely the first cell type to encounter Mycobacterium tuberculosis in a pulmonary infection, resulting in the production of chemokines. In order to evaluate this response, alveolar macrophages harvested from nonvaccinated and Mycobacterium bovis BCG-vaccinated guinea pigs were infected in vitro with live M. tuberculosis H37Ra or H37Rv (multiplicity of infection, 1:1) or cultured with lipopolysaccharide (10 mug/ml) for 3, 12, and 24 h. Interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) mRNA expression was determined by real-time PCR. Culture supernatants were assayed for guinea pig IL-8 protein by using a human IL-8 enzyme-linked immunosorbent assay kit. Alveolar macrophages harvested from BCG-vaccinated guinea pigs produced significantly more mRNA and protein for IL-8 than alveolar macrophages harvested from nonvaccinated guinea pigs at 12 and 24 h poststimulation or postinfection. Infection with attenuated M. tuberculosis (H37Ra) stimulated alveolar macrophages isolated from BCG-vaccinated guinea pigs to produce significantly more IL-8 mRNA than did alveolar macrophages infected with a virulent strain (H37Rv) at 12 and 24 h postinfection. Significant MCP-1 mRNA production was also detected in stimulated or infected alveolar macrophages; however, prior vaccination did not significantly affect levels of MCP-1 mRNA. Alveolar macrophages isolated from BCG-vaccinated guinea pigs produced significantly more IL-8 mRNA and protein when stimulated for 24 h with heat-killed H37Ra, heat-killed H37Rv, and H37Rv cell wall, but not mannose-capped lipoarabinomannan (ManLAM), than did cells stimulated with media alone. These observations indicate that prior vaccination may alter very early events in the M. tuberculosis-infected lung. C1 Texas A&M Univ Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP McMurray, DN (reprint author), Texas A&M Univ Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, 407 Reynolds Med Bldg, College Stn, TX 77843 USA. FU NIAID NIH HHS [R01-AI-15495, R01 AI015495] NR 55 TC 32 Z9 35 U1 0 U2 0 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 2002 VL 70 IS 10 BP 5471 EP 5478 DI 10.1128/IAI.70.10.5471-5478.2002 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 595TU UT WOS:000178125500016 PM 12228272 ER PT J AU Gieffers, J Belland, RJ Whitmire, W Ouellette, S Crane, D Maass, M Byrne, GI Caldwell, HD AF Gieffers, J Belland, RJ Whitmire, W Ouellette, S Crane, D Maass, M Byrne, GI Caldwell, HD TI Isolation of Chlamydia pneumoniae clonal variants by a focus-forming assay SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; GENOME SEQUENCES; STRAIN TWAR; TRACHOMATIS; CELLS AB Chlamydia pneumoniae is an obligate intracellular prokaryotic human pathogen that causes community-acquired respiratory infection and has been associated with atherosclerosis and cardiovascular disease. Unexpected results from genomic sequencing indicate that significant intrastrain polymorphism exists for some C. pneumoniae isolates. These polymorphisms could reflect genotypes with differing disease-causing characteristics. A definitive means to test this hypothesis is to obtain genetically homogeneous clonal populations of the pathogen and test them in models of infection and disease. To date, methods for cloning C. pneumoniae have not been reported. In this study, we describe the isolation of clonal variants with genetic differences in the tyrP locus from a polymorphic respiratory isolate, using a novel focus-forming assay. These results now allow investigations on the biology and pathogenesis of C. pneumoniae clonal genovars that could lead to new insights into the pathogenesis of this important human pathogen. C1 NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Wisconsin, Sch Med, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. Med Univ Lubeck, Inst Med Microbiol & Hyg, D-23538 Lubeck, Germany. RP Caldwell, HD (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. FU NIAID NIH HHS [AI42790, R01 AI042790] NR 20 TC 23 Z9 23 U1 0 U2 0 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 2002 VL 70 IS 10 BP 5827 EP 5834 DI 10.1128/IAI.70.10.5827-5834.2002 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 595TU UT WOS:000178125500058 PM 12228314 ER PT J AU Sidorov, IA Hosack, DA Gee, D Yang, J Cam, MC Lempicki, RA Dimitrov, DS AF Sidorov, IA Hosack, DA Gee, D Yang, J Cam, MC Lempicki, RA Dimitrov, DS TI Oligonucleotide microarray data distribution and normalization SO INFORMATION SCIENCES LA English DT Article ID GENE-EXPRESSION; DNA ARRAYS AB Variations in oligonucleotide microarray probe signals that result from various factors, including differences in sample concentrations, can lead to major problems in the interpretation of data obtained from different experiments. Normalization of such signals is typically performed by procedures involving division by a constant approximately determined by average signal intensities as, e.g., in the Affymetrix software. Here we show that Affymetrix oligonucleotide probe signal distributions can be fitted by using a superposition of two normal or two extreme distributions, and that by using such distributions we can normalize data with high accuracy (parametric algorithm). We also developed a second algorithm (nonparametric) based on ranking of signal intensities which gave equal or better normalization than the parametric one. These approaches have been used for normalization of three sets of data obtained from cancer cell lines, peripheral blood mononuclear cells from patients with HIV infections, and adipose cells from patients with diabetes, and others. Both, parametric and nonparametric normalization procedures, were found to be superior when compared to the standard global normalization approach [Affymetrix Microarray Suite User Guide. Version 4.0 (2000)]. These results suggest that the new approaches may be helpful for microarray data normalization especially for comparison of clinical data where interpatient differences can be large and difficult to avoid. (C) 2002 Published by Elsevier Science Inc. C1 NCI, NIH, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Sidorov, IA (reprint author), NCI, NIH, Frederick, MD 21702 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 6 TC 16 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0020-0255 J9 INFORM SCIENCES JI Inf. Sci. PD OCT PY 2002 VL 146 IS 1-4 BP 67 EP 73 AR PII S0020-0255(02)00215-3 DI 10.1016/S0020-0255(02)00215-3 PG 7 WC Computer Science, Information Systems SC Computer Science GA 612BW UT WOS:000179054800005 ER PT J AU Valenzuela, JG AF Valenzuela, JG TI High-throughput approaches to study salivary proteins and genes from vectors of disease SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE insect saliva; massive cDNA sequencing; proteomics; salivary vaccine ID FLY LUTZOMYIA-LONGIPALPIS; MOSQUITO ANOPHELES-ALBIMANUS; INDUCED PLATELET-AGGREGATION; SIMULIUM-VITTATUM DIPTERA; NORTH-AMERICAN VECTOR; BUG CIMEX-LECTULARIUS; RHODNIUS-PROLIXUS; AEDES-AEGYPTI; CULICOIDES-VARIIPENNIS; ANTICOAGULANT ACTIVITY AB Blood-feeding arthropods have in their saliva a variety of molecules that affect the vertebrate host's hemostatic, inflammatory, and immune systems. The saliva of blood feeders also helps to facilitate infection of the pathogens they carry to the host, making vector saliva an attractive target to control pathogen transmission. The isolation and identification of salivary molecules from vectors of disease has been slow and difficult. Emerging technologies and new approaches in the fields of molecular biology and protein chemistry are facilitating this work. Massive sequencing of high quality, full-length cDNA libraries, coupled with proteomics and functional genomic approaches has led to the discovery of novel proteins, transcription products (genes), and biologic activities from the salivary glands of blood-feeding arthropods. This review focuses on the biologic activities identified in the saliva of various vectors of disease using classic biochemical and molecular biology approaches and new types of molecules and activities identified with high-throughput strategies. Published by Elsevier Science Ltd. C1 NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Valenzuela, JG (reprint author), NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, Bldg 4,Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 NR 68 TC 38 Z9 44 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD OCT PY 2002 VL 32 IS 10 BP 1199 EP 1209 AR PII S0965-1748(02)00083-8 DI 10.1016/S0965-1748(02)00083-8 PG 11 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 603QD UT WOS:000178570300003 PM 12225911 ER PT J AU Wang, TL Zhang, X Li, JJ AF Wang, TL Zhang, X Li, JJ TI The role of NF-kappa B in the regulation of cell stress responses SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Review DE antioxidant responses; NF-kappa B; oxidative stress; signal transduction; transcription factors ID MANGANESE SUPEROXIDE-DISMUTASE; NECROSIS-FACTOR-ALPHA; BREAST-CANCER CELLS; HUMAN-IMMUNODEFICIENCY-VIRUS; RADIATION-INDUCED APOPTOSIS; IONIZING-RADIATION; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; HELA-CELLS AB Nuclear factor-kappaB (NF-kappaB) is one of the key regulatory molecules in oxidative stress-induced cell activation. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and must translocate into the nucleus to regulate effector gene expression. A family of inhibitory proteins, IkappaBs, binds to NF-kappaB and masks its nuclear localization signal domain and therefore controls the translocation of NF-kappaB. Exposure of cells to extracellular stimuli that perturb redox balance results in rapid phosphorylation, ubiquitination, and proteolytic degradation Of IkappaBs. This process frees NF-kappaB from the NF-kappaB/IkappaB complexes and enables NF-kappaB to translocate to the nucleus where it regulates gene transcription. Many effector genes including those encoding cytokines and adhesion molecules are in turn regulated by NF-kappaB. NF-kappaB is also an essential component of ionizing radiation (IR)-triggered signal transduction pathways that can lead to cell death or survival. The purpose of this review is to briefly summarize the recent progress in the studies of the role of reactive oxygen species (ROS), cytokines and ionizing radiation in NF-kappaB activation. (C) 2002 Elsevier Science B.V All rights reserved. C1 City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Res, Duarte, CA 91010 USA. NCI, Ctr Canc Res, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. RP Li, JJ (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Res, 1500 Duarte Rd, Duarte, CA 91010 USA. RI Zhang, Xia/B-8152-2008 OI Zhang, Xia/0000-0002-9040-1486 NR 110 TC 192 Z9 204 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD OCT PY 2002 VL 2 IS 11 BP 1509 EP 1520 AR PII S1567-5769(02)00058-9 DI 10.1016/S1567-5769(02)00058-9 PG 12 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 612VG UT WOS:000179095700001 PM 12433052 ER PT J AU Debrabant, A Lee, N Pogue, GP Dwyer, DM Nakhasi, HL AF Debrabant, A Lee, N Pogue, GP Dwyer, DM Nakhasi, HL TI Expression of calreticulin P-domain results in impairment of secretory pathway in Leishmania donovani and reduced parasite survival in macrophages SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Leishmania; chaperone; calreticulin; folding; macrophage; secretion ID PROTEIN-DISULFIDE-ISOMERASE; ENDOPLASMIC-RETICULUM; ACID-PHOSPHATASE; TRYPANOSOMATID PARASITES; QUALITY-CONTROL; GENE; CHAPERONES; IDENTIFICATION; PROMASTIGOTES; GLYCOPROTEINS AB The secretory proteins of Leishmania are thought to be involved in the parasite survival inside the insect vector or mammalian host. It is clear from studies in higher eukaryotes that proper folding in the endoplasmic reticulum and targeting out of the endoplasmic reticulum is critical for the function of secretory proteins. The endoplasmic reticulum chaperones such as calreticulin play an important role in the quality control of secretory proteins. However, very little is known about the secretory pathway of trypanosomatid parasites such as Leishmania. In the present study, we show that overexpression of the P-domain of Leishmania donovani calreticulin in transfected L donovani resulted in a significant reduction in the secretion of the parasite secretory acid phosphatases. This effect is associated with an intracellular accumulation of active enzyme in these transfected parasites. In addition, parasites expressing the P-domain calreticulin showed a significant decrease in survival inside human macrophages. This study suggests that altering the function of an endoplasmic reticulum chaperone such as calreticulin in Leishmania may affect the targeting of proteins that are associated with the virulence of the parasite during their trafficking through the parasite secretory pathway. (C) 2002 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. C1 US FDA, Div Emerging & Transfus Transmitted Dis, LBPUA, OBRR,CBER, Bethesda, MD 20892 USA. Large Scale Biol, Vacaville, CA USA. NIAID, Cell Biol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Debrabant, A (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, LBPUA, OBRR,CBER, Bldg 29,Room 425,HFM-310,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 42 TC 26 Z9 28 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD OCT PY 2002 VL 32 IS 11 BP 1423 EP 1434 AR PII S0020-7519(02)00134-0 DI 10.1016/S0020-7519(02)00134-0 PG 12 WC Parasitology SC Parasitology GA 612KK UT WOS:000179073800009 PM 12350377 ER PT J AU Engels, EA Sarkar, C Daniel, RW Gravitt, PE Verma, K Quezado, M Shah, KV AF Engels, EA Sarkar, C Daniel, RW Gravitt, PE Verma, K Quezado, M Shah, KV TI Absence of simian virus 40 in human brain tumors from northern India SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE simian virus 40; brain tumor; India; ependymoma; choroid plexus tumor ID HUMAN PLEURAL MESOTHELIOMA; DNA-SEQUENCES; T-ANTIGEN; JC VIRUS; BK VIRUS; SV40; SIMIAN-VIRUS-40; POLYOMAVIRUSES; CONTAMINATION; EPENDYMOMAS AB Simian virus 40 (SV40), a monkey polyomavirus, was a contaminant of early poliovirus vaccines administered to millions of individuals in the 1950s and early 1960s. SV40 causes brain tumors in laboratory animals, and SV40 DNA sequences have been variably identified in human choroid plexus tumors and ependymomas. We studied the possible association between SV40 and human brain tumors in northern India, where humans have frequent contact with SV40-infected rhesus macaques. DNA from pathologic specimens from 33 ependymomas, 14 choroid plexus tumors and 18 control brain tissues (contused brain, brain metastases) was extracted and analyzed under masked conditions. We used real-time PCR to detect and quantify SV40 (T antigen) and human (GAPDH) DNA sequences. The SV40 PCR assay detected as few as 10 copies of SV40 DNA and had a linear range from 1x10(2) to 1x10(6) copies. SV40 DNA was detected in I specimen (an ependymoma). However, few SV40 DNA copies were detected in this sample (<10 copies, equivalent to <1 copy/350 cells, based on simultaneous GAPDH quantification), and SV40 was not detected when this sample was retested. Our findings do not support a role for SV40 in choroid plexus tumors or ependymomas from northern India. (C) 2002 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. All India Inst Med Sci, Dept Pathol, New Delhi 110029, India. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NCI, Dept Pathol, Rockville, MD USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8010, Rockville, MD 20852 USA. NR 32 TC 32 Z9 35 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2002 VL 101 IS 4 BP 348 EP 352 DI 10.1002/ijc.10621 PG 5 WC Oncology SC Oncology GA 590EN UT WOS:000177805500007 PM 12209959 ER PT J AU Engels, EA Clark, E Aledort, LM Goedert, JJ Whitby, D AF Engels, EA Clark, E Aledort, LM Goedert, JJ Whitby, D TI Kaposi's sarcoma-associated herpesvirus infection in elderly Jews and non-Jews from New York City SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus); Kaposi's sarcoma; aged (elderly); Jews ID HUMAN-HERPESVIRUS-8 SEROPREVALENCE; POPULATION; ISRAEL; PREVALENCE AB Background Worldwide, Kaposi's sarcoma (KS) occurs in immunocompetent elderly adults, especially men. Elderly Jews have relatively high KS risk, but it is unclear whether this indicates heightened prevalence of KS-associated herpesvirus (KSHV), the KS agent. We studied Jewish and non-Jewish patients at a New York City geriatrics clinic. Methods We measured plasma antibodies against K8.1 (a KSHV glycoprotein) by enzyme immunoassay and against viral latency antigens by immunofluorescence assay. Individuals positive by either were considered KSHV-seropositive. Titres were performed for positive subjects. We used polymerase chain reaction to quantify circulating KSHV DNA. Results Of 467 subjects (median age 80 years), 40 were KSHV-seropositive (8.6%). Seroprevalence was 8.8% among Jews (18 of 204), similar to other religious groups, and did not differ by sex or region of birth. However, K8.1 antibody titres were higher in men than women (geometric mean titre 177 versus 35, P = 0.03) and increased with age (P = 0.02). The K8.1 titres were higher in three people from Central/Eastern Europe (1280, 1280, 320), all of whom were Jewish, than in others (geometric mean titre 39, P = 0.006). The single person with detectable circulating KSHV (457 copies/million cells) had the highest titre (5120). Conclusions The KSHV seroprevalence was not elevated among elderly Jews, despite their known high risk for KS. However, among KSHV-seropositive individuals, K8.1 titres were highest in subgroups at greatest risk for KS (men, older individuals, people from Central/Eastern Europe) and may identify individuals with poor immune control of KSHV replication during asymptomatic infection. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Mt Sinai Hosp, Dept Geriatr, New York, NY 10029 USA. Mt Sinai Hosp, Dept Med, New York, NY 10029 USA. NCI, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD 21701 USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. FU PHS HHS [N01-C0-56000, N01-C0-12400] NR 19 TC 7 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2002 VL 31 IS 5 BP 946 EP 950 DI 10.1093/ije/31.5.946 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 621MM UT WOS:000179593600011 PM 12435765 ER PT J AU Katdare, M Kopelovich, L Telang, N AF Katdare, M Kopelovich, L Telang, N TI Efficacy of chemopreventive agents for growth inhibition of Apc [+/-] 1638NCOL colonic epithelial cells SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE chemopreventive agents; growth inhibition; colonic epithelial cells ID FAMILIAL ADENOMATOUS POLYPOSIS; BREAST-CANCER PREVENTION; ABERRANT PROLIFERATION; INTERMEDIATE BIOMARKERS; ESTRADIOL METABOLISM; INTESTINAL TUMORS; MIN MOUSE; MICE; APOPTOSIS; ONCOGENE AB Germline mutations of the Apc tumor suppressor gene result in increased risk for gastrointestinal carcinogenesis. The Apc1638N [+/-] mouse exhibits accelerated gastrointestinal carcinogenesis that is modifiable by select pharmacological and dietary agents. Experiments in the present study were conducted on a subculturable epithelial 1638NCOL cell line established from histologically normal colon of Apc1638N [+/-] mouse to examine the effects of selected chemopreventive agents that differ in their mechanism of action. Extent of growth arrest, number of cell population doublings, cell cycle progression and aneuploid G(0)/G(1): S + G(2)/M ratio represented the quantitative endpoints for the susceptibility and efficacy of chemopreventive agents. Treatment of exponentially growing 1638NCOL cells with maximum cytostatic dose of 9cisRA, DFMO or SUL (100 muM) produced a 60-70% growth arrest, that with TAM and AMF (10 muM) produced a 20-40% growth arrest, while that with OLT (100 muM) produced a 25% growth arrest. This response was associated with corresponding decrease in the number of cell population doubling. 9cisRA, SUL or AMF increased the aneuploid G(0/)G(1): S + G(2)/M ratio by inducing G(1) checkpoint arrest, while DFMO, TAM and OLT decreased the ratio by inducing G(2) checkpoint arrest. Thus, cell cycle phase-dependent susceptibility of the Apc [+/-] 1638NCOL cell line to mechanistically distinct chernopreventive agents validates a novel colon epithelial cell culture model for mechanistic, preventive or therapeutic studies on Apc regulated colon carcinogenesis. C1 Rockefeller Univ, Strang Canc Res Lab, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Telang, N (reprint author), Rockefeller Univ, Strang Canc Res Lab, 1230 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [N01-CN-85141, CA 29502-S1] NR 35 TC 7 Z9 7 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD OCT PY 2002 VL 10 IS 4 BP 427 EP 432 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 596JT UT WOS:000178162100011 PM 12239589 ER PT J AU Tchounwou, PB Ashour, BA Moreland-Young, C Ragheb, DA Romeh, AA Goma, E El-Sheikh, S Lidell, FP Ibitayo, O Assad, JC AF Tchounwou, Paul B. Ashour, Bassem A. Moreland-Young, Curtina Ragheb, Didair A. Romeh, Ahmed A. Goma, El-Adarosy El-Sheikh, Sayed Lidell, Frances P. Ibitayo, Olurominiyi Assad, Jean-Claude TI Health Risk Assessment of Pesticide Usage in Menia El-Kamh Province of Sharkia Governorate in Egypt SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE Pesticides; rural communities; Egypt; health risk assessment AB Menia El-Kamh province of the Sharkia Governorate constitutes one of the largest agricultural areas in Egypt. About 88% of the nearly 472,000 people living in this province rely on agricultural activities for subsistence. Several pesticides including organochloride, organophosphorus, carbamate, and pyrethroid insecticides, fungicides, and herbicides are commonly used in citrus, vegetable and other crop-growing areas to increase agricultural productivity. However, their use has also been associated with several cases of pesticide poisoning. In this research, we conducted a field survey to assess the knowledge, attitudes, and practices of the farmer's community regarding the safe use of pesticides. We also evaluated the residual concentrations of selected pesticides in water, soil, milk, fish, and orange samples, and estimated the potential health risks associated with the exposure to these pesticides. Data obtained from the field survey indicate that more than 95% of farm workers do not practice safety precautions during pesticide formulation and application; leading to a considerable prevalence of pesticide-related illnesses in this agricultural community. Pesticide residues in various environmental samples varied greatly; from below detection levels (3-5 ng) to as high as 325 ppb depending on the matrix of interest, and the specific pesticide of concern. The analysis of health risk estimates indicated that chlorpyrifos, DDT, dimethoate, methomyl, and larvin did not pose a direct hazard to human health, although present in water, milk, orange, and/or fish. However, aldicarb, and carbosulfan levels exceeded the reference doses, indicating a great potential for systemic toxicity, especially in children who are considered to be the most vulnerable population subgroup. The upper-bound values of cancer risk from DDT exposure were estimated to be about 8 (adults), and 55 (children) excess cancers in a population of one million. C1 [Tchounwou, Paul B.] Jackson State Univ, Sch Sci & Technol, Environm Toxicol Res Lab, NIH Ctr Environm Hlth, Jackson, MS 39217 USA. [Ashour, Bassem A.; Ragheb, Didair A.; Romeh, Ahmed A.; Goma, El-Adarosy; El-Sheikh, Sayed] Zagazig Univ, Dept Plant Protect, Fac Agr, Zagazig, Egypt. [Moreland-Young, Curtina; Lidell, Frances P.; Ibitayo, Olurominiyi] Jackson State Univ, Sch Liberal Arts, Dept Publ Policy, Jackson, MS USA. [Assad, Jean-Claude] Jackson State Univ, Sch Business, Dept Business Adm, Jackson, MS USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Sch Sci & Technol, Environm Toxicol Res Lab, NIH Ctr Environm Hlth, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsums.edu FU American-Egyptian Universities Linkage Project [FRCU/USAID 263-0211, 93/04/16] FX This research was financially supported the American-Egyptian Universities Linkage Project Phase II, FRCU/USAID 263-0211, Grant No. 93/04/16. This paper was recently presented orally at Workshop on "Environmental Risk Assessment and Its Role in Fostering Sustainable and Just Public Policies" on May 22, 2002 at the Four Seasons Hotel in Cairo, Egypt. From Jackson State University (USA), we thank Dr. Ronald Mason-President, Dr. Abdul Mohamed-Dean of the School of Science and Technology, and Dr. Ally Mack-Director of the Office of International Programs; and from Zagazig University (Egypt) we thank Dr. Mohamed Amer-President, Dr. Hassan Rabei-Dean of the Faculty of Agriculture, and Dr. Abdel Menen Badr-Director of Six-of-October Agriculture Project, for their technical support in this project. Our sincere thanks and appreciations are extended to all the farmers from Menia El-Kamh province who kindly participated in our field survey. NR 31 TC 4 Z9 4 U1 0 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD OCT PY 2002 VL 3 IS 10 BP 1082 EP 1094 DI 10.3390/i3101082 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA V33IC UT WOS:000209011500006 ER PT J AU Yan, X Fong, YT Wolf, D Shen, H Zaharia, M Wang, J Wolf, G Li, F Lee, GD Cao, W AF Yan, X Fong, YT Wolf, D Shen, H Zaharia, M Wang, J Wolf, G Li, F Lee, GD Cao, W TI XY99-5038 promotes long-term survival of cultured retinal neurons SO INTERNATIONAL JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; apoptosis; basic fibroblast growth factor; Yan Xin Life Science Technology ID OXIDATIVE STRESS; ALZHEIMERS-DISEASE; CELL-CULTURE; PROTEIN OXIDATION; APOPTOSIS; AGE; EXPRESSION; GROWTH; PROLIFERATION; PATHOGENESIS AB We have previously reported that XY99-5038, a preparation from a specific formula of Traditional Chinese Medicine, could effectively inhibit hydrogen peroxide-induced retinal cell death. In the present study, we investigated the possibility of XY99-5038 to prolong neuronal survival in a long-term retinal neuronal culture. Basic fibroblast survival factor (bFGF), a potent neurotrophic factor, was employed as comparable agent. Retinas of 0-2 days old Sprague-Dawley rats were isolated and dissociated. The cells were maintained in tissue culture for tip to 9 weeks in a synthetic serum-free media. XY99-5038 (100 ng/ml) or a vehicle was added to culture every 3-4 days, starting at the first week of culturing. The number of cells were counted and compared for each time point and treatment. Cell viability was also determined by MTT assay, whereas apoptotic cell death was evaluated by the TUNEL assay. XY99-5038 treatment significantly reduced cell loss, increased cell viability, and inhibited apoptosis in this long-term retinal neuronal culture. Our data also show that the protective effect of XY99-5038 is more potent than that of bFGF. Our data suggest that XY99-5038 could be beneficial to the prolongation of neuron survival. C1 Univ Oklahoma, Hlth Sci Ctr, Dean A McGee Eye Inst, Dept Ophthalmol, Oklahoma City, OK 73104 USA. Inst Chongqing Tradit Chinese Med, Chongqing, Sichuang, Peoples R China. Amer Biol Engn Sci Res Inst, Glendale, CA USA. Amer New Med Inst, New York, NY USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Sherbrooke, Sherbrooke, PQ J1K 2R1, Canada. NIA, NIH, Baltimore, MD 21224 USA. RP Cao, W (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dean A McGee Eye Inst, Dept Ophthalmol, 608 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. NR 40 TC 4 Z9 4 U1 2 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0020-7454 J9 INT J NEUROSCI JI Int. J. Neurosci. PD OCT PY 2002 VL 112 IS 10 BP 1209 EP + DI 10.1080/00207450290026166 PG 22 WC Neurosciences SC Neurosciences & Neurology GA 615CN UT WOS:000179228400006 PM 12587523 ER PT J AU Sprince, NL Park, H Zwerling, C Lynch, CF Whitten, PA Thu, K Gillette, PP Burmeister, LF Alavanja, MCR AF Sprince, NL Park, H Zwerling, C Lynch, CF Whitten, PA Thu, K Gillette, PP Burmeister, LF Alavanja, MCR TI Risk factors for machinery-related injury among Iowa farmers: A case-control study nested in the agricultural health study SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article DE agriculture; farm machinery; injuries ID NEW-YORK FARMERS; HAZARD SURVEILLANCE; FAMILY HEALTH; PREVALENCE; POPULATION; OPERATORS; ALABAMA AB Farm machinery is a major cause of injury morbidity and mortality among farmers. This case-control study assessed risk factors for machinery-related injuries among Iowa farmers. A screener questionnaire sent to 6,999 farmers in 1998 identified 205 farmers who had machinery-related injuries requiring medical advice/treatment in the previous year. Possible risk factors for injury were assessed among these farmers compared with 473 farmers with no injury in the previous year. A multiple logistic regression analysis showed significant associations between machinery related injury and hours per week spent on farmwork (OR = 2.02; 95% CI 1.38-2.94), fewer years of farming experience (OR = 1.79; 95% CI 1.14-2.79), wearing a hearing aid (OR = 4.37; 95% Cl 1.55-12.25), and a high CAGE score suggesting problem drinking (OR = 2.49; 95% CI 1.00-6.19). This is the first study to show associations between machinery-related injury and hearing impairment, problem drinking, and fewer years of farming experience. These findings may be useful for future interventions to decrease injuries related to farm machinery. C1 Univ Iowa, Coll Publ Hlth, Dept Occupat & Environm Med, Iowa City, IA 52242 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA 52242 USA. NCI, Rockville, MD USA. No Illinois Univ, Dept Anthropol, De Kalb, IL 60115 USA. Ewha Womans Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. RP Sprince, NL (reprint author), Univ Iowa, Coll Publ Hlth, Dept Occupat & Environm Med, 100 Oakdale Campus, Iowa City, IA 52242 USA. FU ODCDC CDC HHS [R49/CCR703640-10] NR 34 TC 32 Z9 33 U1 1 U2 4 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD OCT-DEC PY 2002 VL 8 IS 4 BP 332 EP 338 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 609TU UT WOS:000178921300008 PM 12412851 ER PT J AU Bell, W Clapp, R Davis, D Epstein, S Farber, E AF Bell, W Clapp, R Davis, D Epstein, S Farber, E TI Carcinogenicity of saccharin in laboratory animals and humans: Letter to Dr. Harry Conacher of Health Canada SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article ID HUMAN BLADDER-CANCER; ARTIFICIAL SWEETENERS; DOSE-RESPONSE; RAT AB We appreciate this opportunity to provide input to the Health Protection Branch's (HPB's) review of the artificial sweetener saccharin. Concerns with regard to the safety of saccharin are of great public. health significance and of great interest to the public because saccharin is consumed by tens of millions of people, including children and fetuses. Any evidence of carcinogenesis-and there is ample such evidence-of such a widely used chemical should spur health officials to minimize human exposure to it. It is worth noting that on October 31, 1997, the Board of Scientific Counselors of the National Toxicology Program, a unit of the National Institute of Environmental Health Sciences (NIEHS), voted not to delist saccharin from its Report on Carcinogens.dagger C1 Canadian Assoc Phys Environm, Salmon Arm, BC, Canada. Boston Univ, Dept Environm Hlth, Boston, MA 02215 USA. World Resources Inst, Hlth Environm & Dev Program, Washington, DC 20006 USA. Univ Illinois, Sch Publ Hlth, Med Ctr, Chicago, IL 60680 USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Univ Toronto, Toronto, ON, Canada. Univ Houston, Houston, TX 77004 USA. Univ Guelph, Dept Human Biol & Nutr Sci, Guelph, ON N1G 2W1, Canada. Ctr Sci Publ Interest, Washington, DC USA. Ctr Sci Publ Interest, Ottawa, ON, Canada. Frederick Canc Res Ctr, Pathol Lab, Chem Carcinogenesis Program, Frederick, MD USA. Univ Sussex, Sci Policy Res Unit, Brighton BN1 9RH, E Sussex, England. NCI, Bethesda, MD 20892 USA. Athabasca Univ, Ctr Nat & Human Sci, Athabasca, AB, Canada. RP Bell, W (reprint author), Canadian Assoc Phys Environm, Salmon Arm, BC, Canada. NR 29 TC 7 Z9 7 U1 0 U2 10 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD OCT-DEC PY 2002 VL 8 IS 4 BP 387 EP 393 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 609TU UT WOS:000178921300015 PM 12412858 ER PT J AU Otis, CN Krebs, PA Albuquerque, A Quezado, MM San Juan, X Sobel, ME Merino, MJ AF Otis, CN Krebs, PA Albuquerque, A Quezado, MM San Juan, X Sobel, ME Merino, MJ TI Loss of heterozygosity of p53, BRCA1, VHL, and estrogen receptor genes in breast carcinoma: Correlation with related protein products and morphologic features SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE LOH; breast carcinoma; p53; BRCA1 ID LASER CAPTURE MICRODISSECTION; TUMOR-SUPPRESSOR GENE; TISSUE MICROARRAYS; SOMATIC MUTATIONS; ALLELIC LOSS; CANCER; PROLIFERATION; POLYMORPHISMS; ACCUMULATION; WOMEN AB Correlation of loss of heterozygosity (LOH) of p53, BRCA1, VHL, and estrogen receptor (ER) genes with the expression of related protein products and morphologic features predictive of aggressive biologic behavior was investigated to determine the significance of LOH in these genes. DNA from 35 formalin-fixed, paraffin-embedded breast carcinomas was obtained by microdissection of histologic sections. LOH was determined by polymerase chain reaction (PCR) using primers TP53, D3S1038, D17S855, and ESR for p53, VHL, BRCA1, and ER genes, respectively. p53, ER, and progesterone receptor (PR) protein expression was evaluated by immunohistochemistry. Morphologic evaluation included histologic type, and histologic and nuclear grades. TP53 LOH was identified in 13 (52%), BRCA1 LOH in 3 (17%), VHL LOH in 1 (4%), and ER LOH in 4 (21%) of 25, 17, 24, and 19 informative cases, respectively. p53 and ER protein expression was identified in 20 (57%) and 25 (71%) cases, respectively. TP53 LOH directly correlated with both high histologic and nuclear grade (P<0.01). BRCA1, VHL, and ER LOH was not frequent enough for correlation to morphologic features. Although 4 of 4 ER and 7 of 13 p53 LOH cases expressed related proteins, LOH did not correlate with protein expression. TP53 LOH may be an event contributing to aggressive biologic behavior since it is strongly associated with high histologic and nuclear grade. Missense or nonsense mutations may explain the absence of detectable p53 protein in 6 of 13 cases with p53 LOH All 4 ER LOH cases expressed ER protein. BRCA1 and VHL LOH is infrequent in sporadic breast carcinoma. C1 Tufts Univ, Sch Med, Baystate Med Ctr, Dept Pathol, Springfield, MA 01199 USA. Natl Canc Inst, Surg Pathol Sect, Bethesda, MD USA. Natl Canc Inst, Mol Pathol Sect, Bethesda, MD USA. RP Otis, CN (reprint author), Tufts Univ, Sch Med, Baystate Med Ctr, Dept Pathol, Springfield, MA 01199 USA. NR 35 TC 10 Z9 10 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD OCT PY 2002 VL 10 IS 4 BP 237 EP 245 DI 10.1177/106689690201000401 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 625WH UT WOS:000179838200001 PM 12490973 ER PT J AU Mohri, M Reinach, PS Kanayama, A Shimizu, M Moskovitz, J Hisatsune, T Miyamoto, Y AF Mohri, M Reinach, PS Kanayama, A Shimizu, M Moskovitz, J Hisatsune, T Miyamoto, Y TI Suppression of the TNF alpha-induced increase in IL-1 alpha expression by hypochlorite in human corneal epithelial cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID NF-KAPPA-B; METHIONINE SULFOXIDE REDUCTASE; TAURINE CHLORAMINE; PSEUDOMONAS-AERUGINOSA; GENE-EXPRESSION; NITRIC-OXIDE; ACTIVATION; NEUTROPHILS; INHIBITION; MYELOPEROXIDASE AB PURPOSE. In response to injury, activated neutrophils release tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO). TNFalpha in turn causes human corneal epithelial cells to secrete interleukin (IL)-1alpha, whereas MPO results in formation of HClO/ OCl-. The effect of HClO/OCl- on the expression of the IL-1alpha gene and protein is unknown. The current study was undertaken to examine in immortalized human corneal epithelial cells whether NaOCl alters TNFalpha-induced increases in expression of IL-1alpha gene and protein. METHODS. Semiquantitative RT-PCR and EUSA characterized IL-1alpha gene and protein expression, respectively. TNFalpha-induced nuclear transfer of nuclear factor (NF)-kappaB was measured by electrophoretic mobility shift assay (EMSA). The a isoform of inhibitory protein kappaB (IkappaBalpha) was identified by Western blot analysis. RESULTS. Exposure to NaOCl (0.75 mM) for 10 minutes caused suppression of TNFa-induced increases in IL-1alpha mRNA and protein, declines in NFkappaB nuclear transfer, and a modification of IkappaBalpha, based on a bandshift detected by Western blot analysis. Modified IkappaBalpha became resistant to TNFalpha-induced proteolysis. Methionine sulfoxide reductase A (MsrA, 10 muM) eliminated the NaOCl-induced IkappaBalpha bandshift. CONCLUSIONS. NaOCl oxidizes IkappaBalpha at methionine residues and thereby suppresses dissociation Of IkappaBalpha from NFkappaB. Decreased dissociation could in turn suppress TNFalpha-induced activation of NFkappaB, resulting in declines in expression of IL-1alpha gene and protein. These effects suggest that release of HClO/OCl- in vivo by activated neutrophils may counterbalance TNFalpha-induced NFkappaB-dependent secretion if IL-1alpha and suppress an excessive inflammatory reaction. C1 Univ Tokyo, Grad Sch Frontier Sci, Dept Integrated Biosci, Kashiwa, Chiba 2778562, Japan. SUNY, Dept Biol Sci, Coll Optometry, New York, NY USA. Univ Tokyo, Grad Sch Agr & Life Sci, Dept Appl Biol Chem, Tokyo, Japan. NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Miyamoto, Y (reprint author), Univ Tokyo, Grad Sch Frontier Sci, Dept Integrated Biosci, Biosci Bldg 402,5-1-5 Kashiwanoha, Kashiwa, Chiba 2778562, Japan. NR 35 TC 27 Z9 28 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2002 VL 43 IS 10 BP 3190 EP 3195 PG 6 WC Ophthalmology SC Ophthalmology GA 598WA UT WOS:000178298400008 PM 12356823 ER PT J AU Haughey, NJ Mattson, TP AF Haughey, NJ Mattson, TP TI Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins tat and gp120 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Workshop on Metabolic Disorders in the Pathogenesis of Nervous System Damage in HIV-Infected Drug Abusers CY SEP 28-29, 1999 CL BETHESDA, MARYLAND SP NIDA DE AIDS; Alzheimer; dementia; glutamate; hippocampus; NMDA; oxidative stress ID IMMUNODEFICIENCY-VIRUS TYPE-1; NECROSIS-FACTOR-ALPHA; RECEPTOR-MEDIATED NEUROTOXICITY; ENVELOPE GLYCOPROTEIN GP120; COAT PROTEIN; ARACHIDONIC-ACID; NITRIC-OXIDE; GLUTAMATE UPTAKE; GLIAL-CELLS; TNF-ALPHA AB Patients with AIDS often develop cognitive and motor dysfunction that results from damage to synapses and death of neurons in brain regions such as the hippocampus and basal ganglia. This brain syndrome, called AIDS dementia or HIV encephalitis, is believed to result from the infection of one or more populations of mitotic brain cells with HIV-1, which then release viral proteins that are toxic to neurons. Two neurotoxic HIV-1 proteins have been identified, the viral coat protein gp120 and the transcription regulator Tat. Each of these proteins can induce apoptosis of cultured neurons and can render neurons vulnerable to excitotoxicity and oxidative stress. Gp120 and Tat also cause neuronal dysfunction and death in rodents in vivo. Both gp120 and Tat disrupt neuronal calcium homeostasis by perturbing calcium-regulating systems in the plasma membrane and endoplasmic reticulum. Accordingly, drugs that stabilize cellular calcium homeostasis can protect neurons against the toxic effects of gp120 and Tat. By altering voltage-dependent calcium channels, glutamate receptor channels, and membrane transporters, the HIV-1 proteins promote calcium overload, oxyradical production, and mitochondrial dysfunction. A better understanding of how gp120 and Tat disrupt neuronal calcium homeostasis may lead to the development of novel treatments for AIDS patients. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, TP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 4F02,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 71 TC 111 Z9 118 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS JI JAIDS PD OCT 1 PY 2002 VL 31 SU 2 BP S55 EP S61 DI 10.1097/01.QAI.0000028065.79472.50 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 612ML UT WOS:000179080000005 PM 12394783 ER PT J AU Royal, W Khalsa, JH Francis, H AF Royal, W Khalsa, JH Francis, H TI Proceedings of a workshop on metabolic disorders in the pathogenesis of nervous system damage in HIV-infected drug abusers SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material C1 NIDA, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Khalsa, JH (reprint author), NIDA, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, 6001 Execut Blvd,Room 5198,MSC 9593, 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 1525-4135 J9 JAIDS JI JAIDS PD OCT 1 PY 2002 VL 31 SU 2 BP S27 EP S28 DI 10.1097/01.QAI.0000027928 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 612ML UT WOS:000179080000001 ER PT J AU Hertle, RW Chan, CC Galita, DA Maybodi, M Crawford, MA AF Hertle, RW Chan, CC Galita, DA Maybodi, M Crawford, MA TI Neuroanatomy of the extraocular muscle tendon enthesis in macaque, normal human, and patients with congenital nystagmus SO JOURNAL OF AAPOS LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the American-Association-for-Pediatric-Ophthalmology-and-Strabismus CY MAR 21, 2002 CL SEATTLE, WASHINGTON SP Amer Assoc Pediat Ophthalmol & Strabisum ID EXTRA-OCULAR MUSCLES; INNERVATED MYOTENDINOUS CYLINDERS; NERVE-ENDINGS; PALISADE ENDINGS; FINE-STRUCTURE; PROPRIOCEPTION; STRABISMUS; SURGERY; ORGANS; MONKEY AB Purpose: To search for the presence of, and qualitatively characterize the microscopic anatomy of, nerve terminals in the tendino-scleral (enthesial) area of the extraocular muscle tendon. Methods. Extraocular rectus muscle tendino-scleral specimens from a macaque monkey, a normal human, cadavers, and patients with congenital nystagmus were obtained and studied with transmission electron microscopy. Results: Enthesial neurovascular structures were identified in all specimens. The enthesial area showed structures consisting of myelinated and unmyelinated nerve fibers with associated supporting vascular capillaries. Qualitative analysis showed anomalous neurovascular structures were in the enthesis of patients with congenital nystagmus. Conclusions: This study confirms the presence of normal and abnormal neural anatomy in the enthesial area of the extraocular muscle tendon. Neurovascular abnormalities in the enthesial part of the extraocular muscle tendon may be a result of, or contribute to, disease pathogenesis. If these structures are related to afferent central nervous system input, then disruption of them during surgery might influence postoperative outcome. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Hertle, RW (reprint author), Childrens Hosp Columbus, Pediat Ophthalmol Associates Inc, 555 S 18th St,Suite 4C, Columbus, OH 43205 USA. NR 33 TC 16 Z9 19 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD OCT PY 2002 VL 6 IS 5 BP 319 EP 327 DI 10.1067/mpa.2002.127116 PG 9 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 606QZ UT WOS:000178745800009 PM 12381992 ER PT J AU Santelli, J Rogers, AS AF Santelli, J Rogers, AS TI Parental permission, passive consent, and "children" in research SO JOURNAL OF ADOLESCENT HEALTH LA English DT Letter C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NICHHD, Bethesda, MD 20892 USA. RP Santelli, J (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NR 4 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD OCT PY 2002 VL 31 IS 4 BP 303 EP 304 AR PII S1054-139X(02)00443-3 DI 10.1016/S1054-139X(02)00443-3 PG 2 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 599EF UT WOS:000178320600002 PM 12359374 ER PT J AU Bachrach, C Newcomer, SF AF Bachrach, C Newcomer, SF TI Addressing bias in intervention research: Summary of a workshop SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE adolescents; bias; ethics; intervention research C1 NICHHD, Demog & Behav Sci Branch, Bethesda, MD 20892 USA. RP Newcomer, SF (reprint author), NICHHD, Demog & Behav Sci Branch, Bldg 61E,Room 8B07, Bethesda, MD 20892 USA. NR 1 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD OCT PY 2002 VL 31 IS 4 BP 311 EP 321 AR PII S1054-139X(02)00395-6 DI 10.1016/S1054-139X(02)00395-6 PG 11 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 599EF UT WOS:000178320600004 PM 12359376 ER PT J AU Chang, R White, JD AF Chang, R White, JD TI Asian therapies for cancer - Coming of age SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Editorial Material ID PROMYELOCYTIC LEUKEMIA C1 Inst East West Med, New York, NY 10016 USA. NCI, Off Complementary & Alternat Med, NIH, Bethesda, MD 20892 USA. RP Chang, R (reprint author), Inst East West Med, 102 E 30th St, New York, NY 10016 USA. NR 4 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD OCT PY 2002 VL 8 IS 5 BP 541 EP 543 DI 10.1089/107555302320825039 PG 3 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 612RK UT WOS:000179089100006 PM 12470433 ER PT J AU White, JD AF White, JD TI The National Cancer Institute's perspective and agenda for promoting awareness and research on alternative therapies for cancer SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article; Proceedings Paper CT 1st International Conference on Asian Therapies for Cancer CY FEB 28-MAR 03, 2001 CL NEW YORK, NEW YORK ID CELL LUNG-CANCER; DOSE VITAMIN-C; HYDRAZINE SULFATE; SHARK CARTILAGE; CONTROLLED TRIAL; PLACEBO; MEDICINE; ANGIOGENESIS; PREVALENCE; ONCOLOGY AB The widespread use of a variety of nutritional, psychologic, and natural medical approaches, collectively termed complementary and alternative medicine (CAM), has been well documented. Recent surveys demonstrate that between 9% and 91% of U.S. patients with cancer use CAM therapies at some time after their diagnosis. However, there is a paucity of data available to indicate whether these CAM practices are efficacious and safe. Despite, or possibly because of, this controversy there has been considerable growth of interest in CAM by the American public. This interest has also resulted in a growth of research resources. Concurrently there has been an expansion of interest in the conventional medical establishment manifested by the creation of Departments of CAM or Integrative Medicine in respected conventional medical institutions, privately funded research centers and the National Institutes of Health (NIH) Office of Alternative Medicine (OAM)/National Center for Complementary and Alternative Medicine (NCCAM). Communication between conventional and unconventional practitioners is beginning. These changes are leading to a conversion of the dialogue about CAM from a focus on "quackery" to an exploration of the potential for novel therapeutics and the beginnings of focused, rigorous research. The National Cancer Institute is establishing programs to increase the amount and quality of CAM cancer research, support the production of high-quality CAM cancer information, and facilitate the dialogue between CAM practitioners and cancer researchers. C1 NCI, Off Complementary & Alternat Med, NIH, Bethesda, MD 20892 USA. RP White, JD (reprint author), NCI, Off Complementary & Alternat Med, NIH, Execut Plaza N,Sutie 102, Bethesda, MD 20892 USA. NR 25 TC 15 Z9 15 U1 3 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD OCT PY 2002 VL 8 IS 5 BP 545 EP 550 DI 10.1089/107555302320825048 PG 6 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 612RK UT WOS:000179089100007 PM 12470434 ER PT J AU Jenkins, AJ Keenan, RM Henningfield, JE Cone, EJ AF Jenkins, AJ Keenan, RM Henningfield, JE Cone, EJ TI Correlation between pharmacological effects and plasma cocaine concentrations after smoked administration SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID INTRAVENOUS COCAINE; HUMANS; PHARMACOKINETICS; PHARMACODYNAMICS; ROUTE; BASE C1 NIDA, Addict Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. RP Jenkins, AJ (reprint author), Off Cuyahoga Cty Coroner, 11001 Cedar Ave, Cleveland, OH 44106 USA. NR 27 TC 30 Z9 33 U1 3 U2 10 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2002 VL 26 IS 7 BP 382 EP 392 PG 11 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 610DG UT WOS:000178945000001 PM 12422990 ER PT J AU Preston, KL Epstein, DH Cone, EJ Wtsadik, AT Huestis, MA Moolchan, ET AF Preston, KL Epstein, DH Cone, EJ Wtsadik, AT Huestis, MA Moolchan, ET TI Urinary elimination of cocaine metabolites in chronic cocaine users during cessation SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID HUMANS; SALIVA; PLASMA; DISPOSITION; EXCRETION; MARIJUANA; SMOKING; ABUSE C1 NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. ConeChem Res LLC, Severna Pk, MD USA. RP Preston, KL (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 18 TC 28 Z9 28 U1 0 U2 8 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2002 VL 26 IS 7 BP 393 EP 400 PG 8 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 610DG UT WOS:000178945000002 PM 12422991 ER PT J AU Yu, H Hatzivassiloglou, V Rzhetsky, A Wilbur, WJ AF Yu, H Hatzivassiloglou, V Rzhetsky, A Wilbur, WJ TI Automatically identifying gene/protein terms in MEDLINE abstracts SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE automatic term recognition; synonym; mark up; information extraction; knowledge acquisition; natural language processing ID GENETIC NOMENCLATURE; PROTEIN NAMES; TEXT; LOCUSLINK; ARTICLES; REFSEQ AB Motivation. Natural language processing (NLP) techniques are used to extract information automatically from computer-readable literature. In biology, the identification of terms corresponding to biological substances (e.g., genes and proteins) is a necessary step that precedes the application of other NLP systems that extract biological information (e.g., protein-protein interactions, gene regulation events, and biochemical pathways). We have developed GPmarkup (for "gene/protein-full name mark up"), a software system that automatically identifies gene/protein terms (i.e., symbols or full names) in MEDLINE abstracts. As a part of marking up process, we also generated automatically a knowledge source of paired gene/protein symbols and full names (e.g., LARD for lymphocyte associated receptor of death) from MEDLINE. We found that many of the pairs in our knowledge source do not appear in the current GenBank database. Therefore our methods may also be used for automatic lexicon generation. Results. GPmarkup has 73% recall and 93% precision in identifying and marking up gene/protein terms in MEDLINE abstracts. Availability: A random sample of gene/protein symbols and full names and a sample set of marked up abstracts can be viewed at http://www.cpmc.columbia.edu/homepages/yuh9001/GPmarkup/.Contact. hy52@columbia.edu. Voice: 212-939-7028; fax: 212-666-0140. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. Columbia Univ, Columbia Genome Ctr, Dept Med Informat, New York, NY 10032 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, H (reprint author), Columbia Univ, Dept Comp Sci, Mudd 471,116th, New York, NY 10029 USA. RI rzhetsky, andrey/B-6118-2012; OI Rzhetsky, Andrey/0000-0001-6959-7405 FU NIGMS NIH HHS [R01 GM61372-01A2] NR 33 TC 17 Z9 19 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 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT-DEC PY 2002 VL 35 IS 5-6 BP 322 EP 330 DI 10.1016/S1532-0464(03)00032-7 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 713VQ UT WOS:000184879000006 PM 12968781 ER PT J AU Powell, DA Anderson, LM Cheng, RYS Alvord, WG AF Powell, DA Anderson, LM Cheng, RYS Alvord, WG TI Robustness of the Chen-Dougherty-Bittner procedure against non-normality and heterogeneity in the coefficient of variation SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE DNA microarray technology; robustness; normality; coefficient of variation AB Chen, Dougherty, and Bittner [Y. Chen, E. R. Dougherty, and M. L. Bittner, J. Biomed. Opt. 2(4), 364-374 (1997)] provided the derivation of a probability density function (PDF) for a signal ratio from a DNA microarray. This PDF is potentially useful for testing whether a pair of signals from the same gene has a common mean. The derivation of the PDF assumes the normality of all signal distributions and a common coefficient of variation (CV) for all signals within a microarray. The testing procedure requires the calculation of a common confidence interval for a microarray, based on a maximum likelihood estimator of the "common" CV, and the determination of whether or not a ratio for a particular gene falls within this interval. This study used Monte Carlo techniques and demonstrated that the procedure is robust to violations of normality and also to constancy in the coefficients of variation. A closer examination of the dynamics of the procedure found that the robustness was the result of offsetting effects. The size of the confidence interval was increased as a result of higher estimates of the common CV, as the actual CV pattern became heterogeneous. This effect mitigated the inflation in the size of the ratio as a result of increasing CV heterogeneity. These findings suggest that the Chen-Dougherty-Bittner procedure may be used even if underlying assumptions do not hold. (C) 2002 Society of Photo-Optical Instrumentalion Engineers. C1 Natl Canc Inst, Data Management Serv, Frederick, MD 21702 USA. Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Alvord, WG (reprint author), Natl Canc Inst, Data Management Serv, POB B, Frederick, MD 21702 USA. OI Cheng, Robert/0000-0003-0287-6439 NR 6 TC 6 Z9 6 U1 0 U2 1 PU SPIE-INT SOCIETY OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2002 VL 7 IS 4 BP 650 EP 660 DI 10.1117/1.1501561 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 611KZ UT WOS:000179017400018 PM 12421134 ER PT J AU Gaponenko, V Altieri, AS Li, J Byrd, RA AF Gaponenko, V Altieri, AS Li, J Byrd, RA TI Breaking symmetry in the structure determination of (large) symmetric protein dimers SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE asymmetry; protein dimer; protein structure; pseudocontact shifts; residual dipolar coupling ID RESIDUAL DIPOLAR COUPLINGS; NUCLEAR-MAGNETIC-RESONANCE; HIGH-RESOLUTION STRUCTURE; PSEUDOCONTACT SHIFTS; MULTIDIMENSIONAL NMR; COMPLEX; MACROMOLECULES; SPECTRA; DOMAIN; DNA AB We demonstrate a novel methodology to disrupt the symmetry in the NMR spectra of homodimers. A paramagnetic probe is introduced sub-stoichiometrically to create an asymmetric system with the paramagnetic probe residing on only one monomer within the dimer. This creates sufficient magnetic anisotropy for resolution of symmetry-related overlapped resonances and, consequently, detection of pseudocontact shifts and residual dipolar couplings specific to each monomeric component. These pseudocontact shifts can be readily incorporated into existing structure refinement calculations and enable determination of monomer orientation within the dimeric protein. This methodology can be widely used for solution structure determination of symmetric dimers. C1 NCI, Struct Biophys Lab, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Struct Biophys Lab, POB B, Frederick, MD 21702 USA. RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 NR 39 TC 56 Z9 56 U1 5 U2 17 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2002 VL 24 IS 2 BP 143 EP 148 DI 10.1023/A:1020948529076 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 610FF UT WOS:000178949500006 PM 12495030 ER PT J AU Dobbins, DE Joe, B Hashiramoto, A Salstrom, JL Dracheva, S Ge, L Wilder, RL Remmers, EF AF Dobbins, DE Joe, B Hashiramoto, A Salstrom, JL Dracheva, S Ge, L Wilder, RL Remmers, EF TI Localization of the mutation responsible for osteopetrosis in the op rat to a 1.5-cM genetic interval on rat chromosome 10: Identification of positional candidate genes by radiation hybrid mapping SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE osteopetrosis; osteoclasts; bone homeostasis; op rats; radiation hybrid mapping ID CARBONIC-ANHYDRASE-II; BONE-RESORPTION; LINKAGE MAP; F2 CROSSES; H+-ATPASE; OSTEOCLASTS; DISEASE; EXPRESSION; RECEPTOR; ADHESION AB Osteopetrosis is caused by a heterogenous group of bone diseases that result in an increase in skeletal mass because of inadequate osteoclastic bone resorption. In the op osteopetrotic rat, the disease has been linked to a single genetic locus located at the proximal end of rat chromosome 10. In this study, we identified a 1.5-cM genetic interval that contains the mutation. We then generated an improved radiation hybrid (RH) map of this region to identify potential functional and positional candidates for the op gene. Using the rat genome radiation hybrid panel, we mapped 57 markers including 24 genes (14 that have not yet been mapped in the rat) and 10 expressed sequence tag markers. Included in the mapped genes are several candidate genes that might significantly influence the biochemical pathways involved in osteopetrosis. These include genes involved in osteoclast differentiation, apoptosis, and the functional capabilities of mature osteoclasts to resorb bone. Further analysis of the genes and expressed transcripts mapped to this region may yield important insights into the multifactorial control of osteoclast function and the mechanisms of failed bone homeostasis in diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis in which failed bone homeostasis is an instigating or exacerbating circumstance of the disease process. C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Dobbins, DE (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 30 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2002 VL 17 IS 10 BP 1761 EP 1767 DI 10.1359/jbmr.2002.17.10.1761 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 595GU UT WOS:000178100900004 PM 12369779 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, CE Everhart, JE TI Relationship of serum leptin concentration with bone mineral density in the United States population SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE leptin; bone mineral density; osteoporosis; epidemiology; Third National Health and Nutrition Examination Survey ID POSTMENOPAUSAL WOMEN; BIOCHEMICAL MARKERS; HORMONE REPLACEMENT; VERTEBRAL FRACTURES; BODY-COMPOSITION; MEN; MASS; OSTEOPOROSIS; PLASMA; ESTROGEN AB Overweight is associated with both higher bone mineral density (BMD) and higher serum leptin concentrations. In humans, little is known about the relationship of leptin concentration and bone density. We studied this relationship in a large, national population-based sample. Participants included 5815 adults in the Third U.S. National Health and Nutrition Examination Survey (NHANES III; 1988-1994) who underwent DXA of the proximal femur and measurement of fasting serum leptin. Mean +/- SE BMD (gm/cm(2)) of the total hip was 1.01 +/- 0.005 in men, 0.94 +/- 0.004 in premenopausal women, and 0.78 +/- 0.007 in postmenopausal women. Bone density increased with increasing leptin concentration in men (p = 0.003), premenopausal women (p < 0.001), and postmenopausal women (p < 0.001). However, after adjusting for body mass index (BMI) and other bone density-related factors, an inverse association emerged in men (p < 0.001), being most evident among men <60 years old. There was no association of leptin and BMD in premenopausal women (p = 0.66) or postmenopausal women (p = 0.69) in multivariate analysis. Controlling for leptin had no effect on the strong positive association of BMI and BMD in either men or women. Serum leptin concentration did not appear to affect directly BMD. If present, the association appeared to be limited to younger men who are at lower risk of osteoporosis. C1 Social & Sci Syst Inc, Silver Spring, MD 20910 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. FU NIDDK NIH HHS [N01-DK-6-2220] NR 40 TC 86 Z9 102 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2002 VL 17 IS 10 BP 1896 EP 1903 DI 10.1359/jbmr.2002.17.10.1896 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 595GU UT WOS:000178100900018 PM 12369793 ER PT J AU Limke, TL Rao, MS AF Limke, TL Rao, MS TI Neural stem cells in aging and disease SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE neural stem cell; Alzheimer's; Parkinson's; stroke; aging ID CILIARY NEUROTROPHIC FACTOR; CENTRAL-NERVOUS-SYSTEM; OLIGODENDROCYTES IN-VITRO; EPIDERMAL GROWTH-FACTOR; PSA-NCAM EXPRESSION; HUMAN SPINAL-CORD; PROGENITOR CELLS; PRECURSOR CELLS; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE AB Aging in the central nervous system is associated with progressive loss of function which is exacerbated by neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The two primary cell replacement strategies involve transplantation of exogenous tissue, and activation of proliferation of endogenous cells. Transplanted tissue is used to either directly replace lost tissue, or to implant genetically engineered cells that secrete factors which promote survival and/or proliferation. However, successful application of any cell replacement therapy requires knowledge of the complex relationships between neural stem cells and the more restricted neural and glial progenitor cells. This review focuses on recent advances in the field of stem cell biology of the central nervous system, with an emphasis on cellular and molecular approaches to replacing cells lost in neurodegenerative disorders. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Limke, TL (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 134 TC 28 Z9 37 U1 3 U2 9 PU CAROL DAVILA UNIV PRESS PI BUCHARESST PA 8 EROILOR SANITARI BLVD, BUCHARESST 76241, ROMANIA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD OCT-DEC PY 2002 VL 6 IS 4 BP 475 EP 496 DI 10.1111/j.1582-4934.2002.tb00451.x PG 22 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 650EA UT WOS:000181248600004 PM 12611637 ER PT J AU Ichise, M Toyama, H Innis, RB Carson, RE AF Ichise, M Toyama, H Innis, RB Carson, RE TI Strategies to improve neuroreceptor parameter estimation by linear regression analysis SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE positron emission tomography; graphical analysis; linear regression analysis; parameter estimation; noise-induced bias ID POSITRON EMISSION TOMOGRAPHY; GRAPHICAL ANALYSIS; PET; BINDING AB In an attempt to improve neuroreceptor distribution volume (V) estimates, the authors evaluated three alternative linear methods to Logan graphical analysis (GA): GA using total least squares (TLS), and two multilinear analyses, MA1 and MA2, based on mathematical rearrangement of GA equation and two-tissue compartments, respectively, using simulated and actual PET data of two receptor tracers, [(18)F]FCWAY and [(11)C]MDL 100,907. For simulations, all three methods decreased the noise-induced GA bias (up to 30%) at the expense of increased variability. The bias reduction was most pronounced for MA1, moderate to large for MA2, and modest to moderate for TLS. In addition, GA, TLS, and MA1, methods that used only a portion of the data (T > t*, chosen by an automatic process), showed a small V underestimation for [(11)C]MDL 100,907 with its slow kinetics, due to selection of t* before the true point of linearity. These noniterative methods are computationally simple, allowing efficient pixelwise parameter estimation. For tracers with kinetics that permit t* to be accurately identified within the study duration, MA1 appears to be the best. For tracers with slow kinetics and low to moderate noise, however, MA2 may provide the lowest bias while maintaining computational ease for pixelwise parameter estimation. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Ichise, M (reprint author), NIMH, Mol Imaging Branch, Bldg 1 B3-10,1 Ctr Ctr MSC0135, Bethesda, MD 20892 USA. EM masanori.ichise@nih.gov RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 22 TC 155 Z9 155 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2002 VL 22 IS 10 BP 1271 EP 1281 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 600PF UT WOS:000178399200015 PM 12368666 ER PT J AU Papanicolaou, DA Mullen, N Kyrou, I Nieman, LK AF Papanicolaou, DA Mullen, N Kyrou, I Nieman, LK TI Nighttime salivary cortisol: A useful test for the diagnosis of Cushing's syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL-FUNCTION; SCREENING-TEST; DEXAMETHASONE; HYPERCORTISOLISM; DISEASE; PLASMA; STATES; SENSITIVITY; DEPRESSION AB Clinical features such as weight gain, depression, hypertension, and menstrual irregularities, although common in the general population, may raise the possibility of Cushing's syndrome. Up to 30% of urine cortisol. and dexamethasone suppression screening tests may return an incorrect result, suggesting that better tests are needed. This study evaluated the utility of nighttime salivary cortisol measurement as a screening test for Cushing's syndrome. We evaluated 139 inpatients and 4 outpatients with possible Cushing's syndrome, 16 inpatients and 7 outpatients with other nonadrenal disorders, and 34 healthy outpatients. Using cut points that excluded all subjects without Cushing's syndrome, we compared the sensitivity for the detection of Cushing's syndrome of nighttime salivary cortisol levels (2330 and 2400 h for inpatients and bedtime for outpatients), simultaneous inpatient serum cortisol levels, and urine glucocorticoid excretion. An assay-specific inpatient 2400-h salivary cortisol or an outpatient bedtime salivary cortisol greater than 550 ng/dl (15.2 nmol/liter) identified 93% of patients with Cushing's syndrome (confidence interval, 89-98%) and excluded all individuals without the disorder. Salivary cortisol measurements worked as well as plasma measurements and better than urine glucocorticoid excretion. We concluded that bedtime salivary cortisol measurement is a practical and accurate screening test for the diagnosis of Cushing's syndrome. C1 NICHHD, NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Emory Univ, Dept Internal Med, Atlanta, GA 30322 USA. NICHHD, NIH, Warren Grant Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), NICHHD, NIH, Pediat & Reprod Endocrinol Branch, Bldg 10,Room 9D42 MSC 1583,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@nih.gov NR 33 TC 131 Z9 140 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2002 VL 87 IS 10 BP 4515 EP 4521 DI 10.1210/jc.2002-020534 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 604YZ UT WOS:000178649800019 PM 12364428 ER PT J AU Stefan, N Bunt, JC Salbe, AD Funahashi, T Matsuzawa, Y Tataranni, PA AF Stefan, N Bunt, JC Salbe, AD Funahashi, T Matsuzawa, Y Tataranni, PA TI Plasma adiponectin concentrations in children: Relationships with obesity and insulinemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADIPOSE-SPECIFIC PROTEIN; PIMA-INDIANS; RISK-FACTORS; RESISTANCE; WEIGHT; APM1; ADOLESCENTS; EXPRESSION; SECRETION; PUBERTY AB Adiponectin, a novel adipokine with anti-inflammatory and insulin-sensitizing properties, has been found to have independent negative associations with obesity and hyperinsulinemia/insulin resistance in adults. We measured fasting plasma adiponectin and insulin concentrations and body composition (dual-energy x-ray absorptiometry or doubly labeled water) in 30 5-yr-old (11 boys and 19 girls) and 53 10-yr-old (17 boys and 36 girls) Pima Indian children. A subgroup of 20 children (5 boys and 15 girls) had all measurements at both 5 and 10 yr of age. Cross-sectionally, plasma adiponectin concentrations were negatively correlated with percentage body fat and fasting plasma insulin concentrations at both 5 yr (r = -0.35, P = 0.06, r = -0.42, P = 0.02) and 10 yr (r = -0.46, P = 0.001, r = -0.38, P = 0.005) of age. At age 10 yr, percentage body fat (P = 0.03) but not fasting plasma insulin (P = 0.59) was independently associated with fasting plasma adiponectin concentrations. Longitudinally, plasma adiponectin concentrations decreased with increasing adiposity. In summary, these results confirm our previously reported findings in adults of an inverse relationship between plasma adiponectin concentrations and adiposity in children. Longitudinal analyses indicated that hypoadiponectinemia is a consequence of the development of obesity in childhood. We did not find evidence that adiponectin is an early mediator of obesity-induced insulin resistance, a preliminary observation that needs to be confirmed in studies using a more direct measurement of insulin action than the one used in this investigation. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Suita, Osaka 5650871, Japan. RP Stefan, N (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St,Room 5-41, Phoenix, AZ 85016 USA. EM nstefan@mail.nih.gov OI Stefan, Norbert/0000-0002-2186-9595 NR 34 TC 196 Z9 206 U1 0 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2002 VL 87 IS 10 BP 4652 EP 4656 DI 10.1210/jc.2002-020694 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 604YZ UT WOS:000178649800041 PM 12364452 ER PT J AU Coon, SL del Olmo, E Young, WS Klein, DC AF Coon, SL del Olmo, E Young, WS Klein, DC TI Melatonin synthesis enzymes in Macaca mulatta: Focus on arylalkylamine N-acetyltransferase (EC 2.3.1.87) SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HYDROXYINDOLE-O-METHYLTRANSFERASE; PINEAL-GLAND; MESSENGER-RNA; EXPRESSION; RETINA; CELLS; LIGHT; LOCALIZATION; SUPPRESSION; PRIMATE AB Arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC 2.3.1.87) plays a unique transduction role in vertebrate physiology as the key interface between melatonin production and regulatory mechanisms. Circulating melatonin is elevated at night in all vertebrates, because AANAT activity increases in the pineal gland in response to signals from the circadian clock. Circadian regulation of melatonin synthesis is implicated in a variety of human problems, including jet lag, shift work, insomnia, and abnormal activity rhythms in blind persons. In this report AANAT was studied in the rhesus macaque to better understand human melatonin regulation. AANAT mRNA is abundant in the pineal gland and retina, but not elsewhere; AANAT mRNA is uniformly distributed in the pineal gland, but is limited primarily to the photoreceptor outer segments in the retina. Day and night levels of pineal and retinal AANAT mRNA are similar. In contrast, AANAT activity and protein increase more than 4-fold at night in both tissues. The activity of hydroxyindole-O-methyltransferase, the last enzyme in melatonin synthesis, is tonically high in the pineal gland, but is nearly undetectable in the retina; hydroxyindole O-methyltransferase mRNA levels exhibited a similar pattern. This supports the view that the source of circulating melatonin in primates is the pineal gland. The discovery in this study that rhesus pineal AANAT mRNA is high at all times is of special importance because it shows that posttranscriptional control of this enzyme plays a dominant role in regulating melatonin synthesis. C1 NICHHD, Dev Neurobiol Lab, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. NIMH, Sect Neural Gene Express, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHHD, Dev Neurobiol Lab, Sect Neuroendocrinol, NIH, 49 Convent Dr,MSC 4480,Bldg 49,Room 6A-82, Bethesda, MD 20892 USA. EM klein@helix.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 NR 37 TC 61 Z9 64 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2002 VL 87 IS 10 BP 4699 EP 4706 DI 10.1210/jc.2002-020683 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 604YZ UT WOS:000178649800049 PM 12364461 ER PT J AU Cooper, GS Dooley, MA Treadwell, EL Clair, EWS Gilkeson, GS AF Cooper, GS Dooley, MA Treadwell, EL Clair, EWS Gilkeson, GS TI Risk factors for development of systemic lupus erythematosus: Allergies, infections, and family history SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE systemic lupus erythematosus; autoimmune disease; sulfa drug; herpes zoster; infections ID BARR-VIRUS INFECTION; AUTOIMMUNE-DISEASES; MULTIPLE-SCLEROSIS; REVISED CRITERIA; UNITED-STATES; HERPES-ZOSTER; EPIDEMIOLOGY; ENGLAND; CLASSIFICATION; ANTIBODIES AB We examined risk factors for systemic lupus erythematosus (SLE) in 265 recently diagnosed patients in North Carolina and South Carolina and 355 control subjects identified through driver's license records and frequency matched to patients by age, sex, and state. Analyses were limited to exposures before diagnosis (cases) or reference year (control subjects). SLE patients were more likely than control subjects to report a history of allergy to medications (odds ratio [OR] 3.1, 95% confidence interval [CI], 2.1-4.5), particularly to antibiotics. SLE risk increased with history of shingles (OR 2.5, 95 % CI 1.1-5.9) and with frequent (more than once per year) cold sores in the 3 years before diagnosis (OR 2.8, 95 % CI 1.4-5.4). There was little association with history of mononucleosis, a marker of late infection with Epstein-Barr virus, implanted medical devices, or hepatitis B vaccination. History of lupus in parents or siblings was associated with an increased risk (OR 3.3, 95% CI 1.2-8.6). Further research is needed to clarify whether medication allergies and specific infectious agents are involved in the etiology of SLE. Published by Elsevier Science Inc. C1 NIEHS, Epidemiol Branch, Durham, NC 27709 USA. Univ N Carolina, Div Rheumatol, Chapel Hill, NC USA. E Carolina Univ, Sch Med, Div Rheumatol, Greenville, NC USA. Duke Univ, Med Ctr, Div Rheumatol Allergy & Clin Immunol, Durham, NC USA. Ralph H Johnson Vet Adm Med Ctr, Med Res Serv, Charleston, SC USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch, A3-05,POB 12233, Durham, NC 27709 USA. NR 35 TC 50 Z9 52 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD OCT PY 2002 VL 55 IS 10 BP 982 EP 989 AR PII S0895-4356(02)00429-8 DI 10.1016/S0895-4356(02)00429-8 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 615JE UT WOS:000179241400005 PM 12464374 ER PT J AU Crowell, DH Kulp, TD Kapuniai, LE Hunt, CE Brooks, LJ Weese-Mayer, DE Silvestri, J Ward, SD Corwin, M Tinsley, L Peucker, M AF Crowell, DH Kulp, TD Kapuniai, LE Hunt, CE Brooks, LJ Weese-Mayer, DE Silvestri, J Ward, SD Corwin, M Tinsley, L Peucker, M CA CHIME Study Grp TI Infant polysomnography: Reliability and validity of infant arousal assessment SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article; Proceedings Paper CT 8th Conference of the European-Society-for-the-Study-and-Prevention-of-Infant-Death CY MAY 30-JUN 03, 1999 CL JERUSALEM, ISRAEL SP European Soc Study & Prevent Infant Death DE infant; polysomnography; transient EEG arousal; reliability; validity ID FULL-TERM; DEATH-SYNDROME; SLEEP STATES; AGE; EEG; ORGANIZATION; PREMATURE; NEWBORNS; CHILDREN; APNEA AB Infant arousal scoring based on the Atlas Task Force definition of transient EEG arousal was evaluated to determine (1) whether transient arousals can be identified and assessed reliably in infants and (2) whether arousal and no-arousal epochs scored previously by trained raters can be validated reliably by independent sleep experts. Phase I for inter-and intrarater reliability scoring was based on two datasets of sleep epochs selected randomly from nocturnal polysomnograms of healthy full-term, preterm, idiopathic apparent life-threatening event cases, and siblings of Sudden Infant Death Syndrome infants of 35 to 64 weeks postconceptional age. After training, test set I reliability was assessed and discrepancies identified. After retraining, test set 2 was scored by the same raters to determine interrater reliability. Later, three raters from the trained group rescored test set 2 to assess inter- and intrarater reliabilities. Interrater and intrarater reliability k's, With 95% confidence intervals, ranged from substantial to almost perfect levels of agreement. Interrater reliabilities for spontaneous arousals were initially moderate and then substantial. During the validation phase, 315 previously scored epochs were presented to four sleep experts to rate as containing arousal or no-arousal events. Interrater expert agreements were diverse and considered as noninterpretable. Concordance in sleep experts' agreements, based on identification of the previously sampled arousal and no-arousal epochs, was used as a secondary evaluative technique. Results showed agreement by two or more experts on 86% of the Collaborative Home Infant Monitoring Evaluation Study arousal scored events. Conversely, only 1% of the Collaborative Home Infant Monitoring Evaluation Study-scored no-arousal epochs were rated as an arousal. In summary, this study presents an empirically tested model with procedures and criteria for attaining improved reliability in transient EEG arousal assessments in infants using the modified Atlas Task Force standards. With training based on specific criteria, substantial inter- and intrarater agreement in identifying infant arousals was demonstrated. Corroborative validation results were too disparate for meaningful interpretation. Alternate evaluation based on concordance agreements supports reliance on infant EEG criteria for assessment. Results mandate additional confirmatory validation studies with specific training on infant EEG arousal assessment criteria. C1 John A Burns Sch Med, Dept Pediat, Honolulu, HI 96826 USA. Kapiolani Med Ctr Women & Children, Honolulu, HI 96826 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Rush Univ, Rush Presbyterian St Lukes Med Ctr, Rush Childrens Hosp, Dept Pediat, Chicago, IL 60612 USA. Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NHLBI, Natl Ctr Sleep Disorders Res, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. RP Crowell, DH (reprint author), John A Burns Sch Med, Dept Pediat, 1319 Punahou St, Honolulu, HI 96826 USA. FU NICHD NIH HHS [HD29060, HD29056, HD28971, HD29071, HD29073, HD34625, HD29067] NR 45 TC 14 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0736-0258 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD OCT PY 2002 VL 19 IS 5 BP 469 EP 483 DI 10.1097/00004691-200210000-00010 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 624LR UT WOS:000179761600010 PM 12477992 ER PT J AU Tan, AR Headlee, D Messmann, R Sausville, EA Arbuck, SG Murgo, AJ Melillo, G Zhai, SP Figg, WD Swain, SM Senderowicz, AM AF Tan, AR Headlee, D Messmann, R Sausville, EA Arbuck, SG Murgo, AJ Melillo, G Zhai, SP Figg, WD Swain, SM Senderowicz, AM TI Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DEPENDENT KINASE INHIBITOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; BREAST-CARCINOMA CELLS; DRUG FLAVOPIRIDOL; CYCLE ARREST; APOPTOSIS; CANCER; GROWTH; BCL-2; INDUCTION AB Purpose: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. Patients and Methods: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. Results: Dose-limiting neutropenia developed at doses 2: 52.5 mg/m(2)/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 mumol/L (range, 1.3 to 4.2 mumol/L), 3.2 mumol/L (range, 1.7 to 4.8 mumol/L), and 3.9 mumol/L (1.8 to 5.1 mumol/L), respectively. Twelve patients had stable disease for 3 months, with a median duration of 6 months (range, 3 to 11 months). Conclusion: The recommended phase 11 doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway. C1 NCI, Canc Res Ctr, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. Aventis Pharmaceut, Bridgewater, NJ USA. RP Senderowicz, AM (reprint author), NIDCR, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Rm 211,30 Convent Dr, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016; OI Swain, Sandra/0000-0002-1320-3830 NR 37 TC 102 Z9 107 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2002 VL 20 IS 19 BP 4074 EP 4082 DI 10.1200/JCO.2002.01.043 PG 9 WC Oncology SC Oncology GA 601LK UT WOS:000178447300017 PM 12351605 ER PT J AU Leonard, GD Zhuang, SH Grem, JL AF Leonard, GD Zhuang, SH Grem, JL TI Epirubicin, cisplatin, and protracted venous-infusion fluorouracil in advanced esophagogastric cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ESOPHAGEAL CANCER; TRIAL; 5-FLUOROURACIL C1 NCI, Bethesda, MD 20892 USA. RP Leonard, GD (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 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 1 PY 2002 VL 20 IS 19 BP 4124 EP 4125 DI 10.1200/JCO.2002.99.125 PG 2 WC Oncology SC Oncology GA 601LK UT WOS:000178447300028 PM 12351613 ER PT J AU Penzak, SR Acosta, EP Turner, M Edwards, DJ Hon, YY Desai, HD Jann, MW AF Penzak, SR Acosta, EP Turner, M Edwards, DJ Hon, YY Desai, HD Jann, MW TI Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT 41st Interscience Conference on Antimicrobial Agents and Chemotherapy CY DEC 16-20, 2001 CL CHICAGO, ILLINOIS ID IMMUNODEFICIENCY-VIRUS INFECTION; P-GLYCOPROTEIN; PROTEASE INHIBITORS; CYTOCHROME-P450 3A; ENTEROCYTE CYP3A4; ORAL AVAILABILITY; DRUG TRANSPORT; ABSORPTION; HUMANS; CELLS AB Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small. C1 Mercer Univ, So Sch Pharm, Dept Pharm Practice, Atlanta, GA USA. Univ Alabama, Div Clin Pharmacol, Birmingham, AL 35294 USA. Wayne State Univ, Coll Pharm, Detroit, MI USA. RP Penzak, SR (reprint author), NIH, Clin Pharmacokinet Res Lab, Ctr Clin, Dept Pharm, Bldg 10,Room 1N 257, Bethesda, MD 20892 USA. NR 35 TC 31 Z9 33 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2002 VL 42 IS 10 BP 1165 EP 1170 DI 10.1177/009127002237991 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 597BN UT WOS:000178202400013 PM 12362932 ER PT J AU Pezawas, L Stamenkovic, M Jagsch, R Ackerl, S Putz, C Stelzer, B Moffat, RR Schindler, S Aschauer, H Kasper, S AF Pezawas, L Stamenkovic, M Jagsch, R Ackerl, S Putz, C Stelzer, B Moffat, RR Schindler, S Aschauer, H Kasper, S TI A longitudinal view of triggers and thresholds of suicidal behavior in depression SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID RECURRENT BRIEF DEPRESSION; GENERAL HEALTH-CARE; PSYCHIATRIC OUTPATIENTS; PSYCHOLOGICAL-PROBLEMS; CLINICAL-FEATURES; AFFECTIVE-ILLNESS; MAJOR DEPRESSION; PREVALENCE; PERSONALITY; COMORBIDITY AB Background. Recurrent brief depressive disorder (RBD) and major depressive disorder (MDD) share the same diagnostic picture of full-blown depression and are both associated with increased suicide attempt rates. However, longitudinal diagnostic shifts from RBD to MDD or vice versa, called "combined depression" (CD), have demonstrated a substantially higher risk of suicide attempts in epidemiologic and clinical studies. Following the stress-diathesis model of suicidal behavior, we compared possible triggers and thresholds for suicidal behavior among patients with RBD, MDD and CD. RBD and MDD diag noses were based on DSM-IV criteria. Furthermore, the goal of this study was to determine if impulsivity as an underlying factor could explain high suicide attempt rates in CD. Method: A structured clinical interview evaluating comorbid Axis I and II disorders and RBD and a battery of instruments assessing suicidal behavior were administered to 10 1 patients with RBD (N = 27), MDD (N = 33), or CD (N = 41). Results: Patients with CD showed significantly higher (p < .05) scores on measures of suicidal behavior in comparison with RBD and MDD patients. Together with comorbid substance abuse and marital status, CD was among the highest-ranking risk factors for suicide attempts. Impulsivity was identified as a major underlying factor, predicting 80.7% of suicide attempts. Conclusion: CD seems to be an important clinical risk factor for the prediction of suicide attempts, similar to risk factors such as substance use disorders and borderline personality disorder. All of these factors share the same diathesis for increased impulsivity and suicidal ideation, which could explain comorbidity and suicidal behavior. The coexistence of a greater propensity for suicidal ideation and impulsivity in RBD might also explain why such patients are more prone to attempt suicide, even if they do not, in the case of RBD, meet the duration criteria for MDD. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Univ Vienna, Dept Clin Psychol, Vienna, Austria. RP Pezawas, L (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr 4S235, Bethesda, MD 20892 USA. OI Pezawas, Lukas/0000-0002-1329-6352 NR 60 TC 21 Z9 21 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2002 VL 63 IS 10 BP 866 EP 873 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 608VA UT WOS:000178866700003 PM 12416595 ER PT J AU Kohama, K Nonaka, K Hosokawa, R Shum, L Ohishi, M AF Kohama, K Nonaka, K Hosokawa, R Shum, L Ohishi, M TI TGF-beta-3 promotes scarless repair of cleft lip in mouse fetuses SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE fetal surgery; mesenchymal cells; organ culture; cyclin; tenascin ID GROWTH-FACTOR-BETA; FETAL WOUND REPAIR; TGF-BETA; PALATE; EXPRESSION; MICE; CELLS; FIBROBLASTS; FUSION; FACTOR-BETA-3 AB TGF-P3 mediates epithelial-mesenchymal transformation during normal fusion of lip and palate, but how TGF-P3 functions during cleft lip repair remains unexplored. We hypothesize that TGF-P3 promotes fetal cleft lip repair and fusion by increasing the availability of mesenchymal cells. In this investigation, we demonstrated that cleft lips in mouse fetuses were repaired by fetal surgery, producing scarless fusion. At the site of the operation, we first observed an infusion of platelets expressing TGF-beta3, followed by increased expression of cyclin D1 and tenascin-C, and coupled with increased mesenchymal cell proliferation. In an ex vivo serumless culture system, cleft lip explants fused in the presence of exogenous TGF-beta3. Cultured lips also showed up-regulation in cyclin D1 and tenascin-C expression. These findings suggest that microsurgical repair of cleft lip in the fetus that produced scarless fusion is mediated by TGF-P3 regulation of mesenchymal cell proliferation and migration at the site of repair. C1 Kyushu Univ, Grad Sch Dent Sci, Higashi Ku, Fukuoka 8128582, Japan. Kyushu Univ, Div Oral Hlth Growth & Dev, Higashi Ku, Fukuoka 8128582, Japan. Kyushu Univ, Fac Med Dent, Div Maxillofacial Diagnost & Surg, Higashi Ku, Fukuoka 8128582, Japan. NIH, Cartilage Biol & Orthopaed Branch, Bethesda, MD 20892 USA. RP Ohishi, M (reprint author), Kyushu Univ, Grad Sch Dent Sci, Higashi Ku, Maidashi 3-1-1, Fukuoka 8128582, Japan. NR 30 TC 25 Z9 32 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2002 VL 81 IS 10 BP 688 EP 694 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 599FP UT WOS:000178323700007 PM 12351667 ER PT J AU Silver, J Slud, E Takamoto, K AF Silver, J Slud, E Takamoto, K TI Statistical equilibrium wealth distributions in an exchange economy with stochastic preferences SO JOURNAL OF ECONOMIC THEORY LA English DT Article DE equilibrium; wealth distribution; stochastic preferences; gamma distribution; Markov model; exchange market ID MARKETS; AGENTS AB We describe an exchange market consisting of many agents with stochastic preferences for two goods. When individuals are indifferent between goods, statistical mechanics predicts that goods and wealth will have steady-state gamma distributions. Simulation studies show that gamma distributions arise for a broader class of preference distributions. We demonstrate this mathematically in the limit of large numbers of individual agents. These studies illustrate the potential power of a statistical mechanical approach to stochastic models in economics and suggest that gamma distributions will describe steady-state wealths for a class of stochastic models with periodic redistribution of conserved quantities. Journal of Economic Literature Classification Numbers: C15, C62, C73, D3, D5. (C) 2002 Elsevier science (USA). C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Math, College Pk, MD 20742 USA. RP Silver, J (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. OI Silver, Jonathan/0000-0001-9231-6368 NR 22 TC 29 Z9 29 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-0531 J9 J ECON THEORY JI J. Econ. Theory PD OCT PY 2002 VL 106 IS 2 BP 417 EP 435 DI 10.1006/jeth.2001.2897 PG 19 WC Economics SC Business & Economics GA 620EP UT WOS:000179521300008 ER PT J AU Eskandari, F Cizza, G AF Eskandari, F Cizza, G TI Cortisol, DHEA, the Holy Grail and the fountain of youth SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Editorial Material C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Eskandari, F (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 2 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD OCT PY 2002 VL 25 IS 9 BP 753 EP 753 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 603FK UT WOS:000178548000003 PM 12398230 ER PT J AU McKeown, RE Weed, DL AF McKeown, RE Weed, DL TI Ethics in epidemiology and public health II. Applied terms SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID RISK; INFORMATION; SCIENCE; PRIVACY AB This is the second part of a two part glossary on terms used in public health ethics. This glossary focuses on terms related to the professional practice of epidemiology and public health. C1 Univ S Carolina, Dept Epidemiol & Biostat, Norman J Arnold Sch Publ Hlth, Columbia, SC 29208 USA. Natl Canc Inst, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD USA. RP McKeown, RE (reprint author), Univ S Carolina, Dept Epidemiol & Biostat, Norman J Arnold Sch Publ Hlth, Columbia, SC 29208 USA. NR 31 TC 8 Z9 8 U1 0 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD OCT PY 2002 VL 56 IS 10 BP 739 EP 741 DI 10.1136/jech.56.10.739 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 595ZX UT WOS:000178139100011 PM 12239197 ER PT J AU Wang, SQ Lakatta, EG Cheng, H Zhou, ZQ AF Wang, SQ Lakatta, EG Cheng, H Zhou, ZQ TI Adaptive mechanisms of intracellular calcium homeostasis in mammalian hibernators SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Editorial Material DE hibernation; Ca2+ metabolism; adaptation; excitation-contraction coupling; homeostasis ID GROUND-SQUIRREL; SARCOPLASMIC-RETICULUM; TEMPERATURE-DEPENDENCE; CARDIAC MYOCYTES; VENTRICULAR-FIBRILLATION; RAT; CONTRACTION; CELLS; HEART; CA2+ AB Intracellular Ca2+ homeostasis is a prerequisite for a healthy cell life. While cells from some mammals may suffer dysregulation of intracellular Ca2+ levels under certain deleterious and stressful conditions, including hypothermia and ischemia, cells from mammalian hibernators exhibit a remarkable ability to maintain a homeostatic intracellular Ca2+ environment. Compared with cells from non-hibernators, hibernator cells are characterized by downregulation of the activity of Ca2+ channels in the cell membrane, which helps to prevent excessive Ca2+ entry. Concomitantly, sequestration of Ca2+ by intracellular Ca2+ stores, especially the sarcoplasmic/endoplasmic reticulum, is enhanced to keep the resting levels of intracellular Ca2+ stable. An increase in stored Ca2+ in heart cells during hibernation ensures that the levels of Ca2+ messenger are sufficient for forceful cell contraction under conditions of hypothermia. Maintenance of Na+ gradients, via Na+-Ca2+ exchangers, is also important in the Ca2+ homeostasis of hibernator cells. Understanding the adaptive mechanisms of Ca2+ regulation in hibernating mammals may suggest new strategies to protect nonhibernator cells, including those of humans, from Ca2+-induced dysfunction. C1 Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Coll Life Sci, Beijing 100871, Peoples R China. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Wang, SQ (reprint author), Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Coll Life Sci, Beijing 100871, Peoples R China. NR 48 TC 59 Z9 71 U1 2 U2 14 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD OCT PY 2002 VL 205 IS 19 BP 2957 EP 2962 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 604ZZ UT WOS:000178652100001 PM 12200399 ER PT J AU Leveille, SG Fried, L Guralnik, JM AF Leveille, SG Fried, L Guralnik, JM TI Disabling symptoms - What do older women report? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE activities of daily living; aged; epidemiology; pain; balance ID SENIORS TRIAL FAST; KNEE OSTEOARTHRITIS; RANDOMIZED TRIAL; ELDERLY PEOPLE; RISK-FACTORS; HEALTH; DISABILITY; COMMUNITY; ADULTS; EXERCISE AB OBJECTIVE: To answer the question, "What do older disabled women report as the main symptoms causing their disability?" DESIGN: Cross-sectional study of 876 women aged 65 and older who participated in the second interview of the Women's Health and Aging Study, a longitudinal study of community-living women, representing the one third of older women with at least mild to moderate disability. MEASUREMENTS AND MAIN RESULTS: Women were asked to identify the symptom and the condition that was the main cause of disability in basic and instrumental activities of daily living, and lower extremity mobility. Musculoskeletal pain symptoms were reported as the main cause of disability by at least one third of women with each type of disability. Other symptoms that were less frequently reported as main causes of disability were weakness, fatigue, and unsteadiness. Fear of falls was reported by 14% (95% confidence interval, 11.2% to 17.6%) of 472 women with disability in bathing. When asked to report on the main condition causing their disability, many women responded, "old age" or "no specific disease," but were able to identify symptoms causing their disabilities. CONCLUSIONS: Musculoskeletal pain was the most common cause of disability reported by older women, followed by weakness and balance difficulties. Greater attention to symptoms that interfere with daily activities of older persons may reduce the burden of disability. C1 Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Leveille, SG (reprint author), Hebrew Rehabil Ctr Aged, Res & Training Inst, 1200 Ctr St, Boston, MA 02131 USA. FU NCHHSTP CDC HHS [PSC10.11.93004]; NIA NIH HHS [N01 AG12112, N01 AG012112] NR 35 TC 68 Z9 68 U1 1 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2002 VL 17 IS 10 BP 766 EP 773 DI 10.1046/j.1525-1497.2002.20229.x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 605KF UT WOS:000178676500004 PM 12390552 ER PT J AU Fry, TJ Mackall, CL AF Fry, TJ Mackall, CL TI Interleukin-7 and immunorestoration in HIV: Beyond the thymus SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Review ID T-CELL HOMEOSTASIS; BONE-MARROW TRANSPLANTATION; IN-VIVO; IL-7; IMMUNODEFICIENCY; RESPONSES; THYMOPOIESIS; REGENERATION; INCREASES; INFECTION AB One of the hallmarks of untreated HIV infection is a progressive loss of effective immunity to both HIV-associated and non-HIV antigens. Combination antiretroviral therapy can frequently control viral replication, resulting in variable levels of immune reconstitution, but has not resulted in restoration of effective immunity to the virus. Understanding the limitations of immune reconstitution following highly active antiretroviral therapy (HAART) and identifying approaches to enhance immunity in this context may not only improve outcome for patients with HIV infection but could also provide insight for immune reconstitution in other conditions associated with T cell depletion. C1 NIH, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fry, TJ (reprint author), NIH, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res, Bldg 10,Room 13N240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 26 TC 18 Z9 18 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD OCT PY 2002 VL 11 IS 5 BP 803 EP 807 DI 10.1089/152581602760404603 PG 5 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 608ML UT WOS:000178850000007 PM 12427286 ER PT J AU Kang, EM De Witte, M Malech, H Morgan, RA Carter, C Leitman, SF Childs, R Barrett, AJ Little, R Tisdale, JF AF Kang, EM De Witte, M Malech, H Morgan, RA Carter, C Leitman, SF Childs, R Barrett, AJ Little, R Tisdale, JF TI Gene therapy-based treatment for HIV-positive patients with malignancies SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW TRANSPLANTATION; HEMATOPOIETIC PROGENITOR CELLS; CHRONIC MYELOGENOUS LEUKEMIA; FIBRONECTIN FRAGMENT CH-296; GRAFT-VERSUS-LEUKEMIA; NON-HODGKINS-LYMPHOMA; PERIPHERAL-BLOOD; REPOPULATING CELLS; NONHUMAN-PRIMATES AB Gene therapy for the treatment of HIV has long been a goal of many investigators. The majority of trials have involved the use of lymphocytes transduced with vectors promoting resistance to HIV infection or replication. Unfortunately, the results have been less than encouraging with low-level marking and, more importantly, clearance of these lymphocytes from the circulation. Conversely, gene-modified hematopoietic stem cells appear able to introduce foreign transgenes while avoiding immunologic clearance. Furthermore, the use of less toxic conditioning regimens for allogeneic transplantation provides an attractive approach to conferring HIV resistance while allowing treatment of HIV-related disorders such as malignancies. This combination of nonmyeloablative allogeneic transplantation using gene-modified hematopoietic stem cell theoretically overcomes the high transplant mortality associated with traditional conditioning regimens in patients with HIV as well as providing a self-renewing source of HIV-resistant cells. To assess the safety and feasibility of such an approach, a clinical protocol was initiated in those patients infected with HIV with a hematologic malignancy meeting the standard indications for allogeneic transplantation and provided here is an update to the previously published original report. Only patient 1 received genetically modified cells. Both patients tolerated the procedure with no effect on viral load and improved CD4 counts, and patient 1 remains in complete remission from acute myelogenous leukemia 3 years post transplant. Patient 2 also achieved clinical remission from chemorefractory Hodgkin's disease but died of relapsed disease 12 months after transplantation. Vector-transduced cells remain detectable at low levels more than 3 years post-transplantation, suggesting the potential for gene therapy as a reasonable goal for the treatment of HIV. C1 NIDDK, Mol & Clin Hematol Branch, MCHB, NIH, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Kang, EM (reprint author), NIDDK, Mol & Clin Hematol Branch, MCHB, NIH, Bldg 10,Rm 9N116,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 50 TC 10 Z9 14 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD OCT PY 2002 VL 11 IS 5 BP 809 EP 816 DI 10.1089/152581602760404612 PG 8 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 608ML UT WOS:000178850000008 PM 12427287 ER PT J AU Ma, WB Rogers, K Zbar, B Schmidt, L AF Ma, WB Rogers, K Zbar, B Schmidt, L TI Effects of different fixatives on beta-galactosidase activity SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE beta-galactosidase; X-gal staining; fixative; temperature ID RECOMBINATION; EXPRESSION; REPORTER AB beta-Galactosidase (beta-Gal) staining is widely used to demonstrate specific gene expression during evaluation of gene targets in vivo. This technique is extremely sensitive to fixation. Optimal fixation conditions are necessary to obtain the maximal P-Gal activity. In this experiment, Carnoy's and three different aldehyde fixatives were used at different temperatures and over different time points. Kidneys from LacZ-stop-human alkaline phosphatase (ZA/P) double reporter mice were used to generate positive material for the experiment. The results show that glutaraldehyde combinative solution (LacZ) produced the most consistent and reliable results. Paraformaldehyde and formaldehyde were effective as fixatives only at 4C for a period of less than 4 hr, and Carnoy's solution destroyed P-Gal activity. C1 NCI Frederick, SAIC Frederick, IRSP, Ft Detrick, MD 21702 USA. NCI Frederick, SAIC Frederick, Immunobiol Lab, Ft Detrick, MD 21702 USA. NCI Frederick, SAIC Frederick, Pathol & Histol Lab, Ft Detrick, MD 21702 USA. RP Schmidt, L (reprint author), NCI Frederick, SAIC Frederick, IRSP, Bldg 560,Room 12-69, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 7 TC 20 Z9 22 U1 0 U2 1 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD OCT PY 2002 VL 50 IS 10 BP 1421 EP 1424 PG 4 WC Cell Biology SC Cell Biology GA 605GY UT WOS:000178670700015 PM 12364575 ER PT J AU Goertz, CH Grimm, RH Svendsen, K Grandits, G AF Goertz, CH Grimm, RH Svendsen, K Grandits, G TI Treatment of Hypertension with Alternative Therapies (THAT) Study: a randomized clinical trial SO JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; chiropractic; diet; spinal manipulation; high blood pressure; randomized clinical trial AB Objectives To examine the effect of spinal manipulation on blood pressure. Design This randomized clinical trial compared the effects of chiropractic spinal manipulation and diet with diet alone for lowering blood pressure in participants with high-normal blood pressure or stage I hypertension. Blood pressure observers were blinded to treatment group. Setting The study was conducted at the Berman Center for Clinical and Outcomes Research in Minnesota. Chiropractic treatments were administered by chiropractic physicians within private practice settings. Participants One hundred and forty men and women, aged 25-60 years, with high-normal blood pressure or stage I hypertension, were enrolled. One hundred and twenty-eight participants completed the study. Interventions (i) A dietary intervention program administered by a dietitian or (ii) a dietary intervention program administered by a doctor of chiropractic in conjunction with chiropractic spinal manipulation. The frequency of treatment for both groups was three times per week for 4 weeks, for a total of 12 visits. Main outcome measures The primary outcomes for this study were change from baseline in diastolic and systolic blood pressure. Results Study groups were comparable at baseline. Changes in potentially confounding covariates did not differ between groups. Average decreases in systolic/diastolic blood pressure were -4.9/5.6 mmHg for diet group and -3.5/4.0 mmHg for the chiropractic group. Between group changes were not statistically significant. Conclusions For patients with high normal blood pressure or stage I hypertension, chiropractic spinal manipulation in conjunction with a dietary modification program offered no advantage in lowering either diastolic or systolic blood pressure compared to diet alone. J Hypertens 20:2063-2068 (C) 2002 Lippincott Williams Wilkins. C1 Hennepin Cty Med Ctr, Berman Ctr Clin & Outcomes Res, Minneapolis, MN 55415 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55415 USA. Univ Minnesota, Dept Biostat, Minneapolis, MN 55415 USA. RP Goertz, CH (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. FU AHRQ HHS [T32-HS-36] NR 19 TC 7 Z9 7 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD OCT PY 2002 VL 20 IS 10 BP 2063 EP 2068 DI 10.1097/00004872-200210000-00027 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 614EF UT WOS:000179174800027 PM 12359986 ER PT J AU Shah, AH Tabayoyong, WB Kimm, SY Kim, SJ van Parijs, L Lee, C AF Shah, AH Tabayoyong, WB Kimm, SY Kim, SJ van Parijs, L Lee, C TI Reconstitution of lethally irradiated adult mice with dominant negative TGF-beta type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; HEMATOPOIETIC STEM/PROGENITOR CELLS; REPOPULATING STEM-CELLS; NITRIC-OXIDE SYNTHASE; TRANSFORMING GROWTH-FACTOR-BETA-1; NULL MOUSE; IN-VIVO; PROLIFERATION; INACTIVATION; EXPRESSION AB TGF-beta regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-beta null) mice, in which particular TGF-beta isoforms are disrupted throughout the entire organism, as well as in B and T cell-specific transgenic models, but to date the immunoregulatory effects of TGF-beta have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-beta signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-beta insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-beta type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-beta1-deficient mice, the disruption of TGF-beta signaling in bone marrow-derived cells leads to dramatic expansion of myeloid cells, primarily monocytes/macrophages, and is associated with cachexia and mortality in lethally irradiated mice reconstituted with dominant negative receptor-transduced bone marrow. Surprisingly, there was a notable absence of T cell expansion in affected animals despite the observed differentiation of most cells in the T cell compartment to a memory phenotype. These results indicate not only that TGF-beta acts as a negative regulator of immune function, but that lack of functional TGF-beta signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-beta. C1 Northwestern Univ, Sch Med, Dept Urol, Chicago, IL 60611 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Lee, C (reprint author), Northwestern Univ, Sch Med, Dept Urol, Tarry 11-715,303 E Chicago Ave, Chicago, IL 60611 USA. NR 40 TC 33 Z9 35 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2002 VL 169 IS 7 BP 3485 EP 3491 PG 7 WC Immunology SC Immunology GA 598QV UT WOS:000178288800003 PM 12244137 ER PT J AU Edwards, AD Manickasingham, SP Sporri, R Diebold, SS Schulz, O Sher, A Kaisho, T Akira, S Sousa, CRE AF Edwards, AD Manickasingham, SP Sporri, R Diebold, SS Schulz, O Sher, A Kaisho, T Akira, S Sousa, CRE TI Microbial recognition via toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-HELPER CELL; IN-VIVO; ADAPTIVE IMMUNITY; TH2 CELLS; CANDIDA-ALBICANS; IL-12 PRODUCTION; BACTERIAL-DNA; INNATE; ACTIVATION; INTERLEUKIN-12 AB Dendritic cells (DC) can produce Th-polarizing cytokines and direct the class of the adaptive immune response. Microbial stimuli, cytokines, chemokines, and T cell-derived signals all have been shown to trigger cytokine synthesis by DC, but it remains unclear whether these signals are functionally equivalent and whether they determine the nature of the cytokine produced or simply initiate a preprogrammed pattern of cytokine production, which may be DC subtype specific. Here, we demonstrate that Microbial and T cell-derived stimuli can synergize to induce production of high levels of IL-12 p70 or IL-10 by individual murine DC subsets but that the choice of cytokine is dictated by the microbial pattern recognition receptor engaged. We show that bacterial components such as CpG-containing DNA or extracts from Mycobacterium tuberculosis predispose CD8alpha(+) and CD8alpha(-)CD4(-) DC to make IL-12 p70. In contrast, exposure of CD8a(+), CD4(+) and CD8alpha(-)CD4(-) DC to heat-killed yeasts leads to production of IL-10. In both cases, secretion of high levels of cytokine requires a second signal from T cells, which can be replaced by CD40 ligand. Consistent with their differential effects on cytokine production, extracts from M. tuberculosis promote IL-12 production primarily via Toll-like receptor 2 and an MyD88-dependent pathway, whereas heat-killed yeasts activate DC via a Toll-like receptor 2-, MyD88-, and ToII/IL-1R domain containing protein-independent pathway. These results show that T cell feedback amplifies innate signals for cytokine production by DC and suggest that pattern recognition rather than ontogeny determines the production of cytokines by individual DC subsets. C1 Canc Res UK, Immunobiol Lab, London Res Inst, Lincolns Inn Fields Labs, London WC2A 3PX, England. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Osaka Univ, Dept Host Def, Res Inst Microbial Dis, Suita, Osaka, Japan. RIKEN, Res Ctr Allergy & Immunol, Yokohama, Kanagawa, Japan. RP Sousa, CRE (reprint author), Canc Res UK, Immunobiol Lab, London Res Inst, Lincolns Inn Fields Labs, 44 Lincolns Inn Fields, London WC2A 3PX, England. RI Akira, Shizuo/C-3134-2009; Kaisho, Tsuneyasu/B-4130-2012; Edwards, Alexander/F-7440-2010 OI Edwards, Alexander/0000-0003-2369-989X NR 49 TC 171 Z9 175 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 1 PY 2002 VL 169 IS 7 BP 3652 EP 3660 PG 9 WC Immunology SC Immunology GA 598QV UT WOS:000178288800023 PM 12244157 ER PT J AU Yavuz, S Yavuz, AS Kraemer, KH Lipsky, PE AF Yavuz, S Yavuz, AS Kraemer, KH Lipsky, PE TI The role of polymerase eta in somatic Hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; HEAVY-CHAIN GENES; IMMUNOGLOBULIN GENES; MISMATCH REPAIR; DNA-SYNTHESIS; CELLS; REPERTOIRE; MECHANISMS; FIDELITY; IG AB To determine the possible role of polymerase eta (pol eta) in somatic hypermutation of B cells, a mutational analysis of 24 nonproductive rearrangements from a patient with xeroderma pigmentosum variant with a defect in pol eta was conducted. Although the mutational frequency of A and T bases decreased in WA (A/T, A) motifs, regardless of their RGYW (purine, G; pyrimidine, A/T) context, the overall mutational frequency of A or T bases was not affected. Moreover, the overall mutational frequency of the sequences examined was not decreased. There was an apparent increase in the number of insertions and deletions. The results are consistent with the conclusion that pol eta specifically targets WA motifs. However, its overall contribution to the somatic hypermutational process does not appear to be indispensable and in its absence other mechanisms maintain mutational activity. C1 NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Bethesda, MD 20892 USA. RP Lipsky, PE (reprint author), NIAMSD, Autoimmun Branch, NIH, 9000 Rockville Pike,Bldk 10,Room 9N228, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 BC004517-31] NR 28 TC 32 Z9 33 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 1 PY 2002 VL 169 IS 7 BP 3825 EP 3830 PG 6 WC Immunology SC Immunology GA 598QV UT WOS:000178288800044 PM 12244178 ER PT J AU Hale-Donze, H Greenwell-Wild, T Mizel, D Doherty, TM Chatterjee, D Orenstein, JM Wahl, SM AF Hale-Donze, H Greenwell-Wild, T Mizel, D Doherty, TM Chatterjee, D Orenstein, JM Wahl, SM TI Mycobacterium avium complex promotes recruitment of monocyte hosts for HIV-1 and bacteria SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; FACTOR-KAPPA-B; NITRIC-OXIDE SYNTHASE; GENE-EXPRESSION; OPPORTUNISTIC INFECTIONS; CHEMOTACTIC PROTEIN-1; NATURAL-HISTORY; VIRUS INFECTION; CELL CHEMOTAXIS; MACROPHAGES AB In lymphoid tissues coinfected with Mycobacterium avium complex (MAC) and HIV-1, increased viral replication has been observed. This study investigates the role of MAC in perpetuating both infections through the recruitment of monocytes as potential new hosts for bacteria and HIV-1. Increased numbers of macrophages were present in the lymph nodes of patients with dual infection as compared with lymph nodes from HIV+ patients with no known opportunistic pathogens. In a coculture system, monocyte-derived macrophages were treated with HIV-1 or M. avium and its constituents to further define the mechanism whereby MAC infection of macrophages initiates monocyte migration. Monocyte-derived macrophages treated with bacteria or bacterial products, but not HIV-1, induced a rapid 2- to 3-fold increase in recruitment of monocytes. Pretreatment of the monocytes with pertussis toxin inhibited the migration of these cells, indicating a G protein-linked pathway is necessary for induction of chemotaxis and thus suggesting the involvement of chemokines. Analysis of chemokine mRNA and protein levels from M. avium-treated cultures revealed MAC-induced increases in the expression of IL-8, macrophage-inflammatory protein (MIP)-lalpha, and MIP-1beta with donor-dependent changes in monocyte chemotactic protein-1. Pyrrolidine dithiocarbamate, an antioxidant, inhibited the activation of NF-kappaB and significantly diminished the MAC-induced chemotaxis, concurrently lowering the levels of monocyte chemotactic protein-1 and MIP-1beta. These data demonstrate that MAC induces macrophage production of multiple chemotactic factors via NF-kappaB to promote monocyte migration to sites of MAC infection. In vivo, opportunistic infection may act as a recruitment mechanism in which newly arrived monocytes serve as naive hosts for both MAC and HIV-1, thus perpetuating both infections. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Pathol, Washington, DC 20037 USA. Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. RP Wahl, SM (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, 30 Convent Dr,MSC 4352,Bldg 30-332, Bethesda, MD 20892 USA. FU FIC NIH HHS [TW00943]; NIDCR NIH HHS [N01-DE-12585] NR 75 TC 16 Z9 16 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 1 PY 2002 VL 169 IS 7 BP 3854 EP 3862 PG 9 WC Immunology SC Immunology GA 598QV UT WOS:000178288800048 PM 12244182 ER PT J AU Clements, JE Babas, T Mankowski, JL Suryanarayana, K Piatak, M Tarwater, PM Lifson, JD Zink, MC AF Clements, JE Babas, T Mankowski, JL Suryanarayana, K Piatak, M Tarwater, PM Lifson, JD Zink, MC TI The central nervous system as a reservoir for Simian immunodeficiency virus (SIV): Steady-state levels of SIV DNA in brain from acute through asymptomatic infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 3rd Pfizer Symposium on Immunopathogenesis of Infectious Diseases of the Brain CY APR 20-23, 2002 CL CHARLESTPM, SOUTH CAROLINA ID ACTIVE ANTIRETROVIRAL THERAPY; TYPE-1 REVERSE TRANSCRIPTION; CEREBROSPINAL-FLUID; VIRAL LOAD; PRIMARY MACROPHAGES; HIV-1 INFECTION; LATENT HIV-1; REPLICATION; MONOCYTES; PLASMA AB Latent reservoirs of human immunodeficiency virus (HIV) present significant challenges for eradicating HIV from infected persons, particularly reservoirs in the brain established during acute infection. A simian immunodeficiency virus (SIV)/macaque model of HIV dementia was used to show that viral DNA levels in the brain remained at constant levels from acute through asymptomatic infection, despite significant down-regulation of viral RNA in the brain after the acute phase of infection. Viral replication in the brain coincided with activation of macrophages and microglia in the central nervous system; down-regulation of viral replication coincided with increased infiltration of cytotoxic lymphocytes and reduced activation of macrophages and microglia in the brain. Comparison of viral genotypes in the central nervous system and peripheral blood mononuclear cells suggests that recrudescence of viral replication in brain occurs by reactivation of latent viral DNA. Latent virus in the brain must be considered in therapeutic strategies to eliminate HIV from infected persons. C1 Johns Hopkins Univ, Sch Med, Dept Comparat Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NCI, Sci Applicat Int, Lab Retroviral Pathogenesis, Frederick, MD 21701 USA. RP Clements, JE (reprint author), Johns Hopkins Univ, Sch Med, Dept Comparat Med, 600 N Wolfe St,Jefferson St Bldg 3-127, Baltimore, MD 21287 USA. FU NCI NIH HHS [N01-CO-12400.61]; NIMH NIH HHS [MH-61189]; NINDS NIH HHS [NS-35371, NS-36911, NS-38008] NR 35 TC 116 Z9 118 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2002 VL 186 IS 7 BP 905 EP 913 DI 10.1086/343768 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 593KU UT WOS:000177991100004 PM 12232830 ER PT J AU Poast, J Seidel, HM Hendricks, MD Haslam, JA Levy, HB Baron, S AF Poast, J Seidel, HM Hendricks, MD Haslam, JA Levy, HB Baron, S TI Poly I : CLC induction of the interferon system in mice: An initial study of four detection methods SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article AB Induction of a large number of the components of the interferon (IFN) system (IFN genes, their mRNAs, IFN proteins, IFN receptors, IFN signaling molecules, the IFN response genes, and their effector proteins) has been studied. Less well studied is the comparative induction of these components in vivo. Induction of IFN by double-stranded RNA (dsRNA) treatment mimics certain aspects of viral infection and induces the components of the IFN system. To determine the comparative sensitivity of detection of induction in mice, we initially studied the limiting concentrations of polyribinosinic-polyribocytidylic acid, polylysine complex (poly I:CLC, a synthetic dsRNA preparation), for induction of four representative components of the IFN system: (1) IFN in serum, (2) the IFN response gene mRNA ISG54 in spleen and liver, (3) the IFN-beta mRNA in spleen, and (4) resistance of mice to Banzi viral infection. The results of this initial study showed that resistance to infection was 7-fold more sensitive for detection of the IFN response than was ISG54 mRNA and 70-fold more sensitive than either IFN-beta mRNA or IFN production in serum. In comparison, mouse cells in vitro treated with poly I:CLC were 3-10-fold less sensitive to its antiviral action than is the mouse. The results demonstrate that in the four tests in mice, the most sensitive indicator of poly I:CLC induction of the IFN system was protection against Banzi viral infection, followed by ISG54 mRNA levels, IFN-beta mRNA, and IFN protein levels. It is hypothesized that the highest sensitivity of mouse protection may be due to priming by the initial poly I:CLC-induced IFN of the subsequent Banzi virus-induced IFN, resulting in rapid and high concentrations of IFN at the local site of viral replication. Future studies are needed to study other molecular components of the IFN system to identify those that cause the unanticipated high sensitivity of mice to protection against Banzi virus. C1 Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. Ligand Pharmaceut Inc, San Diego, CA 92121 USA. NIH, Bethesda, MD 20814 USA. RP Baron, S (reprint author), Univ Texas, Med Branch, Dept Microbiol & Immunol, 301 Univ Blvd, Galveston, TX 77555 USA. NR 14 TC 8 Z9 8 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD OCT PY 2002 VL 22 IS 10 BP 1035 EP 1040 DI 10.1089/107999002760624260 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 609WK UT WOS:000178928600005 PM 12433283 ER PT J AU Watanabe, T Kawamura, T Jacob, SE Aquilino, EA Orenstein, JM Black, JB Blauvelt, A AF Watanabe, T Kawamura, T Jacob, SE Aquilino, EA Orenstein, JM Black, JB Blauvelt, A TI Pityriasis rosea is associated with systemic active infection with both human herpesvirus-7 and human herpesvirus-6 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE herpesviruses; in situ hybridization; pathogenesis; polymerase chain reactivation ID POLYMERASE-CHAIN-REACTION; HUMAN-HERPESVIRUS-7; VIRUS; REACTIVATION; TROPISM; PLASMA; DNA; CD4 AB Pityriasis rosea is a common skin disease that has been suspected to have a viral etiology. We performed nested polymerase chain reaction to detect human herpesvirus-7, human herpesvirus-6, and cytomegalovirus DNA in lesional skin, nonlesional skin, peripheral blood mononuclear cells, serum, and saliva samples isolated from 14 pityriasis rosea patients. Viral mRNA expression and virion visualization within lesional skin were studied by in situ hybridization and transmission electron microscopy, respectively. By nested polymerase chain reaction, human herpesvirus-7 DNA was present in lesional skin (93%), nonlesional skin (86%), saliva (100%), peripheral blood mononuclear cells (83%), and serum (100%) samples, whereas human herpesvirus-6 DNA was detected in lesional skin (86%), nonlesional skin (79%), saliva (80%), peripheral blood mononuclear cells (83%), and serum (88%) samples. By contrast, cytomegalovirus DNA was not detected in these tissues. Control samples from 12 healthy volunteers and 10 psoriasis patients demonstrated rare positivity for either human herpesvirus-7 or human herpesvirus-6 DNA in skin or serum. By in situ hybridization, infiltrating mononuclear cells expressing human herpesvirus-7 and human herpesvirus-6 mRNA were identified in perivascular and periappendageal areas in 100% and 75% pityriasis rosea skin lesions, respectively, compared to herpesviral mRNA positivity in only 13% normal skin and psoriasis skin controls. Transmission electron microscopy failed to reveal herpesviral virions in pityriasis rosea lesional skin. Nested polymerase chain reaction and in situ hybridization enabled detection of human herpesvirus-7 and human herpesvirus-6 in skin and other tissues isolated from patients with pityriasis rosea. These results suggest that pityriasis rosea is associated with systemic active infection with both human herpesvirus-7 and human herpesvirus-6. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Med Res Scholar Program, Bethesda, MD 20892 USA. George Washington Univ, Dept Pathol, Washington, DC USA. RP Blauvelt, A (reprint author), Bldg 10,Room 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 25 TC 65 Z9 67 U1 0 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2002 VL 119 IS 4 BP 793 EP 797 DI 10.1046/j.1523-1747.2002.00200.x PG 5 WC Dermatology SC Dermatology GA 612KC UT WOS:000179072800005 PM 12406322 ER PT J AU Lee, DY Ahn, KS Lee, CH Rho, NK Lee, JH Lee, ES Steinert, PM Yang, JM AF Lee, DY Ahn, KS Lee, CH Rho, NK Lee, JH Lee, ES Steinert, PM Yang, JM TI Two novel mutations in the keratin 1 gene in epidermolytic hyperkeratosis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID INTERMEDIATE FILAMENTS; ROD DOMAIN; FAMILY; H1; 2B C1 Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Dermatol, Seoul 135710, South Korea. Samsung Biomed Res Inst, Clin Res Ctr, Seoul, South Korea. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. RP Yang, JM (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Dermatol, 50 Ilwon Dong, Seoul 135710, South Korea. EM jmyang@smc.samsung.co.kr NR 17 TC 7 Z9 8 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2002 VL 119 IS 4 BP 976 EP 977 DI 10.1046/j.1523-1747.2002.00061.x PG 2 WC Dermatology SC Dermatology GA 612KC UT WOS:000179072800031 PM 12406348 ER PT J AU Cui, YH Le, YY Yazawa, H Gong, WH Wang, JM AF Cui, YH Le, YY Yazawa, H Gong, WH Wang, JM TI Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE NSAID; central nervous system; A beta; macrophage; microglia ID N-FORMYLPEPTIDE RECEPTOR; PROTEIN-COUPLED RECEPTOR; METHIONYL-LEUCYL-PHENYLALANINE; AMYLOID-BETA-PEPTIDE; MICROGLIAL CELLS; CHEMOKINE RECEPTORS; HUMAN MONOCYTES; POLYMORPHONUCLEAR LEUKOCYTES; BACTERIAL-ENDOTOXIN; SCAVENGER RECEPTOR AB Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by the presence of multiple senile plaques in the brain tissue, which are also associated with considerable inflammatory infiltrates. Although the precise mechanisms of the pathogenesis of AD remain to be determined, the overproduction and precipitation of a 42 amino acid form of beta amyloid (Abeta(42)) in plaques have implicated Abeta in neurodegeneration and proinflammatory responses seen in the AD brain. Our recent studies revealed that the activation of formyl peptide receptor-like 1 (FPRL1), a seven-transmembrane, G-protein-coupled receptor, by Abeta(42) may be responsible for accumulation and activation of mononuclear phagocytes (monocytes and microglia). We further found that upon binding FPRL1, Abeta(42) was rapidly internalized into the cytoplasmic compartment in the form of Abeta(42)/FPRL1 complexes. Persistent exposure of FPRL1-expressing cells to Abeta(42) resulted in intracellular retention of Abeta(42)/FPRL1 complexes and the formation of Congo-red-positive fibrils in mononuclear phagocytes. Our observations suggest that FPRL1 may not only mediate the proinflammatory activity of Abeta(42) but also actively participate in Abeta42 uptake and the resultant fibrillar formation. Therefore, FPRL1 may constitute an additional molecular target for the development of therapeutic agents for AD. C1 Natl Canc Inst, Mol Immunoregulat Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. Natl Canc Inst, Intramural Res Support Program, SAIC Frederick, Ctr Canc Res, Ft Detrick, MD 21702 USA. Lanzhou Mil Med Univ, Biochem Sect, Lanzhou, Peoples R China. RP Wang, JM (reprint author), Natl Canc Inst, Mol Immunoregulat Lab, Ctr Canc Res, Bldg 560,Room 31-40, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 85 TC 56 Z9 59 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2002 VL 72 IS 4 BP 628 EP 635 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 602NV UT WOS:000178512100003 PM 12377930 ER PT J AU Menten, P Saccani, A Dillen, C Wuyts, A Struyf, S Proost, P Mantovani, A Wang, JM Van Damme, J AF Menten, P Saccani, A Dillen, C Wuyts, A Struyf, S Proost, P Mantovani, A Wang, JM Van Damme, J TI Role of the autocrine chemokines MIP-1 alpha and MIP-1 beta in the metastatic behavior of murine T cell lymphoma SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE migration; metastasis; endotoxin ID TUMOR-NECROSIS-FACTOR; RECEPTOR EXPRESSION; GENE-EXPRESSION; DOWN-MODULATION; HUMAN MONOCYTES; IDENTIFICATION; LIPOPOLYSACCHARIDE; INFLAMMATION; GROWTH; CANCER AB The ESb-MP T-cell line is a highly malignant murine lymphoma, which preferentially metastasizes toward the kidney. This could be a result of the local production of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T expressed and secreted (RANTES), which are chemotactic for ESh-MP cells. Here, we demonstrate that ESb-MP cells are already responsive to the chemotactic activity of macrophage inflammatory protein-lot (MIP-1alpha) and MIP-1beta from 1 ng/ml onward. Moreover, upon stimulation with lipopolysaccharide (LPS) or virus, ESb-MP cells themselves produce significant amounts of MIP-1 (similar to200 ng/ml). Indeed, the major autocrine chemoattractants, isolated from ESb-MP cells, were intact MIP-1alpha and MIP-1beta. Pretreatment with LPS or addition of MIP-1 inhibited the in vitro migration of ESh-MP cells toward various chemokines. Moreover, compared with untreated lymphoma cells, LPS-treated cells produced significantly less metastasis in mice. The results represented here suggest that the role of chemokines in attracting tumor cells at secondary sites depends on a balance between autocrine-produced and tissue-derived chemokines. This delicate balance should be considered in the design of antichemokine strategies in different tumor types. C1 Katholieke Univ Leuven, Rega Inst Med Res, Lab Mol Immunol, B-3000 Louvain, Belgium. Ist Ric Farmacol Mario Negri, Milan, Italy. NCI, NIH, Frederick, MD 21701 USA. RP Van Damme, J (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Lab Mol Immunol, Minderbroedersstr 10, B-3000 Louvain, Belgium. EM jozef.vandamme@rega.kuleuven.ae.be OI Mantovani, Alberto/0000-0001-5578-236X NR 34 TC 21 Z9 21 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2002 VL 72 IS 4 BP 780 EP 789 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 602NV UT WOS:000178512100021 PM 12377948 ER PT J AU Nagy, ZS Wang, YL Erwin-Cohen, RA Aradi, J Monia, B Wang, LH Stepkowski, SM Rui, H Kirken, RA AF Nagy, ZS Wang, YL Erwin-Cohen, RA Aradi, J Monia, B Wang, LH Stepkowski, SM Rui, H Kirken, RA TI Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE T lymphocytes; signal transduction; Janus tyrosine kinase; oligodeoxynucletide; mTor ID SEVERE COMBINED IMMUNODEFICIENCY; RECEPTOR-GAMMA CHAIN; DNA-BINDING ACTIVITY; SIGNAL-TRANSDUCTION; JANUS KINASE; TYROSINE PHOSPHORYLATION; TRANSACTIVATION DOMAIN; TARGETED DISRUPTION; MAXIMAL ACTIVATION; CYCLE PROGRESSION AB Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G(1)-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, he constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-29 -7, -9. and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase. C1 Univ Texas, Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, Houston, TX USA. Univ Debrecen, Med & Hlth Sci Ctr, Dept Biochem & Mol Biol, Debrecen, Hungary. ISIS Pharmaceut Inc, Mol Pharmacol, Carlsbad, CA USA. IRSP, SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Univ Texas, Sch Med, Dept Surg, Div Immunol & Organ Transplantat, Houston, TX USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Kirken, RA (reprint author), Univ Texas, Hlth Sci Ctr, Dept Integrat Biol, MSB Room 4-218, Houston, TX 77030 USA. NR 60 TC 32 Z9 33 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2002 VL 72 IS 4 BP 819 EP 828 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 602NV UT WOS:000178512100025 PM 12377952 ER PT J AU Li, KCP AF Li, KCP TI Special issue: Molecular imaging SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Editorial Material C1 NIH, Radiol & Imaging Sci Program, Ctr Clin, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Radiol & Imaging Sci Program, Ctr Clin, Bldg 10,Room 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. NR 3 TC 2 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2002 VL 16 IS 4 BP 335 EP 335 DI 10.1002/jmri.10170 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 601KV UT WOS:000178445700002 PM 12353249 ER PT J AU Li, KCP Bednarski, MD AF Li, KCP Bednarski, MD TI Vascular-targeted molecular imaging using functionalized polymerized vesicles SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Review DE endothelium; angiogenesis; integrin; molecular imaging; contrast media ID IN-VIVO; GENE-EXPRESSION; ANNEXIN-V; APOPTOSIS; LIPOSOMES AB In this review we will discuss the use of multivalent polymerized vesicles (PVs) combined with magnetic resonance imaging (MRI) and gamma scintigraphy to image expression of vascular molecular receptors in vivo. Specifically we will present our data on the use of this technology to design imaging agents toward specific vascular receptors in both a mouse and rabbit tumor model and in the EAE mouse, a model for human multiple sclerosis (MS). Examples will be shown where the in vivo specificity of the targeted molecular imaging agents was validated in the animal models. Since the PVs are designed to carry either contrast or therapeutic agents or both, we can potentially use vascular targeted imaging and therapy approach, personalized treatment can potentially be delivered, maximizing the efficacy and minimizing side effects. C1 NIH, Ctr Clin, Radiol & Imaging Sci Program, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci Program, Bldg 10,Room 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 22 TC 24 Z9 24 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2002 VL 16 IS 4 BP 388 EP 393 DI 10.1002/jmri.10174 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 601KV UT WOS:000178445700007 PM 12353254 ER PT J AU Petricoin, EF Paweletz, CP Liotta, LA AF Petricoin, EF Paweletz, CP Liotta, LA TI Clinical applications of proteomics: Proteomic pattern diagnostics SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE proteomics; patterns diagnostics; nipple fluid; breast cancer; mass spectrometry; genetic algorithms ID NIPPLE ASPIRATE FLUID; BREAST-CANCER RISK; ARTIFICIAL NEURAL NETWORKS; PROTEIN BIOCHIP TECHNOLOGY; PROSTATE-SPECIFIC ANTIGEN; SELDI MASS-SPECTROMETRY; CARCINOEMBRYONIC ANTIGEN; OVARIAN-CANCER; SERUM; IDENTIFICATION AB Clinical proteomics is an exciting new subdiscipline of proteomics that involves bedside application of proteomic technologies. A new and potentially revolutionary technology and approach for early disease detection, surveillance, and monitoring is proteomic pattern diagnostics. Using this approach, high throughput mass spectrometry generates a proteomic fingerprint of a given body fluid, such as serum or nipple fluid aspirants (NAF), in less than 30 s. This information archive is then used by new types of bioinformatic pattern recognition algorithms to identify patterns of protein changes that can discriminate cancer from healthy and unaffected individuals. This entire process can take place in less than a minute and requires only a droplet of blood, NAF, or ductal lavage washings. The new concept that is introduced by this platform is that the underlying identities of the proteins that comprise the patterns are not known and do not need to be known; the pattern itself becomes the diagnostic. C1 US FDA, FDA NCI Clin Proteom Program, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, FDA NCI Clin Proteom Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, FDA NCI Clin Proteom Program, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bldg 29A,Room 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 40 TC 59 Z9 59 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD OCT PY 2002 VL 7 IS 4 BP 433 EP 440 DI 10.1023/A:1024042200521 PG 8 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 685GY UT WOS:000183255100008 PM 12882527 ER PT J AU Weisz, A Andrzejewski, D Fales, HM Mandelbaum, A AF Weisz, A Andrzejewski, D Fales, HM Mandelbaum, A TI Attachment of neutrals during tandem mass spectrometry of sulfonic acid dyes and intermediates in an ion trap SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE ion-neutral attachment; tandem mass spectrometry; ion trap; collision-induced dissociation; triple-stage quadrupole; electrospray mass spectrometry; atmospheric pressure chemical ionization; Quinoline Yellow; naphthaleneaminosulfonic acids ID FRAGMENT IONS; GAS-PHASE; ELECTROSPRAY; CHROMATOGRAPHY; COMPLEXES; WATER AB Several positional isomers of 2-(2-quinolinyl)-1H-indene-1,3(2H)-dione mono- and disulfonic acids prepared as reference materials for development of analytical methods involved in FDA certification of D&C Yellow No. 10 (Quinoline Yellow) were found consistently to show [MH + 14](+) ions when their electrospray- or atmospheric pressure chemical ionization-prepared MH+ ions were subjected to collisional activation. The source of these ions was found to be the methanol used as solvent in these procedures which combined with their [MH - H2O](+) ions under chemical ionization conditions. The reaction was found to be sensitive to their isomeric and chemical structures and other examples of this process are reviewed. Copyright (C) 2002 John Wiley Sons, Ltd. C1 US FDA, Off Cosmet & Colors, Washington, DC 20204 USA. US FDA, Off Sci Anal & Support, Washington, DC 20204 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Dept Chem, IL-32000 Haifa, Israel. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Washington, DC 20204 USA. NR 12 TC 11 Z9 11 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2002 VL 37 IS 10 BP 1025 EP 1033 DI 10.1002/jms.357 PG 9 WC Biophysics; Chemistry, Organic; Spectroscopy SC Biophysics; Chemistry; Spectroscopy GA 607WM UT WOS:000178813800002 PM 12375276 ER PT J AU Martin, CL Waggoner, DJ Wong, A Uhrig, S Roseberry, JA Hedrick, JF Pack, SD Russell, K Zackai, E Dobyns, WB Ledbetter, DH AF Martin, CL Waggoner, DJ Wong, A Uhrig, S Roseberry, JA Hedrick, JF Pack, SD Russell, K Zackai, E Dobyns, WB Ledbetter, DH TI "Molecular rulers" for calibrating phenotypic effects of telomere imbalance SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID IDIOPATHIC MENTAL-RETARDATION; SHORT ARM; SUBTELOMERIC REARRANGEMENTS; CHROMOSOMAL REARRANGEMENTS; TRISOMY 16P; TRANSLOCATION; SEQUENCE; MONOSOMY AB As a result of the increasing use of genome wide telomere screening, it has become evident that a significant proportion of people with idiopathic mental retardation have subtle abnormalities involving the telomeres of human chromosomes. However, during the course of these studies, there have also been telomeric imbalances identified in normal people that are not associated with any apparent phenotype. We have begun to scrutinise cases from both of these groups by determining the extent of the duplication or deletion associated with the imbalance. Five cases were examined where the telomere rearrangement resulted in trisomy for the 16p telomere. The size of the trisomic segment ranged from similar to4-7 Mb and the phenotype included mental and growth retardation, brain malformations, heart defects, cleft palate, pancreatic insufficiency, genitourinary abnormalities, and dysmorphic features. Three cases with telomeric deletions without apparent phenotypic effects were also examined, one from 10q and two from 17p. All three deletions were inherited from a phenotypically normal parent carrying the same deletion, thus without apparent phenotypic effect. The largest deletion among these cases was similar to600 kb on 17p. Similar studies are necessary for all telomeric regions to differentiate between those necessary telomeric rearrangements that are pathogenic and those that are benign variants. Towards this goal, we are developing "molecular rulers" that incorporate multiple clones at each telomere that span the most distal 5 Mb region. While telomere screening has enabled the identification of telomere rearrangements, the use of molecular rulers will allow better phenotype prediction and prognosis related to these findings. C1 Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. NINDS, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. RP Ledbetter, DH (reprint author), Univ Chicago, Dept Human Genet, 920 E 58th St, Chicago, IL 60637 USA. RI Pack, Svetlana/C-2020-2014; OI Dobyns, William/0000-0002-7681-2844 FU NICHD NIH HHS [1 RO1 HD36715-03] NR 28 TC 65 Z9 65 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT PY 2002 VL 39 IS 10 BP 734 EP 740 DI 10.1136/jmg.39.10.734 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 603BJ UT WOS:000178538700005 PM 12362030 ER PT J AU Balaban, RS AF Balaban, RS TI Cardiac energy metabolism homeostasis: Role of cytosolic calcium SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE mitochondria; adenosine triphosphate; adenosine diphosphate; proton-motive force; sarcoplasmic reticulum; respiration ID MITOCHONDRIAL ATP SYNTHASE; DEHYDROGENASE PHOSPHATE PHOSPHATASE; RAT VENTRICULAR MYOCYTES; FREE CA-2+ CONCENTRATION; TO-BEAT OSCILLATIONS; PYRUVATE-DEHYDROGENASE; OXIDATIVE-PHOSPHORYLATION; HEART-MITOCHONDRIA; RUTHENIUM RED; OXYGEN-CONSUMPTION AB The heart is capable of dramatically altering its overall energy flux with minimal changes in the concentrations of metabolites that are associated with energy metabolism. This cardiac energy metabolism homeostasis is discussed with regard to the potential cytosolic control network responsible for controlling the major energy conversion pathway, oxidative phosphorylation in mitochondria. Several models for this cytosolic control network have been proposed, but a cytosolic Ca2+ dependent parallel activation scheme for metabolism and work is consistent with most of the experimental results. That model proposes that cytosolic Ca2+ regulates both the utilization of ATP by the work producing ATPases as well as the mitochondrial production of ATP. Recent studies have provided evidence supporting this role of cytosolic Ca2+. These data include the demonstration that mitochondrial [Ca2+] can track cytosolic [Ca2+] and that the compartmentation of cytosolic [Ca2+] can facilitate this process. On the metabolic side, Ca2+ has been shown to rapidly activate several steps in oxidative phosphorylation, including F1F0-ATPase ATP production as well as several dehydrogenases, which results in a homeostasis of mitochondrial metabolites similar to that observed in the cytosol. Numerous problems with the Ca2+ parallel activation hypothesis remain including the lack of specific mechanisms of mitochondrial Ca2+ transport and regulation of F1F0-ATPase, the time dependence of Ca2+ activation of cytosolic ATPases as well as oxidative phosphorylation, and the role of cytosolic compartmentation. In addition, the lack of cytosolic or mitochondrial [Ca2+] measurements under in vivo conditions is problematic. Several lines of investigation to address these issues are suggested. A model of the cardiac energy metabolism control network is proposed that includes a Ca2+ parallel activation component together with more classical elements including metabolite feedback and cytosolic compartmentation. (C) 2002 Published by Elsevier Science Ltd. C1 NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Bldg 10,Room B1 D161, Bethesda, MD 20892 USA. EM rsb@zeus.nhlbi.nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 91 TC 195 Z9 203 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD OCT PY 2002 VL 34 IS 10 BP 1259 EP 1271 DI 10.1006/jmcc.2002.2082 PG 13 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 613HE UT WOS:000179126200003 PM 12392982 ER PT J AU Kim, MK Chirikjian, GS Jernigan, RL AF Kim, MK Chirikjian, GS Jernigan, RL TI Elastic models of conformational transitions in macromolecules SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE conformational transitions; intermediate structure; elastic network model; animation; macromolecules ID MOTIONS; DYNAMICS; PROTEINS; DATABASE AB We develop a computationally efficient and physically realistic method to simulate the transition of a macromolecule between two conformations. Our method is based on a coarse-grained elastic network model in which contact interactions between spatially proximal parts of the macromolecule are modelled with Gaussian/harmonic potentials. To delimit the interactions in such models, we introduce a cutoff to the permitted number of nearest neighbors. This generates stiffness (Hessian) matrices that are both sparse and quite uniform, hence, allowing for efficient computations. Several toy models are tested using our method to mimic simple classes of macromolecular motions such as stretching, hinge bending, shear, compression, ligand binding and nucleic acid structural transitions. Simulation results demonstrate that the method developed here reliably generates sequences of feasible intermediate conformations of macromolecules, since our method observes steric constraints and produces monotonic changes to virtual bond angles and torsion angles. A final application is made to the opening process of the protein lactoferrin. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. NCI, Lab Expt & Computat Biol, Mol Struct Sect, CCR,NIH, Bethesda, MD 20892 USA. RP Chirikjian, GS (reprint author), Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. RI Chirikjian, Gregory/A-3314-2010; Jernigan, Robert/A-5421-2012; kim, moon/H-2647-2012 NR 18 TC 92 Z9 92 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD OCT PY 2002 VL 21 IS 2 BP 151 EP 160 AR PII S1093-3263(02)00143-2 DI 10.1016/S1093-3263(02)00143-2 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 606ZL UT WOS:000178765900007 PM 12398345 ER PT J AU Venkateswarlu, D Krishnaswamy, S Darden, TA Pedersen, LG AF Venkateswarlu, D Krishnaswamy, S Darden, TA Pedersen, LG TI Three-dimensional solution structure of Tropidechis carinatus venom extract trocarin: a structural homologue of Xa and prothrombin activator SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE Tropidechis carinatus; trocarin; snake venom; blood coagulation; homology modeling; molecular dynamics simulations ID COAGULATION-FACTOR-XA; SERINE PROTEASES; MEMBRANE-BINDING; PROTEIN-C; CATALYTIC EFFICIENCY; NA+ BINDING; FACTOR-IX; SITE; COMPLEX; CALCIUM AB Trocarin belongs to group D of prothrombin activators derived from snake venom of Tropidechis carinatus and is a rich non-hepatic source of Xa, the only known hepatic prothrombin activator. The structural and functional similarity with Xa makes trocarin an interesting target for exploring the structure-functional relationship with Xa. Herein we report a predicted complete three-dimensional all-atom structural model of trocarin equilibrated in explicit water using 4 ns of molecular dynamics simulation. The tertiary structure was modeled using the structure of human blood coagulation factor Xa. The conformational and structural features of trocarin are then compared with the X-ray crystal and solution simulation structures of human factor Xa. The modeled structure of trocarin has four individual domains (Gla, EGF1, EGF2 and SP) connected along the long axis with similar secondary structural elements to Xa. The simulations suggest that sodium ion binding in the serine protease domain is impaired in trocarin as compared to Xa. In contrast to Xa, for which the sodium ion forms an octahedral coordination network that brings two loop regions connecting four anti-parallel beta-sheets together, we do not find a similar pattern of network in trocarin. We observe that the difference in the binding pattern of sodium ion leads to a similar to2-Angstrom "shrinkage" of the beta2 strand (B2), in comparison to human Xa, as marked by a shorter distance between (189)Asp373 (S1-site residue) and (195)Ser379 (active-site residue) in the B2 strand. We propose that these differences may be linked to the experimentally observed lower amidolytic activity of trocarin as compared to Xa. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Childrens Hosp Philadelphia, Joseph Stokes Res Inst, Philadelphia, PA 19104 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Venable Hall,CB 3290, Chapel Hill, NC 27599 USA. RI Venkateswarlu, Divi/K-1815-2014 OI Venkateswarlu, Divi/0000-0003-2481-7480 FU NHLBI NIH HHS [HL-06350] NR 43 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0948-5023 J9 J MOL MODEL JI J. Mol. Model. PD OCT PY 2002 VL 8 IS 10 BP 302 EP 313 DI 10.1007/s00894-002-0099-4 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA 627VL UT WOS:000179956800002 PM 12483230 ER PT J AU Schumacher, B Scholle, S Holzl, J Khudeir, N Hess, S Muller, CE AF Schumacher, B Scholle, S Holzl, J Khudeir, N Hess, S Muller, CE TI Lignans isolated from Valerian: Identification and characterization of a new olivil derivative with partial agonistic activity at A(1) adenosine receptors SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID EUCOMMIA-ULMOIDES OLIV; RAT-BRAIN MEMBRANES; NATURAL-PRODUCTS; BINDING; CONSTITUENTS; RADIOLIGAND; GLYCOSIDES; LIGANDS; SLEEP; CELLS AB A methanolic extract of the roots of Valeriana offlicinalis (valerian) was investigated for its lignan content. In addition to the lignans 8'-hydroxypinoresinol (1) and pinoresinol-4-O-beta-D-glucoside (2), which. had already been isolated from valerian in an earlier study, the 7,9'-monoepoxylignans massoniresinol-4'-O-beta-D-glucoside (3), 4'-O-beta-D-glucosyl-9-O-(6"-deoxysaccharosyl)oliviI (4), and berchemol-4'-O-beta-D-glucoside (5) and the 7,9':7',9-diepoxylignans pinoresinol-4,4'-di-beta-D-glucoside (6), 8-hydroxypinoresinol-4'-O-PD-glucoside (7), and 8'-hydroxypinoresinol-4'-O-beta-D-glucoside (8) were identified. While lignans 3, 6, 7, and 8 had already been isolated from other plants, lignans 4 and 5 are new natural products. The lignans were investigated in radioligand binding assays at various receptors of the central nervous system, including GABA(A), benzodiazepine, 5-HT1A, and adenosine A(1) and.A(2A) receptors, to investigate their potential contribution to the pharmacological activity of valerian. The novel olivil derivative 4 proved to be a partial agonist at rat and human A(1) adenosine receptors exhibiting A, affinity and activity in low micromolar to submicromolar concentrations. Lignan 4 is the first nonnucleoside adenosine receptor agonist not structurally related to adenosine. C1 Univ Bonn, Pharmaceut Inst Poppelsdorf, D-5300 Bonn, Germany. Univ Marburg, Dept Pharmaceut Biol, Marburg, Germany. NIDDK, NIH, Mass Spectrometry Grp, Bethesda, MD USA. RP Muller, CE (reprint author), Univ Bonn, Pharmaceut Inst Poppelsdorf, D-5300 Bonn, Germany. EM christa.mueller@uni-bonn.de RI Hess, Sonja/K-4842-2013; Muller, Christa/C-7748-2014 OI Hess, Sonja/0000-0002-5904-9816; Muller, Christa/0000-0002-0013-6624 NR 35 TC 70 Z9 80 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2002 VL 65 IS 10 BP 1479 EP 1485 DI 10.1021/np010464q PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 609YZ UT WOS:000178935100017 PM 12398547 ER PT J AU Bacich, DJ Ramadan, E O'Keefe, DS Bukhari, N Wegorzewska, I Ojeifo, O Olszewski, R Wrenn, CC Bzdega, T Wroblewska, B Heston, WDW Neale, JH AF Bacich, DJ Ramadan, E O'Keefe, DS Bukhari, N Wegorzewska, I Ojeifo, O Olszewski, R Wrenn, CC Bzdega, T Wroblewska, B Heston, WDW Neale, JH TI Deletion of the glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N-acetylaspartylglutamate SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE N-acetylaspartylglutamate (NAAG); N-acetylaspartylglutamate-peptidase (NAAG-peptidase); glutamate carboxypeptidase II metabotropic glutamate receptor ID LINKED ACIDIC DIPEPTIDASE; ENHANCED CARBODIIMIDE FIXATION; RAT NERVOUS-SYSTEM; MEMBRANE ANTIGEN; ACETYLASPARTATE IMMUNOREACTIVITIES; MOLECULAR-CLONING; FOLATE-HYDROLASE; POTENT INHIBITOR; BRAIN; LOCALIZATION AB Glutamate carboxypeptidase II (GCPII, EC 3.14.17.21) is a membrane-bound enzyme found on the extracellular face ofglia. The gene for this enzyme is designated FOLH1 in humans and Folh1 in mice. This enzyme has been proposed to be responsible for inactivation of the neurotransmitter N -acetylaspartylglutamate (NAAG) following synaptic release. Mice harboring a disruption of the gene for GCPII/Folh1 were generated by inserting into the genome a targeting cassette in which the intron-exon boundary sequences of exons 1 and 2 were removed and stop codons were inserted in exons 1 and 2. Messenger RNA for GCPII was not detected by northern blotting or RT-PCR analysis of RNA from the brains of -/- mutant mice nor was GCPII protein detected on western blots of this tissue. These GCPII null mutant mice developed normally to adulthood and exhibited a normal range of neurologic responses and behaviors including mating, open field activity and retention of position in rotorod tests. No significant differences were observed among responses of wild type, heterozygous mutant and homozygous mutant mice on tail flick and hot plate latency tests. Glutamate, NAAG and mRNA for metabotropic glutamate receptor type 3 levels were not significantly altered in response to the deletion of glutamate carboxypeptidase II. A novel membrane-bound NAAG peptidase activity was discovered in brain, spinal cord and kidney of the GCPII knock out mice. The kinetic values for brain NAAG peptidase activity in the wild type and GCPII nullmutant were V (max) = 45 and 3 pmol/mg/min and K (m) = 2650 nm and 2494 nm, respectively. With the exception of magnesium and copper, this novel peptidase activity had a similar requirement for metal ions as GCPII. Two potent inhibitors of GCPII, 4,4'-phosphinicobis-(butane-1,3 dicarboxilic acid) (FN6) and 2-(phosphonomethyl)pentanedioic acid (2-PMPA) inhibited the residual activity. The IC50 value for 2-PMPA was about 1 nm for wild-type brain membrane NAAG peptidase activity consistent with its activity against cloned ratand human GCPII, and 88 nm for the activity in brain membranes of the null mutants. C1 Georgetown Univ, Dept Biol, Washington, DC 20057 USA. Cleveland Clin, Dept Canc Biol, Cleveland, OH 44106 USA. NIMH, Sect Behav Neuropharmacol, NIH, Bethesda, MD 20892 USA. RP Neale, JH (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA. RI O'Keefe, Denise/A-6273-2010; Bacich, Dean/A-6286-2010 FU NCI NIH HHS [CA 47650]; NINDS NIH HHS [NS 38380] NR 62 TC 46 Z9 48 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2002 VL 83 IS 1 BP 20 EP 29 DI 10.1046/j.1471-4159.2002.01117.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 595DB UT WOS:000178090600003 PM 12358725 ER PT J AU Chang, JW Lee, WY Milstien, S Kang, UJ AF Chang, JW Lee, WY Milstien, S Kang, UJ TI A site-specific mutation of tyrosine hydroxylase reduces feedback inhibition by dopamine in genetically modified cells grafted in parkinsonian rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 6-hydroxydopamine; aromatic L-amino acid decarboxylase; catecholamine; gene therapy; microdialysis; Parkinson's disease ID AMINO-ACID DECARBOXYLASE; GTP-CYCLOHYDROLASE-I; ADENOASSOCIATED VIRUS VECTORS; EXOGENOUS L-DOPA; GENE-EXPRESSION; 6-HYDROXYDOPAMINE-TREATED RATS; DIRECTED MUTAGENESIS; BEHAVIORAL RECOVERY; PRIMARY FIBROBLASTS; DISEASE AB Aromatic l-amino acid decarboxylase (AADC) is necessary for conversion of l-DOPA to dopamine. Therefore, AADC gene therapy has been proposed to enhance pharmacological or gene therapies delivering l-DOPA. However, addition of AADC to the grafts of genetically modified cells expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1), which produce l-DOPA in parkinsonian rats, resulted in decreased production of l-DOPA and dopamine owing to feedback inhibition of TH by dopamine. End-product feedback inhibition has been shown to be mediated by the regulatory domain of TH, and site-specific mutation of serine 40 makes TH less susceptible to dopamine inhibition. Therefore, we investigated the efficacy of using TH with serine 40 mutated to leucine (mTH) in an ex vivo gene-therapy paradigm. Primary fibroblasts (PF) from Fischer 344 rats were transduced with retrovirus to express mTH or wild-type rat TH cDNA (wtTH). Both cell types were also transduced with GCH1 to provide the obligate TH cofactor, tetrahydrobiopterin. PF transfected with AADC were used as coculture and cografting partners. TH activities and l-DOPA production in culture were comparable between PFwtTHGC and PFmTHGC cells. In cocultures with PFAADC cells, PFmTHGC cells showed significant reduction in the inhibitory effect of dopamine compared with PFwtTHGC cells. In vivo microdialysis measurement showed that cografting PFAADC cells with PFmTHGC cells resulted in smaller decreases in l-DOPA and no reduction in dopamine levels compared with cografts of PFAADC cells with PFwtTHGC cells, which decreased both l-DOPA and dopamine levels. Maintenance of dopamine levels with lower levels of l-DOPA would result in more focused local delivery of dopamine and less potential side-effects arising from l-DOPA diffusion into other structures. These data support the hypothesis that mutation of serine 40 attenuates TH end-product inhibition in vivo and illustrates the importance of careful consideration of biochemical pathways and interactions between multiple genes in gene therapy. C1 Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. Univ Chicago, Dept Physiol & Pharmacol, Chicago, IL 60637 USA. Univ Chicago, Comm Neurobiol, Chicago, IL 60637 USA. Yonsei Univ, Coll Med, Dept Neurosurg, Project Med Sci BK21, Seoul, South Korea. Sungkyunkwan Univ, Dept Neurol, Seoul, South Korea. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Kang, UJ (reprint author), Univ Chicago, Dept Neurol, MC 2030,5841 S Maryland Ave, Chicago, IL 60637 USA. EM u-kang@uchicago.edu FU NINDS NIH HHS [NS 32080] NR 48 TC 7 Z9 7 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2002 VL 83 IS 1 BP 141 EP 149 DI 10.1046/j.1471-4159.2002.01120.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 595DB UT WOS:000178090600015 PM 12358737 ER PT J AU Lee, G Junn, E Tanaka, M Kim, YM Lee, SS Mouradian, MM AF Lee, G Junn, E Tanaka, M Kim, YM Lee, SS Mouradian, MM TI Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE inclusion; Parkinson; proteasome; synphilin-1; alpha-synuclein; ubiquitin ID LEWY BODY DISEASE; RECESSIVE JUVENILE PARKINSONISM; ALPHA-SYNUCLEIN; PROTEIN LIGASE; NEURODEGENERATIVE DISEASES; BODIES; INCLUSIONS; SYSTEM; MUTATIONS; PROMOTES AB Parkinson's disease is characterized by loss of nigral dopaminergic neurons and the presence of cytoplasmic inclusions known as Lewy bodies. alpha-Synuclein and its interacting partner synphilin-1 are among constituent proteins in these aggregates. The presence of ubiquitin and proteasome subunits in these inclusions supports a role for this protein degradation pathway in the processing of proteins involved in this disease. To begin elucidating the kinetics of synphilin-1 in cells, we studied its degradation pathway in HEK293 cells that had been engineered to stably express FLAG-tagged synphilin-1. Pulse-chase experiments revealed that this protein is relatively stable with a half-life of about 16 h. Treatment with proteasome inhibitors resulted in attenuation of degradation and the accumulation of high molecular weight ubiquitinated synphilin-1 in immunoprecipitation/immunoblot experiments. Additionally, proteasome inhibitors stimulated the formation of peri-nuclear inclusions which were immunoreactive for synphilin-1, ubiquitin and alpha-synuclein. Cell viability studies revealed increased susceptibility of synphilin-1 over-expressing cells to proteasomal dysfunction. These observations indicate that synphilin-1 is ubiquitinated and degraded by the proteasome. Accumulation of ubiquitinated synphilin-1 due to impaired clearance results in its aggregation as peri-nuclear inclusions and in poor cell survival. C1 NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Mouradian, MM (reprint author), NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 29 TC 27 Z9 29 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2002 VL 83 IS 2 BP 346 EP 352 DI 10.1046/j.1471-4159.2002.01136.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 599QG UT WOS:000178346200010 PM 12423244 ER PT J AU Counts, SE McGuire, SO Sortwell, CE Crawley, JN Collier, TJ Mufson, EJ AF Counts, SE McGuire, SO Sortwell, CE Crawley, JN Collier, TJ Mufson, EJ TI Galanin inhibits tyrosine hydroxylase expression in midbrain dopaminergic neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dopamine; galanin; substantia nigra; tyrosine hydroxylase; ventral tegmental area ID CENTRAL-NERVOUS-SYSTEM; LOCUS-COERULEUS NEURONS; RECTIFIER K+ CHANNELS; RECEPTOR SUBTYPES; SUBSTANTIA-NIGRA; GENE-EXPRESSION; VENTRAL HIPPOCAMPUS; MESSENGER-RNAS; CLONED HUMAN; CYCLIC-AMP AB Galanin (GAL) inhibits midbrain dopamine (DA) activity in several experimental paradigms, yet the mechanism underlying this inhibition is unclear. We examined the effects of GAL on the expression of tyrosine hydroxylase (TH) in primary cultures of rat embryonic (E14) ventral mesencephalon (VM). One micromolar GAL had no effect on the number of TH-immunoreactive (ir) neurons in VM cultures. However, 1 mum GAL reduced an approximately 100% increase in TH-ir neurons in 1 mm dibutyryl cAMP (dbcAMP)-treated cultures by similar to50%. TH-ir neuron number in dbcAMP-treated VM cultures was dose-responsive to GAL and the GAL receptor antagonist M40 blocked GAL effects. Semi-quantitative RT-PCR and quantitative immunoblotting experiments revealed that GAL had no effect on TH mRNA levels in VM cultures but reduced TH protein. VM cultures expressed GALR1, GALR2, and GALR3 receptor mRNA. However, dbcAMP treatment resulted in a specific similar to200% increase in GALR1 mRNA. GALR1 activity is linked to a pertussis toxin (PTX)-sensitive opening of G protein-gated K+ channels (GIRKs). GAL reduction of TH-ir neuron number in dbcAMP + GAL-treated cultures was sensitive to both PTX and tertiapin, a GIRK inhibitor. GAL inhibition of midbrain DA activity may involve a GALR1- mediated reduction of TH in midbrain dopaminergic neurons. C1 Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Dept Pharmacol, Chicago, IL 60612 USA. NIMH, Sect Behav Neuropharmacol, NIH, Bethesda, MD 20892 USA. RP Mufson, EJ (reprint author), Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, 2242 W Harrison St Suite 200, Chicago, IL 60612 USA. FU NIA NIH HHS [AG00257, AG10688]; NINDS NIH HHS [NS42125] NR 61 TC 25 Z9 27 U1 1 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2002 VL 83 IS 2 BP 442 EP 451 DI 10.1046/j.1471-4159.2002.01148.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 599QG UT WOS:000178346200020 PM 12423254 ER PT J AU Nadareishvili, ZG Beletsky, V Black, SE Fremes, SE Freedman, M Kurzman, D Leach, L Norris, JW AF Nadareishvili, ZG Beletsky, V Black, SE Fremes, SE Freedman, M Kurzman, D Leach, L Norris, JW TI Is cerebral microembolism in mechanical prosthetic heart valves clinically relevant? SO JOURNAL OF NEUROIMAGING LA English DT Article DE embolism; ultrasonography; Doppler; transcranial; prosthetic heart valves ID CARDIAC VALVES; SIGNALS AB Background and Purpose. High-intensity transient signals (HITS) are frequently detected by transcranial Doppler (TCD) ultrasound in patients with mechanical prosthetic heart valves (PHVs), but published data about their clinical relevance are controversial. This study was undertaken to determine the clinical relevance of HITS in patients with mechanical PHVs Methods. The authors prospectively studied patients with mechanical PHVs using TCD monitoring for microemboli detection with and without 0, inhalation. The cognitive testing of patients included the Mini-Mental State Examination, the Dementia Rating Scale, and MicroCog. Results. The authors studied 36 patients (20 women, aged 58 13 years). HITS were detected in 72% of patients, with a nonsignificant increase of HITS rate in the aortic valve group (P=.07). There was no significant difference in HITS rate between asymptomatic and symptomatic patients. In a multiple linear regression model, HITS rate was predicted only by younger age (P=.024). No correlation was found between HITS rate and the cognitive performance of patients. There was a significant decrease in HITS rate after 100% O-2 inhalation compared to baseline levels (32 8+/-40.2 vs 6.1 +/- 11.3, P = .011). Subgroup analysis in asymptomatic patients confirmed this finding (P = .017), but in symptomatic patients, decreased HITS rate was not statistically significant (P = .18). Conclusion. Only age was a significant predictor of HITS in patients with mechanical PHVs. The lack of association between HITS, clinical symptoms, and cognitive functioning suggests that most of these signals represent harmless epiphenomena, and only HITS detected after O-2 inhalation have any clinical relevance. C1 Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Stroke Res Unit, Toronto, ON, Canada. Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Div Neurol, Toronto, ON, Canada. Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Div Cardiovasc Surg, Toronto, ON, Canada. Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Div Psychol, Toronto, ON, Canada. RP Nadareishvili, ZG (reprint author), NINDS, Stroke Branch, 36 Convent Dr,Bldg 36,4A03, Bethesda, MD 20892 USA. RI Fremes, Stephen/P-7928-2015 OI Black, Sandra/0000-0001-7093-8289; Fremes, Stephen/0000-0003-1723-3049 NR 21 TC 16 Z9 17 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD OCT PY 2002 VL 12 IS 4 BP 310 EP 315 DI 10.1177/105122802237974 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 598AE UT WOS:000178252300003 PM 12380477 ER PT J AU Wei, RT Phillips, TM Sternberg, EM AF Wei, RT Phillips, TM Sternberg, EM TI Specific up-regulation of CRH or AVP secretion by acetylcholine or lipopolysaccharide in inflammatory susceptible Lewis rat fetal hypothalamic cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE HPA axis; neuroendocrine; stress response; LEW/N; F344/N ID CORTICOTROPIN-RELEASING FACTOR; IMMUNOAFFINITY CAPILLARY-ELECTROPHORESIS; ARGININE-VASOPRESSIN; NITRIC-OXIDE; PARAVENTRICULAR NUCLEUS; INDUCED ARTHRITIS; GENE-EXPRESSION; IN-VITRO; NEURONS; HORMONE AB Lewis (LEW/N) rats, compared to Fischer (F344/N) rats, are susceptible to inflammatory/autoimmune diseases, in part, as a result of their blunted hypothalamic-pituitary-adrenal (HPA) axis responses. We examined regulation of LEW/N and F344/N fetal hypothalamic cell secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), two major HPA axis mediators, by inflammatory and neurotransmitter stimuli. Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and protein kinase A (PKA) and protein kinase C (PKC) activators did not affect LEW/N basal secretion. Compared to F344/N, LEW/N cells were hyporesponsive to lipopolysaccharide (LPS), serotonin (5-HT), and acetylcholine chloride (ACh). However, LPS-induced AVP release and ACh-evoked CRH secretion in LEW/N were comparable with those of F344/N. Our findings suggest that the blunted LEWN neuropeptide response was more likely related to components of second messenger systems, rather than to any one specific stimulus. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. NIH, Ultramicro Analyt Immunochem Resource, Div Bioengn & Phys Sci, Off Res Serv,OD, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Integrat Neural Immune Program, NIH, 36 Convent Dr,Room 1A23, Bethesda, MD 20892 USA. NR 35 TC 19 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT PY 2002 VL 131 IS 1-2 BP 31 EP 40 AR PII S0165-5728(02)00251-5 DI 10.1016/S0165-5728(02)00251-5 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 607KW UT WOS:000178791600003 PM 12458034 ER PT J AU Foster, JA Quan, N Stern, EL Kristensson, K Herkenham, M AF Foster, JA Quan, N Stern, EL Kristensson, K Herkenham, M TI Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Sprague-Dawley; neuroimmune; lipopolysaccharide; trypanosome; In vivo ID MHC CLASS-I; NITRIC-OXIDE SYNTHASE; MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; LIPOPOLYSACCHARIDE-INDUCED EXPRESSION; BRAIN ENDOTHELIAL-CELLS; PRIMARY SENSORY NEURONS; FACTOR-KAPPA-B; RAT-BRAIN; GENE-EXPRESSION AB Studies have demonstrated neuronal expression of class I major histocompatibility complex (MHC) mRNA and protein in normal and developing brain and in response to injury or viral infection. We report neuronal expression of class I MHC mRNA in hypothalamic paraventricular nucleus (PVN) neurons in rats following systemic infection with Trypanosoma brucei brucei parasites (chronic) and in response to intravenous 1 mg/kg lipopolysaccharide administration (acute peripheral) and in striatal neurons following intrastriatal 5 mug lipopolysaccharide injection (acute central). These results demonstrate that neurons can be a source of immune signaling molecules and establish class I MHC as part of the neuronal component of immune responses. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. Ohio State Univ, Dept Oral Biol, Columbus, OH 43210 USA. Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. RP Foster, JA (reprint author), NIMH, Funct Neuroanat Sect, 36 Convent Dr,Bldg 36,Room 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 57 TC 40 Z9 40 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT PY 2002 VL 131 IS 1-2 BP 83 EP 91 AR PII S0165-5728(02)00258-8 DI 10.1016/S0165-5728(02)00258-8 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 607KW UT WOS:000178791600008 PM 12458039 ER PT J AU Proescholdt, MA Jacobson, S Tresser, N Oldfield, EH Merrill, MJ AF Proescholdt, MA Jacobson, S Tresser, N Oldfield, EH Merrill, MJ TI Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE astrocytes; experimental allergic encephalomyelitis (EAE) multiple sclerosis; neuroinflammation; vascular endothelial growth factor (VEGF); vascular permeability factor ID BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ADHESION MOLECULE-1 ICAM-1; PERMEABILITY FACTOR; TUMOR ANGIOGENESIS; SPINAL-CORD; MICROVASCULAR PERMEABILITY; ENHANCED MRI; FACTOR VEGF AB The active lesions in multiple sclerosis (MS) are characterized by blood-brain-harrier (BBB) breakdown, upregulation of adhesion molecules on capillary endothelial cells, and perivascular inflammation. suggesting that altered vessel permeability and activated endothelial Celts are involved in the pathogenesis of the disease, Vascular endothelial growth factor (VEGF) mediates multiple aspects of blood vessel physiology, including regulation of To investigate a possible relationship between VEGF expression and CNS autoimmune disease, we examined VEGF expression in MS plaques compared to normal white matter by immunohistochemistry and in situ hybridization. VEGF expression was consistently upregulated in both acute and chronic MS plaques. We also examined VEGF expression during the Course of experimental allergic encephalomyelitis (EAE) in rats, VEGF-positive cells with astrocytic morphology increased in the spinal cord during the development of EAE and were found in association with inflammatory Cells. Furthermore, intracerebral infusion of VEGF in animals previously immunized with myelin basic protein induced an inflammatory response in the brain. whereas infusion of vehicle, or infusion of VEGF in naive animals, did not. These results suggest that overexpression of VEGF may exacerbate the inflammatory response in autoimmune diseases of the CNS by inducing, focal BBB breakdown and migration of inflammatory cells into the lesions. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Merrill, MJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. NR 77 TC 90 Z9 94 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD OCT PY 2002 VL 61 IS 10 BP 914 EP 925 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 604DH UT WOS:000178600200009 PM 12387457 ER PT J AU Donchin, O Sawaki, L Madupu, G Cohen, LG Shadmehr, R AF Donchin, O Sawaki, L Madupu, G Cohen, LG Shadmehr, R TI Mechanisms influencing acquisition and recall of motor memories SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; REACHING MOVEMENTS; DEPENDENT PLASTICITY; ANTIEPILEPTIC DRUGS; VISUAL-CORTEX; WATER MAZE; DEXTROMETHORPHAN; DYNAMICS; NMDA; BENZODIAZEPINES AB An internal model of the dynamics of a tool or an object is part of the motor memory acquired when learning to use the tool or to manipulate the object. Changes in synaptic efficacy may underlie acquisition and storage of memories. Here we studied the effect of pharmacological agents that interfere with synaptic plasticity on acquisition of new motor memories and on recall of a previously learned internal model. Forty-nine subjects, divided into six groups, made reaching movements while holding a robotic arm that applied forces to the hand. On day 1, all subjects learned to move in force field A. On day 2, each group of subjects was tested on their ability to recall field A and their ability to learn a new internal model in field B. Four groups participated in the experiments of day 2 under the effects of lorazepam (LZ; a GABA type A receptor-positive allosteric modulator), dextromethorphan [DM; an N-methyl-D-aspartate (NMDA) receptor blocker], lamotrigine (LG, a drug that blocks voltage-gated Na+ and Ca2+ channel), or scopolamine (SP; muscarinic receptor antagonist). Two control groups were tested in a drug-free condition: one group that was not exposed to additional experimental protocols (NP) and another group was tested under similar to24 h of sleep deprivation between completion of learning on day 1 and start of testing on day 2 (SD). Recall of field A was normal in all groups. Learning of field B was reduced by LZ and DM but not by SP, LG, SD or in the NP condition. These results suggest that a 24-h sleep-deprivation period may have little or no effect on consolidation of this motor memory and that NMDA receptor activation and GABAergic inhibition are mechanisms operating in the acquisition but not recall of new motor memories in humans. C1 Johns Hopkins Sch Med, Lab Computat Motor Control, Baltimore, MD 21205 USA. NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Donchin, O (reprint author), Johns Hopkins Sch Med, Lab Computat Motor Control, 416 Traylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Donchin, Opher/A-4389-2008 OI Donchin, Opher/0000-0003-0963-4467 FU NINDS NIH HHS [NS-11163, NS-37422] NR 53 TC 74 Z9 75 U1 3 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT PY 2002 VL 88 IS 4 BP 2114 EP 2123 DI 10.1152/jn.00033.2002 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 600BF UT WOS:000178370200046 PM 12364533 ER PT J AU Belachew, S Aguirre, AA Wang, H Vautier, FO Yuan, XQ Anderson, S Kirby, M Gallo, V AF Belachew, S Aguirre, AA Wang, H Vautier, FO Yuan, XQ Anderson, S Kirby, M Gallo, V TI Cyclin-dependent kinase-2 controls oligodendrocyte progenitor cell cycle progression and is downregulated in adult oligodendrocyte progenitors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cell cycle; cell differentiation; checkpoint genes; CDK; cyclin; fluorescence-activated cell sorting; glia; myelin ID RAT OPTIC-NERVE; MULTIPLE-SCLEROSIS LESIONS; PRECURSOR CELLS; GROWTH-FACTOR; DIFFERENTIATION; ARREST; PDGF; WITHDRAWAL; EXPRESSION; P21(CIP1) AB Proliferation of oligodendrocyte progenitor (OP) cells is a crucial process controlling myelination in the CNS. Previous studies demonstrated a correlation between OP proliferation rate and cyclin E/cyclin-dependent kinase-2 (cdk2) activity. To establish a causal link between cyclin E/cdk2 activity and OP proliferation, we selectively modulated cdk2 activity in vitro by transfection of cultured OP cells. Dominant-negative (Dn)-cdk2 overexpression inhibited mitogen-induced OP cell proliferation, whereas wild-type (wt)-cdk2 prevented cell cycle arrest caused by anti-mitotic signals. Dn-cdk2- or wt-cdk2-mediated regulation of G(1)/S transition, per se, did not influence initiation of OP differentiation. To study the function of cyclin E/cdk2 in OP cells during development in vivo, we analyzed cdk2 and cyclin E expression in cells acutely isolated from transgenic mice expressing the green fluorescent protein (GFP) under the control of the 2'-3'- cyclic nucleotide 3'-phosphodiesterase gene promoter. Both cyclin E/cdk2 protein levels and activity were decreased in GFP(+) oligodendrocyte lineage cells between postnatal days 4 and 30. Immunostaining of NG2(+)/GFP(+)OP cells in brain tissue sections showed a 90% decrease in overall cell proliferation and cdk2 expression between perinatal and adult cells. However, cdk2 expression within the proliferating (i.e., expressing the proliferating cell nuclear antigen) OP cell population was maintained throughout development. Our data indicate that: (1) cyclin E/cdk2 activity plays a pivotal function in OP cell cycle decisions occurring at G(1)/S checkpoint; (2) initiation of OP differentiation is independent of cyclinE/cdk2 checkpoint, and (3) intrinsic differences in cyclin E/cdk2 expression and activity may underlie the slowly proliferative state that characterizes so-called "quiescent" adult OP cells in vivo. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. NHGRI, Gene Transfer Lab, Hematopoiesis Sect, Flow Cytometry Core Unit,NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), Childrens Natl Med Ctr, Childrens Res Inst, Ctr Res Neurosci, 111 Michigan Ave, Washington, DC 20010 USA. NR 51 TC 45 Z9 46 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 1 PY 2002 VL 22 IS 19 BP 8553 EP 8562 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 597XL UT WOS:000178246000023 PM 12351729 ER PT J AU Lonser, RR Walbridge, S Garmestani, K Butman, JA Walters, HA Vortmeyer, AO Morrison, PF Brechbiel, MW Oldfield, EH AF Lonser, RR Walbridge, S Garmestani, K Butman, JA Walters, HA Vortmeyer, AO Morrison, PF Brechbiel, MW Oldfield, EH TI Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion SO JOURNAL OF NEUROSURGERY LA English DT Article DE brainstem; convection-enhanced delivery; magnetic resonance imaging; Macaca mulatta; rat ID CONVECTION-ENHANCED DELIVERY; TISSUE AB Object. Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood-brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem. Methods. Three primates (Macaca midatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 mul) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and raidbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R-2 = 0.94), with a Vd/Vi ratio of 8.7 +/- 1.2 (mean +/- standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal,gliosis that was limited to the region immediately surrounding the cannula track. Conclusions. First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biomed Engn & Instrumentat Program, NIH, Bethesda, MD 20892 USA. NCI, Sect Radioimmune & Inorgan Chem, Div Clin Sci, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Neuroradiol Sect, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. RI Butman, John/A-2694-2008; Kipke, Daryl/A-2167-2009; OI Butman, John/0000-0002-1547-9195 NR 17 TC 109 Z9 111 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2002 VL 97 IS 4 BP 905 EP 913 DI 10.3171/jns.2002.97.4.0905 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 604MY UT WOS:000178626400029 PM 12405380 ER PT J AU Khasar, SG Miao, FJP Gear, RW Green, PG Isenberg, WM Levine, JD AF Khasar, SG Miao, FJP Gear, RW Green, PG Isenberg, WM Levine, JD TI Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat SO JOURNAL OF PAIN LA English DT Article DE primary afferent; sensitization; sympathectomy; vagal afferents ID DEPENDENT PROTEIN-KINASE; 2ND MESSENGER SYSTEM; NORADRENALINE HYPERALGESIA; VAGAL AFFERENTS; SENSORY NEURONS; BINDING-SITES; KININ B-1; RECEPTOR; EXPRESSION; PAIN AB Bradykinin-induced mechanical hyperalgesia is sympathetically dependent and B-2-type bradykinin receptor-mediated in the rat; however, a sympathetically independent component of bradykinin hyperalgesia is shown after subdiaphragmatic vagotomy. We evaluated the mechanism of this bradykinin-induced sympathetic-independent mechanical hyperalgesia. The dose-response curve for bradykinin mechanical hyperalgesia in sympathectomized plus vagotomized rats was similar in magnitude to that for sympathetically dependent bradykinin hyperalgesia in normal rats. Although bradykinin mechanical hyperalgesia was mediated by the B-2-type bradykinin receptors after sympathectomy plus vagotomy, it had a much more rapid latency to onset. This hyperalgesia was significantly attenuated by inhibition of protein kinase A but not protein kinase C, similar to the hyperalgesia produced by prostaglandin E-2 an agent that directly sensitizes primary afferent nociceptors. However, unlike prostaglandin E-2-induced mechanical hyperalgesia in normal rats, after sympathectomy plus vagotomy, bradykinin-induced hyperalgesia was not attenuated by inhibition of nitric oxide synthesis. Peripheral administration of a mu opioid agonist, [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, significantly attenuated bradykinin mechanical hyperalgesia after sympathectomy plus vagotomy. These data suggest that after sympathectomy plus subdiaphragmatic vagotomy, bradykinin acts directly on primary afferents to produce mechanical hyperalgesia via a novel protein kinase A-dependent signaling mechanism. (C) 2002 by the American Pain Society. C1 Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Neurosci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, Box 0440,C-522, San Francisco, CA 94143 USA. RI Green, Paul/C-5943-2011 NR 40 TC 6 Z9 6 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD OCT PY 2002 VL 3 IS 5 BP 369 EP 376 DI 10.1054/jpai.2002.126610 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 604DA UT WOS:000178599500007 PM 14622740 ER PT J AU Zeltzer, LK Tsao, JCI Stelling, C Powers, M Levy, S Waterhouse, M AF Zeltzer, LK Tsao, JCI Stelling, C Powers, M Levy, S Waterhouse, M TI A phase I study on the feasibility and acceptability of an acupuncture/hypnosis intervention for chronic pediatric pain SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE acupuncture; hypnosis; chronic pain; pediatric patients; complementary medicine; alternative medicine ID RANDOMIZED CONTROLLED TRIALS; CHRONIC MUSCULOSKELETAL PAIN; COLD PRESSOR PAIN; ALTERNATIVE MEDICINE; UNITED-STATES; CHILDREN; HYPNOSIS; ADOLESCENTS; REDUCTION; PARENT AB The purpose of the present study was to conduct a Phase I investigation examining the feasibility and acceptability of a complementary and alternative medicine (CAM) package combining acupuncture and hypnosis for chronic pediatric Pain. Thirty-three sequentially referred children (21 girls) aged 6-18 years were offered 6 weekly sessions consisting of individually tailored acupuncture treatment together with a 20-minute hypnosis session (conducted while the needles were in place). Parent and child ratings of pain and pain-related interferences in functioning, as well as child ratings of anxiety and depression, were obtained at Pre- and post-treatment. The treatment was highly acceptable (only 2 patients refused; greater than or equal to 90 % completed treatment) and there were no adverse effects. Both parents and children reported significant improvements in children's pain and interference following treatment. Children's anticipatory anxiety declined significantly across treatment sessions. Our results support the feasibility and acceptability of a combined acupuncture/hypnosis intervention for chronic pediatric pain. C1 Univ Calif Los Angeles, Pediat Pain Program, Dept Pediat, Sch Med, Los Angeles, CA 90095 USA. Univ Florida, NIMH, Ctr Study Emot & Attent, Dept Clin & Hlth Psychol,Coll Hlth Profess, Gainesville, FL USA. Univ Texas, UT Anxiety Disorders Clin, Dept Psychol, Austin, TX 78712 USA. RP Zeltzer, LK (reprint author), Univ Calif Los Angeles, Pediat Pain Program, Dept Pediat, Sch Med, 22-464 MDCC,10833 Le Conte Ave, Los Angeles, CA 90095 USA. OI Zeltzer, Lonnie/0000-0001-9306-9450 NR 33 TC 61 Z9 63 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD OCT PY 2002 VL 24 IS 4 BP 437 EP 446 AR PII S0885-3924(02)00506-7 DI 10.1016/S0885-3924(02)00506-7 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 623PC UT WOS:000179711200012 PM 12505213 ER PT J AU Rice, AM Currier, MA Adams, LC Bharatan, NS Collins, MH Snyder, JD Khan, J Cripe, TP AF Rice, AM Currier, MA Adams, LC Bharatan, NS Collins, MH Snyder, JD Khan, J Cripe, TP TI Ewing sarcoma family of tumors express adenovirus receptors and are susceptible to adenovirus-mediated oncolysis SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE adenovirus; Ewing sarcoma; gene therapy; oncolysis; osteosarcoma; rhabdomyosarcoma ID SELECTIVELY-REPLICATING ADENOVIRUS; CANCER GENE-THERAPY; NECK-CANCER; ATTENUATED ADENOVIRUS; ANTITUMORAL EFFICACY; RECURRENT HEAD; ONYX-015; CELLS; VECTOR; COXSACKIEVIRUS AB Purpose: Attenuated viruses derived from adenoviruses (Ad) that kill tumor cells (oncolysis) are currently in clinical trials for selected cancers. Some cancers have proven resistant to Ad infection due to low expression of viral receptors. The authors sought to determine whether members of the Ewing sarcoma family of tumors (ESFTs) express Ad receptors and are sensitive to Ad-mediated oncolysis. Methods: Using flow cytometry, the authors tested a panel of cell lines derived from ESFTs for expression of both the Ad receptor, coxsackie-adenovirus receptor (CAR), and the cellular mediator of Ad uptake, alpha(v)-integrins, as well as for Ad-mediated gene transduction. Cell survival assays were used to assess the sensitivity to Ad-mediated oncolysis. Immunohistochemistry was used to assess CAR expression in primary tumors. mRNA levels of CAR in cell lines and tumor samples were also queried from a cDNA expression database. Results: The ESFT cell lines expressed CAR and alpha(v)-integrins, showed high levels of gene transduction, and were highly sensitive to viral oncolysis. Primary tumor samples were positive for CAR expression by immunohistochemistry. Microarray analysis confirmed CAR expression in ESFT cell lines and tumors. Conclusions: Ewing sarcoma cells express the Ad receptors and are sensitive to Ad oncolysis. Treatment of Ewing sarcoma using conditionally replicative adenoviruses should be explored. C1 Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. Cincinnati Childrens Hosp Med Ctr, Dept Pathol, Cincinnati, OH 45229 USA. Univ Wisconsin, Childrens Hosp, Div Pediat Hematol Oncol, Madison, WI USA. Ctr Comprehens Canc, Madison, WI USA. NCI, Pediat Oncol Branch, Gaithersburg, MD USA. RP Cripe, TP (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NCI NIH HHS [CA75113, P30-CA-14520-25] NR 35 TC 10 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2002 VL 24 IS 7 BP 527 EP 533 DI 10.1097/00043426-200210000-00006 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 601WC UT WOS:000178470800006 PM 12368688 ER PT J AU Hemrick-Luecke, SK Bymaster, FP Evans, DC Wess, J Felder, CC AF Hemrick-Luecke, SK Bymaster, FP Evans, DC Wess, J Felder, CC TI Muscarinic agonist-mediated increases in serum corticosterone levels are abolished in M-2 muscarinic acetylcholine receptor knockout mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CORTICOTROPIN-RELEASING FACTOR; ANTIPSYCHOTIC-LIKE ACTIVITY; ALZHEIMERS-DISEASE; CHOLINERGIC RECEPTORS; PARKINSONS-DISEASE; DEPRESSION; PITUITARY; BRAIN; STIMULATION; HYPOTHESIS AB Muscarinic acetylcholine receptors (M-1-M-5) regulate many key functions in the central and peripheral nervous system. Due to the lack of receptor subtype-selective ligands, however, the physiological roles of individual muscarinic receptor subtypes remain to be determined. In this study, we examined the effects of the muscarinic M-2/M-4 receptor-preferring agonist [5R-(exo)]-6[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane (BuTAC) on serum corticosterone levels in M-2 and M-4 receptor single knockout (KO) and M-2,M-4 receptor double KO mice. Responses were compared with those obtained with the corresponding wild-type (WT) mice. BuTAC (0.03-0.3 mg/kg s.c.) dose dependently and significantly increased serum corticosterone concentrations in WT mice to 5-fold or greater levels compared with vehicle controls. In muscarinic M-2 and M-2,M-4 KO mice, however, BuTAC had no significant effect on corticosterone concentrations at doses of 0.1, 0.3, and 1 mg/kg s.c. In both WT and muscarinic M-4 KO mice increases in serum corticosterone concentrations induced by BuTAC (0.1 and 0.3 mg/kg) were not significantly different and were blocked by scopolamine. In summary, the muscarinic M-2,M-4-preferring agonist BuTAC had no effect on corticosterone levels in mice lacking functional muscarinic M-2 receptors. These data suggest that the muscarinic M-2 receptor subtype mediates muscarinic agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis in mice. C1 Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Div Neurosci, Indianapolis, IN 46285 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Hemrick-Luecke, SK (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Div Neurosci, DC 0150, Indianapolis, IN 46285 USA. NR 41 TC 12 Z9 12 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2002 VL 303 IS 1 BP 99 EP 103 DI 10.1124/jpet.102.036020 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 594EE UT WOS:000178035100013 PM 12235238 ER PT J AU Wilkemeyer, MF Menkari, CE Spong, CY Charness, ME AF Wilkemeyer, MF Menkari, CE Spong, CY Charness, ME TI Peptide antagonists of ethanol inhibition of L1-mediated cell-cell adhesion SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DEPENDENT NEUROTROPHIC FACTOR; ACTING NEUROPROTECTIVE PEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; NEURAL CREST CELLS; L1 KNOCKOUT MICE; NEURITE OUTGROWTH; OSTEOGENIC PROTEIN-1; ALCOHOL INHIBITION; ANKYRIN-BINDING; NEURONS AB Ethanol inhibits cell-cell adhesion mediated by the L1 cell adhesion molecule. 1-Octanol potently antagonizes this cellular action of ethanol and also prevents ethanol-induced dysmorphology and cell death in mouse whole embryo culture. NAPVSIPQ (NAP) and SALLRSIPA (SAL) are active peptide fragments of two neuroprotective proteins: activity-dependent neuroprotective protein and activity-dependent neurotrophic factor. NAP and SAL are neuroprotective at femtomolar concentrations against a variety of neurotoxins and also prevent ethanol teratogenesis in mice. To explore the cellular basis for this action, we asked whether NAP and SAL antagonize ethanol inhibition of L1 adhesion. Aggregation assays were carried out in ethanol-sensitive, human L1-transfected NIH/3T3 cells in the absence and presence of NAP and SAL. Neither NAP nor SAL altered L1 adhesion or L1 expression; however, both peptides potently and completely antagonized the inhibition of L1 adhesion by 100 mM ethanol (EC50 : NAP, 6 x 10(-14) M; SAL, 4 x 10(-11) M). NAP also antagonized ethanol inhibition of cell-cell adhesion in bone morphogenetic protein-7-treated NG108-15 cells. In L1-expressing NIH/3T3 cells, SAL antagonism was reversible and could be overcome by increasing concentrations of ethanol. In contrast, NAP antagonism was irreversible and could not be overcome by increasing agonist concentration. Two scrambled NAP peptides (ASPNQPIV and PNIQVASP) were not antagonists at concentrations as high as 10(-7) M. Thus, two structurally unrelated classes of compounds, alcohols and small polypeptides, share two common actions: antagonism of ethanol inhibition of L1-mediated cell adhesion and prevention of ethanol teratogenesis. These findings support the hypothesis that ethanol inhibition of L1 adhesion contributes to ethanol teratogenesis. C1 Harvard Univ, Sch Med, Vet Adm Boston Healthcare Syst,Neurol Serv, Dept Neurol 127, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Charness, ME (reprint author), Harvard Univ, Sch Med, Vet Adm Boston Healthcare Syst,Neurol Serv, Dept Neurol 127, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. OI Charness, Michael/0000-0002-3301-8966 FU NIAAA NIH HHS [AA11297, AA12974] NR 44 TC 37 Z9 38 U1 2 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2002 VL 303 IS 1 BP 110 EP 116 DI 10.1124/jpet.102.036277 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 594EE UT WOS:000178035100015 PM 12235240 ER PT J AU Narimatsu, S Takemi, C Tsuzuki, D Kataoka, H Yamamoto, S Shimada, N Suzuki, S Satoh, T Meyer, UA Gonzalez, FJ AF Narimatsu, S Takemi, C Tsuzuki, D Kataoka, H Yamamoto, S Shimada, N Suzuki, S Satoh, T Meyer, UA Gonzalez, FJ TI Stereoselective metabolism of bufuralol racemate and enantiomers in human liver microsomes SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID BUNITROLOL 4-HYDROXYLATION; HYDROXYLATION; ENANTIOSELECTIVITY; INHIBITORS; ENZYMES AB A new HPLC method was developed using a chiral column to efficiently separate four 1"-hydroxybufuralol (1"-OH-BF) diastereomers that are major metabolites of bufuralol (BF). Employing this method, we examined diastereomer selectivity in the formation of 1"-OH-BF from BF racemate or enantiomers in four individual samples of human liver microsomes. Three different human liver microsomes showed a selectivity of 1"R-OH <1"S-OH for BF enantiomers, which was similar to that of recombinant CYP2D6 expressed in insect cell microsomes, whereas one human liver microsomal fraction yielded a selectivity of 1"R-OH > 1"S-OH for BF enantiomers, which was similar to those of recombinant CYP2C19 expressed in insect cell microsomes. Recombinant CYP1A2 and CYP3A4 showed a selectivity similar to that of CYP2D6, but their BF 1"-hydroxylase activities were much lower than those of CYP2D6. In inhibition studies, quinidine, a known CYP2D6 inhibitor, markedly inhibited BF 1"-hydroxylation in the fractions of human liver microsomes that showed the CYP2D6-type selectivity. Furthermore, omeprazole, a known CYP2C19 inhibitor, efficiently suppressed the formation of 1"-OH-BF diastereomers from BF in the microsomal fraction that showed the CYP2C19-type selectivity. From these results, we concluded that the diastereomer selectivity in the formation of 1"-OH-BF from BF differs between CYP2D6 and CYP2C19, both of which can be determinant enzymes in the diastereoselective 1"-hydroxylation of BF in human liver microsomes. C1 Okayama Univ, Fac Pharmaceut Sci, Lab Hlth Chem, Okayama 7008530, Japan. Okayama Univ, Fac Pharmaceut Sci, Lab Biomol Sci, Okayama 7008530, Japan. Daiichi Pure Chem, Tokyo, Japan. Biomed Res Inst, Chiba, Japan. Univ Basel, Biozentrum, Basel, Switzerland. NCI, NIH, Bethesda, MD 20892 USA. RP Narimatsu, S (reprint author), Okayama Univ, Fac Pharmaceut Sci, Lab Hlth Chem, 1-1-1 Tsushima Naka, Okayama 7008530, Japan. NR 21 TC 17 Z9 18 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2002 VL 303 IS 1 BP 172 EP 178 DI 10.1124/jpet.102.036533 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 594EE UT WOS:000178035100023 PM 12235248 ER PT J AU Mozer, B Ivanov, A Li, HP Higashida, H Rovescalli, A Nirenberg, M AF Mozer, B Ivanov, A Li, HP Higashida, H Rovescalli, A Nirenberg, M TI Searching for new genes required for embryonic nervous system development in Drosophila using RNAi SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract CT Conference of the Physiological-Society CY JUL 08-11, 2002 CL UNIV LIVERPOOL, LIVERPOOL, ENGLAND SP Physiol Soc HO UNIV LIVERPOOL C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD OCT PY 2002 VL 543 SU S BP 23S EP 24S PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 612KM UT WOS:000179074100264 ER PT J AU Garfield, SA AF Garfield, SA TI Depression and mental disorders in patients with diabetes, kidney disease, and obesity and eating with disorders SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Editorial Material ID CONTROLLED TRIAL; ADULTS C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Garfield, SA (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. NR 4 TC 2 Z9 2 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2002 VL 53 IS 4 BP 841 EP 841 AR PII S0022-3999(02)00520-2 DI 10.1016/S0022-3999(02)00520-2 PG 1 WC Psychiatry SC Psychiatry GA 606ME UT WOS:000178737100001 ER PT J AU Muehrer, P AF Muehrer, P TI Research on co-morbidity, contextual barriers, and stigma - An introduction to the special issue SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Editorial Material ID PRIMARY-CARE; MENTAL-DISORDERS; DEPRESSION; HEALTH; DANGEROUSNESS; OUTCOMES C1 NIMH, Div Mental Disorders Behav Res & AIDS, NIH, Bethesda, MD 20892 USA. RP Muehrer, P (reprint author), NIMH, Div Mental Disorders Behav Res & AIDS, NIH, 6001 Execut Blvd,Room 6189,MSC 9615, Bethesda, MD 20892 USA. NR 22 TC 10 Z9 10 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2002 VL 53 IS 4 BP 843 EP 845 AR PII S0022-3999(02)00519-6 DI 10.1016/S0022-3999(02)00519-6 PG 3 WC Psychiatry SC Psychiatry GA 606ME UT WOS:000178737100002 PM 12377291 ER PT J AU Abeles, RP AF Abeles, RP TI Depression and mental disorders in chronic disease - An introduction to the special issue SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Editorial Material C1 NIH, Off Director, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Abeles, RP (reprint author), NIH, Off Director, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2002 VL 53 IS 4 BP 847 EP 847 AR PII S0022-3999(02)00521-4 DI 10.1016/S0022-3999(02)00521-4 PG 1 WC Psychiatry SC Psychiatry GA 606ME UT WOS:000178737100003 ER PT J AU Tsigos, C Chrousos, GP AF Tsigos, C Chrousos, GP TI Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE stress; glucocorticoids; corticotropin-releasing hormone or factor (CRH or CRF) ID CORTICOTROPIN-RELEASING HORMONE; RECOMBINANT HUMAN INTERLEUKIN-6; BIOCHEMICAL MANIFESTATIONS; NERVOUS-SYSTEM; BETA-ENDORPHIN; SECRETION; DEPRESSION; RECEPTORS; IMMUNE; BRAIN AB The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1) The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholarninergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LCNE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T-4) to triiodothyronine (T-3) contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LCNE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Athens, Sch Med, GR-11527 Athens, Greece. Hellen Natl Diabet Ctr, Athens, Greece. RP Chrousos, GP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42, Bethesda, MD 20892 USA. NR 47 TC 940 Z9 989 U1 36 U2 273 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2002 VL 53 IS 4 BP 865 EP 871 AR PII S0022-3999(02)00429-4 DI 10.1016/S0022-3999(02)00429-4 PG 7 WC Psychiatry SC Psychiatry GA 606ME UT WOS:000178737100006 PM 12377295 ER PT J AU Kimmel, PL AF Kimmel, PL TI Depression in patients with chronic renal disease - What we know and what we need to know SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE depression; chronic kidney disease; prevalence; survival; peritoneal dialysis; hemodialysis; chronic renal insufficiency; compliance; suicide; immune dysfunction; marriage ID URBAN HEMODIALYSIS-PATIENTS; CHRONIC DIALYSIS PATIENTS; LONG-TERM DIALYSIS; QUALITY-OF-LIFE; MAJOR DEPRESSION; PSYCHOSOCIAL ADJUSTMENT; PSYCHOLOGICAL-FACTORS; SURVIVAL; FAILURE; MORTALITY AB Depression is a common, but underdiagnosed and understudied problem in patients with renal disease. The overlap between symptoms of chronic medical illness and those of depression make for a particularly challenging diagnosis in this illness. The prevalence of depression varies with the diagnostic tool employed. The gold standard for the psychiatric diagnosis is the interview, using DSM-IV TR criteria. Researchers in the field of renal disease have often not distinguished between the diagnosis of major depression and high levels of depressive affect in studies. There are almost no data regarding the magnitude of depression in patients with chronic renal insufficiency, patients treated with peritoneal dialysis, and children with renal disease, compared with adults with end-stage renal disease treated with hemodialysis. The relationships between age, ethnicity, marital status and satisfaction, and perception of quality of life and level of depressive affect and diagnosis of depression, and medical outcomes have not been determined in patients with renal disease. The mediators which may underlie the deleterious effects of depression in patients with renal disease, and their relationship with stage of renal dysfunction have not been delineated. More emphasis must be placed on well-designed treatment studies and survival analyses in these populations, using longitudinal techniques. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC USA. RP Kimmel, PL (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, NIH, 2 Democracy Plaza,6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 47 TC 174 Z9 183 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2002 VL 53 IS 4 BP 951 EP 956 AR PII S0022-3999(02)00310-0 DI 10.1016/S0022-3999(02)00310-0 PG 6 WC Psychiatry SC Psychiatry GA 606ME UT WOS:000178737100019 PM 12377308 ER PT J AU Dwyer, JT Larive, B Leung, J Rocco, M Burrowes, JD Chumlea, WC Frydrych, A Kusck, JW Uhlin, L AF Dwyer, JT Larive, B Leung, J Rocco, M Burrowes, JD Chumlea, WC Frydrych, A Kusck, JW Uhlin, L CA HEMO Study Grp TI Nutritional status affects quality of life in hemodialysis (HEMO) study patients at baseline SO JOURNAL OF RENAL NUTRITION LA English DT Article ID STAGE RENAL-DISEASE; CHRONIC DIALYSIS PATIENTS; OF-LIFE; FUNCTIONAL HEALTH; UREA KINETICS; ADEQUACY; MORTALITY; MALNUTRITION; PREDICTORS AB Objective: To evaluate associations between frequently used indicators for assessing nutritional status and health-related quality of life in hemodialysis patients after controlling for demographics, comorbidity, and dialysis dose. Design: Survey of 1,387 hemodialysis patients enrolled at baseline in the Hemodialysis (HEMO) Study. Nutritional status indicators included dietary energy intake, equilibrated normalized protein catabolic rate (enPCR), serum creatinine (SCr), serum albumin (SAlb), body mass index (BMI), calf circumference, and appetite. Health-related quality of life was measured by the Medical Outcomes Study Short Form-36 (MOS-SF-36) summary measures: the Physical Component Scale (PCS) and Mental Component Scale (MCS). Setting: Fifteen clinical sites throughout the United States providing in-center hemodialysis. Results: The mean PCS score was 36.1 +/- 10 SD, lower than normative data in healthy populations. PCS scores were lower among women, whites, and those with diabetes, severe comorbidities, and poor appetites. Appetite, dietary energy intake, SAlb, and SCr were strongly associated with PCS scores even after controlling for demographics and comorbidity. The sum of the parameter estimates for the effects of nutritional status on PCS was large, 7 points or more depending on the individual's nutritional status indicators. The mean MCS score was 49.7 +/- 10.1 SD, similar to scores in healthy populations, but lower among those with severe comorbidities, poor appetites, advanced age, and more years on dialysis. Appetite, age, and years on dialysis were significantly associated with MCS after controlling for other demographics and comorbidity. Dialysis dose did not significantly alter these relationships. Conclusion: Easy-to-use indicators for assessing nutritional status (appetite, energy intake, SAlb, and SCr) together are strongly associated with health-related quality of life, even after controlling for comorbidities and dose of dialysis in hemodialysis patients, providing an additional reason for maximizing patients' nutritional status and health. (C) 2002 by the National Kidney Foundation, Inc. C1 Tufts New England Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Tufts Univ, Sch Nutr, Boston, MA 02111 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC USA. Beth Israel Med Ctr, New York, NY 10003 USA. Wright State Univ, Sch Med, Div Human Biol, Dept Community Hlth, Kettering, OH USA. Univ Illinois, Chicago, IL USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Dwyer, JT (reprint author), Tufts New England Med Ctr, Frances Stern Nutr Ctr, 750 Washington St,Box 783, Boston, MA 02111 USA. NR 39 TC 55 Z9 61 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD OCT PY 2002 VL 12 IS 4 BP 213 EP 223 DI 10.1053/jren.2002.35297 PG 11 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 604LX UT WOS:000178623700002 PM 12382213 ER PT J AU Poola, I Abraham, J Liu, A AF Poola, I Abraham, J Liu, A TI Estrogen receptor beta splice variant rnRNAs are differentially altered during breast carcinogenesis SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE breast cancer; ER beta splice variants; menopausal status and ER beta variants; tumor grade and ER beta variants; carcinogenesis ID ALPHA MESSENGER-RNAS; CANCER CELL-LINES; TRANSCRIPTIONAL ACTIVATION; WILD-TYPE; ER-ALPHA; EXPRESSION; TUMORS; GENE; IDENTIFICATION; LOCALIZATION AB We previously identified 10 exon deletion ERbeta variant mRNAs in various human tissues [FEBS Lett. 516 (2002) 133]. In the current study, we have investigated the expression of these variant mRNAs in normal breast tissues and their alterations in cancer tissues. A total of 43 cancer tissues in comparison with their matched normal tissues were analyzed by RT PCR using the newly developed 'Splice Targeted Primer Approach'. The data presented here show that normal breast tissues express 9 of the 10 identified variant mRNAs. Of the nine variants, the mRNAs with exons 5-6 deletions were significantly decreased (similar to80%) in a large majority of cancer tissues (two-sided paired t-test, n = 43 patients, P < 0.00001). The expression of ERbeta exon 5Delta, that could potentially have transactivating property in the absence of hormone, was changed differently among different grade tumors (analysis of variance F-test, n = 43 patients, P = 0.0452; Kruskal-Wallis test, n = 43 patients, P = 0.0356). When change in expression of ERbeta exon 5Delta mRNA levels was used as a categorical variable, a significant association was found between the change status (increase, no change, decrease) of this variant and grade of the tumor (Fischer's exact test, n = 43 patients, P = 0.0129). In particular, it was significantly increased in grade III tumors and decreased in grade 11 tumors. This variant was also changed differently in pre- and post-menopausal women. Its expression levels were increased in the tumors of post-menopausal women (mean change = 3.6685), while they were decreased in pre-menopausal women (mean change = -24.3662). Thus a significant association was observed between the expression of this variant and menopausal status (a two-sided paired t-test, n = 43 patients, P = 0.03). Other variants were either expressed at very low frequency or not significantly altered. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Howard Univ, Sch Med, Dept Anat, Washington, DC 20059 USA. Howard Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. NICHHD, NIH, Biomet & Math Stat Branch, Bethesda, MD 20892 USA. RP Poola, I (reprint author), Howard Univ, Sch Med, Dept Anat, Washington, DC 20059 USA. FU NCI NIH HHS [CA88347] NR 28 TC 38 Z9 40 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD OCT PY 2002 VL 82 IS 2-3 BP 169 EP 179 AR PII S0960-0760(02)00185-1 DI 10.1016/S0960-0760(02)00185-1 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 629AZ UT WOS:000180029400001 PM 12477483 ER PT J AU Shackleton, C Roitman, E Guo, LW Wilson, WK Porter, FD AF Shackleton, C Roitman, E Guo, LW Wilson, WK Porter, FD TI Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-Delta(7)-reductase deficiency (Smith-Lemli-Opitz syndrome) SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Smith-Lemli-Opitz syndrome; GC/MS; urinary steroids; cholesterol biosynthetic disorders ID CHROMATOGRAPHY MASS-SPECTROMETRY; 7-DEHYDROCHOLESTEROL REDUCTASE; CHOLESTEROL-BIOSYNTHESIS; URINARY STEROIDS; MUTATIONS; GENE; PLASMA AB Patients with Smith-Lemli-Opitz syndrome have impaired ability to synthesize cholesterol due to attenuated activity of 7-dehydrosterol-Delta(7)-reductase which catalyses the final step in cholesterol synthesis. Accumulation of 7- and 8-dehydrocholesterol is a result of the disorder and potentially these sterols could be used as precursors of a novel class of Delta(7) and Delta(8) unsaturated adrenal steroids and their metabolites. In this study, we have analyzed urine from SLOS patients in the anticipation of characterizing such metabolites. Gas chromatography/mass spectrometry (GUMS) was used in the identification of two major metabolites as 7- and 8-dehydroversions of the well-known steroid pregnanetriol. Other steroids, such as 8-dehydro dehydroepiandrosterone (8-dehydro DHEA) and 7- or 8-dehydroandrostenediol were also identified, and several more steroids are present in urine but remain uncharacterized. As yet, the study provides no evidence for the production of ring-B unsaturated metabolites of complex steroids, such as conisol. We believe that the following transformations can utilize ring-B dehydroprecursors: StAR transport of cholesterol, p450 side chain cleavage, 17-hydroxylase/17,20-lyase, 3beta-hydroxysteroid dehydrogenase, 3alpha-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, 20alpha-hydroxysteroid dehydrogenase and 5beta-reductase. We have yet to prove the activity of adrenal 21-hydroxylase, 11beta-hydroxylase or 5alpha-reductase towards 7- or 8-dehydroprecursors. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77005 USA. NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Shackleton, C (reprint author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. FU NICHD NIH HHS [R03 HD39707] NR 18 TC 40 Z9 40 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD OCT PY 2002 VL 82 IS 2-3 BP 225 EP 232 AR PII S0960-0760(02)00155-3 DI 10.1016/S0960-0760(02)00155-3 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 629AZ UT WOS:000180029400007 PM 12477489 ER PT J AU Leondires, MP Hu, ZZ Dong, JY Tsai-Morris, CH Dufau, ML AF Leondires, MP Hu, ZZ Dong, JY Tsai-Morris, CH Dufau, ML TI Estradiol stimulates expression of two human prolactin receptor isoforms with alternative exons-1 in T47D breast cancer cells SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE estradiol; human prolactin receptor; breast cancer cells ID ESTROGEN-RECEPTOR; GENE-EXPRESSION; HORMONE RECEPTOR; CROSS-TALK; C/EBP-BETA; FACTOR-I; KAPPA-B; PROMOTER; ACTIVATION; RAT AB Human prolactin receptor (hPRLR) expression is regulated by estradiol-17beta (E-2) in vivo in animal tissues, and in vitro in normal human endometrial cells and in MCF7 human breast cancer cells. The objective of this study was to determine the effect of E-2 on the expression of two recently described hPRLR isoforms with distinct exons-1, hE1(3) and hE1(N1) that are transcribed from the generic hPIII promoter, also present in the rat and mouse, and the human-specific promoter hP(NI), respectively. Also, to determine the effect of estradiol on the hPIII promoter activity in cancer cells. T47D breast cancer cells were examined using quantitative competitive RT-PCR for the level of expression of two alternative non-coding exon-1 transcripts, hE1(3) and hE1(N1) following incubation with E-2 in presence or absence of the E-2 receptor antagonist ICI 182,780. The effects of estradiol were also evaluated in cells transiently transfected with constructs of hPIII promoter luciferase reporter gene. E-2 Significantly increased the expression of both hPRLR mRNA transcripts, hE1(3) and hE1(N1). In transfection studies E-2 activated the hPIII promoter. This effect of estradiol was markedly inhibited by coincubation with the E-2 receptor antagonist. Our results demonstrate a stimulatory effect of estradiol on the expression of hPRLR mRNA species with alternative exons-1, hE1(3) and hE1(N1) possibly through activation of their corresponding promoters. The lack of a formal ERE in these promoters suggested that the effect of estradiol is mediated through association of the activated ER with relevant DNA binding transfactor(s). These findings support the role of E-2 in the regulation of hPRLR expression in human breast cancer cell lines. Published by Elsevier Science Ltd. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NR 37 TC 9 Z9 13 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD OCT PY 2002 VL 82 IS 2-3 BP 263 EP 268 AR PII S0960-0760(02)00184-X DI 10.1016/S0960-0760(02)00184-X PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 629AZ UT WOS:000180029400012 PM 12477494 ER PT J AU Dundr, M McNally, JG Cohen, J Misteli, T AF Dundr, M McNally, JG Cohen, J Misteli, T TI Quantitation of GFP-fusion proteins in single living cells SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT EMBO Workshop on Functional Organization of the Cell Nucleus CY APR 18-21, 2002 CL PRAGUE, CZECH REPUBLIC SP EMBO DE GFP; quantitation; microscopy; nucleolus; RNA polymerase I and II; VLP ID RNA-POLYMERASE-I; ROTAVIRUS-LIKE PARTICLES; FLUORESCENT PROTEIN; CAJAL BODIES; TRANSCRIPTION; MOLECULES; RECEPTOR; SITES; DNA; VP2 AB The green fluorescent protein (GFP) has revolutionized cell biology. The ability to observe genetically encoded fluorescently tagged fusion proteins in intact cells has made virtually any biological process amenable to investigation in living cells. However, most in vivo imaging studies are qualitative and little information about the number of fluorescently labeled molecules observed in a cell or a cellular structure is available. This deficiency severely limits the interpretation of imaging experiments and it impedes the application of in vivo imaging methods for biophysical purposes. Here we describe a simple method for the quantitative determination of the number of GFP-tagged molecules in cellular structures in single living cells. The method is based on the use of rotavirus-like particles containing a known number of GFP molecules as an internal calibration standard during in vivo imaging. We have applied this method to estimate in single living cells the number of fluorescent transcription factor molecules on RNA polymerase I and polymerase II genes. In addition, we have estimated the number of molecules for several proteins in subnuclear compartments and in exocytic vesicles. VLP-GFP calibration is a simple, convenient, rapid, and noninvasive method for routine quantification of GFP-labeled molecules in single, living cells. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, NIH, Bethesda, MD 20892 USA. INRA, UMR CNRS Virol Mol & Struct, Gif Sur Yvette, France. RP Misteli, T (reprint author), NCI, NIH, 41 Lib Dr,Bldg 41, Bethesda, MD 20892 USA. NR 25 TC 73 Z9 75 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD OCT-DEC PY 2002 VL 140 IS 1-3 BP 92 EP 99 AR PII S1047-8477(02)00521-X DI 10.1016/S1047-8477(02)00521-X PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 627VW UT WOS:000179957700011 PM 12490157 ER PT J AU DiPaula, BA Schwartz, R Montoya, ID Barrett, D Tang, C AF DiPaula, BA Schwartz, R Montoya, ID Barrett, D Tang, C TI Heroin detoxification with buprenorphine on an inpatient psychiatric unit SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE buprenorphine; detoxification; heroin dependence; psychiatric comorbidity; psychiatric hospitalization ID SUBSTANCE USE DISORDERS; OPIOID DETOXIFICATION; RANDOMIZED TRIAL; MENTAL-ILLNESS; DEPENDENCE; COMORBIDITY; CLONIDINE; NALOXONE; CARE AB The purpose of this open-label, uncontrolled study was to evaluate the feasibility of administering off-label buprenorphine in combination with ancillary medications for inpatient short-term detoxification of heroin-dependent patients at a psychiatric facility. A sample of 20 heroin-dependent patients admitted to an urban psychiatric hospital was administered buprenorphine 6, 4, and 2 mg/day during the first, second, and third day of detoxification, respectively, and then observed during the fourth and fifth day. Eighty-five percent of the subjects abused other substances, 75% reported cocaine abuse/dependence, 75% had comorbid mood disorders. All subjects completed the medication phase of the study. No clinically significant adverse events were reported. There was a significant decrease in the Clinical Investigation Narcotic Assessment (CINA) total score between baseline and days 2 through 5. The results suggest that buprenorphine is well tolerated and may be beneficial for medically supervised short-term withdrawal from heroin for hospitalized psychiatric patients. (C) 2002 Elsevier Science Inc. All fights reserved. C1 Walter P Carter Ctr, Dept Pharm Serv, Baltimore, MD 21201 USA. Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. Friends Res Inst, Baltimore, MD 21285 USA. NIDA, Div Treatment Res & Dev, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Walter P Carter Ctr, Baltimore, MD 21201 USA. RP DiPaula, BA (reprint author), Walter P Carter Ctr, Dept Pharm Serv, 630 W Fayette St, Baltimore, MD 21201 USA. FU Intramural NIH HHS [Z99 DA999999] NR 21 TC 13 Z9 13 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2002 VL 23 IS 3 BP 163 EP 169 AR PII S0740-5472(02)00244-1 DI 10.1016/S0740-5472(02)00244-1 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 611XY UT WOS:000179044200001 PM 12392802 ER PT J AU Covi, L Hess, JM Schroeder, JR Preston, KL AF Covi, L Hess, JM Schroeder, JR Preston, KL TI A dose response study of cognitive behavioral therapy in cocaine abusers SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article; Proceedings Paper CT 146th Annual Meeting of the American-Psychiatric-Association CY MAY 22-27, 1993 CL SAN FRANCISCO, CALIFORNIA SP Amer Psychiat Assoc DE dose response; cognitive behavioral therapy; cocaine abuse; manual driven psychotherapy ID PSYCHOSOCIAL TREATMENTS; TREATMENT OUTCOMES; DRUG-TREATMENT; PSYCHOTHERAPY; PARTICIPATION; DEPENDENCE; DATOS AB In order to evaluate the effect of frequency of counseling sessions, we studied retention, cocaine use and craving, and psychiatric symptoms of 68 cocaine-dependent outpatients randomly assigned to twice weekly, once weekly, or biweekly sessions in a 12-week treatment program that utilized manual-based, individual cognitive behavioral psychotherapy. All participants were tested and monitored twice a week. Retention was comparable among treatment groups, and improvement was found regardless of counseling frequency. Cocaine use (urine toxicology and self-report), cocaine craving (VAS), and total psychiatric symptoms (SCL-90) decreased by modest but statistically significant (p < 0.05) amounts in all treatment groups. Findings suggest that cognitive behavioral therapy is effective in reducing cocaine use even if a less intensive schedule is used. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Covi, L (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 24 TC 19 Z9 19 U1 5 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2002 VL 23 IS 3 BP 191 EP 197 AR PII S0740-5472(02)00247-7 DI 10.1016/S0740-5472(02)00247-7 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 611XY UT WOS:000179044200004 PM 12392805 ER PT J AU Weiss, SC Kimball, AB Liewehr, DJ Blauvelt, A Turner, ML Emanuel, EJ AF Weiss, SC Kimball, AB Liewehr, DJ Blauvelt, A Turner, ML Emanuel, EJ TI Quantifying the harmful effect of psoriasis on health-related quality of life SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID OF-LIFE; ATOPIC-DERMATITIS; IMPACT; DISEASE; STATES; QUESTIONNAIRE; CYCLOSPORINE; RELIABILITY; INSTRUMENTS; DERMATOLOGY AB Background: Psoriasis affects 7 million people in the United States, causing substantial cost, social stigma, and disability. Objective: The purpose of this study was to evaluate the health effects of skin disease by comparing psoriasis to other primary medical disorders using 3 different scales of health-related quality of life. Methods: A self-administered questionnaire consisting of 3 health-related quality of life measures was given sequentially to 35 eligible patients with psoriasis presenting to the Dermatology Branch of the National Cancer Institute (NCI) for an investigational therapeutic protocol. Results: All patients (100%) agreed to participate. The median Psoriasis Area and Severity Index (PASI) score was 13.0. Overall, 82.9% at least often felt the need to hide their psoriasis, and 74.3% claimed their self-confidence was at least often affected by their psoriasis. The median EQ-5D) health state utility score was 13.0% less than healthy individuals (P <.001). On the SF-36, the mean general health score was 13.2% less (P =.005) and the median social functioning score 18.7% less (P =.005) than that of patients with no chronic conditions. Conclusion: Individuals with psoriasis are significantly affected in their health state utility, perception of general health, and social functioning when compared with individuals without chronic disease and those with certain primary medical conditions. C1 NCI, Div Clin Bioeth, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Kimball, AB (reprint author), 900 Blake Wilbur Dr,Room W0024, Stanford, CA 94305 USA. NR 50 TC 135 Z9 142 U1 1 U2 10 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2002 VL 47 IS 4 BP 512 EP 518 DI 10.1067/mjd.2002.122755 PG 7 WC Dermatology SC Dermatology GA 600MZ UT WOS:000178395900007 PM 12271293 ER PT J AU Mehwald, PS Rusk, RA Mori, Y Li, XN Zetts, AD Jones, M Sahn, DJ AF Mehwald, PS Rusk, RA Mori, Y Li, XN Zetts, AD Jones, M Sahn, DJ TI A validation study of aortic stroke volume using dynamic 4-dimensional color Doppler: An in vivo study SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID IMAGED VENA-CONTRACTA; CHRONIC ANIMAL-MODEL; REGURGITANT VOLUME; IN-VITRO; CARDIAC-OUTPUT; FLOW; PULMONARY; VELOCITY; ECHOCARDIOGRAPHY; QUANTIFICATION AB Objective: To explore the feasibility of directly quantifying transaortic stroke volume with a newly developed dynamic 3-dimensional (3D) color Doppler flow measurement technique, an in vivo experimental study was performed. Background: Traditional methods for flow quantification require geometric assumptions about flow area and flow profiles. Accurate quantification of flow across the aortic valve is clinically important as a means of estimating cardiac output. Methods: Eight open-chest sheep were scanned with apical epicardial placement of a 7 to 4 MHz multiplane transesophageal probe scanning parallel to aortic flow and running on an An HDI 5000 system. An electromagnetic flow meter implanted on the ascending aorta was used as reference. Thirty different hemodynamic conditions were studied after steady states were obtained in the animals by administration of blood, angiotensin, and sodium nitroprusside. Electrocardiogram-gated digital color 3D velocity data were acquired for each of the 30 steady states. The aortic stroke volumes were computed by temporal and spatial integration of flow areas and actual velocities across a projected surface perpendicular to the direction of flow, at a level just below the aortic valve. Results: There was close correlation between the 3D color Doppler calculated aortic stroke volumes and the electromagnetic data (r = 0.91, y = 0.96x + 1.01, standard error of the estimate = 2.6 mL/beat). Conclusion: Our results showed that dynamic 3D color Doppler measurements obtained in an open-chest animals provide the basis for accurate, geometry-independent quantitative evaluation of the aortic flow. Therefore, 3D digital color Doppler flow computation could potentially represent an important method for noninvasively determining cardiac output in patients. C1 Univ Freiburg, Childrens Hosp, Freiburg, Germany. Oregon Hlth & Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97201 USA. ATL Ultrasound, Bothell, WA USA. NHLBI, Bethesda, MD 20892 USA. RP Sahn, DJ (reprint author), Oregon Hlth & Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 SW Jackson Pk Rd,L608, Portland, OR 97201 USA. NR 26 TC 20 Z9 21 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD OCT PY 2002 VL 15 IS 10 BP 1045 EP 1050 DI 10.1067/mje.2002.122103 PN 1 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 605FE UT WOS:000178666100004 PM 12373245 ER PT J AU Yang, H Jones, M Shiota, T Qin, JX Kim, YJ Popovic, ZB Pu, M Greenberg, NL Cardon, LA Eto, Y Sitges, M Zetts, AD Thomas, JD AF Yang, H Jones, M Shiota, T Qin, JX Kim, YJ Popovic, ZB Pu, M Greenberg, NL Cardon, LA Eto, Y Sitges, M Zetts, AD Thomas, JD TI Pulmonary venous flow determinants of left atrial pressure under different loading conditions in a chronic animal model with mitral regurgitation SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID TRANSESOPHAGEAL DOPPLER ECHOCARDIOGRAPHY; SEVERITY; VELOCITIES; VALIDATION; REVERSAL AB Background. The aim of our study was to quantitatively compare the changes and correlations between pulmonary venous flow variables and mean left atrial pressure (mLAP) under different loading conditions in animals with chronic initial regurgitation (MR) and without MR. Methods. A total of 85 hemodynamic conditions were studied in 22 sheep, 12 without MR as control (NO-MR group) and 10 with MR (MR group). We obtained pulmonary venous flow systolic velocity (Sv) and diastolic velocity (Dv), Sv and Dv time integrals, their ratios (Sv/Dv and Sv/Dv time integral), mLAP, left ventricular end-diastolic pressure, and MR stroke volume. We also measured left atrial a, x, v, and y pressures and calculated the difference between v and y pressures. Results. Average MR stroke volume was 10.6 +/- 4.3 mL/beat. There were good correlations between Sv (r = -0.64 and r = -0.59, P < .01), Sv/Dv (r = 0.62 and r = -0.74, P < .01), and mL&P in the MR and NO-MR groups, respectively. Correlations were also observed between Dv time integral (r = 0.61 and r = 0.57, P < .01) and left ventricular end-diastolic pressure in the MR and NO-MR groups. In velocity variables, Sv (r = -0.79, P < .001) was the best predictor of mLAP in both groups. The sensitivity and specificity of Sv = 0 in predicting mLAP 15 mm Hg or greater were 86% and 85%, respectively. Conclusion: Pulmonary venous flow variables correlated well with mLAP under altered loading conditions in the MR and NO-MR groups. They may be applied clinically as substitutes for invasively acquired indexes of mLAP to assess left atrial and left ventricular functional status. C1 Cleveland Clin Fdn, Dept Cardiovasc Med, Cardiovasc Imaging Sect, Cleveland, OH 44195 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Dept Cardiovasc Med, Cardiovasc Imaging Sect, 9500 Euclid Ave,Desk F-15, Cleveland, OH 44195 USA. NR 20 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD OCT PY 2002 VL 15 IS 10 BP 1181 EP 1188 DI 10.1067/mje.2002.123959 PN 2 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 605FL UT WOS:000178666700011 PM 12411903 ER PT J AU Abbott, KC Bucci, JR Cruess, D Taylor, AJ Agodoa, LYC AF Abbott, KC Bucci, JR Cruess, D Taylor, AJ Agodoa, LYC TI Graft loss and acute coronary syndromes after renal transplantation in the United States SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID DIALYSIS PATIENTS; ARTERY DISEASE; HEART-DISEASE; RISK-FACTORS; RECIPIENTS; HOSPITALIZATIONS; PREVALENCE; SURVIVAL AB The impact of graft loss on acute coronary syndromes (ACS) after renal transplantation has not been studied in a national population. It was hypothesized that ACS might be more frequent after graft loss, as many of the benefits of a functioning allograft on metabolism and volume regulation would be lost. Data from the 2000 United States Renal Data System (USRDS) was used to conduct an historical cohort study of ACS in 14,237 patients who received renal transplants between April 1, 1995, and June 30, 1998, (followed until April 28, 2000) with valid information from CMS Form 2728, excluding patients with hospitalized ACS before renal transplant. Cox nonproportional regression models were used to calculate the time-dependent adjusted hazard ratio (AHR) of graft loss (censored for death) for time-to-first hospitalization for ACS (International Classification of Diseases 9th Modification Diagnosis Codes [ICD9] code 410.x or 411.x) occurring after transplant. The incidence of ACS was 12.1 per 1000 patient-years (PY) in patients after graft loss versus 6.5 per 1000 PY after transplantation (excluding patients with graft loss). As a time-dependent variable, graft loss had an AHR of 2.54 (95% confidence interval, 1.09 to 5.96; P = 0.031 by Cox regression). Other risk factors associated with ACS included diabetes, older recipient, and male recipient. Allograft rejection was NS. Renal transplant recipients share some of the risk factors for ACS with the general population. In addition, graft loss was identified as a unique risk factor for ACS in this population. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Serv Cardiol, Washington, DC 20307 USA. NIDDK, NIH, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 32 TC 40 Z9 40 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2002 VL 13 IS 10 BP 2560 EP 2569 DI 10.1097/01.ASN.0000028800.84746.CB PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 595HV UT WOS:000178103800021 PM 12239246 ER PT J AU Knecht, LWS Nelson, SJ AF Knecht, LWS Nelson, SJ TI Mapping in PubMed SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Letter C1 Natl Lib Med, Lib Operat, Bibliog Serv Div, Bethesda, MD 20209 USA. Natl Lib Med, Lib Operat, Med Subject Headings Sect, Bethesda, MD USA. RP Knecht, LWS (reprint author), Natl Lib Med, Lib Operat, Bibliog Serv Div, Bethesda, MD 20209 USA. NR 1 TC 5 Z9 5 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2002 VL 90 IS 4 BP 475 EP 475 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 604LE UT WOS:000178621600013 PM 12398255 ER PT J AU Colaianni, LA AF Colaianni, LA TI Barbara Coe Johnson, 1923-2001 - Obituary SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Biographical-Item C1 Natl Lib Med, Bethesda, MD 20209 USA. RP Colaianni, LA (reprint author), Natl Lib Med, Bethesda, MD 20209 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2002 VL 90 IS 4 BP 477 EP 478 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 604LE UT WOS:000178621600014 ER PT J AU Pautler, SE Choyke, PL Pavlovich, CP Daryanani, K Walther, MM AF Pautler, SE Choyke, PL Pavlovich, CP Daryanani, K Walther, MM TI Intraoperative ultrasound aids in dissection during laparoscopic partial adrenalectomy SO JOURNAL OF UROLOGY LA English DT Article DE adrenal glands laparoscopy ultrasonography ID CORTICAL-SPARING ADRENALECTOMY; HEREDITARY PHEOCHROMOCYTOMA; SURGERY AB Purpose: Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic partial nephrectomy is a technically feasible but challenging operation. We describe the use of intraoperative ultrasound to facilitate laparoscopic partial nephrectomy in a population with a hereditary predisposition to multifocal pheochromocytoma. Materials and Methods: All patients underwent a history, physical examination, serum and urine catecholamine determinations, abdominal computerized tomography-magnetic resonance imaging and metaiodobenzylguanidine scan. The adrenal gland was exposed using a standard 3 or 4 port approach. Intraoperative ultrasound was performed using a 7.5 MHz. 10 mm. transducer placed through a 12 mm. port. After imaging the whole gland and adjacent structures partial adrenalectomy was performed based on intraoperative ultrasound images using a harmonic scalpel or alternatively using a cut and sew technique that provided a 5 mm. margin. Tumors were removed intact and sent for pathological examination. Results: Since 1998, 11 patients have undergone laparoscopic partial adrenalectomy. Intraoperative ultrasound was performed in 7 patients with suspected multiple adrenal masses, including 4 and 3 who underwent unilateral and bilateral laparoscopic partial nephrectomy, respectively. Six of the 7 patients had germline defects in the von Hippel-Lindau disease gene and 1 had no identifiable alteration in the von Hippel-Lindau disease or RET gene. A solitary tumor was identified in 3 cases and multiple lesions were noted in 4. In 1 case intraoperative ultrasound localized a tumor not identified on preoperative imaging that was not readily visible via laparoscopy. Intraoperative ultrasound guided surgical dissection in all cases and identified an extra-adrenal mass in 1 patient with bilateral adrenal masses. There were no complications due to intraoperative ultrasound and no conversions to open surgery. Mean operative time was 335 minutes and mean estimated blood loss was 179 ml. Histological study demonstrated pheochromocytoma in 14 lesions and the extra-adrenal mass proved to be a splenic rest. At short-term followup no recurrences have been noted. All patients retained sufficient adrenal cortical function to avoid steroid replacement therapy. Conclusions: Laparoscopic ultrasound differentiates normal adrenal parenchyma from adrenal tumors and facilitates laparoscopic partial adrenalectomy. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD USA. RP Pautler, SE (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 20 TC 30 Z9 30 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2002 VL 168 IS 4 BP 1352 EP 1355 DI 10.1097/01.ju.0000031272.56889.28 PN 1 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 596VU UT WOS:000178187800009 PM 12352391 ER PT J AU Kino, T Gragerov, A Slobodskaya, O Tsopanomichalou, M Chrousos, GP Pavlakis, GN AF Kino, T Gragerov, A Slobodskaya, O Tsopanomichalou, M Chrousos, GP Pavlakis, GN TI Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators SO JOURNAL OF VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; CELL-CYCLE ARREST; NUCLEAR RECEPTOR COACTIVATORS; THYROID-HORMONE RECEPTOR; VIRAL REPLICATION; GENE-EXPRESSION; IN-VITRO; T-CELLS; ACTIVATION; COMPLEX AB The accessory Vpr protein of human immunodeficiency virus type 1 (HIV-1) is a promiscuous activator of viral and cellular promoters. We report that Vpr enhances expression of the glucocorticoid receptor-induced mouse mammary tumor virus (MMTV) promoter and of the Tat-induced HIV-1 long terminal repeat promoter by directly binding to p300/CBP coactivators. In contrast, Vpr does not bind to p/CAF or to members of the p160 family of nuclear receptor coactivators, such as steroid receptor coactivator la and glucocorticoid receptor (GR)-interacting protein 1. Vpr forms a stable complex with p300 and also interacts with the ligand-hound glucocorticoid receptor in vivo. Mutation analysis showed that the C-terminal part of Vpr binds to the C-terminal portion of p300/CBP within amino acids 2045 to 2191. The same p300 region interacts with the p160 coactivators and with the adenovirus E1A protein. Accordingly, E1A competed for binding to p300 in vitro. Coexpression of E1A or of small fragments of p300 containing the Vpr binding site resulted in inhibition of Vpr's transcriptional effects. The C-terminal part of p300 containing the transactivating region is required for Vpr transactivation, whereas the histone acetyltransferase enzymatic region is dispensable. Vpr mutants that bind p300 but not the GR did not activate expression of the MMTV promoter and had dominant-negative effects. These results indicate that Vpr activates transcription by acting as an adapter linking transcription components and coactivators. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Human Retrovirus Sect, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Kino, T (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. OI tsopanomichalou, maria/0000-0002-1886-2376 NR 67 TC 94 Z9 96 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 19 BP 9724 EP 9734 DI 10.1128/JVI.76.19.9724-9734.2002 PG 11 WC Virology SC Virology GA 590XE UT WOS:000177849100016 PM 12208951 ER PT J AU Xiang, SH Kwong, PD Gupta, R Rizzuto, CD Casper, DJ Wyatt, R Wang, LP Hendrickson, WA Doyle, ML Sodroski, J AF Xiang, SH Kwong, PD Gupta, R Rizzuto, CD Casper, DJ Wyatt, R Wang, LP Hendrickson, WA Doyle, ML Sodroski, J TI Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein SO JOURNAL OF VIROLOGY LA English DT Review ID CAVITY-CREATING MUTATIONS; HUMAN MONOCLONAL-ANTIBODY; AMINO-ACID CHANGES; T-CELL-LINE; RECEPTOR-BINDING; HUMAN CD4; CHEMOKINE RECEPTORS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; HYDROPHOBIC CORE AB The human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein is conformationally flexible. Upon binding to the host cell receptor CD4, gp120 assumes a conformation that is recognized by the second receptor, CCR5 and/or CXCR4, and by the CD4-induced (CD4i) antibodies. Guided by the X-ray crystal structure of a gp120-CD4-CD4i antibody complex, we introduced changes into gp120 that were designed to stabilize or disrupt this conformation. One mutant, 375 S/W, in which the tryptophan indole group is predicted to occupy the Phe 43 cavity in the gp120 interior, apparently favors a gp120 conformation closer to that of the CD4-bound state. The 375 S/W mutant was recognized, as well as or better than wild-type gp120 by CD4 and CD4i antibodies, and the large decrease in entropy observed when wild-type gp120 bound CD4 was reduced for the 375 S/W mutant. The recognition of the 375 S/W mutant by CD4BS antibodies, which are directed against the CD4-binding region of gp120, was markedly reduced compared with that of the wild-type gp120. Compared with the wild-type virus, viruses with the 375 S/W envelope glycoproteins were resistant to neutralization by IgG1b12, a CD4BS antibody, were slightly more sensitive to soluble CD4 neutralization and were neutralized more efficiently by the 2G12 antibody. Another mutant, 423 I/P, in which the gp120 bridging sheet was disrupted, did not bind CD4, CCR5, or CD4i antibodies, even though recognition by CD4BS antibodies was efficient. These results indicate that CD4BS antibodies recognize conformations of gp120 different from that recognized by CD4 and CD4i antibodies. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Div AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. GlaxoSmithKline Pharmaceut, Dept Biol Struct, King Of Prussia, PA 19406 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Jimmy Fund Bldg,Room 824,44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI41815, AI24030, AI24755, AI31783, AI42848, P30 AI042848, R01 AI024030, R01 AI031783, R01 AI041851, R37 AI024755] NR 102 TC 138 Z9 140 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 19 BP 9888 EP 9899 DI 10.1128/JVI.76.19.9888-9899.2002 PG 12 WC Virology SC Virology GA 590XE UT WOS:000177849100031 PM 12208966 ER PT J AU Sodora, DL Milush, JM Ware, F Wozniakowski, A Montgomery, L McClure, HM Lackner, AA Marthas, M Hirsch, V Johnson, RP Douek, DC Koup, RA AF Sodora, DL Milush, JM Ware, F Wozniakowski, A Montgomery, L McClure, HM Lackner, AA Marthas, M Hirsch, V Johnson, RP Douek, DC Koup, RA TI Decreased levels of recent thymic emigrants in peripheral blood of simian immunodeficiency virus-infected macaques correlate with alterations within the thymus SO JOURNAL OF VIROLOGY LA English DT Article ID SCID-HU MOUSE; BONE-MARROW TRANSPLANTATION; POLYMERASE CHAIN-REACTION; T-CELL REGENERATION; HIV-1 INFECTION; IN-VIVO; THYMOCYTE DEPLETION; DNA FRAGMENTATION; RHESUS-MONKEYS; REPERTOIRE AB The thymus is responsible for de novo production of CD4(+) and CD8(+) T cells and therefore is essential for T-cell renewal. The goal of this study was to assess the impact of simian immunodeficiency virus (SIV) infection on the production of T cells by the thymus. Levels of recent thymic emigrants within the peripheral blood were assessed through quantification of macaque T-cell receptor excision circles (TREC). Comparison of SIV-infected macaques (n = 15) to uninfected macaques (n = 23) revealed stable or increased TREC levels at 20 to 34 weeks postinfection. Further assessment of SIV-infected macaques (n = 4) determined that TREC levels decreased between 24 and 48 weeks postinfection. Through the assessment of longitudinal time points in three additional SIVmac239-infected macaques, the SIV infection was divided into two distinct phases. During phase 1 (16 to 30 weeks), TREC levels remained stable or increased within both the CD4 and CD8 T-cell populations. During phase 2 (after 16 to 30 weeks), TREC levels declined in both T-cell populations. As has been described for human immunodeficiency virus (HIV)-infected patients, this decline in TREC levels did at times correlate with an increased level of T-cell proliferation (KJ67(+) cells). However, not all TREC decreases could be attributed to increased T-cell proliferation. Further evidence for thymic dysfunction was observed directly in a SIVmac239-infected macaque that succumbed to simian AIDS at 65 weeks postinfection. The thymus of this macaque contained an increased number of memory/effector CD8(+) T cells and an increased level of apoptotic cells. In summary, reduced levels of TREC can be observed beginning at 16 to 30 weeks post-SIV infection and correlate with changes indicative of dysfunction within the thymic tissue. SIV infection of macaques will be a useful model system to elucidate the mechanisms responsible for the thymic dysfunction observed in HIV-infected patients. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75235 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. Tulane Reg Primate Res Ctr, Covington, LA USA. Calif Reg Primate Res Ctr, Davis, CA USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Sodora, DL (reprint author), Univ Texas, SW Med Ctr, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. OI Milush, Jeffrey M./0000-0002-0773-6411 FU NCRR NIH HHS [RR00169, P51 RR000169, RR00168, P51 RR000168, K26 RR000168]; NIAID NIH HHS [R37 AI035522, AI35522, R01 AI035522]; NIDCR NIH HHS [R01 DE012926, DE12926] NR 61 TC 31 Z9 33 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 19 BP 9981 EP 9990 DI 10.1128/JVI.76.19.9981-9990.2002 PG 10 WC Virology SC Virology GA 590XE UT WOS:000177849100039 PM 12208974 ER PT J AU Campbell, S Oshima, M Mirro, J Nagashima, K Rein, A AF Campbell, S Oshima, M Mirro, J Nagashima, K Rein, A TI Reversal by dithiothreitol treatment of the block in murine leukemia virus maturation induced by disulfide cross-linking SO JOURNAL OF VIROLOGY LA English DT Article ID NUCLEOCAPSID PROTEIN; TYPE-1 PROTEINASE; ZINC FINGERS; VIRAL-RNA; CLEAVAGE; GAG; MUTATION; INFECTIVITY; PRECURSORS; INHIBITORS AB We previously reported that if murine leukemia virus particles are produced in the presence of the mild oxidizing agent disulfide-substituted benzamide-2, they fail to undergo the normal process of virus maturation. We now show that treatment of these immature particles with a reducing agent (dithiothreitol) induces their maturation in vitro, as evidenced by proteolytic cleavage of Gag, Gag-Pol, and Env proteins and by their morphology. The identification of partial cleavage products in these particles suggests the sequence with which the cleavages occur under these conditions. This may be a useful experimental system for further analysis of retroviral maturation under controlled conditions in vitro. C1 NCI, HIV Drug Resistance Program, SAIC, Frederick, MD 21702 USA. NCI, Image Anal Lab, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, SAIC, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 24 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 19 BP 10050 EP 10055 DI 10.1128/JVI.76.19.10050-10055.2002 PG 6 WC Virology SC Virology GA 590XE UT WOS:000177849100049 PM 12208984 ER PT J AU Kostrikis, LG Touloumi, G Karanicolas, R Pantazis, N Anastassopoulou, C Karafoulidou, A Goedert, JJ Hatzakis, A AF Kostrikis, LG Touloumi, G Karanicolas, R Pantazis, N Anastassopoulou, C Karafoulidou, A Goedert, JJ Hatzakis, A CA Multictr Hemophilia Cohort Study G TI Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; POLYMERASE CHAIN-REACTION; PRIMARY HIV-1 INFECTION; PCR-BASED ASSAY; MONONUCLEAR-CELLS; PROVIRAL DNA; VIRAL LOAD; HIV-1-INFECTED PATIENTS; REVERSE TRANSCRIPTION; INHIBITOR THERAPY AB There are several forms of human immunodeficiency virus type 1 (HIV-1-) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 7321 copies per 106 PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval {CI}, 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 106 PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virology response to combination antiretroviral therapy. C1 Univ Athens, Sch Med, Dept Hyg & Epidemiol, GR-11527 Athens, Greece. Laikon Gen Hosp, Hemophilia, Athens, Greece. NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Rockville, MD USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Kostrikis, LG (reprint author), Univ Athens, Sch Med, Dept Hyg & Epidemiol, 75 Mikras Asias, GR-11527 Athens, Greece. RI Kostrikis, Leondios/A-5330-2016 OI Kostrikis, Leondios/0000-0002-5340-7109 FU NCI NIH HHS [N01 CP 33002] NR 66 TC 70 Z9 70 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 20 BP 10099 EP 10108 DI 10.1128/JVI.76.20.10099-10108.2002 PG 10 WC Virology SC Virology GA 599DV UT WOS:000178319600002 PM 12239284 ER PT J AU Chen, WS Bennink, JR Morton, PA Yewdell, JW AF Chen, WS Bennink, JR Morton, PA Yewdell, JW TI Mice deficient in perforin, CD4(+) T cells, or CD28-mediated signaling maintain the typical immunodominance hierarchies of CD8(+) T-cell responses to influenza virus SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; DENDRITIC CELL; LYMPHOCYTE RESPONSES; SECONDARY; COSTIMULATION; EPITOPES; CTLA-4; EXPRESSION; INFECTION; IMMUNITY AB CD8 T-cell (TCD8+) responses elicited by viral infection demonstrate the phenomenon of immunodominance: the numbers of TCD8+ responding to different viral peptides vary over a wide range in a reproducible manner for individuals with the same major histocompatibility complex class I alleles. To better understand immunodominance, we examined TCD8+ responses to multiple defined viral peptides following infection of mice with influenza virus. The immunodominance hierarchy of influenza virus-specific TCD8+ was not greatly perturbed by the absence of either perforin or T-helper cells or by interference with B7 (CD80)-mediated signaling. These findings indicate that costimulation by antigen-presenting cells (APCs) or killing of APCs by TCD8+ plays only a minor role in establishing the immunodominance hierarchy of antiviral TCD8+ in this system. This points to intrinsic features of the TCD8+ repertoire as major contributors to immunodominance. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Pharmacia, Discovery Res, St Louis, MO USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Room 211,Bldg 4,4 Ctr Dr,MSC 0440, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 46 TC 43 Z9 44 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 20 BP 10332 EP 10337 DI 10.1128/JVI.76.20.10332-10337.2002 PG 6 WC Virology SC Virology GA 599DV UT WOS:000178319600027 PM 12239309 ER PT J AU Rooney, CP Denning, GM Davis, BP Flaherty, DM Chiorini, JA Zabner, J AF Rooney, CP Denning, GM Davis, BP Flaherty, DM Chiorini, JA Zabner, J TI Bronchoalveolar fluid is not a major hindrance to virus-mediated gene therapy in cystic fibrosis SO JOURNAL OF VIROLOGY LA English DT Article ID SECRETORY LEUKOPROTEASE INHIBITOR; PSEUDOMONAS-AERUGINOSA ELASTASE; RESPIRATORY EPITHELIAL SURFACE; COXSACKIE-ADENOVIRUS RECEPTOR; LEUKOCYTE PROTEASE INHIBITOR; CILIATED AIRWAY EPITHELIA; ADENOASSOCIATED VIRUS; RECOMBINANT ADENOVIRUS; IMMUNE-RESPONSES; IN-VITRO AB Successfully targeting the airway epithelium is essential for gene therapy of some pulmonary diseases. However, the airway epithelium is resistant to virus-mediated gene transfer with commonly used vectors. Vectors that interact with endogenously expressed receptors on the apical surface significantly increase gene transfer efficiency. However, other endogenous components involved in host immunity may hinder virus-mediated gene transfer. We tested the effect of bronchoalveolar lavage liquid (BAL) from patients with cystic fibrosis (CF), BAL from subjects without CF (non-CF BAL), Pseudomonas aeruginosa-derived proteins, and an array of inflammatory proteins on gene transfer mediated by adeno-associated virus type 5 (AAV5) and adenovirus targeted to an apically expressed glycosylphosphatidylinositol-modified coxsackie-adenovirus receptor. We found that neither CF BAL nor its components had a significant effect on gene transfer to human airway epithelium by these vectors. Non-CF BAL significantly impaired adenovirus-mediated gene transfer. Removal of immunoglobulins in non-CF BAL restored gene transfer efficiency. As virus vectors are improved and mechanisms of Immoral immunity are elucidated, barriers to successful gene therapy found in the complex environment of the human lung can be circumvented. C1 Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Natl Inst Dent & Craniofacial Res, Gene Therapeut branch, NIH, Bethesda, MD 20892 USA. RP Zabner, J (reprint author), Univ Iowa, Coll Med, Dept Internal Med, 540 EMRB, Iowa City, IA 52242 USA. FU NHLBI NIH HHS [P01 HL051670, HL 51670]; NIDDK NIH HHS [P30 DK054759, DK 54759] NR 56 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 20 BP 10437 EP 10443 DI 10.1128/JVI.76.20.10437-10443.2002 PG 7 WC Virology SC Virology GA 599DV UT WOS:000178319600038 PM 12239320 ER PT J AU Allen, TM Jing, PC Calore, B Horton, H O'Connor, DH Hanke, T Piekarczyk, M Ruddersdorf, R Mothe, BR Emerson, C Wilson, N Lifson, JD Belyakov, IM Berzofsky, JA Wang, CX Allison, DB Montefiori, DC Desrosiers, RC Wolinsky, S Kunstman, KJ Altman, JD Sette, A McMichael, AJ Watkins, DI AF Allen, TM Jing, PC Calore, B Horton, H O'Connor, DH Hanke, T Piekarczyk, M Ruddersdorf, R Mothe, BR Emerson, C Wilson, N Lifson, JD Belyakov, IM Berzofsky, JA Wang, CX Allison, DB Montefiori, DC Desrosiers, RC Wolinsky, S Kunstman, KJ Altman, JD Sette, A McMichael, AJ Watkins, DI TI Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS-MONKEYS; VIRAL REPLICATION; HIV-1 INFECTION; PATHOGENIC SIV; VACCINE; AIDS; PROTECTION; INDUCTION; MACAQUES; VIREMIA AB Vaccine-induced cytotoxic T lymphocytes (CTL) have been implicated in the control of virus replication in simian immunodeficiency virus (SIV)-challenged and simian-human immunodeficiency virus-challenged macaques. Therefore, we wanted to test the impact that vaccine-induced CTL responses against an immunodominant Gag epitope might have in the absence of other immune responses. By themselves, these strong CTL responses failed to control SIVmac239 replication. C1 Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. John Radcliffe Hosp, Inst Mol Med, Oxford OX3 9DS, England. NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, SAIC Frederick,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Alabama, Sect Stat Genet, Dept Biostat, Birmingham, AL 35294 USA. Univ Alabama, Clin Nutr Res Ctr, Birmingham, AL 35294 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Epimmune Inc, San Diego, CA 92121 USA. Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI 53706 USA. RP Allen, TM (reprint author), Massachusetts Gen Hosp, AIDS Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Wolinsky, Steven/B-2893-2012; Allen, Todd/F-5473-2011; OI Wolinsky, Steven/0000-0002-9625-6697; o'connor, david/0000-0003-2139-470X; Allison, David/0000-0003-3566-9399 FU NCI NIH HHS [CA 79458, N01 CO 56000]; NCRR NIH HHS [P51 RR000167, RR 00167]; NIAID NIH HHS [AI 46366, AI 38081, AI 49120, R01 AI046366, R01 AI049120, R56 AI049120] NR 41 TC 54 Z9 54 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2002 VL 76 IS 20 BP 10507 EP 10511 DI 10.1128/JVI.76.20.10507-10511.2002 PG 5 WC Virology SC Virology GA 599DV UT WOS:000178319600046 PM 12239328 ER PT J AU Bank, MS Sarno, RJ Campbell, NK Franklin, WL AF Bank, MS Sarno, RJ Campbell, NK Franklin, WL TI Predation of guanacos (Lama guanicoe) by southernmost mountain lions (Puma concolor) during a historically severe winter in Torres del Paine National Park, Chile SO JOURNAL OF ZOOLOGY LA English DT Article DE Puma concolor; behaviour; Lama guanicoe; predation; winter ID SOCIAL-ORGANIZATION; POPULATION-SIZE; PATAGONIA PUMA; BIGHORN SHEEP; BODY-SIZE; ECOLOGY; SNOW; CONSERVATION; MORTALITY; SELECTION AB The effects of mountain lion Puma concolor predation on guanaco Lama guanicoe mortality was investigated during the historically severe winter of 1995 in Torres del Paine National Park, Chile. The 45 guanaco carcasses located represented 3% of the entire guanaco population of which 74% were mountain lion kills, 13% died from malnutrition, 2% died from fence entanglement and 11% died from unknown causes. Depleted bone marrow fat was observed in 20% of all carcasses. The number of guanaco deaths differed among sex and age classes, particularly in juveniles (< 1 year of age), which died more often than expected (P < 0.001). Fresh guanaco carcasses (n = 19) killed by mountain lions were located in tree and shrub habitats 79% of the time and were significantly greater than expected values based on the relative availability of these habitats (P < 0.001). Observations of the spatial distribution of mountain lion kills and guanaco mixed-sex groups were similar (P = 0.10), suggesting that mountain lions responded to winter migratory movements made by guanacos. Overall, adult guanacos experienced surprisingly lower levels of mortality (adult male = 1%, adult female = 2%) than expected, despite the severe winter conditions, while juveniles experienced higher levels of mortality (13%) than expected. In comparison to other years (1991-96), the severe winter of 1995 (i.e. this investigation) had the greatest total mortality for juveniles, although the proportion of deaths caused by mountain lion predation for juveniles was greatest during other winters. C1 Univ Maine, Dept Biol Sci, Program Ecol & Environm Sci, Orono, ME 04469 USA. NCI, FCRDC, Lab Genom Divers, Frederick, MD 21702 USA. USDA, Amityville, NY 11701 USA. Iowa State Univ, Dept Anim Ecol, Ames, IA 50011 USA. RP Bank, MS (reprint author), Univ Maine, Dept Biol Sci, Program Ecol & Environm Sci, 5722 Deering Hall,Room 202, Orono, ME 04469 USA. NR 59 TC 18 Z9 23 U1 0 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0952-8369 J9 J ZOOL JI J. Zool. PD OCT PY 2002 VL 258 BP 215 EP 222 DI 10.1017/S0952836902001334 PN 2 PG 8 WC Zoology SC Zoology GA 611MY UT WOS:000179022600007 ER PT J AU Metter, EJ Talbot, LA Schrager, M Conwit, R AF Metter, EJ Talbot, LA Schrager, M Conwit, R TI Skeletal muscle strength as a predictor of all-cause mortality in healthy men SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID URINARY CREATININE EXCRETION; PHYSICAL ACTIVITIES; GRIP STRENGTH; BODY-MASS; OLD-AGE; WOMEN; SARCOPENIA; QUALITY; TIME AB Low muscle strength is associated with mortality, presumably as a result of low muscle mass (sarcopenia) and physical inactivity. Grip strength was longitudinally collected in 1071 men over a 25-year period. Muscle mass was estimated by using 24-hour creatinine excretion and physical activity values, obtained by questionnaire. Survival analysis examined the impact of grip strength and rate of change in strength on all-cause mortality over 40 years. Lower and declining strength are associated with increased mortality, independent of physical activity and muscle mass. In men <60 years, rate of loss of strength was more important than the actual levels. In men greater than or equal to60 years, strength was more protective than the rate of loss, which persisted when muscle mass was considered. Strength and rate of change in strength contribute to the impact of sarcopenia on mortality. Although muscle mass and physical activity are important, they do not completely account for the impact of strength and changes in strength. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. RP Metter, EJ (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 294 Z9 300 U1 1 U2 16 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2002 VL 57 IS 10 BP B359 EP B365 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 598TB UT WOS:000178291600002 PM 12242311 ER PT J AU Wolff, A AF Wolff, A TI Correct conduct of full-committee and designated-member protocol reviews SO LAB ANIMAL LA English DT Article ID CARE AB Only two protocol review methods fulfill USDA and PHS requirements-full committee and designated member. The author attempts to lessen the confusion surrounding this issue by describing these methods, a long with examples of faulty hybrids and convenient strategies to bring unacceptable methods into compliance. C1 NIH, Off Lab Anim Welf, Div Assurances, Bethesda, MD 20892 USA. RP Wolff, A (reprint author), NIH, Off Lab Anim Welf, Div Assurances, RKL 1,6705 Rockledge Dr,Suite 360, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2002 VL 31 IS 9 BP 28 EP 31 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 604YQ UT WOS:000178649000007 PM 12271327 ER PT J AU Foo, TKF Ho, VB Marcos, HB Hood, MN Choyke, PL AF Foo, TKF Ho, VB Marcos, HB Hood, MN Choyke, PL TI MR angiography using steady-state free precession SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE pulse sequences; vascular imaging; peripheral angiography; contrast MRA; FIESTA; trueFISP; techniques; steady-state free precession ID FEASIBILITY; ARTERIES AB Contrast-enhanced MR angiography (CE-MRA) using steady-state free precession (SSFP) pulse sequences is described. Using SSFP, vascular structures can be visualized with high signal-to-noise ratio (SNR) at a substantial (delay) time after the initial arterial pass of contrast media. The peak blood SSFP signal was diminished by <20% 30 min after the initial administration of 0.2 mmol/kg of Gd-chelate. The proposed method allows a second opportunity to study arterial or venous structures with high image SNR and high spatial resolution. A mask subtraction scheme using spin echo SSFP-SH acquisition is also described to reduce stationary background signal from the delayed SSFP angiography images. (C) 2002 Wiley-Liss, Inc. C1 GE Med Syst, Appl Sci Lab, Baltimore, MD USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Foo, TKF (reprint author), Johns Hopkins Univ Hosp, Appl Sci Lab, GE Med Syst, Room 110-MRI,600 N Wolfe St, Baltimore, MD 21287 USA. NR 20 TC 27 Z9 28 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2002 VL 48 IS 4 BP 699 EP 706 DI 10.1002/mrm.10278 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 599XT UT WOS:000178361000017 PM 12353288 ER PT J AU Ilangovan, G Li, HQ Zweier, JL Krishna, MC Mitchell, JB Kuppusamy, P AF Ilangovan, G Li, HQ Zweier, JL Krishna, MC Mitchell, JB Kuppusamy, P TI In vivo measurement of regional oxygenation and Imaging of redox status in RIF-1 murine tumor: Effect of carbogen-breathing SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE electron paramagnetic resonance (EPR); oximetry; tumor hypoxia; RIF-1 tumor; redox imaging; carbogen-breathing; lithium phthalocyanine (LiPc) ID ELECTRON-PARAMAGNETIC-RESONANCE; IN-VIVO; LITHIUM PHTHALOCYANINE; ELECTROCHEMICAL PREPARATION; ACCELERATED RADIOTHERAPY; EPR OXIMETRY; NICOTINAMIDE; TISSUES; PROBE; CELL AB The purpose of this study was to noninvasively monitor tumor oxygenation and redox status during hyperoxygenation treatment, such as carbogen-breathing, in a murine tumor model using in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging techniques. The study was performed using implanted lithium phthalocyanine (LiPc) microcrystals as the oximetry probe and 3-carbamoylproxyl (3-CP) as the redox probe in RIF-1 tumors implanted in the upper hind leg of C3H mice. Repetitive measurements of pO(2) from the same tumors as a function of tumor growth (8-24 mm in size) showed that the tumors were hypoxic and that the tumor pO(2) values were decreasing with tumor growth. Carbogen-breathing mostly showed an increase in the tumor oxygenation, although there were considerable variations in the magnitude of change among the tumors. The pharmacokinetic studies with 3-CP showed a significant decrease in the overall tumor reduction status in the carbogen-breathing mice. Spatially resolved (imaging) pharmacokinetic data over the tumor volume were obtained to visualize the distribution of the redox status within the tumor. The redox images of the tumor in the air-breathing mice showed significant heterogeneity in the magnitude and spatial distribution of reducing equivalents. On carbogen-breathing the tissue reduction status decreased considerably, with a concomitant decrease in the heterogeneity of distribution of the redox status. The results suggest that 1) carbogen-breathing considerably enhances tissue oxygenation and significantly decreases the redox status in RIF-1 tumor, and 2) changes in the magnitude and distribution of the redox status within the tumor volume during carbogen-breathing are correlated with the increased tissue oxygenation. (C) 2002 Wiley-Liss, Inc. C1 Johns Hopkins Univ, EPR Ctr, Div Cardiol, Dept Med,Sch Med, Baltimore, MD USA. NCI, NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Kuppusamy, P (reprint author), Ohio State Univ, Davis Heart & Lung Res Inst, 420 W 12th Ave,TMRF-114, Columbus, OH 43210 USA. FU NCI NIH HHS [CA 78886]; NCRR NIH HHS [RR 12190]; NIBIB NIH HHS [R01 EB000890, R01 EB000890-04] NR 36 TC 58 Z9 58 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2002 VL 48 IS 4 BP 723 EP 730 DI 10.1002/mrm.10254 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 599XT UT WOS:000178361000020 PM 12353291 ER PT J AU Barbier, EL Marrett, S Danek, A Vortmeyer, A van Gelderen, P Duyn, J Bandettini, P Grafman, J Koretskyk, AP AF Barbier, EL Marrett, S Danek, A Vortmeyer, A van Gelderen, P Duyn, J Bandettini, P Grafman, J Koretskyk, AP TI Imaging cortical anatomy by high-resolution MR at 3.0T: Detection of the stripe of Gennari in visual area 17 SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE human; cortical architecture; brain maps; myelin; Area V1 ID HUMAN STRIATE; CORTEX; BRAIN; INVIVO; IMAGES; SPACE AB The brain can be parcellated into numerous anatomical and functional subunits. The classic work by Brodmann (Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909) identified areas of the cerebral cortex based on histological differences. An alternative to his cytoarchitectonic approach is the myeloarchitectonic approach. MRI has excellent white/gray matter contrast in the brain due to the presence of myelin, and thus seems uniquely suited for in vivo studies of cortical myeloarchitecture. Here it is demonstrated that the stripe or stria of Gennari can be consistently detected in human occipital cortex. T-1-weighted images obtained at 3T from six of 10 normal volunteers, with resolutions of 350 x 350 x 600 mu, clearly demonstrate this myelin-rich intracortical layer. It is concluded that the striate cortex (area 17 of Brodmann) of the human brain can be delineated in vivo on T-1-weighted images, potentially enabling detection of specific cortical boundaries within individual brains. Published 2002 Wiley-Liss, Inc. C1 NINDS, LFMI, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, Lab Mixte, INSERM, U438,RMN Bioclin,LRC,CEA,Hop Albert Michallon, Grenoble, France. NIMH, NIH, Tesla Funct Neuroimaging Facil 3, Bethesda, MD 20892 USA. NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Univ Munich, Neurol Klin, Munich, Germany. NINDS, Mol Pathologenesis Unit, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Koretskyk, AP (reprint author), NINDS, LFMI, NIH, Room 10-B1D118,MSC 1065, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010; Barbier, Emmanuel/E-6302-2011; Bandettini, Peter/F-5871-2012; Danek, Adrian/G-7339-2011; Koretsky, Alan/C-7940-2015; OI Barbier, Emmanuel/0000-0002-4952-1240; Danek, Adrian/0000-0001-8857-5383; Koretsky, Alan/0000-0002-8085-4756; Marrett, Sean/0000-0001-8179-6511; Grafman, Jordan H./0000-0001-8645-4457 NR 18 TC 98 Z9 99 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2002 VL 48 IS 4 BP 735 EP 738 DI 10.1002/mrm.10255 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 599XT UT WOS:000178361000022 PM 12353293 ER PT J AU Mukhopadhyay, A Wei, BX Zullo, SJ Wood, LV Weiner, H AF Mukhopadhyay, A Wei, BX Zullo, SJ Wood, LV Weiner, H TI In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible contribution to lipodystrophy syndrome SO MITOCHONDRION LA English DT Article DE lipodystrophy; mitochondria; inhibition; protease ID REVERSE-TRANSCRIPTASE INHIBITORS; THERAPY-RELATED LIPODYSTROPHY; ALDEHYDE DEHYDROGENASE; ESCHERICHIA-COLI; PEPTIDASE; PRECURSOR; INFECTION; TOXICITY; IMPORT; DYSFUNCTION AB Highly active antiretroviral therapy has been associated with the emergence of lipodystrophy syndromes that have clinical features commonly seen in patients with mitochondrial dysfunction. The effect of therapeutic protease inhibitors (PIs) on mitochondrial function is unknown. Mitochondrial matrix space proteins possess an amino-terminal leader peptide that is removed by the mitochondrial processing protease (MPP). Lack of cleavage could result in non- or dysfunctional mitochondrial proteins. The effects of different PIs on protease processing using pure MPP or yeast mitochondria, recognized models for mammalian counterparts, were examined in vitro. Multiple PIs were found to inhibit MPP, evidenced by accumulation of immature pALDH and decreased levels of processed ALDH. Both indinavir and amprenavir at 5.0 mg/ml resulted in significant inhibition of NIPP. Although inhibition of MPP was also observed with ritonavir and saquinavir, the inhibition was difficult to quantify due to background inhibition of MPP by DMSO that was required to solubilize the drugs for the in vitro studies. Indinavir was also shown to inhibit MPP within yeast mitochondria. Lack of processing may impair mitochondrial function and contribute to the observed mitochondrial dysfunctions in patients receiving HAART and implicated in antiretroviral-associated lipodystrophy. (C) 2002 Elsevier Science B.V. and Mitochondria Research Society. All rights reserved. C1 NIST, Adv Technol Program, Gaithersburg, MD 20899 USA. Purdue Univ, W Lafayette, IN 47907 USA. NIMH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Zullo, SJ (reprint author), NIST, Adv Technol Program, Gaithersburg, MD 20899 USA. NR 33 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD OCT PY 2002 VL 1 IS 6 BP 511 EP 518 AR PII S1567-7249(02)00042-9 DI 10.1016/S1567-7249(02)00042-9 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 601FK UT WOS:000178435700004 PM 16120303 ER PT J AU Prymakowska-Bosak, M Hock, R Catez, F Lim, JH Birger, Y Shirakawa, H Lee, K Bustin, M AF Prymakowska-Bosak, M Hock, R Catez, F Lim, JH Birger, Y Shirakawa, H Lee, K Bustin, M TI Mitotic phosphorylation of chromosomal protein HMGN1 inhibits nuclear import and promotes interaction with 14.3.3 proteins SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HIGH-MOBILITY; CELL-CYCLE; SUBCELLULAR-LOCALIZATION; TRANSCRIPTIONAL ACTIVITY; HISTONE DEACETYLASE-4; 14-3-3 PROTEINS; DNA-BINDING; CHROMATIN; TRANSPORT; COMPLEX AB Progression through mitosis is associated with reversible phosphorylation of many nuclear proteins including that of the high-mobility group N (HMGN) nucleosomal binding protein family. Here we use immunofluorescence and in vitro nuclear import studies to demonstrate that mitotic phosphorylation of the nucleosomal binding domain (NBD) of the HMGN1 protein prevents its reentry into the newly formed nucleus in late telophase. By microinjecting wild-type and mutant proteins into the cytoplasm of HeLa cells and expressing these proteins in HmgN1(-/-) cells, we demonstrate that the inability to enter the nucleus is a consequence of phosphorylation and is not due to the presence of negative charges. Using amity chromatography with recombinant proteins and nuclear extracts prepared from logarithmically growing or mitotically arrested cells, we demonstrate that phosphorylation of the NBD of HMGN1 promotes interaction with specific 14.3.3 isotypes. We conclude that mitotic phosphorylation of HMGN1 protein promotes interaction with 14.3.3 proteins and suggest that this interaction impedes the reentry of the proteins into the nucleus during telophase. Taken together with the results of previous studies, our results suggest a dual role for mitotic phosphorylation of HMGN1: abolishment of chromatin binding and inhibition of nuclear import. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Cell & Dev Biol, D-97070 Wurzburg, Germany. Tohoku Univ, Lab Nutr, Sendai, Miyagi 980, Japan. RP Bustin, M (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 2D-21, Bethesda, MD 20892 USA. RI Shirakawa, Hitoshi/D-1406-2009; Bustin, Michael/G-6155-2015 NR 42 TC 24 Z9 25 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2002 VL 22 IS 19 BP 6809 EP 6819 DI 10.1128/MCB.22.19.6809-6819.2002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 592XJ UT WOS:000177961900016 PM 12215538 ER PT J AU Lee, PR Song, S Ro, HS Park, CJ Lippincott, J Li, R Pringle, JR De Virgilio, C Longtine, MS Lee, KS AF Lee, PR Song, S Ro, HS Park, CJ Lippincott, J Li, R Pringle, JR De Virgilio, C Longtine, MS Lee, KS TI Bni5p, a septin-interacting protein, is required for normal septin function and cytokinesis in Saccharomyces cerevisiae SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MOTHER-BUD NECK; CELL-CYCLE; BUDDING YEAST; GENE-PRODUCT; ESCHERICHIA-COLI; SHUTTLE VECTORS; COILED COILS; POLO-BOX; KINASE; RING AB In the budding yeast Saccharomyces cerevisiae, the Cdc3p, Cdc10p, Cdc11p, Cdc12p, and Sep7p/Shs1p septins assemble early in the cell cycle in a ring that marks the future cytokinetic site. The septins appear to be major structural components of a set of filaments at the mother-bud neck and function as a scaffold for recruiting proteins involved in cytokinesis and other processes. We isolated a novel gene, BN15, as a dosage suppressor of the cdc12-6 growth defect. Overexpression of BN15 also suppressed the growth defects of cdc10-1, cdc11-6, and sep70 strains. Loss of BN15 resulted in a cytokinesis defect, as evidenced by the formation of connected cells with shared cytoplasms, and deletion of BN15 in a cdc3-6, cde10-1, cdc11-6, cdc12-6, or sep70 mutant strain resulted in enhanced defects in septin localization and cytokinesis. Bni5p localizes to the mother-bud neck in a septin-dependent manner shortly after bud emergence and disappears from the neck approximately 2 to 3 min before spindle disassembly. Two-hybrid, in vitro binding, and protein-localization studies suggest that Bni5p interacts with the N-terminal domain of Cdc11p, which also appears to be sufficient for the localization of Cdc11p, its interaction with other septins, and other critical aspects of its function. Our data suggest that the Bni5p-septin interaction is important for septin ring stability and function, which is in turn critical for normal cytokinesis. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Program Mol Biol & Biotechnol, Chapel Hill, NC 27599 USA. Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Rm 3D25, Bethesda, MD 20892 USA. RI De Virgilio, Claudio/B-4707-2012 FU NIGMS NIH HHS [GM59964, GM31006, R01 GM031006, R01 GM059964, R37 GM031006] NR 57 TC 51 Z9 52 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2002 VL 22 IS 19 BP 6906 EP 6920 DI 10.1128/MCB.22.19.6096-6920.2002 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 592XJ UT WOS:000177961900025 PM 12215547 ER PT J AU Zhan, K Vattem, KM Bauer, BN Dever, TE Chen, JJ Wek, RC AF Zhan, K Vattem, KM Bauer, BN Dever, TE Chen, JJ Wek, RC TI Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for resistance to environmental stresses SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FACTOR-2-ALPHA EIF-2-ALPHA KINASE; FACTOR 2-ALPHA KINASE; TRANSFER-RNA-BINDING; ATF1 TRANSCRIPTION FACTOR; AMINO-ACID AVAILABILITY; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; TRANSLATIONAL REGULATION; DROSOPHILA-MELANOGASTER; EIF2-ALPHA KINASE AB Protein synthesis is regulated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) in response to different environmental stresses. One member of the eIF2alpha kinase family, hemeregulated inhibitor kinase (HRI), is activated under heme-deficient conditions and blocks protein synthesis, principally globin, in mammalian erythroid cells. We identified two HRI-related kinases from Schizosaccharomyces pombe which have full-length homology with mammalian HRI. The two HRI-related kinases, named Hri1p and Hri2p, exhibit autokinase and kinase activity specific for Ser-51 of eIF2alpha, and both activities were inhibited in vitro by hemin, as previously described for mammalian HRI. Overexpression of Hri1p, Hri2p, or the human eIF2alpha kinase, double-stranded-RNA-dependent protein kinase (PKR), impeded growth of S. pombe due to elevated phosphorylation of eIF2alpha. Cells from strains with deletions of the hri1(+) and hri2(+) genes, individually or in combination, exhibited a reduced growth rate when exposed to heat shock or to arsenic compounds. Measurements of in vivo phosphorylation of eIF2alpha suggest that Hri1p and Hri2p differentially phosphorylate eIF2alpha in response to these stress conditions. These results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2alpha kinases are important participants in diverse stress response pathways in some lower eukaryotes. C1 Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. EM rwek@iupui.edu FU NIDDK NIH HHS [R01DK53223, R01 DK053223]; NIGMS NIH HHS [R01 GM049164, R01GM49164, R01GM643540] NR 89 TC 44 Z9 48 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2002 VL 22 IS 20 BP 7134 EP 7146 DI 10.1128/MCB.22.20.7134-7146.2002 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 598FZ UT WOS:000178266400017 PM 12242291 ER PT J AU Simpson, AGB Roger, AJ Silberman, JD Leipe, DD Edgcomb, VP Jermiin, LS Patterson, DJ Sogin, ML AF Simpson, AGB Roger, AJ Silberman, JD Leipe, DD Edgcomb, VP Jermiin, LS Patterson, DJ Sogin, ML TI Evolutionary history of "early-diverging" eukaryotes: The excavate taxon Carpediemonas is a close relative of Giardia SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE Archezoa; diplomonads; jakobids; eukaryote evolution; mitochondria; protists ID EARLY-BRANCHING EUKARYOTES; TRANSFER-RNA SYNTHETASE; TRICHOMONAS-VAGINALIS; PHYLOGENETIC PLACE; LACKING PROTOZOAN; LAMBLIA; MITOCHONDRIA; ULTRASTRUCTURE; ORIGIN; GENE AB Diplomonads, such as Giardia, and their close relatives retortamonads have been proposed as early-branching eukaryotes that diverged before the acquisition-retention of mitochondria, and they have become key organisms in attempts to understand the evolution of eukaryotic cells. In this phylogenetic study we focus on a series of eukaryotes suggested to be relatives of diplomonads on morphological grounds, the "excavate taxa". Phylogenies of small subunit ribosomal RNA (SSU rRNA) genes, alpha-tubulin, beta-tubulin, and combined alpha- + beta-tubulin all scatter the various excavate taxa across the diversity of eukaryotes. But all phylogenies place the excavate taxon Carpediemonas as the closest relative of diplomonads (and, where data are available, retortamonads). This novel relationship is recovered across phylogenetic methods and across various taxon-deletion experiments. Statistical support is strongest under maximum-likelihood (ML) (when among-site rate variation is modeled) and when the most divergent diplomonad sequences are excluded, suggesting a true relationship rather than an artifact of long-branch attraction. When all diplomonads are excluded, our NIL SSU rRNA tree actually places retortamonads and Carpediemonas away from the base of the eukaryotes. The branches separating excavate taxa are mostly not well supported (especially in analyses of SSU rRNA data). Statistical tests of the SSU rRNA data, including an "expected likelihood weights" approach, do not reject trees where excavate taxa are constrained to be a clade (with or without parabasalids and Euglenozoa). Although diplomonads and retortamonads lack any mitochondria-like organelle, Carpediemonas contains double membrane-bounded structures physically resembling hydrogenosomes. The phylogenetic position of Carpediemonas suggests that it will be valuable in interpreting the evolutionary significance of many molecular and cellular peculiarities of diplomonads. C1 Dalhousie Univ, Dept Biochem, Halifax, NS B3H 4H7, Canada. Univ Calif Los Angeles, Inst Geophys & Planetary Phys, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Microbiol & Immunol, Los Angeles, CA 90024 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Marine Biol Lab, Woods Hole, MA USA. Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. RP Dalhousie Univ, Dept Biochem, Halifax, NS B3H 4H7, Canada. EM simpson@hades.biochem.dal.ca RI Jermiin, Lars/C-2458-2009; OI Jermiin, Lars/0000-0002-9619-3809; Patterson, David/0000-0003-2645-7335 NR 51 TC 68 Z9 73 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD OCT PY 2002 VL 19 IS 10 BP 1782 EP 1791 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 602GH UT WOS:000178497200013 PM 12270904 ER PT J AU Russell, JS Tofilon, PJ AF Russell, JS Tofilon, PJ TI Radiation-induced activation of nuclear factor-kappa B involves selective degradation of plasma membrane-associated I kappa Ba SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NORMAL RAT ASTROCYTES; IONIZING-RADIATION; TRANSCRIPTIONAL ACTIVATION; SIGNAL-TRANSDUCTION; ALPHA DEGRADATION; TNF RECEPTOR; CELLS; PHOSPHORYLATION; PATHWAY; KINASE AB In contrast to nuclear factor-kappaB (NF-kappaB) activation by tumor necrosis factor-alpha (TNF-alpha), the specific processes involved in the activation of this transcription factor by ionizing radiation (IR) have not been completely defined. According to the classical paradigm, a critical event in NF-kappaB activation is the degradation Of IkappaBalpha. Data presented herein show that, in contrast to treatment with TNF-alpha, IR-induced NF-kappaB activation was not accompanied by degradation Of IkappaBalpha in the U251 glioblastoma cell line as determined in whole cell lysates. However, treatment with the proteosome inhibitor MG-132 inhibited NF-kappaB activation induced by IR, suggesting that IkappaBalpha degradation was a critical event in this process. To reconcile these results, U251 cell lysates were separated into soluble and insoluble fractions and IkappaBalpha levels evaluated. Although IkappaBalpha was found in both subcellular fractions, treatment with IR resulted in the degradation Of IkappaBalpha only in the insoluble fraction. Further subcellular fractionation suggested that the IR-sensitive, insoluble Pool Of IkappaBalpha was associated with the plasma membrane. These data suggest that the subcellular location of IkappaBalpha is a critical determinant in IR-induced NF-kappaB activation. C1 NCI, Mol Radiat Therapeut Branch, Radiat Oncol Sci Program, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. RP Tofilon, PJ (reprint author), NCI, Mol Radiat Therapeut Branch, Radiat Oncol Sci Program, Bethesda, MD 20892 USA. NR 39 TC 29 Z9 30 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2002 VL 13 IS 10 BP 3431 EP 3440 DI 10.1091/mbc.E02-05-0252 PG 10 WC Cell Biology SC Cell Biology GA 607GT UT WOS:000178784300006 PM 12388747 ER PT J AU Kawakami, M Kawakami, K Puri, RK AF Kawakami, M Kawakami, K Puri, RK TI Intratumor administration of interleukin 13 receptor-targeted cytotoxin induces apoptotic glioma tumor xenografts SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; CYTOCHROME-C; CANCER-CELLS; MITOCHONDRIAL DYSFUNCTION; CASPASE ACTIVATION; ALPHA CHAIN; THERAPY; PROTEIN; RELEASE; DEATH AB Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response. C1 US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr,MSC4555, Bethesda, MD 20892 USA. NR 34 TC 39 Z9 42 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2002 VL 1 IS 12 BP 999 EP 1007 PG 9 WC Oncology SC Oncology GA 607BQ UT WOS:000178770900003 PM 12481422 ER PT J AU Gasparian, AV Yao, YJ Lu, JX Yemelyanov, AY Lyakh, LA Slaga, TJ Budunova, IV AF Gasparian, AV Yao, YJ Lu, JX Yemelyanov, AY Lyakh, LA Slaga, TJ Budunova, IV TI Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID THIOREDOXIN REDUCTASE; ADENOCARCINOMA CELLS; METHYLSELENINIC ACID; PREVENTION; EXPRESSION; APOPTOSIS; CARCINOMA; PROTEINS; ALPHA; FAMILY AB Selenium compounds are potential chemopreventive agents for prostate cancer. There are several proposed mechanisms for their anticancer effect, including enhanced apoptosis of transformed cells. Because the transcription factor nuclear factor-kappaB (NF-kappaB) is often constitutively activated in tumors and is a key antiapoptotic factor in mammalian cells, we tested whether selenium inhibited NF-kappaB activity in prostate cancer cells. In our work, we used sodium selenite and a novel synthetic compound, methylseleninic acid (MSeA), that served as a precursor of the putative active monomethyl metabolite methylselenol. We found that both selenium forms inhibited cell growth and induced apoptosis in DU145 and JCA1 prostate carcinoma cells. Sodium selenite and MeSeA, at the concentrations that induced apoptosis, inhibited NF-kappaB DNA binding induced by tumor necrosis factor-alpha and lipopolysaccharide in DU145 and JCA1 prostate cells. Both compounds also inhibited kappaB.Luciferase reporter activity in prostate cells. A key to NF-kappaB regulation is the inhibitory kappaB (IkappaB) proteins that in response to diverse stimuli are rapidly phosphorylated by IkappaB kinase complex, ubiquitinated, and undergo degradation, releasing NF-kappaB factor. We showed that sodium selenite and MSeA inhibited IkappaB kinase activation and IkappaB-alpha phosphorylation and degradation induced by TNF-alpha and lipopolysaccharide in prostate cells. NF-kappaB blockage by IkappaB-alpha d.n. mutant resulted in the sensitization of prostate carcinoma cells to apoptosis induced by selenium compounds. These results suggest that selenium may target the NF-kappaB activation pathway to exert, at least in part, its cancer chemopreventive effect in prostate. C1 AMC Canc Res Ctr, Denver, CO 80214 USA. NCI, Lab Cell Regulat & Carcinogenesis, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Budunova, IV (reprint author), AMC Canc Res Ctr, 1600 Pierce St, Denver, CO 80214 USA. NR 47 TC 85 Z9 87 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2002 VL 1 IS 12 BP 1079 EP 1087 PG 9 WC Oncology SC Oncology GA 607BQ UT WOS:000178770900012 PM 12481431 ER PT J AU Madhukar, BV Dimitrov, NV Meyer-Leece, C Contreras, ML Crowell, J AF Madhukar, BV Dimitrov, NV Meyer-Leece, C Contreras, ML Crowell, J TI Inhibition of mitogen-activated protein kinase activity of human lymphocytes after oral administration of Oltipraz SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DRUG-METABOLIZING-ENZYMES; CHEMOPREVENTIVE AGENT; MAP KINASES; PATHWAYS; INDUCTION; CELLS AB Several preclinical studies indicated that Oltipraz appears to be one of the most potent cancer chemopreventive agents. Pharmacological studies in humans provided substantial amounts of information related to doses and schedules. Oltipraz has been reported to induce phase II drug-metabolizing enzymes. However, its chemopreventive activity suggests that it may also interact with cellular processes associated with cancer cell growth and proliferation. During a clinical trial designed to monitor eventual Oltipraz toxicity in high-risk population for development of lung cancer, we performed companion studies related to cell proliferation. Human lymphocytes were chosen as surrogate tissue to assess the in vivo effects of Oltipraz on cell signaling pathways involved in cell proliferation. The results of this study demonstrate that Oltipraz markedly inhibited the activation state of the extracellular signal-regulated kinases of the mitogen-activated protein kinase family of kinases in lymphocytes of subjects treated with two different doses and schedules of Oltipraz. Individual variations were observed that were not related to Oltipraz dosing or schedule of administration. The results from this study indicate that lymphocytes could be used as surrogate tissue for the development of biomarkers for studies of anticarcinogenic agents. C1 Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Pediat Human Dev, E Lansing, MI 48824 USA. Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Dimitrov, NV (reprint author), Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. FU NCI NIH HHS [N01-CN-75125] NR 22 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2002 VL 1 IS 12 BP 1125 EP 1128 PG 4 WC Oncology SC Oncology GA 607BQ UT WOS:000178770900017 PM 12481436 ER PT J AU Zhang, YJ Ahsan, H Chen, Y Lunn, RM Wang, LY Chen, SY Lee, PH Chen, CJ Santella, RM AF Zhang, YJ Ahsan, H Chen, Y Lunn, RM Wang, LY Chen, SY Lee, PH Chen, CJ Santella, RM TI High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B-1-DNA adduct levels in human hepatocellular carcinoma SO MOLECULAR CARCINOGENESIS LA English DT Article DE gene expression; epigenetic changes; hyper methylation; hepatocellular carcinoma; CpG island; aflatoxin B-1 ID TUMOR-SUPPRESSOR GENE; ABERRANT DNA METHYLATION; EPIGENETIC INACTIVATION; CPG ISLAND; CHRONIC HEPATITIS; BREAST CANCERS; FOREIGN DNA; 3P21.3; LUNG; EXPRESSION AB Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p 16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B-1 (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development. (C) 2002 Wiley-Liss, Inc. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY 10032 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Tzu Chi Univ, Inst Aboriginal Hlth, Hualien, Taiwan. Natl Hlth Res Inst, Div Biostat & Bioinformat, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Dept Surg, Taipei 10764, Taiwan. Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. RP Santella, RM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Room 505,701 W 168th St, New York, NY 10032 USA. RI Chen, Chien-Jen/C-6976-2008; 王, 豊裕/C-1460-2010; OI LEE, PO-HUANG/0000-0001-5831-035X FU NIEHS NIH HHS [ES05116] NR 41 TC 73 Z9 79 U1 1 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2002 VL 35 IS 2 BP 85 EP 92 DI 10.1002/mc.10076 PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 601KL UT WOS:000178444800005 PM 12325038 ER PT J AU Tao, LH Li, YZ Wang, W Kramer, PM Gunning, WT Lubet, RA Steele, VE Pereira, MA AF Tao, LH Li, YZ Wang, W Kramer, PM Gunning, WT Lubet, RA Steele, VE Pereira, MA TI Effect of budesonide on the methylation and mRNA expression of the insulin-like growth factor 2 and c-myc genes in mouse lung tumors SO MOLECULAR CARCINOGENESIS LA English DT Article DE budesonide; chemoprevention; DNA methylation; insulin-like growth factor 2; c-myc ID FEMALE A/J MICE; FACTOR-II GENE; ALLELE-SPECIFIC METHYLATION; DNA METHYLATION; TRICHLOROACETIC-ACID; PULMONARY CARCINOGENESIS; DICHLOROACETIC ACID; IMPRINTED GENES; FREQUENT LOSS; IGF2 GENE AB The use of surrogate end-point biomarkers could help in the development of chemopreventive agents. To define potential surrogate end-point biomarkers, the ability of budesonide to decrease mRNA expression of the insulin-like growth factor-2 (Igf-II) and c-myc genes and to cause the remethylation of the genes was investigated in lung tumors. Lung tumors were induced in female strain A mice by administering i.p. 16 mg/kg vinyl carbarnate for 2 consecutive wk or by a single dose of 100 mg/kg benzo[a]pyrene (B[a]P). Thirty-four weeks later, the mice given vinyl carbarnate received budesonide (0.6 or 2.4 mg/kg diet) for 7 d and then were killed. Mice were killed 24 wk after administration of B[a]P. The mRNA expression of the Igf-II and c-myc genes was increased in lung tumors relative to normal lung tissue. Budesonide decreased mRNA expression of both genes in tumors. The methylation status of 27 CpG sites in the differentially methylated region 2 in the Igf-II gene was determined with the bisulfite-treated DNA-sequencing procedure. The numbers of methylated CpG sites were 17-21 in normal lung (70.4 +/- 2.6%); 0-2, and 1-2 in lung tumors induced by vinyl carbarnate and B[a]P (4.9 +/- 1.2% and 4.6 +/- 1.2%, respectively); and 4-5 or 7-16 in tumors after treatment with 0.6 or 2.4 mg/kg budesonide (16.0 +/- 1.2% and 46.2 +/- 5.1%, respectively). Thus, lung tumors had strikingly less methylated CpG sites than normal lung tissue, while even limited treatment with budesonide resulted in remethylation of the CpG sites in tumors. With Hpall digestion followed by Southern blot analysis, the internal cytosine of CCGG sites in the c-myc gene was found to be methylated in normal lung tissue, whereas some of the sites were unmethylated in lung tumors. Treatment for 7 d with budesonide resulted in the remethylation of these sites. In conclusion, mouse lung tumors showed decreased methylation of the Igf-II and c-myc genes that was associated with increased expression of these genes. Budesonide treatment caused remethylation and decreased expression of both genes. The results support the possibility of using decreased mRNA expression and remethylation of the Igf-II and c-myc genes as biomarkers for the efficacy of budesonide. (C) 2002 Wiley-Liss, Inc. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Tao, LH (reprint author), Med Coll Ohio, Dept Pathol, Hlth Educ Bldg,Room 202,3055 Arlington Ave, Toledo, OH 43614 USA. RI Gunning, William/E-4681-2010 FU NCI NIH HHS [N01-CN-95107] NR 41 TC 22 Z9 23 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2002 VL 35 IS 2 BP 93 EP 102 DI 10.1002/mc.10078 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 601KL UT WOS:000178444800006 PM 12325039 ER PT J AU Hegde, RS AF Hegde, RS TI Targeting and beyond: New roles for old signal sequences SO MOLECULAR CELL LA English DT Editorial Material C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Hegde, Ramanujan/0000-0001-8338-852X NR 10 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT PY 2002 VL 10 IS 4 BP 697 EP 698 DI 10.1016/S1097-2765(02)00692-5 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 609DU UT WOS:000178889000003 PM 12419211 ER PT J AU Palomares, F Godoy, JA Piriz, A O'Brien, SJ Johnson, WE AF Palomares, F Godoy, JA Piriz, A O'Brien, SJ Johnson, WE TI Faecal genetic analysis to determine the presence and distribution of elusive carnivores: design and feasibility for the Iberian lynx SO MOLECULAR ECOLOGY LA English DT Article DE cytochrome b; D-loop; faecal DNA; genetic analyses; Iberian lynx; mitochondrial DNA markers; presence and distribution ID ESTIMATING POPULATION-SIZE; FELIS-PARDINA TEMMINCK; SCENT MARKING; SPANISH LYNX; COTO-DONANA; BROWN BEAR; DNA; FECES; PCR; SEQUENCES AB Noninvasive methods using genetic markers have been suggested as ways to overcome difficulties associated with documenting the presence of elusive species. We present and assess a novel, reliable and effective molecular genetic technique for the unequivocal genetic identification of faeces from the endangered Iberian lynx (Lynx pardinus ). From mitochondrial DNA (mtDNA) cytochrome b and D-loop region sequences, we designed four species-specific primers (for products 130-161 bp long) that were considered to be likely to amplify degraded DNA. We compared two DNA extraction methods, various DNA amplification conditions and the robustness and specificity of the primer pairs with 87 lynx samples from 5 potentially different lynx populations and with 328 samples of other carnivore species. The utility of the identification technique was tested with faeces of different ages, with faeces from controlled field experiments, and with faeces collected from locales with possible lynx populations from throughout the state of Andalusia, Spain (8052 km(2) ). Faecal mtDNA extraction was more efficient using PBS wash of the faeces instead of a faeces homogenate. Our assay increased from 92.6 to 99% efficiency with a second amplification and a reduction in template concentration to overcome polymerase chain reaction (PCR) inhibition. Our assay never produced false positives, and correctly identified all lynx faeces. Of 252 faeces samples of unknown species collected throughout Andalusia, 26.6% (from three different areas) were classified as Iberian lynx, 1.4% showed evidence of PCR inhibition and 1.2% were of uncertain origin. This method has proven to be a reliable technique that can be incorporated into large-scale surveys of Iberian lynx populations and exemplifies an approach that can easily be extended to other species. C1 CSIC, Estac Biol Donana, Dept Appl Biol, Seville 41013, Spain. Natl Canc Inst, Lab Genom Divers, FCRDC, Frederick, MD USA. RP Palomares, F (reprint author), CSIC, Estac Biol Donana, Dept Appl Biol, Avda Maria Luisa S-N, Seville 41013, Spain. EM ffpaloma@ebd.csic.es RI Godoy, Jose A./B-9288-2008; Johnson, Warren/D-4149-2016; CSIC, EBD Donana/C-4157-2011; Palomares, Francisco/F-5327-2016 OI Godoy, Jose A./0000-0001-7502-9471; Johnson, Warren/0000-0002-5954-186X; CSIC, EBD Donana/0000-0003-4318-6602; Palomares, Francisco/0000-0002-4655-7205 NR 56 TC 120 Z9 128 U1 6 U2 106 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD OCT PY 2002 VL 11 IS 10 BP 2171 EP 2182 DI 10.1046/j.1365-294X.2002.01608.x PG 12 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 595XX UT WOS:000178134500026 PM 12296958 ER PT J AU Yewdell, J AF Yewdell, J TI To DRiP or not to DRiP: generating peptide ligands for MHC class I molecules from biosynthesized proteins SO MOLECULAR IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; ANTIGEN-PROCESSING PATHWAY; NEWLY SYNTHESIZED PROTEINS; HEAT-SHOCK PROTEINS; T-CELL RESPONSES; PROTEASOMAL DEGRADATION; ENDOPLASMIC-RETICULUM; GAMMA-INTERFERON; INFECTED-CELLS; 26S PROTEASOME C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, J (reprint author), NIAID, Viral Dis Lab, Room 211 Bldg 4,4 Ctr Dr, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 75 TC 48 Z9 48 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2002 VL 39 IS 3-4 BP 139 EP 146 AR PII S0161-5890(02)00097-4 DI 10.1016/S0161-5890(02)00097-4 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 601PN UT WOS:000178455500003 PM 12200046 ER PT J AU Sun, M Ma, LF Xu, LD Li, J Zhang, W Petrovics, G Makarem, M Sesterhenn, I Zhang, M Blanchette-Mackie, EJ Moul, J Srivastava, S Zou, ZQ AF Sun, M Ma, LF Xu, LD Li, J Zhang, W Petrovics, G Makarem, M Sesterhenn, I Zhang, M Blanchette-Mackie, EJ Moul, J Srivastava, S Zou, ZQ TI A human novel gene DERPC located on 16q22.1 inhibits prostate tumor cell growth and its expression is decreased in prostate and renal tumors SO MOLECULAR MEDICINE LA English DT Article ID E-CADHERIN EXPRESSION; COMPARATIVE GENOMIC HYBRIDIZATION; SIGNAL-TRANSDUCTION; SUPPRESSOR GENE; BREAST-CANCER; HETEROZYGOSITY; IDENTIFICATION; CHROMOSOME-8; PROTEINS; REGIONS AB Background: Deletion of chromosome 16q is frequently associated with diverse tumors. Numerous studies strongly suggest the presence of one or more tumor suppressor genes on chromosome 16q22 to 16qter including the widely studied cadherin gene family. However, the specific tumor suppressor genes residing in this region need better definition and characterization. Material and Methods: Standard molecular biology approaches have been used to clone and characterize the DERPC cDNA and its protein product on chromosome 16q22.1. Northern blotting was used to define the expression pattern in a multiple human tissue blots. DERPC expression was examined in multi-tumor array (Clontech, CA, USA) dot blot as well as in laser capture microdissection (LCM) derived prostate cancer (CaP) specimens by quantitative RT-PCR. Western blot analysis and a fluorescent microscopy were used to characterize the molecular size and the cellular location of green fluorescent protein (GFP)-tagged DERPC fusion proteins. A colony formation assay was conducted to determine the effects of DERPC expression on tumor cell growth. Results: A novel gene DERPC (Decreased Expression in Renal and Prostate Cancer) was identified and characterized. DERPC encoded a strong basic, proline- and glycine-rich nuclear protein. DERPC was ubiquitously expressed, with abundant expression in kidney, skeletal muscle, testis, liver, ovary, and heart and moderate expression in prostate. DERPC expression was reduced in renal (67%) and prostate tumors (33%). Expression of DERPC has inhibitory potential on CaP cell growth. Further, overexpression of DERPC in LNCaP cells caused alterations of nuclear morphology. Conclusion: This study suggests that decreased expression of DERPC may be implicated in tumorigenesis of renal and CaPs. C1 Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Rockville, MD 20852 USA. Armed Forces Inst Pathol, Dept Genitourinary Pathol, Washington, DC USA. NIH, NIDDKD, Lab Cell Biochem & Biol, Sect Lipid Cell Biol, Bethesda, MD USA. Walter Reed Army Med Ctr, Dept Surg, Serv Urol, Washington, DC USA. RP Zou, ZQ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, 1530 E Jefferson St, Rockville, MD 20852 USA. NR 40 TC 7 Z9 11 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD OCT PY 2002 VL 8 IS 10 BP 655 EP 663 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 621BV UT WOS:000179569400010 PM 12477976 ER PT J AU Li, YF Austin, S AF Li, YF Austin, S TI The P1 plasmid is segregated to daughter cells by a 'capture and ejection' mechanism coordinated with Escherichia coli cell division SO MOLECULAR MICROBIOLOGY LA English DT Article ID PARB PROTEIN; DNA SEGREGATION; F-PLASMID; CHROMOSOME; PARTITION; CENTROMERE; CYCLE; REPLICATION; REGION; LOCALIZATION AB The fate of the P1 plasmid of Escherichia coli was followed by time-lapse photomicroscopy. A GFP-ParB fusion marked the plasmid during partition (segregation) to daughter cells at slow growth rate. The process differs from that previously inferred from statistical analysis of fixed cells. A focus of plasmid copies is captured at the cell centre. Immediately before cell division, the copies eject bidirectionally along the long axis of the cell. Cell division traps one or more plasmid copies in each daughter. They are not directed to a prescribed position but are free to move, associate and disassociate. Later, they are captured to the new cell centre to restart the cycle. A null P1 par mutant associates to form a focus, but it is neither captured nor ejected. A dominant negative ParB protein forms a plasmid focus that attaches to the cell centre but never ejects. It remains captive at the centre and blocks host cell division. The cells elongate. Eventually the intact focus is pushed to one side and the cells divide simultaneously in several places at the same time. This suggests that the wild-type plasmid imposes a regulatory node on the host cell cycle, preventing cell division until its own segregation is completed. C1 NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Frederick, MD 21702 USA. NR 31 TC 50 Z9 50 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2002 VL 46 IS 1 BP 63 EP 74 DI 10.1046/j.1365-2958.2002.03156.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 600CG UT WOS:000178372600006 PM 12366831 ER PT J AU Sen, R King, RA Mzhavia, N Madsen, PL Weisberg, RA AF Sen, R King, RA Mzhavia, N Madsen, PL Weisberg, RA TI Sequence-specific interaction of nascent antiterminator RNA with the zinc-finger motif of Escherichia coli RNA polymerase SO MOLECULAR MICROBIOLOGY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; TRANSCRIPTION TERMINATION; CHAIN-REACTION; ELONGATION; PHAGE-HK022; SUBUNIT; VECTORS; REGION; LAMBDA; ENZYME AB The N-terminal Zn-finger motif of the beta' subunit of RNA polymerase contains two pairs of invariant cysteines flanking a moderately well-conserved segment of 13 amino acids that is rich in basic residues. Previous work showed that replacement of certain Zn-finger residues prevented transcription antitermination in response to phage HK022 put sites. Nascent put RNA binds to and modifies transcribing polymerase, so that it becomes resistant to termination. To characterize the Zn finger further, we replaced each of the basic residues with alanine and determined the effects of the substitutions on termination, antitermination and cell viability. All the mutants were defective in put-mediated antitermination. The severity of the defect depended on the mutant and on the sequence of the upstream stem-loop of put RNA. Some, but not all, mutants distinguished between put variants that differed in this region. This suggests that the Zn-finger motif interacts directly and specifically with put RNA. All the mutants in the basic residues complemented a temperature-sensitive beta' mutant for cell growth at a non-permissive temperature, and those mutant enzymes that were tested transcribed and terminated normally in vitro on a template that lacked a put site. C1 NICHHD, Sect Microbial Genet, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weisberg, RA (reprint author), NICHHD, Sect Microbial Genet, Mol Genet Lab, NIH, 6B-3B308, Bethesda, MD 20892 USA. NR 26 TC 15 Z9 15 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2002 VL 46 IS 1 BP 215 EP 222 DI 10.1046/j.1365-2958.2002.03154.x PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 600CG UT WOS:000178372600019 PM 12366844 ER PT J AU Hinnebusch, BJ Rosso, ML Schwan, TG Carniel, E AF Hinnebusch, BJ Rosso, ML Schwan, TG Carniel, E TI High-frequency conjugative transfer of antibiotic resistance genes to Yersinia pestis in the flea midgut SO MOLECULAR MICROBIOLOGY LA English DT Article ID MULTIDRUG-RESISTANCE; ESCHERICHIA-COLI; PLASMID; BACTERIA; PLAGUE AB The acquisition of foreign DNA by horizontal transfer from unrelated organisms is a major source of variation leading to new strains of bacterial pathogens. The extent to which this occurs varies widely, due in part to lifestyle factors that determine exposure to potential donors. Yersinia pestis, the plague bacillus, infects normally sterile sites in its mammalian host, but forms dense aggregates in the non-sterile digestive tract of its flea vector to produce a transmissible infection. Here we show that unrelated co-infecting bacteria in the flea midgut are readily incorporated into these aggregates, and that this close physical contact leads to high-frequency conjugative genetic exchange. Transfer of an antibiotic resistance plasmid from an Escherichia coli donor to Y. pestis occurred in the flea midgut at a frequency of 10(-3) after only 3 days of co-infection, and after 4 weeks 95% of co-infected fleas contained an average of 10(-3) antibiotic-resistant Y. pestis transconjugants. Thus, transit in its arthropod vector exposes Y. pestis to favourable conditions for efficient genetic exchange with microbial flora of the flea gut. Horizontal gene transfer in the flea may be the source of antibiotic-resistant Y. pestis strains recently isolated from plague patients in Madagascar. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Inst Pasteur Madagascar, Antananarivo 101, Malagasy Republ. Inst Pasteur, Yersinia Lab, F-75724 Paris, France. RP Hinnebusch, BJ (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 26 TC 82 Z9 87 U1 2 U2 17 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2002 VL 46 IS 2 BP 349 EP 354 DI 10.1046/j.1365-2958.2002.03159.x PG 6 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 608RU UT WOS:000178861100005 PM 12406213 ER PT J AU Koh, AS Simmons-Willis, TA Pritchard, JB Grassl, SM Ballatori, N AF Koh, AS Simmons-Willis, TA Pritchard, JB Grassl, SM Ballatori, N TI Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: Transport by the renal organic anion transporter-1 SO MOLECULAR PHARMACOLOGY LA English DT Article ID RAT-KIDNEY; EXPRESSION CLONING; HEMODIALYSIS; MERCURY; FAMILY; OAT1; GENE AB N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevis oocytes expressing rat Oat1 showed increased uptake of [(14)C] MeHg when complexed with either NAC or DMPS but not when complexed with L-cysteine, glutathione, dimercaptosuccinate, penicillamine, or gamma-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparent K(m) values for Oat1-mediated transport were 31 +/- 2 muM for MeHg-NAC and 9 +/- 2 muM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [(14)C] MeHg-NAC and [(14)C] MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p-aminohippurate (PAH), and was trans-stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [(3)H] PAH from Oat1-expressing oocytes was trans-stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [(3)H] PAH uptake was competitively inhibited by NAC (K(i) of 2.0 +/- 0.3 mM) and DMPS (K(i) of 0.10 +/- 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals. C1 Univ Rochester, Sch Med, Dept Environm Med, Rochester, NY 14642 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY USA. RP Ballatori, N (reprint author), Univ Rochester, Sch Med, Dept Environm Med, 575 Elmwood Ave,Box EHSC, Rochester, NY 14642 USA. EM ned_ballatori@urmc.rochester.edu FU NIDDK NIH HHS [DK48823]; NIEHS NIH HHS [ES06484, ES01247, ES07026] NR 29 TC 51 Z9 53 U1 1 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2002 VL 62 IS 4 BP 921 EP 926 DI 10.1124/mol.62.4.921 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 594DV UT WOS:000178034200018 PM 12237339 ER PT J AU Wang, Y Szabo, T Welter, JD Toth, A Tran, R Lee, JY Kang, SU Suh, YG Blumberg, PM Lee, J AF Wang, Y Szabo, T Welter, JD Toth, A Tran, R Lee, JY Kang, SU Suh, YG Blumberg, PM Lee, J TI High affinity antagonists of the vanilloid receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID ROOT GANGLION NEURONS; CAPSAICIN-RECEPTOR; ANALGESIC AGENTS; AGONIST ACTIVITY; CHANNEL ACTIVITY; RAT; ANALOGS; CAPSAZEPINE; BINDING; RESINIFERATOXIN AB The vanilloid receptor VR1 has attracted great interest as a sensory transducer for capsaicin, protons, and heat, and as a therapeutic target. Here we characterize two novel VR1 antagonists, KJM429 [N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino) benzyl] thiourea] and JYL1421 [N-(4-tertbutylbenzyl)- N'-[3-fluoro-4-( methylsulfonylamino) benzyl] thiourea], with enhanced activity compared with capsazepine on rat VR1 expressed in Chinese hamster ovary (CHO) cells. JYL1421, the more potent of the two novel antagonists, inhibited [H-3] resiniferatoxin binding to rVR1 with an affinity of 53.5 +/- 6.5 nM and antagonized capsaicin-induced calcium uptake with an EC50 of 9.2 +/- 1.6 nM, reflecting 25- and 60-fold greater potencies than capsazepine. Both JYL1421 and KJM429 antagonized RTX as well as capsaicin and their mechanism was competitive. The responses to JYL1421 and KJM429 differed for calcium uptake by rVR1 induced by heat or pH. JYL1421 antagonized the response to both pH 6.0 and 5.5, whereas KJM429 antagonized at pH 6.0 but was an agonist at lower pH (<5.5). For heat, JYL1421 fully antagonized and KJM429 partially antagonized. Capsazepine showed only weak antagonism for both pH and heat. Responses of rVR1 to different activators could thus be differentially affected by different ligands. In cultured dorsal root ganglion neurons, JYL1421 and KJM429 likewise behaved as antagonists for capsaicin, confirming that the antagonism is not limited to heterologous expression systems. Finally, JYL1421 and KJM429 had little or no effect on ATP-induced calcium uptake in CHO cells lacking rVR1, unlike capsazepine. We conclude that JYL1421 is a competitive antagonist of rVR1, blocking response to all three of the agonists (capsaicin, heat, and protons) with enhanced potency relative to capsazepine. C1 NCI, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Pharm, Seoul, South Korea. RP Blumberg, PM (reprint author), NCI, Bldg 37,Room 3A01,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. RI Toth, Attila/F-4859-2010; OI Toth, Attila/0000-0001-6503-3653; Lee, Jiyoun/0000-0003-3819-5889 NR 40 TC 79 Z9 81 U1 1 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2002 VL 62 IS 4 BP 947 EP 956 DI 10.1124/mol.62.4.947 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 594DV UT WOS:000178034200021 PM 12237342 ER PT J AU McCart, JA Wang, ZH Xu, H Hu, Y Park, B Alexander, HR Bartlett, DL AF McCart, JA Wang, ZH Xu, H Hu, Y Park, B Alexander, HR Bartlett, DL TI Development of a melanoma-specific adenovirus SO MOLECULAR THERAPY LA English DT Article DE adenovirus; melanoma; cancer; gene therapy; tissue-specific promoter; tissue-specific replication ID REPLICATION-COMPETENT ADENOVIRUS; PURINE NUCLEOSIDE PHOSPHORYLASE; GENE-THERAPY; CANCER; EXPRESSION; CELLS; VECTORS; CONSTRUCTION; CARCINOMA; ANTIGEN AB Concerns regarding the hepatotoxicity of adenovirus for cancer gene therapy have led to attempts to engineer viruses for tissue-specific gene expression and tissue-specific replication. The Tyrex2 (a tandem murine melanocyte-specific enhancer) system was used to express luciferase, purine nucleoside phosphorylase (PNP), and the essential adenoviral gene E1A. In non-melanoma cell lines, the CMV promoter/enhancer (CMV p/e) was 969 times stronger than the Tyrex2 construct, whereas in melanoma cells it was only 2.6 times stronger. An adenovirus with Tyrex2 regulating PNP (Ad2Tyr2-PNP) was tested for cytotoxicity. In melanoma cells, treatment with Ad2Tyr2-PNP plus the prodrug 6-methylpurine deoxyriboside (6-MPDR) resulted in 90% cytotoxicity by day 4. In non-melanoma cell lines, only the CMV p/e resulted in significant cytotoxicity. We compared the intrinsic E1A promoter/enhancer (E1A p/e) system with the melanoma-specific constructs and found that the Tyrex2 system achieved higher levels of luciferase than the E1A p/e in all melanoma lines tested. In non-melanoma cell lines, the E1A p/e is 12.4 times stronger than the Tyrex2 construct. Tyrex2 was then used to regulate adenoviral E1A expression to construct a melanoma-specific replicating adenovirus. We were unable to achieve selective replication. As E1A is a known transactivator of the adenovirus major late promoter (MLP), we studied the ability of the MLP to express a transgene in the context of tissue-selective E1A expression. We were able to demonstrate high levels of luciferase activity with this construct; however, selectivity was lost. Melanoma-specific adenovirus expression was achieved with the Tyrex2 construct, and this led to melanoma-specific cytotoxicity by the potent PNP suicide gene. Selective melanoma-specific replication was not successful. The MLP may be a useful promoter in the context of a tissue-specific replicating adenovirus. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Bartlett, DL (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD OCT PY 2002 VL 6 IS 4 BP 471 EP 480 DI 10.1006/mthe.2002.0692 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 601WR UT WOS:000178472200008 PM 12377188 ER PT J AU Leigh, R Ostuni, J Pham, D Goldszal, A Lewis, BK Howard, T Richert, N McFarland, H Frank, JA AF Leigh, R Ostuni, J Pham, D Goldszal, A Lewis, BK Howard, T Richert, N McFarland, H Frank, JA TI Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences SO MULTIPLE SCLEROSIS LA English DT Article DE cerebral atrophy; clinical trials; image segmentation; MRI; MS ID RELAPSING-REMITTING MS; SPINAL-CORD ATROPHY; SECONDARY PROGRESSIVE MS; QUANTITATIVE FOLLOW-UP; WHOLE-BRAIN ATROPHY; VOLUMETRIC-ANALYSIS; ENHANCING LESIONS; WHITE-MATTER; AXONAL LOSS; DISEASE AB Purpose: The purpose of this study was to determine how measures reflecting cerebral atrophy (CA) are influenced by pulse sequence (PS) and segmentation algorithm (SA) used in multiple sclerosis (MS) patients and healthy control (HC)s. Methods: Magnetic resonance imaging (MRI) scans from 10 relapsing-remitting MS (RRMS) patients and five HCs were used to determine the change in brain fractional volume (BFV) over a two-year period. T1-weighted, fluid-attenuated inversion recovery (FLAIR), and proton density (PD)/T2-weighted sequences were analysed Image segmentation to determine brain volume was performed using the following: a histogram SA, an adaptive fuzzy c-means algorithm (AFCM), and an adaptive Bayesian segmentation with a K-means clustering. Results: Combinations of the SA and PS in MS patients demonstrated significant differences in the per cent change in BFV from baseline. For the combination of PS and SA the per cent change in BFV for year one and year two varied from +2.05% to -1.6% and +0.79% to -3.11%, respectively. Analysis of the HCs data revealed fluctuations in BFV varying from +0.26% to -0.29%. Conclusions: MRI estimates of CA are dependent on both the type of PS and SA; therefore, the choice of SA technique and PS should be consistent during an MS treatment trial. The progression of CA in MS should only be used as a secondary or tertiary outcome measure in treatment trials until a better understanding of how this measurement is affected by the disease, the image acquisition and analysis techniques. C1 NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. NIA, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Lab Diagnost Radiol Res, Ctr Clin, Bldg 10,Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. OI Leigh, Richard/0000-0002-8285-1815 NR 60 TC 17 Z9 17 U1 0 U2 2 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD OCT PY 2002 VL 8 IS 5 BP 420 EP 429 DI 10.1191/1352458502ms801oa PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 595VX UT WOS:000178130200012 PM 12356210 ER PT J AU Muenke, M AF Muenke, M TI The pit, the cleft and the web SO NATURE GENETICS LA English DT Editorial Material AB Orofacial clefts (cleft lip and/or palate) are among the most common birth defects in humans, affecting up to 1 in 500 infants at birth. The cause of the most common syndromic clefting condition, Van der Woude syndrome, has now been identified as haploinsufficiency of the gene encoding interferon regulatory factor 6 (IRF6). Furthermore, dominant-negative mutations of IRF6 lead to webbing of the skin in popliteal pterygium syndrome, demonstrating beyond doubt that these syndromes are allelic. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NR 10 TC 9 Z9 10 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2002 VL 32 IS 2 BP 219 EP 220 DI 10.1038/ng1002-219 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 599AP UT WOS:000178311100004 PM 12355077 ER PT J AU Xu, JF Zheng, SL Komiya, A Mychaleckyj, JC Isaacs, SD Hu, JJ Sterling, D Lange, EM Hawkins, GA Turner, A Ewing, CM Faith, DA Johnson, JR Suzuki, H Bujnovszky, P Wiley, KE DeMarzo, AM Bova, GS Chang, BL Hall, MC McCullough, DL Partin, AW Kassabian, VS Carpten, JD Bailey-Wilson, JE Trent, JM Ohar, J Bleecker, ER Walsh, PC Isaacs, WB Meyers, DA AF Xu, JF Zheng, SL Komiya, A Mychaleckyj, JC Isaacs, SD Hu, JJ Sterling, D Lange, EM Hawkins, GA Turner, A Ewing, CM Faith, DA Johnson, JR Suzuki, H Bujnovszky, P Wiley, KE DeMarzo, AM Bova, GS Chang, BL Hall, MC McCullough, DL Partin, AW Kassabian, VS Carpten, JD Bailey-Wilson, JE Trent, JM Ohar, J Bleecker, ER Walsh, PC Isaacs, WB Meyers, DA TI Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk SO NATURE GENETICS LA English DT Article ID TUMOR-ASSOCIATED MACROPHAGES; LINKAGE ANALYSIS; SUSCEPTIBILITY; CHROMOSOME-1; EXPRESSION; INFECTION; TOPOLOGY; BINDING; MODEL AB Deletions on human chromosome 8p22-23 in prostate cancer cells 1 and linkage studies in families affected with hereditary prostate cancer (HPC)(2-4) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis (5-10). Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent. C1 Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genet, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Urol, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. St Louis Univ, Dept Med, St Louis, MO 63103 USA. Georgia Urol, Atlanta, GA USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Isaacs, WB (reprint author), Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. OI Bailey-Wilson, Joan/0000-0002-9153-2920 NR 30 TC 213 Z9 224 U1 1 U2 6 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2002 VL 32 IS 2 BP 321 EP 325 DI 10.1038/ng994 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 599AP UT WOS:000178311100025 PM 12244320 ER PT J AU Hackett, CJ Sharma, OK AF Hackett, CJ Sharma, OK TI Frontiers in peptide-MHC class II multimer technology SO NATURE IMMUNOLOGY LA English DT Editorial Material ID T-CELL ACTIVATION; ANTIGEN; BINDING; LYMPHOCYTES; SELECTION; MOLECULES; AFFINITY C1 NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20817 USA. NIAID, Div Acquired Immunodeficiency Syndrome, NIH, Bethesda, MD 20817 USA. RP Hackett, CJ (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20817 USA. OI Hackett, Charles/0000-0003-4586-9669 NR 19 TC 20 Z9 20 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2002 VL 3 IS 10 BP 887 EP 889 DI 10.1038/ni1002-887 PG 3 WC Immunology SC Immunology GA 597VU UT WOS:000178242100003 PM 12352960 ER PT J AU Claudio, E Brown, K Park, S Wang, HS Siebenlist, U AF Claudio, E Brown, K Park, S Wang, HS Siebenlist, U TI BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells SO NATURE IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; SPLENIC MICROARCHITECTURE; ACTIVATION; KINASE; MICE; RECEPTOR; ALPHA; LYMPHOCYTES; RESPONSES; PATHWAY AB NF-kappaB is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, IkappaB. This process is initiated by phosphorylation of IkappaB by the IkappaB kinase (IKK) complex, predominantly by the IKKbeta catalytic subunit, and requires the regulatory subunit IKKgamma (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-kappaB2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKKalpha. We show here that B cell-activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-kappaB-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 34 TC 474 Z9 496 U1 1 U2 8 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2002 VL 3 IS 10 BP 958 EP 965 DI 10.1038/ni842 PG 8 WC Immunology SC Immunology GA 597VU UT WOS:000178242100017 PM 12352969 ER PT J AU Lei, BF DeLeo, FR Musser, JM AF Lei, BF DeLeo, FR Musser, JM TI Streptococcus pyogenes and phagocytic killing - Reply SO NATURE MEDICINE LA English DT Letter ID PLASMA C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Lei, BF (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. NR 13 TC 0 Z9 0 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2002 VL 8 IS 10 BP 1044 EP 1045 DI 10.1038/nm1002-1045 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 599AN UT WOS:000178311000006 ER PT J AU Werhahn, KJ Mortensen, J Van Boven, RW Zeuner, KE Cohen, LG AF Werhahn, KJ Mortensen, J Van Boven, RW Zeuner, KE Cohen, LG TI Enhanced tactile spatial acuity and cortical processing during acute hand deafferentation SO NATURE NEUROSCIENCE LA English DT Article ID RESOLUTION; ATTENTION; CORTEX; REPRESENTATION C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 12 TC 91 Z9 91 U1 1 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2002 VL 5 IS 10 BP 936 EP 938 DI 10.1038/nn917 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 597VV UT WOS:000178242200011 PM 12219095 ER PT J AU Naitow, H Tang, JH Canady, M Wickner, RB Johnson, JE AF Naitow, H Tang, JH Canady, M Wickner, RB Johnson, JE TI L-A virus at 3.4 angstrom resolution reveals particle architecture and mRNA decapping mechanism SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; CAP STRUCTURE; YEAST VIRUS; PROTEIN; CRYSTALLOGRAPHY; POLYMERASE; DENSITY; PROGRAM AB The structure of the yeast L-A virus was determined by X-ray crystallography at 3.4 Angstrom resolution. The L-A dsRNA virus is 400 Angstrom in diameter and contains a single protein shell of 60 asymmetric dimers of the coat protein, a feature common among the inner protein shells of dsRNA viruses and probably related to their unique mode of transcription and replication. The two identical subunits in each dimer are in non-equivalent environments and show substantially different conformations in specific surface regions. The L-A virus decaps cellular mRNA to efficiently translate its own uncapped mRNA. Our structure reveals a trench at the active site of the decapping reaction and suggests a role for nearby residues in the reaction. C1 Scripps Res Inst, Dept Biol Mol, La Jolla, CA 92037 USA. NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Johnson, JE (reprint author), Scripps Res Inst, Dept Biol Mol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. NR 31 TC 92 Z9 98 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD OCT PY 2002 VL 9 IS 10 BP 725 EP 728 DI 10.1038/nsb844 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 597VW UT WOS:000178242300006 PM 12244300 ER PT J AU Gadlin, H AF Gadlin, H TI Framing new directions for theory from the experience of practitioners SO NEGOTIATION JOURNAL-ON THE PROCESS OF DISPUTE SETTLEMENT LA English DT Article; Proceedings Paper CT 2002 Hewlett Theory Centers Conference CY 2002 CL NEW YORK, NEW YORK AB Parallel, powerful tensions exist both in mediation and in the general worlds of the scholar and the practitioner. One response to balancing these tensions, which could be called "practice romanticism," has evolved from the reflective practitioner model. But more could be done to improve our analysis and build practice-oriented theory. A key ingredient in this investigation is a healthy critical approach. C1 NIH, Bethesda, MD 20892 USA. RP Gadlin, H (reprint author), NIH, Bldg 31,Room 1B37, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0748-4526 J9 NEGOTIATION J JI Negot. J.-Process Disput. Settl. PD OCT PY 2002 VL 18 IS 4 BP 327 EP 330 DI 10.1023/A:1021046004864 PG 4 WC Management; Social Sciences, Interdisciplinary SC Business & Economics; Social Sciences - Other Topics GA 615CD UT WOS:000179227500005 ER PT J AU Chan, SL Culmsee, C Haughey, N Klapper, W Mattson, MP AF Chan, SL Culmsee, C Haughey, N Klapper, W Mattson, MP TI Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12 SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Alzheimer's disease; endoplasmic reticulum; hippocampal neurons; PARP; topoisomerase ID TUMOR-SUPPRESSOR P53; AMYLOID BETA-PEPTIDE; MANGANESE SUPEROXIDE-DISMUTASE; ALZHEIMERS-DISEASE; INDUCED APOPTOSIS; OXIDATIVE STRESS; CELL-DEATH; CORTICAL-NEURONS; PROTEIN-KINASE; NEURODEGENERATIVE DISORDERS AB Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca(2+) levels, induction of p53, upregulation of the Ca(2+)-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and 11, by an intracellular Ca(2+) chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca(2+) from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptatic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage. (C) 2002 Elsevier Science (USA). C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Univ Marburg, Inst Pharmakol & Toxikol, D-35037 Marburg, Germany. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Chan, SL (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Klapper, Wolfram/D-2516-2010; Mattson, Mark/F-6038-2012; Klapper, Wolfram/S-6314-2016 NR 80 TC 70 Z9 81 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2002 VL 11 IS 1 BP 2 EP 19 DI 10.1006/bbdu,2002.0542 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 616QH UT WOS:000179314100001 PM 12460542 ER PT J AU Zhao, WQ Ravindranath, L Mohamed, AS Zohar, O Chen, GH Lyketsos, CG Etcheberrigaray, R Alkon, DL AF Zhao, WQ Ravindranath, L Mohamed, AS Zohar, O Chen, GH Lyketsos, CG Etcheberrigaray, R Alkon, DL TI MAP kinase signaling cascade dysfunction specific to Alzheimer's disease in fibroblasts SO NEUROBIOLOGY OF DISEASE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; SMOOTH-MUSCLE CELLS; PERTURBED CALCIUM HOMEOSTASIS; HUMAN LUNG FIBROBLASTS; PC12 CELLS; TYROSINE PHOSPHORYLATION; HIPPOCAMPAL-NEURONS; COUPLED RECEPTOR; PHOSPHOLIPASE-C; BRADYKININ AB Mitogen-activated protein kinases (such as Erk1/2) regulate phosphorylation of the microtubule-associated protein tau and processing of the annyloid protein 13, both events critical to the pathophysiology of Alzheimer's disease (AD). Here we report that enhanced and prolonged Erk1/2 phosphorylation in response to bradykinin (BK) was detected in fibroblasts of both familial and sporadic AD, but not age-matched controls (AC). The AD-associated abnormality in Erk1/2 phosphorylation was not seen in fibroblasts from Huntington's disease patients with dementia. The elevation of Erk1/2 phosphorylation occurred immediately after BK stimulation and required an IP3-sensitive Ca2+ release as well as activation of PKC and c-src as upstream events. Treatment of cells with the PI-3 kinase blocker LY924002 partially inhibited the BK-stimulated Erk1/2 phosphorylation in AC, but had no effect in AD cells, suggesting that the BK-induced Erk1/2 phosphorylation in AD cells is independent of PI-3 kinase. Activation of the cAMP-responsive element binding protein (CREB) monitored as an increase in phosphorylation at Ser-133 was also observed after BK stimulation. Unlike the AD-specific differences for Erk1/2, however, the BK-stimulated CREB phosphorylation was not different between AC and AD cells. Abnormal Erk1/2 activities may alter downstream cellular processes such as gene transcription, amyloid precursor protein processing, and tau protein phosphorylation, which contribute to the pathogenesis of AD. Moreover, detection of AD-specific differences in MAP kinase in peripheral tissues may provide an efficient means for early diagnosis of AD as well as help us to identify therapeutic targets for drug discovery. (C) 2002 Elsevier Science (USA). C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. NeuroLogic Inc, Rockville, MD 20850 USA. Johns Hopkins Univ, Johns Hopkins Hosp, Dept Psychiat & Behav Sci, Neuropsychiat Serv, Rockville, MD 20850 USA. RP Zhao, WQ (reprint author), Blanchette Rockefeller Neurosci Inst, 9601 Med Ctr Dr,Acad & Res Bldg,3rd Floor, Rockville, MD 20850 USA. NR 72 TC 39 Z9 40 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2002 VL 11 IS 1 BP 166 EP 183 DI 10.1006/nbdi.2002.0520 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 616QH UT WOS:000179314100015 PM 12460556 ER PT J AU Winterer, G Adams, CM Jones, DW Knutson, B AF Winterer, G Adams, CM Jones, DW Knutson, B TI Volition to action - An event-related fMRI study SO NEUROIMAGE LA English DT Article ID ANTERIOR CINGULATE CORTEX; TO-NOISE RATIO; ERROR-DETECTION; NEURAL SYSTEM; MOTOR AREAS; ATTENTION; SCHIZOPHRENIA; PERFORMANCE; SIGNAL; TASK AB Current concepts of the anterior cingulate cortex (ACC) increasingly emphasize its role as an interface between limbic and neocortical functions. It has been pointed out that ACC activation reflects the intentional amount of effort (volition) that a subject uses in a task. In previous electrophysiological source localization investigations during a choice reaction task, we described a strong early activation in the ACC region approximately 120-150 ms after stimulus presentation. The degree of midline ACC activation correlated negatively with reaction time. This observation together with the finding that ACC activation precedes information processing in cortical association areas provided preliminary support to the notion that the extent of ACC activation is related to a subject's task engagement. However, due to the inverse problem and the relatively low spatial resolution of the electrophysiological measurements, we were not able to make inferences about the validity and the exact localization of the observed midline activation maximum. We addressed this question and performed an event-related fMRI study in six healthy volunteers during a visual choice reaction task. Two checker-board stimuli were presented either in the left or right visual hemifield in randomized order and with an interstimulus interval requiring an appropriate motor response (left-right button press). A bilateral BOLD maximum was observed in the region of the supplementary motor area confluent with the neighboring motor area of the dorsal ACC. The degree of ACC activation correlated significantly with reaction time. These results are in line with our previous electrophysiological findings and provide further evidence that early ACC activation during a choice reaction task reflects the intentional effort of a subject to carry out a task. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD 20892 USA. RP Winterer, G (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. OI Knutson, Brian/0000-0002-7669-426X NR 49 TC 54 Z9 55 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2002 VL 17 IS 2 BP 851 EP 858 DI 10.1006/nimg.2002.1232 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 604VP UT WOS:000178642000029 PM 12377159 ER PT J AU Xu, B Grafman, J Gaillard, WD Spanaki, M Ishii, K Balsamo, L Makale, M Theodore, WH AF Xu, B Grafman, J Gaillard, WD Spanaki, M Ishii, K Balsamo, L Makale, M Theodore, WH TI Neuroimaging reveals automatic speech coding during perception of written word meaning SO NEUROIMAGE LA English DT Article ID INFERIOR PREFRONTAL CORTEX; HUMAN-BRAIN; UNCONSCIOUS PERCEPTION; SEMANTIC ACTIVATION; FUNCTIONAL-ANATOMY; VISUAL MASKING; TASK; RECOGNITION; MEMORY; SOUND AB The extent to which visual word perception engages speech codes (i.e., phonological recoding) remains a crucial question in understanding mechanisms of reading. In this study, we used functional magnetic resonance imaging techniques combined with behavioral response measures to examine neural responses to focused versus incidental phonological and semantic processing of written words. Three groups of subjects made simple button-pressing responses in either phonologically (rhyming judgment) or semantically (category judgment) focused tasks or both tasks with identical sets of visual stimuli. In the phonological tasks, subjects were given both words and pseudowords separated in different scan runs. The baseline task required feature search of scrambled letter strings created from the stimuli for the experimental conditions. The results showed that cortical regions associated with both semantic and phonological processes were strongly activated when the task required active processing of word meaning. However, when subjects were actively processing the speech sounds of the same set of written words, brain areas typically engaged in semantic processing became silent. In addition, subjects who performed both the rhyming and the semantic tasks showed diverse and significant bilateral activation in the prefrontal, temporal, and other brain regions. Taken together, the pattern of brain activity provides evidence of a neural basis supporting the theory that in normal word reading, phonological recoding is automatic and facilitates semantic processing of written words, while rapid comprehension of word meaning requires devoted attention. These results also raise questions about including multiple cognitive tasks in the same neuroimaging sessions. (C) 2002 Elsevier Science (USA). C1 NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Tokyo Metropolitan Inst Gerontol, Tokyo, Japan. RP Xu, B (reprint author), NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457 NR 74 TC 17 Z9 18 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2002 VL 17 IS 2 BP 859 EP 870 DI 10.1006/nimg.2002.1215 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 604VP UT WOS:000178642000030 PM 12377160 ER PT J AU Job, DE Whalley, HC McConnell, S Glabus, M Johnstone, EC Lawrie, SM AF Job, DE Whalley, HC McConnell, S Glabus, M Johnstone, EC Lawrie, SM TI Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry SO NEUROIMAGE LA English DT Article ID EDINBURGH HIGH-RISK; BRAIN STRUCTURE; CEREBRAL GRAY; IMAGES; NEUROPATHOLOGY; REDUCTIONS; SYMPTOMS; DISEASE; ISSUES AB The aim of this study was to compare the gray matter segments from T1 structural MR images of the brain in first-episode schizophrenic subjects (n = 34) and normal control subjects (n = 36) using automated voxel-based morphometry (VBM). This study is novel in that few studies have examined subjects in their first episode of schizophrenia. The subjects were recruited for the Edinburgh High Risk project and regional brain volumes were previously measured using a semi-automated volumetric region of interest (ROI) method of analysis. The primary interest was to compare the results from the compatible parts of the ROI study and the primary VBM approach. Our secondary interest was to compare the results of a study-specific template that was constructed from the control group to those using the generic T1 template (152 Montreal Neurological Institute brains) supplied with SPM99 (statistical parametric mapping). The images were processed and statistically analyzed using the SPM99 program. VBM analysis identified significant decreases in gray matter in the schizophrenics relative to the normal control group at the corrected voxel level (P < 0.05) in the right anterior cingulate, right medial frontal lobe, left middle temporal gyrus, left postcentral gyrus, and the left limbic lobe. There were no increases in gray matter in the schizophrenics relative to the control group. The construction of a customized template appeared to improve the detection of structural abnormalities. The analyses were subsequently restricted to voxels within the amygdala-hippocampal complex using the SPM small-volume correction. This identified gray matter decreases in the schizophrenics, at the corrected voxel level (P < 0.05), in the left and right uncus and parahippocampal gyri and the right amygdala. These results are compatible with and extend the relevant findings of the previous volumetric ROI analysis, when allowing for the differences between the methods and interpretation of their results. (C) 2002 Elsevier Science (USA). C1 Univ Edinburgh, Royal Edinburgh Hosp, Dept Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Job, DE (reprint author), Univ Edinburgh, Royal Edinburgh Hosp, Dept Psychiat, Kennedy Tower,Morningside Pk, Edinburgh EH10 5HF, Midlothian, Scotland. OI Job, Dominic/0000-0002-7829-7217; Whalley, Heather/0000-0002-4505-8869 NR 37 TC 171 Z9 172 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2002 VL 17 IS 2 BP 880 EP 889 DI 10.1006/nimg.2002.1180 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 604VP UT WOS:000178642000032 PM 12377162 ER PT J AU Hardy, J AF Hardy, J TI Pathways to primary neurodegenerative disease SO NEUROLOGIA LA English DT Article DE Alzheimer's disease; Parkinson's disease; genetics ID FAMILIAL ALZHEIMERS-DISEASE; STRAUSSLER-SCHEINKER DISEASE; PRION PROTEIN GENE; ALPHA-SYNUCLEIN; FRONTOTEMPORAL DEMENTIA; PARKINSONS-DISEASE; SENILE PLAQUES; CANDIDATE GENE; MUTATIONS; MISSENSE AB The neurodegenerative diseases are an increasing medical and social burden in developed societies. During the last century, and the early part of this, these diseases were defined and classified as separate clinicopathologic entities. However, during this decade, detailed genetic investigations and the use of molecular pathologic tools have suggested that many of these diseases share common mechanisms of pathogenesis. Here I argue that while these diseases have separate and distinct etiologies, these initiate few pathogenic processes that lead to cell death. C1 NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Lab Neurogenet, NIH, Bldg 10,Room 6C103,MSC1589,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Hardy, John/C-2451-2009 NR 21 TC 3 Z9 6 U1 0 U2 0 PU S T M EDITORES PI MADRID PA PRINCIPE DE VERGARA, 211-ESC.IZDA. 6 D, 28002 MADRID, SPAIN SN 0213-4853 J9 NEUROLOGIA JI Neurologia PD OCT PY 2002 VL 17 IS 8 BP 399 EP 401 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 613YL UT WOS:000179159300001 PM 12396967 ER PT J AU Mayevsky, A Barbiro-Michaely, E Ligeti, L MacLaughlin, AC AF Mayevsky, A Barbiro-Michaely, E Ligeti, L MacLaughlin, AC TI Effects of euthanasia on brain physiological activities monitored in real-time SO NEUROLOGICAL RESEARCH LA English DT Article DE euthanasia; T-61; KCL; CBF; NADH; ion homeostasis ID CARBON-DIOXIDE; LABORATORY-ANIMALS; RATS; DAMAGE; ARREST; T-61; HYPERGLYCEMIA; EMBUTRAMIDE; HEMOLYSIS; ISCHEMIA AB Animal experimentation is terminated by the euthanasia procedure in order to avoid pain and minimize suffering. Very little is known about the real time physiological changes taking place in the brain of animals during the euthanasia. Since there is no way to evaluate the suffering of animals under euthanasia, it is assumed that objective physiological changes taking place could serve as a good way to compare various types of euthanasia procedures. In the present study we compared the effect of euthanasia induced by i.v. injection of concentrated KCL to that of Taxan T-61 (a standard mixture used by veterinarians). The responses of the cat brain were evaluated by monitoring the hemodynamic (CBF), metabolic (NADH redox state), electrical (EcoG) and extracellular ion levels, as an indicator to the ionic homeostasis. C1 Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. NIMH, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Dept Physiol, H-1085 Budapest, Hungary. RP Mayevsky, A (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM mayevsa@mail.biu.ac.il NR 36 TC 1 Z9 1 U1 0 U2 1 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 0161-6412 J9 NEUROL RES JI Neurol. Res. PD OCT PY 2002 VL 24 IS 7 BP 647 EP 651 DI 10.1179/016164102101200690 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 604AE UT WOS:000178592800004 PM 12392199 ER PT J AU Plotz, PH Howard, OMZ Oppenheim, JJ AF Plotz, PH Howard, OMZ Oppenheim, JJ TI Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, are chemo-attractants for T lymphocytes and immature dendritic cells SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 7th International Congress of the World-Muscle-Society CY OCT 02-05, 2002 CL ROTTERDAM, NETHERLANDS SP World Muscle Soc C1 NIAMS, NIH, Bethesda, MD USA. NCI, Frederick, MD 21701 USA. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2002 VL 12 IS 7-8 BP 753 EP 754 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 602HA UT WOS:000178498800163 ER PT J AU Parkinson, FE Sinclair, CJD Othman, T Haughey, NJ Geiger, JD AF Parkinson, FE Sinclair, CJD Othman, T Haughey, NJ Geiger, JD TI Differences between rat primary cortical neurons and astrocytes in purine release evoked by ischemic conditions SO NEUROPHARMACOLOGY LA English DT Article DE adenosine; inosine; hypoxanthine; adenine nucleotides; adenosine kinase; adenosine deaminase; purine nucleoside phosphorylase; nucleoside transport ID ADENOSINE KINASE INHIBITORS; CEREBRAL-ISCHEMIA; NUCLEOSIDE PHOSPHORYLASE; EXTRACELLULAR ADENOSINE; ENDOGENOUS ADENOSINE; HIPPOCAMPAL SLICES; ATP RELEASE; METABOLISM; CELLS; HYPOXIA AB In the brain, the levels of adenosine increase up to 100-fold during cerebral ischemia; however, the roles of specific cell types, enzymatic pathways and membrane transport processes in regulating intra- and extracellular concentrations of adenosine are poorly characterized. Rat primary cortical neurons and astrocytes were incubated with [H-3]adenine for 30 min to radiolabel intracellular ATP. Cells were then treated with buffer, glucose deprivation (GD), oxygen-glucose deprivation (OGD), 100 muM sodium cyanide (NaCN) or 500 muM iodoacetate (IAA) for I h to stimulate the metabolism of ATP and cellular release of [H-3]purines. The nucleoside transport inhibitor dipyridamole (DPR) (10 muM), the adenosine kinase inhibitor iodotubercidin (ITU) (I muM), the adenosine deaminase inhibitor EHNA (I muM) and the purine nucleoside phosphorylase inhibitor BCX-34 (10 muM) were tested to investigate the contribution of specific enzymes and transporters in the metabolism and release of purines from each cell type. Our results indicate that (a) under basal conditions astrocytes released significantly more [H-3]adenine nucleotides and [H-3]adenosine than neurons, (b) OGD, NaCN and IAA conditions produced significant increases in [H-3]adenosine release from neurons but not astrocytes, and (c) DPR blocked [H-3]inosine release from both astrocytes and neurons but only blocked [H-3]adenosine release from neurons. These data suggest that, in these experimental conditions, adenosine was formed by an intracellular pathway in neurons and then released via a nucleoside transporter. In contrast, adenine nucleotide release and extracellular metabolism to adenosine appeared to predominate in astrocytes. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB R3E 0T6, Canada. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Parkinson, FE (reprint author), Univ Manitoba, Dept Pharmacol & Therapeut, 753 McDermot Ave, Winnipeg, MB R3E 0T6, Canada. NR 44 TC 41 Z9 42 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD OCT PY 2002 VL 43 IS 5 BP 836 EP 846 AR PII S0028-3908(02)00083-7 DI 10.1016/S0028-3908(02)00083-7 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 608BX UT WOS:000178826200005 PM 12384169 ER PT J AU Weinberger, DR AF Weinberger, DR TI Richard Jed Wyatt, 1939-2002 - In memoriam SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2002 VL 27 IS 4 BP 687 EP 689 AR PII S0893-133X(02)00414-1 DI 10.1016/S0893-133X(02)00414-1 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 593GY UT WOS:000177983700019 ER PT J AU Gould, TD Manji, HK AF Gould, TD Manji, HK TI The Wnt signaling pathway in bipolar disorder SO NEUROSCIENTIST LA English DT Review DE Wnt signaling; glycogen synthase kinase; lithium; valproic acid; neuroprotection; circadian rhythms; bipolar disorder ID GLYCOGEN-SYNTHASE KINASE-3; MANIC-DEPRESSIVE ILLNESS; ANIMAL-VEGETAL AXIS; SMALL-MOLECULE INHIBITORS; MOOD-STABILIZING AGENTS; N-ACETYL-ASPARTATE; SEA-URCHIN EMBRYO; BETA-CATENIN; TRANSDUCTION PATHWAYS; CEREBELLAR NEURONS AB The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development. However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase kinase 3beta, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in the mature CNS-all of which have been implicated in the pathophysiology and treatment of bipolar disorder. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors review the modulation of the Wnt/GSK-3beta signaling pathway by mood-stabilizing agents, focusing on two therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future development of selective GSK-3beta inhibitors may have considerable utility not only for the treatment of bipolar disorder but also for a variety of classical neurodegenerative disorders. C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. NR 143 TC 125 Z9 128 U1 3 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2002 VL 8 IS 5 BP 497 EP 511 DI 10.1177/107385802237176 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 598CA UT WOS:000178256500020 PM 12374432 ER PT J AU Olden, K Guthrie, J Lawler, C AF Olden, K Guthrie, J Lawler, C TI Partnership for Parkinson's disease research: Patient-researcher-clinician-sponsor SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 19th International Neurotoxicology Conference CY AUG 25-28, 2001 CL COLORADO SPRINGS, COLORADO DE Parkinson's disease; environment; consortium; oxidative stress ID GENE AB Parkinson's disease (PD) appears to arise from the interaction of three events-an individual's inherited genetic susceptibility, their subsequent environmental exposures, and their age. We clearly need to intensify efforts to understand the environmental triggers of PD, the importance of the timing of exposure to these triggers, and the interplay between these exposures and a persons underlying genetic constitution and susceptibilities. This knowledge, once generated, will lead to better detection of the earliest stages of PD, to improved therapeutics, and most importantly, to viable prevention strategies so that people need not suffer from environmentally-caused PD. Many promising lines of investigation are already supported by the National Institute of Environmental Health Sciences (NIEHS), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Aging (NIA) and other public and private organizations. In order to accelerate the pace of progress in this field, the NIEHS is developing a Consortium Centers Program that will provide a formal mechanism for "cross-talk" between PD clinicians, basic research scientists, and patient advocates. The Consortium will seek to identify and support novel approaches and research ventures that might not otherwise be pursued by scientists working in isolation. The NIEHS will also continue to explore ways to promote more mechanism-based research to understand putative environmental triggers for PD in concert with defined genetic susceptibilities. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 9 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 2002 VL 23 IS 4-5 BP 451 EP 456 AR PII S0161-813X(02)00030-X DI 10.1016/S0161-813X(02)00030-X PG 6 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 610WT UT WOS:000178985400003 PM 12428716 ER PT J AU Sanchez-Pernaute, R Brownell, A Isacson, O AF Sanchez-Pernaute, R Brownell, A Isacson, O TI Functional imaging of the dopamine system: In vivo evaluation of dopamine deficiency and restoration SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 19th International Neurotoxicology Conference CY AUG 25-28, 2001 CL COLORADO SPRINGS, COLORADO DE dopamine; Parkinson's disease; PET ID POSITRON-EMISSION-TOMOGRAPHY; EARLY PARKINSONS-DISEASE; MPTP-INDUCED PARKINSONISM; C-11 WIN 35,428; IN-VIVO; BASAL GANGLIA; PRIMATE MODEL; UP-REGULATION; D2 RECEPTORS; SUBTHALAMIC NUCLEUS AB Dopamine deficiency causes a severe impairment in motorfunction in patients with Parkinson's disease (PD) and in experimental animal models. Recent developments in neuroimaging techniques provide a means to assess in vivo the state of the dopamine system. From a functional perspective, four levels need to be operative and integrated in the system: the dopamine cell (pre-synaptic), the striatal dopamine receptors (post-synaptic), adequate release of dopamine (intra-synaptic), and the cortico-subcortical motor projections. Neuroimaging functional methods can be used to estimate, at these four levels, dopamine cell degeneration, adaptive responses to injury and, importantly, the effect of therapeutic interventions. In this respect, data from functional imaging studies at clinical and pre-clinical stages, support the idea that cell replacement therapy might achieve a more physiological restoration of the dopamine motor system than other therapies (such as ablative surgery, administration of precursor deep brain stimulation) that currently are equally or more effective in relieving motor symptoms. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Harvard Univ, McLean Hosp, Sch Med,Neuroregenerat Lab, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Sch Med,Neuroregenerat Lab, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. FU NINDS NIH HHS [NS-41263, P50 NS39793] NR 84 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 2002 VL 23 IS 4-5 BP 469 EP 478 AR PII S0161-813X(02)00064-5 DI 10.1016/S0161-813X(02)00064-5 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 610WT UT WOS:000178985400006 PM 12428719 ER PT J AU Thiruchelvam, M Richfield, EK Goodman, BM Baggs, RB Cory-Slechta, DA AF Thiruchelvam, M Richfield, EK Goodman, BM Baggs, RB Cory-Slechta, DA TI Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 19th International Neurotoxicology Conference CY AUG 25-28, 2001 CL COLORADO SPRINGS, COLORADO DE Parkinson's disease; development; substantia nigra; pesticides; striatum ID BLOOD-BRAIN-BARRIER; PERFORMANCE LIQUID-CHROMATOGRAPHY; ADULT MICE; MUSCARINIC RECEPTORS; NEONATAL EXPOSURE; PERMANENT CHANGES; DIETHYLDITHIOCARBAMATE INTOXICATION; PRENATAL EXPOSURE; DEFINED PERIOD; RAT-BRAIN AB Idiopathic Parkinson's disease (PD) is associated with advanced age, but it is still unclear whether dopaminergic neuronal death results from events initiated during development, adulthood, or represents a cumulative effect across the span of life. This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. C57BL/6 mice were treated daily with saline, 0.3 mg/kg PQ, I mg/kg MB or PQ + MB from post-natal (PN) days 5 to 19. At 6 weeks, a 20% decrease in activity was evident only in the PQ + MB group, with a further decline (40%) observed at 6 months. A subset of mice were re-challenged as adults with saline, 10 mg/kg PQ, 30 mg/kg MB, or PQ + MB 2 x a week for 3 weeks. Mice exposed developmentally to PQ + MB and re-challenged as adults were the most affected, showing a 70% reduction in motor activity 2 weeks following the last re-challenge dose. Striatal DA levels were reduced by 37% following developmental exposure to PQ + MB only, but following adult re-challenge levels were reduced by 62%. A similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB treated group exhibiting the greatest reduction, with this loss being amplified by adult re-challenge. Developmental exposure to PQ or MB alone produced minimal changes. However following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Div Lab Anim Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, NIEHS, Environm Hlth Sci Ctr, Rochester, NY 14642 USA. RP Cory-Slechta, DA (reprint author), Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. FU NIEHS NIH HHS [ES05017, ES01247, ES05903] NR 65 TC 139 Z9 146 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 2002 VL 23 IS 4-5 BP 621 EP 633 AR PII S0161-813X(02)00092-X DI 10.1016/S0161-813X(02)00092-X PG 13 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 610WT UT WOS:000178985400021 PM 12428734 ER PT J AU Rogozin, IB Makarova, KS Natale, DA Spiridonov, AN Tatusov, RL Wolf, YI Yin, J Koonin, EV AF Rogozin, IB Makarova, KS Natale, DA Spiridonov, AN Tatusov, RL Wolf, YI Yin, J Koonin, EV TI Congruent evolution of different classes of non-coding DNA in prokaryotic genomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; MICROBIAL GENOMES; COG DATABASE; GENE ORDER; OPERONS; SIZE; CONSERVATION; ORGANIZATION; ANNOTATION; MECHANISMS AB Prokaryotic genomes are considered to be 'wall-to-wall' genomes, which consist largely of genes for proteins and structural RNAs, with only a small fraction of the genomic DNA allotted to intergenic regions, which are thought to typically contain regulatory signals. The majority of bacterial and archaeal genomes contain 6-14% non-coding DNA. Significant positive correlations were detected between the fraction of non-coding DNA and inter- and intra-operonic distances, suggesting that different classes of non-coding DNA evolve congruently. In contrast, no correlation was found between any of these characteristics of non-coding sequences and the number of genes or genome size. Thus, the non-coding regions and the gene sets in prokaryotes seem to evolve in different regimes. The evolution of non-coding regions appears to be determined primarily by the selective pressure to minimize the amount of non-functional DNA, while maintaining essential regulatory signals, because of which the content of non-coding DNA in different genomes is relatively uniform and intra- and inter-operonic non-coding regions evolve congruently. In contrast, the gene set is optimized for the particular environmental niche of the given microbe, which results in the lack of correlation between the gene number and the characteristics of non-coding regions. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 42 TC 49 Z9 51 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2002 VL 30 IS 19 BP 4264 EP 4271 DI 10.1093/nar/gkf549 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 603KM UT WOS:000178558500025 PM 12364605 ER PT J AU Yang, SW Astatke, M Potter, J Chatterjee, DK AF Yang, SW Astatke, M Potter, J Chatterjee, DK TI Mutant Thermotoga neapolitana DNA polymerase I: altered catalytic properties for non-templated nucleotide addition and incorporation of correct nucleotides SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; THERMUS-AQUATICUS; KLENOW FRAGMENT; CRYSTAL-STRUCTURE; ACTIVE-SITE; SIDE-CHAINS; O-HELIX; FIDELITY; MUTAGENESIS; RESOLUTION AB Thermotoga neapolitana (Tne) DNA polymerase belongs to the DNA polymerase I (Pol I) family. The O-helix region of these polymerases is involved in dNTP binding and also plays a role in binding primer-template during DNA synthesis. Here we report that mutations in the O-helix region of Tne DNA polymerase (Arg722 to His, Tyr or Lys) almost completely abolished the enzyme's ability to catalyze the template-independent addition of a single base at the 3'-end of newly synthesized DNA in vitro. The mutations did not significantly affect the DNA polymerase catalytic activity and reduced base misinsertions 5- to 50-fold. The same Arg722 mutations dramatically increased the ability of the enzyme's 3'-->5' exonuclease to remove mispaired 3' bases in a primer extension assay. These mutant DNA polymerases can be used to accurately amplify target DNA in vitro for gene cloning and genotyping analysis. C1 Invitrogen Corp, Carlsbad, CA 92008 USA. Genecopoeia Inc, Frederick, MD 21701 USA. RP Chatterjee, DK (reprint author), NCI, SAIC Frederick, Prot Express Lab, Ft Detrick, MD 21702 USA. NR 29 TC 3 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2002 VL 30 IS 19 BP 4314 EP 4320 DI 10.1093/nar/gkf547 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 603KM UT WOS:000178558500031 PM 12364611 ER PT J AU Schisterman, EF Faraggi, D Browne, R Freudenheim, J Dorn, J Muti, P Armstrong, D Reiser, B Trevisan, M AF Schisterman, EF Faraggi, D Browne, R Freudenheim, J Dorn, J Muti, P Armstrong, D Reiser, B Trevisan, M TI Minimal and best linear combination of oxidative stress and antioxidant biomarkers to discriminate cardiovascular disease SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE atherosclerosis; TBARS; discriminant analysis; cardiovascular disease; ROC curve; free radicals ID CORONARY HEART-DISEASE; GENERALIZED ROC CRITERION; HIGH-DENSITY-LIPOPROTEIN; FREE-RADICAL ACTIVITY; SERUM URIC-ACID; MYOCARDIAL-INFARCTION; CLINICAL-CHEMISTRY; QUALITY-CONTROL; VARIANT ANGINA; TUMOR-MARKERS AB Background and Aim: Free radicals have been implicated in the atherosclerotic process of coronary, heart disease (CHD). Well-developed laboratory methods may, make available a large number of biomarkers of individual oxidative stress and antioxidant status. Such markers are able to quantify different phases of the oxidative stress and antioxidant status of an individual. However, limited knowledge is available on how to combine these biomarkers to best discriminate between individuals with and without CHD. Methods and Results: We evaluated combined discrimination properties of six biomarkers of oxidative stress and antioxidant status, as indicators of CHD, in a cross-sectional random sample of 968 white men and women from Buffalo, New York. Individuals with CHD had significantly higher levels of thiobarbuturic acid reacting substances (TBARS) and uric acid, and significantly lower levels of high-density, lipoproteins (HDL) after adjusting forage and gender, when compared to healthy, subjects. There were no significant differences in erythrocyte glutathione (GSH), trolox equivalent antioxidant capacity (TEAC), and glutathione peroxidase (GSHPx) levels. TBARS were found to be the best discriminating of the biomarkers when it was individually evaluated, TBARS discriminate 76.2% (95% C.I. 0.66-6.82) of the CHD cases from healthy controls. When combining TBARS, GSH, TEAC, HDL, uric acid and GSHPx, they discriminate 81.5% (95% C.I.: 0.67-0.90) of the area under the curve. Conclusions: These preliminary findings suggest that the combination of multiple markers of oxidative stress does not greatly improve ability, to differentiate between individuals with and without CHD compared to the use of TBARS alone. C1 SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. SUNY Buffalo, Dept Biotechnol & Clin Lab Sci, Buffalo, NY 14214 USA. Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent, NIH, Bldg 6100,Suite 7B03,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Reiser, Benjamin/G-6591-2012; OI Reiser, Benjamin/0000-0002-9797-9029; Schisterman, Enrique/0000-0003-3757-641X NR 42 TC 18 Z9 18 U1 0 U2 0 PU MEDIKAL PRESS S R L PI MILAN PA VIA LUIGI ZOJA, 30, 20153 MILAN, ITALY SN 0939-4753 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD OCT PY 2002 VL 12 IS 5 BP 259 EP 266 PG 8 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 639DU UT WOS:000180613000002 PM 12616805 ER PT J AU Stefan, N Vozarova, B Funahashi, T Matsuzawa, Y Ravussin, E Weyer, C Tataranni, PA AF Stefan, N Vozarova, B Funahashi, T Matsuzawa, Y Ravussin, E Weyer, C Tataranni, PA TI Plasma adiponectin levels are not associated with fat oxidation in humans SO OBESITY RESEARCH LA English DT Article DE respiratory quotient; adipocytokines; energy expenditure; ethnicity ID ADIPOSE-SPECIFIC PROTEIN; ENERGY-EXPENDITURE; INSULIN-RESISTANCE; OBESITY AB Objective: To test the hypothesis that low adiponectin is associated with low fat oxidation in humans. Research Methods and Procedures: We measured plasma adiponectin concentrations in 75 healthy, nondiabetic Pima Indians (age, 28 +/- 7 years; 55 men and 20 women; body fat, 29.7 +/- 7.5%) and 18 whites [(age, 33 +/- 8 years; 14 men and 4 women; body fat, 28.2 +/- 10.8% (means +/- SD)] whose body composition was measured by DXA and 24-hour energy expenditure (24-hour EE) by a respiratory chamber. Respiratory quotient (an estimate of whole-body carbohydrate/lipid oxidation rate) was calculated over 24 hours (24-hour RQ). Results: Before correlational analyses, waist-to-thigh ratio (WTR) and percentage of body fat (PFAT) were adjusted for age, sex, and race; 24-hour EE was adjusted for fat mass and fat-free mass, and 24-hour RQ were adjusted for energy balance. Plasma adiponectin concentrations were negatively correlated with WTR (r = -0.42, p < 0.0001) and PFAT (r = - 0.46, p < 0.0001). There was no correlation between plasma adiponectin concentrations and 24-hour RQ, (r = 0.09, p = 0.36) before or after adjustment for PFAT (r = 0.001, p = 0.99, respectively, partial correlation), and no correlation was found between plasma adiponectin concentrations and 24-hour EE (r = - 0.12, p = 0.27). Discussion: Our cross-sectional data do not suggest physiological concentrations of fasting plasma adiponectin play a role in the regulation of whole-body fat oxidation or energy expenditure in resting conditions. Whether administration of adiponectin to individuals with low levels of this hormone will increase their fat oxidation rates/energy expenditure remains to be established. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Osaka, Japan. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Stefan, N (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Rm 5-41, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 17 TC 26 Z9 26 U1 0 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD OCT PY 2002 VL 10 IS 10 BP 1016 EP 1020 DI 10.1038/oby.2002.138 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 603FV UT WOS:000178549000007 PM 12376582 ER PT J AU Mbulaiteye, SM Reeves, BC Karabalinde, A Ruberantwari, A Mulwanyi, F Whitworth, JAG Johnson, GJ AF Mbulaiteye, SM Reeves, BC Karabalinde, A Ruberantwari, A Mulwanyi, F Whitworth, JAG Johnson, GJ TI Evaluation of E-optotypes as a screening test and the prevalence and causes of visual loss in a rural population in SW Uganda SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE visual impairment; blindness; E-optotypes; vision screening; Snellen's charts; population-based survey; sub-Saharan Africa; Uganda ID METHODOLOGICAL STANDARDS; DIAGNOSTIC-TEST; BLINDNESS; KENYA AB BACKGROUND Few population-based eye surveys have been conducted in sub-Saharan Africa, limiting the quality of epidemiological information on visual loss from Africa. In the present paper, we describe the prevalence of visual loss in rural Uganda and the screening accuracy of E-optotypes when used by non-medical staff. METHODS Residents of 15 neighbouring villages were screened for visual loss (<6/18 in either eye) using Snellen's E-optotypes. Individuals who failed were initially referred to an ophthalmic clinical officer (OCO), who retested visual acuity and subsequently referred to an ophthalmologist to determine the cause of visual loss. Subjects from two villages (248 individuals) who passed visual acuity screening were re-examined by the OCO to estimate the accuracy of the screening procedure. RESULTS Of the 4076 adults (aged 13 years and over, 69.3% of the censused population) who participated, 191 (4.7%) failed the vision screening criteria and 648 (15.9%) had non-vision impairing conditions. The prevalence of visual loss was at least 3.9%: 0.4% had bilateral blindness, 1.6% had bilateral visual impairment, 0.7% had unilateral blindness and 1.2% unilateral visual impairment. Cataract was the leading cause for all categories of visual loss except bilateral blindness, for which suspected glaucoma was most frequent. Refractive errors were the second leading cause of bilateral and unilateral visual impairment. Based on one subject (0.4%) in the validation sample who was found to have low vision, we estimated the sensitivity and specificity of E-optotypes for detecting visual loss to be 93% and 99%, respectively. CONCLUSIONS Cataract and refractive errors were responsible for most of the visual loss in rural Uganda. Snellen's E-optotypes provide a suitable cost-saving tool for conducting population-based eye surveys in sub-Saharan Africa. C1 Uganda Virus Res Inst, Med Res Council Programme AIDS, Entebbe, Uganda. Masaka Reg Referral Hosp, Eye Dept, Masaka, Uganda. London Sch Hyg & Trop Med, Hlth Serv Res Unit, London WC1, England. UCL, Inst Ophthalmol, Int Ctr Eye Hlth, London, England. RP Mbulaiteye, SM (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Plaza Blvd,Rm 8007,MSC 7248, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov NR 21 TC 12 Z9 12 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0928-6586 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD OCT PY 2002 VL 9 IS 4 BP 251 EP 262 DI 10.1076/opep.9.4.251.1509 PG 12 WC Ophthalmology SC Ophthalmology GA 606FF UT WOS:000178723000003 PM 12187423 ER PT J AU Kazaura, MR Lie, RT AF Kazaura, MR Lie, RT TI Down's syndrome and paternal age in Norway SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID MATERNAL AGE; BIRTH-DEFECTS; RISK; DIAGNOSIS AB There is strong evidence for an effect of maternal age on the risk of Down's syndrome. An effect of paternal age has been suspected, but so far neither confirmed nor completely excluded. Large population-based data that allow detailed adjustment for maternal age are needed for a definitive analysis of the paternal age effect. We used data from the Medical Birth Registry of Norway recorded from 1967 to 1998. A total of 1 738852 children were included in the analysis. A total of 10.3 per 10 000 newborns had Down's syndrome. The data were fitted to logistic regression models with careful control for maternal age, birth calendar year and place of birth. When maternal age was adjusted for using categories of 5-year intervals, residual confounding still resulted in a strong effect of paternal age. However, when the shape of the effect of maternal age was well captured by the model, the estimated effect of paternal age was weak (1.11-fold increased risk per 10 years of paternal age, 95% CI of odds ratio 0.99, 1.22) and not statistically significant. C1 Univ Bergen, Ctr Int Hlth, N-5021 Bergen, Norway. Univ Bergen, Sect Med Stat, N-5021 Bergen, Norway. Univ Bergen, Med Birth Registry Norway, N-5021 Bergen, Norway. NIEHS, Res Triangle Pk, NC 27709 USA. RP Kazaura, MR (reprint author), Univ Bergen, Ctr Int Hlth, Armauer Hansen Bldg, N-5021 Bergen, Norway. NR 28 TC 22 Z9 24 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD OCT PY 2002 VL 16 IS 4 BP 314 EP 319 DI 10.1046/j.1365-3016.2002.00446.x PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 618HX UT WOS:000179413600005 PM 12445147 ER PT J AU Alter, BP AF Alter, BP TI Bone marrow failure syndromes in children SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID SHWACHMAN-DIAMOND-SYNDROME; ENCODING NEUTROPHIL ELASTASE; COLONY-STIMULATING-FACTOR; EXOCRINE PANCREATIC DYSFUNCTION; CARTILAGE-HAIR HYPOPLASIA; ACUTE MYELOID-LEUKEMIA; FANCONI-ANEMIA; DYSKERATOSIS-CONGENITA; BLACKFAN ANEMIA; AMEGAKARYOCYTIC THROMBOCYTOPENIA AB Many forms of bone marrow failure are inherited. The disorders in which pancytopenia is a major complication include Fanconi's Anemia, dyskeratosis congenita, Shwachman-Diamond syndrome (which may begin with neutropenia), amegakaryocytic thrombocytopenia (which begins with thrombocytopenia), and other more rare familial syndromes. The single cytopenias which usually do not evolve to pancytopenia include pure red cell aplasia (Diamond-Blackfan Anemia), pure neutropenia (Severe Congenital Neutropenia), and thrombocytopenia (thrombocytopenia with absent radii). Some of the genes involved in some of these sydromes have been identified. The risk of malignancies, both leukemia and solid tumors, is increased in many of these conditions. C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20854 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7020,Execut Plaza S, Rockville, MD 20854 USA. NR 70 TC 39 Z9 39 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD OCT PY 2002 VL 49 IS 5 BP 973 EP + AR PII S0031-3955(02)00031-7 DI 10.1016/S0031-3955(02)00031-7 PG 17 WC Pediatrics SC Pediatrics GA 610GK UT WOS:000178952200006 PM 12430621 ER PT J AU Obaro, SK Enwere, GC Deloria, M Jaffar, S Goldblatt, D Brainsby, K Hallander, H McInnes, P Greenwood, BM McAdam, KPWJ AF Obaro, SK Enwere, GC Deloria, M Jaffar, S Goldblatt, D Brainsby, K Hallander, H McInnes, P Greenwood, BM McAdam, KPWJ TI Safety and immunogenicity of pneumococcal conjugate vaccine in combination with diphtheria, tetanus toxoid, pertussis and Haemophilus influenzae type b conjugate vaccine SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT 2nd International Symposium on Pneumococci and Pneumococcal Diseases CY MAR 19-23, 2000 CL SUN CITY, SOUTH AFRICA DE pneumococcal conjugate vaccine; TETRAMUNE; safety; immunogenicity; African infant ID GAMBIAN INFANTS; SERUM AB Background. Pneumococcal polysaccharide/protein conjugate vaccines (PnCV) are immunogenic and effective in infancy. However, an addition to the nine currently recommended vaccine injections during the first year of life of African children may be a deterrent to participation in a PnCV program. Thus we have evaluated the safety and immunogenicity of a 9-valent PnCV (Wyeth Lederle Pediatrics and Vaccines) mixed with diphtheria, tetanus toxoid, cell pertussis and Haemophilus influenzae type b (TETRAMUNE). Methods. Healthy Gambian infants were randomized at the age of 2 months to receive three doses 1 month apart of either (1) placebo reconstituted in TETRAMUNE in the right thigh (control) or (2) PnCV in the left thigh and TETRAMUNE in the right thigh (separate) or (3) PnCV reconstituted in TETRAMUNE as a single injection in the right thigh (combined). The vaccines were given together with routine Expanded Program on Immunization vaccines. Adverse reactions were recorded after vaccination, and antibody concentrations were measured by enzyme-linked immunosorbent assays. Results. Local induration and tenderness were observed more commonly at the site of injection of TETRAMUNE than at the site of injection with PnCV after each dose of vaccination. Swelling at the site of injection was encountered more frequently at the site of administration of TETRAMUNE than at the site of administration PnCV (P < 0.00001 for Doses 1 and 2 and P < 0.0009 for Dose 3). Swelling at the site of administration of TETRAMUNE mixed with PnCV was comparable with that observed for TETRAMUNE alone. Although most mothers reported that the babies "felt hot" 24 h after each injection, febrile reactions (temperature, greater than or equal to38degreesC) were infrequent and resolved with antipyretics. Geometric mean titer for anti-polyribosylribitol phosphate antibody was 11.6 mug/ml [95% confidence limits (95% CI), 9.2, 14.6] in the control group and comparable with 13.3 mug/ml (95% CI 11.0, 16.0) in the combined group and significantly higher at 17.9 mug/ml (95% CI 14.7, 21.9; P = 0.01) in the separate group. Geometric mean concentrations of serotype-specific pneumococcal antibodies were higher in the combined group than the separate group for all nine serotypes. Antibody responses to diphtheria and pertussis antigens were similar in all groups. Anti-tetanus toxoid antibody concentrations were lowest in the combined group (6.66 IU/ml, 95% CI 5.77, 7.68 in the control group; 5.15 IU/ml, 95% CI 4.39, 6.03 in the combined group; P = 0.02). However, all vaccinees achieved protective antibody values. Conclusion. The combination of TETRAMUNE and PnCV is safe and immunogenic. C1 Univ London Imperial Coll Sci Technol & Med, Sch Med, London, England. London Sch Hyg & Trop Med, London WC1, England. Inst Child Hlth, London, England. MRC Labs, Fajara, Gambia. NIH, Bethesda, MD 20892 USA. Swedish Inst Infect Dis Control, Stockholm, Sweden. RP Obaro, SK (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Med, London, England. RI Goldblatt, David/C-5972-2008 OI Goldblatt, David/0000-0002-0769-5242 NR 15 TC 23 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2002 VL 21 IS 10 BP 940 EP 946 DI 10.1097/01.inf.0000034245.88174.3c PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 605AY UT WOS:000178654300010 PM 12394817 ER PT J AU Ron, E AF Ron, E TI Let's not relive the past: a review of cancer risk after diagnostic or therapeutic irradiation SO PEDIATRIC RADIOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; CANADIAN FLUOROSCOPY COHORT; RATE IONIZING-RADIATION; 2 SWEDISH COHORTS; THYROID-CANCER; X-RAY; CHILDHOOD-CANCER; SKIN HEMANGIOMA; POOLED ANALYSIS; TUBERCULOSIS PATIENTS C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ron, E (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, MS 7238,Rm 7048,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 43 TC 19 Z9 19 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD OCT PY 2002 VL 32 IS 10 BP 739 EP 744 DI 10.1007/s00247-002-0803-7 PG 6 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 608JV UT WOS:000178843500011 PM 12244466 ER PT J AU Poznanski, A Ron, E Eggli, K Frush, D Slovis, T Jacobson, J Huda, W Culham, G Post, A Hall, E Lee AF Poznanski, A Ron, E Eggli, K Frush, D Slovis, T Jacobson, J Huda, W Culham, G Post, A Hall, E Lee TI SPR Seminar in Radiation Dose Reduction 2002 - Panel discussion SO PEDIATRIC RADIOLOGY LA English DT Editorial Material C1 Childrens Mem Hosp, Chicago, IL 60614 USA. NCI, NIH, Rockville, MD USA. Penn State Hershey Med Ctr, Hershey, PA USA. Duke Univ, Durham, NC USA. British Columbia Childrens Hosp, Vancouver, BC, Canada. Columbia Univ, Ctr Radiol Res, New York, NY 10032 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Poznanski, A (reprint author), Childrens Mem Hosp, Chicago, IL 60614 USA. NR 0 TC 19 Z9 19 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD OCT PY 2002 VL 32 IS 10 BP 751 EP 754 DI 10.1007/s00247-002-0805-5 PG 4 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 608JV UT WOS:000178843500013 ER PT J AU Blood-Siegfried, J Nyska, A Lieder, H Joe, M Vega, L Patterson, R Germolec, D AF Blood-Siegfried, J Nyska, A Lieder, H Joe, M Vega, L Patterson, R Germolec, D TI Synergistic effect of influenza A virus on endotoxin-induced mortality in rat pups: A potential model for sudden infant death syndrome SO PEDIATRIC RESEARCH LA English DT Article ID UPPER RESPIRATORY-TRACT; NITRIC-OXIDE SYNTHASE; A VIRUS; CEREBROSPINAL-FLUID; BACTERIAL TOXINS; LETHAL SYNERGY; IMMUNE-SYSTEM; SYNDROME SIDS; CELL-DEATH; INFECTION AB Sudden infant death syndrome is the most common cause of postneonatal infant mortality in the developed world. It is a diagnosis of exclusion with peak age of incidence between 2 and 6 mo. Fifty to 63% of these infants have a preexisting upper respiratory tract infection before death. We hypothesized that the immature immune system may be altered by a primary infection, preventing a protective response after secondary challenge. To mimic dual infection, we used a nonlethal strain of a rat-adapted influenza A virus and a sublethal dose of endotoxin to establish a model that results in pathology and death in 12-d-old rat pups similar to that seen in infants dying of sudden infant death syndrome. Mortality only occurred when specific criteria such as timing between infectious insults and developmental age of the pup were met. Results suggest that mortality is caused by a rapid systemic shock event rather than lung-specific damage. Gross pathologic findings such as lung petechiae and liquid blood around the heart on necropsy were consistent with those seen in infants dying of sudden infant death syndrome. Histopathologic lesions including subendocardial hemorrhage and mild cortical thymocyte necrosis were found with greater severity and frequency in dually challenged animals. Macrophage subpopulation in rat-adapted influenza A virus-inoculated animals was significantly elevated in the spleen at the time of death. Our model suggests that the developing immune system can be primed to respond in an exaggerated way to a second immune challenge resulting in unexpected death. C1 Duke Univ, Sch Nursing, Durham, NC 27710 USA. NIEHS, Environm Immunol Lab, Res Triangle Pk, NC 27709 USA. CINVESTAV, Secc Externa Toxicol, Mexico City 07360, DF, Mexico. RP Blood-Siegfried, J (reprint author), Duke Univ, Sch Nursing, Box 3322, Durham, NC 27710 USA. RI Vega, Libia/C-3391-2013; OI Vega, Libia/0000-0002-4993-5267; Blood-Siegfried, Jane/0000-0003-1926-9758 NR 49 TC 20 Z9 20 U1 0 U2 4 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2002 VL 52 IS 4 BP 481 EP 490 DI 10.1203/01.PDR.0000028250.96650.D7 PG 10 WC Pediatrics SC Pediatrics GA 598TA UT WOS:000178291500005 PM 12357040 ER PT J AU Ward, LP Hill, JM McCune, SK AF Ward, LP Hill, JM McCune, SK TI Alpha-2A adrenergic receptor subtype gene expression in the intestines of cocaine-exposed rat embryos SO PEDIATRIC RESEARCH LA English DT Article ID NECROTIZING ENTEROCOLITIS; MESSENGER-RNAS; PERFORATION; ABUSE; ALPHA(2)-ADRENOCEPTORS; COMPLICATION; TRANSPORT; INFANTS; BOWEL AB Cocaine has become a popular illicit drug in our society, and pregnant women are not immune from this epidemic. Recently, there have been several references in the literature describing an association between prenatal cocaine exposure and the subsequent development of necrotizing enterocolitis in the neonate, but the mechanism underlying this relationship remains speculative. Because alpha-2 adrenergic receptors are thought to play a role in the autoregulatory mechanism in the newborn intestine that responds to hypoxia and ischemia, we examined the expression of this receptor in the intestine of embryonic rats exposed to low- and high-dose cocaine in utero. Pregnant Sprague Dawley rats were injected daily with either saline, low-dose cocaine, or high-dose cocaine beginning on embryonic d 5 (E 5) and continuing to E 20. Mothers were killed on E 16, E 17, E 18, E 19, and E 20. Embryos were frozen and stored at -80degreesC. In situ hybridization was performed on 20-mum sections with S-35-labeled oligonucleotide probes specific for the alpha-2A adrenergic receptor subtype. Densitometric analysis revealed a significant decrease in the alpha-2A receptor expression in the intestine of both the low-dose and hi h-dose cocaine-exposed animals compared with controls. This down-regulation was demonstrated by E 17, and continued through the remainder of gestation. These changes may limit the normal adaptation to vasoconstriction, thus exacerbating the already insufficient compensatory mechanisms for responding to ischemic injury, and thus may be one of the important factors predisposing cocaine-exposed infants to necrotizing enterocolitis. C1 Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Ward, LP (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Neonatol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. NR 27 TC 3 Z9 3 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2002 VL 52 IS 4 BP 504 EP 508 DI 10.1203/01.PDR.0000030883.20888.E6 PG 5 WC Pediatrics SC Pediatrics GA 598TA UT WOS:000178291500008 PM 12357043 ER PT J AU Bonat, S Pathomvanich, A Keil, MF Field, AE Yanovski, JA AF Bonat, S Pathomvanich, A Keil, MF Field, AE Yanovski, JA TI Self-assessment of pubertal stage in overweight children SO PEDIATRICS LA English DT Article DE lipomastia; Tanner stage; maturation; child; development; puberty ID BODY-MASS INDEX; GIRLS; ADOLESCENTS; PERCENTILES; MATURATION; AGE AB Objective. For those with normal body habitus, self-assessments have been reported to yield Tanner stage ratings similar to those found by actual examinations. Little is known about whether such self-assessments are accurate in obese children. We therefore determined the reliability of Tanner stage self-assessments in both nonobese and obese children. Methods. We studied 244 children age 6 to 12 years, 135 girls and 109 boys, 41% of whom were obese (body mass index greater than or equal to95th percentile for age and gender). Girls rated both breast and pubic hair development and boys rated pubic hair development using a standardized series of drawings accompanied by explanatory text. After self-ratings were completed, a pediatric endocrinologist or trained nurse practitioner who was blinded to subjects' self-ratings examined each subject. Results. Self-ratings of breast Tanner stage were concordant with actual stage in 48%, overestimated in 25%, and underestimated in 27% of nonobese girls. By contrast, breast Tanner stage was overestimated by 38% of obese girls and was underestimated by only 12%. On average, obese girls overestimated actual Tanner breast stage by 0.47 +/- 0.9 stages. Pubic hair ratings were largely concordant with actual pubic hair stage in both obese and nonobese girls. Both nonobese and obese boys significantly overestimated actual Tanner pubic hair stage, by 0.51 +/- 1.1 stages and 0.31 +/- 0.8 stages, respectively. Conclusions. We conclude that, in children 6 to 12 years of age, self-assessment cannot be used to determine reliably the breast Tanner stage of obese girls or the pubic hair stage of boys. C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bonat, S (reprint author), NICHD, Unit Growth & Obes, DEB, NIH, 10 Ctr Dr,MSC 1862,Bldg 10,Rm 10N262, Bethesda, MD 20892 USA. FU NICHD NIH HHS [Z-01-HD-04-00641] NR 17 TC 71 Z9 75 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2002 VL 110 IS 4 BP 743 EP 747 DI 10.1542/peds.110.4.743 PG 5 WC Pediatrics SC Pediatrics GA 599JF UT WOS:000178330200023 PM 12359788 ER PT J AU Wu, TJ Mendola, P Buck, GM AF Wu, TJ Mendola, P Buck, GM TI Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: The Third National Health and Nutrition Examination Survey, 1988-1994 SO PEDIATRICS LA English DT Article DE menarche; puberty; race; secondary sex characteristics ID PUBERTAL DEVELOPMENT; AGE; CHILDREN; GROWTH AB Objective. To assess measures of puberty-presence of pubic hair, breast development, and menarche- for 3 racial/ethnic groups of girls in the United States. Methods. Using data from the Third National Health and Nutrition Examination Survey, this study sample was restricted to 1623 girls aged 8 to 16 years (466 non-Hispanic white, 589 non-Hispanic black, and 568 Mexican American) for whom information was available on Tanner stages of pubic hair and breast development. Subsequently, the sample was restricted to 1168 girls aged 10 to 16 years (330 non-Hispanic white, 419 non-Hispanic black, and 419 Mexican American) for whom menarche data were available. Tanner stage II or higher was used to define pubic hair and breast development; menarche status was self-reported. The percentage of girls who had pubic hair and breast development and had achieved menarche was computed by age and race/ethnicity. Probit and failure time models were applied to estimate mean ages at onset of pubic hair, breast development, and menarche. The racial/ethnic differences also were examined after adjustment for social and economic variables and current body mass index. Results. Black and Mexican American girls had pubic hair and breast development and had achieved menarche at younger ages than white girls. For example, 49.4% of black girls aged 9 years had breast development compared with 24.5% of Mexican American girls and 15.8% of white girls. The mean age at onset of pubic hair, breast development, and menarche was 9.5, 9.5, and 12.1 year for black girls; 10.3, 9.8, and 12.2 years for Mexican American girls; and 10.5, 10.3, and 12.7 years for white girls. These ethnic differences remained even after adjustment for current body mass index and several social and economic variables. Conclusion. Black girls on average enter puberty first, followed by Mexican American and then white girls. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Buck, GM (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. OI Mendola, Pauline/0000-0001-5330-2844; Buck Louis, Germaine/0000-0002-1774-4490 NR 28 TC 170 Z9 174 U1 1 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2002 VL 110 IS 4 BP 752 EP 757 DI 10.1542/peds.110.4.752 PG 6 WC Pediatrics SC Pediatrics GA 599JF UT WOS:000178330200025 PM 12359790 ER PT J AU Hauck, FR Moore, CM Herman, SM Donovan, M Kalelkar, M Christoffel, KK Hoffman, HJ Rowley, D AF Hauck, FR Moore, CM Herman, SM Donovan, M Kalelkar, M Christoffel, KK Hoffman, HJ Rowley, D TI The contribution of prone sleeping position to the racial disparity in sudden infant death syndrome: The Chicago Infant Mortality Study SO PEDIATRICS LA English DT Article DE sudden infant death; infant care; African Americans; sleep ID RISK-FACTORS; AFRICAN-AMERICANS; UNITED-STATES; CLINICAL RESEARCH; NEW-ZEALAND; COT DEATH; SIDS; PREVENTION; PARTICIPATION; EPIDEMIOLOGY AB Background. Rates of sudden infant death syndrome (SIDS) are over twice as high among African Americans compared with Caucasians. Little is known, however, about the relationship between prone sleeping, other sleep environment factors, and the risk of SIDS in the United States and how differences in risk factors may account for disparities in mortality. Objective. To assess the contribution of prone sleeping position and other potential risk factors to SIDS risk in a primarily high-risk, urban African American population. Design, Setting, and Population. Case-control study consisting of 260 infants ages birth to 1 year who died of SIDS between November 1993 and April 1996. The control group consists of an equal number of infants matched on race, age, and birth weight. Prospectively collected data from the death scene investigation and a follow-up home interview for case infants were compared with equivalent questions for living control participants to identify risk factors for SIDS. Main Outcome Measures. Risk of SIDS related to prone sleeping position adjusting for potential confounding variables and other risk factors for SIDS, and comparisons by race-ethnicity. Results. Three quarters of the SIDS infants were African American. There was more than a twofold increased risk of SIDS associated with being placed prone for last sleep compared with the nonprone positions (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.6-3.7). This OR increased after adjusting for potential confounding variables and other sleep environment factors (OR: 4.0; 95% CI: 1.8-8.8). Differences were found for African Americans compared with others (OR: 1.8; 95% CI: 1.2-2.6 and OR: 10.3, 95% CI: 10.3 [3.2-33.8, respectively]). The population attributable risk was 31%. Fewer case mothers (46%) than control mothers (64%) reported being advised about sleep position in the hospital after delivery. Of those advised, a similar proportion of case mothers as control mothers were incorrectly told or recalled being told to use the prone position, but prone was recommended in a higher proportion of black mothers (cases and controls combined) compared with nonblack mothers. Conclusions. Prone sleeping was found to be a significant risk factor for SIDS in this primarily African American urban sample, and approximately one third of the SIDS deaths could be attributed to this factor. Greater and more effective educational outreach must be extended to African American families and the health personnel serving them to reduce prone prevalence during sleep, which appears, in part, to contribute to the higher rates of SIDS among African American infants. C1 Loyola Univ, Chicago Stritch Sch Med, Dept Family Med, Maywood, IL 60153 USA. Off Med Examiner Cook Cty, Chicago, IL USA. NW Univ, Sch Med, Childrens Mem Hosp, Chicago, IL USA. NW Univ, Sch Med, Dept Pediat, Chicago, IL USA. NW Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. Natl Inst Deafness & Other Commun Disorders, Epidemiol Stat & Data Syst Branch, Bethesda, MD USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. RP Hauck, FR (reprint author), Univ Virginia, Hlth Syst, Dept Family Med, Box 800729, Charlottesville, VA 22908 USA. FU NICHD NIH HHS [N01-HD-3-3188]; ODCDC CDC HHS [U50/CCU300860-06] NR 73 TC 68 Z9 70 U1 1 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2002 VL 110 IS 4 BP 772 EP 780 DI 10.1542/peds.110.4.772 PG 9 WC Pediatrics SC Pediatrics GA 599JF UT WOS:000178330200029 PM 12359794 ER PT J AU Liu, XC Dietrich, KN Radcliffe, J Ragan, NB Rhoads, GG Rogan, WJ AF Liu, XC Dietrich, KN Radcliffe, J Ragan, NB Rhoads, GG Rogan, WJ TI Do children with falling blood lead levels have improved cognition? SO PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 14, 2001 CL TORONTO, CANADA SP Soc Epidemiol Res DE child, preschool; environmental exposure; lead poisoning/blood/etiology; cognition/physiology; chelation therapy ID INTELLIGENCE; CHELATION; SUCCIMER AB Objective. Exposure to lead at levels encountered by urban children impairs cognitive development. An observational study suggested improvement in IQ when blood lead level fell, but the only randomized trial of chelation showed no benefit in IQ. Methods. We did a new analysis of the data from the clinical trial using change in blood lead level as the independent variable. The 741 children began with blood lead levels between 20 and 44 mug/dL, and were 13 to 33 months old at randomization to chelation or placebo. Blood lead levels were measured repeatedly, and cognitive tests were given at baseline, 6 months, and 36 months follow-up. Results. By 6 months after randomization, blood lead levels had fallen by similar amounts in both chelated and placebo children, despite the immediate drops in the chelated group; there was no association between change in blood lead level and change in cognitive test score. Blood lead levels continued to fall. At 36 months follow-up, in the placebo group only, cognitive test scores had increased 4.0 points per 10 mug/dL fall in blood lead level from baseline to 36 months follow-up and 5.1 points from 6 to 36 months. Conclusions. The improvement in scores in the placebo group only implies that factors other than declining blood lead levels per se are responsible for cognitive improvement; it is possible but less likely that succimer, the active drug, impairs cognition. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Dept Psychol, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, Mail Drop A3-05,Box 12233, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 12 TC 27 Z9 29 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2002 VL 110 IS 4 BP 787 EP 791 DI 10.1542/peds.110.4.787 PG 5 WC Pediatrics SC Pediatrics GA 599JF UT WOS:000178330200031 PM 12359796 ER PT J AU Gorman, R Bates, BA Benitz, WE Burchfield, DJ Ring, JC Walls, RP Walson, PD Alexander, J Bennett, DR Hagino, OR Matsui, D Riley, LE Giacoia, GP Cote, CJ Koteras, RJ AF Gorman, R Bates, BA Benitz, WE Burchfield, DJ Ring, JC Walls, RP Walson, PD Alexander, J Bennett, DR Hagino, OR Matsui, D Riley, LE Giacoia, GP Cote, CJ Koteras, RJ CA Amer Acad Pediat TI Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum SO PEDIATRICS LA English DT Article ID NON-ANESTHESIOLOGISTS; ADVERSE SEDATION; ANALGESIA; EVENTS AB The purpose of this addendum to the 1992 policy statement is to clarify some of the terms used in that document and to more thoroughly delineate the responsibilities of the practitioner when sedating children. C1 Amer Acad Pediat, Comm Drugs, Elk Grove Village, IL 60007 USA. Amer Med Assoc, Chicago, IL 60610 USA. Amer Acad Child & Adolescent Psychiat, Washington, DC 20016 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20090 USA. NIH, Bethesda, MD 20892 USA. RP Gorman, R (reprint author), Amer Acad Pediat, Comm Drugs, Elk Grove Village, IL 60007 USA. NR 9 TC 129 Z9 132 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD OCT PY 2002 VL 110 IS 4 BP 836 EP 838 PG 3 WC Pediatrics SC Pediatrics GA 599JF UT WOS:000178330200040 ER PT J AU Hill, JM Mehnert, J McCune, SK Brenneman, DE AF Hill, JM Mehnert, J McCune, SK Brenneman, DE TI Vasoactive intestinal peptide regulation of nerve growth factor in the embryonic mouse SO PEPTIDES LA English DT Article DE neural tube; nerve growth factor; vasoactive intestinal peptide; pituitary adenylate cyclase activating peptide; embryogenesis; neuroepithelium ID DEPENDENT NEUROTROPHIC FACTOR; NEURONAL DEATH; BINDING-SITES; CELL-LINE; EXPRESSION; ASTROCYTES; SURVIVAL; PROTEIN; BRAIN; NGF AB Vasoactive intestinal peptide (VIP), a regulator of embryonic growth, increased the concentration of nerve growth factor (NGF)-like immunoreactivity in the conditioned medium of cultured explanted embryonic day (E) 9.5 neural tube preparations compared to control preparations. VIP treatment also induced an increase of NGF-like immunoreactivity (NGF-IR) within the neural tube preparation tissue. A 60 kDa isoform was the primary form of NGF detected. VIP is shown to be a regulator of NGF in the E9.5 embryonic mouse and stimulates the release of a high molecular weight isoform of NGF. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NICHHD, NIH, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. RP Hill, JM (reprint author), NICHHD, NIH, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, Bldg 49,Room 5A38,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 43 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD OCT PY 2002 VL 23 IS 10 BP 1803 EP 1808 AR PII S0196-9781(02)00137-7 DI 10.1016/S0196-9781(02)00137-7 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 611KN UT WOS:000179016400012 PM 12383868 ER PT J AU Furuno, T Landi, MT Ceroni, M Caporaso, N Bernucci, I Nappi, G Martignoni, E Schaeffeler, E Eichelbaum, M Schwab, M Zanger, UM AF Furuno, T Landi, MT Ceroni, M Caporaso, N Bernucci, I Nappi, G Martignoni, E Schaeffeler, E Eichelbaum, M Schwab, M Zanger, UM TI Expression polymorphism of the blood-brain barrier component P-glycoprotein (MDR1) in relation to Parkinson's disease SO PHARMACOGENETICS LA English DT Article DE ABC-transporters; genetic polymorphism; morbus parkinson; multi-drug resistance gene; P-glycoprotein; pharmacogenetics ID MULTIDRUG-RESISTANCE GENE; C3435T MUTATION; FREQUENCY; CELLS; METAANALYSIS; SENSITIVITY; ABSORPTION; DIAGNOSIS; EXPOSURE; PRODUCT AB Because drug transporters such as P-glycoprotein, the product of the multidrug resistance (MDR1) gene, contribute to the function of the blood-brain barrier, we hypothesized that differences in their expression could affect the uptake of neurotoxic xenobiotics, thereby modulating interindividual susceptibility for neurological disorders such as Parkinson's disease. In a pilot case-control study comprising 95 Parkinson's disease patients (25 early-onset patients with onset age less than or equal to 45 years) and 106 controls we analysed the three common MDR1 polymorphisms, 3435C>T in exon 26, 2677G>T,A in exon 21, and -129T>C in exon 1b. There were no statistically significant associations between any of these polymorphisms and Parkinson's disease. However, a distribution pattern consistent with our hypothesis was observed in that the frequency of the 3435T/T genotype, which had previously been associated with decreased P-glycoprotein expression and function, was highest in the early-onset Parkinson's disease group (36.0%), second-highest in the late-onset Parkinson's disease group (22.9%), and lowest in the control group (18.9%). Furthermore, we confirmed that the MDR1 exon 21 and exon 26 polymorphisms are in significant linkage disequilibrium since the [2677G, 3435C] and [2677T, 3435T] haplotypes were far more frequently observed than expected. In conclusion, MDR1 and other drug transporters represent plausible candidates as Parkinson's disease risk genes. Larger studies are required to confirm this role in the etiology of Parkinson's disease. C1 Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. NCI, NIH, Bethesda, MD 20892 USA. Univ Pavia, Ist Neurol IRCCS Mondino, I-27100 Pavia, Italy. Univ Piemonte Orientale, Novara, Italy. RP Zanger, UM (reprint author), Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, D-70376 Stuttgart, Germany. RI ceroni, mauro/G-7080-2011 OI ceroni, mauro/0000-0002-8947-5007 NR 34 TC 138 Z9 146 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD OCT PY 2002 VL 12 IS 7 BP 529 EP 534 DI 10.1097/00008571-200210000-00004 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 604RY UT WOS:000178635900004 PM 12360103 ER PT J AU Ando, Y Price, DK Dahut, WL Cox, MC Reed, E Figg, WD AF Ando, Y Price, DK Dahut, WL Cox, MC Reed, E Figg, WD TI Pharmacogenetics of thalidomide: drug response, in vivo metabolism and genetic polymorphism of CYP2C19. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 20-23, 2002 CL ALBUQUERQUE, NEW MEXICO SP Amer Coll Clin Pharmacy C1 NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2002 VL 22 IS 10 MA 243 BP 1362 EP 1362 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 601GN UT WOS:000178438300195 ER PT J AU Yoshida, N Arie, T Akita, S Nakayama, Y AF Yoshida, N Arie, T Akita, S Nakayama, Y TI Improvement of MFM tips using Fe-alloy-capped carbon nanotubes SO PHYSICA B-CONDENSED MATTER LA English DT Article; Proceedings Paper CT Tsukuba Symposium on Carbon Nanotube in Commemoration of the 10th Anniversary of its Discovery CY OCT 03-05, 2001 CL TSUKUBA, JAPAN DE Fe-capped carbon nanotubes; MFM; dipole moment; monopole moment AB The magnetic properties of Fe-alloy-capped carbon nanotube synthesized by chemical vapor deposition have been demonstrated in magnetic force microscopy (MFM) using a metal current ring, which produces well-defined magnetic field. The dipole and monopole moments of the Fe-capped carbon nanotube are measured to be 1.9 x 10(-12) emu and 2.6 x 10(-8) emu/cm, respectively. These values are 2 times and 4 times lager than those of the Ni-capped carbon nanotube, respectively. The result suggests that the Fe-capped carbon nanotubes are more suitable for MFM tips. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Osaka Prefecture, Dept Phys & Elect, Osaka 5998531, Japan. NIH, Bethesda, MD 20892 USA. RP Nakayama, Y (reprint author), Univ Osaka Prefecture, Dept Phys & Elect, Sakai 1-1 Gakuen Cho, Osaka 5998531, Japan. RI akita, seiji/G-4679-2012 OI akita, seiji/0000-0002-2116-4034 NR 4 TC 12 Z9 15 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-4526 J9 PHYSICA B JI Physica B PD OCT PY 2002 VL 323 IS 1-4 BP 149 EP 150 AR PII S0921-4526(02)00883-9 DI 10.1016/S0921-4526(02)00883-9 PG 2 WC Physics, Condensed Matter SC Physics GA 616RT UT WOS:000179317300031 ER PT J AU Chen, SN Fabricant, DS Lu, ZZ Zhang, HJ Fong, HHS Farnsworth, NR AF Chen, SN Fabricant, DS Lu, ZZ Zhang, HJ Fong, HHS Farnsworth, NR TI Cimiracemates A-D, phenylpropanoid esters from the rhizomes of Cimicifuga racemosa SO PHYTOCHEMISTRY LA English DT Article DE Cimicifuga racemosa; Ranunculaceae; black cohosh; chemical components; phenylpropanoid esters; cimiracemates A-D ID BLACK COHOSH; EFFICACY; SAFETY AB Four phenylpropanoid esters, cimiracemates A-D (1-4), along with three known compounds, isoferulic acid, ferulic acid and methyl caffeate were isolated from the EtOAc fraction of the rhizome of Cimicifuga racemosa. The structures of the esters were elucidated by means of spectral data, including 2D NMR spectroscopy. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Illinois, PCRPS, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP Fong, HHS (reprint author), Univ Illinois, PCRPS, M-C 877,833 S Wood St, Chicago, IL 60612 USA. EM hfong@uic.edu RI ZHANG, HONGJIE/N-4186-2013 OI ZHANG, HONGJIE/0000-0002-7175-5166 FU NCCIH NIH HHS [P50 AT00155] NR 20 TC 32 Z9 32 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9422 J9 PHYTOCHEMISTRY JI Phytochemistry PD OCT PY 2002 VL 61 IS 4 BP 409 EP 413 AR PII S0031-9422(02)00209-1 DI 10.1016/S0031-9422(02)00209-1 PG 5 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 613CQ UT WOS:000179114500011 PM 12377235 ER PT J AU Gooding, HC Boehm, K Thompson, RE Hadley, D Francomano, CA Biesecker, BB AF Gooding, HC Boehm, K Thompson, RE Hadley, D Francomano, CA Biesecker, BB TI Issues surrounding prenatal genetic testing for achondroplasia SO PRENATAL DIAGNOSIS LA English DT Article DE achondroplasia; prenatal genetic testing; reproductive decisions; illness perception ID GROWTH-FACTOR RECEPTOR-3; TRANSMEMBRANE DOMAIN; MUTATIONS; DIAGNOSIS; FGFR3 AB Objectives Mutations in the gene encoding fibroblast growth factor receptor 3 cause achondroplasia, the most prevalent form of dwarfism. Since the discovery of the mutations and gene in 1994, commercial testing has been available for use in prenatal diagnosis. This study sought to determine the awareness of, interest in and use of prenatal genetic testing for achondroplasia. Methods Surveys were collected from both individuals affected with achondroplasia (n = 189) and their average statured relatives (n = 136). Results The majority of participants were aware of the prenatal genetic testing at the tune they were surveyed, but less than 10% had actually used the testing. Affected individuals were much more interested in using the testing if they became pregnant (62%) than were their relatives (28%). The groups were remarkably similar in their interest in using the testing to identify the lethal, homozygous form of achondroplasia and in their unwillingness to consider termination of pregnancies based on a diagnosis of either achondroplasia or average stature. Affected status and perception of the condition were correlated with the importance placed on knowing the prenatal diagnoses of achondroplasia and average stature. Views on abortion were highly correlated with all aspects of interest in prenatal diagnosis for achondroplasia. Conclusion These results elucidate the role of selected attitudes and beliefs that contribute to reproductive decision making about achondroplasia. Furthermore, the findings provide insights into education and counseling issues for families and health care practitioners. Copyright (C) 2002 John Wiley Sons, Ltd. C1 NHGRI, NIH, Med Genet Branch, Bethesda, MD 20824 USA. Natl Inst Dent & Craniofacial Res, NIH, Off Commun & Hlth Educ, Bethesda, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. NIA, NIH, Human Genet & Integrat Med Sect, Baltimore, MD 21224 USA. RP Biesecker, BB (reprint author), NHGRI, NIH, Med Genet Branch, 10 Ctr Dr,Bldg 10,Room 3C710, Bethesda, MD 20824 USA. NR 21 TC 14 Z9 15 U1 0 U2 9 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD OCT PY 2002 VL 22 IS 10 BP 933 EP 940 DI 10.1002/pd.437 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 604NN UT WOS:000178627900019 PM 12378581 ER PT J AU Siahpush, M Singh, GK AF Siahpush, M Singh, GK TI Sociodemographic predictors of pap test receipt, currency and knowledge among Australian women SO PREVENTIVE MEDICINE LA English DT Article DE cervical cancer screening; sociodemographic; ethnicity; Australia ID CANCER SCREENING PRACTICES; VIETNAMESE-AMERICAN WOMEN; CERVICAL-CANCER; WESTERN-AUSTRALIA; SMEAR; BREAST; HEALTH; ACCURACY AB Background. Knowledge of sociodemographic variations in cervical cancer screening can help identify population groups at risk of underutilization of cervical cancer procedures and practices. The aim of this research was to examine sociodemographic predictors of receipt, currency being up-to-date for), and knowledge of Pap test. Methods. We used data from the 1995 National Health Survey. A subsample of women was given self-administered questionnaires that included questions about the Pap test. The sample size was 7,572. Using multiple logistic regression, we examined the association of age, marital status, region of residence, country of birth, Index of Relative Socioeconomic Disadvantage (IRSD), and education with Pap test receipt, currency,and knowledge. Results. Women under 30 and over 49 years of age, those not presently married, those with lower levels of education, and those born in the Middle East or Asia (compared with the Australian/New Zealand-born women) were at a greater risk of not receiving and having no knowledge of Pap test. Conclusions. The results of this study suggest that, as part of a comprehensive cancer screening strategy, women who are unlikely to obtain a Pap smear might benefit from targeted interventions to improve adherence to cervical cancer screening programs. (C) 2002 American Health Foundation and Elsevier Science (USA). C1 Canc Council Victoria, Canc Control Res Inst, VicHlth Ctr Tobacco Control, Carlton 3053, Australia. NCI, NIH, Bethesda, MD 20892 USA. RP Siahpush, M (reprint author), Canc Council Victoria, Canc Control Res Inst, VicHlth Ctr Tobacco Control, 1 Rathdowne St, Carlton 3053, Australia. NR 45 TC 30 Z9 31 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD OCT PY 2002 VL 35 IS 4 BP 362 EP 368 DI 10.1006/pmed.2002.1086 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 596VZ UT WOS:000178188300009 PM 12453713 ER PT J AU Stewart, SA Hahn, WC O'Connor, BF Banner, EN Lundberg, AS Modha, P Mizuno, H Brooks, MW Fleming, M Zimonjic, DB Popescu, NC Weinberg, RA AF Stewart, SA Hahn, WC O'Connor, BF Banner, EN Lundberg, AS Modha, P Mizuno, H Brooks, MW Fleming, M Zimonjic, DB Popescu, NC Weinberg, RA TI Telomerase contributes to turnorigenesis by a telomere length-independent mechanism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMORTAL HUMAN-CELLS; HUMAN TUMOR-CELLS; CATALYTIC SUBUNIT; LIFE-SPAN; CANCER-CELLS; MAINTENANCE; RECOMBINATION; APOPTOSIS; PATHWAY; RECONSTITUTION AB Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase. We have examined whether ALT could substitute for telomerase in the processes of transformation in vitro and tumorigenesis in vivo. Expression of oncogenic H-Ras in the immortal ALT cell line GM847 did not result in their transformation. However, subsequent ectopic expression of hTERT in these cells imparted a tumorigenic phenotype. Indeed, this outcome was also observed after introduction of a mutant hTERT that retained catalytic activity but was incapable of maintaining telomere length. These studies indicate that hTERT confers an additional function that is required for tumorigenesis but does not depend on its ability to maintain telomeres. C1 NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Genzyme Inc, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Weinberg, RA (reprint author), NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RI Stewart, Sheila/C-5213-2012 FU NCI NIH HHS [K01 CA094223, R01 CA078461, R01 CA78461] NR 51 TC 319 Z9 336 U1 1 U2 10 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 1 PY 2002 VL 99 IS 20 BP 12606 EP 12611 DI 10.1073/pnas.182407599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700023 PM 12193655 ER PT J AU Thomas, DD Espey, MG Vitek, MP Miranda, KM Wink, DA AF Thomas, DD Espey, MG Vitek, MP Miranda, KM Wink, DA TI Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O-2(-) reaction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nitrotyrosine; nitric oxide; peroxynitrite; oxidation; hemin ID NITRIC-OXIDE SYNTHASE; TYROSINE NITRATION; IN-VIVO; PEROXYNITRITE FORMATION; OXIDATIVE DAMAGE; SUPEROXIDE-DISMUTASE; CATALYZED OXIDATION; PHYSIOLOGICAL PH; NITROTYROSINE; MECHANISM AB The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO-) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. Cogeneration of nitric oxide (NO) and superoxide (O-2(-)), from spermine/NO (2.7 muM/min) and xanthine oxidase (1-28 muM O-2(-)/min), respectively, resulted in protein nitration only when these species were produced at approximately equivalent rates. Addition of ferriprotoporphyrin IX (hemin) to this system increased nitration over a broad range of O-2(-) concentrations with respect to NO. Nitration in the presence of superoxide dismutase but not catalase suggested that ONOO- might not be obligatory to this process. Hemin-mediated NT formation required only the presence of NO2- and H2O2, which are stable end-products of NO and O-2(-) degradation. Ferrous, ferric, and cupric ions were also effective catalysts, indicating that nitration is mediated by species capable of Fenton-type chemistry. Although ONOO- can nitrate proteins, there are severe spatial and temporal constraints on this reaction. In contrast, accumulation of metals and NO2- subsequent to NO synthase activity can result in far less discriminate nitration in the presence of an H2O2 source. Metal catalyzed nitration may account for the observed specificity of protein nitration seen under pathological conditions, suggesting a major role for translocated metals and the labilization of heme in NT formation. C1 NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Wink, DA (reprint author), NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 58 TC 143 Z9 147 U1 3 U2 10 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 1 PY 2002 VL 99 IS 20 BP 12691 EP 12696 DI 10.1073/pnas.202312699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700038 PM 12226478 ER PT J AU Wang, LH Chmelik, R Nirenberg, M AF Wang, LH Chmelik, R Nirenberg, M TI Sequence-specific DNA binding by the vnd/NK-2 homeodomain of Drosophila SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE homeobox; DNA binding site; neurobiology ID CENTRAL-NERVOUS-SYSTEM; FACTOR-I TTF-1; TRANSCRIPTION FACTOR; HOMEOBOX GENE; NK-2 HOMEODOMAIN; RECOGNITION; PROTEINS; TINMAN; HEART; EXPRESSION AB The ventral nervous system defective (vnd)/NK-2 homeodomain and some flanking amino acid residues were expressed in Escherichia coli, purified to homogeneity, and the protein was covalently coupled to Sepharose. Oligodeoxynucleotides that contained 16-bp random sequences were purified by vnd/NK-2 affinity column chromatography, cloned, and sequenced. The consensus nucleotide sequence of the vnd/NK-2 homeodomain binding site was shown to be T(T/C)AAGTG(G/C). The apparent equilibrium dissociation constant (K-D) of the vnd/NK-2 homeodomain for the consensus sequence is 1.9 x 10(-10) M. In addition, results of competition between oligodeoxynucleotides for binding to the vnd/NK-2 homeodomain and determination of the apparent K-D values of oligodeoxynucleotides that differ from the consensus sequence by only a single base pair demonstrate that the four central nucleotides, AAGT, in this sequence play a major role in determining the affinity of binding. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 16 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 1 PY 2002 VL 99 IS 20 BP 12721 EP 12726 DI 10.1073/pnas.202461199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700043 PM 12232052 ER PT J AU Xu, WP Marcu, M Yuan, XT Mimnaugh, E Patterson, C Neckers, L AF Xu, WP Marcu, M Yuan, XT Mimnaugh, E Patterson, C Neckers, L TI Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2 Neu SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR RECEPTOR; HEAT-SHOCK PROTEINS; HUMAN BREAST-CANCER; C-CBL; PROTEASOMAL DEGRADATION; EGF RECEPTOR; GELDANAMYCIN; PHOSPHORYLATION; IDENTIFICATION; HETERODIMERS AB Overexpression of the transmembrane receptor tyrosine kinase ErbB2 is common in multiple malignancies, including breast and ovarian cancer. ErbB2 is resistant to degradation mediated by c-Cbl, the E3 ubiquitin ligase responsible for ligand-induced ubiquitination of ErbB1 (epidermal growth factor receptor). Because of its resistance to degradation, ErbB2 is the preferred dimerization partner for other members of the ErbB family, and its overexpression in vivo is associated with poor prognosis. We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase. Furthermore, CHIP association with ErbB2 requires a chaperone intermediate and is increased by the chaperone-binding drug geldanamycin, a potent stimulator of ErbB2 ubiquitination and degradation. These data describe a previously unrecognized pathway, amenable to pharmacologic manipulation, that mediates ErbB2 stability. C1 Univ N Carolina, Program Mol Cardiol, Chapel Hill, NC 27599 USA. RP Neckers, L (reprint author), NCI, Canc Cell Biol Branch, Ctr Canc Res, Rockville, MD 20850 USA. NR 29 TC 273 Z9 284 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 1 PY 2002 VL 99 IS 20 BP 12847 EP 12852 DI 10.1073/pnas.202365899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700064 PM 12239347 ER PT J AU Lozier, JN Dutra, A Pak, E Zhou, N Zheng, ZL Nichols, TC Bellinger, DA Read, M Morgan, RA AF Lozier, JN Dutra, A Pak, E Zhou, N Zheng, ZL Nichols, TC Bellinger, DA Read, M Morgan, RA TI The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VONWILLEBRAND DISEASE; RNA REPAIR; CANIS-FAMILIARIS; SEQUENCE; MUTATION; PROTEIN; EFFICIENCY; THERAPY; MODEL AB In the Chapel Hill colony of factor VIII-deficient dogs, abnormal sequence (ch8, for canine hemophilia 8, GenBank no. AF361485) follows exons 1-22 in the factor VIII transcript in place of exons 23-26. The canine hemophilia 8 locus (ch8) sequence was found in a 140-kb normal dog genomic DNA bacterial artificial chromosome (BAC) clone that was completely outside the factor VIII gene, but not in BAC clones containing the factor VIII gene. The BAC clone that contained ch8 also contained a homologue of F8A (factor 8 associated) sequence, which participates in a common inversion that causes severe hemophilia A in humans. Fluorescence in situ hybridization analysis indicated that exons 1-26 normally proceed sequentially from telomere to centromere at Xq28, and ch8 is telomeric to the factor VIII gene. The appearance of an "upstream" genomic sequence element (ch8) at the end of the aberrant factor VIII transcript suggested that an inversion of genomic DNA replaced factor VIII exons 22-26 with ch8. The F8A sequence appeared also in overlapping normal BAC clones containing factor VIII sequence. We hypothesized that homologous recombination between copies of canine F8A inside and outside the factor VIII gene had occurred, as in human hemophilia A. High-resolution fluorescent in situ hybridization on hemophilia A dog DNA revealed a pattern consistent with this inversion mechanism. We also identified a Hindill restriction fragment length polymorphism of F8A fragments that distinguished hemophilia A, carrier, and normal dogs' DNA. The Chapel Hill hemophilia A dog colony therefore replicates the factor VIII gene inversion commonly seen in humans with severe hemophilia A. C1 US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. Univ N Carolina, Dept Pathol, Francis Owen Blood Res Lab, Chapel Hill, NC 27516 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. RP Lozier, JN (reprint author), US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. FU NHLBI NIH HHS [HL63098, R24 HL063098] NR 31 TC 58 Z9 59 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 1 PY 2002 VL 99 IS 20 BP 12991 EP 12996 DI 10.1073/pnas.192219599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700090 PM 12242334 ER PT J AU Ahlers, JD Belyakov, IM Terabe, M Koka, R Donaldson, DD Thomas, EK Berzofsky, JA AF Ahlers, JD Belyakov, IM Terabe, M Koka, R Donaldson, DD Thomas, EK Berzofsky, JA TI A push-pull approach to maximize vaccine efficacy: Abrogating suppression with an IL-13 inhibitor while augmenting help with granulocyte/macrophage colony-stimulating factor and CD40L SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS ENVELOPE; TOXIC LYMPHOCYTES-T; IMMUNE-RESPONSE; NEUTRALIZING ANTIBODY; PROTECTIVE IMMUNITY; ANTITUMOR IMMUNITY; PEPTIDE VACCINE; DENDRITIC CELL; IN-VITRO AB Although a role for CD4(+) helper cells in CD8(+) cytotoxic T lymphocyte (CTL) induction by vaccines is widely recognized, much less is known about a counterbalancing role of CD4(+) T cells in down-modulating this response, or about ways to optimize vaccine responses through abrogation of this negative regulatory mechanism. Here, we discovered a synergistic enhancement of vaccine-mediated CTL induction and protection by the relief of suppression through depletion of regulatory CD4(+) cells, including CD4(+) NKT cells, or blockade of IL-13 made by these cells, combined with the cytokine granulocyte/macrophage colony-stimulating factor and the costimulatory molecule CD40L. Indeed, in the absence of helper epitopes, granulocyte/macrophage colony-stimulating factor and the helper-mimetic molecule CD40L are not sufficient to replace help to induce CTL without abrogation of CD4+ T cell-mediated suppression, suggesting a role for T cell help in overcoming suppression. The increased CTL induction translated to striking protection against viral infection by a vaccine by using this synergistic combined approach. These results argue for a push-pull approach to maximize vaccine efficacy, especially for HIV and cancer. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. Wyeth Genet Inst, Andover, MA 01810 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 50 TC 76 Z9 78 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 1 PY 2002 VL 99 IS 20 BP 13020 EP 13025 DI 10.1073/pnas.192251199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700095 PM 12232042 ER PT J AU Pfutzner, W Terunuma, A Tock, CL Snead, EK Kolodka, TM Gottesman, MM Taichman, L Vogel, JC AF Pfutzner, W Terunuma, A Tock, CL Snead, EK Kolodka, TM Gottesman, MM Taichman, L Vogel, JC TI Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW CELLS; PRODUCT P-GLYCOPROTEIN; LONG-TERM EXPRESSION; IN-VIVO; EPIDERMAL-KERATINOCYTES; THERAPY; MICE; SKIN; RETROVIRUS AB For skin gene therapy, achieving prolonged high-level gene expression in a significant percentage of keratinocytes (KC) is difficult because we cannot selectively target KC stem cells. We now demonstrate that topical colchicine treatment can be used to select, in vivo, KC progenitor cells transduced with the multidrug resistance gene (MDR1). When human skin equivalents containing MDR1-transduced KC were grafted onto immunocompromised mice, topical colchicine treatments significantly increased (7-fold) the percentage of KC expressing MDR1, compared to vehicle-treated controls, for up to 24 wk. Topical colchicine treatment also significantly enhanced the amount of MDR1 protein expressed in individual KC. Furthermore, quantitative real-time PCR analysis of MDR1 transgene copy number demonstrates that topical colchicine treatment selects and enriches for KC progenitor cells in the skin that contain and express MDR1. For clinical skin gene therapy applications, this in vivo selection approach promises to enhance both the duration and expression level of a desired therapeutic gene in KC, by linking its expression to the MDR1 selectable marker gene. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Stony Brook, NY 11794 USA. RP Pfutzner, W (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N260,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 45 TC 26 Z9 26 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 1 PY 2002 VL 99 IS 20 BP 13096 EP 13101 DI 10.1073/pnas.192247899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 600LK UT WOS:000178391700108 PM 12235361 ER PT J AU Qualls, SH Segal, DL Norman, S Niederehe, G Gallagher-Thompson, D AF Qualls, SH Segal, DL Norman, S Niederehe, G Gallagher-Thompson, D TI Psychologists in practice with older adults: Current patterns, source's of training, and need for continuing education SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article ID MENTAL-HEALTH; GEROPSYCHOLOGY; CARE; PREVALENCE; SERVICES AB Rapid population growth among older adults means an increased need for psychologists prepared to provide mental health services to this population. A representative survey of 1,227 practitioner members of the American Psychological Association yielded information about current patterns of practice with older adults, sources of training in geropsychology, perceived need for continuing education (CE) in geropsychology, and preferred CE formats. Most respondents provided some services to older adults, but typically very little. The services provided are inadequate to meet projected demand. Most respondents lacked formal training in geropsychology and perceived themselves as needing additional training. CE workshops at the regional level and distance education were the most popular formats. These data serve as a call to the field to expand training opportunities at all levels of training, with an emphasis on the need for empirically based, broadly accessible CE offerings. C1 Univ Colorado, Dept Psychol, Colorado Springs, CO 80933 USA. NIMH, Bethesda, MD 20892 USA. VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. Stanford Univ, Stanford, CA 94305 USA. RP Qualls, SH (reprint author), Univ Colorado, Dept Psychol, Colorado Springs, CO 80933 USA. NR 28 TC 66 Z9 66 U1 1 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD OCT PY 2002 VL 33 IS 5 BP 435 EP 442 DI 10.1037//0735-7028.35.5.435 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 596VT UT WOS:000178187700001 ER PT J AU Gulley, J Chen, AP Dahut, W Arlen, PM Bastian, A Steinberg, SM Tsang, K Panicali, D Poole, D Schlom, J Hamilton, JM AF Gulley, J Chen, AP Dahut, W Arlen, PM Bastian, A Steinberg, SM Tsang, K Panicali, D Poole, D Schlom, J Hamilton, JM TI Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer SO PROSTATE LA English DT Article DE PSA; vaccine; prostate cancer; T cells ID COLONY-STIMULATING FACTOR; CYTOTOXIC T-LYMPHOCYTES; IMMUNE-RESPONSES; ANTIGEN PSA; DIVERSIFIED PRIME; ELISPOT ASSAY; CELL IMMUNITY; GENERATION; PEPTIDE; COMBINATION AB BACKGROUND. A Phase I trial of recombinant vaccinia prostate specific antigen (rV-PSA) in patients with advanced metastatic prostate cancer was conducted. This report describes 42 patients who were treated with up to three monthly vaccinations. METHODS. All patients were entered on a dose-escalation phase I study of recombinant vaccinia containing the gene for PSA (rV-PSA). The primary objective of this study was to determine the safety of this vaccine in metastatic androgen-independent prostate cancer patients. A secondary objective was to assess evidence of anti-tumor activity by PSA measurements, radiologic findings, and immunologic methods. RESULTS. There was no significant treatment-related toxicity apart from erythema, tenderness, and vesicle formation that lasted several days at the site of injection in some patients. There were immunologic responses, in selected patients, as evidenced by an increase in the proportion of PSA-specific T cells after vaccination. Furthermore, we show that these patients' T cells can lyse PSA-expressing tumor cells in vitro. CONCLUSION. Given the low toxicity profile and the evidence of immunologic activity, we believe future study is warranted with PSA-based vaccines in prostate cancer. New PSA-based vaccines and vaccine strategies are currently being evaluated. (C) 2002 Wiley-Liss, Inc. C1 NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MA USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Med Oncl Res Unit, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 24 TC 157 Z9 161 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD OCT 1 PY 2002 VL 53 IS 2 BP 109 EP 117 DI 10.1002/pros.10130 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 600ZG UT WOS:000178421200003 PM 12242725 ER PT J AU Sinha, N Smith-Gill, SJ AF Sinha, N Smith-Gill, SJ TI Protein structure to function via dynamics SO PROTEIN AND PEPTIDE LETTERS LA English DT Article ID CRYSTAL-STRUCTURE; GLUTAMATE-DEHYDROGENASE; ANGSTROM RESOLUTION; MOLECULAR-DYNAMICS; SALT BRIDGES; STABILITY; ANTIGEN; DOMAIN; ANTIBODIES; THERMOSTABILITY AB Protein folding, binding, catalytic activity. and molecular recognition all involve molecular movements, with varying extents. The molecular movements are brought upon via flexible regions. Stemming from sequence, a fine tuning of electrostatic and hydrophobic properties of the protein fold determine flexible and rigid regions. Studies show flexible regions usually lack electrostatic interactions, such as salt-bridges and hydrogen-bonds, while the rigid regions often have larger number of such electrostatic interactions. Protein flexible regions are not simply an outcome of looser packing or instability, rather they are evolutionally selected. In this review article we highlight the significance of protein flexibilities in folding, binding and function, and their structural and thermodynamic determinants. Our electrostatic calculations and molecular dynamic simulations on an antibody-antigen complex further illustrate the importance of protein flexibilities in binding and function. C1 NCI, Basic Res Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NR 61 TC 22 Z9 23 U1 5 U2 12 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD OCT PY 2002 VL 9 IS 5 BP 367 EP 377 DI 10.2174/0929866023408508 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592AV UT WOS:000177915300001 PM 12370024 ER PT J AU Mori, T Barrientos, LG Han, ZZ Gronenborn, AM Turpin, JA Boyd, MR AF Mori, T Barrientos, LG Han, ZZ Gronenborn, AM Turpin, JA Boyd, MR TI Functional homologs of cyanovirin-N amenable to mass production in prokaryotic and eukaryotic hosts SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE cyanovirin-N; CV-N; cyanovirins; microbicides; HIV; anti-HIV ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-INACTIVATING PROTEIN; ENVELOPE GLYCOPROTEIN; ANTIBODY-PRODUCTION; GP120; POTENT; PLANTS; BINDING; CD4; CYANOBACTERIUM AB Cyanovirin-N (CV-N) is under development as a topical (vaginal or rectal) microbicide to prevent sexual transmission of human immunodeficiency virus (HIV), and an economically feasible means for very large-scale production of the protein is all urgent priority. We observed that N-glycosylation of CV-N in yeast eliminated the anti-HIV activity, and that dimeric forms and aggregates of CV-N occurred under certain conditions, potentially complicating the efficient large-scale manufacture of pure monomeric CV-N. We therefore expressed and tested CV-N homologs in which the Asn residue at position 30 was replaced with Ala, Gin, or Val, and/or the Pro at position 51 was replaced by Gly to eliminate potential conformational heterogeneity. All homologs exhibited anti-HIV activity comparable to wild-type CV-N and the Pro51Gly homologs were significantly more stable proteins. These glycosylation-resistant, functional cyanovirins should he amenable to large-scale production either in bacteria or in eukaryotic hosts. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. So Res Inst, Infect Dis Res Dept, Frederick, MD 21701 USA. RP Mori, T (reprint author), NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. NR 36 TC 26 Z9 36 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD OCT PY 2002 VL 26 IS 1 BP 42 EP 49 AR PII S1046-5928(02)00513-2 DI 10.1016/S1046-5928(02)00513-2 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 613CJ UT WOS:000179113700007 PM 12356469 ER PT J AU Ma, BY Nussinov, R AF Ma, BY Nussinov, R TI Molecular dynamics simulations of alanine rich beta-sheet oligomers: Insight into amyloid formation SO PROTEIN SCIENCE LA English DT Article DE amyloid; prion; beta-sheet; molecular dynamics simulation; protein folding; protein unfolding; conformational conversion ID ALZHEIMERS-DISEASE; PRION DETERMINANT; FIBRIL FORMATION; CELL-DEATH; PROTEIN; FRAGMENT; PEPTIDES; TOXICITY; REPLICATION; AGGREGATION AB The aggregation observed in protein conformational diseases is the outcome of significant new P-sheet structure not present in the native state. Peptide model systems have been useful in studies of fibril aggregate formation. Experimentally, it was found that a short peptide AGAAAAGA is one of the most highly amyloidogenic peptides. This peptide corresponds to the Syrian hamster prion protein (ShPrP) residues 113-120. The peptide was observed to be conserved in all species for which the PrP sequence has been determined. We have simulated the stabilities of oligomeric AGAAAAGA and AAAAAAAA (A8) by molecular dynamic simulations. Oligomers of both AGAAAAGA and AAAAAAAA were found to be stable when the size is 6 to 8 (hexamer to octamer). Subsequent simulation of an additional alpha-helical AAAAAAAA placed on the A8-octamer surface has revealed molecular events related to conformational change and oligomer growth. Our study addresses both the minimal oligomeric size of an aggregate seed and the mechanism of seed growth. Our simulations of the prion-derived 8-residue amyloidogenic peptide and its variant have indicated that an octamer is stable enough to be a seed and that the driving force for stabilization is the hydrophobic effect. C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. SAIC Inc, Intramural Res Support Program, Lab Expt & Computat Biol, NCI, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 36 TC 120 Z9 122 U1 1 U2 17 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2002 VL 11 IS 10 BP 2335 EP 2350 DI 10.1110/ps.4270102 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 594PP UT WOS:000178059800007 PM 12237456 ER PT J AU Kimbrell, TA Dunn, RT George, MS Danielson, AL Willis, MW Repella, JD Benson, BE Herscovitch, P Post, RM Wassermann, EM AF Kimbrell, TA Dunn, RT George, MS Danielson, AL Willis, MW Repella, JD Benson, BE Herscovitch, P Post, RM Wassermann, EM TI Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE neurocircuitry; prefrontal cortex; positron emission tomography; rTMS; rCMRglu ID RESISTANT MAJOR DEPRESSION; MOTOR CORTEX EXCITABILITY; CORTICAL STIMULATION; SENSORIMOTOR CORTEX; EVOKED-RESPONSES; SILENT PERIOD; BLOOD-FLOW; MOOD; TMS; CONNECTIVITY AB Repetitive transcranial magnetic stimulation (rTMS) holds promise as a probe into the pathophysiology and possible treatment of neuropsychiatric disorders. To explore its regional effects, we combined rTMS with positron emission tomography (PET). Fourteen healthy volunteers participated in a baseline 18-fluorodeoxyglucose (FDG) PET scan. During a second FDG infusion on the same day, seven subjects received 30 ruin of 1 Hz rTMS at 80% of motor threshold to left prefrontal cortex, and seven other subjects received sham rTMS under identical conditions. Global and normalized regional cerebral glucose metabolic rates (rCMRglu) from the active and sham conditions were compared to baseline and then to each other. Sham, but not active I Hz rTMS, was associated with significantly increased global CMRglu. Compared to baseline, active rTMS induced normalized decreases in rCMRglu in right prefromal cortex, bilateral anterior cingulate, basal ganglia (L > R), hypothalamus, midbrain, and cerebellum. Increases in rCMRglu were seen in bilateral posterior temporal and occipital cortices. Sham rTMS compared to baseline resulted in isolated normalized decreases in rCMRglu in left dorsal anterior cingulate and left basal ganglia, and increases in posterior association and occiptal regions. Differences between the 1 Hz active versus sham changes from baseline revealed that active rTMS induced relative decrements in rCMRglu in the left superior frontal gyrus and increases in the cuneus (L > R). One Hertz rTMS at 80% motor threshold over the left prefrontal cortex in healthy subjects compared to sham rTMS in another group (each compared to baseline) induced an area of decreased normalized left prefrontal rCMRglu not directly under the stimulation site, as well as increases in occipital cortex. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. RP Post, RM (reprint author), 10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. NR 57 TC 60 Z9 65 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 1 PY 2002 VL 115 IS 3 BP 101 EP 113 AR PII S0925-4927(02)00041-0 DI 10.1016/S0925-4927(02)00041-0 PG 13 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 600XQ UT WOS:000178417400001 PM 12208488 ER PT J AU Thayer, JF Lane, RD AF Thayer, JF Lane, RD TI Perseverative thinking and health: Neurovisceral concomitants SO PSYCHOLOGY & HEALTH LA English DT Article DE worry; heart rate variablility; cerebral blood flow; autonomic nervous system; parasympathetic ID HEART-RATE-VARIABILITY; GENERALIZED ANXIETY DISORDER; MECHANISMS; WORRY; DEPRESSION; BALANCE; IMAGERY; EMOTION; SYSTEM; MODEL AB In the present paper we present the outlines of a model that may help to guide us in our understanding of the relationship between perseverative thinking and health. We will emphasize the relationship between perseverative thinking and vagal cardiac control and propose a group of underlying neural structures that serve to integrate these functions in the service of self-regulation and adaptability of the organism. We will attempt to place this network in the context of systems models which involve feedback and feedforward circuits with special attention to negative feedback mechanisms and inhibitory processes. From a systems perspective, inhibitory processes can be viewed as negative feedback circuits that allow for the interruption of ongoing behavior and the re-deployment of resources to other tasks. When these negative feedback mechanisms are compromised, positive feedback loops may develop as a result of dis-inhibition. From this perspective, the relative sympathetic activation seen in perseverative thinking may represent dis-inhibition due to faulty inhibitory mechanisms. C1 Natl Inst Aging Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Arizona, Tucson, AZ 85721 USA. RP Thayer, JF (reprint author), Natl Inst Aging Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 46 TC 24 Z9 26 U1 3 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 J9 PSYCHOL HEALTH JI Psychol. Health PD OCT PY 2002 VL 17 IS 5 BP 685 EP 695 DI 10.1080/08870440290025867 PG 11 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 608LQ UT WOS:000178848200013 ER PT J AU Broom, DC Jutkiewicz, EM Folk, JE Traynor, JR Rice, KC Woods, JH AF Broom, DC Jutkiewicz, EM Folk, JE Traynor, JR Rice, KC Woods, JH TI Convulsant activity of a non-peptidic delta-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats SO PSYCHOPHARMACOLOGY LA English DT Article DE delta-opioid receptor; forced swim assay; depression; convulsions; (+)BW373U86; SNC80 ID TRANSCRANIAL MAGNETIC STIMULATION; FORCED SWIMMING TEST; ENDOGENOUS ENKEPHALINS; SQUIRREL-MONKEYS; RHESUS-MONKEYS; BW373U86; SNC-80; MICE; IMMUNOREACTIVITY; DEPRESSION AB Rationale: Non-peptidic delta-opioid receptor agonists possess antidepressant-like activity in the forced swim assay in the rat. These compounds have also previously been shown to possess convulsant properties in mice. Objective: The aim of the present study was to examine whether such convulsions occurred in rats and to investigate if delta-mediated convulsant activity was necessary for the mediation of delta-opioid agonist-induced antidepressant-like activity. Methods: The peripheral administration of delta-opioid receptor agonists to male Sprague-Dawley rats was followed by a period of observation for convulsant activity. Following this period and 60 min after delta-opioid agonist administration, rats were tested in the forced swim assay. Results: The non-peptidic delta-opioid receptor agonists (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methox- yphenyl)methyl]-N,N-diethylbenzamide (SNC80) and (+)-4- [(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide dihydrochloride [(+)BW373U86] both produced dose-dependent convulsant activity in rats and decreased immobility in the forced swim assay. The delta-opioid receptor antagonist naltrindole prevented the convulsant activity of (+)BW373U86 and its effects in the forced swim assay. This suggested a delta-opioid mechanism for both effects. Midazolam prevented convulsions but did not prevent activity in the forced swim assay. Rats tolerant to the convulsive effects of (+)BW373U86 still displayed antidepressant-like effects. Conclusion: delta-Mediated convulsions do occur in rats and can be prevented without affecting the delta-mediated effects in the forced swim assay. Therefore the convulsant activity of (+)BW373U86 and possibly other non-peptidic delta-agonists is not required for activity in the forced swim assay. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Woods, JH (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 Med Sci Res Bldg 3, Ann Arbor, MI 48109 USA. FU NIDA NIH HHS [DA00254, DA07267]; NIGMS NIH HHS [GM07767] NR 26 TC 55 Z9 55 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2002 VL 164 IS 1 BP 42 EP 48 DI 10.1007/s00213-002-1179-y PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 611KY UT WOS:000179017300006 PM 12373418 ER PT J AU Bergman, J Katz, JL Miczek, KA AF Bergman, J Katz, JL Miczek, KA TI The experimental imperative - Introduction SO PSYCHOPHARMACOLOGY LA English DT Editorial Material ID BEHAVIOR C1 Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Absue Res Ctr, Belmont, MA 02478 USA. NIDA, Medicat Discovery Res Branch, NIH, Baltimore, MD 21224 USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. RP Bergman, J (reprint author), Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Absue Res Ctr, 115 Mill St, Belmont, MA 02478 USA. NR 4 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2002 VL 163 IS 3-4 BP 249 EP 250 DI 10.1007/s00213-002-1226-8 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 611AX UT WOS:000178995200001 PM 12373426 ER PT J AU McMillan, DE Katz, JL AF McMillan, DE Katz, JL TI Continuing implications of the early evidence against the drive-reduction hypothesis of the behavioral effects of drugs SO PSYCHOPHARMACOLOGY LA English DT Review DE behavioral effects; reinforcement; maintained response; drugs; drives; schedule control; environmental conditions; drug self-administration; craving ID FIXED-INTERVAL SCHEDULES; SELF-ADMINISTERED COCAINE; FOOD PRESENTATION; 2ND-ORDER SCHEDULES; SQUIRREL-MONKEYS; RHESUS-MONKEYS; SHOCK PRESENTATION; ELECTRIC-SHOCK; D-AMPHETAMINE; INJECTION AB Rationale: Early psychopharmacologists often explained the behavioral effects of drugs as due to changes in the hypothetical construct of motivation, implying that drug effects would depend on the inherent properties of the reinforcer that maintains responding. The work of Dews, Morse, and Kelleher offered an alternative explanation that the scheduling of reinforcers, and the patterns and rates of responding maintained, were more important determinants of drug effects. Objective: The present paper reviews the literature on the influence on drug effects of the type of reinforcer that maintains responding. Methods: Studies that examined the effects of drugs on behaviors maintained by different reinforcers were compared with studies that examined behaviors maintained by the same reinforcer under various conditions. Results: Over a wide range of conditions, the effects of drugs depend more on the schedule-controlled patterns and rates of responding than on the particular reinforcer. However, there are some conditions under which the reinforcer that maintains behavior can also determine drug effects. The broad implications of these findings in selected areas of psychopharmacology are discussed. Conclusions: Under some conditions drug effects are ostensibly consistent with explanations in terms of traditional hypothetical constructs, though under a wide range of other conditions they are not. A more general understanding of the behavioral effects of drugs comes from directing the emphasis of research away from hypothetical constructs and towards the empirically defined determinants of the behavioral effects of drugs. C1 Univ Arkansas Med Sci, Dept Pharmacol, Little Rock, AR 72205 USA. NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program, Baltimore, MD USA. RP McMillan, DE (reprint author), Univ Arkansas Med Sci, Dept Pharmacol, 4301 W Markham St, Little Rock, AR 72205 USA. OI Katz, Jonathan/0000-0002-1068-1159 NR 61 TC 18 Z9 18 U1 4 U2 8 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2002 VL 163 IS 3-4 BP 251 EP 264 DI 10.1007/s00213-002-1185-0 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 611AX UT WOS:000178995200002 PM 12373427 ER PT J AU Schindler, CW Panlilio, LV Goldberg, SR AF Schindler, CW Panlilio, LV Goldberg, SR TI Second-order schedules of drug self-administration in animals SO PSYCHOPHARMACOLOGY LA English DT Review DE second-order schedules; drug abuse; psychomotor stimulants; opioids; primates; rats ID COCAINE-SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS CORE; DOPAMINE UPTAKE INHIBITOR; FIXED-INTERVAL SCHEDULES; RHESUS-MONKEYS; 2ND-ORDER SCHEDULES; SQUIRREL-MONKEY; FOOD PRESENTATION; SPEEDBALL COMBINATIONS; BASOLATERAL AMYGDALA AB On a second-order schedule, a subject responds according to one schedule (the unit schedule) for a brief presentation of a stimulus such as a light. Responding by the subject on this unit schedule is then reinforced according to another schedule of reinforcement. Second-order schedules of drug injection allow the study of more complex behavioral sequences than do simple schedules and may more accurately reflect the human drug-abuse situation. Much of the early work in this area used primates as subjects and focused on the behavioral variables controlling responding. It was shown that long sequences of behavior could be maintained on second-order schedules with relatively infrequent injections of drug and that the second-order, brief-stimulus presentations were critical to the acquisition and maintenance of responding. Also, the continued presentation of the brief stimulus in extinction often led to prolonged extinction behavior. These studies clearly showed that environmental stimuli greatly influence drug self-administration behavior under second-order schedules. The focus of much of the more recent work with second-order schedules has been on the evaluation of pharmacological treatments for drug addiction, both as antagonist and substitution therapies. Both types of potential therapies have shown promise in these preclinical models of addictive behavior. The recent extension of second-order self-administration studies to rats as subjects has facilitated the investigation of neural mechanisms involved in this behavior. While this use of second-order schedules is a relatively recent phenomenon, significant contributions have already been made in identifying neural mechanisms critical to second-order schedule drug self-administration. This active area of research holds great promise for delineating specific brain regions critical to different aspects of drug addiction. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 107 TC 87 Z9 90 U1 5 U2 12 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2002 VL 163 IS 3-4 BP 327 EP 344 DI 10.1007/s00213-002-1157-4 PG 18 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 611AX UT WOS:000178995200009 PM 12373434 ER PT J AU Sedelnikova, OA Rogakou, EP Panyutin, IG Bonner, WM AF Sedelnikova, OA Rogakou, EP Panyutin, IG Bonner, WM TI Quantitative detection of (125) IdU-induced DNA double-strand breaks with gamma-H2AX antibody SO RADIATION RESEARCH LA English DT Article ID MAMMALIAN-CELLS; HISTONE H2AX; DAMAGE; DECAY; REPAIR; I-125 AB When mammalian cells are exposed to ionizing radiation and other agents that introduce DSBs into DNA, histone H2AX molecules in megabase chromatin regions adjacent to the breaks become phosphorylated within minutes on a specific serine residue. An antibody to this phosphoserine motif of human H2AX (gamma-H2AX) demonstrates that gamma-H2AX molecules appear in discrete nuclear foci. To establish the quantitative relationship between the number of these foci and the number of DSBs, we took advantage of the ability of 1251, when incorporated into DNA, to generate one DNA DSB per radioactive disintegration. SF-268 and HT-1080 cell cultures were grown in the presence of (125)IdU and processed immunocytochemically to determine the number of gamma-H2AX foci. The numbers of (IDU)-I-125 disintegrations per cell were measured by exposing the same immunocytochemically processed samples to a radiation-sensitive screen with known standards. Under appropriate conditions, the data yielded a direct correlation between the number of I-125 decays and the number of foci per cell, consistent with the assumptions that each I-125 decay yields a DNA DSB and each DNA DSB yields a visible gamma-112AX focus. Based on these findings, we conclude that gamma-H2AX antibody may form the basis of a sensitive quantitative method for the detection of DNA DSBs in eukaryotic cells. (C) 2002 by Radiation Research Society. C1 NCI, CCR, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. RP Sedelnikova, OA (reprint author), NCI, CCR, Mol Pharmacol Lab, NIH, Bld 37-5A5050,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 405 Z9 424 U1 1 U2 17 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2002 VL 158 IS 4 BP 486 EP 492 DI 10.1667/0033-7587(2002)158[0486:QDOIID]2.0.CO;2 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 599LZ UT WOS:000178337300009 PM 12236816 ER PT J AU Arbab, AS Ichikawa, T Sou, H Araki, T Nakajima, H Ishigame, K Yoshikawa, T Kumagai, H AF Arbab, AS Ichikawa, T Sou, H Araki, T Nakajima, H Ishigame, K Yoshikawa, T Kumagai, H TI Ferumoxides-enhanced double-echo T2-weighted MR imaging in differentiating metastases from nonsolid benign lesions of the liver SO RADIOLOGY LA English DT Article DE liver, cysts; liver, hemangioma; liver neoplasms, metastases; magnetic resonance (MR), contrast enhancement ID SUPERPARAMAGNETIC IRON-OXIDE; HEPATOCELLULAR-CARCINOMA; HEPATIC-LESIONS; ARTERIAL PORTOGRAPHY; SPIRAL-CT; PULSE SEQUENCES; HELICAL CT; GD-DTPA; TUMORS; T2 AB PURPOSE: To investigate whether ferumoxides-enhanced double-echo T2-weighted magnetic resonance (MR) imaging alone can allow differentiation of metastases from benign lesions in the noncirrhotic liver. MATERIALS AND METHODS: At retrospective review of files and images, 60 lesions (22 metastases, 20 hemangiomas, and 18 cysts) were identified in 42 patients. All fast spin-echo T2-weighted MR images obtained before and after administration of ferumoxides with short (80-90 msec) and long (180-250 msec) echo times (TEs) were acquired with a 1.5-T system. Differences in lesion-to-liver signal intensity ratio between images obtained with long and short TEs were calculated. Data from all 60 lesions were entered into a receiver operating characteristic analysis. Three independent readers scored their observations of each lesion with a confidence level of 1-5. The diagnostic accuracy of each analysis method was determined by calculating the area under each reader-specific receiver operating characteristic curve. Interobserver agreement was calculated with the use of chance of characterizing Relative sensitivity, specificity and accuracy corrected kappa statistics benign lesions with each method were calculated. RESULTS: Markedly low signal intensity and lesion-to-liver ratio on ferumoxides-enhanced images were observed with hemangioma. The difference of lesion-to-liver ratio between long and short TEs on ferumoxides-enhanced images was significantly different from that of unenhanced images and that of metastases or cysts. Interobserver agreement was good to excellent. Ferumoxides-enhanced images (with short and long TEs) showed significantly higher diagnostic accuracy than that of unenhanced images (with short or short and long TEs). Ferumoxides-enhanced images showed similar sensitivity, specificity, and accuracy when all images were reviewed together. CONCLUSION: Ferumoxides-enhanced T2-weighted MR images appear useful in differentiating metastases from benign (nonsolid) lesions in the liver. (C) RSNA, 2002. C1 Yamanashi Med Univ, Dept Radiol, Yamanashi, Japan. RP Arbab, AS (reprint author), NIH, LDRR, CC, Bldg 10,Rm B1N256, Bethesda, MD 20892 USA. EM saali@cc.nih.gov NR 28 TC 17 Z9 18 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD OCT PY 2002 VL 225 IS 1 BP 151 EP 158 DI 10.1148/radiol.2251011090 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 598FE UT WOS:000178264300024 PM 12354999 ER PT J AU Dalakas, MC AF Dalakas, MC TI Understanding the immunopathogenesis of inclusion-body myositis: present and future prospects SO REVUE NEUROLOGIQUE LA English DT Article; Proceedings Paper CT International Meeting of the French-Society-of-Neurology CY OCT 03-04, 2002 CL PARIS, FRANCE SP Frence Soc Neurol ID NECROSIS-FACTOR-ALPHA; MHC CLASS-I; IDIOPATHIC INFLAMMATORY MYOPATHIES; CELL RECEPTOR REPERTOIRE; INFILTRATING T-CELLS; HUMAN MUSCLE-CELLS; INTERFERON-GAMMA; HUMAN MYOBLASTS; INTRAVENOUS IMMUNOGLOBULIN; INCREASED EXPRESSION AB Sporadic Inclusion Body Myositis (s-IBM) is the most common acquired inflammatory myopathy. It has a stereotypic clinical presentation and a predictably progressive course that leads to severe muscle weakness and permanent disability. The combination of primary endomysial inflammation with autoimmune features identical to those seen in Polymyositis, and degenerative features with vacuolization of muscle fibers and deposits of tiny speckles of amyloid, are characteristic for the disease. In this review, the immunopathology of IBM is detailed. The inflammation which is prominent even late in the disease, is characterized by activated, CD8+ cytotoxic T cells that secrete perforin and invade MHC-I-expressing muscle fibers. The autoinvasive T cells are probably antigen driven because of specific rearrangement of their T Cell Receptor profile, restriction of the CDR3 region, upregulation of co-stimulatory molecules and their ligands on the muscle fibers, and activation of various cytokines, chemokines and adhesion molecules. The disease can be seen in association with HIV and HTLV-1 infection, but viruses have not been amplified from the muscle fibers and the antigen or the factors that trigger inflammation are still unknown. The disease is mysteriously resistant to conventional immunotherapies in spite of the immunopathologic similarities with PM. The cause of the vacuolar formation in IBM is also unknown and the role, that the tiny amyloid deposits play in the disease remain unclear. The treatment approaches and the prospects for future immunotherapeutic interventions are discussed. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 90 TC 16 Z9 18 U1 0 U2 0 PU MASSON EDITEUR PI PARIS 06 PA 120 BLVD SAINT-GERMAIN, 75280 PARIS 06, FRANCE SN 0035-3787 J9 REV NEUROL-FRANCE JI Rev. Neurol. PD OCT PY 2002 VL 158 IS 10 BP 948 EP 958 PN 1 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 619FT UT WOS:000179465700011 PM 12407303 ER PT J AU Frisch, M Gridley, G AF Frisch, M Gridley, G TI Appendectomy in adulthood and the risk of inflammatory bowel diseases SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article DE appendectomy; Crohn disease; ulcerative colitis ID ULCERATIVE-COLITIS; CROHNS-DISEASE; TONSILLECTOMY; PROTECTION; HYGIENE AB Background: There is controversy as to whether appendectomy protects against the development of ulcerative colitis, but the possible impact of appendectomies performed in adulthood has not been systematically investigated. Methods: We conducted a large case-control study based on inpatient records from Veterans Affairs hospitals in the United States for the period 1969-96. We identified 6,172 male patients with ulcerative colitis (age range 19-101 years, mean 57.4 years) and 4,498 male patients with Crohn disease (age range 18-99 years, mean 52.9 years). Each of these case patients was individually age- and race-matched to five other male veterans without recorded history of inflammatory bowel disease. We compared records of prior appendectomies in adulthood for the matched case-control sets using conditional logistic regression. Results: Overall, both ulcerative colitis (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.3-2.1) and Crohn disease (OR = 2.5, 95% CI: 2.0-3.3) were significantly and positively associated with history of appendectomy in adulthood. However, risks were not increased at intervals of 15 years or more between appendectomy and inflammatory bowel disease (ulcerative colitis: OR = 0.9, 95% CI: 0.4-2.1; Crohn disease: OR = 1.2, 95% CI: 0.5-2.5). Conclusions: The elevated risk of inflammatory bowel disease, notably Crohn disease, after appendectomy probably reflects differential diagnostic difficulties in patients with abdominal pain. Appendectomy carried out during adulthood seems not to confer protection against ulcerative colitis. C1 Danish Epidemiol Sci Ctr, Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. RP Frisch, M (reprint author), Danish Epidemiol Sci Ctr, Statens Serum Inst, Dept Epidemiol Res, 5 Artillerivej, DK-2300 Copenhagen S, Denmark. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 20 TC 9 Z9 9 U1 0 U2 2 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD OCT PY 2002 VL 37 IS 10 BP 1175 EP 1177 DI 10.1080/003655202760373380 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 604FN UT WOS:000178606100009 PM 12408522 ER PT J AU Blaszczyk-Thurin, M O, I Ertl, HCJ AF Blaszczyk-Thurin, M O, I Ertl, HCJ TI An experimental vaccine expressing wild-type p53 induces protective immunity against glioblastoma cells with high levels of endogenous p53 SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTE; CYTOKINE GENE-THERAPY; METH-A SARCOMA; RABIES VIRUS; PEPTIDE VACCINATION; GAMMA PRODUCTION; HIGH-AVIDITY; IN-VITRO; INTERLEUKIN-12; PROTEIN AB Inoculation of mice with a recombinant vaccinia virus expressing the full-length mouse wild-type p53 protein (Vp53-wt) was shown to induce partial protection against peripheral challenge with a mouse glioblastoma cell line, termed GL261, expressing high levels of nuclear, endogenous wild-type p53. In vivo experiments with knockout (KO) mice and mice treated with depleting doses of antibodies specific to lymphocyte subsets revealed that vaccine efficacy depended on CD4(+) and CD8(+) T cells as well as on natural killer (NK) cells. Vp53-wt virus-vaccinated mice that failed to develop tumours upon challenge with a minimal tumourigenic dose of GL261 cells remained completely resistant to further challenge with increased doses to GL261 cells. The efficacy of the Vp53-wt vaccine was improved by adding recombinant mouse interleukin-12 (rIL-12) as an adjuvant at the time of tumour challenge. The induction of T cells to p53 in Vp53-wt virus-immune mice was also demonstrated at the tumour site by immunochemistry and was further confirmed by a delayed-type hypersensitivity response to the p53 protein, although in vitro experiments using splenocytes from vaccinated mice failed to demonstrate CD4(+) or CD8(+) T-cell activity to p53. C1 Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. NCI, EPN, Rockville, MD USA. RP Ertl, HCJ (reprint author), Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. NR 54 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD OCT PY 2002 VL 56 IS 4 BP 361 EP 375 DI 10.1046/j.1365-3083.2002.01119.x PG 15 WC Immunology SC Immunology GA 594HP UT WOS:000178044100004 PM 12234257 ER PT J AU Travier, N Gridley, G De Roos, AJ Plato, N Moradi, T Boffetta, P AF Travier, N Gridley, G De Roos, AJ Plato, N Moradi, T Boffetta, P TI Cancer incidence of dry cleaning, laundry and ironing workers in Sweden SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE epidemiology; lymphohematopoietic neoplasms; occupational exposure; record-linkage study; respiratory neoplasms ID OCCUPATIONAL RISKS; BLADDER-CANCER; UNITED-STATES; LUNG-CANCER; MORTALITY; CLEANERS; EXPOSURE; COHORT; FEMALE; DEATH AB Objectives This study investigated the risk of cancer among dry cleaners, launderers, and pressers in a large record-linkage study in Sweden. Methods The Swedish Cancer Register III contains nationwide data on cancer incidence between 1971 and 1989, by occupation and industry of employment, as reported in the 1960 and 1970 censuses. Dry cleaners, launderers, and pressers were compared with the remaining part of the employed population using multivariable Poisson regression models and standardized incidence ratios. Results Dry cleaners, launderers, and pressers employed in the laundry, ironing, or dyeing industry in both censuses showed an increased risk of Hodgkin's disease [relative risk (RR) 2.69, 95% confidence interval (95% CI) 1.01-7.19], an elevated risk of leukemia among women (RR 2.53, 95% Cl 1.44-4.46), and increased risks of stomach (RR 1.80,95% CI 1.05-3.11) and laryngeal (RR 2.42,95% CI 0.91-6.45) cancers among men. The results of the analyses of launderers and dry cleaners as a separate occupational group reflected those of the whole exposure group, while pressers showed an elevated lung cancer risk (RR 1.67, 95% Cl 0.75-3.72). Conclusions If they are not due to chance or confounding, the results of this study reflect either the potentiation of other carcinogens by solvents or direct effects. The results are limited by the use of job and industry titles as proxies for occupational exposures. C1 Int Agcy Res Canc, Unit Environm Canc Epidemiol, FR-69008 Lyon, France. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Karolinska Inst, Dept Publ Hlth Sci, Div Occupat Med, Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Karolinska Inst, Dept Family Med, Stockholm, Sweden. RP Boffetta, P (reprint author), Int Agcy Res Canc, Unit Environm Canc Epidemiol, 150 Cours Albert Thomas, FR-69008 Lyon, France. NR 31 TC 22 Z9 23 U1 1 U2 2 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD OCT PY 2002 VL 28 IS 5 BP 341 EP 348 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 611LZ UT WOS:000179020100008 PM 12432988 ER PT J AU Marenco, S Egan, MF Goldberg, TE Knable, MB McClure, RK Winterer, G Weinberger, DR AF Marenco, S Egan, MF Goldberg, TE Knable, MB McClure, RK Winterer, G Weinberger, DR TI Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series SO SCHIZOPHRENIA RESEARCH LA English DT Article DE CX516; AMPA; schizophrenia; clinical trial ID D-CYCLOSERINE; ENHANCEMENT; DYSKINESIA; CLOZAPINE; MODULATOR; RECEPTORS; KETAMINE; MEMORY; HUMANS; TRIAL AB We used L-(quinoxalin -6-ylcarbonyl)piperidine (CX516) (a modulator of the (alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics, The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings. neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited. Published by Elsevier Science B.V. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Stanley Fdn, Bethesda, MD 20814 USA. RP Marenco, S (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, Bldg 10,Room 4S235, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 21 TC 41 Z9 42 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD OCT 1 PY 2002 VL 57 IS 2-3 BP 221 EP 226 AR PII S0920-9964(01)00311-5 DI 10.1016/S0920-9964(01)00311-5 PG 6 WC Psychiatry SC Psychiatry GA 599WL UT WOS:000178358100011 PM 12223253 ER PT J AU Klenova, EA Morse, HC Ohlsson, RF Lobanenkov, VV AF Klenova, EA Morse, HC Ohlsson, RF Lobanenkov, VV TI The novel BORIS+CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE gene imprinting; transcription regulation; DNA-methylation; male germ cells; CTCF at 16q22; tumor suppressor; 16q22 LOH; BORIS at 20q13; oncogene; 20q13 amplification; cancer genetics and epigenetics ID C-MYC GENE; CTCF-BINDING SITES; ENHANCER-BLOCKING ACTIVITY; GROWTH-FACTOR-II; PROTEIN CTCF; 5'-FLANKING SEQUENCE; NUCLEAR FACTOR; DNA-SEQUENCE; COPY NUMBER; 20Q GAIN C1 NIAID, Immunopathol Lab, Sect Mol Pathol, NIH, Rockville, MD 20852 USA. Univ Essex, Dept Biol Sci, Colchester CQ4 3SQ, Essex, England. Uppsala Univ, Dept Genet & Pathol, S-75236 Uppsala, Sweden. Uppsala Univ, Dept Genet & Dev, S-75236 Uppsala, Sweden. RP Lobanenkov, VV (reprint author), NIAID, Immunopathol Lab, Sect Mol Pathol, NIH, Twinbrook 1 Bldg,5640 Fishers Lane, Rockville, MD 20852 USA. OI Lobanenkov, Victor/0000-0001-6665-3635; Morse, Herbert/0000-0002-9331-3705 NR 58 TC 170 Z9 176 U1 1 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2002 VL 12 IS 5 BP 399 EP 414 DI 10.1016/S1044-579(02)00060-3 PG 16 WC Oncology SC Oncology GA 596KG UT WOS:000178163600009 PM 12191639 ER PT J AU Bezrukov, SM Kish, LB AF Bezrukov, SM Kish, LB TI How much power does neural propagation need? SO SMART MATERIALS & STRUCTURES LA English DT Article; Proceedings Paper CT Symposium on BioMEMS and Smart Nanostructures CY DEC 17-19, 2001 CL ADELAIDE, AUSTRALIA SP SPIE, USAF, Off Sci Res, Asian Off Aerosp Res & Dev, Adelaide Univ, Ctr Biomed Engn, Def Sci & Technol Org, S Australia, Dept Ind & Trade ID STOCHASTIC RESONANCE; ION CHANNELS; NOISE; NEURONS; WHITE AB Two well known, biologically inspired non-dynamical models of stochastic resonance, the threshold-crossing model and the fluctuating rate model, are analyzed in terms of channel information capacity and dissipation of energy necessary for small-signal transduction. Using analogies to spike propagation in neurons we postulate the average output pulse rate as a measure of dissipation. The dissipation increases monotonically with the input noise. We find that for small dissipation both models give a close to linear dependence of the channel information capacity on dissipation. In both models the channel information capacity, as a function of dissipation, has a maximum at input noise amplitude that is different from that in the standard signal-to-noise ratio versus input noise plot. Though a direct comparison is not straightforward, for small signals the threshold model gives appreciably higher density of information per dissipation than the exponential fluctuating rate model. We show that a formal introduction of cooperativity in the rate fluctuating model permits us to imitate the response function of the threshold model and to enhance performance. This finding may have direct relevance to real neural spike generation where, due to a strong positive feedback, the ion channel currents add up in a synchronized way. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. NR 19 TC 10 Z9 10 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0964-1726 J9 SMART MATER STRUCT JI Smart Mater. Struct. PD OCT PY 2002 VL 11 IS 5 BP 800 EP 803 AR PII S0964-1726(02)52657-4 DI 10.1088/0964-1726/11/5/327 PG 4 WC Instruments & Instrumentation; Materials Science, Multidisciplinary SC Instruments & Instrumentation; Materials Science GA 612LH UT WOS:000179076600028 ER PT J AU Longstreth, WT Dulberg, C Manolio, TA Lewis, MR Beauchamp, NJ O'Leary, D Carr, J Furberg, CD AF Longstreth, WT Dulberg, C Manolio, TA Lewis, MR Beauchamp, NJ O'Leary, D Carr, J Furberg, CD TI Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly - The Cardiovascular Health Study SO STROKE LA English DT Article DE brain infarction; creatinine; incidence; leukoariosis; magnetic resonance imaging ID OLDER ADULTS; STROKE; RISK; DISEASE; HOMOCYSTEINE; PEOPLE; INDEX AB Background and Purpose-MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts. Methods-The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged greater than or equal to65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI. Results-On follow-up MRI, 254 participants (17.7%) had 1 or more infarcts. Most were single (75.6%), subcortical (79.9%), and small (3 to 20 mm in 87.0%). Only 11.4% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P<0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index. Conclusions-Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation. C1 Univ Washington, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. Univ Washington, Dept Biostat, Seattle, WA 98104 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Vermont, Dept Pathol, Colchester, VT USA. Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. Tufts New England Med Ctr, Dept Radiol, Boston, MA USA. Wake Forest Univ, Dept Radiol, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP Longstreth, WT (reprint author), Univ Washington, Harborview Med Ctr, Dept Neurol, Box 359775,325 9th Ave, Seattle, WA 98104 USA. FU NHLBI NIH HHS [N01-HC-85082, N01-HC-85079, N01-HC-35129, N01-HC-85081, N01-HC-85085, N01-HC-85086, N01-HC-85083, N01-HC-85084, N01-HC-15103, N01-HC-85080] NR 25 TC 155 Z9 157 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2002 VL 33 IS 10 BP 2376 EP 2382 DI 10.1161/01.STR.0000032241.58727.49 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 602QK UT WOS:000178515800014 PM 12364724 ER PT J AU Hawk, ET Limburg, PJ Viner, JL AF Hawk, ET Limburg, PJ Viner, JL TI Epidemiology and prevention of colorectal cancer SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; EPITHELIAL-CELL PROLIFERATION; RECTAL MUCOSAL PROLIFERATION; RANDOMIZED CONTROLLED TRIAL; BOWMAN-BIRK INHIBITOR; FATAL COLON-CANCER; WHEAT BRAN FIBER; PRIMARY BILIARY-CIRRHOSIS; COA REDUCTASE INHIBITORS; PROSTAGLANDIN E-2 LEVELS AB Cancer is but one late stage in a long disease process driven by cumulative molecular alterations that affect genomic integrity and the control of cellular identity and growth. Improved understanding of this process affords time and targets for prevention. This article reviews the distribution of colorectal cancer in the population, known etiologic factors, and the emerging field of molecular prevention (ie, cancer chemoprevention). C1 NCI, Div Canc Prevent, EPN, Gastrointestinal & Other Canc Res Grp, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Mayo Med Sch, Div Gastroenterol, Rochester, MN 55905 USA. RP Hawk, ET (reprint author), NCI, Div Canc Prevent, EPN, Gastrointestinal & Other Canc Res Grp, Suite 2141,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 235 TC 71 Z9 76 U1 0 U2 8 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD OCT PY 2002 VL 82 IS 5 BP 905 EP + AR PII S0039-6109(02)00046-4 DI 10.1016/S0039-6109(02)00046-4 PG 38 WC Surgery SC Surgery GA 626NX UT WOS:000179880400003 PM 12507200 ER PT J AU Miles, JR Beetham, PK Segerson, EC AF Miles, JR Beetham, PK Segerson, EC TI Suppressor cell activity of ovine caruncular and intercaruncular tissues during the placentation period SO THERIOGENOLOGY LA English DT Article DE ovine; immunosuppression; uterus; lymphocytes ID GROWTH-FACTOR-BETA; VS-GRAFT REACTION; ACTIVATED KILLER-CELLS; PREGNANT MICE; NK-CELLS; IN-VITRO; DECIDUA; MURINE; PERCOLL; LOCALIZATION AB We assessed the suppression of lymphocyte proliferation ovine endometrial cells recovered during each trimester (Days 45, 90, and 135) of pregnancy. We evaluated fractionated and unfractionated caruncular (C) and intercarunlar (IC) cells for suppression of cocultured peripheral blood lymphocytes (PBL) in phytohemagglutinin (PHA)-treated cultures. We also evaluated cells for the release of the suppressor factor into the culture medium and tested the factor for transforming,growth factor-beta (TGF-beta) activity. Suppression of PHA-induced proliferation of PBL was evident for C and IC cells recovered from each day of pregnancy, and the activity was predominantly attributed to the population(s) of low-density (1.006-1.054 g/ml) cells. The activity was greater for unfractionated C than for IC cells on Day 45, whereas the pattern was reversed by Day 135 of pregnancy. For the C cells, the activity was greatest on Day 45 and least by Day 135. Although suppressor factor was released into the medium from cultured C and IC cells, its activity was not apparently mediated by TGF-beta. In conclusion, we observed a temporal pattern in suppressor activity for unfractionated endometrial cells during pregnancy. Suppression was predominately mediated by a population(s) of low-density cells. In addition, the cells released a soluble suppressor factor that seems to be unrelated to TGF-beta. The suppressor cells may provide immunological protection to the fetoplacental unit by suppressing specific lymphocyte responses directed toward conceptus tissues. (C) 2002 Elsevier Science Inc. All rights reserved. C1 N Carolina Agr & Tech State Univ, Dept Anim Sci, Greensboro, NC 27411 USA. N Carolina State Univ, Coll Vet Med, Dept Farm Anim Hlth & Resource Management, Raleigh, NC 27695 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Segerson, EC (reprint author), N Carolina Agr & Tech State Univ, Dept Anim Sci, 101 Webb Hall, Greensboro, NC 27411 USA. RI Miles, Jeremy/A-7572-2009 NR 40 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0093-691X J9 THERIOGENOLOGY JI Theriogenology PD OCT 1 PY 2002 VL 58 IS 6 BP 1097 EP 1109 AR PII S0093-691X(01)00681-1 DI 10.1016/S0093-691X(01)00681-1 PG 13 WC Reproductive Biology; Veterinary Sciences SC Reproductive Biology; Veterinary Sciences GA 594BG UT WOS:000178028500003 PM 12240913 ER PT J AU Rick, ME Moll, S Taylor, MA Krizek, DM White, GC Aronson, DL AF Rick, ME Moll, S Taylor, MA Krizek, DM White, GC Aronson, DL TI Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE vWF protease assay; TTP; HUS; collagen; multimers ID HEMOLYTIC-UREMIC SYNDROME; PLASMA-EXCHANGE; METALLOPROTEASE; PLATELETS; VWF AB A simple collagen binding assay (CBA) for measuring activity of the von Willebrand factor cleaving protease in clinical samples is described, and results of fifty masked plasmapheresis samples from patients with TTP/HUS and other diseases are presented. There was 97.5% concordance between the CBA and a multimer gel assay. The CBA identified low protease activity in 78% of patients who had a clinical syndrome consistent with TTP/HUS and in 2 of 10 sick controls, giving it a positive predictive value of 0.94. The heterogeneity regarding the presence or absence of vWF protease activity in patients with TTP/HUS was confirmed by finding a low negative predictive value of 0.50 with the CBA. The CBA detected inhibitors of the protease in 26 of 29 patients (90%) with TTP/HUS and low protease activity levels. The CBA is a useful clinical assay for examining von Willebrand factor protease activity and detecting inhibitors against the protease. C1 NIH, Warren Grant Magnuson Clin Ctr, Hematol Serv, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. RP Rick, ME (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Hematol Serv, Bld 10,Rm 2C390,10 Ctr Dr, Bethesda, MD 20892 USA. NR 21 TC 34 Z9 48 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD OCT PY 2002 VL 88 IS 4 BP 598 EP 604 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 605DV UT WOS:000178660900010 PM 12362230 ER PT J AU Aframian, DJ Tran, SD Cukierman, E Yamada, KM Baum, BJ AF Aframian, DJ Tran, SD Cukierman, E Yamada, KM Baum, BJ TI Absence of tight junction formation in an allogeneic graft cell line used for developing an engineered artificial salivary gland SO TISSUE ENGINEERING LA English DT Article ID EPITHELIAL-CELLS; MOLECULAR PHYSIOLOGY; PROTEIN; STRANDS; PATHOPHYSIOLOGY; CLAUDIN-2; MEMBRANE; KINASE AB An essential structural feature of fluid-secreting epithelial tissues is the presence of tight junctions. To develop a tissue-engineered organ capable of fluid secretion, the cellular component must establish these structures. As part of efforts to create an engineered artificial salivary gland, we have examined the ability of a candidate allogeneic graft cell line, HSG, to produce several key tight junction proteins, as well as to exhibit functional activities consistent with effective tight junction strand formation. In contrast to results obtained with a control kidney cell line, MDCK-II, HSG cells were unable to synthesize four important tight junction-associated proteins: ZO-1, occludin, claudin-1, and claudin-2. In addition, unlike MDCK-II cells, HSG cell monolayers could not restrict paracellular permeability. HSG cells were, thus, unable to generate significant transepithelial electrical resistance or serve as an effective barrier to osmotically imposed fluid movement. Furthermore, these two functional activities could not be reconstituted via the stable transfection of HSG cells with cDNAs encoding either claudin-1 or claudin-2. We conclude that because of their inability to form tight junctions, HSG cells are unsuitable for use as an allogeneic graft cell in an artificial salivary fluid secretory device. These studies also emphasize the importance of graft cell selection in artificial organ development, as certain required characteristics may be difficult to reengineer. C1 NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N113,MSC-1190, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 24 TC 33 Z9 37 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD OCT PY 2002 VL 8 IS 5 BP 871 EP 878 DI 10.1089/10763270260424231 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA 610AH UT WOS:000178938200015 PM 12459066 ER PT J AU Hamadeh, HK Trouba, KJ Afshari, CA Germolec, D AF Hamadeh, HK Trouba, KJ Afshari, CA Germolec, D TI Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes SO TOXICOLOGICAL SCIENCES LA English DT Article DE arsenic; keratinocytes; microarray; toxicity ID CELL-PROLIFERATION; HUMAN FIBROBLASTS; ANIMAL-MODEL; EXPRESSION; CARCINOGENESIS; GENE; P53; DISRUPTION; RESPONSES; MECHANISM AB Human exposure to arsenic, a ubiquitous and toxic environmental pollutant, is associated with an increased incidence of skin cancer. However, the mechanism(s) associated with AsIII-mediated toxicity and carcinogenesis at low levels of exposure remains elusive. Aberrations in cell proliferation, oxidative damage, and DNA-repair fidelity have been implicated in sodium arsenite (AsIII)-mediated carcinogenicity and toxicity, but these events have been examined in isolation in the majority of biological models of arsenic exposure. We hypothesized that the simultaneous interaction of these effects may be important in arsenic-mediated neoplasia in the skin. To evaluate this, normal human epidermal keratinocytes (NHEK) were exposed to nontoxic doses (0.005-5 muM) of AsIII and monitored for several physiological endpoints at the times when cells were harvested for gene expression measurements (1-24 h). Two-fluor cDNA microarray analyses indicated that AsIII treatment decreased the expression of genes associated with DNA repair (e.g., p53 and Damage-specific DNA-binding protein 2) and increased the expression of genes indicative of the cellular response to oxidative stress (e.g., Superoxide dismutase 1, NAD(P)H quinone oxidoreductase, and Serine/threonine kinase 25). AsIII also modulated the expression of certain transcripts associated with increased cell proliferation (e.g., Cyclin G1, Protein kinase C delta), oncogenes, and genes associated with cellular transformation (e.g., Gro-1 and V-yes). These observations correlated with measurements of cell proliferation and mitotic measurements as AsIII treatment resulted in a dose-dependent increase in cellular mitoses at 24 h and an increase in cell proliferation at 48 h of exposure. Data in this manuscript demonstrates that AsIII exposure simultaneously modulates DNA repair, cell proliferation, and redox-related gene expression in nontransformed, normal NHEK. It is anticipated that data in this report will serve as a foundation for furthering our knowledge of AsIII-regulated gene expression in skin and other tissues and contribute to a better understanding of arsenic toxicity and carcinogenesis. C1 NIEHS, Intramural Microarray Ctr, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Afshari, CA (reprint author), Amgen Inc, 1 Amgen Ctr Dr,Mailstop 5-1-A, Newbury Pk, CA 91320 USA. NR 47 TC 78 Z9 82 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2002 VL 69 IS 2 BP 306 EP 316 DI 10.1093/toxsci/69.2.306 PG 11 WC Toxicology SC Toxicology GA 603KW UT WOS:000178559500004 PM 12377979 ER PT J AU Martinez, JM Afshari, CA Bushel, PR Masuda, A Takahashi, T Walker, NJ AF Martinez, JM Afshari, CA Bushel, PR Masuda, A Takahashi, T Walker, NJ TI Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells SO TOXICOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the Society-of-Toxicology CY MAR 24-29, 2001 CL SAN FRANCISCO, CALIFORNIA SP Soc Toxicol DE toxicogenomics; microarray analysis; dioxin; TCDD; AhR; lung cells; A549; HPL1A; real time RT-PCR ID ARYL-HYDROCARBON RECEPTOR; RETINOIC ACID RECEPTOR; INTERFERON REGULATORY FACTOR-4; FACTOR SIGNALING PATHWAYS; NF-KAPPA-B; AH RECEPTOR; GENE-EXPRESSION; GROWTH-FACTOR; TRANSCRIPTIONAL ACTIVATION; RETINOBLASTOMA PROTEIN AB In humans, exposure to high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with chronic obstructive pulmonary disease and lung cancer. While several studies have shown that the lung is a target organ for TCDD toxicity, little is known on the specific biological pathways altered by TCDD. Studies have shown that the transcriptional response of TCDD (in vivo and in vitro) is complex, and exhibits cell type and tissue specificity. Thus, the purpose of this study was to look at global and concentration-dependent effects of TCDD on gene expression in human lung cells. Gene expression profiling of both a nontumorigenic (HPL1A) and a malignant, tumorigenic lung cell line (A549) was performed by microarray dual fluorescence hybridizations in cells treated with increasing concentrations of TCDD (0, 0.1, 1, 10 nM) for 24 h. Real time RT-PCR was used to verify alterations in specific genes. Results showed that 68 out of 2091 genes were changed in each cell line, and 15 of those genes were found altered in both cell lines. Common gene responses altered by TCDD were identified and included known xenobiotic metabolizing genes, genes known to alter cell cycle, as well as genes that are involved with cell signaling and that mediate cell motility or communication. Cell line specific differences in gene expression were found that indicate the nonmalignant HPL1A cells are retinoic acid responsive. In addition, TCDD altered specific immunomodulatory genes in the HPL1A cells. These data show that TCDD alters multiple integrated networks of signaling pathways associated with pulmonary disease, particularly that of lung cancer. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Aichi Canc Ctr, Res Inst, Chikusa Ku, Nagoya, Aichi 4648681, Japan. RP Walker, NJ (reprint author), NIEHS, Rall Bldg 101,Room D452,111 Alexander Dr,POB 1223, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012; Takahashi, Takashi/I-7262-2014 OI Walker, Nigel/0000-0002-9111-6855; NR 101 TC 71 Z9 74 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2002 VL 69 IS 2 BP 409 EP 423 DI 10.1093/toxsci/69.2.409 PG 15 WC Toxicology SC Toxicology GA 603KW UT WOS:000178559500015 PM 12377990 ER PT J AU Campbell, JL Cohen-Fix, O AF Campbell, JL Cohen-Fix, O TI Chromosome cohesion: ring around the sisters? SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID CHROMATID COHESION; DNA-REPLICATION; PROTEIN; IDENTIFICATION; SEPARATION; COMPLEXES; BINDING; SITES; MCD1P; ARMS AB Sister chromatid cohesion is a key aspect of accurate chromosome transmission during mitosis, yet little is known about the structure of cohesin, the protein complex that links the two sister chromatids. Recent studies shed light on the structure of the cohesin complex, leading to intriguing models that could explain how sister chromatids are held together. C1 NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Campbell, JL (reprint author), NIDDK, Lab Mol & Cellular Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2002 VL 27 IS 10 BP 492 EP 495 AR PII S0968-0004(02)02194-1 DI 10.1016/S0968-0004(02)02194-1 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 604EJ UT WOS:000178603100002 PM 12368077 ER PT J AU Segars, JH Driggers, PH AF Segars, JH Driggers, PH TI Estrogen action and cytoplasmic signaling cascades. Part 1: membrane-associated signaling complexes SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID NITRIC-OXIDE SYNTHASE; VASCULAR ENDOTHELIAL-CELLS; ACTIVATED PROTEIN-KINASE; KAINATE-INDUCED CURRENTS; RECEPTOR-ALPHA; BINDING-SITES; MICE LACKING; CROSS-TALK; GENE-TRANSCRIPTION; NUCLEAR RECEPTORS AB Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors alpha and beta. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes. C1 Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. NICHD, PREB, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU Intramural NIH HHS [Z99 HD999999] NR 63 TC 130 Z9 142 U1 1 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD OCT PY 2002 VL 13 IS 8 BP 349 EP 354 AR PII S1043-2760(02)00633-1 DI 10.1016/S1043-2760(02)00633-1 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 594WX UT WOS:000178076000010 PM 12217492 ER PT J AU Nagai, Y Matsumoto, M Metter, EJ AF Nagai, Y Matsumoto, M Metter, EJ TI The carotid artery as a noninvasive window for cardiovascular risk in apparently healthy individuals SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Review DE carotid arteries; atherosclerosis; arterial elasticity; ultrasound; cardiovascular diseases ID INTIMA-MEDIA THICKNESS; B-MODE ULTRASOUND; ESTROGEN REPLACEMENT THERAPY; DEPENDENT DIABETES-MELLITUS; TRANSIENT ISCHEMIC ATTACK; WALL THICKNESS; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK; GENERAL-POPULATION; ULTRASONOGRAPHIC ASSESSMENT C1 Osaka Univ, Grad Sch Med, Dept Internal Med & Therapeut, Suita, Osaka 5650871, Japan. NIA, Lab Clin Investigat, NIH, Baltimore, MD USA. RP Nagai, Y (reprint author), Osaka Univ, Grad Sch Med, Dept Internal Med & Therapeut, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. NR 97 TC 14 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD OCT PY 2002 VL 28 IS 10 BP 1231 EP 1238 AR PII S0301-5629(02)00578-1 DI 10.1016/S0301-5629(02)00578-1 PG 8 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 623GH UT WOS:000179694600001 PM 12467848 ER PT J AU Storey, N Latchman, D Bevan, S AF Storey, N Latchman, D Bevan, S TI Selective internalization of sodium channels in rat dorsal root ganglion neurons infected with herpes simplex virus-1 SO JOURNAL OF CELL BIOLOGY LA English DT Article DE voltage-gated sodium channels; sensory neurons; sodium channel regulation; calcium channels; potassium channels ID SENSORY NEURONS; PROTEIN; TYPE-1; EXPRESSION; CELLS; EXCITABILITY; REPLICATION; INHIBITION; UBIQUITIN; CURRENTS AB The neurotropic virus, herpes simplex type 1 (HSV-1), inhibits the excitability of peripheral mammalian neurons, but the molecular mechanism of this effect has not been identified. Here, we use voltage-clamp measurement of ionic currents and an antibody against sodium channels to show that loss of excitability results from the selective, precipitous, and complete internalization of voltage-activated sodium channel proteins from the plasma membrane of neurons dissociated from rat dorsal root ganglion. The internalization process requires viral protein synthesis but not viral encapsulation, and does not alter the density of voltage-activated calcium or potassium channels. However, internalization is blocked completely when viruses lack the neurovirulence factor, infected cell protein 34.5, or when endocytosis is inhibited with bafilomycin A, or chloroquine. Although it has been recognized for many years that viruses cause cell pathology by interfering with signal transduction pathways, this is the first example of viral pathology resulting from selective internalization of an integral membrane protein. In studying the HSV-induced redistribution of sodium channels, we have uncovered a previously unknown pathway for the rapid and dynamic control of excitability in sensory neurons by internalization of sodium channels. C1 Novartis Inst Med Sci, London WC1E 6BS, England. UCL, Sch Med, Windeyer Inst Med Sci, Windeyer Dept Mol Pathol, London W1P 6DB, England. RP Storey, N (reprint author), NIEHS, POB 12233,111 Alexander Dr,Mail Drop F205, Res Triangle Pk, NC 27709 USA. EM storey@niehs.nih.gov RI Bevan, Stuart/A-8821-2008 NR 32 TC 22 Z9 22 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 30 PY 2002 VL 158 IS 7 BP 1251 EP 1262 DI 10.1083/jcb.200204010 PG 12 WC Cell Biology SC Cell Biology GA 600TL UT WOS:000178407500011 PM 12356869 ER PT J AU Bunnell, SC Hong, DI Kardon, JR Yamazaki, T McGlade, CJ Barr, VA Samelson, LE AF Bunnell, SC Hong, DI Kardon, JR Yamazaki, T McGlade, CJ Barr, VA Samelson, LE TI T cell receptor ligation induces the formation of dynamically regulated signaling assemblies SO JOURNAL OF CELL BIOLOGY LA English DT Article ID FC-EPSILON-RI; IMMUNOLOGICAL SYNAPSE; ACTIN CYTOSKELETON; ANTIGEN RECOGNITION; MEDIATED ACTIVATION; TYROSINE KINASES; ADAPTER PROTEIN; LAT; SLP-76; PLC-GAMMA-1 AB T cell antigen receptor (TCR) ligation initiates tyrosine kinase activation, signaling complex assembly, and immune synapse formation. Here, we studied the kinetics and mechanics of signaling complex formation in live jurkat leukemic T cells using signaling proteins fluorescently tagged with variants of enhanced GFP (EGFP). Within seconds of contacting coverslips coated with stimulatory antibodies, T cells developed small, dynamically regulated clusters which were enriched in the TCR, phosphotyrosine, ZAP-70, LAT, Grb2, Gads, and SLP-76, excluded the lipid raft marker enhanced yellow fluorescent protein-GPI, and were competent to induce calcium elevations. LAT, Grb2, and Gads were transiently associated with the TCR. Although ZAP-70-containing clusters persisted for more than 20 min, photobleaching studies revealed that ZAP-70 continuously dissociated from and returned to these complexes. Strikingly, SLP-76 translocated to a perinuclear structure after clustering with the TCR. Our results emphasize the dynamically changing composition of signaling complexes and indicate that these complexes can form within seconds of TCR engagement, in the absence of either lipid raft aggregation or the formation of a central TCR-rich cluster. C1 NCI, Cellular & Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Hosp Sick Children, Dept Med Biophys, Toronto, ON M5G 1X8, Canada. Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Canc Res Ctr, NIH, Bldg 37,Rm 1E24, Bethesda, MD 20892 USA. NR 55 TC 385 Z9 389 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 30 PY 2002 VL 158 IS 7 BP 1263 EP 1275 DI 10.1083/jcb.200203043 PG 13 WC Cell Biology SC Cell Biology GA 600TL UT WOS:000178407500012 PM 12356870 ER PT J AU Puyal, J Devau, G Venteo, S Sans, N Raymond, J AF Puyal, J Devau, G Venteo, S Sans, N Raymond, J TI Calcium-binding proteins map the postnatal development of rat vestibular nuclei and their vestibular and cerebellar projections SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE calbindin-D28k; calretinin; parvalbumin; in situ hybridization; immunoblotting; immunocytochemistry ID EXCITATORY AMINO-ACIDS; NERVOUS-SYSTEM; CALBINDIN D-28K; CALRETININ IMMUNOREACTIVITY; PRENATAL DEVELOPMENT; PURKINJE-CELLS; BRAIN-STEM; GUINEA-PIG; PARVALBUMIN; NEURONS AB We investigated whether three calcium-binding proteins, calretinin, parvalbumin, and calbindin, could identify specific aspects of the postnatal development of the rat lateral (LVN) and medial (MVN) vestibular nuclei and their vestibular and cerebellar connections. Calretinin levels in the vestibular nuclei, increased significantly between birth and postnatal day (P) 45. In situ hybridization and immunocytochemical staining showed that calretinin-immunoreactive neurons were mostly located in the parvocellular MVN at birth and that somatic and dendritic growth occurred between birth and P14. During the first week, parvalbumin-immunoreactive fibers and endings were confined to specific areas, i.e., the ventral LVN and magnocellular MVN, and identified exclusively the maturation of the vestibular afferents. Calbindin was located within the dorsal LVN and the parvocellular MVN and identified the first arrival of the corticocerebellar afferents. From the second week, in addition to labeling vestibular afferents in their specific target areas, parvalbumin was also found colocalized with calbindin in mature Purkinje cell afferents. Thus, the specific spatiotemporal distribution of parvalbumin and calbindin could correspond to two successive phases of synaptic remodeling involving integration of the vestibular sensory messages and their cerebellar control. On the basis of the sequence of distribution patterns of these proteins during the development of the vestibular nuclei, calretinin is an effective marker for neuronal development of the parvocellular MVN, parvalbumin is a specific marker identifying maturation of the vestibular afferents and endings, and calbindin is a marker of the first appearance and development of Purkinje cell afferents. (C) 2002 Wiley-Liss, Inc. C1 Univ Montpellier 2, INSERM U432, F-34095 Montpellier 5, France. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Puyal, J (reprint author), Univ Montpellier 2, INSERM U432, CP089, F-34095 Montpellier 5, France. NR 65 TC 14 Z9 14 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 30 PY 2002 VL 451 IS 4 BP 374 EP 391 DI 10.1002/cne.10366 PG 18 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 589EG UT WOS:000177745100006 PM 12210131 ER PT J AU Snyderwine, EG Sinha, R Felton, JS Ferguson, LR AF Snyderwine, EG Sinha, R Felton, JS Ferguson, LR TI Highlights of the Eighth International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Editorial Material DE aromatic amines; carcinogenesis; epidemiology; mutagenesis; human exposure and risk; metabolism; molecular alterations; DNA adducts; biomonitoring; heterocyclic amines ID BLADDER-CANCER RISK; HETEROCYCLIC AMINES; DNA-ADDUCTS; COOKED MEAT; WELL-DONE; RED MEAT; FOOD; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; COLON; CARCINOGEN AB Research in the 20th century initially identified arylamines as causative factors in occupational carcinogenesis, especially bladder cancer, and subsequently identified arylamines as a major class of mutagens/carcinogens in the environment and diet that are potential risk factors in a variety of human cancers. Current research focuses on understanding of mechanisms of arylamine carcinogenesis, such as therole of metabolic processing, DNA adduct formation, and mutagenesis, and learning more about the molecular alterations in carcinomas induced by these compounds. Furthermore, research to identify human exposures, including developing more sensitive methods for analyzing environmental samples and identifying suitable biomarkers are important aspects of contemporary investigations. In addition, better evaluation of the risk of these compounds in human cancer especially with regard to the impact of genetic polymorphisms is a major focus of research in this field. Although current population studies have sometimes been described as equivocal, improved tools for epidemiology, refined human biomonitoring methods and collaborative endeavors to study multiple population groups now provide a better means to ultimately define the role of arylamines in human carcinogenesis. The purpose of the Eighth International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds, held in Washington, DC, 12-14 November 2001, was to explore the current scope of studies on arylamine carcinogenesis among scientists in basic research and epidemiology and to discuss future research priorities. With the intent of providing a view to the current field of research on aromatic amines, this review presents a synopsis of the Proceedings of the Eighth International Conference and highlights the manuscripts contained in this special issue of Mutation Research. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. Univ Auckland, Nutr ACSRC, Auckland 1, New Zealand. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RI Ferguson, Lynnette/F-5989-2011; Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 65 TC 15 Z9 15 U1 0 U2 1 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 SEP 30 PY 2002 VL 506 SI SI BP 1 EP 8 AR PII S0027-5107(02)00146-X DI 10.1016/S0027-5107(02)00146-X PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400001 PM 12351139 ER PT J AU Christian, AT Snyderwine, EG Tucker, JD AF Christian, AT Snyderwine, EG Tucker, JD TI Comparative genomic hybridization analysis of PhIP-induced mammary carcinomas in rats reveals a cytogenetic signature SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE mammary cancer; rats; food mutagen; 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine (PhIP); 7,12-dimethylbenz[a]anthracene (DMBA); comparative genomic hybridization; cytogenetic signature ID SPRAGUE-DAWLEY RATS; BREAST-CANCER; MOLECULAR CYTOGENETICS; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; CHROMOSOMES; IMBALANCE; RADIATION; TUMORS; FAT AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a mutagen/carcinogen belonging to the class of heterocyclic amines (HCAs) found in cooked meats, is a known rat mammary gland carcinogen. To gain insight into the genomic alterations associated with PhIP-induced carcinogenesis, we used comparative genomic hybridization (CGH) to examine chromosomal abnormalities in rat mammary gland carcinomas induced by PhIP. The alterations were compared to those induced by 7,12-dimethylbenz[a]anthracene (DMBA), a potent and well-studied mammary carcinogen. All six PhIP-induced carcinomas examined by CGH showed losses in the same specific regions of chromosomes 2, 3, 11, 18, and X, whereas three carcinomas induced by DMBA showed no consistent patterns of chromosomal gain or loss. This indicates that PhIP has a recognizable cytogenetic signature in rat mammary gland carcinomas. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Christian, AT (reprint author), Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, POB 808,L-452, Livermore, CA 94551 USA. FU NCI NIH HHS [CA55861] NR 20 TC 11 Z9 11 U1 0 U2 1 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 SEP 30 PY 2002 VL 506 SI SI BP 113 EP 119 AR PII S0027-5107(02)00157-4 DI 10.1016/S0027-5107(02)00157-4 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400012 PM 12351150 ER PT J AU Snyderwine, EG Venugopal, M Yu, MH AF Snyderwine, EG Venugopal, M Yu, MH TI Mammary gland carcinogenesis by food-derived heterocyclic amines and studies on the mechanisms of carcinogenesis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE DNA adducts; mutagenesis; mammary gland; rat; proliferation; gene expression; PhIP; genomic alterations; allelic imbalance ID SPRAGUE-DAWLEY RATS; RAS GENE-MUTATIONS; DNA-ADDUCTS; HUMAN-LIVER; HA-RAS; MICROSATELLITE INSTABILITY; METABOLIC-ACTIVATION; DIETARY-FAT; CANCER RISK; COOKED MEAT AB The heterocyclic amines (HCAs) comprise a family of mutagenic/carcinogenic compounds found in cooked meat. Several HCAs including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-Aquinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are mammary gland carcinogens in rats. One mammary gland carcinogen, PhIP, is the most prevalent in the human diet. This article reviews the mechanisms of mammary gland carcinogenesis of PhIP including metabolic processing, DNA adduct formation, effects on mammary gland development, cell signaling, and the genomic alterations found in PhIP-induced rat mammary gland carcinomas. Published by Elsevier Science B.V. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 3C28,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. NR 48 TC 38 Z9 38 U1 1 U2 2 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 SEP 30 PY 2002 VL 506 SI SI BP 145 EP 152 AR PII S0027-5107(02)00161-6 DI 10.1016/S0027-5107(02)00161-6 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400016 PM 12351154 ER PT J AU Strickland, PT Qian, Z Friesen, MD Rothman, N Sinha, R AF Strickland, PT Qian, Z Friesen, MD Rothman, N Sinha, R TI Metabolites of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) in human urine after consumption of charbroiled or fried beef SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE urine metabolites; PhIP; HPLC; biomarker; heterocyclic amines; dietary carcinogens ID FOOD MUTAGEN 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; HETEROCYCLIC AROMATIC-AMINES; CYTOCHROME P4501A2; HYDROLYZED URINE; COOKED FOOD; 2-AMINO-3,8-DIMETHYLIMIDAZO<4,5-F>QUINOXALINE; IDENTIFICATION; CARCINOGENS; ACTIVATION; EXCRETION AB Heterocyclic amines (HAs) are carcinogenic combustion products formed during the cooking of meat at moderate to high temperatures. PhIP is the most common HA formed in fried, grilled or broiled meat, and is a colon, breast, and prostate carcinogen in rodents. The major metabolites of PhIP detected in human urine are N-2-OH-PhIP-N-2-glucuronide, PhIP-N-2-glucuronide, N-2-OH-PhIP-M-glucuronide, and 4'-PhIP-sulphate. We have measured the time course of PhIP in untreated and acid- or alkali-hydrolyzed urines from 10 healthy non-smoking subjects ingesting identical amounts of char-broiled beef (containing both HAs and PAHs) for 5 days. The morning after the first day of broiled beef consumption (containing 7.7 mug PhIP), urinary concentration of PhIP increased 14- to 38-fold above mean prefeed concentration. Following cessation of broiled meat consumption, urinary PhIP declined to near prefeed levels within 48-72 h. The ratio of alkali-labile PhIP metabolites to unmetabolized PhIP varied by 2.7-fold among subjects, ranging from 18:1 to 48:1. In a subsequent study we measured PhIP in acid-hydrolyzed urine from 66 subjects ingesting beef pan-fried at high temperature. A significant correlation (r = 0.61, P < 0.0001) was observed between the amount of fried meat ingested and concentration of PhIP in urines collected between 0 and 12 h after feeding. Other investigators have identified 2-OH-PhIP in acid-hydrolyzed urine from these subjects, and also observed a significant coffelation (r = 0.52, P < 0.0001) with the amount of fried meat ingested. Additional studies have measured PhIP metabolites in subjects consuming their normal (unrestricted) diet. PhIP was detected in acid-hydrolyzed urine from 20 to 50% of these subjects, depending on ethnic group. Taken together, these studies indicate that significant amounts of PhIP are bioavailable from ingestion of fried or char-broiled meats, and that urinary PhIP metabolites reflect recent (12-24b) ingestion. Furthermore, significant interindividual differences in the amounts of urinary PhIP metabolite excreted are observed following ingestion of similar amounts of PhIP. These differences do not correlate with interindividual differences in excretion of urinary pyrene metabolites in the same individuals after ingestion of char-broiled beef, indicating that levels of PhIP and pyrene metabolites in human urine are mediated by compound-specific metabolic factors. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. Int Agcy Res Canc, Unit Nutr & Canc, F-69372 Lyon, France. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Strickland, PT (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RI Friesen, Marlin/D-7328-2012; Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NIEHS NIH HHS [P30-ES03819, P01-ES06052] NR 26 TC 31 Z9 33 U1 1 U2 4 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 SEP 30 PY 2002 VL 506 SI SI BP 163 EP 173 AR PII S0027-5107(02)00163-X DI 10.1016/S0027-5107(02)00163-X PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400018 PM 12351156 ER PT J AU Nowell, S Coles, B Sinha, R MacLeod, S Ratnasinghe, DL Stotts, C Kadlubar, FF Ambrosone, CB Lang, NP AF Nowell, S Coles, B Sinha, R MacLeod, S Ratnasinghe, DL Stotts, C Kadlubar, FF Ambrosone, CB Lang, NP TI Analysis of total meat intake and exposure to individual heterocyclic amines in a case-control study of colorectal cancer: contribution of metabolic variation to risk SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE colorectal cancer; heterocyclic amines (HCA); glutathione S-transferase A1; sulfotransferase 1A1; cytochrome P450 2A6; genotype; caffeine phenotype ID GLUTATHIONE S-TRANSFERASES; CYTOCHROME P4501A2; POSSIBLE MECHANISM; VARYING DEGREES; UNITED-STATES; COLON-CANCER; DNA-ADDUCTS; WELL-DONE; RED MEAT; PHIP AB A case-control study of colorectal cancer, consisting of 157 cases and 380 controls matched by sex, ethnicity, decade of age and county of residence was performed to explore the associations between environmental exposure, metabolic polymorphisms and cancer risk. Participants were required to provide a blood sample, undergo caffeine phenotyping and complete an in-person interview that evaluated meat consumption, cooking methods and degree of doneness. A color atlas of foods cooked to different degrees of doneness was used to estimate food preparation techniques and food models were used to estimate serving portion sizes. Data was analyzed using a reference database of heterocyclic amine (HCA) exposure based on the food preferences chosen from the atlas. Data regarding individual food items cooked to different levels of doneness, as well as summary variables of foods and of food groups cooked to different degrees of doneness were also evaluated in a univariate analysis for association with colorectal cancer case status. Three measures of metabolic variation, hGSTA1 genotype, SULT1A1 genotype and the phenotype for CYP2A6 were also evaluated for possible association with colon cancer. While higher exposure to HCAs was strongly associated with colorectal cancer risk, increased consumption of five red meats cooked well done or very well done produced comparable odds ratios (OR) for colorectal cancer risk (OR = 4.36, 95% CI 2.08-9.60) for the highest quartile of exposure. Similarly, individuals in the most rapid CYP2A6 phenotype quartile showed an odds ratio (OR = 4.18, 95 % CI 2.03-8.90). The ORs for the low activity hGSTA1 and low activity SULT1A1 alleles were 2.0, 95% CI 1.0-3.7 and 0.6, 95% CI 0.3-1.1, respectively. Individual measures of specific HCAs provided little improvement in risk assessment over the measure of meat consumption, suggesting that exposure to other environmental or dietary carcinogens such as nitrosamines or undefined HCAs may contribute to colorectal cancer risk. Published by Elsevier Science B.V. C1 Cent Arkansas Vet Hlth Care Syst, Little Rock, AR 72205 USA. Arkansas Canc Res Ctr, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Mt Sinai Sch Med, New York, NY USA. RP Lang, NP (reprint author), Cent Arkansas Vet Hlth Care Syst, 4300 W 7th St, Little Rock, AR 72205 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NCI NIH HHS [R01CA55751]; NIA NIH HHS [R01AG15722] NR 42 TC 93 Z9 98 U1 1 U2 4 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 SEP 30 PY 2002 VL 506 SI SI BP 175 EP 185 AR PII S0027-5107(02)00164-1 DI 10.1016/S0027-5107(02)00164-1 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400019 PM 12351157 ER PT J AU Sinha, R AF Sinha, R TI An epidemiologic approach to studying heterocyclic amines SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE heterocyclic amines; cooking method; MeIQx; PhIP ID AROMATIC-AMINES; BREAST-CANCER; WELL-DONE; 2-AMINO-3,8-DIMETHYLIMIDAZO<4,5-F>QUINOXALINE MEIQX; COLORECTAL ADENOMAS; CYTOCHROME P4501A2; VARYING DEGREES; COOKING METHOD; LUNG-CANCER; RED MEAT AB Diets containing substantial amounts of red meat may increase the risk of colorectal, pancreatic, breast, prostate, and renal cancer. The association with red meat intake may be due to a combination of factors, such as content of fat, protein, and iron, and/or meat preparation (e.g. cooking or preserving methods). Laboratory results have shown that meats cooked at high temperatures contain heterocyclic amines (HCAs) known to be mutagenic and carcinogenic in animals. Many older epidemiologic studies of colon cancer using surrogates for HCA exposure from meat (for example, doneness level, surface browning, frying, intake of gravy) have produced suggestive but inconsistent results. These discrepancies may have resulted in part from having used dietary questionnaires that combined meat-cooking practices in ways that made the intake of HCAs difficult to estimate. Thus, over the last decade we have taken a multidisciplinary approach to investigating whether the association with red meat intake can be explained by meat-cooking practices that produce mutagens/carcinogens. To estimate intake, a database for HCAs have been developed and used in conjunction with a validated meat-cooking food frequency questionnaire (FFQ). To develop biological markers of internal exposure, a metabolic study was conducted where subjects consumed controlled amounts of meat cooked at low and high temperatures. The role of meat type, cooking methods, doneness levels, and meat-cooking mutagens were examined in case-control studies of colorectal adenomas, lung, and breast cancers using both questionnaire information and biomarkers. In a case-control study of colorectal adenomas, an increased risk was associated with a high intake of red meat. Most of this risk was due to intake of red meat cooked until well/very well done and/or by high-temperature cooking techniques such as grilling. Linking the FFQ information to HCA database, the impact several HCAs on risk was evaluated. An increased risk was associated with higher intake of MeIQx, possibly PhIP. Red meat, especially fried and/or well-done red meat, was associated with increased risk of lung cancer in a population-based case-control study. In addition, an increase in risk was demonstrated among non-smokers and moderate smokers for MeIQx intake. In a case-control study of breast cancer well-done red meat and PhIP was associated with increased risk of breast cancer. In this manuscript I will provide one approach to studying the relation of meat cooking-mutagens and cancer risk and will suggest the types of studies that may be required in the future to clarify these associations. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Sinha, R (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Rm 7028,6120 Execut Blvd,EPS 3024, Bethesda, MD 20892 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 23 TC 120 Z9 124 U1 0 U2 6 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 SEP 30 PY 2002 VL 506 SI SI BP 197 EP 204 AR PII S0027-5107(02)00166-5 DI 10.1016/S0027-5107(02)00166-5 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400021 PM 12351159 ER PT J AU Le Marchand, L Hankin, JH Pierce, LM Sinha, R Nerurkar, PV Franke, AA Wilkens, LR Kolonel, LN Donlon, T Seifried, A Custer, LJ Lum-Jones, A Chang, W AF Le Marchand, L Hankin, JH Pierce, LM Sinha, R Nerurkar, PV Franke, AA Wilkens, LR Kolonel, LN Donlon, T Seifried, A Custer, LJ Lum-Jones, A Chang, W TI Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE colorectal neoplasm; CYP1A2; diet; heterocyclic aromatic amines; NAT2 ID CAFFEINE URINARY METABOLITES; N-ACETYLTRANSFERASE ACTIVITY; HETEROCYCLIC AMINES; COOKED FOODS; CYP1A2 GENE; LIFE-STYLE; RISK; POLYMORPHISMS; CONSUMPTION; JAPANESE AB Heterocyclic amines (HAAs) and polycyclic hydrocarbons are suspected colorectal cancer (CRC) carcinogens that are found in well-done meat. They require metabolic activation by phase I enzymes, such as the smoking-inducible CYP1A isoenzymes. N-acetyltransferase 2 (NAT2) also play a role in the further activation of HAAs. We conducted a population-based case-control study in Hawaii to test the associations of preference for well-done red meat and HAA intake with colon and rectal cancers, as well as the modifying effects of NAT2 and CYP1A2. We interviewed 727 Japanese, Caucasian or Native Hawaiian cases and 727 controls matched on sex, age, and ethnicity. HAA intake was estimated based on consumption of meat and fish for each of several cooking methods and doneness levels. A subgroup of 349 cases and 467 controls was phenotyped for CYP1A2 by a caffeine test. We found that preference for well-done red meat was associated with a 8.8-fold increased risk of CRC (95% CI: 1.7-44.9) among ever-smokers with the NAT2 and CYP1A2 rapid phenotypes, compared to ever-smokers with low NAT2 and CYP1A2 activities and who preferred their red meat rare or medium. A dose-dependent association was also found between the HAA intake estimates and male rectal cancer, with a two- to three-fold increase in risk from the low (T-1) to high (T-3) tertile of intake for each HAA. This association was strongest for MeIQx. HAA intake was not associated with male colon cancer or colon or rectal cancer in women. These data provide support to the hypothesis that exposure to pyrolysis products through consumption of well-done meat increases the risk of CRC, particularly in individuals who smoke and are genetically susceptible (as determined by a rapid phenotype for both NAT2 and CYP1A2). An attempt to examine the risk associated with specific HAAs suggested that the main HAAs increase risk of rectal cancer in men and that they do not appreciably affect risk of rectal cancer in women or of colon cancer in either sex. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Hawaii, Canc Res Ctr Hawaii, Etiol Program, Honolulu, HI 96813 USA. NCI, Nutrit Epidemiol Branch, DCEG, Bethesda, MD USA. RP Le Marchand, L (reprint author), Univ Hawaii, Canc Res Ctr Hawaii, Etiol Program, 1236 Lauhala St,Suite 407, Honolulu, HI 96813 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NCI NIH HHS [N01-CN55424, R01-CA60987] NR 31 TC 90 Z9 92 U1 0 U2 5 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 SEP 30 PY 2002 VL 506 SI SI BP 205 EP 214 AR PII S0027-5107(02)00167-7 DI 10.1016/S0027-5107(02)00167-7 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400022 PM 12351160 ER PT J AU Anderson, KE Sinha, R Kulldorff, M Gross, M Lang, NP Barber, C Harnack, L DiMagno, E Bliss, R Kadlubar, FF AF Anderson, KE Sinha, R Kulldorff, M Gross, M Lang, NP Barber, C Harnack, L DiMagno, E Bliss, R Kadlubar, FF TI Meat intake and cooking techniques: associations with pancreatic cancer SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 8th International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds CY NOV 12-14, 2001 CL WASHINGTON, D.C. SP NCI, US FDA, Natl Ctr Toxicol Res, Toronto Res Chem Inc, Nestle Res Ctr, Oregon State Univ, Linus Pauling Inst DE epidemiology; pancreas cancer; meat intake; cooking practices ID HETEROCYCLIC AMINES HCAS; PAST MEDICAL HISTORY; RISK-FACTORS; DIET; FOOD; MUTAGENS; ALCOHOL; HABITS; COFFEE; BEEF AB Heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), formed in temperature and time-dependent manners during cooking of meat, may increase the risk of certain cancers. As these compounds could be carcinogenic for the pancreas, we assessed meat intake, preparation methods, and doneness preferences as risk factors for exocrine pancreatic cancer. In a case-control study (cases = 193, controls = 674), subjects provided information on their usual meat intake and how it was cooked, e.g. fried, grilled or barbecued (BBQ), etc. Meat doneness preferences were measured using photographs that showed internal doneness and external brownness with a numerical scale. Data were analyzed with unconditional logistic regression. Odds ratios (ORs) increased with increased intake of grilled/BBQ red meat in an analysis adjusted for age, sex, smoking, education, race, and diabetes. Based on amount of BBQ meat consumed, the OR and 95% confidence interval (0) for the fifth quintile relative to the reference group (quintiles 1 and 2) was 2.19 (1.4, 3.4). Findings were not substantively changed by further adjustment for calories, total fat, fruit and vegetables, or alcohol consumption (from a food frequency questionnaire (FFQ)). Other meat variables did not show statistically significant associations with risk nor did they substantively alter the findings for BBQ. These included total meat, processed meat, total red meat, total white meat, total broiled meat, total fried meat, or total meat cooked by means other than grilling. We conclude that grilled red meat intake is a risk factor for pancreatic cancer and that method of meat preparation in addition to total intake is important in assessing the effects of meat consumption in epidemiologic studies. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Minnesota, Minneapolis, MN 55454 USA. NCI, Rockville, MD 20852 USA. Univ Connecticut, Sch Med, Farmington, CT 06030 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Mayo Clin, Rochester, MN 55905 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Anderson, KE (reprint author), Univ Minnesota, Minneapolis, MN 55454 USA. RI Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 FU NCI NIH HHS [R01-CA58697] NR 35 TC 83 Z9 84 U1 3 U2 17 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 SEP 30 PY 2002 VL 506 SI SI BP 225 EP 231 AR PII S0027-5107(02)00169-0 DI 10.1016/S0027-5107(02)00169-0 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 602PJ UT WOS:000178513400024 PM 12351162 ER PT J AU Kumar, A Mukherjee, S Shen, J Buch, S Li, Z Adany, I Liu, ZQ Zhuge, W Piatak, M Lifson, JD McClure, HM Narayan, O AF Kumar, A Mukherjee, S Shen, J Buch, S Li, Z Adany, I Liu, ZQ Zhuge, W Piatak, M Lifson, JD McClure, HM Narayan, O TI Immunization of macaques with live simian human immunodeficiency virus (SHIV) vaccines conferred protection against AIDS induced by homologous and heterologous SHIVs and simian immunodeficiency virus SO VIROLOGY LA English DT Article ID CD8(+) T-CELLS; HIV-1/SIV CHIMERIC VIRUS; LYMPH-NODE IMMUNIZATION; PIG-TAILED MACAQUES; RHESUS MACAQUES; IMMUNE-RESPONSES; IN-VIVO; ANTIBODY-RESPONSES; INFECTED MACAQUES; PERIPHERAL-BLOOD AB To evaluate the vaccine potential of SHIVs attenuated by deletion of viral accessory genes, seven rhesus macaques were sequentially immunized with DeltavpuDeltanefSHIV-4 (vaccine-I) followed by DeltavpuSHIV(PPC) (vaccine-II). Despite the absence of virological evidence of productive infection with the vaccine strains, based on analysis of infectivity among peripheral blood mononuclear cells (PBMC) of the vaccinated animals, all seven animals developed binding as well as neutralizing antibodies against both vaccine-I and -II. The animals also developed vaccine virus-specific CTLs that recognized homologous as well as heterologous pathogenic SHIVs and SIV, and also soluble inhibitory factors that blocked the in vitro replication of the vaccine strains and different challenge viruses. Virus-specific cellular and humoral responses were sustained throughout a 58-week prechallenge period, To model aspects of natural transmission, the animals received a mucosal (rectal) challenge, with a mixture of three challenge viruses, SHIVKU, SHIV89.6 P, and SIV(mac)R71/17E. Two mock-vaccinated control animals inoculated with the same mixture of challenge viruses developed large numbers of infectious PBMC, high plasma viremia, and precipitous loss of CD4(+) T cells. The control animals did not develop any immune responses and succumbed to AIDS between 6 and 7 weeks postchallenge. All seven vaccinated animals became infected with challenge viruses as indicated by the presence of infectious cells in the PBMC and/or viral RNA in plasma, However, peak plasma viremia in vaccinates was two to nearly five logs lower than in the control animals and later plasma viral RNA became undetectable in all vaccinates. Vaccinated animals maintained normal CD4(+) T cell levels throughout the study, Challenge with pathogenic viruses caused massive anamnestic responses as determined by quantitation of virus-specific CD4(+) and CD8(+) T cells by intracellular IFN-gamma staining, and these cells persisted for at least 74 weeks. The study is still in progress and at this time DNA of SIV has become undetectable in lymph nodes of six of the seven vaccinates, SHIV89.6P in five of the seven, and SHIVKU in three of the seven animals. (C) 2002 Elsevier Science (USA). C1 Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Lab Viral Pathogenesis, Kansas City, KS 66160 USA. NCI, SAIC Frederick, AIDS Vaccine Program, Retroviral Pathogenesis Lab, Frederick, MD 21702 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. RP Kumar, A (reprint author), Ponce Sch Med, Dept Microbiol, POB 7004, Ponce, PR 00732 USA. OI Buch, Shilpa/0000-0002-3103-6685 FU NCI NIH HHS [N01-CO-56000]; NCRR NIH HHS [RR13152, RR06753]; NIDA NIH HHS [DA15013]; NINDS NIH HHS [NS40238] NR 87 TC 32 Z9 33 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 SEP 30 PY 2002 VL 301 IS 2 BP 189 EP 205 DI 10.1006/viro.2002.1544 PG 17 WC Virology SC Virology GA 600DY UT WOS:000178376400001 PM 12359422 ER PT J AU Nguyen, QT Wong, S Heegaard, ED Brown, KE AF Nguyen, QT Wong, S Heegaard, ED Brown, KE TI Identification and characterization of a second novel human Erythrovirus variant, A6 SO VIROLOGY LA English DT Article ID HUMAN PARVOVIRUS B19; SEQUENCE VARIABILITY; SIMIAN PARVOVIRUS; GENETIC DIVERSITY; UNIQUE REGION; INFECTION; INVITRO; ANEMIA; VIRUS; TRANSCRIPTION AB Parvovirus B19 (B19), currently the only accepted member of the Erythrovirus genus, is the only parvovirus known to be pathogenic in humans, Recently a viral sequence, tentatively termed V9 which showed 11% variability from the published B19 sequences, was described from a patient with aplastic crisis. To search for additional parvovirus variants, we used the new NS1/7.5EC PCR assay whose primers were designed from a conserved region of the B19/V9 sequence and encompasses an Mfel restriction enzyme site that would allow differentiation between B19- and V9-like sequences. Screening of 225 serum and bone marrow samples and 62 plasma pools identified one new atypical parvovirus sequence, A6, from an anemic HIV-positive patient, AS exhibited 88% similarity to B19 and 92% to V9, compared to >98% correspondence between reported B19 isolates Based on the genome similarity to B19, an RT-PCR for As capsid transcripts was developed and used to test for A6 infectivity of UT7/Epo/S1 cells. Despite high viral titers, A6 viral transcripts were not detected. Thus, although the prevalence of B19 variants probably is low, the true clinical significance remains unknown. Current PCR analyses are unlikely to detect novel variants without the design of specific primers to the A6/V9/B19 common sequences. (C) 2002 Elsevier Science (USA). C1 NHLBI, Virus Discovery Grp, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Inst Med Microbiol & Immunol, Copenhagen, Denmark. RP Brown, KE (reprint author), NHLBI, Virus Discovery Grp, Hematol Branch, NIH, Bldg 10,Room 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 29 TC 104 Z9 111 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2002 VL 301 IS 2 BP 374 EP 380 DI 10.1006/viro.2002.1585 PG 7 WC Virology SC Virology GA 600DY UT WOS:000178376400018 PM 12359439 ER PT J AU Valdez, H Connick, E Smith, KY Lederman, MM Bosch, RJ Kim, RS St Clair, M Kuritzkes, DR Kessler, H Fox, L Blanchard-Vargas, M Landay, A AF Valdez, H Connick, E Smith, KY Lederman, MM Bosch, RJ Kim, RS St Clair, M Kuritzkes, DR Kessler, H Fox, L Blanchard-Vargas, M Landay, A CA AIDS Clin Trials Grp Protocol 375 TI Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease SO AIDS LA English DT Article DE antiretroviral therapy; CD4 lymphocytes; immune activation; immune competence; CD28 ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; T-CELL FUNCTION; INFECTED PATIENTS; MARROW TRANSPLANTATION; CONTROLLED TRIAL; THYMIC FUNCTION; HOMOSEXUAL MEN; BONE-MARROW; VIRAL-LOAD AB Objective: To describe the magnitude of immune restoration after long-term control of HIV-1 replication. Design: Prospective study of immune restoration in patients starting highly active antiretroviral therapy (HAART). Methods: Patients with moderately advanced HIV-1 infection (CD4 cells between 100 x 10(6) and 300 x 10(6)/1) who enrolled in a trial of HAART and who had suppression of HIV-1 replication during 3 years of therapy were evaluated for phenotypic and functional indices of immune restoration. Results: Almost all immune restoration achieved occurred during the first year, The median CD4 lymphocyte count increased by 159 x 10(6) cells/l during the first year (P < 0.001); CD4 lymphocyte rises during the second and third years were not significant. Most decreases in activation antigen expression (CD38/HLA-DR) on CD4 and CD8 lymphocytes occurred during the first year, and after 3 years, patient lymphocytes were still abnormally activated. The proportion of CD4 lymphocytes expressing CD28 increased during the first and second years, but even after 3 years, CD28 expression on CD4 cells remained abnormally low, Lymphocyte proliferative responses to Candida normalized during the first 12 weeks of HAART while responses to tetanus increased only after immunization and enhanced responses to HIV-1 p24 antigen were not observed. Conclusions: Immune restoration was incomplete in patients who started HAART with moderately advanced HIV-1 disease and most changes occurred during the first year. These data suggest that this degree of suppression of HIV-1 replication alone will not suffice to restore immune competence. The clinical significance of incomplete reconstitution of CD4 lymphocyte number, phenotype, and proliferative function in HIV-1 infection remains to be determined. (C) 2002 Lippincott Williams & Wilkins. C1 Case Western Reserve Univ, Univ Hosp, Cleveland Ctr AIDS Res, Cleveland, OH 44106 USA. Univ Colorado, Ctr Hlth Sci, Denver, CO 80202 USA. VA Med Ctr, Denver, CO USA. Rush Med Coll, Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. GlaxoSmithKline, Res Triangle Pk, NC USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. AIDS Clin Trials Grp Operat Ctr, Rockville, MD USA. RP Lederman, MM (reprint author), 2061 Cornell Rd Rm 301C, Cleveland, OH 44106 USA. FU NCI NIH HHS [CA46934]; NCRR NIH HHS [RR00080, RR0051]; NIAID NIH HHS [AI 25879, AI 25915, AI 32770, AI 36219, AI 38858, AI 44748, AI-38858] NR 56 TC 143 Z9 148 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 27 PY 2002 VL 16 IS 14 BP 1859 EP 1866 DI 10.1097/00002030-200209270-00002 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 611WE UT WOS:000179040100002 PM 12351945 ER PT J AU Billing-Marczak, K Buzanska, L Winsky, L Nowotny, M Rudka, T Isaacs, K Belin, MF Kuznicki, J AF Billing-Marczak, K Buzanska, L Winsky, L Nowotny, M Rudka, T Isaacs, K Belin, MF Kuznicki, J TI AP2-like cis element is required for calretinin gene promoter activity in cells of neuronal phenotype differentiated from multipotent human cell line DEV SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE EF-hand calcium binding protein; calretinin gene promoter; AP2 element; EMSA; cell transfection; multipotent neural stem cell DEV ID TRANSCRIPTION FACTOR AP-2; CALCIUM-BINDING PROTEIN; TERM POTENTIATION INDUCTION; IMMUNOHISTOCHEMICAL LOCALIZATION; DENTATE GYRUS; RAT-BRAIN; EXPRESSION; MESOTHELIOMA; CALBINDIN; MICE AB Calretinin (CR) is an EF-hand calcium binding protein expressed at high level in neurons. To identify regulatory elements in CR gene promoter, cultured rat cortical cells were transfected with constructs containing its 5' -end deletion mutants and the luciferase reporter gene. A fragment ending at - 115 bp upstream of the transcription start site had high promoter activity and was able to induce expression of luciferase specifically in neuronal cells of cortical cultures. The wild type sequence of - 115/ + 54 CR promoter fragment preferentially drove the expression of green fluorescent protein analog in cells of neuronal phenotype differentiated from multipotent human cell line DEV. Electrophoretic mobility shift assays (EMSA) revealed that the - 115/ - 71 CR gene promoter region contains a binding site for a factor present in brain nuclear extract. Among oligonucleotides containing consensus binding sites for transcription factors within this region, the one representing AP2 binding site was able to compete formation of a protein complex. Mutations of this site prevented the binding between brain protein(s) and the - 115/ + 54 CR gene promoter region and abolished the preferential expression of reporter gene in neuronal cells of DEV line. Thus, the AP2-like element seems to be essential for the neuron-specific activity of the CR gene promoter. (C) 2002 Elsevier Science B.V. All rights reserved. C1 M Nencki Inst Expt Biol, Dept Mol & Cellular Neurobiol, PL-02093 Warsaw, Poland. Polish Acad Sci, Med Res Ctr, PL-02106 Warsaw, Poland. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Fed Med Laennec, INSERM, U433, F-69372 Lyon 8, France. Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland. RP Kuznicki, J (reprint author), M Nencki Inst Expt Biol, Dept Mol & Cellular Neurobiol, 3 Pasteur St, PL-02093 Warsaw, Poland. FU PHS HHS [6P05A04920, 6P04A04618] NR 43 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD SEP 27 PY 2002 VL 1577 IS 3 BP 412 EP 420 AR PII S0167-4781(02)00443-8 DI 10.1016/S0167-4781(02)00443-8 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 602TA UT WOS:000178519500006 PM 12359331 ER PT J AU Opi, S Peloponese, JM Esquieu, D Campbell, G de Mareuil, J Walburger, A Solomiac, M Gregoire, C Bouveret, E Yirrell, DL Loret, EP AF Opi, S Peloponese, JM Esquieu, D Campbell, G de Mareuil, J Walburger, A Solomiac, M Gregoire, C Bouveret, E Yirrell, DL Loret, EP TI Tat HIV-1 primary and tertiary structures critical to immune response against non-homologous variants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE-SEQUENCE; KAPOSIS-SARCOMA; AIDS VIRUS; T-CELLS; PROTEIN; TRANSCRIPTION; TRANSACTIVATOR; LYMPHOCYTES; VACCINATION; ASSIGNMENT AB Clinical studies show that in the absence of anti-retroviral therapy an immune response against the human immunodeficiency virus type 1 (HIV-1), transacting transcriptional activator (Tat) protein correlates with long term non-progression. The purpose of this study is to try to understand what can trigger an effective immune response against Tat. We used five Tat variants from HIV strains identified in different parts of the world and showed that mutations of as much as 38% exist without any change in activity. Rabbit sera were raised against Tat variants identified in rapid-progressor patients (Tat HXB2, a European variant and Tat Eli, an African variant) and a long term non-progressor patient (Tat Oyi, an inactive African variant). Enzymelinked immunosorbent assay (ELISA) results showed that anti-Tat Oyi serum had the highest antibody titer and was the only one to have a broad antibody response against heterologous Tat variants. Surprisingly, Tat HXB2 was better recognized by anti-Tat Oyi serum compared with anti-Tat HXB2 serum. Western blots showed that non-homologous Tat variants were recognized by antibodies directed against conformational epitopes. This study suggests that the primary and tertiary structures of the Tat variant from the long term non-progressor patient are critical to the induction of a broad and effective antibody response against Tat. C1 Inst Biol Struct & Microbiol, Lab Ingn Syst Macromol, CNRS, UPR 9027, F-13402 Marseille, France. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Edinburgh, Ctr HIV Res, Edinburgh EH9 3JN, Midlothian, Scotland. Uganda Virus Res Inst, Programme AIDS Uganda, MRC, Entebbe, Uganda. RP Loret, EP (reprint author), Inst Biol Struct & Microbiol, Lab Ingn Syst Macromol, CNRS, UPR 9027, 31 Chemin Joseph Aiguier, F-13402 Marseille, France. OI Campbell, Grant/0000-0003-3927-1994 NR 36 TC 28 Z9 32 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 SEP 27 PY 2002 VL 277 IS 39 BP 35915 EP 35919 DI 10.1074/jbc.M204393200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100021 PM 12080071 ER PT J AU Munoz, E Brewer, M Baler, R AF Munoz, E Brewer, M Baler, R TI Circadian transcription - Thinking outside the E-Box SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING; C-MYC; GENE-EXPRESSION; REGULATORY ELEMENTS; FIRST INTRON; IN-VIVO; PROMOTER; LOOP; UPSTREAM; PROTEINS AB The E-Box is a widely used DNA control element. Despite its brevity and broad distribution the E-Box is a remarkably versatile sequence that affects many different genetic programs, including proliferation, differentiation, tissue-specific responses, and cell death. The circadian clock is one of the latest pathways shown to employ this element. In this context, E-Boxes are likely to play a key role in establishing the robust waves of gene expression characteristic of circadian transcription. The regulatory flexibility of the E-Box hinges on the sequence ambiguity allowed at its core, the strong influence of the surrounding sequences, and the recruitment of spatially and temporally regulated E-Box-binding factors. Therefore, understanding how a particular E-Box can accomplish a specific task entails the identification and systematic analysis of these cis- and transacting E-Box modifiers. In the present study we compared the E-Box-containing minimal promoters of vasopressin and cyclin B1, two genes that can respond to the transcriptional oscillators driving the circadian clock and cell cycle, respectively. Results of this comparison will help elucidate the manner in which discreet DNA modules associate to either augment or restrain the activation of potential circadian E-Boxes in response to competing regulatory signals. C1 NIMH, Unit Temporal Gene Express, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Baler, R (reprint author), NIH, Bldg 36,Rm 2A-09, Bethesda, MD 20892 USA. OI Munoz, Estela/0000-0002-6701-1535 NR 54 TC 57 Z9 58 U1 2 U2 5 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 SEP 27 PY 2002 VL 277 IS 39 BP 36009 EP 36017 DI 10.1074/jbc.M203909200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100032 PM 12130638 ER PT J AU Fuda, H Lee, YC Shimizu, C Javitt, NB Strott, CA AF Fuda, H Lee, YC Shimizu, C Javitt, NB Strott, CA TI Mutational analysis of human hydroxysteroid sulfotransferase SULT2B1 isoforms reveals that exon 1B of the SULT2B1 gene produces cholesterol sulfotransferase, whereas exon 1A yields pregnenolone sulfotransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN CYTOSOLIC SULFOTRANSFERASES; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; ESTROGEN SULFOTRANSFERASE; CRYSTAL-STRUCTURE; HUMAN LIVER; SULFATE; KERATINOCYTES; EXPRESSION; DIFFERENTIATION; NEUROSTEROIDS AB As a result of an alternative exon 1, the gene for human hydroxysteroid sulfotransferase (SULTB1) encodes for two peptides differing only at their amino termini. The SULT2B1b isoform preferentially sulfonates cholesterol. Conversely, the SULT2B1a isoform avidly sulfonates pregnenolone but not cholesterol. The outstanding structural feature that distinguishes the SULT2B1 isoforms from the prototypical SLTLT2A1 isozyme is the presence of extended amino- and carboxyl-terminal ends in the former. Investigating the functional significance of this unique characteristic reveals that removal of 53 amino acids from the relatively long carboxyl-terminal end that is common to both SULT2B1 isoforms has no effect on the catalytic activity of either isoform. On the other hand, removal of 23 amino acids from the amino-terminal end that is unique to SULT2B1b results in loss of cholesterol sulfotransferase activity, whereas removal of 8 amino acids from the amino-terminal end that is unique to SULT2B1a has no effect on pregnenolone sulfotransferase activity. Deletion analysis along with site-directed mutagenesis of SLTLT2B1b reveal that the amino acid segment 19-23 residues from the amino terminus and particularly isoleucines at positions 21 and 23 are crucial for cholesterol catalysis. In the gene for SULT2B1, exon 1B encodes for only the unique amino-terminal region of SULT2B1b; however, exon 1A encodes for the unique amino-terminal end of SULT2B1a plus an additional 48 amino acids. Thus, if the gene for SULT2B1 employs exon 1B, cholesterol sulfotransferase is synthesized, whereas if exon 1A is used, pregnenolone sulfotransferase is produced. C1 NICHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 25 TC 58 Z9 60 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 SEP 27 PY 2002 VL 277 IS 39 BP 36161 EP 36166 DI 10.1074/jbc.M207165200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100051 PM 12145317 ER PT J AU Kaul, S Murphy, PJM Chen, J Brown, L Pratt, WB Simons, SS AF Kaul, S Murphy, PJM Chen, J Brown, L Pratt, WB Simons, SS TI Mutations at positions 547-553 of rat glucocorticoid receptors reveal that hsp90 binding requires the presence, but not defined composition, of a seven-amino acid sequence at the amino terminus of the ligand binding domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK-PROTEIN; NUCLEAR-RECEPTOR; STEROID-BINDING; PROGESTERONE-RECEPTOR; INTERDOMAIN COMMUNICATION; CONFORMATIONAL-CHANGES; RETICULOCYTE LYSATE; ESTROGEN-RECEPTOR; GENE-EXPRESSION; DNA-BINDING AB Glucocorticoid receptors (GRs) must heterocomplex with hsp90 to have an open steroid binding cleft that can be accessed by steroid. We reported that a seven-amino acid sequence (547-553 of rat GR) overlapping the amino-terminal end of the ligand binding domain is required for hsp90 binding to GR. We have now conducted saturation mutagenesis of this sequence, which appears to be part of the surface where the ligand binding cleft merges with the surface of the ligand binding domain. No single point mutation causes significant changes in any of a variety of biochemical and biological properties in addition to hsp90 binding. A triple mutation (P548A/T549A/V551A) increases by > 100-fold the steroid concentration required for half-maximal induction without affecting the level of maximal induction or coactivator response. Interestingly, this triple mutant displays reduced binding of steroid and hsp90 in whole cells, but it possesses wild type affinity for steroid and normal hsp90 binding capacity under cell-free conditions. This phenotype of a dramatic shift in the dose response for transactivation would be expected from an increase in the rate of disassembly of the triple mutant GR-hsp90 heterocomplex in the cell. Mutation of the entire seven-amino acid region to CAAAAAC maintains the presence of a critical alpha-helical structure and heterocomplex formation with hsp90 but eliminates steroid binding and transcriptional activation, thus disconnecting hsp90 binding from opening of the ligand binding cleft and steroid binding. C1 NIDDK, LMCB, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Simons, SS (reprint author), NIDDK, LMCB, Steroid Hormones Sect, NIH, Bldg 8,Rm B2A-07, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK31753] NR 56 TC 32 Z9 33 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 SEP 27 PY 2002 VL 277 IS 39 BP 36223 EP 36232 DI 10.1074/jbc.M206748200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100058 PM 12145311 ER PT J AU Chen, AJ Zhou, GS Juan, T Colicos, SM Cannon, JP Cabriera-Hansen, M Meyer, CF Jurecic, R Copeland, NG Gilbert, DJ Jenkins, NA Fletcher, F Tan, TH Belmont, JW AF Chen, AJ Zhou, GS Juan, T Colicos, SM Cannon, JP Cabriera-Hansen, M Meyer, CF Jurecic, R Copeland, NG Gilbert, DJ Jenkins, NA Fletcher, F Tan, TH Belmont, JW TI The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; GROWTH-FACTOR-BETA; HEMATOPOIETIC-CELLS; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; MITOGEN; MAP; PHOSPHORYLATION; JNK; APOPTOSIS AB The involvement of dual specificity phosphatases (DSPs) in the mitogen-activated protein kinase (MAPK) signaling has been mostly limited to the inactivation of MAPKs by the direct dephosphorylation of the TXY motif within their activation loop. We report the cloning and characterization of a murine DSP, called JNK pathway-associated phosphatase (JKAP), which lacks the regulatory region present in most other MAP kinase phosphatases (MKPs) and is preferentially expressed in murine Lin(-)Sca-1(+) stem cells. Overexpression of JKAP in human embryonic kidney 293T cells specifically activated c-Jun N-terminal kinase (JNK) but not p38 and extracellular signal-regulated kinase 2. Overexpression of a mutant JKAP, JKAP-C88S, blocked tumor necrosis factor-a-induced JNK activation. Targeted gene disruption in murine embryonic stem cells abolished JNK activation by tumor necrosis factor-a and transforming growth factor-beta, but not by ultraviolet-C irradiation, indicating that JKAP is necessary for optimal JNK activation. JKAP associated with JNK and MKK7, but not SEK1, in vivo. However, JKAP did not interact with JNK in vitro, suggesting that JKAP exerts its effect on JNK in an indirect manner. Taken together, these studies identify a positive regulator for the JNK pathway and suggest a novel role for DSP in mitogen-activated protein kinase regulation. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. Amgen Inc, Dept Expt Hematol, Newbury Pk, CA 91320 USA. NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, ABL Basic Res Program, Ft Detrick, MD 21702 USA. RP Belmont, JW (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RI Tan, Tse-Hua/E-3983-2010; OI Tan, Tse-Hua/0000-0003-4969-3170; Belmont, John/0000-0001-7409-3578 FU NCI NIH HHS [R01 CA87076]; NHGRI NIH HHS [T32 HG00003]; NIAID NIH HHS [R01 AI42532]; NICHD NIH HHS [HD36280]; NIDDK NIH HHS [R01 DK48647]; NIGMS NIH HHS [T32 GM08307] NR 51 TC 48 Z9 50 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 27 PY 2002 VL 277 IS 39 BP 36592 EP 36601 DI 10.1074/jbc.M200453200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100103 PM 12138158 ER PT J AU Korkmaz, KS Elbi, C Korkmaz, CG Loda, M Hager, GL Saatcioglu, F AF Korkmaz, KS Elbi, C Korkmaz, CG Loda, M Hager, GL Saatcioglu, F TI Molecular cloning and characterization of STAMP1, a highly prostate-specific six transmembrane protein that is overexpressed in prostate cancer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GREEN FLUORESCENT PROTEIN; COMPLEX IN-VIVO; HOMEOBOX GENE; GOLGI-COMPLEX; ANTIGEN; CARCINOMA; ORGANIZATION; EXPRESSION; ANDROGENS; XENOGRAFT AB We have identified a novel gene, six transmembrane protein of prostate 1 (STAMP1), which is largely specific to prostate for expression and is predicted to code for a 490-amino acid six transmembrane protein. Using a form of STAMP1 labeled with green fluorescent protein in quantitative time-lapse and immunofluorescence confocal microscopy, we show that STAMP1 is localized to the Golgi complex, predominantly to the trans-Golgi network, and to the plasma membrane. STAMP1 also localizes to vesicular tubular structures in the cytosol and colocalizes with the early endosome antigen 1 (EEA1), suggesting that it may be involved in the secretory/endocytic pathways. STAMP1 is highly expressed in the androgen-sensitive, androgen receptor-positive prostate cancer cell line LNCaP, but not in androgen receptor-negative prostate cancer cell lines PC-3 and DU145. Furthermore, STAMP1 expression is significantly lower in the androgen-dependent human prostate xenograft CWR22 compared with the relapsed derivative CWR22R, suggesting that its expression may be deregulated during prostate cancer progression. Consistent with this notion, in situ analysis of human prostate cancer specimens indicated that STAMP1 is expressed exclusively in the epithelial cells of the prostate and its expression is significantly increased in prostate tumors compared with normal glands. Taken together, these data suggest that STAMP1 may have an important role in the normal prostate cell as well as in prostate cancer progression. C1 Univ Oslo, Dept Biol, N-0316 Oslo, Norway. Univ Oslo, Biotechnol Ctr Oslo, N-0316 Oslo, Norway. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Saatcioglu, F (reprint author), Univ Oslo, Dept Biol, Postboks 1050 Blindern, N-0316 Oslo, Norway. NR 51 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 SEP 27 PY 2002 VL 277 IS 39 BP 36689 EP 36696 DI 10.1074/jbc.M202414200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100115 PM 12095985 ER PT J AU Vorberg, I Priola, SA AF Vorberg, I Priola, SA TI Molecular basis of scrapie strain glycoform variation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRION PROTEIN ISOFORMS; TRANSMISSIBLE MINK ENCEPHALOPATHY; CREUTZFELDT-JAKOB-DISEASE; CULTURED-CELLS; AGENT; PRP; BSE; CONVERSION; PHOSPHOLIPASE; CONFORMATIONS AB Transmissible spongiform encephalopathies (TSE) are characterized by the conversion of a protease-sensitive host glycoprotein, prion protein or PrP-sen, to a protease-resistant form (PrP-res). PrP-res molecules that accumulate in the brain and lymphoreticular system of the host consist of three differentially glycosylated forms. Analysis of the relative amounts of the PrP-res glycoforms has been used to discriminate TSE strains and has become increasingly important in the differential diagnosis of human TSEs. However, the molecular basis of PrP-res glycoform. variation between different TSE agents is unknown. Here we report that PrP-res itself can dictate strain-specific PrP-res glycoforms. The final PrP-res glycoform pattern, however, can be influenced by the cell and significantly altered by subtle changes in the glycosylation state of PrP-sen. Thus, strain-specific PrP-res glycosylation profiles are likely the consequence of a complex interaction between PrP-res, PrP-sen, and the cell and may indicate the cellular compartment in which the strain-specific formation of PrP-res occurs. C1 NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. NR 47 TC 58 Z9 60 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 SEP 27 PY 2002 VL 277 IS 39 BP 36775 EP 36781 DI 10.1074/jbc.M206865200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100127 PM 12138171 ER PT J AU Xu, XL Lockamy, VL Chen, KJ Huang, Z Shields, H King, SB Ballas, SK Nichols, JS Gladwin, MT Noguchi, CT Schechter, AN Kim-Shapiro, DB AF Xu, XL Lockamy, VL Chen, KJ Huang, Z Shields, H King, SB Ballas, SK Nichols, JS Gladwin, MT Noguchi, CT Schechter, AN Kim-Shapiro, DB TI Effects of iron nitrosylation on sickle cell hemoglobin solubility SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; NITRIC-OXIDE HEMOGLOBIN; DEOXYHEMOGLOBIN-S; OXYGEN-BINDING; LIGAND-BINDING; SPIN-RESONANCE; TREATED RATS; IN-VIVO; TRANSPORT; 2,3-DIPHOSPHOGLYCERATE AB One mechanism by which nitric oxide (NO) has been proposed to benefit patients with sickle cell disease is by reducing intracellular polymerization of sickle hemoglobin (HbS). In this study we have examined the ability of nitric oxide to inhibit polymerization by measuring the solubilizing effect of iron nitrosyl sickle hemoglobin (HbS-NO). Electron paramagnetic resonance spectroscopy was used to confirm that, as found in vivo, the primary type of NO ligation produced in our partially saturated NO samples is pentacoordinate a-nitrosyl. Linear dichroism spectroscopy and delay time measurements were used to confirm polymerization. Based on sedimentation studies we found that, although fully ligated (100% tetranitrosyl) HbS is very soluble, the physiologically relevant, partially ligated species do not provide a significant solubilizing effect. The average solubilizing effect of 26% NO saturation was 0.045; much less than the 0.15 calculated for the effect of 26% oxygen saturation. Given the small amounts of NO-ligated hemoglobin achievable through any kind of NO therapy, we conclude that NO therapy does not benefit patients through any direct solubilizing effect. C1 Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. Jefferson Med Coll, Cardeza Fdn Hematol Res, Dept Med, Philadelphia, PA 19107 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NIH, Biol Chem Lab, Bethesda, MD 20892 USA. RP Kim-Shapiro, DB (reprint author), Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. OI Lockamy, Virginia/0000-0002-6545-7859; Schechter, Alan N/0000-0002-5235-9408 FU NCRR NIH HHS [RR15018]; NHLBI NIH HHS [R01 HL058091, R29 HL058091, HL62198, HL58091] NR 46 TC 15 Z9 15 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 SEP 27 PY 2002 VL 277 IS 39 BP 36787 EP 36792 DI 10.1074/jbc.M205350200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100129 PM 12138112 ER PT J AU Deming, PB Flores, KG Downes, CS Paules, RS Kaufmann, WK AF Deming, PB Flores, KG Downes, CS Paules, RS Kaufmann, WK TI ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLO-LIKE KINASE; CELL-CYCLE CHECKPOINTS; DNA-DAMAGE CHECKPOINT; NUCLEAR EXPORT; HUMAN FIBROBLASTS; MAMMALIAN-CELLS; PROTEIN-KINASE; PHOSPHORYLATION; B1; LOCALIZATION AB An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase 11 and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase H catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase 11 inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Ctr Environm Hlth & Susceptibil, Chapel Hill, NC 27599 USA. NIEHS, Growth Control & Canc Grp, NIH, Res Triangle Pk, NC 27709 USA. Univ Ulster, Sch Biomed Sci, Coleraine BT52 1SA, Londonderry, North Ireland. RP Kaufmann, WK (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA42765, P30-CA16086, R01 CA081343]; NIEHS NIH HHS [T32-ES07017, P30-ES10126] NR 46 TC 43 Z9 44 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 SEP 27 PY 2002 VL 277 IS 39 BP 36832 EP 36838 DI 10.1074/jbc.M206109200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 598KN UT WOS:000178275100135 PM 12147700 ER PT J AU Bewley, CA Kiyonaka, S Hamachi, I AF Bewley, CA Kiyonaka, S Hamachi, I TI Site-specific discrimination by cyanovirin-N for alpha-linked trisaccharides comprising the three arms of Man(8) and Man(9) SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE NMR; Man(8) D1D3 and Man(9); carbohydrate-binding proteins; HIV; isothermal titration calorimetry ID VIRUS-INACTIVATING PROTEIN; GP120; BINDING; OLIGOSACCHARIDES; AFFINITY; CD4 AB Cyanovirin-N (CVN) is a novel cyanobacterial protein that selectively binds with nanomolar affinities the mammalian oligosaccharides Man(8) and Man(9). Consequently, CVN potently blocks HIV entry through highly avid carbohydrate-mediated interactions with the HIV-envelope glycoprotein gp120, and is under preclinical investigation as an anti-HIV microbicide. CVN contains two non-overlapping carbohydrate-binding sites that bind the disaccharide Manalpha(1-2)Manalpha (which represents the terminal disaccharide of all three arms of Man(9)) with low to sub-micromolar affinities. The solution structure of a 1:2 CVN:Manalpha(1-2)Manalpha complex revealed that CVN recognizes the stacked conformation of Manu(1-2)Manalpha through a deep hydrophilic-binding pocket on one side of the protein (site 2) and a semi-circular cleft on the other (site 1). With the prominent exception of the C1 hydroxyl group of the reducing mannopyranose ring, the bound disaccharide is positioned so that each hydroxyl group is involved in a direct or water-mediated hydrogen bond to the polar or charged side-chains comprising the binding pocket. Thus, to determine whether the next-most reducing mannopyranose ring will augment CVN affinity and selectivity, we have characterized by NMR and ITC the binding of CVN to three synthetic trisaccharides representing the full-length D1, D2 and D3 arms of mammalian oligomannosides. Our findings demonstrate that site 1 is able to discriminate between the three related trisaccharides methyl Manalpha(1-2)Manalpha(1-2)Man, m.ethyl Manalpha(1-2)Manalpha(1-3)Man and methyl Manalpha(1-2)Manalpha(1-6)Man with remarkable selectivity; and binds these trisaccharides with K-A values ranging from 8.1 x 10(3) M-1 to 6.6 x 10(6) M-1. Site 2 is less selective in that it binds all three trisaccharides with similar K-A values ranging from 1.7 to 3.7(+/-0.3) x 10(5) M-1, but overall binds these trimannosides with higher affinities than site 1. The diversity of pathogenic organisms that display alpha(1-2)-linked mannosides on their cell surfaces suggests a broad defensive role for CVN in its cyanobacterial source. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Dept Chem & Biochem, Fukuoka 8128581, Japan. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI U-ID, Kyushu/C-5291-2016 NR 21 TC 47 Z9 47 U1 0 U2 4 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 SEP 27 PY 2002 VL 322 IS 4 BP 881 EP 889 DI 10.1016/S0022-2836(02)00842-2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 601YB UT WOS:000178475900020 PM 12270721 ER PT J AU Plewnia, C Hoppe, J Hiemke, C Bartels, M Cohen, LG Gerloff, C AF Plewnia, C Hoppe, J Hiemke, C Bartels, M Cohen, LG Gerloff, C TI Enhancement of human cortico-motoneuronal excitability by the selective norepinephrine reuptake inhibitor reboxetine SO NEUROSCIENCE LETTERS LA English DT Article DE transcranial magnetic stimulation; reboxetine; motor cortex; norepinephrine; cortical excitability; human; plasma level ID HUMAN MOTOR CORTEX; DEPENDENT PLASTICITY; RECOVERY; MECHANISMS; MODULATION; DAMAGE AB It has been proposed that norepinephrine plays a critical role in the modulation of cortical excitability, which in turn is thought to influence functional recovery from brain lesions. The purpose of the present experiments was to determine if it is possible to modulate cortical excitability with the selective norepinephrine reuptake inhibitor reboxetine in intact humans. Recruitment curve and intracortical facilitation, assessed by transcranial magnetic stimulation, were increased after oral intake of 8 and 4 mg reboxetine, in the absence of changes in motor threshold, intracortical inhibition, M-response, F-wave or H-reflex. These results demonstrate that reboxetine enhances cortical excitability and raise the possibility that it could act as a plasticity enhancing substance potentially useful in combination with neurorehabilitative strategies geared to enhance neurorehabilitation. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Tubingen, Sch Med, Dept Neurol, Cort Phys Res Grp, D-72076 Tubingen, Germany. Univ Tubingen, Dept Psychiat, Neurophysiol Sect, D-72076 Tubingen, Germany. Univ Mainz, Dept Psychiat, Neurochem Lab, D-55101 Mainz, Germany. NINDS, Med Neurol Branch, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Gerloff, C (reprint author), Univ Tubingen, Sch Med, Dept Neurol, Cort Phys Res Grp, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. RI Plewnia, Christian/D-1652-2015 NR 16 TC 45 Z9 45 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 27 PY 2002 VL 330 IS 3 BP 231 EP 234 AR PII S0304-3940(02)00803-0 DI 10.1016/S0304-3940(02)00803-0 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 611HP UT WOS:000179010800005 PM 12270635 ER PT J AU Kammermeier, PJ Ikeda, SR AF Kammermeier, PJ Ikeda, SR TI Metabotropic glutamate receptor expression in the rat superior cervical ganglion SO NEUROSCIENCE LETTERS LA English DT Article DE sympathetic neurons; reverse transcriptase-polymerase chain reaction; calcium channel modulation; patch-clamp ID LONG-TERM POTENTIATION; CA2+ CHANNELS; NEURONS; CALCIUM; PROTEINS; COCAINE; HOMER; MICE AB To begin to determine what role metabotropic glutamate receptors (mGluRs) play in the peripheral nervous system, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to probe RNA isolated from sympathetic neurons of the rat superior cervical ganglion (SCG). RT-PCR primers were designed to detect each of the eight rat mGluR transcripts. Only one, mGluR7, was detected in RNA from rat SCG, though each appeared to be present in RNA from whole rat brain. Although mGluR7 messenger RNA is apparently present in rat SCG, functional mGluR7 was not observed, as application of neither glutamate nor the group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) produced calcium current modulation in isolated SCG neurons, as would be expected. However, following mGluR7 heterologous expression, application Of L-AP4 did produce moderate calcium current modulation in isolated neurons, indicating that mGluR7 can express on the surface of SCG soma, and that its activation can modulate calcium currents. (C) 2002 Published by Elsevier Science Ireland Ltd. C1 Guthrie Res Inst, Lab Mol Physiol, Sayre, PA 18840 USA. RP Kammermeier, PJ (reprint author), NIAAA, DICBR, LMP, NIH, Pk Bldg Room 150,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. NR 21 TC 9 Z9 9 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 27 PY 2002 VL 330 IS 3 BP 260 EP 264 AR PII S0304-3940(02)00822-4 DI 10.1016/S0304-3940(02)00822-4 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 611HP UT WOS:000179010800012 PM 12270642 ER PT J AU Kaiser, J Zerhouni, E AF Kaiser, J Zerhouni, E TI An interview with Elias Zerhouni: Piloting high-flying NIH to a soft landing SO SCIENCE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Kaiser, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 27 PY 2002 VL 297 IS 5590 BP 2197 EP 2198 DI 10.1126/science.297.5590.2197 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 597LA UT WOS:000178222000017 PM 12351769 ER PT J AU Gao, ZG Kim, SK Biadatti, T Chen, WZ Lee, K Barak, D Kim, SG Johnson, CR Jacobson, KA AF Gao, ZG Kim, SK Biadatti, T Chen, WZ Lee, K Barak, D Kim, SG Johnson, CR Jacobson, KA TI Structural determinants of A(3) adenosine receptor activation: Nucleoside ligands at the agonist/antagonist boundary SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; ACID RELATED-COMPOUNDS; PARTIAL AGONISTS; DERIVATIVES; ANALOGS; ANTAGONISTS; RHODOPSIN; BINDING; RESOLUTION AB Mutagenesis of the human A(3) adenosine receptor (AR) suggested that certain amino acid residues contributed differently to ligand binding and activation processes. Here We demonstrated that various adenosine modifications, including adenine substitution and ribose ring constraints, also contributed differentially to these processes. The ligand effects on cyclic AMP production in intact CHO cells expressing the A(3)AR and in receptor binding were compared. Notably, the simple 2-fluoro group alone or 2-chloro in combination with N-6-substitution dramatically diminished the efficacy of adenosine derivatives, even converting agonist into antagonist. Other affinity-increasing substitutions, including N-6-(3-iodobenzyl) 4 and the (Northern)-methanocarba 15, also reduced efficacy, except in combination with a flexible 5'-fluronamide. 2-Cl-N-6-(3-iodobenzyl) derivatives, both in the (N)-methanocarba (i.e., of the Northern conformation) and riboside series 18 and 5, respectively, were potent antagonists with little residual agonism. Ring-constrained 2',3'-epoxide derivatives in both riboside and (AT)-methanocarba series 13 and 21, respectively, and a cyclized (spiral) 4',5'-uronamide derivative 14 were synthesized and found to be human A(3)AR antagonists. 14 bound potently at both human (26 nM) and rat (49 nM) A(3)ARs. A rhodopsin-based A(3)AR model, containing all domains except the C-terminal region, indicated separate structural requirements for receptor binding and activation for these adenosine analogues. Ligand docking, taking into account binding of selected derivatives at mutant A(3)ARs, featured interactions of TM3 (His95) with the adenine moiety and TMs 6 and 7 with the ribose 5'-region. The 5'-OH group of antagonist N-6-(3-iodobenzyl)-2-chloroadenosine 5 formed a H-bond with N274 but not with S271. The 5'-substituent of nucleoside antagonists moved toward TM7 and away from TM6. The conserved Trp243 (6.48) side chain, involved in recognition of the classical (nonnucleoside) A(3)AR antagonists but not adenosine-derived ligands, displayed a characteristic movement exclusively upon docking of agonists. Thus, A(3)AR activation appeared to require flexibility at the 5'- and 3'-positions, which was diminished in (AT)-methanocarba, spiro, and epoxide analogues, and was characteristic of ribose interactions at TM6 and TM7. C1 NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, LBC, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 62 TC 115 Z9 118 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 26 PY 2002 VL 45 IS 20 BP 4471 EP 4484 DI 10.1021/jm020211 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 596BL UT WOS:000178143900013 PM 12238926 ER PT J AU Chun, HJ Zheng, LX Ahmad, M Wang, J Speirs, CK Siegel, RM Dale, MK Puck, J Davis, J Hall, CG Skoda-Smith, S Atkinson, TP Straus, SE Lenardo, MJ AF Chun, HJ Zheng, LX Ahmad, M Wang, J Speirs, CK Siegel, RM Dale, MK Puck, J Davis, J Hall, CG Skoda-Smith, S Atkinson, TP Straus, SE Lenardo, MJ TI Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency SO NATURE LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; NATURAL-KILLER-CELLS; FAS GENE-MUTATIONS; T-CELLS; APOPTOSIS; INITIATION; CLEAVAGE; DISORDER; SIGNAL AB Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity(1,2). The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex(3,4). Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity(5-14). Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Sch Med, Birmingham, AL 35294 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009; Chun, Hyung/K-1859-2013 OI Siegel, Richard/0000-0001-5953-9893; NR 26 TC 406 Z9 425 U1 7 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 26 PY 2002 VL 419 IS 6905 BP 395 EP 399 DI 10.1038/nature01063 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 596ZB UT WOS:000178195400046 PM 12353035 ER PT J AU Warren, HS Suffredini, AF Eichacker, PQ Munford, RS AF Warren, HS Suffredini, AF Eichacker, PQ Munford, RS TI Risks and benefits of activated protein C treatment for severe sepsis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID APACHE-II; VARIABILITY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. RP Warren, HS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. FU NIAID NIH HHS [AI18188]; NIGMS NIH HHS [R01-GM59694-02] NR 14 TC 161 Z9 167 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 26 PY 2002 VL 347 IS 13 BP 1027 EP 1030 DI 10.1056/NEJMsb020574 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 596RD UT WOS:000178178400012 PM 12324562 ER PT J AU Zhuang, SH Leonard, GD Swain, SM AF Zhuang, SH Leonard, GD Swain, SM TI Oophorectomy in carriers of BRCA mutations. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID BREAST-CANCER C1 NCI, Bethesda, MD 20892 USA. RP Zhuang, SH (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 2 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 26 PY 2002 VL 347 IS 13 BP 1037 EP 1038 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 596RD UT WOS:000178178400016 PM 12324566 ER PT J AU Anderson, WF Brawley, OW Chang, S AF Anderson, WF Brawley, OW Chang, S TI Oophorectomy in carriers of BRCA mutations. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CANCER C1 NCI, Bethesda, MD 20892 USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30303 USA. RP Anderson, WF (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 26 PY 2002 VL 347 IS 13 BP 1038 EP 1039 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 596RD UT WOS:000178178400018 ER PT J AU Rhee, CS Sen, M Lu, DS Wu, C Leoni, L Rubin, J Corr, M Carson, DA AF Rhee, CS Sen, M Lu, DS Wu, C Leoni, L Rubin, J Corr, M Carson, DA TI Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas SO ONCOGENE LA English DT Article DE head and neck squamous cell carcinomas; frizzled; beta-catenin; apoptosis ID VERTEBRATE LIMB DEVELOPMENT; BETA-CATENIN; EXPRESSION; PATTERN; LINES; ESTABLISHMENT; GENES; LMX1 AB The diverse receptor-ligand pairs of the Wnt and frizzled (Fz) families play important roles during embryonic development, and thus may be overexpressed in cancers that arise from immature cells. Hence, we investigated the expression and function of five Writ (Wnt-1, 5a, 7a, 10b, 13) and two Fz (Fz-2, 5) genes in 10 head and neck squamous carcinoma cell lines (HNSCC). In comparison to normal bronchial or oral epithelial cells, all the HNSCC had markedly increased mRNA levels of Wnt-1, 7a, 10b, and 13, as well as Fz-2. Moreover, the levels of Wnt-1, 10b, and Fz-2 proteins were also markedly increased in HNSCC, relative to normal epithelial cells. Treatment of one HNSCC cell line (SNU 1076) with anti-Wnt-1 antibodies reduced the activity of the Wnt/Fz dependent transcription factor LEF/TCF, and diminished the expression of cyclin D1 and beta-catenin proteins. Blocking Wnt-1 signaling also inhibited proliferation and induced apoptosis in these cells. These results show that HNSCC cell lines often overexpress one or more Wnt and Fz genes, and suggest that the growth and survival of a subset of HNSCC may depend on the Wnt/Fz pathway. Hence, the Writ and Fz receptors may be possible targets for immunotherapy therapy of this common cancer. C1 Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Sam & Rose Stein Inst Res Aging, La Jolla, CA 92093 USA. NCI, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Med, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea. RP Carson, DA (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. RI Rhee, Chae-Seo/D-5904-2012; Lu, desheng/E-4822-2013 OI Lu, desheng/0000-0002-3616-6657 FU NIGMS NIH HHS [GM23200] NR 22 TC 131 Z9 140 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 26 PY 2002 VL 21 IS 43 BP 6598 EP 6605 DI 10.1038/sj.onc.1205920 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 597BM UT WOS:000178202300005 PM 12242657 ER PT J AU Lee, YJ Park, JH Ju, SK You, KH Ko, JS Kim, HM AF Lee, YJ Park, JH Ju, SK You, KH Ko, JS Kim, HM TI Leptin receptor isoform expression in rat osteoblasts and their functional analysis SO FEBS LETTERS LA English DT Article DE bone; flow cytometry; leptin; leptin receptor; osteoblasts; STAT3 ID RECOMBINANT EXPRESSION; SIGNAL-TRANSDUCTION; BONE-FORMATION; MESSENGER-RNA; CLONING; IDENTIFICATION; TISSUES; CELLS; ACID; MICE AB The genetic defect in producing the adipose hormone leptin results among others in a drastic increase of bone mass. The current understanding is that under normal circumstances, osteoblast activity is indirectly suppressed by a hypothalamic relay induced by leptin-signalling in the brain. To investigate whether leptin might also regulate osteoblast activity in a direct manner, expression of leptin receptors in rat osteoblasts was determined and their functionality was analyzed upon recombinant leptin treatment. Reverse transcription-PCR confirmed the expression of four among the six currently described receptor isoforms, which were also able to transduce cell signalling as shown by STAT3 phosphorylation after activation. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Seoul Natl Univ, Lab Study Mol Biointerface, Dept Oral Anat, Coll Dent,Chongro Ku, Seoul 110749, South Korea. Seoul Natl Univ, IBEC, Chongro Ku, Seoul 110749, South Korea. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Chungnam Natl Univ, Coll Nat Sci, Dept Biol, Taejon 305764, South Korea. RP Kim, HM (reprint author), Seoul Natl Univ, Lab Study Mol Biointerface, Dept Oral Anat, Coll Dent,Chongro Ku, BK21 HLS, Seoul 110749, South Korea. EM hyunmkim@plaza.snu.ac.kr RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 21 TC 44 Z9 53 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD SEP 25 PY 2002 VL 528 IS 1-3 BP 43 EP 47 AR PII S0014-5793(02)02889-2 DI 10.1016/S0014-5793(02)02889-2 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 598NL UT WOS:000178282500010 PM 12297277 ER PT J AU Jefferson, WN Padilla-Banks, E Clark, G Newbold, RR AF Jefferson, WN Padilla-Banks, E Clark, G Newbold, RR TI Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE endocrine disrupter testing; phytoestrogens; diethylstilbestrol; estrogen receptor; lactoferrin ID SPRAGUE-DAWLEY RATS; SOY-BASED FORMULA; IN-VIVO; UTERINE ADENOCARCINOMA; GENISTEIN EXPOSURE; PHYTOESTROGENS; MICE; DIETHYLSTILBESTROL; CHEMICALS; TRACT AB The estrogenic responses of several phytoestrogens including genistein, daidzein, coumestrol, alpha-zearalanol, zearalenone, naringenin, taxifolin and biochanin A were compared over a wide dose range using an in vitro assay that measures transcriptional activation of the estrogen receptor (ER) and an in vivo immature mouse uterotrophic assay consisting of measuring uterine wet weight increase plus sensitive morphological and biochemical endpoints in the uterus. The transcriptional activation assay showed activation of the ER by all compounds tested except taxifolin with varying magnitudes of response as compared to estradiol or diethylstilbestrol. Results from the uterotropic bioassay showed that genistein, coumestrol, zearalanol, and zearalenone caused an increase in uterine wet weight, while naringenin, taxifolin, daidzein and biochanin A failed to do so over the dose range tested. However, sensitive morphological and biochemical parameters such as uterine epithelial cell height increase, uterine gland number increase, and induction of the estrogen-responsive protein lactoferrin demonstrated that all compounds tested in this study gave some measure of estrogenicity although a wide range of estrogenic responses across compounds was shown. Use of multiple in vitro and in vivo estrogenic endpoints as described in this paper will be useful in developing estrogenic profiles for individual compounds and ultimately mixtures of compounds. Furthermore, having an estrogenic "fingerprint" for each phytochemical is an essential first step in determining potential adverse effects of exposure to phytoestrogens. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Xenobiot Detect Syst Inc, Durham, NC 27704 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 82 Z9 89 U1 1 U2 12 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 SEP 25 PY 2002 VL 777 IS 1-2 BP 179 EP 189 AR PII S1570-0232(02)00493-2 DI 10.1016/S1570-0232(02)00493-2 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 609ZM UT WOS:000178936300016 PM 12270211 ER PT J AU Hill, JM Dick, AJ Thompson, RB Raman, VK Guttman, MA Peters, DC McVeigh, ER Lederman, R AF Hill, JM Dick, AJ Thompson, RB Raman, VK Guttman, MA Peters, DC McVeigh, ER Lederman, R TI Serial in vivo magnetic resonance imaging of labeled stem cells after endomyocardial delivery. SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 14th Annual Symposium on Transcatheter Cardiovascular Therapeutics CY SEP 24, 2002 CL WASHINGTON, D.C. SP Cardiovasc Res Fdn, Lenoz Hill Heart, Vasc Inst New York C1 NIH, Cardiovasc Intervent Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 24 PY 2002 VL 90 IS 6A SU S MA TCT53 BP 25H EP 25H PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 594XH UT WOS:000178077400053 ER PT J AU Dick, AJ Guttman, MA Hill, JM Raman, VK Peters, DC McVeigh, E Lederman, RJ AF Dick, AJ Guttman, MA Hill, JM Raman, VK Peters, DC McVeigh, E Lederman, RJ TI Targeted delivery of stem cells to porcine myocardial infarction guided by real-time magnetic resonance imaging. SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 14th Annual Symposium on Transcatheter Cardiovascular Therapeutics CY SEP 24, 2002 CL WASHINGTON, D.C. SP Cardiovasc Res Fdn, Lenoz Hill Heart, Vasc Inst New York C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 24 PY 2002 VL 90 IS 6A SU S MA TCT313 BP 123H EP 123H PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 594XH UT WOS:000178077400311 ER PT J AU Bonow, RO Smaha, LA Smith, SC Mensah, GA Lenfant, C AF Bonow, RO Smaha, LA Smith, SC Mensah, GA Lenfant, C TI World Heart Day 2002 - The international burden of cardiovascular disease: Responding to the emerging global epidemic SO CIRCULATION LA English DT Article DE epidemiology; risk factors; hypertension; diabetes; obesity ID UNITED-STATES; OBESITY C1 NHLBI, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Bonow, RO (reprint author), Amer Heart Assoc, Off Sci Affairs, 7272 Greenville Ave, Dallas, TX 75231 USA. OI Mensah, George/0000-0002-0387-5326 NR 27 TC 206 Z9 214 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 SEP 24 PY 2002 VL 106 IS 13 BP 1602 EP 1605 DI 10.1161/01.CIR.0000035036.22612.2B PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 599AQ UT WOS:000178311500014 PM 12270848 ER PT J AU Cid, MC Hernandez-Rodriguez, J Esteban, MJ Cebrian, M Gho, YS Font, C Urbano-Marquez, A Grau, JM Kleinman, HK AF Cid, MC Hernandez-Rodriguez, J Esteban, MJ Cebrian, M Gho, YS Font, C Urbano-Marquez, A Grau, JM Kleinman, HK TI Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis SO CIRCULATION LA English DT Article DE angiogenesis; inflammation; vasculature ID INTERCELLULAR-ADHESION MOLECULE-1; HUMAN-ENDOTHELIAL-CELLS; POLYMYALGIA-RHEUMATICA; POLYARTERITIS-NODOSA; MYOCARDIAL-ISCHEMIA; TEMPORAL ARTERITIS; VISUAL-LOSS; VASCULITIS; DISEASE; MANIFESTATIONS AB Background-Vascular inflammatory lesions from patients with giant-cell arteritis show a remarkable amount of neovascularization, but its clinical implications have never been investigated. Methods and Results-To assess the clinical relevance of neovascularization in giant-cell arteritis, angiogenesis was measured in temporal artery sections from 31 patients with biopsy-proven giant-cell arteritis by staining endothelial cells with Ulex europaeus lectin. Angiogenesis was highly variable among these patients. Patients without ischemic complications had higher tissue angiogenesis scores than patients with ischemic events (5.69+/-0.6 versus 2.91+/-0.6, P=0.003). Angiogenesis was also more prominent in patients with a strong acute phase response (score: 5.31+/-0.6) compared with those with a weak systemic inflammatory reaction (2.30+/-0.44; P=0.0007). Serum angiogenic activity was studied in an additional series of 38 biopsy-proven patients. Sera from patients without ischemic events tended to be more active in stimulating human umbilical vein endothelial cell growth (optical density X 1000, 270+/-15 versus 192+/-14, P=0.065) and differentiation into capillary-like structures (107+/-5 versus 84+/-8 relative units, P=0.0058) than patients with ischemic complications. Sera from patients without ischemic events had more in vivo full angiogenic activity tested in the chick chorioallantoic membrane than sera from patients with ischemic complications. Conclusion-Inflammation-induced angiogenic activity may play a compensatory role for ischemia in patients with giant-cell arteritis. C1 Univ Barcelona, Hosp Clin Barcelona, IDIBAPS,Vasculitis Res Unit, Dept Internal Med, E-08036 Barcelona, Spain. Natl Inst Dent & Craniofacial Res, Craniofacial Dev & Regenerat Branch, NIH, Bethesda, MD USA. RP Cid, MC (reprint author), Univ Barcelona, Hosp Clin Barcelona, IDIBAPS,Vasculitis Res Unit, Dept Internal Med, Villarroel 170, E-08036 Barcelona, Spain. OI Font, Carme/0000-0002-3547-7373; Cid Xutgla, Maria Cinta/0000-0002-4730-0938 NR 35 TC 67 Z9 68 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 SEP 24 PY 2002 VL 106 IS 13 BP 1664 EP 1671 DI 10.1161/01.CIR.0000030185.67510.C0 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 599AQ UT WOS:000178311500026 PM 12270860 ER PT J AU Taylor, JP Galetta, SL Asbury, AK Volpe, NJ AF Taylor, JP Galetta, SL Asbury, AK Volpe, NJ TI Hemolytic anemia presenting as idiopathic intracranial hypertension SO NEUROLOGY LA English DT Editorial Material C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Med Ctr, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Ophthalmol, Philadelphia, PA 19104 USA. Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. RP Taylor, JP (reprint author), Bldg 10,Room 3B-11,10 Ctr Dr, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 3 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 SEP 24 PY 2002 VL 59 IS 6 BP 960 EP 961 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 596JH UT WOS:000178161100039 PM 12297596 ER PT J AU Anastos, K Barron, Y Miotti, P Weiser, B Young, M Hessol, N Greenblatt, RM Cohen, M Augenbraun, M Levine, A Munoz, A AF Anastos, K Barron, Y Miotti, P Weiser, B Young, M Hessol, N Greenblatt, RM Cohen, M Augenbraun, M Levine, A Munoz, A CA Womens Interagency HIV Study Colla TI Risk of progression to AIDS and death in women infected with HIV-1 initiating highly active antiretroviral treatment at different stages of disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4 CELL COUNT; VIRAL LOAD; RNA LEVELS; PROTEASE INHIBITORS; SEX-DIFFERENCES; TYPE-1 RNA; THERAPY; PLASMA; TIME AB Background: The optimal virologic and immunologic stage at which to initiate antiretroviral therapy in individuals infected with human immunodeficiency virus type 1 (HIV-1) is undefined. Methods: Among 1054 HIV-1-infected women in a prospective cohort study, we determined the time from initiation of highly active antiretroviral treatment (HAART) to acquired immunodeficiency syndrome (AIDS) and death. Results: Median follow-up was 3.4 years. Of 553 women without AIDS at HAART initiation, 62 (11%) developed AIDS. Compared with women with CD4(+) cell counts greater than 350/muL at HAART initiation, women with cell counts of 200 to 350/muL and less than 200/muL had relative hazards (RHs) for progression to AIDS of 0.93 (95% confidence interval [CI], 0.46-1.86) and 2.48 (95% CI, 1.39-4.42), respectively. Compared with those with HIV-1 RNA values less than 5000 copies/mL, women with 5000 to 50000 copies/mL and greater than 50000 copies/mL had RHs of 1.39 (95% CI, 0.74-2.64) and 2.09 (95% CI, 1.09-3.99), respectively. Among women with AIDS at HAART initiation (n=501), RHs of death were 1.97 (95% Cl, 0.84-4.66) and 3.35 (95% CI, 1.59-7.08) with CD4(+) cell counts of 200 to 350/muL and less than 200/muL, respectively, relative to those with greater than 350/muL, and 1.90 (95% CI, 0.84-4.30) and 3.70 (95% CI, 1.81-7.54) for those with HIV-1 RNA values of 5000 to 50 000 and greater than 50000 copies/mL, respectively, relative to those with less than 5000 copies/mL. Conclusions: Progression to AIDS and death was predicted by pre-HAART values of less than 200/muL for CD4(+) cells and greater than 50 000 HIV-1 RNA copies/mL, indicating that deferral of HAART until the CD4(+) cell count is between 350 and 200/muL is a valid strategy in the clinical management of HIV-1 infection. C1 Montefiore Med Ctr, Womens Interagcy HIV Study, Dept Internal Med, Bronx, NY 10451 USA. Lincoln Med & Mental Hlth Ctr, Bronx, NY 10451 USA. Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Hlth, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. Georgetown Univ, Med Ctr, Dept Infect Dis, Washington, DC 20007 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA. Univ Calif San Francisco, Dept Internal Med, San Francisco, CA USA. Cook Cty Hosp, Dept Internal Med, Chicago, IL 60612 USA. Hlth Sci Ctr Brooklyn, Dept Internal Med, Brooklyn, NY USA. Hlth Sci Ctr Brooklyn, Dept Epidemiol, Brooklyn, NY USA. Univ So Calif, Dept Internal Med, Div Hematol, Los Angeles, CA USA. RP Anastos, K (reprint author), Montefiore Med Ctr, Womens Interagcy HIV Study, Dept Internal Med, 234 E 149th St,Suite 2D3, Bronx, NY 10451 USA. FU NIAID NIH HHS [U01-AI31834, U01-AI-42590, U01-AI-34993, U01-AI-34994, N01-AI-35161, U01-AI-34989, U01-AI35004]; NICHD NIH HHS [U01-HD-32632] NR 33 TC 45 Z9 48 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 SEP 23 PY 2002 VL 162 IS 17 BP 1973 EP 1980 DI 10.1001/archinte.162.17.1973 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 594TM UT WOS:000178067100007 PM 12230420 ER PT J AU Clegg, LX Li, FP Hankey, BG Chu, K Edwards, BK AF Clegg, LX Li, FP Hankey, BG Chu, K Edwards, BK TI Cancer survival among US whites and minorities - A SEER (Surveillance, Epidemiology, and End Results) program population-based study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID FECAL-OCCULT-BLOOD; LOCALIZED PROSTATE-CANCER; BREAST-CANCER; COLORECTAL-CANCER; RACIAL-DIFFERENCES; DECISION-ANALYSIS; BLACK-WOMEN; LUNG-CANCER; RACE; STAGE AB Background: Available cancer statistics pertain primarily to white and African American populations. This study describes racial or ethnic patterns of cancer-specific survival and relative risks (RRs) of cancer death for all cancers combined and for cancers of the colon and rectum, lung and bronchus, prostate, and female breast for the 6 major US racial or ethnic groups. Methods: Cancer-specific survival rates were analyzed for more than 1.78 million patients who resided in the 9 SEER (Surveillance, Epidemiology, and End Results) Program geographic areas and were diagnosed between 1975 and 1997 as having an incident invasive cancer, by 6 racial or ethnic groups (non-Hispanic whites, Hispanic whites, African Americans, Asian Americans, Hawaiian natives, and American Indians and Alaskan natives). Results: Survival rates improved between 1988 to 1997 for virtually all racial or ethnic groups. However, racial or ethnic differences in RRs of cancer death persisted after controlling for age for all cancers combined and for age and stage for specific cancer sites (P<.01). African American, American Indian and Alaskan native, and Hawaiian native patients tended to have higher RRs of cancer death than the other groups. American Indians and Alaskan natives generally exhibited the highest RRs of cancer death, except for colorectal cancer in males. Conclusions: Survival rates in patients with cancer have improved in recent years, but racial or ethnic differences in survival rates and in RRs of cancer death persist. Additional studies are needed to clarify the socioeconomic, medical, biological, cultural, and other determinants of these findings. C1 NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Clegg, LX (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,MSC 8316,Suite 504, Bethesda, MD 20892 USA. FU NCI NIH HHS [U01CA86322] NR 52 TC 325 Z9 329 U1 1 U2 7 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 SEP 23 PY 2002 VL 162 IS 17 BP 1985 EP 1993 DI 10.1001/archinte.162.17.1985 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 594TM UT WOS:000178067100009 PM 12230422 ER PT J AU Gonzalez-Nilo, FD Krautwurst, H Yevenes, A Cardemil, E Cachau, R AF Gonzalez-Nilo, FD Krautwurst, H Yevenes, A Cardemil, E Cachau, R TI Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase: theoretical and experimental study of the effect of glutamic acid 284 on the protonation state of lysine 213 SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE phosphoenolpyruvate carboxykinase; Saccharomyces cerevisiae; lysine pK(a); theoretical calculation ID PHOSPHORYL-TRANSFER; OXALOACETATE DECARBOXYLASE; EPR SPECTROSCOPY; CHLOROPLAST; MECHANISM; PYRUVATE; ENZYME; SITE AB The crystal structure of Escherichia coli phosphoenolpyruvate (PEP) carboxykinase shows Lys(213) is one of the ligands of enzyme-bound Mn2+ [Nat. Struct. Biol. 4 (1997) 990]. The direct coordination of Mn2+ by N-epsilon of Lys(213) is only consistent with a neutral (uncharged) Lys(213), suggesting a low pK(a) for this residue. This work shows, through theoretical calculations and experimental analyses on homologous Saccharomyces cerevisiae PEP carboxykinase, how the microenvironment affects Mn2+ binding and the protonation state of Lys(213). We show that Glu(284), a residue close to Lys(212), is required for correct protonation states of Lys(212) and Lys(213), and for Mn2(+) binding. DeltaG and DeltaH values for the proton reorganization processes were calculated to analyze the energetic stability of the two different protonation states of Lys(212) and Lys(213) in wild-type and Glu(284)Gln S. cerevisiae PEP carboxykinase. Calculations were done using two modeling approaches, ab-initio density functional calculations and free energy perturbation (FEP) calculations. Both methods suggest that Lys(212) must be protonated and Lys(213) neutral in the wild-type enzyme. On the other hand, the calculations on the Glu284Gln mutant suggest a more stable neutral Lys(212) and protonated Lys(213). Experimental measurements showed 3 orders of magnitude lower activity and a threefold increase in Km for Mn2+ for Glu284Gln S. cerevisiae PEP carboxykinase when compared to wild type. The data here presented suggest that Glu(284) is required for Mn2+ binding by S. cerevisiae PEP carboxykinase. We propose that Glu(284) modulates the pK(a) value of Lys(213) through electrostatic effects mediated by Lys(212). (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, SAIC, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. Univ Santiago Chile, Fac Quim & Biol, Dept Ciencias Quim, Santiago 33, Chile. RP Cachau, R (reprint author), NCI, SAIC, Adv Biomed Comp Ctr, 430 Miller Dr, Frederick, MD 21702 USA. RI Gonzalez-Nilo, Fernando/M-5671-2016 OI Yevenes, Alejandro/0000-0003-3799-1509; Gonzalez-Nilo, Fernando/0000-0001-6857-3575 FU NCI NIH HHS [N01-CO-12400] NR 23 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD SEP 23 PY 2002 VL 1599 IS 1-2 BP 65 EP 71 AR PII S1570-9639(02)00400-4 DI 10.1016/S1570-9639(02)00400-4 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 599HW UT WOS:000178329100008 PM 12479406 ER PT J AU Aft, RL Zhang, FW Gius, D AF Aft, RL Zhang, FW Gius, D TI Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death SO BRITISH JOURNAL OF CANCER LA English DT Article DE apoptosis; breast cancer; glucose metabolism; tumour metabolism ID HUMAN BREAST-CARCINOMA; DEPRIVATION-INDUCED CYTOTOXICITY; HUMAN TUMOR-CELLS; GLUCOSE-TRANSPORTER; CANCER-CELLS; OXIDATIVE STRESS; GENE-EXPRESSION; MCF-7/ADR CELLS; 3T3-L1 ADIPOCYTES; C-MYC AB Nutrient deprivation has been shown to cause cancer cell death, To exploit nutrient deprivation as anti-cancer therapy, we investigated the effects of the anti-metabolite 2-deoxy-D-glucose on breast cancer cells in vitro. This compound has been shown to inhibit glucose metabolism. Treatment of human breast cancer cell lines with 2-deoxy-D-glucose results in cessation of cell growth in a dose dependent manner. Cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide conversion assay and clonogenic survival are decreased with 2-deoxy-D-glucose treatment indicating that 2-deoxy-D-glucose causes breast cancer cell death. The cell death induced by 2-deoxy-D-glucose was found to be due to apoptosis as demonstrated by induction of caspase 3 activity and cleavage of poly (ADP-ribose) polymerase. Breast cancer cells treated with 2-deoxy-D-glucose express higher levels of Glut I transporter protein as measured by Western blot analysis and have increased glucose uptake compared to non-treated breast cancer cells. From these results we conclude that 2-deoxy-D-glucose treatment causes death in human breast cancer cell lines by the activation of the apoptotic pathway. Our data suggest that breast cancer cells treated with 2-deoxy-D-glucose accelerate their own demise by initially expressing high levels of glucose transporter protein, which allows increased uptake of 2-deoxy-D-glucose, and subsequent induction of cell death. These data support the targeting of glucose metabolism as a site for chemotherapeutic intervention by agents such as 2-deoxy-D-glucose. (C) 2002 Cancer Research UK. C1 Washington Univ, Dept Surg, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. John Cochron Vet Adm Hosp, St Louis, MO 63110 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Aft, RL (reprint author), Washington Univ, Dept Surg, Sch Med, Alvin J Siteman Canc Ctr, Cmapus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. NR 72 TC 115 Z9 118 U1 1 U2 9 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 SEP 23 PY 2002 VL 87 IS 7 BP 805 EP 812 DI 10.1038/sj.bjc.6600547 PG 8 WC Oncology SC Oncology GA 603WK UT WOS:000178583900021 PM 12232767 ER PT J AU Yang, OO Boscardin, WJ Matud, J Hausner, MA Hultin, LE Hultin, PM Shih, R Ferbas, J Siegal, FP Shodell, M Shearer, GM Grene, E Carrington, M O'Brien, S Price, CB Detels, R Jamieson, BD Giorgi, JV AF Yang, OO Boscardin, WJ Matud, J Hausner, MA Hultin, LE Hultin, PM Shih, R Ferbas, J Siegal, FP Shodell, M Shearer, GM Grene, E Carrington, M O'Brien, S Price, CB Detels, R Jamieson, BD Giorgi, JV TI Immunologic profile of highly exposed yet HIV type 1-seronegative men SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; LONG-TERM NONPROGRESSORS; LOW VIRAL LOAD; CELL-ACTIVITY; HOMOSEXUAL MEN; CD8(+) CELLS; INFECTION; RESPONSES; QUANTITATION; REPLICATION AB The host immune factors that determine susceptibility to HIV-1 infection are poorly understood. We compared multiple immunologic parameters in three groups of HIV-1-seronegative men: 14 highly exposed (HR10), 7 previously reported possibly to have sustained transient infection (PTI), and a control group of 14 low risk blood bank donors (BB). Virus-specific cellular immune assays were performed for CD4(+) T helper cell responses, CD8(+) cytotoxic T lymphocyte activity, CD8(+) cell chemokine release, and CD8(+) cell-derived antiviral soluble factor activity. General immune parameters evaluated included CCR5 genotype and phenotype, interferon a production by PBMCs, leukocyte subset analysis, and detailed T lymphocyte phenotyping. Comparisons revealed no detectable group-specific differences in measures of virus-specific immunity. However, the HR10 group differed from the BB group in several general immune parameters, having higher absolute monocyte counts, higher absolute CD8(+) T cell counts and percentages, lower naive and higher terminal effector CD8(+) cells, and lower levels of CD28(+) CD8(+) cells. These changes were not associated with seropositivity for other chronic viral infections. The PTI men appeared to have normal levels of monocytes and slightly elevated levels of CD8(+) T cells (also with increased effector and decreased naive cells). Although we cannot entirely exclude the contribution of other chronic viral infections, these findings suggest that long-lived systemic cellular antiviral immunity as detected by our assays is not a common mechanism for resistance to infection, and that resistance may be multifactorial. General immune parameters reflected by CD8(+) T cell levels and activation, and monocyte concentrations may affect the risk of infection with HIV-1, and/or serve as markers of exposure. C1 Univ Calif Los Angeles, Med Ctr, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. St Vincent Catholic Med Ctr, New York, NY 10011 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Yang, OO (reprint author), Univ Calif Los Angeles, Med Ctr, Dept Med, Los Angeles, CA 90095 USA. NR 48 TC 27 Z9 27 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP 20 PY 2002 VL 18 IS 14 BP 1051 EP 1065 DI 10.1089/08892220260235416 PG 15 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 595JR UT WOS:000178105900007 PM 12396457 ER PT J AU Litman, T Jensen, U Hansen, A Covitz, KM Zhan, ZR Fetsch, P Abati, A Hansen, PR Horn, T Skovsgaard, T Bates, SE AF Litman, T Jensen, U Hansen, A Covitz, KM Zhan, ZR Fetsch, P Abati, A Hansen, PR Horn, T Skovsgaard, T Bates, SE TI Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2 SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE polyclonal antibody; western blot; immunohistochemistry; atypical multidrug resistance; MXR/BCRP/ABCP/ABCG2; ABC half-transporter ID BINDING CASSETTE ABC; BREAST-CANCER CELLS; MULTIDRUG-RESISTANCE; HALF-TRANSPORTER; FUMITREMORGIN-C; PLASMA-MEMBRANE; MXR; OVEREXPRESSION; PHENOTYPE AB Recent studies have characterized the ABC half-transporter associated with mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to mitoxantrone. We developed four polyclonal antibodies against peptides corresponding to four different epitopes on the mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed a single major band of the expected 72-kDa molecular size of ABCG2 under denaturing conditions. Immunoblot analysis performed under non-reducing conditions and after treatment with cross-linking reagents demonstrated a molecular weight shift from 72 kDa to several bands of 180 kDa and higher molecular weight, suggesting detection of dimerization products of ABCG2. Evidence of N-linked glycosylation was also obtained using tunicamycin and N-glycosidase F. Finally, both by light, fluorescence and electron microscopic immunohistochemical staining, we demonstrate cytoplasmic and predominantly plasma membrane localization of ABCG2 in cell lines with high levels of expression. Plasma membrane staining was observed on the surface of the chorionic villi in placenta. These results support the hypothesis that ABCG2 is an ABC half-transporter that forms dimers in the plasma membrane, functioning as an ATP-dependent outward pump for substrate transport. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. Herlev Univ Hosp, Lab Oncol, DK-2730 Herlev, Denmark. Herlev Univ Hosp, Dept Pathol, DK-2730 Herlev, Denmark. Royal Vet & Agr Univ, Dept Chem, DK-1871 Frederiksberg, Denmark. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Hansen, Paul /E-6572-2010 NR 37 TC 93 Z9 94 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD SEP 20 PY 2002 VL 1565 IS 1 BP 6 EP 16 AR PII S0005-2736(02)00492-3 DI 10.1016/S0005-2736(02)00492-3 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 598YR UT WOS:000178305400002 PM 12225847 ER PT J AU Portela, LVC Oses, JP Silveira, AL Schmidt, AP Lara, DR Battastini, AMO Ramirez, G Vinade, L Sarkis, JJF Souza, DO AF Portela, LVC Oses, JP Silveira, AL Schmidt, AP Lara, DR Battastini, AMO Ramirez, G Vinade, L Sarkis, JJF Souza, DO TI Guanine and adenine nucleotidase activities in rat cerebrospinal fluid SO BRAIN RESEARCH LA English DT Article DE nucleotidase; rat CSF; adenosine; guanosine; ADPase and GDPase ID CENTRAL-NERVOUS-SYSTEM; ISOLATED VAS-DEFERENS; QUINOLINIC ACID; GLUTAMATE; BRAIN; GUANOSINE; ADENOSINE; ATPASE; RECEPTORS; SEIZURES AB Adenine and guanine nucleotides have been shown to exert multiple roles in central and peripheral nervous systems, and the sequential breakdown of these nucleotides by enzymatic systems is an important step in the modulation of their extracellular effects. The aim of this study was to investigate whether nucleotide hydrolysis also Occurs in the cerebrospinal fluid (CSF) of rats. CSF was able to hydrolyze all guanine and adenine nucleotides investigated (2.0 mM): GDP>> ADP=ATP=GTP>> AMP=GMP. More detailed studies with the diphosphate nucleotides showed that the hydrolysis of ADP and GDP was linear with incubation time and protein concentration. The apparent K-M (Henry-Michaelis-Menten constant) and V (maximal velocity) values for ADP and GDP were 164.3+/-54.7 muM and 12.2+/-3.8 nmol P-i/min per mg protein, and 841.0+/-90.2 muM and 22.8+/-8.0 nmol P-i/min per mg protein. The sum of ADP, GDP and UDP hydrolysis (2.0 mM) upon individual incubations with CSF was similar to the hydrolysis observed when all three nucleotides were incubated together. This pattern of hydrolysis strongly suggests the involvement of more than one enzyme activity. The higher maximum activity for GDP and UDP compared to ADP is compatible with presence of a soluble NTDPase5. (C) 2002 Published by Elsevier Science B.V. C1 Univ Fed Rio Grande do Sul, ICBS, Dept Bioquim, BR-90035003 Porto Alegre, RS, Brazil. SEMSA, Lab Municipal Novo Hamburgo, Novo Hamburgo, RS, Brazil. PUC RS, Fac Biociencias, Dept Ciencias Fisiol, Porto Alegre, RS, Brazil. Univ Autonoma Madrid, CSIC, Ctr Biol Mol, Madrid, Spain. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Souza, DO (reprint author), Univ Fed Rio Grande do Sul, ICBS, Dept Bioquim, Rua Ramiro Barcelos 2600, BR-90035003 Porto Alegre, RS, Brazil. EM diogo@vortex.ufrgs.br RI Schmidt, Andre/E-4652-2012; Oses, Jean Pierre/E-2534-2013; Souza, Diogo/J-8894-2014 OI Souza, Diogo/0000-0002-4322-0404 NR 38 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 20 PY 2002 VL 950 IS 1-2 BP 74 EP 78 AR PII S0006-8993(02)02987-6 DI 10.1016/S0006-8993(02)02987-6 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 601YU UT WOS:000178477600008 ER PT J AU Calvo, A Yokoyama, Y Smith, LE Ali, I Shih, SC Feldman, AL Libutti, SK Sundaram, R Green, JE AF Calvo, A Yokoyama, Y Smith, LE Ali, I Shih, SC Feldman, AL Libutti, SK Sundaram, R Green, JE TI Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE angiogenesis; endostatin; vascular endothelial growth factor; mammary cancer ID ENDOTHELIAL GROWTH-FACTOR; TUMOR ANGIOGENESIS; BREAST-CANCER; MOUSE MODEL; FACTOR VEGF; EXPRESSION; RECEPTORS; GENE; RAT; VASCULATURE AB Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinorna tumor progression in the C3(1)/Tag transgenic model. (C) 2002 Wiley-Liss, Inc. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012 FU NCI NIH HHS [R01 CA073871] NR 32 TC 34 Z9 37 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 20 PY 2002 VL 101 IS 3 BP 224 EP 234 DI 10.1002/ijc.10589 PG 11 WC Oncology SC Oncology GA 589GE UT WOS:000177749800004 PM 12209972 ER PT J AU Lavoie, C Mercier, JF Salahpour, A Umapathy, D Breit, A Villeneuve, LR Zhu, WZ Xiao, RP Lakatta, EG Bouvier, M Hebert, TE AF Lavoie, C Mercier, JF Salahpour, A Umapathy, D Breit, A Villeneuve, LR Zhu, WZ Xiao, RP Lakatta, EG Bouvier, M Hebert, TE TI beta(1)/beta(2)-adrenergic receptor heterodimerization regulates beta(2)-adrenergic receptor internalization and ERK signaling efficacy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESONANCE ENERGY-TRANSFER; FUNCTIONAL GABA(B) RECEPTOR; PROTEIN-COUPLED RECEPTORS; BETA-2-ADRENERGIC RECEPTORS; BETA(1)-ADRENERGIC RECEPTOR; BETA-1-ADRENERGIC RECEPTOR; VENTRICULAR CARDIOMYOCYTES; HETEROMERIC COMPLEXES; MOUSE CARDIOMYOCYTES; CARDIAC MYOCYTES AB beta(1)- and beta(2)-adrenergic receptors (beta(1)AR and beta(2)AR) are co-expressed in numerous tissues where they play a central role in the responses of various organs to sympathetic stimulation. Although the two receptor subtypes share some signaling pathways, each has been shown to have specific signaling and regulatory properties. Given the recent recognition that many G protein-coupled receptors can form homo- and heterodimers, the present study was undertaken to determine whether the beta(1)AR and beta(2)AR can form dimers in cells and, if so, to investigate the potential functional consequences of such heterodimerization. Using co-immunoprecipitation and bioluminescence resonance energy transfer, we show that beta(1)AR and beta(2)AR can form heterodimers in HEK 293 cells co-expressing the two receptors. Functionally, beta-adrenergic stimulated adenylyl cyclase activity was found to be identical in cells expressing beta(1)AR, beta(2)AR, or both receptors at similar levels, indicating that heterodimerization did not affect this signaling pathway. When considering ERK1/2 MAPK activity, a significant agonist-promoted activation was detected in beta(2)AR- but not beta(1)AR-expressing cells. Similarly to what was observed in cells expressing the beta(1)AR alone, no beta-adrenergic stimulated ERK1/2 phosphorylation was observed in cells co-expressing the two receptors. A similar inhibition of agonist-promoted internalization of the beta(2)AR was observed upon co-expression of the beta(1)AR, which by itself internalized to a lesser extent. Taken together, our data suggest that heterodimerization between beta(1)AR and beta(2)AR inhibits the agonist-promoted internalization of the beta(2)AR and its ability to activate the ERK1/2 MAPK signaling pathway. C1 Inst Cardiol Montreal, Ctr Rech, Montreal, PQ H1T 1C8, Canada. Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Grp Rech Syst Nerveux Auton, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Dept Anesthesiol, Montreal, PQ H3C 3J7, Canada. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Hebert, TE (reprint author), Inst Cardiol Montreal, Ctr Rech, 5000 Rue Belanger Est, Montreal, PQ H1T 1C8, Canada. RI Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 NR 60 TC 154 Z9 158 U1 0 U2 5 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 SEP 20 PY 2002 VL 277 IS 38 BP 35402 EP 35410 DI 10.1074/jbc.M204163200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 595PB UT WOS:000178117000096 PM 12140284 ER PT J AU Olah, Z Karai, L Iadarola, MJ AF Olah, Z Karai, L Iadarola, MJ TI Protein kinase C alpha is required for vanilloid receptor 1 activation - Evidence for multiple signaling pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE-D ACTIVITY; ROOT GANGLION NEURONS; RAT SENSORY NEURONS; CAPSAICIN RECEPTOR; PHORBOL ESTER; MICE LACKING; ADULT-RAT; EPSILON; CELLS; PAIN AB Activation of vanilloid receptor (VR1) by protein kinase C (PKC) was investigated in cells ectopically expressing VR1 and primary cultures of dorsal root ganglion neurons. Submicromolar phorbol 12,13-dibutyrate (PDBu), which stimulates PKC, acutely activated Ca2+ uptake in VR1-expressing cells at pH 5.5, but not at mildly acidic or neutral pH. PDBu was antagonized by bisindolylmaleimide, a PKC inhibitor, and ruthenium red, a VR1 ionophore blocker, but not capsazepine, a vanilloid antagonist indicating that catalytic activity of PKC is required for PDBu activation of VR1 ion conductance, and is independent of the vanilloid site. Chronic PDBu dramatically down-regulated PKCalpha in dorsal root ganglion neurons or the VR1 cell lines, whereas only partially influencing PKCbeta, -delta, -epsilon, and zeta. Loss of PKCalpha correlated with loss of response to acute re-challenge with PDBu. Anandamide, a VR1 agonist in acidic conditions, acts additively with PDBu and remains effective after chronic PKC down-regulation. Thus, two independent VR1 activation pathways can be discriminated: M direct ligand binding (anandamide, vanilloids) or (ii) extracellular ligands coupled to PKC by intracellular signaling. Experiments in cell lines co-expressing VR1 with different sets of PKC isozymes showed that acute PDBu-induced activation requires PKCalpha, but not PKCepsilon. These studies suggest that PKCalpha in sensory neurons may elicit or enhance pain during inflammation or ischemia. C1 NIDCR, Neuronal Gene Express Unit, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Olah, Z (reprint author), NIDCR, Neuronal Gene Express Unit, Pain & Neurosensory Mech Branch, NIH, 49 Convent Dr,MSC-4410, Bethesda, MD 20892 USA. NR 50 TC 75 Z9 82 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 SEP 20 PY 2002 VL 277 IS 38 BP 35752 EP 35759 DI 10.1074/jbc.M201551200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 595PB UT WOS:000178117000138 PM 12095983 ER PT J AU Han, X Zhang, TY Wei, Y Cao, XL Ito, Y AF Han, X Zhang, TY Wei, Y Cao, XL Ito, Y TI Separation of salidroside from Rhodiola crenulata by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; Rhodiola crenulata; salidroside AB High-speed counter-current chromatography (HSCCC) was used to purify salidroside from an extract of Rhodiola crenulata with two steps using a two-phase solvent system composed of ethyl acetate-n-butanol-water (1:4:5, v/v) in the first run and chloroform-methanol-isopropanol-water (5:6:1:4) in the second run. The method yielded 21.9 mg of salidroside from 1.216 g of the crude sample at 98% purity determined by HPLC analyses. Identification was performed by H-1 NMR, C-13 NMR, and MS. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing Res Ctr Separat & Purificat Technol Nat P, Beijing 100035, Peoples R China. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3334, Bethesda, MD 20892 USA. NR 6 TC 37 Z9 53 U1 2 U2 10 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 SEP 20 PY 2002 VL 971 IS 1-2 BP 237 EP 241 AR PII S0021-9673(02)01041-5 DI 10.1016/S0021-9673(02)01041-5 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 595PQ UT WOS:000178118300021 PM 12350119 ER PT J AU Meragelman, KM West, LM Northcote, PT Pannell, LK McKee, TC Boyd, MR AF Meragelman, KM West, LM Northcote, PT Pannell, LK McKee, TC Boyd, MR TI Unusual sulfamate indoles and a novel indolo[3,2-a]carbazole from Ancorina sp. SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SPECIFICALLY INHIBITS BLASTULATION; MARINE SPONGE; STARFISH EMBRYOS; ALKALOIDS AB Four new indoles, ancorinolates A-C and bis-ancorinolate B, which contain sulfamate and sulfate groups, were isolated from the aqueous extract of the sponge Ancorina sp. In addition, ancorinazole, an indolo[3, 2-a]carbazole also possessing sulfamate and sulfate groups, was isolated from two separate New Zealand collections of Ancorina sp. Ancorinazole is the first indolo[3, 2-alpha]carbazole described as a natural product. Ancorinolates A (1) and C (3) showed weak HIV-inhibitory activity in the XTT-based, anticytopathicity assay. C1 NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. Victoria Univ Wellington, Sch Chem & Phys Sci, Wellington, New Zealand. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Meragelman, KM (reprint author), NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. NR 30 TC 44 Z9 44 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 20 PY 2002 VL 67 IS 19 BP 6671 EP 6677 AR UNSP JO020120K DI 10.1021/jo020120k PG 7 WC Chemistry, Organic SC Chemistry GA 593WJ UT WOS:000178017200012 PM 12227796 ER PT J AU Yagi, H Ramesha, AR Kalena, G Sayer, JM Kumar, S Jerina, DM AF Yagi, H Ramesha, AR Kalena, G Sayer, JM Kumar, S Jerina, DM TI Novel stereoselective control over cis vs trans opening of benzo[c]phenanthrene 3,4-diol 1,2-epoxides by the exocyclic N-2-amino group of deoxyguanosine in the presence of hexafluoropropan-2-ol SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID 7,8-DIOL 9,10-EPOXIDE ADDUCTS; POLYCYCLIC AROMATIC-HYDROCARBONS; DIOL EPOXIDE ADDUCTS; SITE-SPECIFIC INCORPORATION; DNA-ADDUCTS; DEOXYADENOSINE ADDUCT; PROTECTING GROUP; AMINO GROUP; MOUSE SKIN; BENZOPYRENE AB We describe a novel and efficient synthesis (62-84% yields) of the eight possible, diastereomerically pure, cis and trans, R and S O-6-allyl-protected N-2-dGuo phosphoramidite building blocks derived through cis and trans opening of (+/-)-3alpha, 4beta-dihydroxy-1beta, 2beta-epoxy-1, 2, 3, 4-tetrahydrobenzo[c]-phenanthrene [BcPh DE-1 (1)] and (+/-)-3alpha, 4beta-dihydroxy-1alpha, 2beta-epoxy-1, 2, 3, 4-tetrahydrobenzo[c]-phenanthrene [BcPh DE-2 (2)] by hexafluoropropan-2-ol (HFP)-mediated addition of O-6-allyl-3', 5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine(3) at C-1 of the epoxides. Simply changing the relative amount of HFP used in the reaction mixture can achieve a wide ratio of cishrans addition products. Thus, the observed cishrans adduct ratio for the reaction of DE-1 (1) in the presence of 5 equiv of 3 varied from 17/83 to 91/9 over the range of 5-532 equiv of HFP. The corresponding ratios for DE-2 (2) varied from 2/98 to 61/39 under the same set of conditions. When 1 or 2 was fused with a 20-fold excess of 3 at 140 degreesC in the absence of solvent HFP, almost exclusive trans addition (> 95%) was observed for the both DEs. Through the use of varying amounts of HFP in the reaction mixture as described above, each of the eight possible phosphoramidite oligonucleotide building blocks (DE-1/DE-2, cis/trans, RIS) of the BcPh DE N2-dGuo adducts can be prepared in an efficient fashion. To rationalize the varying cis-to-trans ratio, we propose that the addition of 3 to 1 or 2 in the absence of solvent or in the presence of small amounts of HFP proceeds primarily via an S(N)2 mechanism to produce mainly trans-opened adducts. In contrast, increasing amounts of HFP promote increased participation of an S(N)1 Mechanism involving a relatively stable carbocation with two possible conformations. One of these conformations reacts with 3 to give mostly trans adduct, while the other conformation reacts with 3 to give mostly cis adduct. C1 NIDDK, Sect Oxidat Mech, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. SUNY Coll Buffalo, Great Lakes Ctr, Environm Toxicol & Chem Lab, Buffalo, NY 14222 USA. RP Yagi, H (reprint author), NIDDK, Sect Oxidat Mech, Lab Bioorgan Chem, NIH, Bldg 8A,Room 1A01, Bethesda, MD 20892 USA. NR 56 TC 12 Z9 12 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD SEP 20 PY 2002 VL 67 IS 19 BP 6678 EP 6689 AR UNSP JO020418A DI 10.1021/jo020418a PG 12 WC Chemistry, Organic SC Chemistry GA 593WJ UT WOS:000178017200013 PM 12227797 ER PT J AU de Silva, R Hardy, J Crook, J Khan, N Graham, EA Morris, CM Wood, NW Lees, AJ AF de Silva, R Hardy, J Crook, J Khan, N Graham, EA Morris, CM Wood, NW Lees, AJ TI The tau locus is not significantly associated with pathologically confirmed sporadic Parkinson's disease SO NEUROSCIENCE LETTERS LA English DT Article DE tau; Parkinson's disease; neurodegeneration; genetics ID PROGRESSIVE SUPRANUCLEAR PALSY; CORTICOBASAL DEGENERATION; LEWY BODY; A0 ALLELE; GENE; HAPLOTYPE; DEMENTIA AB Mutations of the tau gene in frontotemporal dementia with parkinsonism and genetic association of the tau locus with progressive supranuclear palsy and corticobasal degeneration directly implicate the tau gene in the aetiology of these tauopathies. Three studies have also shown an association of the tau locus with clinically diagnosed Parkinson's disease. Noting the significant incidence of clinical misdiagnosis of Parkinson's disease, we investigated this tau gene association in a series of 157 pathologically confirmed cases of brain stem Lewy body Parkinson's disease by analysing their tau haplotype status. Although H1H1 homozygotes are elevated in the Parkinson's disease cases (63.1%) compared to controls (56.1%) this difference is not significant (P = 0.22). These results indicate that any association must either be weak (with an odds ratio of less than 2) or that previous positive associations were due to contamination of clinically diagnosed cases with other diagnostic clinico-pathological entities such as neurofibrillary tangle Parkinson's syndrome. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 UCL Royal Free & Univ Coll Med Sch, Reta Lila Weston Inst Neurol Studies, London W1T 4JF, England. Inst Neurol, Dept Mol Pathogenesis, London WC1N 3BG, England. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Newcastle Gen Hosp, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. Inst Human Genet, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. RP de Silva, R (reprint author), UCL Royal Free & Univ Coll Med Sch, Reta Lila Weston Inst Neurol Studies, Windeyer Bldg,49 Cleveland St, London W1T 4JF, England. EM rsilva@ion.ucl.ac.uk RI de Silva, Rohan/C-1734-2008; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; Wood, Nicholas/C-2505-2009 OI de Silva, Rohan/0000-0002-5052-5775; Wood, Nicholas/0000-0002-9500-3348 NR 16 TC 33 Z9 33 U1 0 U2 3 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 SEP 20 PY 2002 VL 330 IS 2 BP 201 EP 203 AR PII S0304-3940(02)00742-5 DI 10.1016/S0304-3940(02)00742-5 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 606GC UT WOS:000178725400019 PM 12231446 ER PT J AU Goulas, A Fidani, L Kotsis, A Mirtsou, V Petersen, RC Tangalos, E Hardy, J AF Goulas, A Fidani, L Kotsis, A Mirtsou, V Petersen, RC Tangalos, E Hardy, J TI An association study of a functional catalase gene polymorphism,-262C -> T, and patients with Alzheimer's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Alzheimer's disease; oxidative stress; catalase; polymorphism; genetics ID APOLIPOPROTEIN-E GENOTYPE; OXIDATIVE STRESS; GLUTAMATE AB According to the oxidative stress hypothesis which has been proposed as one of a number of possible mechanisms underlying pathogenesis of Alzheimer's disease (AD), accumulation of hydrogen peroxide in the brain of affected individuals, due to overproduction and/or insufficient detoxification, can trigger a cascade of neurotoxic events, thus contributing to the neuronal damage characteristic of the disease. The upregulation of enzymes that are able to neutralize hydrogen peroxide (catalase, peroxidases) would then be conceivably able to offer at least some protection from the damaging effects of this agent. In this study we examined the distribution of a functional polymorphism in the gene for catalase, -262C --> T, in an independent population of 137 AD patients and 130 control individuals. The presence of the polymorphism, which results in the elimination of a Smal restriction site, was tested with a PCR amplification/Smal digestion-based assay. No significant difference has emerged from the comparison of either genotype or allele frequencies (P > 0.5). We conclude that the catalase gene -262C --> T polymorphism does not confer a protective effect with respect to AD. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Aristotle Univ Thessaloniki, Sch Med, Dept Pharmacol, Thessaloniki 54124, Greece. Aristotle Univ Thessaloniki, Sch Med, Dept Gen Biol, Thessaloniki 54124, Greece. Mayo Clin, Dept Community Med, Rochester, MN 55055 USA. Mayo Clin, Dept Neurol, Rochester, MN 55055 USA. Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London WC2, England. Inst Neurol, Dept Mol Pathogenesis, London WC2, England. RP Fidani, L (reprint author), 6D Gounari Str, Thessaloniki 54621, Greece. RI Hardy, John/C-2451-2009 FU NIA NIH HHS [AG 16574, AG 06786] NR 12 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 20 PY 2002 VL 330 IS 2 BP 210 EP 212 AR PII S0304-3940(02)00780-2 DI 10.1016/S0304-3940(02)00780-2 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 606GC UT WOS:000178725400022 PM 12231449 ER PT J AU Gruber, SB Ellis, NA Rennert, G Offit, K AF Gruber, SB Ellis, NA Rennert, G Offit, K TI BLM heterozygosity and the risk of colorectal cancer SO SCIENCE LA English DT Article ID FREQUENCY; MUTATION; JEWS C1 Carmel Hosp, Clalit Hlth Serv Natl Canc Control Ctr, Haifa, Israel. Technion Israel Inst Technol, Fac Med, Haifa, Israel. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Mem Sloan Kettering Canc Ctr, Dept Med Pathol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol, New York, NY 10021 USA. Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. N Shore Long Island Jewish Res Inst, Manhasset, NY 11030 USA. Columbia Univ, Dept Med Informat, New York, NY 10032 USA. NCI, Bethesda, MD 20892 USA. RP Rennert, G (reprint author), Carmel Hosp, Clalit Hlth Serv Natl Canc Control Ctr, Haifa, Israel. FU NCI NIH HHS [R01CA81488] NR 7 TC 115 Z9 118 U1 0 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 20 PY 2002 VL 297 IS 5589 BP 2013 EP 2013 DI 10.1126/science.1074399 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 594XV UT WOS:000178078500035 PM 12242432 ER PT J AU Nguyen, KB Watford, WT Salomon, R Hofmann, SR Pien, GC Morinobu, A Gadina, M O'Shea, JJ Biron, CA AF Nguyen, KB Watford, WT Salomon, R Hofmann, SR Pien, GC Morinobu, A Gadina, M O'Shea, JJ Biron, CA TI Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection SO SCIENCE LA English DT Article ID IFN-GAMMA; T-CELLS; NATURAL-KILLER; ANTIVIRAL DEFENSE; GENE-EXPRESSION; I IFNS; ALPHA/BETA; IL-12; INTERLEUKIN-12; REQUIREMENT AB Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. Here we show that IFN-alpha/beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma production during viral infections of mice, in concert with T cell receptor derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha/beta induction of IFN-gamma. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs. C1 Brown Univ, Dept Mol Microbiol & Immunol, Div Biol & Med, Providence, RI 02912 USA. NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Biron, CA (reprint author), Brown Univ, Dept Mol Microbiol & Immunol, Div Biol & Med, Providence, RI 02912 USA. FU NCI NIH HHS [R01-CA41268]; NIGMS NIH HHS [F31-GM20760-02] NR 30 TC 308 Z9 318 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 20 PY 2002 VL 297 IS 5589 BP 2063 EP 2066 DI 10.1126/science.1074900 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 594XV UT WOS:000178078500050 PM 12242445 ER PT J AU Belluscio, L Lodovichi, C Feinstein, P Mombaerts, P Katz, LC AF Belluscio, L Lodovichi, C Feinstein, P Mombaerts, P Katz, LC TI Odorant receptors instruct functional circuitry in the mouse olfactory bulb SO NATURE LA English DT Article ID INTRABULBAR ASSOCIATIONAL SYSTEM; SENSORY MAP; TOPOGRAPHIC ORGANIZATION; REPRESENTATIONS; MICE; PROJECTIONS; GLOMERULUS; DENDRITES; SYNAPSE AB The mammalian olfactory system detects and discriminates thousands of odorants using many different receptors expressed by sensory neurons in the nasal epithelium(1). Axonal projections from these neurons to the main olfactory bulbs form reproducible patterns of glomeruli in two widely separated regions of each bulb, creating two mirror-symmetric maps of odorant receptor projections(2). To investigate whether odorant receptors organize neural circuitry in the olfactory bulb, we have examined a genetically modified mouse line, rI7 --> M71, in which a functionally characterized receptor, rI7(3,4), has been substituted into the M71 receptor locus(5). Here we show that despite their ectopic location the resulting glomeruli are responsive to known ligands of the rI7 receptor, attract postsynaptic innervation by mitral/tufted cell dendrites, and endow these cells with responses that are characteristic of the rI7 receptor. External tufted cells receiving input from rI7 --> M71 glomeruli form precise intrabulbar projections that link medial and lateral rI7 --> M71 glomeruli anatomically, thus providing a substrate for coordinating isofunctional glomeruli. We conclude that odorant receptor identity in epithelial neurons determines not only glomerular convergence and function, but also functional circuitry in the olfactory bulb. C1 Duke Univ, Med Ctr, Dept Neurobiol, Howard Hughes Med Inst, Durham, NC 27710 USA. Rockefeller Univ, New York, NY 10021 USA. RP Belluscio, L (reprint author), NINDS, NIH, 36 Convent Dr, Bethesda, MD 20892 USA. NR 29 TC 103 Z9 104 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 19 PY 2002 VL 419 IS 6904 BP 296 EP 300 DI 10.1038/nature01001 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 594NH UT WOS:000178056300045 PM 12239567 ER PT J AU Soteriades, ES Evans, JC Larson, MG Chen, MH Chen, L Benjamin, EJ Levy, D AF Soteriades, ES Evans, JC Larson, MG Chen, MH Chen, L Benjamin, EJ Levy, D TI Incidence and prognosis of syncope SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TERM FOLLOW-UP; RECURRENT UNEXPLAINED SYNCOPE; UNKNOWN ORIGIN; UNDETERMINED ORIGIN; DIAGNOSING SYNCOPE; HISTORY; BIAS; RISK AB Background: Little is known about the epidemiology and prognosis of syncope in the general population. Methods: We evaluated the incidence, specific causes, and prognosis of syncope among women and men participating in the Framingham Heart Study from 1971 to 1998. Results: Of 7814 study participants followed for an average of 17 years, 822 reported syncope. The incidence of a first report of syncope was 6.2 per 1000 person-years. The most frequently identified causes were vasovagal (21.2 percent), cardiac (9.5 percent), and orthostatic (9.4 percent); for 36.6 percent the cause was unknown. The multivariable-adjusted hazard ratios among participants with syncope from any cause, as compared with those who did not have syncope, were 1.31 (95 percent confidence interval, 1.14 to 1.51) for death from any cause, 1.27 (95 percent confidence interval, 0.99 to 1.64) for myocardial infarction or death from coronary heart disease, and 1.06 (95 percent confidence interval, 0.77 to 1.45) for fatal or nonfatal stroke. The corresponding hazard ratios among participants with cardiac syncope were 2.01 (95 percent confidence interval, 1.48 to 2.73), 2.66 (95 percent confidence interval, 1.69 to 4.19), and 2.01 (95 percent confidence interval, 1.06 to 3.80). Participants with syncope of unknown cause and those with neurologic syncope had increased risks of death from any cause, with multivariable-adjusted hazard ratios of 1.32 (95 percent confidence interval, 1.09 to 1.60) and 1.54 (95 percent confidence interval, 1.12 to 2.12), respectively. There was no increased risk of cardiovascular morbidity or mortality associated with vasovagal (including orthostatic and medication-related) syncope. Conclusions: Persons with cardiac syncope are at increased risk for death from any cause and cardiovascular events, and persons with syncope of unknown cause are at increased risk for death from any cause. Vasovagal syncope appears to have a benign prognosis. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Med Ctr, Dept Cardiol, Boston, MA USA. Boston Med Ctr, Dept Prevent Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-38038]; NINDS NIH HHS [NS-17950] NR 43 TC 484 Z9 519 U1 3 U2 10 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 19 PY 2002 VL 347 IS 12 BP 878 EP 885 DI 10.1056/NEJMoa012407 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 594GJ UT WOS:000178040700003 PM 12239256 ER PT J AU Takino, T Yoshioka, K Miyamori, H Yamada, KM Sato, H AF Takino, T Yoshioka, K Miyamori, H Yamada, KM Sato, H TI A scaffold protein in the c-Jun N-terminal kinase signaling pathway is associated with focal adhesion kinase and tyrosine-phosphorylated SO ONCOGENE LA English DT Article DE FAK; JSAP1; Src; tyrosine phosphorylation ID PROMOTED CELL-MIGRATION; SRC FAMILY KINASES; NH2-TERMINAL KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; V-SRC; P130(CAS); FIBRONECTIN; ACTIVATION; AUTOPHOSPHORYLATION; INVOLVEMENT AB Focal adhesion kinase (FAK) becomes activated and tyrosine-phosphorylated in response to cell adhesion to extracellular matrix proteins in a variety of cell types, and associates with a number of signaling molecules, structural proteins, and beta integrin cytoplasmic domains. Here we demonstrated that c-Jun N-terminal kinase (JNK)/stress activated protein kinase-associated protein 1 (JSAP1), a scaffold factor in the mitogen-activated protein kinase (MAPK) cascades, forms a complex with the N-terminus of FAK. The complex formation was further stimulated by c-Src, in which JSAP1 was tyrosine-phosphorylated and other FAK/Src signaling molecules were recruited. Fibronectin (FN) stimulation of cells expressing JSAP1 induced its tyrosine phosphorylation concomitant with association with FAK. Expression of JSAP1 in Hela cells facilitated formation of well-organized focal contacts and actin stress fibers, and promoted cell spreading onto FN. Taken together, these results suggest that JSAP1 is involved an integrin-mediated signaling pathway through FAK/Src by recruiting other signaling molecules, resulting in promotion of cell spreading onto FN. C1 Kanazawa Univ, Canc Res Inst, Div Mol Virol & Oncol, Kanazawa, Ishikawa 9200934, Japan. Kanazawa Univ, Canc Res Inst, Div Cell Cycle Regulat, Kanazawa, Ishikawa 9200934, Japan. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Takino, T (reprint author), Kanazawa Univ, Canc Res Inst, Div Mol Virol & Oncol, 13-1 Takara Machi, Kanazawa, Ishikawa 9200934, Japan. RI TAKINO, Takahisa/D-8460-2015; SATO, Hiroshi/D-8454-2015; OI Yamada, Kenneth/0000-0003-1512-6805 NR 28 TC 27 Z9 27 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 SEP 19 PY 2002 VL 21 IS 42 BP 6488 EP 6497 DI 10.1038/sj.onc.1205840 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 592FD UT WOS:000177925300009 PM 12226752 ER PT J AU Pozsgay, V Vieira, NE Yergey, A AF Pozsgay, V Vieira, NE Yergey, A TI A method for bioconjugation of carbohydrates using Diels-Alder cycloaddition SO ORGANIC LETTERS LA English DT Article ID SHIGELLA-DYSENTERIAE TYPE-1; POLYSACCHARIDE; PROTEIN; VACCINES AB Diels-Alder-type cycloaddition of an electronically matched pair of saccharide-linked conjugated dienes and a dienophile-equipped protein gives negoglycoproteins at ambient temperature in pure water with a reaction half-life of approximately 2 h. Uncoupled saccharides can be recovered by diafiltration with complete conservation of the diene moiety, thus allowing their repeated use. The procedure described is the first for creating a carbon-carbon covalent bond in the bioconjugation step between a saccharide and a protein. C1 NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), NICHHD, Dev & Mol Immun Lab, NIH, 6 Ctr Dr MSC 2720, Bethesda, MD 20892 USA. NR 21 TC 40 Z9 40 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD SEP 19 PY 2002 VL 4 IS 19 BP 3191 EP 3194 DI 10.1021/ol026179v PG 4 WC Chemistry, Organic SC Chemistry GA 595DC UT WOS:000178090700006 PM 12227746 ER PT J AU Rashid, MA Gustafson, KR Crouch, RC Groweiss, A Pannell, LK Van, QN Boyd, MR AF Rashid, MA Gustafson, KR Crouch, RC Groweiss, A Pannell, LK Van, QN Boyd, MR TI Application of high-field NMR and cryogenic probe technologies in the structural elucidation of poecillastrin A, a new antitumor macrolide lactam from the sponge Poecillastra species SO ORGANIC LETTERS LA English DT Article ID 2-SPONGE ASSOCIATION; MARINE; PROTEINS AB Poecillastrin A (1) a new polyketide-derived macrolide lactam, was isolated from a deep-water collection of the marine sponge Poecillastra species. The structure of poecillastrin A (1) was assigned using NMR data acquired at 500 MHz with an inverse-detection cryogenic probe and at 800 MHz with a room-temperature probe. C1 NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. TAMI IMI Inst Res & Dev, IL-26111 Haifa, Israel. RP Gustafson, KR (reprint author), NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, Bldg 1052,Room 121, Frederick, MD 21702 USA. NR 20 TC 18 Z9 18 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD SEP 19 PY 2002 VL 4 IS 19 BP 3293 EP 3296 DI 10.1021/ol026564k PG 4 WC Chemistry, Organic SC Chemistry GA 595DC UT WOS:000178090700032 PM 12227772 ER PT J AU Boisbouvier, J Bax, A AF Boisbouvier, J Bax, A TI Long-range magnetization transfer between uncoupled nuclei by dipole-dipole cross-correlated relaxation: A precise probe of beta-sheet geometry in proteins SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL-SHIFT ANISOTROPY; IGG-BINDING DOMAIN; SPIN RELAXATION; HIV-1 PROTEASE; PARAMAGNETIC PROTEINS; RELATIVE ORIENTATION; SECONDARY STRUCTURE; NATURAL-ABUNDANCE; COSY SPECTRA; BASE-PAIRS AB Interference between dipolar interactions in covalently linked C-13-H-1 and nonlinked H-1-H-1 pairs can be used to generate antiphase magnetization between noncoupled spins. The buildup rate of such antiphase terms is highly sensitive to local geometry, in particular the interproton distance and the C-13-H-1-H-1 internuclear angle. These rates have been measured for opposing CalphaHalpha pairs in antiparallel beta-sheets in the third Igg-binding domain of protein G (GB3) and in HIV protease, complexed with the inhibitor DMP323. For GB3, good agreement with the 1.1-Angstrom crystal structure is found. However, this agreement rapidly deteriorates with decreasing resolution of the corresponding X-ray structure. For HIV protease, two separate crystal structures that differ by less than 0.2 Angstrom from one another exhibit lower agreement in their predicted cross-correlated relaxation rates relative to one another than is found between experimental rates and the average of the rates predicted for the two structures. These data indicate that quantitative measurement of these cross-correlated relaxation rates can provide highly accurate structural information in macromolecules. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 61 TC 9 Z9 9 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 18 PY 2002 VL 124 IS 37 BP 11038 EP 11045 DI 10.1021/ja020511g PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 593XL UT WOS:000178019700037 PM 12224951 ER PT J AU Mori, Y Rusk, RA Jones, M Li, XN Irvine, T Zetts, AD Sahn, DJ AF Mori, Y Rusk, RA Jones, M Li, XN Irvine, T Zetts, AD Sahn, DJ TI A new dynamic three-dimensional digital color Doppler method for quantification of pulmonary regurgitation: Validation study in an animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID QUANTIFYING AORTIC REGURGITATION; IMAGED VENA-CONTRACTA; 3-DIMENSIONAL VISUALIZATION; EXERCISE CAPACITY; VELOCITY PROFILES; VOLUMETRIC FLOW; IN-VITRO; TETRALOGY; FALLOT; REPAIR AB OBJECTIVES The purpose of the present study was to validate a newly developed three-dimensional (3D) digital color Doppler method for quantifying pulmonary regurgitation (PR), using an animal model of chronic PR. BACKGROUND Spectral Doppler methods cannot reliably be used to assess pulmonary regurgitation. METHODS In eight sheep with surgically created PR, 27 different hemodynamic states were studied. Pulmonary and aortic electromagnetic (EM) probes and meters were used to provide reference right ventricular (RV) for-ward and pulmonary regurgitant stroke volumes. A multiplane transesophageal probe was placed directly on the RV and aimed at the RV outflow tract. Electrocardiogram-gated and rotational 3D scans were performed for acquiring dynamic 3D digital velocity data. After 3D digital Doppler data were transferred to a computer workstation, the RV forward and pulmonary regurgitant flow volumes were obtained by a program that computes the velocity vectors over a spherical surface perpendicular to the direction of scanning. RESULTS Pulmonary regurgitant volumes and RV forward stroke volumes computed by the 3D method correlated well with those by the EM method (r = 0.95, mean difference = 0.51 +/- 1.89 ml/beat for the pulmonary regurgitant volume; and r = 0.91, mean difference = -0.22 +/- 3.44 ml/beat for the RV stroke volume). As a result of these measurements, the regurgitant fractions derived by the 3D method agreed well with the reference data (r = 0.94, mean difference = 2.06 +/- 6.11%). CONCLUSIONS The 3D digital color Doppler technique is a promising method for determining pulmonary regurgitant volumes and regurgitant fractions. It should have an important application in clinical settings. C1 Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97201 USA. NHLBI, Lab Anim Med & Surg, Bethesda, MD 20892 USA. Philips Ultrasound, Bothell, WA USA. RP Sahn, DJ (reprint author), Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 SW Sam Jackson Pk Rd,L608, Portland, OR 97201 USA. NR 32 TC 16 Z9 16 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 SEP 18 PY 2002 VL 40 IS 6 BP 1179 EP 1185 AR PII S0735-1097(02)020740-0 DI 10.1016/S0735-1097(02)02074-0 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 593TQ UT WOS:000178009900025 PM 12354447 ER PT J AU Castle, PE Wacholder, S Lorincz, AT Scott, DR Sherman, ME Glass, AG Rush, BB Schussler, JE Schiffman, M AF Castle, PE Wacholder, S Lorincz, AT Scott, DR Sherman, ME Glass, AG Rush, BB Schussler, JE Schiffman, M TI A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; COSTA-RICA; INTRAEPITHELIAL NEOPLASIA; EPIDEMIOLOGIC EVIDENCE; CANCER; SMOKING; DNA; ADENOCARCINOMAS; WORLDWIDE; COLOMBIA AB Background: In case-control studies, smoking, parity, and oral contraceptive use have been associated with an increased risk of cervical intraepithelial neoplasia grade 3 (CIN3) and cervical cancer among women who are infected with oncogenic human papillomavirus (HPV). However, these potential risk factors have not been adequately studied in prospective studies. Methods: We studied 1812 women who were enrolled in a 10-year prospective study of cervical neoplasia at Kaiser Permanente in Portland, Oregon, and who at enrollment had tested positive for oncogenic HPV DNA and had responded to a questionnaire that included questions on smoking, oral contraceptive use, and parity. Absolute risks and crude relative risks (RRs) with 95% confidence intervals (CIs) for CIN3 or cervical cancer were computed for three time intervals (0-8, 9-68, and 69-122 months after enrollment) using the Kaplan-Meier method. Conditional logistic regression models were used to control for factors that may have influenced our risk estimates, specifically the cytologic interpretation of baseline Pap smear, number of Pap smears during follow-up, age at enrollment, age at prediagnosis visit, and age at diagnosis. All statistical tests were two-sided. Results: Oral contraceptive use and parity were not associated with risk of CIN3 or cervical cancer. Former smokers, women who smoked less than one pack of cigarettes per day, and women who smoked one or more packs per day had crude RRs for CIN3 or cervical cancer for the entire follow-up period of 2.1 (95 % CI = 1.1 to 3.9), 2.2 (95 % CI = 1.2 to 4.2), and 2.9 (95 % CI = 1.5 to 5.6), respectively, compared with never smokers. In the multivariable model, former smokers, women who smoked less than one pack/day, and women who smoked one or more packs/day had RRs of 3.3 (95 % CI = 1.6 to 6.7), 2.9 (95 % CI = 1.4 to 6.1), and 4.3 (95% CI = 2.0 to 9.3), respectively, for CIN3 or cervical cancer compared with never smokers. Conclusions: Smoking is associated with an increased risk of invasive cervical cancer in women who are infected with oncogenic HPIV. Subsequent studies should examine the role of smoking in the multistage pathogenesis of cervical cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Digene Corp, Gaithersburg, MD USA. Kaiser Permanente, Portland, OR USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 7074,MSC 7234, Bethesda, MD 20892 USA. NR 30 TC 132 Z9 144 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 18 PY 2002 VL 94 IS 18 BP 1406 EP 1414 PG 9 WC Oncology SC Oncology GA 593VZ UT WOS:000178016300013 PM 12237286 ER PT J AU Chalmers, JM Everall, NJ Schaeberle, MD Levin, IW Lewis, EN Kidder, LH Wilson, J Crocombe, R AF Chalmers, JM Everall, NJ Schaeberle, MD Levin, IW Lewis, EN Kidder, LH Wilson, J Crocombe, R TI FT-IR imaging of polymers: an industrial appraisal SO VIBRATIONAL SPECTROSCOPY LA English DT Article; Proceedings Paper CT 1st International Conference on Advanced Vibrational Spectroscopy CY AUG 19-24, 2001 CL TURKU, FINLAND DE FT-IR microscopy; focal plan array; polymers; imaging ID PLANE ARRAY DETECTION; MICROSCOPY; ROUTE AB Chemical structure and conformation and physical property anisotropy at the microscopic level can have a major influence on the macroscopic performance characteristics of polymer products. Images based on infrared spectral differences and changes generated using FT-IR microscopy techniques are becoming increasingly used to highlight both chemical structure variations and morphology gradients within polymer articles. This paper illustrates potential industrial applications to polymer characterisation and analysis using mid-infrared FT-IR microscopy systems fitted with focal plane array (FPA) detectors. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Nottingham, Sch Chem, Nottingham NG7 2RD, England. VSConsulting, Stokesley TS9 5NW, England. Wilton Ctr, ICI Measurement Sci Grp, Wilton TS10 4RF, Redcar, England. NIH, Bethesda, MD 20892 USA. Spectral Dimens Inc, Olney, MD 20832 USA. BioRad Labs Ltd, Hemel Hempstead HP2 7TD, Herts, England. BioRad Labs Ltd, Digilab Div, Randolph, MA 02368 USA. RP Chalmers, JM (reprint author), Univ Nottingham, Sch Chem, Univ Pk, Nottingham NG7 2RD, England. NR 14 TC 36 Z9 36 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-2031 J9 VIB SPECTROSC JI Vib. Spectrosc. PD SEP 18 PY 2002 VL 30 IS 1 BP 43 EP 52 AR PII S0924-2031(02)00037-1 DI 10.1016/S0924-2031(02)00037-1 PG 10 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 598BR UT WOS:000178255700007 ER PT J AU Illei, GG Balow, JE Boumpas, DT AF Illei, GG Balow, JE Boumpas, DT TI Long-term outcome in lupus nephritis - In response SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID CONTROLLED TRIAL C1 NIH, Bethesda, MD 20892 USA. Univ Crete, Sch Med, Iraklion 71110, Greece. RP Illei, GG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 17 PY 2002 VL 137 IS 6 BP 545 EP 546 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 594UJ UT WOS:000178069100012 ER PT J AU Young, NS Tisdale, JF AF Young, NS Tisdale, JF TI High-dose cyclophosphamide for treatment of aplastic anemia SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 17 PY 2002 VL 137 IS 6 BP 549 EP 550 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 594UJ UT WOS:000178069100023 PM 12230370 ER PT J AU Reeves, JE Anderson, WF AF Reeves, JE Anderson, WF TI Permanent paralysis of the right phrenic nerve SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID PALSY; COMPLICATION; CATHETER C1 Canc Care Associates, Oklahoma City, OK 73120 USA. NCI, Bethesda, MD 20892 USA. RP Reeves, JE (reprint author), Canc Care Associates, Oklahoma City, OK 73120 USA. NR 4 TC 1 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 17 PY 2002 VL 137 IS 6 BP 551 EP 552 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 594UJ UT WOS:000178069100027 PM 12230375 ER PT J AU Daigle, DM Rossi, L Berghuis, AM Aravind, L Koonin, EV Brown, ED AF Daigle, DM Rossi, L Berghuis, AM Aravind, L Koonin, EV Brown, ED TI YjeQ, an essential, conserved, uncharacterized protein from Escherichia coli, is an unusual GTPase with circularly permuted G-motifs and marked burst kinetics SO BIOCHEMISTRY LA English DT Article ID DNA METHYLTRANSFERASES; BINDING PROTEINS; P21(H-RAS); MECHANISM; COMMON; PERMUTATIONS; HYDROLYSIS; DATABASE; PROGRAM; GENES AB The Escherichia coli protein YjeQ represents a protein family whose members are broadly conserved in bacteria and have been shown to be indispensable to the growth of E. coli and Bacillus subtilis [Arigoni, F., et a]. (1998) Nat. Biotechnol. 16, 851]. Proteins of the YjeQ family contain all sequence motifs typical of the vast class of P-loop-containing GTPases, but show a circular permutation, with a G4-G1-G3 pattern of motifs as opposed to the regular G1-G3-G4 pattern seen in most GTPases. All YjeQ family proteins display a unique domain architecture, which includes a predicted N-terminal OB-fold RNA-binding domain, the central permuted GTPase module, and a zinc knuckle-like C-terminal cysteine cluster. This domain architecture suggests a possible role for YjeQ as a regulator of translation. YjeQ was overexpressed, purified to homogeneity, and shown to contain 0.6 equiv of GDP. Steady state kinetic analyses indicated slow GTP hydrolysis, with a k(cat) of 9.4 h(-1) and a K-m for GTP of 120 muM (k(cat)/K-m = 21.7 M-1 s(-1)). YjeQ also hydrolyzed other nucleoside triphosphates and deoxynucleotide triphosphates such as ATP, ITP, and CTP with specificity constants (k(cat)/k(m)) ranging from 0.2 to 1.0 M-1 s(-1). Pre-steady state kinetic analysis of YjeQ revealed a burst of nucleotide hydrolysis for GTP described by a first-order rate constant of 100 s(-1) as compared to a burst rate of 0.2 s(-1) for ATP. In addition, a variant in the G1 motif of YjeQ (S221A) was substantially impaired for GTP hydrolysis (0.3 s(-1)) with a less significant impact on the steady state rate (1.8 h(-1)). In summary, E. coli YjeQ is an unusual, circularly permuted P-loop-containing GTPase, which catalyzes GTP hydrolysis at a rate 45 000 times greater than that of turnover. C1 McMaster Univ, Dept Biochem, Antimicrobial Res Ctr, Hamilton, ON L8N 3Z5, Canada. Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Brown, ED (reprint author), McMaster Univ, Dept Biochem, Antimicrobial Res Ctr, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. RI Berghuis, Albert/A-6495-2008 NR 35 TC 59 Z9 60 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 17 PY 2002 VL 41 IS 37 BP 11109 EP 11117 DI 10.1021/bi020355q PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593UH UT WOS:000178011700006 PM 12220175 ER PT J AU Eidelman, O BarNoy, S Razin, M Zhang, J McPhie, P Lee, G Huang, Z Sorscher, EJ Pollard, HB AF Eidelman, O BarNoy, S Razin, M Zhang, J McPhie, P Lee, G Huang, Z Sorscher, EJ Pollard, HB TI Role for phospholipid interactions in the trafficking defect of Delta F508-CFTR SO BIOCHEMISTRY LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; NUCLEOTIDE-BINDING FOLD; CYSTIC-FIBROSIS GENE; SECONDARY STRUCTURE; WILD-TYPE; PROTEIN; CFTR; IDENTIFICATION; MEMBRANE; MUTATION AB Cystic fibrosis commonly occurs as a consequence of the DeltaF508 mutation in the first nucleotide binding fold domain (NBF-1) of CFTR. The mutation causes retention of the mutant CFTR molecule in the endoplasmic reticulum, and this aberrant trafficking event is believed to be due to defective interactions between the mutant NBF-1 domain and other cellular factors in the endoplasmic reticulum. Since the NBF- I domain has been shown to interact with membranes, we wanted to investigate whether NBF-1 and CFTR interactions with specific phospholipid chaperones might play a role in trafficking. We have found that the recombinant wild-type NBF-1 interacts selectively with phosphatidylserine (PS) rather than phosphatidylcholine (PC). By contrast, NBF-1 carrying the DeltaF508 mutation loses the ability to discriminate between these two phospholipids. In cells expressing DeltaF508-CFTR, replacement of PC by noncharged analogues results in an absolute increase in CFTR expression. In addition, we detected progressive expression of higher molecular weight CFTR forms. Thus, phospholipid chaperones may be important for CFTR trafficking, and contribute to the pathology of cystic fibrosis. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Inst Mol Med, Bethesda, MD 20814 USA. NIDDK, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Physiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU NIDDK NIH HHS [R01-DK-53051] NR 27 TC 11 Z9 12 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 17 PY 2002 VL 41 IS 37 BP 11161 EP 11170 DI 10.1021/bi020289s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593UH UT WOS:000178011700012 PM 12220181 ER PT J AU Peculis, BA AF Peculis, BA TI Ribosome biogenesis: Ribosomal RNA synthesis as a package deal SO CURRENT BIOLOGY LA English DT Editorial Material ID SMALL NUCLEOLAR RIBONUCLEOPROTEIN; SACCHAROMYCES-CEREVISIAE; U3 AB Ribosome biogenesis encompasses a complicated series of events involving hundreds of transiently interacting components. Insight into a mechanism for coordinating some of these events may come from characterization of a functional processing complex. C1 NIDDK, NIH, GBB, Bethesda, MD 20892 USA. RP Peculis, BA (reprint author), NIDDK, NIH, GBB, Bldg 8 Room 106, Bethesda, MD 20892 USA. NR 15 TC 8 Z9 8 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 17 PY 2002 VL 12 IS 18 BP R623 EP R624 AR PII S0960-9822(02)01135-1 DI 10.1016/S0960-9822(02)01135-1 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 595WR UT WOS:000178132000009 PM 12372268 ER PT J AU Aurandt, J Vikis, HG Gutkind, JS Ahn, N Guan, KL AF Aurandt, J Vikis, HG Gutkind, JS Ahn, N Guan, KL TI The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HETEROTRIMERIC G-PROTEINS; ACTIVE RAC; AXONAL GUIDANCE; DBL FAMILY; LEUKEMIA; GTPASES; CYTOSKELETON; NEUROPILIN; DOMAIN; GENE AB Semaphorins are axon guidance molecules that signal through the plexin family of receptors. Semaphorins also play a role in other processes such as immune regulation and tumorigenesis. However, the molecular signaling mechanisms downstream of plexin receptors have not been elucidated. Semaphorin 4D is the ligand for the plexin-B1 receptor and stimulation of the plexin-B1 receptor activates the small GTPase RhoA. Using the intracellular domain of plexin-B1 as an affinity ligand, two Rho-specific guanine nucleotide exchange factors, leukemia-associated Rho GEF (LARG; GEF, guanine nucleotide exchange factors) and PSD-95/Dlg/ZO-1 homology (PDZ)-RhoGEF, were isolated from mouse brain as plexin-B1-specific interacting proteins. LARG and PDZ-RhoGEF contain several functional domains, including a PDZ domain. Biochemical characterizations showed that the PDZ domain of LARG is directly involved in the interaction with the carboxy-terminal sequence of plexin-B1. Mutation of either the PDZ domain in LARG or the PDZ binding site in plexin-B1 eliminates the interaction. The interaction between plexin-B1 and LARG is specific for the PDZ domain of LARG and LARG does not interact with plexin-A1. A LARG-interaction defective mutant of the plexin-B1 receptor was created and was unable to stimulate RhoA activation. The data in this report suggest that LARG plays a critical role in plexin-B1 signaling to stimulate Rho activation and cytoskeletal reorganization. C1 Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Colorado, Howard Hughes Med Inst, Dept Biochem & Chem, Boulder, CO 80309 USA. RP Guan, KL (reprint author), Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. RI Gutkind, J. Silvio/A-1053-2009 FU NIGMS NIH HHS [GMO7767] NR 34 TC 141 Z9 148 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 17 PY 2002 VL 99 IS 19 BP 12085 EP 12090 DI 10.1073/pnas.142433199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 596VK UT WOS:000178187000019 PM 12196628 ER PT J AU Lesher, DTT Pommier, Y Stewart, L Redinbo, MR AF Lesher, DTT Pommier, Y Stewart, L Redinbo, MR TI 8-oxoguanine rearranges the active site of human topoisomerase I SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CRYSTAL-STRUCTURE; CLEAVAGE COMPLEXES; DNA; RECOMBINASE; INDUCTION; FLEXIBILITY; MOLSCRIPT; MECHANISM; REPAIR; DOMAIN AB 7,8-Dihydro-8-oxoguanine (8-oxoG) is the most common form of oxidative DNA damage in human cells. Biochemical studies have shown that 8-oxoG decreases the DNA cleavage activity of human topoisomerase I, an enzyme vital to DNA metabolism and stability. We present the 3.1-Angstrom crystal structure of human topoisomerase I in noncovalent complex with a DNA oligonucleotide containing 8-oxoG at the +1 position in the scissile strand. We find that 8-oxoG reorganizes the active site of human topoisomerase I into an inactive conformation relative to the structures of topoisomerase I-DNA complexes elucidated previously. The catalytic Tyr-723-Phe rotates away from the DNA cleavage site and packs into the body of the molecule. A second active-site residue, Arg-590, becomes disordered and is not observed in the structure. The docked, inactive conformation of Tyr-723-Phe is reminiscent of the related tyrosine recombinase family of integrases and recombinases, suggesting a common regulatory mechanism. We propose that human topoisomerase I binds to DNA first in an inactive conformation and then rearranges its active site for catalysis. 8-OxoG appears to impact topoisomerase I by stabilizing the inactive, DNA-bound state. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Emerald BioStruct, Bainbridge Isl, WA 98110 USA. RP Redinbo, MR (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. NR 31 TC 52 Z9 54 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 17 PY 2002 VL 99 IS 19 BP 12102 EP 12107 DI 10.1073/pnas.192282699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 596VK UT WOS:000178187000022 PM 12209008 ER PT J AU Morinobu, A Gadina, M Strober, W Visconti, R Fornace, A Montagna, C Feldman, GM Nishikomori, R O'Shea, JJ AF Morinobu, A Gadina, M Strober, W Visconti, R Fornace, A Montagna, C Feldman, GM Nishikomori, R O'Shea, JJ TI STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVATED PROTEIN-KINASE; P38 MAP KINASE; T-CELLS; TYROSINE PHOSPHORYLATION; TRANSCRIPTIONAL ACTIVITY; SIGNAL TRANSDUCER; IL-12 RECEPTOR; T(H)1 CELLS; DNA-BINDING; TH2 CELLS AB T helper 1 (T(H)1) differentiation and IFN-gamma production are crucial in cell-mediated immune responses. IL-12 is an important regulator of this process and mediates its effects through signal transducer and activator of transcription 4 (STAT4). IFN-gamma production is also regulated by the p38 mitogen-activated kinase pathway, although the mechanisms are ill-defined. We show here that GADD45-beta and GADD45-gamma can induce STAT4 S721 phosphorylation via the MKK6/p38 pathway. Thus, STAT4 could be a target that accounts for the defects in cell-mediated immunity associated with perturbations in the p38 pathway. To investigate the biological significance of STAT4 S721 phosphorylation, we reconstituted primary spleen cells from STAT4-deficient mice with wild-type and mutated STAT4, by using a retroviral gene transduction. We demonstrated that expression of wild-type STAT4, but not the S721A mutant, restored normal THII differentiation and IFN-gamma synthesis. The inability of STAT4 S721 to restore IFN-gamma production was not caused by decreased IL-12R expression because the STAT4 S721 mutant also failed to restore IFN-gamma production in STAT4-deficient IL-12Rbeta2 transgenic cells. Importantly, STAT4 S721A-transduced cells showed normal proliferative response to IL-12, illustrating that serine phosphorylation is not required for IL-12-induced proliferation. Additionally, the results imply the existence of STAT4 serine phosphoryiation-dependent and -independent target genes. We conclude that phosphorylation of STAT4 on both tyrosine and serine residues is important in promoting normal TH1 differentiation and IFN-gamma secretion. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD 20892 USA. RP Morinobu, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008; Visconti, Roberta/C-5299-2009 OI Fornace, Albert/0000-0001-9695-085X; NR 53 TC 97 Z9 100 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 SEP 17 PY 2002 VL 99 IS 19 BP 12281 EP 12286 DI 10.1073/pnas.182618999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 596VK UT WOS:000178187000053 PM 12213961 ER PT J AU Domi, A Moss, B AF Domi, A Moss, B TI Cloning the vaccinia virus genome as a bacterial artificial chromosome in Escherichia coli and recovery of infectious virus in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LINEAR MINICHROMOSOMES; CONCATEMER JUNCTIONS; MOLECULAR-CLONING; GENE-EXPRESSION; FOREIGN GENES; DNA; CONSTRUCTION; REPLICATION; RESOLUTION; SELECTION AB The ability to manipulate the vaccinia virus (VAC) genome, as a plasmid in bacteria, would greatly facilitate genetic studies and provide a powerful alternative method of making recombinant viruses. VAC, like other poxviruses, has a linear, double-stranded DNA genome with covalently closed hairpin ends that are resolved from transient head-to-head and tail-to-tail concatemers; during replication in the cytoplasm of infected cells. Our strategy to construct a nearly 200,000-bp VAC-bacterial artificial chromosome (BAC) was based on circularization of head-to-tail concatemers of. VAC DNA. Cells were infected with a recombinant VAC containing inserted sequences for plasmid replication and maintenance in Escherichia coli; DNA concatemer resolution was inhibited leading to formation and accumulation of head-to-tail concatemers, in addition to the usual head-to-head and tail-to-tail forms; the concatemers were circularized by homologous or Cre-IoxP-mediated recombination; and E. coli were transformed with DNA from the infected cell lysates. Stable plasmids containing the entire VAC genome, with an intact concatemer junction sequence, were identified. Rescue of infectious VAC was consistently achieved by transfecting the VAC-BAC plasmids into mammalian cells that were infected with a helper nonreplicating fowlpox virus. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 37 TC 50 Z9 52 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 17 PY 2002 VL 99 IS 19 BP 12415 EP 12420 DI 10.1073/pnas.192420599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 596VK UT WOS:000178187000076 PM 12196634 ER PT J AU Modis, Y Trus, BL Harrison, SC AF Modis, Y Trus, BL Harrison, SC TI Atomic model of the papillomavirus capsid SO EMBO JOURNAL LA English DT Article DE disulfide bond; electron microscopy; papillomavirus; vaccine design; virus assembly ID VIRUS-LIKE PARTICLES; ANGSTROM RESOLUTION; PROTEIN; RECONSTRUCTION; MOLSCRIPT; FEATURES; DENSITY; BOVINE AB Papillomaviruses propagate in differentiating skin cells, and certain types are responsible for the onset of cervical cancer. We have combined image reconstructions from electron cryomicroscopy (cryoEM) of bovine papillomavirus at 9 Angstrom resolution with coordinates from the crystal structure of small virus-like particles of the human papillomavirus type 16 L1 protein to generate an atomic model of the virion. The overall fit of the L1 model into the cryoEM map is excellent, but residues 402-446 in the 'C-terminal arm' must be rebuilt. We propose a detailed model for the structure of this arm, based on two constraints: the presence of an intermolecular disulfide bond linking residues 175 and 428, and the clear identification of a feature in the image reconstruction corresponding to an alpha-helix near the C-terminus of L1. We have confirmed the presence of the disulfide bond by mass spectrometry. Our 'invading arm' model shows that papilloma- and polyomaviruses have a conserved capsid architecture. Most of the rebuilt C-terminal arm is exposed on the viral surface; it is likely to have a role in infection and in immunogenicity. C1 Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIAMSD, Computat Biosci & Engn Lab, Div Comp Res & Technol, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Harrison, SC (reprint author), Childrens Hosp, Howard Hughes Med Inst, 320 Longwood Ave, Boston, MA 02115 USA. OI Modis, Yorgo/0000-0002-6084-0429 FU NCI NIH HHS [CA-13202, R01 CA013202, R37 CA013202]; NIGMS NIH HHS [GM-62580, P01 GM062580] NR 33 TC 164 Z9 179 U1 0 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 16 PY 2002 VL 21 IS 18 BP 4754 EP 4762 DI 10.1093/emboj/cdf494 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 595RT UT WOS:000178123100002 PM 12234916 ER PT J AU Ortega, J Lee, HS Maurizi, MR Steven, AC AF Ortega, J Lee, HS Maurizi, MR Steven, AC TI Alternating translocation of protein substrates from both ends of ClpXP protease SO EMBO JOURNAL LA English DT Article DE AAA-ATPase; ATP-dependent proteolysis; chaperone; ClpXP protease; electron microscopy ID ATP-DEPENDENT PROTEASES; ESCHERICHIA-COLI; CLPAP PROTEASE; TAGGING SYSTEM; PROTEOLYSIS; DEGRADATION; COMPLEX; RECOGNITION; CRYSTAL; GROEL AB In ClpXP protease complexes, hexameric rings of the ATP-dependent ClpX chaperone stack on one or both faces of the double-heptameric rings of ClpP. We used electron microscopy to record the initial binding of protein substrates to ClpXP and their accumulation inside proteolytically inactive ClpP. Proteins with N- or C-terminal recognition motifs bound to complexes at the distal surface of ClpX and, upon addition of ATP, were translocated to ClpP. With a partially translocated substrate, the non-translocated portion remained on the surface of ClpX, aligned with the central axis of the complex, confirming that translocation proceeds through the axial channel of ClpXP. Starting with substrate bound on both ends, most complexes translocated substrate from only one end, and rarely (<5%) from both ends. We propose that translocation from one side is favored for two reasons: initiation of translocation is infrequent, making the probability of simultaneous initiation low; and, further, the presence of protein within the cis side translocation channel or within ClpP generates an inhibitory signal blocking translocation from the trans side. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 44 TC 50 Z9 50 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 16 PY 2002 VL 21 IS 18 BP 4938 EP 4949 DI 10.1093/emboj/cdf483 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 595RT UT WOS:000178123100019 PM 12234933 ER PT J AU Le Stunff, H Galve-Roperh, I Peterson, C Milstien, S Spiegel, S AF Le Stunff, H Galve-Roperh, I Peterson, C Milstien, S Spiegel, S TI Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis SO JOURNAL OF CELL BIOLOGY LA English DT Article DE S1P phosphaxtase-1; sphingosine-1-phosphate; ceramide; sphingosine; apoptosis ID LIPID PHOSPHATE PHOSPHATASE-1; SPHINGOSINE-INDUCED APOPTOSIS; LONG-CHAIN BASES; SACCHAROMYCES-CEREVISIAE; HEAT-STRESS; GOLGI-APPARATUS; DE-NOVO; ENDOPLASMIC-RETICULUM; CERAMIDE SYNTHASE; KINASE PATHWAY AB Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein-coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with SIP markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-SI P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin 131, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [H-3]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate. C1 Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Univ Complutense, Dept Biochem & Mol Biol, Madrid 38040, Spain. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Med Coll Virginia Campus, Richmond, VA 23298 USA. FU NIGMS NIH HHS [R01 GM043880, R37 GM043880, GM 43880] NR 60 TC 114 Z9 116 U1 2 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 16 PY 2002 VL 158 IS 6 BP 1039 EP 1049 DI 10.1083/jcb.200203123 PG 11 WC Cell Biology SC Cell Biology GA 596WP UT WOS:000178189700008 PM 12235122 ER PT J AU Howard, OMZ Dong, HJF Yang, D Raben, N Nagaraju, K Rosen, A Casciola-Rosen, L Hartlein, M Kron, M Yang, D Yiadom, K Dwivedi, S Plotz, PH Oppenheim, JJ AF Howard, OMZ Dong, HJF Yang, D Raben, N Nagaraju, K Rosen, A Casciola-Rosen, L Hartlein, M Kron, M Yang, D Yiadom, K Dwivedi, S Plotz, PH Oppenheim, JJ TI Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE myopathy; chemokine receptor; aminoacyl-tRNA synthetase; autoantibody; autoimmunity ID TRANSFER-RNA-SYNTHETASE; IDIOPATHIC INFLAMMATORY MYOPATHIES; POSTTRANSLATIONAL PROTEIN MODIFICATIONS; SYSTEMIC LUPUS-ERYTHEMATOSUS; ANTIGEN-PRESENTING CELLS; APOPTOTIC CELLS; BETA-CHEMOKINES; CDNA SEQUENCE; HIV-1 ENTRY; CLASS-I AB Autoantibodies to histidyl-tRNA synthetase (HisRS) or to alanyl-, asparaginyl-, glycyl-, isoleucyl-, or threonyl-tRNA synthetase occur in similar to25% of patients with polymyositis or dermatomyositis. We tested the ability of several aminoacyl-tRNA synthetases to induce leukocyte migration. I HisRS induced CD4(+) and CD8(+) lymphocytes, interleukin (IL)-2-activated monocytes, and immature dendritic cells (iDCs) to migrate, but not neutrophils, mature DCs, or unstimulated monocytes. An NH2-terminal domain, 1-48 HisRS, was chemotactic for lymphocytes and activated monocytes, whereas a deletion mutant, HisRS-M, was inactive. HisRS selectively activated CC chemokine receptor (CCR)5-transfected HEK-293 cells, inducing migration by interacting with extracellular domain three. Furthermore, monoclonal anti-CCR5 blocked HisRS-induced chemotaxis and conversely, HisRS blocked anti-CCR5 binding. Asparaginyl-tRNA synthetase induced migration of lymphocytes, activated monocytes, iDCs, and CCR3-transfected HEK-293 cells. Seryl-tRNA synthetase induced migration of CCR3-transfected cells but not DC. Non-autoantigenic aspartyl-tRNA and lysyl-tRNA synthetases were not chemotactic. Thus, autoantigenic aminoacyl-tRNA synthetases, perhaps liberated from damaged muscle cells, may Perpetuate the development of myositis by recruiting mononuclear cells that induce innate and adaptive immune responses. Therefore, the selection of a self-molecule as a target for an autoantibody response may be a consequence of the proinflammatory properties of the molecule itself. C1 NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Rheumatol, Baltimore, MD 21218 USA. Inst Max Von Laue Paul Langevin, F-38042 Grenoble, France. Michigan State Univ, Dept Med, E Lansing, MI 48823 USA. Georgetown Univ, Dept Biochem, Washington, DC 20057 USA. RP Howard, OMZ (reprint author), NCI, Ctr Canc Res, Mol Immunoregulat Lab, POB B, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012; Yang, David/A-7294-2009 OI Howard, O M Zack/0000-0002-0505-7052; FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 58 TC 154 Z9 165 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 16 PY 2002 VL 196 IS 6 BP 781 EP 791 DI 10.1084/jem.20020186 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 596BD UT WOS:000178143100007 PM 12235211 ER PT J AU Polack, FP Teng, MN Collins, PL Prince, GA Exner, M Regele, H Lirman, DD Rabold, R Hoffman, SJ Karp, CL Kleeberger, SR Wills-Karp, M Karron, RA AF Polack, FP Teng, MN Collins, PL Prince, GA Exner, M Regele, H Lirman, DD Rabold, R Hoffman, SJ Karp, CL Kleeberger, SR Wills-Karp, M Karron, RA TI A role for immune complexes in enhanced respiratory syncytial virus disease SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE respiratory syncytial virus; enhanced disease; immune complexes; airway hyperresponsiveness; compliment ID FORMALIN-INACTIVATED RSV; COTTON RATS; BALB/C MICE; INFLAMMATORY RESPONSES; PULMONARY PATHOLOGY; ALLERGIC-ASTHMA; T-CELLS; IMMUNIZATION; INFECTION; VACCINE AB Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral Pneumonia in infants and young children. Administration of a formalin inactivated vaccine against RSV to children in the 1960s resulted in increased morbidity and mortality in vaccine recipients who subsequently contracted RSV. This incident precluded development of subunit RSV vaccines for infants for over 30 years, because the mechanism of illness was never clarified. An RSV vaccine for infants is still not available. Here, we demonstrate that enhanced RSV disease is mediated by immune complexes and abrogated in complement component C3 and B cell-deficient mice but not in controls. Further, we show correlation with the enhanced disease observed in children by providing evidence of complement activation in postmortem lung sections from children with enhanced RSV disease. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. NIAID, NIH, Rockville, MD 20850 USA. Virion Syst Inc, Rockville, MD 20850 USA. Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria. Univ Vienna, Dept Clin Pathol, A-1090 Vienna, Austria. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Childrens Hosp Res Fdn, Div Mol Immunol, Cincinnati, OH 45229 USA. Childrens Hosp Res Fdn, Div Immunobiol, Cincinnati, OH 45229 USA. RP Polack, FP (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth, 615 N Wolfe St,W5102, Baltimore, MD 21205 USA. RI Teng, Michael/I-5006-2012; OI Teng, Michael/0000-0002-0722-3659; Karp, Christopher/0000-0002-0832-2659 NR 30 TC 165 Z9 172 U1 2 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 16 PY 2002 VL 196 IS 6 BP 859 EP 865 DI 10.1084/jem.20020781 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 596BD UT WOS:000178143100014 PM 12235218 ER PT J AU Huff, J Castleman, B LaDou, J Epstein, SS AF Huff, J Castleman, B LaDou, J Epstein, SS TI Primary prevention of cancer SO SCIENTIST LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, Sch Med, Int Ctr Occupat Med, San Francisco, CA USA. Univ Illinois, Chicago Sch Publ Hlth, Chicago, IL 60680 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD SEP 16 PY 2002 VL 16 IS 18 BP 10 EP 11 PG 2 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 602UZ UT WOS:000178524000009 ER PT J AU Johnson, DR Guo, GL Klaassen, CD AF Johnson, DR Guo, GL Klaassen, CD TI Expression of rat Multidrug Resistance Protein 2 (Mrp2) in male and female rats during normal and pregnenolone-16 alpha-carbonitrile (PCN)-induced postnatal ontogeny SO TOXICOLOGY LA English DT Article DE Mrp2; ontogeny; transporter; pregnenolone-16 alpha-carbonitrile (PCN); organic anion ID DUBIN-JOHNSON-SYNDROME; HEPATOCYTE CANALICULAR ISOFORM; MUTANT RATS; TRANSPORTER; GENE; HYPERBILIRUBINEMIA; GLUTATHIONE; METHYLMERCURY; INHIBITION; EXCRETION AB The normal maturation of biliary organic anion excretion in newborn rats can be enhanced by microsomal enzyme-inducing chemical treatment, yet the mechanism for this phenomenon is not known. Multidrug Resistance Protein 2 (Mrp2) is a biliary efflux transporter that is inducible by select microsomal enzyme-inducing chemicals. Thus, the aims of this study were to compare the normal and pregnenolone-16alpha-carbonitrile (PCN)-induced postnatal ontogeny of Mrp2 in male and female rats. Mrp2 protein increased in an age-dependent manner in both sexes between 0 and 90 days of age. At birth, Mrp2 protein in both male and female rats was the same, approximately 70% of adult levels. Mrp2 protein in both sexes reached maximal expression levels that were higher than adult levels (male: days 25-40; female: day 45), then decreased to adult levels, at which age Mrp2 protein expression in male and female rats was the same. Second, male and female rats of various ages were treated with PCN (75 mg/kg, ip) or corn oil for 4 days, after which livers were removed and analyzed for Mrp2 protein and mRNA expression. PCN accelerated the expression of Mrp2 protein in male and female rats as early as 10 days of age, whereas, PCN did not affect male and female Mrp2 mRNA ontogeny. These data suggest that PCN increased Mrp2 protein by a sex-independent posttranscriptional mechanism. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. Univ Massachusetts, Med Ctr, Dept Mol Pharmacol & Biochem, Worcester, MA 01605 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Klaassen, CD (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. FU NIEHS NIH HHS [ES 03192, ES 07079, ES 09716] NR 30 TC 26 Z9 27 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 SEP 16 PY 2002 VL 178 IS 3 BP 209 EP 219 AR PII S0300-483X(02)00231-7 DI 10.1016/S0300-483X(02)00231-7 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 595CU UT WOS:000178089900003 PM 12167307 ER PT J AU Britton, JA Gammon, MD Schoenberg, JB Stanford, JL Coates, RJ Swanson, CA Potischman, N Malone, KE Brogan, DJ Daling, JR Brinton, LA AF Britton, JA Gammon, MD Schoenberg, JB Stanford, JL Coates, RJ Swanson, CA Potischman, N Malone, KE Brogan, DJ Daling, JR Brinton, LA TI Risk of breast cancer classified by joint estrogen receptor and progesterone receptor status among women 20-44 years of age SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; case-control studies; receptors; estrogen; receptors; progesterone; risk factors ID BODY-SIZE; ENDOCRINE THERAPY; PHYSICAL-ACTIVITY; YOUNGER WOMEN; UNITED-STATES; ALCOHOL-CONSUMPTION; WHITE WOMEN; EARLY-ONSET; PREVENTION; EPIDEMIOLOGY AB To gain insight into whether breast cancer tumors jointly classified by estrogen receptor (ER) and progesterone receptor (PR) status represent diseases with differing etiologies, data from a population-based case-control study of US women 20-44 years of age were analyzed. Cases included 1,556 women diagnosed between 1990 and 1992. Age- and geographic-frequency-matched controls included 1,397 women identified by random digit dialing. Heterogeneity between ER+PR+ and ER-PR- tumors was most pronounced in relation to age, race, and recreational exercise at 12-13 years of age. Multivariate-adjusted odds ratios for ER+PR+ tumors were 0.64 (95% confidence interval (CI): 0.47, 0.89) for 30-34 versus 40-44 years of age, 0.89 (95% CI: 0.63, 1.25) for Black versus White race, and 0.84 (95% CI: 0.68, 1.03) for exercise at 12-13 years of age above versus at or below the median. Corresponding odds ratios for ER-PR- tumors were 1.24 (95% CI: 0.86, 1.77), 1.51 (95% CI: 1.07, 2.14), and 1.15 (95% CI: 0.90, 1.48). Risk of ER-PR- cancer in relation to menstrual and reproductive (parity and lactation) characteristics, alcohol consumption, and family history of breast cancer was similar to that observed for ER+PR+ tumors. These findings only modestly support the hypothesis that hormonally related risk factors have differing relations with ER+PR+ versus ER-PR- tumors among younger women. C1 Mt Sinai Sch Med, Div Environm Hlth Sci, New York, NY 10029 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. Natl Canc Inst, Appl Res Branch, Bethesda, MD USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Brinton, LA (reprint author), Mt Sinai Sch Med, Div Environm Hlth Sci, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 50 TC 59 Z9 60 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2002 VL 156 IS 6 BP 507 EP 516 DI 10.1093/aje/kwf065 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 595UH UT WOS:000178126800003 PM 12225998 ER PT J AU Rauscher, GH Sandler, DP Poole, C Pankow, J Mitchell, B Bloomfield, CD Olshan, AF AF Rauscher, GH Sandler, DP Poole, C Pankow, J Mitchell, B Bloomfield, CD Olshan, AF TI Family history of cancer and incidence of acute leukemia in adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; leukemia; proxy; risk factors ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BREAST-CANCER; UNITED-STATES; LUNG-CANCER; CHILDHOOD LEUKEMIA; COLORECTAL-CANCER; CIGARETTE-SMOKING; PROXY RESPONDENTS; RISK; ACCURACY AB Family history of cancer may represent shared genetic and environmental risk factors for leukemia. The authors examined associations of first-degree family history of cancer with adult acute leukemia incidence by using data on 811 patients (or their proxies) identified at diagnosis and 637 population-based controls in the United States and Canada during 1986-1990. For proxy-interviewed patients, relative risks were elevated for family history of any cancer (relative risk = 1.7, 95% confidence interval (CI): 1.3, 2.4), hematopoietic cancer (relative risk = 1.8, 95% CI: 1.1, 3.0), leukemia (relative risk = 2.4, 95% CI: 1.3, 4.6), and breast cancer (relative risk = 1.7, 95% CI: 1.0, 3.0) but not for colorectal, prostate, or lung cancer. For self-interviewed patients, family history of hematopoietic cancer was inversely associated with leukemia incidence (relative risk = 0.6, 95% CI: 0.4, 1.1). Regardless of patient interview type, history of breast cancer in sisters was positively associated with adult acute leukemia, whereas history of breast cancer in mothers was not. The role of family history of cancer in leukemia etiology is unclear because of differential reporting by patients and proxies. Specifically, self-interviewed patients may underreport cancer in their first-degree relatives. Associations between family history of breast cancer and leukemia incidence may be the result of unmeasured, shared etiologies specific to these cancers. C1 Univ Illinois, Div Epidemiol & Biostat, Sch Publ Hlth, Chicago, IL 60612 USA. Natl Inst Environm Hlth Studies, Res Triangle Pk, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. Ohio State Univ, Canc & Leukemia Grp B, Columbus, OH 43210 USA. RP Rauscher, GH (reprint author), Univ Illinois, Div Epidemiol & Biostat, Sch Publ Hlth, 816 SPHPI M-C 923,1603 W Taylor, Chicago, IL 60612 USA. OI Rauscher, Garth/0000-0003-0374-944X; Sandler, Dale/0000-0002-6776-0018; Pankow, James/0000-0001-7076-483X FU NCI NIH HHS [CA31946, CA09330-20, CA57699-06] NR 46 TC 20 Z9 21 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 SEP 15 PY 2002 VL 156 IS 6 BP 517 EP 526 DI 10.1093/aje/kwf075 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 595UH UT WOS:000178126800004 PM 12225999 ER PT J AU Holick, CN Michaud, DS Stolzenberg-Solomon, R Mayne, ST Pietinen, P Taylor, PR Virtamo, J Albanes, D AF Holick, CN Michaud, DS Stolzenberg-Solomon, R Mayne, ST Pietinen, P Taylor, PR Virtamo, J Albanes, D TI Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE beta-carotene; carotenoids; lung neoplasms; prospective studies; vitamin A ID ACUTE-PHASE RESPONSE; VITAMIN-A; FINNISH FOODS; CARDIOVASCULAR-DISEASE; VEGETABLE CONSUMPTION; CIGARETTE-SMOKING; PLASMA; WOMEN; ANTIOXIDANT; PREVENTION AB Findings from several beta-carotene supplementation trials were unexpected and conflicted with most observational studies. Carotenoids other than beta-carotene are found in a variety of fruits and vegetables and may play a role in this important malignancy, but previous findings regarding the five major carotenoids are inconsistent. The authors analyzed the associations between dietary beta-carotene, beta-carotene, lutein/zeaxanthin, lycopene, beta-cryptoxanthin, vitamin A, serum beta-carotene, and serum retinol and the lung cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers conducted in southwestern Finland between 1985 and 1993. Of the 27,084 male smokers aged 50-69 years who completed the 276-food item dietary questionnaire at baseline, 1,644 developed lung cancer during up to 14 years of follow-up. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals. Consumption of fruits and vegetables was associated with a lower lung cancer risk (relative risk = 0.73, 95% confidence interval: 0.62, 0.86, highest vs. lowest quintile). Lower risks of lung cancer were observed for the highest versus the lowest quintiles of lycopene (28%), lutein/zeaxanthin (17%), beta-cryptoxanthin (15%), total carotenoids (16%), serum beta-carotene (19%), and serum retinol (27%). These findings suggest that high fruit and vegetable consumption, particularly a diet rich in carotenoids, tomatoes, and tomato-based products, may reduce the risk of lung cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Natl Canc Inst, Ctr Canc Res, Bethesda, MD USA. RP Michaud, DS (reprint author), NCI, Div Canc Epidemiol & Genet, EPS-320 MSC 7232,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01CN45035, N01CN45165] NR 54 TC 123 Z9 129 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2002 VL 156 IS 6 BP 536 EP 547 DI 10.1093/aje/kwf072 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 595UH UT WOS:000178126800006 PM 12226001 ER PT J AU Madhavarao, CN Hammer, JA Quarles, RH Namboodiri, MAA AF Madhavarao, CN Hammer, JA Quarles, RH Namboodiri, MAA TI A radiometric assay for aspartoacylase activity in cultured oligodendrocytes SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE TLC; Canavan disease; NAA; myelin synthesis ID GLIAL-CELL LINE; N-ACETYLASPARTATE; CANAVAN DISEASE; RAT-BRAIN; EXPRESSION; DIFFERENTIATION; ASPARTATE; TISSUE; ENZYME; CG-4 AB Recent studies have shown that aspartoacylase (ASPA), the defective enzyme in Canavan disease, is detectable in the brain only in the oligodendrocytes. Studying the regulation of ASPA is central to the understanding the pathogenesis of Canavan disease and to the development of therapeutic strategies. Toward this goal, we have developed a sensitive method for the assay of ASPA in cultured oligodendrocytes. The method involves: (a) chemical synthesis of [C-14]N-acetylaspartate (NAA) from L-[C-14]Asp; (b) use of [C-14]NAA as substrate in the assay; and (c) separation and quantitation of the product L-[C-14]Asp using a TLC system. This method can detect as low as 10 pmol of product and has been optimized for cultured oligodendrocytes. Thus, this method promises to be a valuable tool for understanding the biochemical mechanisms involved in the cell-specific expression and regulation of ASPA in oligodendrocytes. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NINDS, Myelin & Brain Dev Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Namboodiri, MAA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. FU NINDS NIH HHS [R01 NS39387] NR 21 TC 19 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2002 VL 308 IS 2 BP 314 EP 319 AR PII S0003-2697(02)00225-7 DI 10.1016/S0003-2697(02)00225-7 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 603NA UT WOS:000178564800016 PM 12419345 ER PT J AU Jozwiak, K Haginaka, J Moaddel, R Wainer, IW AF Jozwiak, K Haginaka, J Moaddel, R Wainer, IW TI Displacement and nonlinear chromatographic techniques in the investigation of interaction of noncompetitive inhibitors with an immobilized alpha 3 beta 4 nicotinic acetylcholine receptor liquid chromatographic stationary phase SO ANALYTICAL CHEMISTRY LA English DT Article ID PERFORMANCE AFFINITY-CHROMATOGRAPHY; BLOCKADE; SUBTYPES; KETAMINE; BINDING AB A liquid chromatographic column containing immobilized alpha3beta4 nicotinic acetylcholine receptors (alpha3beta4-nAChRs) has been used to determine the equilibrium association constants (K-a), desorption rate constants (k(d)), and adsorption rate constants (k(a)) for the noncompetitive inhibitors: mecamylamine, ketamine, bupropion, and dextromethorphan. Displacement chromatography, with mecamylamine as the displacer, was used to verify that the four compounds bound to the same site on the immobilized alpha3beta4-nChRs. Nonlinear chromatographic techniques were then utilized to calculate the K-a, k(a), and k(d) values associated with the formation of the noncompetitive inhibitor-alpha3beta4-nAChR complexes. The k(a) values determined in this study ranged from 19.7 to 10.5 muM(-1)sec(-1), with a relative order of mecamylamine > dextromethorphan greater than or equal to ketamine > bupropion. The kd values determined in this study indicated that dextromethorphan-induced inhibition should produce a longer recovery time than the other three NCIs. This was consistent with results from a previous in vitro study. ne data from this study indicate that the immobilized alpha3beta4-nAChR column and nonlinear chromatography can be used in the study of NCIs at the alpha3beta4-nAChR. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Med Univ Lubeck, Dept Inorgan & Analyt Chem, Lublin, Poland. Mukogawa Womens Univ, Nishinomiya, Hyogo, Japan. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. NR 23 TC 58 Z9 59 U1 0 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 SEP 15 PY 2002 VL 74 IS 18 BP 4618 EP 4624 DI 10.1021/ac0202029 PG 7 WC Chemistry, Analytical SC Chemistry GA 594TX UT WOS:000178068000004 PM 12349962 ER PT J AU Singh, S Awasthi, N Egwuagu, CE Wagner, BJ AF Singh, S Awasthi, N Egwuagu, CE Wagner, BJ TI Immunoproteasome expression in a nonimmune tissue, the ocular lens SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE proteasome; immunoproteasome; interferon gamma; RT-PCR; ocular lens; mouse; transgenic; alpha TN4-1 cells ID MULTICATALYTIC PROTEINASE COMPLEX; PROTEASOME SUBUNIT COMPOSITION; SEQUENCE-BINDING PROTEIN; INTERFERON-GAMMA; GENE-EXPRESSION; 20S PROTEASOMES; CELLS; DIFFERENTIATION; LMP7; ACTIVATION AB Interferon gamma (IFNgamma) induces the expression of three catalytic subunits of the 208 proteasome that can replace their constitutive homologues to form the "immunoproteasome," named to reflect its antigen presentation function. However, immunoproteasome levels and their modulation in nonimmune tissues remain unknown. A disrupted lens differentiation program observed in transgenic mice that constitutively express IFN-gamma in the immune-privileged lens tissue suggests a role for this cytokine in differentiation. We have developed a competitive RT-PCR assay that demonstrates substantially increased levels of immuno subunits and unchanged levels of constitutive subunits in transgenic compared to wild-type lenses. Similar results were observed with IFNgamma treated alphaTN4-1 lens epithelial cells. A comparison of these subunits in different immune and nonimmune mouse tissues revealed unique expression patterns. The presence of immuno subunits in nonimmune tissues such as lens suggests that the immunoproteasome may also have nonimmune functions, such as that in lens differentiation. Published by Elsevier Science (USA). C1 Univ Med & Dent New Jersey, Sch Med, Dept Biochem & Mol Biol, Newark, NJ 07101 USA. Univ Med & Dent New Jersey, Sch Med, Dept Ophthalmol, Newark, NJ 07101 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Wagner, BJ (reprint author), Univ Med & Dent New Jersey, Sch Med, Dept Biochem & Mol Biol, Newark, NJ 07101 USA. RI Awasthi, Niranjan/B-2512-2009 FU NEI NIH HHS [EY02299] NR 45 TC 26 Z9 26 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD SEP 15 PY 2002 VL 405 IS 2 BP 147 EP 153 AR PII S0003-9861(02)00341-7 DI 10.1016/S0003-9861(02)00341-7 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 598NV UT WOS:000178283500001 PM 12220526 ER PT J AU Gong, PF Stewart, D Hu, B Vinson, C Alam, J AF Gong, PF Stewart, D Hu, B Vinson, C Alam, J TI Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE heme oxygenase-1; arsenite; Nrf2; basic-leucine zippers; transcription factors ID ANTIOXIDANT RESPONSE ELEMENT; TRANSCRIPTION FACTOR NRF2; DEPENDENT TRANSCRIPTION; MEDIATED INDUCTION; PRIMARY CULTURES; HEAVY-METALS; BASAL LEVEL; DNA-BINDING; C-FOS; EXPRESSION AB The mechanism of hone oxygenase-1 (ho-1) gene activation by arsenite was examined. Arsenite-stimulated expression of a ho-1 promoter/luciferase chimera in a dose-dependent manner in mouse hepatoma (Hepa) cells. Mutation analyses identified the arsenite-responsive sequence as the stress-response element (StRE), which resembles the binding sites for the AP-1 superfamily of basic-leucine zipper factors. In electrophoretic mobility shift assays, up to seven specific StRE-protein complexes were routinely detected using extracts from untreated Hepa cells whereas a single complex was typically observed after treatment with arsenite. Antibody "supershift" experiments identified Nrf2, JunD, and ATF3 in control complexes and the amount of these factors increased significantly in the arsenite-induced complex. MafG, ATF2. FosB, and JunB were also detected in the arsenite complex. Activation of a StRE-dependent luciferase gene by arsenite was inhibited to varying degrees by dominant-negative mutants of Nrf2, MafK, c-Fos, and CREB but most strongly with the latter. Together, these results implicate multiple basic-leucine zipper transcription factors in ho-1 gene activation by arsenite. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Alton Ochsner Med Fdn & Ochsner Clin, Dept Mol Genet, New Orleans, LA 70121 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Alam, J (reprint author), Alton Ochsner Med Fdn & Ochsner Clin, Dept Mol Genet, 1516 Jefferson Highway, New Orleans, LA 70121 USA. RI Alam, Jawed/F-2596-2010 OI Alam, Jawed/0000-0001-6520-482X FU NIDDK NIH HHS [DK-43135] NR 41 TC 48 Z9 48 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD SEP 15 PY 2002 VL 405 IS 2 BP 265 EP 274 AR PII S0003-9861(02)00404-6 DI 10.1016/S0003-9861(02)00404-6 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 598NV UT WOS:000178283500016 PM 12220541 ER PT J AU Charney, DS Babich, KS AF Charney, DS Babich, KS TI Foundation for the NIMH strategic plan for mood disorders research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 NIMH, Mood & Anxiety Disorder Res Program, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. NIMH, Mood Disorders Strateg Res Plan, Bethesda, MD 20892 USA. NIMH, Off Sci Policy & Program Planning, Rockville, MD 20857 USA. NIMH, Mood Disorders Strateg Res Plant, Rockville, MD 20857 USA. RP Charney, DS (reprint author), NIMH, Mood & Anxiety Disorder Res Program, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. NR 0 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2002 VL 52 IS 6 BP 455 EP 456 AR PII S0006-3223(02)01543-3 DI 10.1016/S0006-3223(02)01543-3 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000001 PM 12361663 ER PT J AU Merikangas, KR Chakravarti, A Moldin, SO Araj, H Blangero, J Burmeister, M Crabbe, JC Depaulo, JR Foulks, E Freimer, NB Koretz, DS Lichtenstein, W Mignot, E Reiss, AL Risch, NJ Takahashi, JS AF Merikangas, KR Chakravarti, A Moldin, SO Araj, H Blangero, J Burmeister, M Crabbe, JC Depaulo, JR Foulks, E Freimer, NB Koretz, DS Lichtenstein, W Mignot, E Reiss, AL Risch, NJ Takahashi, JS TI Workgroup reports: NIMH strategic plan for mood disorders research - Future of genetics of mood disorders research SO BIOLOGICAL PSYCHIATRY LA English DT Review DE genetics; epidemiology; mood disorders; linkage; training ID BIPOLAR AFFECTIVE-DISORDER; COMPLEX HUMAN-DISEASES; GENOME-WIDE SEARCH; POSSIBLE SUSCEPTIBILITY LOCUS; MAJOR DEPRESSIVE DISORDER; SLEEP PHASE SYNDROME; PSYCHIATRIC-DISORDERS; HIGH-RISK; CONTROLLED FAMILY; COMMUNITY SAMPLE AB This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research. C1 NIMH, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. SW Fdn Biomed Res, Dallas, TX USA. Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI USA. Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Portland Alcohol Res Ctr, Portland, OR 97201 USA. Dept Vet Affairs, Res Serv, Portland, OR USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Tulane Univ, Sch Med, Dept Psychiat Neurol, New Orleans, LA 70112 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci Human Genet, Los Angeles, CA USA. Lichtenstein Creat Media, New York, NY USA. Stanford Univ, Sch Med, Stanford Sleep Ctr, Ctr Narcolepsy, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Northwestern Univ, Dept Psychiat, Chicago, IL 60611 USA. RP Merikangas, KR (reprint author), 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. RI Takahashi, Joseph/E-8482-2012; Burmeister, Margit/A-3157-2013 OI Takahashi, Joseph/0000-0003-0384-8878; Burmeister, Margit/0000-0002-1914-2434 NR 140 TC 93 Z9 95 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2002 VL 52 IS 6 BP 457 EP 477 AR PII S0006-3223(02)01471-3 DI 10.1016/S0006-3223(02)01471-3 PG 21 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000002 PM 12361664 ER PT J AU Davidson, RJ Lewis, DA Alloy, LB Amaral, DG Bush, G Cohen, JD Drevets, WC Farah, MJ Kagan, J McClelland, JL Nolen-Hoeksema, S Peterson, BS AF Davidson, RJ Lewis, DA Alloy, LB Amaral, DG Bush, G Cohen, JD Drevets, WC Farah, MJ Kagan, J McClelland, JL Nolen-Hoeksema, S Peterson, BS TI Neural and Behavioral substrates of mood and mood regulation SO BIOLOGICAL PSYCHIATRY LA English DT Review DE mood; mood disorders; behavior; neurobiology ID CEREBRAL-BLOOD-FLOW; ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; MONOZYGOTIC TWINS DISCORDANT; NATIONAL-COMORBIDITY-SURVEY; RECURRENT MAJOR DEPRESSION; EEG ALPHA ASYMMETRY; LONG-TERM-MEMORY AB A review of behavioral and neurobiological data on mood and mood regulation as they pertain to an understanding of mood disorders is presented. Four approaches are considered: 1) behavioral and cognitive; 2) neurobiological; 3) computational; and 4) developmental. Within each of these four sections, we summarize the current status of the field and present our vision for the future, including particular challenges and opportunities. We conclude with a series of specific recommendations for National Institute of Mental Health priorities. Recommendations arc presented for the behavioral domain, the neural domain, the domain of behavioral-neural interaction, for training, and for dissemination. It is in the domain of behavioral-neural interaction, in particular, that new research is required that brings together traditions that have developed relatively independently. Training interdisciplinary clinical scientists who meaningfully draw upon both behavioral and neuroscientific literatures and methods is critically required for the realization of these goals. C1 Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. Univ Pittsburgh, Pittsburgh, PA USA. Temple Univ, Philadelphia, PA 19122 USA. Univ Calif Davis, Davis, CA 95616 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. Princeton Univ, Princeton, NJ 08544 USA. NIMH, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Davidson, RJ (reprint author), Univ Wisconsin, Dept Psychol, 1202 W Johnson St, Madison, WI 53706 USA. RI McClelland, James/F-6004-2011; Lewis, David/G-4053-2014 OI Lewis, David/0000-0002-3225-6778 NR 213 TC 204 Z9 218 U1 7 U2 37 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 SEP 15 PY 2002 VL 52 IS 6 BP 478 EP 502 AR PII S0006-3223(02)01458-0 DI 10.1016/S0006-3223(02)01458-0 PG 25 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000003 PM 12361665 ER PT J AU Nestler, EJ Gould, E Manji, H Bucan, M Duman, RS Gershenfeld, HK Hen, R Koester, S Lederhendler, I Meaney, MJ Robbins, T Winsky, L Zalcman, S AF Nestler, EJ Gould, E Manji, H Bucan, M Duman, RS Gershenfeld, HK Hen, R Koester, S Lederhendler, I Meaney, MJ Robbins, T Winsky, L Zalcman, S TI Preclinical models: Status of basic research in depression SO BIOLOGICAL PSYCHIATRY LA English DT Review DE depression; mania; bipolar disorder; animal models; genetic basis of behavior; biomarkers ID CORTICOTROPIN-RELEASING FACTOR; QUANTITATIVE TRAIT LOCI; SITE-SPECIFIC RECOMBINATION; FORCED SWIMMING TEST; D-ASPARTATE RECEPTOR; ANIMAL-MODELS; GENE-EXPRESSION; MAMMALIAN-CELLS; MOOD DISORDERS; IN-VIVO AB Approximately one half-century ago several classes of medications, discovered by serendipity, were introduced for the treatment of depression and bipolar disorder. These highly effective medications revolutionized our approach to mood disorders and helped launch the modem era of psychiatry. Yet our progress since those serendipitous discoveries has been disappointing. We still do not understand with certainty how those medications produce their desired clinical effects. We have not introduced newer medications with fundamentally different mechanisms of action than the older agents. We have not identified the genetic and neurobiological mechanisms underlying depression and mania, nor do we understand the mechanisms by which nongenetic factors influence these disorders. We have only a rudimentary understanding of the circuits in the brain responsible for the normal regulation of mood and affect, and of those circuits that function abnormally in mood disorders. In approaching these gaps in our knowledge, this workgroup highlighted four major areas for future investment. These include developing better animal models of mood disorders; identifying genetic determinants of normal and abnormal mood in humans and animals; discovering novel targets and biomarkers of mood disorders and treatments; and increasing the recruitment of investigators from diverse backgrounds to mood disorders research. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. NIMH, Bethesda, MD 20892 USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. McGill Univ, Douglas Hosp, Res Ctr, Montreal, PQ, Canada. Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Nestler, EJ (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. NR 124 TC 335 Z9 353 U1 5 U2 37 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 SEP 15 PY 2002 VL 52 IS 6 BP 503 EP 528 AR PII S0006-3223(02)01405-1 DI 10.1016/S0006-3223(02)01405-1 PG 26 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000004 PM 12361666 ER PT J AU Costello, EJ Pine, DS Hammen, C March, JS Plotsky, PM Weissman, MA Biederman, J Goldsmith, HH Kaufman, J Lewinsohn, PM Hellander, M Hoagwood, K Koretz, DS Nelson, CA Leckman, JF AF Costello, EJ Pine, DS Hammen, C March, JS Plotsky, PM Weissman, MA Biederman, J Goldsmith, HH Kaufman, J Lewinsohn, PM Hellander, M Hoagwood, K Koretz, DS Nelson, CA Leckman, JF TI Development and natural history of mood disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE depession; bipolar disorder; evidence-based treatments; prevention; research training ID BIPOLAR AFFECTIVE-DISORDER; MAJOR DEPRESSIVE DISORDER; DEFICIT HYPERACTIVITY DISORDER; GROUP COGNITIVE INTERVENTION; SUICIDE-PREVENTION PROGRAMS; NATIONAL COMORBIDITY SURVEY; RANDOMIZED CLINICAL-TRIAL; ADOLESCENT DEPRESSION; ANXIETY DISORDERS; GENERAL-POPULATION AB To expand and accelerate research on mood disorders, the National Institute of Mental Health (NIMH) developed a project to formulate a strategic research plan for mood disorder research. One of the areas selected for review concerns the development and natural history of these disorders. The NIMH convened a multidisciplinary Workgroup of scientists to review the field and the NIMH portfolio and to generate specific recommendations. To encourage a balanced and creative set of proposals, experts were included within and outside this area of research, as well as public stakeholders. The Workgroup identified the need for expanded knowledge of mood disorders in children and adolescents, noting important gaps in understanding the onset, course, and recurrence of early-onset unipolar and bipolar disorder. Recommendations included the need for a multidisciplinary research initiative on the pathogenesis of unipolar depression encompassing genetic and environmental risk and protective factors. Specifically, we encourage the NIMH to convene a panel of experts and advocates to review the findings concerning children at high risk for unipolar depression. Joint analyses of existing data sets should examine specific risk factors to refine models of pathogenesis in preparation for the next era of multidisciplinary research. Other priority areas include the need to assess the long-term impact of successful treatment of juvenile depression and known precursors of depression, in particular, childhood anxiety disorders. Expanded knowledge of pediatric-onset bipolar disorder was identified as a particularly pressing issue because of the severity of the disorder, the controversies surrounding its diagnosis and treatment, and the possibility that widespread use of psychotropic medications in vulnerable children may precipitate the condition. The Workgroup recommends that the NIMH establish a collaborative multisite multidisciplinary Network of Research Programs on PediatricOnset Bipolar Disorder to achieve a better understanding of its causes, course, treatment, and prevention. The NIMH should develop a capacity-building plan to ensure the availability of trained investigators in the child and adolescent field. Mood disorders are among the most prevalent, recurrent, and disabling of all illnesses. They are often disorders of early onset. Although the NIMH has made important strides in mood disorders research, more data, beginning with at-risk infants, children, and adolescents, are needed concerning the etiology and developmental course of these disorders. A diverse program of multidisciplinary research is recommended to reduce the burden on children and families affected with these conditions. C1 Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06520 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NIMH, Extramural Res Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Dept Clin & Genet Epidemiol, New York, NY USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Psychol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. Oregon Res Inst, Eugene, OR 97403 USA. Child & Adolescent Bipolar Fdn, Wilmette, IL USA. Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. RP Leckman, JF (reprint author), Yale Univ, Sch Med, Ctr Child Study, 230 S Frontage Rd,Rm I-269 SHM, New Haven, CT 06520 USA. OI Weissman, Myrna/0000-0003-3490-3075 NR 130 TC 220 Z9 223 U1 10 U2 52 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 SEP 15 PY 2002 VL 52 IS 6 BP 529 EP 542 AR PII S0006-3223(02)01372-0 DI 10.1016/S0006-3223(02)01372-0 PG 14 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000005 PM 12361667 ER PT J AU Alexopoulos, GS Buckwalter, K Olin, J Martinez, R Wainscott, C Krishnan, KRR AF Alexopoulos, GS Buckwalter, K Olin, J Martinez, R Wainscott, C Krishnan, KRR TI Comorbidity of late life depression: An opportunity for research on mechanisms and treatment SO BIOLOGICAL PSYCHIATRY LA English DT Review DE comorbidity; late-life depression; research ID PRIMARY-CARE PATIENTS; RECURRENT MAJOR DEPRESSION; NURSING-HOME RESIDENTS; CEREBRAL-BLOOD-FLOW; DEFINED VASCULAR DEPRESSION; SUBGENUAL PREFRONTAL CORTEX; RANDOMIZED CONTROLLED-TRIAL; MENTAL-HEALTH-SERVICES; GERIATRIC DEPRESSION; ALZHEIMERS-DISEASE AB Late life depression principally affects individuals with other medical and psychosocial problems, including cognitive dysfunction, disability, medical illnesses, and social isolation. The clinical associations of late life depression have guided the development of hypotheses on mechanisms predisposing, initiating, and perpetuating specific mood syndromes. Comorbidity studies have demonstrated a relationship between frontostriatal impairment and late life depression. Further research has the potential to identify dysfunctions of specific frontostriatal systems critical for antidepressant response and to lead to novel pharmacological treatments and targeted psychosocial interventions. The reciprocal interactions of depression with disability, medical illnesses, treatment adherence, and other psychosocial factors complicate the care of depressed older adults. Growing knowledge of the clinical complexity introduced by the comorbidity of late life depression can guide the development of comprehensive treatment models. Targeting the interacting clinical characteristics associated with poor outcomes has the potential to interrupt the spiral of deterioration of depressed elderly patients. Treatment models can be most effective if they focus on amelioration of depressive symptoms, but also on treatment adherence, prevention of relapse and recurrence, reduction of medical burden and disability, and improvement of the quality of life of patients and their families. C1 Cornell Univ, Weill Med Coll, Cornell Inst Geriatr Psychiat, White Plains, NY 10605 USA. Univ Iowa, Iowa City, IA USA. NIMH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC USA. RP Alexopoulos, GS (reprint author), Cornell Univ, Weill Med Coll, Cornell Inst Geriatr Psychiat, 1 Bloomingdale Rd, White Plains, NY 10605 USA. FU NIMH NIH HHS [P30 MH49762, P50 MH60451, R01 MH50570, R01 MH59366]; NINR NIH HHS [P30 NR03979] NR 190 TC 106 Z9 107 U1 4 U2 25 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 SEP 15 PY 2002 VL 52 IS 6 BP 543 EP 558 AR PII S0006-3223(02)01468-3 DI 10.1016/S0006-3223(02)01468-3 PG 16 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000006 PM 12361668 ER PT J AU Krishnan, KRR Delong, M Kraemer, H Carney, R Spiegel, D Gordon, C McDonald, W Dew, MA Alexopoulos, G Buckwalter, K Cohen, PD Evans, D Kaufmann, PG Olin, J Otey, E Wainscott, C AF Krishnan, KRR Delong, M Kraemer, H Carney, R Spiegel, D Gordon, C McDonald, W Dew, MA Alexopoulos, G Buckwalter, K Cohen, PD Evans, D Kaufmann, PG Olin, J Otey, E Wainscott, C TI Comorbidity of depression with other medical diseases in the elderly SO BIOLOGICAL PSYCHIATRY LA English DT Review DE age; depression; medical; cardiac; cancer; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; CORONARY-ARTERY-DISEASE; PLACEBO-CONTROLLED TRIAL; ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-LIFE; METASTATIC BREAST-CANCER; KILLER-CELL-ACTIVITY; POSTTRAUMATIC-STRESS-DISORDER; SEROTONIN REUPTAKE INHIBITORS; CONGESTIVE-HEART-FAILURE AB A major factor in the context of evaluating depression in the elderly is the role of medical problems. With aging there is a rapid increase in the prevalence of a number of medical disorders, including cancer, heart disease, Parkinson's disease, Alzheimer's disease, stroke, and arthritis. In this article, we hope to bring clarity to the definition of comorbidity and then discuss a number of medical disorders as they relate to depression. We evaluate medical comorbidity as a risk factor for depression as well as the converse, that is, depression as a risk factor for medical illness. Most of the disorders that we focus on occur in the elderly, with the exception of HIV infection. This review focuses exclusively on unipolar disorder. The review summarizes the current state of the art and also makes recommendations for future directions. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Emory Univ, Sch Med, Atlanta, GA USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Washington Univ, Sch Med, St Louis, MO USA. NIMH, Bethesda, MD 20892 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Cornell Univ, Ithaca, NY USA. Univ Iowa, Iowa City, IA USA. Parkinsons Dis Fdn, New York, NY USA. Univ Penn, Philadelphia, PA 19104 USA. NHLBI, Bethesda, MD 20892 USA. Natl Mental Hlth Assoc Georgia, Atlanta, GA USA. RP Krishnan, KRR (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3950, Durham, NC 27710 USA. NR 320 TC 127 Z9 134 U1 6 U2 19 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 SEP 15 PY 2002 VL 52 IS 6 BP 559 EP 588 AR PII S0006-3223(02)01472-5 DI 10.1016/S0006-3223(02)01472-5 PG 30 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000007 PM 12361669 ER PT J AU Tamminga, CA Nemeroff, CB Blakely, RD Brady, L Carter, CS Davis, KL Dingledine, R Gorman, JM Grigoriadis, DE Henderson, DC Innis, RB Killen, J Laughren, TP McDonald, WM Murphy, GM Paul, SM Rudorfer, MV Sausville, E Schatzberg, AF Scolnick, EM Suppes, T AF Tamminga, CA Nemeroff, CB Blakely, RD Brady, L Carter, CS Davis, KL Dingledine, R Gorman, JM Grigoriadis, DE Henderson, DC Innis, RB Killen, J Laughren, TP McDonald, WM Murphy, GM Paul, SM Rudorfer, MV Sausville, E Schatzberg, AF Scolnick, EM Suppes, T TI Developing novel treatments for mood disorders: Accelerating discovery SO BIOLOGICAL PSYCHIATRY LA English DT Article DE depression bipolar disorder research resources; government/industry collaboration ID SEROTONIN TRANSPORTER GENE; ANTIDEPRESSANT-INDUCED MANIA; ELECTROCONVULSIVE-THERAPY; ELECTRODE PLACEMENT; MAJOR DEPRESSION; PHARMACOLOGICAL PROFILE; ENDOGENOUS-DEPRESSION; REFRACTORY DEPRESSION; PSYCHOTIC DEPRESSION; REUPTAKE INHIBITORS AB This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder therapeutics is the topic of this article. C1 Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. Emory Univ, Dept Pharmacol, Atlanta, GA 30322 USA. Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. NIMH, Neuropharmacol Program, Mol & Cellular Neurosci Res Branch, Bethesda, MD 20892 USA. NIMH, Drug Discovery Program, Mol & Cellular Neurosci Res Branch, Bethesda, MD 20892 USA. NIMH, Clin Therapeut Program, Mol & Cellular Neurosci Res Branch, Bethesda, MD 20892 USA. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY USA. Neurocrine Biosci Inc, San Diego, CA USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20857 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Rockville, MD USA. Merck Res Labs, W Point, PA USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. RP Tamminga, CA (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. RI dingledine, Ray/F-5173-2011 NR 83 TC 52 Z9 55 U1 3 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 SEP 15 PY 2002 VL 52 IS 6 BP 589 EP 609 AR PII S0006-3223(02)01470-1 DI 10.1016/S0006-3223(02)01470-1 PG 21 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000008 PM 12361670 ER PT J AU Hollon, SD Munoz, RF Barlow, DH Beardslee, WR Bell, CC Bernal, G Clarke, GN Franciosi, LP Kazdin, AE Kohn, L Linehan, MM Markowitz, JC Miklowitz, DJ Persons, JB Niederehe, G Sommers, D AF Hollon, SD Munoz, RF Barlow, DH Beardslee, WR Bell, CC Bernal, G Clarke, GN Franciosi, LP Kazdin, AE Kohn, L Linehan, MM Markowitz, JC Miklowitz, DJ Persons, JB Niederehe, G Sommers, D TI Psychosocial intervention development for the prevention and treatment of depression: Promoting innovation and increasing access SO BIOLOGICAL PSYCHIATRY LA English DT Review DE depression; suicide; treatment; prevention; translational; transportability ID COGNITIVE-BEHAVIORAL TREATMENT; RANDOMIZED CONTROLLED TRIAL; COLLABORATIVE RESEARCH-PROGRAM; NATURALISTIC FOLLOW-UP; BIPOLAR DISORDER; INTERPERSONAL PSYCHOTHERAPY; ADOLESCENT DEPRESSION; RECURRENT DEPRESSION; MAJOR DEPRESSION; PERSONALITY-DISORDERS AB Great strides have been made in developing psychosocial interventions for the treatment of depression and bipolar disorder over the last three decades, but more remains to be done. The National Institute of Mental Health Psychosocial Intervention Development Workgroup recommends three priorities for future innovation: 1) development of new and more effective interventions that address both symptom change and functional capacity, 2) development of interventions that prevent onset and recurrence of clinical episodes in at-risk populations, and 3) development of user-friendly interventions and nontraditional delivery methods to increase access to evidence-based interventions. In each of these areas, the Workgroup recommends systematic study of the mediating mechanisms that drive the process of change and the moderators that influence their effects. This information will highlight the elements of psychosocial interventions that most contribute to the prevention and treatment of mood disorders across diagnostic groups, populations served, and community settings. The process of developing innovative interventions should have as its goal a mental health service delivery system that prevents the onset and recurrence of the mood disorders, furnishes increasingly effective treatment for those who seek it, and provides access to evidence-based psychosocial interventions via all feasible means. C1 Vanderbilt Univ, Dept Psychol, Nashville, TN 37203 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Boston Univ, Dept Psychol, Boston, MA 02215 USA. Harvard Univ, Dept Psychiat, Boston, MA 02115 USA. Community Mental Hlth Council Inc, Chicago, IL USA. Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. Univ Puerto Rico, Dept Psychol, San Juan, PR 00936 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. World Federat Mental Hlth, Milwaukee, WI USA. Yale Univ, Dept Psychol, New Haven, CT USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. Cornell Univ, Dept Psychiat, New York, NY USA. Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. San Francisco Bay Area Ctr Cognit Therapy, Oakland, CA USA. NIMH, Bethesda, MD 20892 USA. RP Hollon, SD (reprint author), Vanderbilt Univ, Dept Psychol, 306 Wilson Hall, Nashville, TN 37203 USA. RI Bernal, Guillermo/E-6360-2010 OI Bernal, Guillermo/0000-0001-8855-1314 NR 154 TC 131 Z9 135 U1 12 U2 36 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 SEP 15 PY 2002 VL 52 IS 6 BP 610 EP 630 AR PII S0006-3223(02)01384-7 DI 10.1016/S0006-3223(02)01384-7 PG 21 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000009 PM 12361671 ER PT J AU Frank, E Rush, AJ Blehar, M Essock, S Hargreaves, W Hogan, M Jarrett, R Johnson, RL Katon, WJ Lavori, P McNulty, JP Niederehe, G Ryan, N Stuart, G Thomas, SB Tollefson, GD Vitiello, B AF Frank, E Rush, AJ Blehar, M Essock, S Hargreaves, W Hogan, M Jarrett, R Johnson, RL Katon, WJ Lavori, P McNulty, JP Niederehe, G Ryan, N Stuart, G Thomas, SB Tollefson, GD Vitiello, B TI Skating to where the puck is going to be: A plan for clinical trials and translation research in mood disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE clinical trials; translation research; mood disorders ID PREMENSTRUAL DYSPHORIC DISORDER; COLLABORATIVE RESEARCH-PROGRAM; MENTAL-HEALTH TREATMENT; COGNITIVE-BEHAVIORAL TREATMENT; BIPOLAR AFFECTIVE-DISORDERS; RANDOMIZED CONTROLLED TRIAL; PANIC-AGORAPHOBIC SPECTRUM; RECURRENT MAJOR DEPRESSION; PHASE SERTRALINE TREATMENT; PLACEBO-CONTROLLED TRIAL AB As part of the National Institute of Mental Health Strategic Plan for Mood Disorders Research effort, the Clinical Trials and Translation Workgroup was asked to define priorities for clinical trials in mood disorders and for research on how best to translate the results of such research to clinical practice settings. Through two face-to-face meetings and a series of conference calls, we established priorities based on the literature to date and what was known about research currently in progress in this area. We defined five areas of priority that cut across developmental stages, while noting that research on adult mood disorders was at a more advanced stage in each of these areas than research on child or geriatric disorders. The five areas of priority are: 1) maximizing the effectiveness and cost-effectiveness of initial (acute) treatments for mood disorders already known to be efficacious in selected populations and settings when they are applied across all populations and care settings; 2) learning what further treatments or services are most likely to reduce symptoms and improve functioning when the first treatment is delivered well, but the mood disorder does not remit or show adequate improvement; 3) learning what treatments or services are most cost-effective in preventing recurrence or relapse and maintaining optimal functioning after a patient's mood disorder has remitted or responded maximally to treatment; 4) developing and validating clinical, psychosocial, biological, or other markers that predict: a) which treatments are most effective, b) course of illness, c) risk of adverse events/tolerability and acceptability for individual patients or well-defined subgroups of patients; 5) developing clinical trial designs and methods that result in lower research costs and greater generalizability earlier in the treatment development and testing process. A rationale for the importance of each of these priorities is provided. C1 Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. NIMH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Ohio Dept Mental Hlth, Columbus, OH USA. New Jersey Med Ctr, Dept Pediat, Newark, NJ USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. Natl Man Depress & Depress Assoc Rhode Isl, Providence, RI USA. Med Univ S Carolina, Coll Nursing & Med, Charleston, SC 29425 USA. Univ Pittsburgh, Dept Community Hlth & Socail Justice, Pittsburgh, PA USA. Eli Lilly & Co, Neurosci Prod, Indianapolis, IN 46285 USA. RP Frank, E (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat & Psychol, 3811 Ohara St, Pittsburgh, PA 15213 USA. OI Rush, Augustus/0000-0003-2004-2382 NR 166 TC 14 Z9 14 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2002 VL 52 IS 6 BP 631 EP 654 AR PII S0006-3223(02)01467-1 DI 10.1016/S0006-3223(02)01467-1 PG 24 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000010 PM 12361672 ER PT J AU Wells, KB Miranda, J Bauer, MS Bruce, ML Durham, M Escobar, J Ford, D Gonzalez, J Hoagwood, K Horwitz, SM Lawson, W Lewis, L McGuire, T Pincus, H Scheffler, R Smith, WA Unutzer, J AF Wells, KB Miranda, J Bauer, MS Bruce, ML Durham, M Escobar, J Ford, D Gonzalez, J Hoagwood, K Horwitz, SM Lawson, W Lewis, L McGuire, T Pincus, H Scheffler, R Smith, WA Unutzer, J TI Overcoming barriers to reducing the burden of affective disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE affective disorders; barriers; burden of illness; interventions; unmet need ID MENTAL-HEALTH-SERVICES; PRIMARY-CARE PRACTICES; RANDOMIZED CONTROLLED TRIAL; QUALITY IMPROVEMENT PROGRAMS; NATIONAL-COMORBIDITY-SURVEY; MAJOR DEPRESSIVE DISORDER; R PSYCHIATRIC-DISORDERS; MANAGED PRIMARY-CARE; LONG-TERM TREATMENT; PATIENTS AGED 65 AB Affective disorders impose a substantial individual and societal burden. Despite availability of efficacious treatments and practice guidelines, unmet need remains high. To reduce unmet need and the burden of affective disorders, information is needed on the distribution of burden across stakeholders, on barriers to reducing burden, and on interventions that effectively reduce burden at the levels of practice, community, and policy. This article provides the report of the Working Group on Overcoming Barriers to Reducing the Burden of Affective Disorders, for the National Institute of Mental Health Strategic Plan on Mood Disorders. We review the literature, identify key gaps, and recommend new research to guide national efforts to reduce the burden of affective disorders. C1 Univ Calif Los Angeles, Hlth Serv Res Ctr, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. Georgetown Univ, Dept Psychiat, Washington, DC USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Providence Vet Affairs Med Ctr, Providence, RI USA. Cornell Univ, Dept Psychiat, Ithaca, NY USA. Kaiser Fdn Hosp, Portland, OR USA. Robert Wood Johnson Med Sch, Dept Psychiat, Piscataway, NJ USA. Johns Hopkins Univ, Baltimore, MD USA. NIMH, Washington, DC USA. Columbia Univ, Dept Psychiat, New York, NY USA. Yale Univ, Sch Publ Hlth, New Haven, CT USA. Howard Univ, Dept Psychiat, Washington, DC 20059 USA. Natl Depress & Man Depress Assoc, Chicago, IL USA. Boston Univ, Dept Econ, Boston, MA 02215 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. RAND Corp, Pittsburgh, PA USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Acad Educ Dev, Washington, DC USA. RP Wells, KB (reprint author), Univ Calif Los Angeles, Hlth Serv Res Ctr, Dept Psychiat & Behav Sci, 10920 Wilshire Blvd,Suite 300, Los Angeles, CA 90024 USA. OI Lawson, William/0000-0002-9324-7090 NR 219 TC 44 Z9 44 U1 7 U2 8 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 SEP 15 PY 2002 VL 52 IS 6 BP 655 EP 675 AR PII S0006-3223(02)01403-8 DI 10.1016/S0006-3223(02)01403-8 PG 21 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 598VK UT WOS:000178297000011 PM 12361673 ER PT J AU Sereti, I Martinez-Wilson, H Metcalf, JA Baseler, MW Hallahan, CW Hahn, B Hengel, RL Davey, RT Kovacs, JA Lane, HC AF Sereti, I Martinez-Wilson, H Metcalf, JA Baseler, MW Hallahan, CW Hahn, B Hengel, RL Davey, RT Kovacs, JA Lane, HC TI Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4(+)/CD25(+) T cells SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DOSE SUBCUTANEOUS INTERLEUKIN-2; ACTIVE ANTIRETROVIRAL THERAPY; RECEPTOR SUBUNIT EXPRESSION; RANDOMIZED CONTROLLED TRIAL; HUMAN PERIPHERAL-BLOOD; IL-2 RECEPTOR; ALPHA-CHAIN; IN-VITRO; INTRAVENOUS INTERLEUKIN-2 AB The long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV+) patients receiving highly active antiretroviral therapy (HAART), and HIV+ patients receiving HAART and intermittent IL-2. Whole-blood immunophenotyping was performed to study expression of the IL-2 receptor chains on T lymphocytes and natural killer cells and to further characterize CD4(+)/CD25(+) T cells. Increased CD25 expression, especially in CD4(+) T cells but also in CD8(+) T cells, without increases in expression of the beta and gamma chains of the IL-2 receptor was detected in the IL-2 group. Up to 79% of naive CD4(+) T cells (median, 61%) from patients in the IL-2 group expressed CD25, and the number of naive CD4(+)/CD25(+) T cells correlated positively with both the total and naive CD4(+) T-cell counts. A discrete population of CD45 double intermediate RA(+)/RO+ CD4(+) cells was also preferentially expanded in the IL-2 group, and the number of these cells strongly correlated with the total CD4(+) count. Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67). Both CD4(+)/CD25(+) and CD4(+)/CD25(-) cells from IL-2-treated HIV+ patients proliferated in response to mitogens, specific antigens, and T-cell-receptor-mediated stimuli. Thus, intermittent administration of IL-2 in HIV+ patients leads to preferential expansion of a unique subset of CD4(+) T cells that may represent a critical population in T-cell homeostasis. C1 NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, NC USA. Georgetown Univ, Washington, DC USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lane, HC (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11S-231,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01 CO 56000] NR 49 TC 59 Z9 60 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2002 VL 100 IS 6 BP 2159 EP 2167 PG 9 WC Hematology SC Hematology GA 591MT UT WOS:000177884800032 PM 12200381 ER PT J AU Hegde, UP Wilson, WH White, T Cheson, BD AF Hegde, UP Wilson, WH White, T Cheson, BD TI Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID ANTI-CD20 MONOCLONAL-ANTIBODY; AUTOIMMUNE HEMOLYTIC-ANEMIA; EVANS-SYNDROME; THERAPY; DISEASES; PATIENT; CLL AB Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141000/muL, 118000/muL, and 70000/muL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/muL, 1000/muL, and 2000/muL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m(2) per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50000/muL at day 21 and more than 133000/muL at day 28, patient 2 achieved a platelet count of more than 50000/muL at day 4 and more than 150000/muL at day 10, and patient 3 achieved a platelet count of more than 50000/muL at day 5 and 72000/muL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP. C1 Natl Canc Inst, Ctr Canc Res, NIH, Bethesda, MD USA. RP Cheson, BD (reprint author), Georgetown Univ Hosp, Lombardi Canc Ctr, 3800 Reservoir Rd, Washington, DC 20007 USA. NR 25 TC 50 Z9 52 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2002 VL 100 IS 6 BP 2260 EP 2262 PG 3 WC Hematology SC Hematology GA 591MT UT WOS:000177884800047 PM 12200396 ER PT J AU Touloukian, CE Leitner, WW Robbins, PF Li, YF Kang, XQ Lapointe, R Hwu, P Rosenberg, SA Restifo, NP AF Touloukian, CE Leitner, WW Robbins, PF Li, YF Kang, XQ Lapointe, R Hwu, P Rosenberg, SA Restifo, NP TI Expression of a "self-"antigen by human tumor cells enhances tumor antigen-specific CD4(+) T-cell function SO CANCER RESEARCH LA English DT Article ID ANTITUMOR IMMUNITY; MELANOMA PATIENTS; MICE; LYMPHOCYTES; RESPONSES AB CD4(+) T cells can recognize "self" tumor antigens, but the impact of tumor cell expression of self-antigens on CD4+ T-cell function in humans is unknown. Here, we identify a new epitope (ISPNSVFSQWRVVCDSLEDYD) derived from tyrosinase-related protein-1 (TRP-1) using a predictive algorithm and mice transgenic for a chimeric HLA-DRB1*0401 molecule. We then compared the functions of TRP-1-epitope-specific, CD4(+) T-cell responses in normal healthy individuals to those found in patients with metastatic malignant melanoma. Surprisingly, we found that tumor-bearing patients had significantly higher levels of TRP-1-specific, CD4(+) T-cell function than healthy volunteers as measured ex vivo. Thus, the net effect of "self" antigen expression by tumor cells was the enhancement of tumor antigen-specific CD4(+) T-cell function, rather than immunosuppression. These findings indicate that antigens expressed by malignant melanoma cells can partially activate CD4(+) T lymphocytes. C1 NCI, NIH, Bethesda, MD 20892 USA. ImClone Syst Inc, New York, NY 10014 USA. RP Restifo, NP (reprint author), NCI, NIH, Bldg 10,Room 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Leitner, Wolfgang/F-5741-2011; OI Leitner, Wolfgang/0000-0003-3125-5922; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 17 TC 20 Z9 20 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5144 EP 5147 PG 4 WC Oncology SC Oncology GA 594TE UT WOS:000178066400006 PM 12234976 ER PT J AU Christov, KT Moon, RC Lantvit, DD Boone, CW Steele, VE Lubet, RA Kelloff, GJ Pezzuto, JM AF Christov, KT Moon, RC Lantvit, DD Boone, CW Steele, VE Lubet, RA Kelloff, GJ Pezzuto, JM TI 9-cis-retinoic acid but not 4-(hydroxyphenyl)retinamide inhibits prostate Intraepithelial neoplasia in noble rats SO CANCER RESEARCH LA English DT Article ID LOBUND-WISTAR RATS; METHYL-N-NITROSOUREA; RETINOID-X RECEPTOR; SEMINAL-VESICLE; CANCER; CHEMOPREVENTION; ADENOCARCINOMA; TESTOSTERONE; TAMOXIFEN; CARCINOMA AB In most previous studies, the incidence and multiplicity of chemically induced prostate tumors have been used as end points for assessing the efficacy of various chemopreventive agents. In this study, we used prostate intraepithelial neoplasia (PIN) in Noble rats as an intermediate end point to examine the chemopreventive efficacy of two retinoids, 9-cis-retinoic acid (9cRA) and 4-(hydroxyphenyl)retinamide, which in previous studies have shown promising inhibitory effects on various carcinogenesis models. We found that 80-100% of Noble rats treated for 36 weeks with testosterone + 17beta-estradiol developed multiple PIN lesions predominantly in the dorso-lateral prostate, which appears relevant to the place of origin of PIN and carcinoma in the human prostate. 9cRA at 50 or 100 mg/kg diet significantly decreased the multiplicity of PIN, whereas 4-(hydroxyphenyl) retinamide at 392 or 784 mg/kg diet, did not have an inhibitory effect on PIN. Thus, we provide for the first time evidence that the testosterone + 17beta-estradiol-induced PIN in Noble rats could be used as a potential intermediate end point in assessing the efficacy of retinoids and possibly of other agents on prostate carcinogenesis, and that 9cRA alone or in combination with other agents may have clinical promise in preventing the development of prostate cancer in men. C1 Univ Illinois, Coll Med, Dept Surg Oncol, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, Chicago, IL 60612 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Christov, KT (reprint author), Univ Illinois, Coll Med, Dept Surg Oncol, 840 S Wood St,MC 820, Chicago, IL 60612 USA. FU NCI NIH HHS [N01 CN 25492-04] NR 20 TC 13 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5178 EP 5182 PG 5 WC Oncology SC Oncology GA 594TE UT WOS:000178066400011 PM 12234981 ER PT J AU Somasundaram, R Jacob, L Swoboda, R Caputo, L Song, H Basak, S Monos, D Peritt, D Marincola, F Cai, DW Birebent, B Bloome, E Kim, J Berencsi, K Mastrangelo, M Herlyn, D AF Somasundaram, R Jacob, L Swoboda, R Caputo, L Song, H Basak, S Monos, D Peritt, D Marincola, F Cai, DW Birebent, B Bloome, E Kim, J Berencsi, K Mastrangelo, M Herlyn, D TI Inhibition of cytolytic T lymphocyte proliferation by autologous CD4(+)/CD25(+) regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta SO CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; IMMUNOLOGICAL SELF-TOLERANCE; HUMAN PERIPHERAL-BLOOD; COLON-CARCINOMA; TGF-BETA; ANTITUMOR RESPONSES; CLONAL ANALYSIS; HUMAN-MELANOMA; IN-VITRO; CD4(+) AB Cancer patients often develop CTLs that lyse autologous tumor cells in culture. However, tumors can progress in vivo despite the presence of CTLs. Various mechanisms have been reported to down-modulate functions. In this study, the role of CD4(+)/CD25(+) regulatory T cells in CTL induction and proliferation of established CTLs was investigated in a patient with CRC. CD4(+) cytotoxic and regulatory T-cell lines were derived from the peripheral blood mononuclear cells of the same patient in mixed-lymphocyte tumor culture. The cytotoxic T-cell line and a clonal derivative specifically lysed the autologous tumor cells but not the B lymphocytes. Only HLA-A1-matched allogeneic CRC cells were lysed by the CTL clone. The clone produced IFN-gamma and TNF-alpha. The regulatory CD4(+)/CD25(+) T-cell line was tumor cell-dependent in its growth but did not lyse autologous tumor cells. This T-cell line suppressed pokeweed mitogen responses of allogeneic lymphocytes, proliferative activity of the established, autologous CTLs, and induction of CTLs in autologous, freshly isolated peripheral blood mononuclear cells. The immunosuppressive effect of the CD4(+)/CD25(+) regulatory T cells was mediated by transforming growth factor-beta and did not require cell-to-cell contact. Thus, although CRC patients can develop specific CTLs against their tumors, the development of regulatory T cells may allow the escape of tumor cells from immune surveillance by the CTLs in vivo. C1 Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Philadelphia, PA 19104 USA. NCI, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Herlyn, D (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA 74294, CA 10815, CA 2587-19, CA 43735] NR 44 TC 140 Z9 160 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5267 EP 5272 PG 6 WC Oncology SC Oncology GA 594TE UT WOS:000178066400025 PM 12234995 ER PT J AU Calvo, A Xiao, NQ Kang, J Best, CJM Leiva, I Emmert-Buck, MR Jorcyk, C Green, JE AF Calvo, A Xiao, NQ Kang, J Best, CJM Leiva, I Emmert-Buck, MR Jorcyk, C Green, JE TI Alterations in gene expression profiles during prostate cancer progression: Functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors SO CANCER RESEARCH LA English DT Article ID ANTIGEN TRANSGENIC MICE; GROWTH-FACTOR VEGF; INTRAEPITHELIAL NEOPLASIA; LIPID-PEROXIDATION; LIVER NECROSIS; ALPHA-CATENIN; BETA-CATENIN; E-CADHERIN; BENIGN; ADENOCARCINOMA AB To identify molecular changes that occur during prostate tumor progression, we have characterized a series of prostate cancer cell lines isolated at different stages of tumorigenesis from C3(1)/Tag transgenic mice. Cell lines derived from low- and high-grade prostatic intraepithelial neoplasia, invasive carcinoma, and a lung metastasis exhibited significant differences in cell growth, tumorigenicity, invasiveness, and angiogenesis. cDNA microarray analysis of 8700 features revealed correlations between the tumorigenicity of the C3(1)/Tag-Pr cells and changes in the expression levels of genes regulating cell growth, angiogenesis, and invasion. Many changes observed in transcriptional regulation in this in vitro system are similar to those reported for human prostate cancer, as well as other types of human tumors. This analysis of expression patterns has also identified novel genes that may be involved in mechanisms of prostate oncogenesis or serve as potential biomarkers or therapeutic targets for prostate cancer. Examples include the L1-cell adhesion molecule, metastasis-associated gene (MTA-2), Rab-25, tumor-associated signal transducer-2 (Trop-2), and Selenoprotein-P, a gene that binds selenium and prevents oxidative stress. Many genes identified in the Pr-cell line model have been shown to be altered in human prostate cancer. The comprehensive microarray data provides a rational basis for using this model system for studies where alterations of specific genes or pathways are of particular interest. Quantitative real-time reverse transcription-PCR for Selenoprotein-P demonstrated a similar down-regulation of the transcript of this gene in a subset of human prostate tumors, mouse tumors, and prostate carcinoma cell lines. This work demonstrates that expression profiling in animal models may lead to the identification of novel genes involved in human prostate cancer biology. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Boise State Univ, Dept Biol, Boise, ID 83725 USA. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD 20892 USA. NR 43 TC 123 Z9 134 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5325 EP 5335 PG 11 WC Oncology SC Oncology GA 594TE UT WOS:000178066400033 PM 12235003 ER PT J AU Kim, IY Kim, BC Seong, DH Lee, DK Seo, JM Hong, YJ Kim, HT Morton, RA Kim, SJ AF Kim, IY Kim, BC Seong, DH Lee, DK Seo, JM Hong, YJ Kim, HT Morton, RA Kim, SJ TI Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis in androgen-independent human prostate cancer cell lines SO CANCER RESEARCH LA English DT Article ID POSTMENOPAUSAL WOMEN; RECEPTOR-BETA; TRIAL; EXPRESSION; ANTIGEN; RISK AB Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed estrogen agonist/antagonist that has been shown to prevent osteoporosis and breast cancer in women. Because the prostate contains high levels of ER-beta, the present study investigated the effect of raloxifene in three well-characterized, androgen-independent human prostate cancer cell lines: (a) PC3; (b) PC3M; and (c) DU145. Reverse transcriptase-PCR and Western blot analysis for ER-alpha and ER-beta demonstrated that all three cell lines express ER-beta, whereas only PC3 and PC3M cells were positive for ER-a. After the treatment with raloxifene, a dramatic increase in cell death was observed in a dose-dependent manner in the three prostate cancer cell lines (10(-9) to 10(-6) m range). Because the three prostate cancer cell lines demonstrated similar morphological changes after the raloxifene treatment, PC3 (ER-alpha/ER-beta+) and DU145 (ER-beta+ only) cells were selected to further characterize the raloxifene-induced cell death. Using the nucleus-specific stain 4',6-diamidino-2-phenylindole, nuclear fragmentation was observed in a time-dependent manner in both cell lines after exposure to 10(-6) m raloxifene. Using the terminal deoxynucleotidyl transferase-mediated nick end labeling apoptotic assay, it was demonstrated that the nuclear fragmentation was caused by apoptosis. To investigate the possibility that caspase activation is involved in raloxifene-induced apoptosis, cells were treated with the pan-caspase inhibitor ZVAD. The results demonstrated that the dramatic change in cellular morphology after treatment with raloxifene was no longer observed when cells were pretreated with ZVAD. Immunoblot demonstrated activation of caspases 8 and 9 in PC3 and DU145 cells, respectively. Taken together, these results demonstrate that the mixed estrogen agonist/antagonist, raloxifene, induces apoptosis in androgen-independent human prostate cancer cell lines. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. Inha Univ, Coll Med, Clin Res Ctr, Inchon 400711, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Rm C629,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 24 TC 74 Z9 77 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5365 EP 5369 PG 5 WC Oncology SC Oncology GA 594TE UT WOS:000178066400038 PM 12235008 ER PT J AU Hecht, D Jung, D Prabhu, VV Munson, PJ Hoffman, MP Kleinman, HK AF Hecht, D Jung, D Prabhu, VV Munson, PJ Hoffman, MP Kleinman, HK TI Metallothionein promotes laminin-1-induced acinar differentiation in vitro and reduces tumor growth in vivo SO CANCER RESEARCH LA English DT Article ID GLAND CELL-LINE; SUBMANDIBULAR-GLAND; IMMUNOHISTOCHEMICAL LOCALIZATION; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; SALIVARY-GLAND; RAT; LAMININ; ZINC; APOPTOSIS AB Laminin-1 was found previously to promote the morphological differentiation of a salivary gland cell line (HSG) into acinar-like structures with polarized nuclei (1). Here, microarray analysis showed that laminin-1 induced mainly one gene family of proteins, the metal binding metallothioneins (MTs), out of more than 10,500 cDNAs screened. Northern and protein analyses demonstrated that MT was increased some 5-10-fold by laminin-1 as early as 6 It after incubation. Cells transfected with this gene formed 3-5-fold larger acinar-like structures on exposure to laminin-1 in vitro and smaller, more differentiated tumors in vivo. We conclude that MTs are important in acinar cell morphological differentiation and may have novel functions other than metal binding. C1 Natl Inst Dent & Craniofacial Res, NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Ctr Informat Technol, 30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. NR 29 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2002 VL 62 IS 18 BP 5370 EP 5374 PG 5 WC Oncology SC Oncology GA 594TE UT WOS:000178066400039 PM 12235009 ER PT J AU Espey, MG Miranda, KM Thomas, DD Wink, DA AF Espey, MG Miranda, KM Thomas, DD Wink, DA TI Ingress and reactive chemistry of nitroxyl-derived species within human cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Angeli's salt; diaminofluorescein; nitric oxide; MCF-7; free radicals ID NITRIC-OXIDE SYNTHASE; HYDROXY-L-ARGININE; NO-CENTER-DOT; AQUEOUS-SOLUTION; SUPEROXIDE-DISMUTASE; S-NITROSOTHIOLS; ANION; PEROXYNITRITE; GENERATION; MECHANISM AB The mechanisms that control the biological signaling and toxicological properties of the nitrogen oxide species nitroxyl (HNO) are largely unknown. The ingress and intracellular reactivity of nitroxyl-derived species were examined using Angeli's salt (AS), which decomposes initially to HNO and nitrite at physiologic pH. Exposure of 4,5-diaminofluorescein (DAF) to AS resulted in fluorescent product formation only in the presence of molecular oxygen. Kinetic analysis and the lack of signal from a nitric oxide (NO)-sensitive electrode suggested that these processes did not involve conversion of HNO to NO. On an equirnolar basis, bolus peroxynitrite (ONOO-) exposure generated only 15% of fluorescent product formation observed from AS decomposition. Moreover, infusion of synthetic ONOO- at a rate comparable to AS decomposition resulted in only 4% of the signal. Quenching of AS-mediated product formation within intact human MCF-7 breast carcinoma cells containing DAF by addition of urate to buffer suggested involvement of an oxidized intermediate formed from reaction between HNO and oxygen. Conversely, intact cells competitively sequestered the HNO-derived species from reaction with DAF in solution. These data show this intermediate to be a long-lived diffusible species. Relative product yield from intracellular DAF was decreased 5- to 8-fold when cells were lysed immediately prior to AS addition, consistent with the partitioning of HNO and/or derived species into the cellular membrane, thereby shielding these reactive intermediates from either hydrolysis or cytoplasmic scavenger pools. These findings establish that oxygen-derived species of nitroxyl can readily penetrate and engage the intracellular milieu of cells and suggest this process to be independent of NO and ONOO- intermediacy. The substantial facilitation of oxygen-dependent nitroxyl chemistry by intact lipid bilayers supports a focusing role for the membrane in modulation of cellular constituents proteins by this unique species. Published by Elsevier Science Inc. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Espey, MG (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 40 TC 61 Z9 61 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2002 VL 33 IS 6 BP 827 EP 834 DI 10.1016/S0891-5849(02)00978-4 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 592MD UT WOS:000177940700011 PM 12208370 ER PT J AU Riccomagno, MM Martinu, L Mulheisen, M Wu, DK Epstein, DJ AF Riccomagno, MM Martinu, L Mulheisen, M Wu, DK Epstein, DJ TI Specification of the mammalian cochlea is dependent on Sonic hedgehog SO GENES & DEVELOPMENT LA English DT Article DE Shh; Pax2; Ngn1; otic vesicle; cochlea; cochleovestibular ganglia ID MOUSE INNER-EAR; SEMICIRCULAR CANAL FORMATION; MICE LACKING; DEVELOPMENTAL DEFECTS; PHARYNGEAL ARCH; 2 RHOMBOMERES; SPINAL-CORD; MUTANT MICE; GENE; INDUCTION AB Organization of the inner ear into auditory and vestibular components is dependent on localized patterns of gene expression within the otic vesicle. Surrounding tissues are known to influence compartmentalization of the otic vesicle, yet the participating signals remain unclear. This study identifies Sonic hedgehog (Shh) secreted by the notochord and/or floor plate as a primary regulator of auditory cell fates within the mouse inner car. Whereas otic induction proceeds normally in Shh(-/-) embryos, morphogenesis of the inner ear is greatly perturbed by midgestation. Ventral otic derivatives including the cochlear duct and cochleovestibular ganglia failed to develop in the absence of Shh. The origin of the inner ear defects in Shh(-/-) embryos could be traced back to alterations in the expression of a number of genes involved in cell fate specification including Pax2, Otx1, Otx2, Tbx1, and Ngn1. We further show that several of these genes are targets of Shh signaling given their ectopic activation in transgenic mice that misexpress Shh in the inner ear. Taken together, our data support a model whereby auditory cell fates in the otic vesicle are established by the direct action of Shh. C1 Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Buenos Aires, Sch Med, Inst Cell Biol & Neurosci, RA-1121 Buenos Aires, DF, Argentina. Natl Inst Deafness & Commun Disorders, Rockville, MD 20850 USA. RP Epstein, DJ (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. RI Riccomagno, Martin/C-2439-2008 FU NINDS NIH HHS [R01 NS039421, R01 NS39421] NR 57 TC 145 Z9 152 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD SEP 15 PY 2002 VL 16 IS 18 BP 2365 EP 2378 DI 10.1101/gad.1013302 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 595VQ UT WOS:000178129600008 PM 12231626 ER PT J AU Greenwald, P AF Greenwald, P TI Cancer prevention clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTATE-CANCER; BREAST-CANCER; UNITED-STATES; GENETIC POLYMORPHISMS; PHYTOESTROGEN INTAKE; OBESITY EPIDEMIC; BETA-CAROTENE; LUNG-CANCER AB Prevention of cancer through interventions based on sound scientific research remains an important strategy of oncology research at the National Cancer Institute (NCI). Reducing the burden of cancer in the United States is focused on clinical investigations in medical settings and public health intervention research on cancer risk factors regarding lifestyle and diet. Chemoprevention research at the NCI has progressed systematically to identify potential agents that reduce cancer risk and to develop public health strategies that take advantage of basic research results. In addition, advances in our understanding of molecular targets and pathways and our use of new and emerging technologies have become important tools for oncology research. Priority areas for chemoprevention research, identified from experimental and clinical research, are investigated in clinical trials to determine their ability to reduce cancer risk in selected populations or in the general population. Priority areas discussed in this review are the relationship of the arachidonic acid pathway to carcinogenesis, lung cancer prevention in former smokers, breast cancer prevention, and prostate cancer prevention. In addition, two lifestyle factors that have potential to influence cancer risk-obesity and functionally enhanced foods-are discussed in the context of their link between clinical and public health-related research. C1 NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Greenwald, P (reprint author), NCI, Div Canc Prevent, NIH, 6130 Execut Blvd,Rm 2040,MSC 2580, Bethesda, MD 20892 USA. NR 84 TC 26 Z9 28 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 SEP 15 PY 2002 VL 20 IS 18 SU S BP 14S EP 22S DI 10.1200/JCO.2002.07.035 PG 9 WC Oncology SC Oncology GA 597HH UT WOS:000178215800002 PM 12235220 ER PT J AU Schwartsmann, G Ratain, MJ Cragg, GM Wong, JE Saijo, N Parkinson, DR Fujiwara, Y Pazdur, R Newman, DJ Dagher, R Di Leone, L AF Schwartsmann, G Ratain, MJ Cragg, GM Wong, JE Saijo, N Parkinson, DR Fujiwara, Y Pazdur, R Newman, DJ Dagher, R Di Leone, L TI Anticancer drug discovery and development throughout the world 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 NATURAL-PRODUCTS; CANCER; PHARMACOGENETICS; THERAPY AB This year's American Society of Clinical Oncology International Symposium devoted 2 hours to a lively discussion of various aspects of anticancer drug discovery and development throughout the world. The scientific program started with an overview of efforts directed toward promoting international collaboration in natural product-derived anticancer drug discovery. This was followed by a discussion on the importance of interethnic differences and pharmacogenetics in anticancer drug development. Thereafter, this part of the program was completed by a description of the activities of the newly created Singapore-Hong Kong-Australia Drug Development Consortium and an overview of the contribution of Japan to anticancer drug development. The logistics and regulatory aspects of clinical trials with new anticancer agents in different parts of the world were then presented, with an emphasis on Europe, North America, and Japan. The program was completed with a panel discussion of the efforts to harmonize the exchange of clinical data originating from one region of the globe with other territories, with input from official representatives of the United States Food and Drug Administration and the Medical Devices Evaluation Center of Japan. C1 Univ Luterana Brasil, Ctr Comprehens Canc, S Amer Off Anticanc Drug Dev, Canoas, Brazil. Univ Fed Rio Grande do Sul, Postgrad Course Med, Porto Alegre, RS, Brazil. Univ Chicago, Dept Med, Comm Clin Pharmacol & Pharmacogenom, Chicago, IL 60637 USA. Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. Natl Univ Singapore, Dept Hematol Oncol, Singapore 117548, Singapore. Natl Canc Ctr, Div Med Oncol, Tokyo, Japan. Minist Hlth Labor & Welf, Natl Inst Hlth Sci, Pharmaceut & Med Devices Evaluat Ctr, Tokyo, Japan. Novartis Oncol, Translat Dev, Clin Res, E Hanover, NJ USA. US FDA, Div Oncol Drug Prod, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Schwartsmann, G (reprint author), Univ Luterana Brasil, Ctr Comprehens Canc, S Amer Off Anticanc Drug Dev, Campus Cent ULBRA,Predio 22-5 Andar, Canoas, Brazil. EM gschwart.ez@terra.com.br RI Schwartsmann, Gilberto/G-4256-2016 OI Schwartsmann, Gilberto/0000-0002-7850-1644 NR 27 TC 36 Z9 39 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2002 VL 20 IS 18 SU S BP 47S EP 59S DI 10.1200/JCO.2002.07.122 PG 13 WC Oncology SC Oncology GA 597HH UT WOS:000178215800007 PM 12235225 ER PT J AU Herbst, RS Hess, KR Tran, HT Tseng, JE Mullani, NA Charnsangavej, C Madden, T Davis, DW McConkey, DJ O'Reilly, MS Ellis, LM Pluda, J Hong, WK Abbruzzese, JL AF Herbst, RS Hess, KR Tran, HT Tseng, JE Mullani, NA Charnsangavej, C Madden, T Davis, DW McConkey, DJ O'Reilly, MS Ellis, LM Pluda, J Hong, WK Abbruzzese, JL TI Phase I study of recombinant human endostatin in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 12-15, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Clin Oncol ID ANGIOGENESIS INHIBITOR; XVIII COLLAGEN; CANCER; THERAPY; GROWTH; ANGIOSTATIN; EFFICACY; AGENTS; MODEL; TRIAL AB Purpose: Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors. Patients and Methods: Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers. Results: Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo's activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed. Conclusion: rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated. (C) 2002 by American Society of Clinical Oncology. C1 Univ Texas, MD Anderson Canc Ctr, Dept Thorac, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Med Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pharmaceut Sci, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. Univ Texas, Houston Hlth Sci Ctr, Houston, TX USA. Natl Canc Inst, Bethesda, MD USA. RP Herbst, RS (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Thorac, 1515 Holcombe Blvd,Box 432, Houston, TX 77030 USA. FU NCI NIH HHS [CA 16672, U01 CA 62461] NR 36 TC 226 Z9 253 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2002 VL 20 IS 18 BP 3792 EP 3803 DI 10.1200/JCO.2002.11.061 PG 12 WC Oncology SC Oncology GA 597HF UT WOS:000178215600007 PM 12228199 ER PT J AU Herbst, RS Mullani, NA Davis, DW Hess, KR McConkey, DJ Charnsangavej, C O'Reilly, MS Kim, HW Baker, C Roach, J Ellis, LM Rashid, A Pluda, J Bucana, C Madden, TL Tran, HT Abbruzzese, JL AF Herbst, RS Mullani, NA Davis, DW Hess, KR McConkey, DJ Charnsangavej, C O'Reilly, MS Kim, HW Baker, C Roach, J Ellis, LM Rashid, A Pluda, J Bucana, C Madden, TL Tran, HT Abbruzzese, JL TI Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; ENDOTHELIAL-CELL APOPTOSIS; BLOOD-FLOW; OXYGEN UTILIZATION; SOLID TUMORS; ANGIOGENESIS; THERAPY; CANCER; GROWTH; ACTIVATION AB Purpose: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. Patients and Methods: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [O-15]H2O) and metabolism (with [F-18]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. Results: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P = .027) and endothelial cell apoptosis (P = .027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. Conclusion: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required. (C) 2002 by American Society of Clinical Oncology. C1 Univ Texas, MD Anderson Canc Ctr, Dept Thorac, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Med Oncol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Pharmaceut Sci, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX USA. Univ Texas, Sch Med, Houston, TX USA. Natl Canc Inst, Bethesda, MD USA. RP Herbst, RS (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Thorac, 1515 Holcombe Blvd,Box 432, Houston, TX 77030 USA. FU NCI NIH HHS [CA 16672, U54 CA90810, U01 CA62461] NR 41 TC 131 Z9 146 U1 0 U2 3 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 SEP 15 PY 2002 VL 20 IS 18 BP 3804 EP 3814 DI 10.1200/JCO.2002.05.102 PG 11 WC Oncology SC Oncology GA 597HF UT WOS:000178215600008 PM 12228200 ER PT J AU Martin, MP Nelson, G Lee, JH Pellett, F Gao, XJ Wade, J Wilson, MJ Trowsdale, J Gladman, D Carrington, M AF Martin, MP Nelson, G Lee, JH Pellett, F Gao, XJ Wade, J Wilson, MJ Trowsdale, J Gladman, D Carrington, M TI Susceptibility to psoriatic arthritis: Influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOGLOBULIN-LIKE RECEPTOR; NK CELL RECEPTORS; COMPLEX CLASS-I; CRYSTAL-STRUCTURE; MOLECULES; BINDING; P58; CYTOMEGALOVIRUS; RECOGNITION; SEQUENCES AB NK cell activity is partially controlled through interactions between killer Ig-like receptors (KIR) on NK cells and their respective HLA class I ligands. Independent segregation of HLA and KIR genes, along with KIR specificity for particular HLA allo-types, raises the possibility that any given individual may express KIR molecules for which no ligand is present. Inhibitory receptor genes KIR2DL2/3 and KIR2DL1 were present in nearly all subjects sampled in this study, whereas their respective activating homologs, KIR2DS2 and KIR2DS1, are each present in about half of the subjects. In this work we report that subjects with activating KIR2DS1 and/or KIR2DS2 genes are susceptible to developing psoriatic arthritis, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, are missing. Absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or 1) cell activation mediated through activating receptors, thereby contributing to pathogenesis of psoriatic arthritis. C1 NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Toronto Western Hosp, Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. Toronto Western Hosp, Ctr Prognosis Studies Rheumat Dis, Toronto, ON M5T 2S8, Canada. Univ Hlth Network, Reg HLA Lab, Toronto, ON, Canada. Univ Cambridge, Dept Pathol, Div Immunol, Cambridge CB2 1QP, England. RP Carrington, M (reprint author), NCI, Basic Res Program, SAIC Frederick, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 31 TC 240 Z9 263 U1 2 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 2818 EP 2822 PG 5 WC Immunology SC Immunology GA 592VU UT WOS:000177958200002 PM 12218090 ER PT J AU De Pascalis, R Iwahashi, M Tamura, M Padlan, EA Gonzales, NR Santos, AD Giuliano, M Schuck, P Schlom, J Kashmiri, SVS AF De Pascalis, R Iwahashi, M Tamura, M Padlan, EA Gonzales, NR Santos, AD Giuliano, M Schuck, P Schlom, J Kashmiri, SVS TI Grafting of "abbreviated" complementarity-determining regions containing specificity-determining residues essential for ligand contact to engineer a less immunogenic humanized monoclonal antibody SO JOURNAL OF IMMUNOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; CARCINOEMBRYONIC ANTIGEN; COLORECTAL-CANCER; ANTIIDIOTYPIC RESPONSE; ANTICARCINOMA ANTIBODY; INTERFERON-GAMMA; PHASE-II; EXPRESSION; THERAPY; TRIAL AB Murine mAb COL-1 reacts with carcinoembryonic Ag (CEA), expressed on a wide range of human carcinomas. In preclinical studies in animals and clinical trials in patients, murine COL-1 showed excellent tumor localization. To circumvent the problem of immunogenicity of the murine Ab in patients, a humanized COL-1 (HuCOL-1) was generated by grafting the complementarity-determining regions (CDRs) of COL-1 onto the frameworks of the variable light and variable heavy regions of human mAbs. To minimize anti-V region responses, a variant of HuCOL-1 was generated by grafting onto the human frameworks only the "abbreviated" CDRs, the stretches of CDR residues that contain the specificity-determining residues that are essential for the surface complementarity of the Ab and its ligand. In competition RIAs, the recombinant variant completely inhibited the binding of radiolabeled murine and humanized COL-1 to CEA. The HuCOL-1 and its variant showed no difference in their binding ability to the CEA expressed on the surface of a CEA-transduced tumor cell line. Compared with HuCOL-1, the HuCOL-1 variant showed lower reactivity to patients' sera carrying anti-V region Abs to COL-1. The final variant of the HuCOL-1, which retains its Ag-binding reactivity and shows significantly lower serum reactivity than that of the parental Ab, can serve as a prototype for the development of a potentially useful clinical reagent. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 58 TC 12 Z9 12 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3076 EP 3084 PG 9 WC Immunology SC Immunology GA 592VU UT WOS:000177958200036 PM 12218124 ER PT J AU Sharma, S Grandvaux, N Mamane, Y Genin, P Azimi, N Waldmann, T Hiscott, J AF Sharma, S Grandvaux, N Mamane, Y Genin, P Azimi, N Waldmann, T Hiscott, J TI Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; COLONY-STIMULATING FACTOR; SEQUENCE BINDING-PROTEIN; LIGATION-MEDIATED PCR; CD28 RESPONSE ELEMENT; NUCLEAR FACTOR; TRANSCRIPTION FACTORS; TAX PROTEIN; HTLV-I; PROMOTER TRANSACTIVATION AB IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However-, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTIV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes. C1 McGill Univ, Lady Davis Inst Med Res, Terry Fox Mol Oncol Lab, Montreal, PQ H3T 1E2, Canada. McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. NCI, NIH, Bethesda, MD 20892 USA. RP Hiscott, J (reprint author), McGill Univ, Lady Davis Inst Med Res, Terry Fox Mol Oncol Lab, 3755 Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada. NR 62 TC 37 Z9 37 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3120 EP 3130 PG 11 WC Immunology SC Immunology GA 592VU UT WOS:000177958200041 PM 12218129 ER PT J AU Wang, ZC Turner, R Baker, BM Biddison, WE AF Wang, ZC Turner, R Baker, BM Biddison, WE TI MHC allele-specific molecular features determine peptide/HLA-A2 conformations that are recognized by HLA-A2-restricted T cell receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-I; ALPHA-BETA; CRYSTAL-STRUCTURE; VIRAL PEPTIDES; VIRUS TYPE-1; HTLV-1 TAX; ANTIGEN; COMPLEX; LYMPHOCYTES; IDENTIFICATION AB The structures of alphabeta TCRs bound to complexes of class I MHC molecules and peptide show that the TCRs make multiple contacts with the alpha1 and alpha2 helixes of the MHC. Previously we have shown that the A6 TCR in complex with the HLA-A2/Tax peptide has 15 contact sites on HLA-A2. Single amino acid mutagenesis of these contact sites demonstrated that mutation of only three amino acids clustered on the alpha1 helix (R65, K66, A69) disrupted recognition by the A6 TCR. In the present study we have asked whether TCRs that recognize four other peptides presented by HLA-A2 interact with the MHC in identical, similar, or different patterns as the A6 TCR. Mutants K66A and Q155A had the highest frequency of negative effects on lysis. A subset of peptide-specific CTL also selectively recognized mutants K66A or Q155A in the absence of exogenous cognate peptides, indicating that these mutations affected the presentation of endogenous peptide/HLA-A2 complexes. These findings suggest that most HLA-A2-restricted TCRs recognize surfaces on the HLA-A2/peptide complex that are dependent upon the side chains of K66 and Q155 in the central portion of the peptide binding groove. Crystallographic structures of several peptide/HLA-A2 structures have shown that the side chains of these critical amino acids that make contact with the A6 TCR also contact the bound peptide. Collectively, our results indicate that the generalized effects of changes at these critical amino acids are probably due to the fact that they can be directly contacted by TCRs as well as influence the binding and presentation of the bound peptides. C1 NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. RP Biddison, WE (reprint author), NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10-Room 5B-16, Bethesda, MD 20892 USA. RI Baker, Brian/B-4584-2009 OI Baker, Brian/0000-0002-0864-0964 NR 52 TC 15 Z9 15 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3146 EP 3154 PG 9 WC Immunology SC Immunology GA 592VU UT WOS:000177958200044 PM 12218132 ER PT J AU Bashir, MEH Andersen, P Fuss, IJ Shi, HN Nagler-Anderson, C AF Bashir, MEH Andersen, P Fuss, IJ Shi, HN Nagler-Anderson, C TI An enteric helminth infection protects against an allergic response to dietary antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL; TH2 RESPONSES; IL-10; ATOPY; MICE; NONRESPONSIVENESS; SENSITIZATION; ANAPHYLAXIS; INHIBITION; REACTIVITY AB Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE. C1 Massachusetts Gen Hosp East, Mucosal Immunol Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. NIH, Mucosal Immun Sect, Bethesda, MD 20892 USA. RP Nagler-Anderson, C (reprint author), Massachusetts Gen Hosp East, Mucosal Immunol Lab, Bldg 114,16th St, Charlestown, MA 02129 USA. FU NIDDK NIH HHS [DK 40561, DK43551, T32-DK07471, DK 55678] NR 36 TC 163 Z9 174 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3284 EP 3292 PG 9 WC Immunology SC Immunology GA 592VU UT WOS:000177958200060 PM 12218148 ER PT J AU Sousa, AE Carneiro, J Meier-Schellersheim, M Grossman, Z Victorino, RMM AF Sousa, AE Carneiro, J Meier-Schellersheim, M Grossman, Z Victorino, RMM TI CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; IN-VIVO; ANTIGENIC-STIMULATION; RHESUS MACAQUES; RAPID TURNOVER; WEST-AFRICA; INFECTION; DISEASE; LYMPHOCYTES AB The causal relationships among CD4 cell depletion, HIV replication, and immune activation are not well understood. HIV-2 infection, "nature's experiment" with inherently attenuated HIV disease, provides additional insights into this issue. We report the finding that in HIV-2 and HIV-1 patients with a comparable degree of CD4 depletion the imbalance in the relative sizes of the naive and memory T cell populations and the up-regulation of CD4 and CD8 cell activation markers (HLA-DR, CD38, CD69, Fas molecules) are similar, even though the viral load in the plasma of HIV-2-infected patients is two orders of magnitude lower than in HIV-1 patients and HIV-2 patients are known to have slower rates of CD4 T cell decline and a better clinical prognosis. Moreover, we found a similar increase in the frequency of cycling CD4 T cells (Ki67(+)), which was in strong correlation with the expression of activation markers. Finally, the level of T cell anergy, as assessed by the proliferative responses to CD3 stimulation and to a panel of microbial Ags, proved to be comparable in HIV-1 and HIV-2 patients with a similar degree of CD4 depletion despite large differences in viral load. Our data are consistent with a direct causal relationship between immune activation and CD4 cell depletion in HIV disease and an only indirect relation of these parameters to the virus replication rate. Invoking the concept of proximal immune activation and virus transmission, which links efficient. transmission of virus to local cell activation and proliferation in response to Ags and inflammation, we propose an integrative interpretation of the data and suggest that strongly elevated immune activation induces CD4 cell depletion and not vice versa, with potential implications for the choice of treatment strategies. C1 Fac Med Lisbon, Clin Immunol Unit, Inst Mol Med, P-1649028 Lisbon, Portugal. Inst Gulbenkian Ciencias, Oeiras, Portugal. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Sousa, AE (reprint author), Fac Med Lisbon, Clin Immunol Unit, Inst Mol Med, Av Prof Egas Moniz, P-1649028 Lisbon, Portugal. RI Grossman, Zvi/A-9643-2008; Sousa, Ana E./L-2642-2014; Victorino, Rui/N-7948-2013 OI Sousa, Ana E./0000-0002-4618-9799; Carneiro, Jorge/0000-0002-7520-3406; Victorino, Rui/0000-0001-7567-1704 NR 52 TC 321 Z9 327 U1 1 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3400 EP 3406 PG 7 WC Immunology SC Immunology GA 592VU UT WOS:000177958200074 PM 12218162 ER PT J AU Wedemeyer, H He, XS Nascimbeni, M Davis, AR Greenberg, HB Hoofnagle, JH Liang, TJ Alter, H Rehermann, B AF Wedemeyer, H He, XS Nascimbeni, M Davis, AR Greenberg, HB Hoofnagle, JH Liang, TJ Alter, H Rehermann, B TI Impaired effector function of hepatitis C virus-specific CD8(+) T cells in chronic hepatitis C virus infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SINGLE-SOURCE OUTBREAK; EPSTEIN-BARR-VIRUS; LYMPHOCYTE RESPONSE; PERIPHERAL-BLOOD; IMMUNE-RESPONSE; VIRAL CLEARANCE; QUANTITATIVE-ANALYSIS; DENDRITIC CELLS; CORE PROTEIN AB The cellular immune response contributes to clearance of hepatitis C virus (HCV) and persists for decades after recovery from infection. The immunological basis for the inefficiency of the cellular immune response in chronically infected persons is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, to investigate at the single-cell level effector function and phenotype of HCV-specific CD8(+) T cells in 20 chronically infected and 12 long-term recovered patients. Overall, HCV-specific, tetramer(+) T cells were more frequently found in PBMCs of chronically infected patients than in those of recovered patients. However, when compared with HCV-tetramer(+) T cells of recovered patients, they displayed an impaired proliferative capacity. As a result of the impaired proliferative capacity, HCV-specific T cell lines derived from chronically infected patients displayed less peptide-specific cytotoxicity than those from recovered patients. In addition, proliferation and ex vivo IFN-gamma production of HCV-tetramer(+) cells, but not influenza-virus-specific T cells, were defective in chronically infected patients and could not be restored by in vitro stimulation with peptide and IL-2. At least three distinct phenotypes of HCV-specific CD8(+) T cells were identified and associated with certain functional characteristics. In addition, impairment of proliferative, cytokine, and cytotoxic effector functions of tetramer(+) T cells in viremic patients was associated with weak ex vivo HCV-specific CD4(+) T cell responses. Thus, the defective functions of HCV-specific CD8(+) T cells might contribute to viral persistence in chronically infected patients, and knowledge on their reversibility may facilitate the development of immunotherapeutic vaccines. C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RI Yang, Chen/G-1379-2010 FU NIAID NIH HHS [AI40034] NR 68 TC 466 Z9 483 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2002 VL 169 IS 6 BP 3447 EP 3458 PG 12 WC Immunology SC Immunology GA 592VU UT WOS:000177958200080 PM 12218168 ER PT J AU Cortez, K Murphy, BR Almeida, KN Beeler, J Levandowski, RA Gill, VJ Childs, RW Barrett, AJ Smolskis, M Bennett, JE AF Cortez, K Murphy, BR Almeida, KN Beeler, J Levandowski, RA Gill, VJ Childs, RW Barrett, AJ Smolskis, M Bennett, JE TI Immune-globulin prophylaxis of respiratory syncytial virus infection in patients undergoing stem-cell transplantation SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ANTIBODY; CHILDREN; INFANTS AB Thirty-two patients undergoing allogeneic hematopoietic stem-cell transplantation were given respiratory syncytial virus (RSV) immune globulin (RSVIG) at the time of transplantation and again 3 weeks later. Antibody titers to RSV, human parainfluenza virus 3, measles, and influenza H1N1, H3N2, and B were measured prior to administration of RSVIG and 6 more times over the course of the subsequent 6 weeks. Baseline antiviral titers and increases in antibody after administration of RSVIG were extremely variable for all the viruses. In 18 patients in whom the baseline titers of antibody titers to RSV-F protein were 1:640-1:2048, there was a 7.7-fold initial increase in these titers after the first dose of RSVIG, compared with a 2.1-fold increase in 14 patients with baseline titers of 1:4096-1:20,840; increases in titers of antibody against the other viruses after the first dose of RSVIG reflected similar variability. The subset of patients with the lowest titers appear to receive the greatest benefit from administration of RSVIG. C1 NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NHLBI, Stem Cell Allotransplant Unit, Hematol Branch, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Lab Pediat & Resp Virus Dis, Div Viral Prod, Bethesda, MD USA. RP Cortez, K (reprint author), NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Rm 11C304,10 Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 22 Z9 23 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2002 VL 186 IS 6 BP 834 EP 838 DI 10.1086/342412 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 588GY UT WOS:000177694800015 PM 12198619 ER PT J AU Le, AD Harding, S Juzytsch, W Fletcher, PJ Shaham, Y AF Le, AD Harding, S Juzytsch, W Fletcher, PJ Shaham, Y TI The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alcohol; corticotropin-releasing factor; reinstatement; relapse; serotonin; stress ID STRESS-INDUCED RELAPSE; COCAINE-SEEKING; PRIMING INJECTIONS; HEROIN-SEEKING; RAT-BRAIN; DORSAL; 8-OH-DPAT; CORTICOSTERONE; REINSTATEMENT; ACTIVATION AB Using an animal model of drug relapse, we found that intermittent footshock stress reinstates alcohol seeking, an effect attenuated by the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT cell body region of the median raphe nucleus (MRN) and CRF receptors in this site in reinstatement of alcohol seeking. Rats were given alcohol in a two-bottle choice procedure (water vs alcohol) for 25 d and were then trained for 1 hr/d to press a lever for alcohol (12% w/v) for 23-30 d. Subsequently, lever pressing for alcohol was extinguished by terminating drug delivery for 5-9 d. Tests for reinstatement of alcohol seeking were then performed under extinction conditions. Intra-MRN infusions of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] (a 5-HT1A agonist that decreases 5-HT cell firing and release) reinstated alcohol seeking. Reinstatement of alcohol seeking also was observed after intra-MRN infusions of low doses of CRF (3-10 ng), which mimicked the effect of ventricular infusions of higher doses of the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF receptor antagonist d-Phe CRF (50 ng) blocked the effect of intermittent footshock (10 min) on reinstatement. These data suggest that an interaction between CRF and 5-HT neurons within the MRN is involved in footshock stress-induced reinstatement of alcohol seeking. C1 Ctr Addict & Mental Hlth, Dept Neurosci, Toronto, ON M5S 2S1, Canada. Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Psychol, Toronto, ON M5S 1A8, Canada. NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21044 USA. RP Le, AD (reprint author), Ctr Addict & Mental Hlth, Dept Neurosci, 33 Russell St, Toronto, ON M5S 2S1, Canada. RI shaham, yavin/G-1306-2014 NR 38 TC 91 Z9 93 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 15 PY 2002 VL 22 IS 18 BP 7844 EP 7849 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 592BC UT WOS:000177916000003 PM 12223536 ER PT J AU Chen, M Conway, K Johnson, KP Martin, R Dhib-Jalbut, S AF Chen, M Conway, K Johnson, KP Martin, R Dhib-Jalbut, S TI Sustained immunological effects of Glatiramer acetate in patients with multiple sclerosis treated for over 6 years SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE multiple sclerosis; Glatiramer acetate; Copaxone (R); immune deviation; immunotherapy ID MYELIN BASIC-PROTEIN; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; T-CELL LINES; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTIGEN-PRESENTING CELLS; SYNTHETIC COPOLYMER-1; BYSTANDER SUPPRESSION; DOUBLE-BLIND; RELAPSE RATE; SPECIFICITY AB The availability of a group of multiple sclerosis (MS) patients at the University of Maryland, who had participated in the pivotal Copaxones trial in the early 1990s, provided an opportunity to examine the long-term immunologic effects of Glatiramer acetate (GA) treatment in MS. Forty-eight GA-reactive T-cell lines (TCL) were generated from 10 MS patients who have been receiving GA treatment for 6-9 years. Proliferative responses, cytokine production, and cross-reactivity with myelin basic protein (MBP) and the MBP immunodominant peptide 83-99 were compared to responses obtained from 10 MS patients who were tested pretreatment and after a shorter period of treatment ranging from 1 to 10 months. The results indicate that while long-term treatment with GA results in a 2.9-fold decrease in the estimated precursor frequency of GA-reactive T-cells, the sustained response to GA remains Th2-biased and in part cross-reactive with MBP and MBP (83-99) as measured by proliferation and cytokine release assays. The results indicate that despite a drop in the precursor frequency of GA-reactive T-cells with long-term treatment, the sustained response remains predominantly Th2-biased and cross-reactive with MBP, which is consistent with the anti-inflammatory effects of the drug and bystander suppression. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Baltimore VA Med Ctr, Baltimore, MD 21201 USA. RP Dhib-Jalbut, S (reprint author), Univ Maryland Hosp, Dept Neurol, Rm N4W46,22 S Greene St, Baltimore, MD 21201 USA. FU NINDS NIH HHS [K-24-NS02082] NR 31 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD SEP 15 PY 2002 VL 201 IS 1-2 BP 71 EP 77 AR PII S0022-510X(02)00201-0 DI 10.1016/S0022-510X(02)00201-0 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 589PJ UT WOS:000177768700012 PM 12163197 ER PT J AU Elvevag, B Weinberger, DR Goldberg, TE AF Elvevag, B Weinberger, DR Goldberg, TE TI The phonological similarity effect in short-term memory serial recall in schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE memory; recall; order; errors ID WORKING-MEMORY; IMPAIRMENT; ORDER; LOOP AB Lists of phonologically similar items are more often recalled in the wrong order than phonologically dissimilar items. At recall, patients with schizophrenia were neither especially susceptible to confusing phonologically similar items nor to making disproportionate movement (i.e. order) errors with phonologically similar lists of items. We conclude that patients with schizophrenia employ recall strategies for phonologically similar items in short-term memory that are equivalent to those of healthy controls. Crown Copyright (C) 2002 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4S235 MSC 1379, Bethesda, MD 20892 USA. NR 14 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 15 PY 2002 VL 112 IS 1 BP 77 EP 81 AR PII S0165-1781(02)00181-6 DI 10.1016/S0165-1781(02)00181-6 PG 5 WC Psychiatry SC Psychiatry GA 613NL UT WOS:000179138300008 PM 12379453 ER PT J AU Zhou, Y Spangler, R Schlussman, SD Yuferov, VP Sora, I Ho, A Uhl, GR Kreek, MJ AF Zhou, Y Spangler, R Schlussman, SD Yuferov, VP Sora, I Ho, A Uhl, GR Kreek, MJ TI Effects of acute "binge" cocaine on preprodynorphin, preproenkephalin, proopiomelanocortin, and corticotropin-releasing hormone receptor mRNA levels in the striatum and hypothalamic-pituitary-adrenal axis of mu-opioid receptor knockout mice SO SYNAPSE LA English DT Article DE corticosterone; RNA solution hybridization ID MESSENGER-RNA EXPRESSION; MORPHINE-INDUCED ANALGESIA; RAT ANTERIOR-PITUITARY; CORTICOSTERONE LEVELS; DOPAMINE RELEASE; GENE-EXPRESSION; DEFICIENT MICE; RHESUS-MONKEYS; BETA-ENDORPHIN; ACTH-SECRETION AB Cocaine administration increases activity at dopamine receptors, increases preprodynorphin (ppDyn) gene expression in the caudate-putamen (CPu), and activates the stress responsive hypothalamic-pituitary-adrenal (HPA) axis. To examine the hypothesis that mu-opioid receptors (MOR) may play roles in these cocaine effects, we tested the effects of acute "binge" pattern cocaine administration in mice with targeted disruption of the MOR gene. Wild-type (+/+) and homozygous MOR-deficient (-/-) mice received three injections of 15 mg/kg cocaine at 1-h intervals. Mice were sacrificed 30 min after the last injection and mRNAs for ppDyn and preproenkephalin (ppEnk) in the CPu and nucleus accumbens (NAc), and for type I corticotropin-releasing hormone receptor (CRH1 receptor) and proopiomelanocortin (POMC) in the hypothalamus and pituitary, were measured by solution hybridization RNase protection assays. Cocaine elevated ppDyn mRNA in the CPu, but not NAc, of both the MOR -/- and wild-type mice. ppEnk mRNA in the CPu, but not NAc, was lower in MOR -/- mice than in wild-type mice following cocaine administration. Hypothalamic CRH, receptor and POMC mRNAs were expressed at similar levels in untreated and in cocaine-treated mice of each genotype. However, there were lower basal levels of CRH, receptor mRNA in the anterior pituitary of the MOR -/- mice than in wild-type mice and the MOR -/- mice failed to show the cocaine-induced decreases in CRH, receptor mRNA found in the wild-type mice. Cocaine activated the HPA axis similarly in MOR -/- and wild-type mice, as reflected in similar increases in plasma corticosterone levels in both genotypes. These results support a specific role for MORs in acute cocaine effects on striatal ppEnk gene expression and fail to support critical roles for these receptors in acute cocaine's effects on either ppDyn gene expression or HPA activation. MOR -/- mice are useful models for studying cocaine effects on ppEnk gene expression that could aid interpretation of the similar postmortem phenomena found in human cocaine addicts. (C) 2002 Wiley-Liss, Inc. C1 Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10021 USA. NIDA, Intramural Res Program, Mol Neurol Branch, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Zhou, Y (reprint author), Rockefeller Univ, Lab Biol Addict Dis, Box 171, New York, NY 10021 USA. OI Zhou, Yan/0000-0002-5545-5681 FU NIDA NIH HHS [DA-00049, P50-DA-05130] NR 67 TC 31 Z9 32 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP 15 PY 2002 VL 45 IS 4 BP 220 EP 229 DI 10.1002/syn.10101 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 580GM UT WOS:000177226900003 PM 12125043 ER PT J AU Tonon, G Luo, XY Greco, NJ Chen, WD Shi, YF Jamieson, GA AF Tonon, G Luo, XY Greco, NJ Chen, WD Shi, YF Jamieson, GA TI Weak platelet agonists and U46619 induce apoptosis-like events in platelets, in the absence of phosphatidylserine exposure SO THROMBOSIS RESEARCH LA English DT Article DE platelet; apoptosis; phosphatidylserine; annexin V; platelet transfusion ID MEMBRANE PHOSPHOLIPID ASYMMETRY; PROGRAMMED CELL-DEATH; AGING IN-VIVO; AMINOPHOSPHOLIPID TRANSLOCASE; PLASMA-MEMBRANE; ACTIVATION; EXPRESSION; RECEPTOR; CASPASE; SURFACE AB Platelets express apoptotic markers during storage, while aging and after stimulation with strong agonists thrombin and collagen. It is unknown if the weak agonists ADP and epinephrine or U46619, a thromboxane analog, induce the expression of apoptotic markers in platelets. To answer this question, we measured phosphatidylserine exposure, gelsolin cleavage and decrease in membrane mitochondrial potential after stimulation with these agonists. No phosphatidylserine exposure was evident, however, gelsolin cleavage and a platelet population with a decreased membrane mitochondrial potential appeared, suggesting that in platelets selective agonists can induce apoptosis in the absence of phosphatidylserine exposure. Interestingly, costimulation by thrombin plus collagen together with each of the other agonists increased the phosphatidylserine exposure induced by strong agonists. These findings may be of importance in platelet activation and apoptosis under pathophysiological conditions where multiple effectors are involved. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIH, Genet Branch, Ctr Canc Res, Natl Naval Med Ctr, Bethesda, MD 20889 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. Univ Milan, Osped Maggiore, IRCCS, Dept Internal Med, I-20122 Milan, Italy. RP Tonon, G (reprint author), NIH, Genet Branch, Ctr Canc Res, Natl Naval Med Ctr, Bldg 8,R 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. FU NHLBI NIH HHS [HL 39438] NR 30 TC 18 Z9 20 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD SEP 15 PY 2002 VL 107 IS 6 BP 345 EP 350 DI 10.1016/S0049-3848(02)00338-9 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 650BV UT WOS:000181243200009 PM 12565722 ER PT J AU Rong, YS AF Rong, YS TI Gene targeting by homologous recombination: a powerful addition to the genetic arsenal for Drosophila geneticists SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID SITE-SPECIFIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; FLP RECOMBINASE; MAMMALIAN-CELLS; STEM-CELLS; YEAST; TRANSFORMATION; ENDONUCLEASE; GENOME; EFFICIENT AB A series of recent publications have firmly established the notion that Drosophila researchers now have a general method to subject genes for targeted modification by homologous recombination (HR) [Science 288 (2000) 2013; Genetics 157 (3),(2001) 1307; Genes Dev. 16 (12) (2002) 1568; Genetics 161 (2002) 1125-1136]. This method allows one to knockout essentially any gene starting with the DNA sequence of the gene. It has greatly enhanced studies of gene function as demonstrated by over 20 years of gene targeting practice in yeast and mouse. Here, I discuss the basic targeting methodology for eukaryotic organisms. I compare the Drosophila method with the traditional targeting scheme in yeast and mouse mainly to show that the targeting mechanism as well as many aspects of the experimental design remain unchanged, and that the Drosophila scheme differs only in the way in which the donor molecule for targeting is generated. I propose that the Drosophila method can be readily adapted in other organisms without culturable stem cells, since the mechanism for in vivo donor generation in Drosophila is likely to be functional in a variety of different organisms. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP NCI, Mol Cell Biol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI rong, yikang/G-6179-2011 NR 32 TC 12 Z9 14 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 13 PY 2002 VL 297 IS 1 BP 1 EP 5 AR PII S0006-291X(02)02066-1 DI 10.1016/S0006-291X(02)02066-1 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 598LE UT WOS:000178276700001 PM 12220499 ER PT J AU Voeller, DM Zajac-Kaye, M Fisher, RJ Allegra, CJ AF Voeller, DM Zajac-Kaye, M Fisher, RJ Allegra, CJ TI The identification of thymidylate synthase peptide domains located in the interface region that bind thymidylate synthase mRNA SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE thymidylate synthase; peptides; protein-RNA interaction ID COLON-CANCER-CELLS; DISSEMINATED COLORECTAL-CANCER; MESSENGER-RNA; INTERFERON-GAMMA; PROTEIN; ENZYME; 5-FLUOROURACIL; AUTOREGULATION; FLUOROURACIL; TRANSLATION AB Thymidylate synthase (TS) is a critical chemotherapeutic target and intracellular levels of TS are an important determinant of sensitivity to TS inhibitors. Translational autoregulation represents one cellular mechanism for controlling the level of expression of TS. This mechanism involves the binding of TS protein to its own messenger RNA (mRNA), thus, repressing translational efficiency. The presence of excess substrate or inhibitors of TS leads to derepression of protein binding to mRNA, resulting in increased translational efficiency and ultimately increased levels of TS protein. TS protein has been shown to bind to two distinct areas on its mRNA. The goal of the present work is to define the TS domains responsible for this interaction. Using a separate series of overlapping 17-mer peptides spanning the length of both the human and Escherichia coli TS sequences, we have identified six potential domains located in the interface region of the TS protein that bind TS mRNA. The identified domains that bind TS mRNA include three concordant regions in both the human and E coli peptide series. Five of the six binding peptides contain at least one invariant arginine residue, which has been shown to be critical in other well-defined protein-RNA interactions. These data suggest that the identified highly conserved protein domains, which occur at the homodimeric interface of TS, represent potential participating sites for binding of TS protein to its mRNA. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Ctr Canc Res, Basci Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Prot Chem Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21072 USA. RP Voeller, DM (reprint author), NCI, Ctr Canc Res, Basci Res Lab, NIH, Bldg 37,Room 6050D,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 30 TC 13 Z9 15 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 SEP 13 PY 2002 VL 297 IS 1 BP 24 EP 31 AR PII S0006-291X(02)02080-6 DI 10.1016/S0006-291X(02)02080-6 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 598LE UT WOS:000178276700005 PM 12220503 ER PT J AU Porciuncula, LO Schmidt, AP Coitinho, AS Vinade, L Izquierdo, I Batista, J Rocha, T Souza, DO AF Porciuncula, LO Schmidt, AP Coitinho, AS Vinade, L Izquierdo, I Batista, J Rocha, T Souza, DO TI Intrahippocampal infusion of ebselen impairs retention of an inhibitory avoidance task in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE ebselen; learning; memory; avoidance inhibitory ID CEREBRAL-ISCHEMIA; RECEPTORS; NEURONS; MEMORY; REDOX; GLUTATHIONE; ANTIOXIDANT; GLUTAMATE; NEUROTOXICITY; HIPPOCAMPUS AB Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutamatergic system. Although ebselen is currently used in clinical trials, the physiological effects of this seleno-compound are poorly known. In this study, we investigated the effects of intrahippocampal infusion of ebselen (0.1-3 nmol) in rats submitted to an inhibitory avoidance task. Ebselen (1-3 nmol) infused after the training session impaired retention of inhibitory avoidance, tested 90 min or 24 h after the training session. Moreover, ebselen also impaired the retention when infused 30 min prior to training or 10 min prior to test sessions. In summary, ebselen impaired memory consolidation, acquisition and retrieval. This amnesic effect of ebselen could be related to oxidant activity at N-methyl-D-aspartate (NMDA) receptors. Our results indicate that more studies must be performed to investigate the mechanisms of this amnesic effect and whether ebselen has a cognition-impairing effect when administered chronically. (C) 2002 Published by Elsevier Science B.V. C1 Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, BR-90035003 Porto Alegre, RS, Brazil. Univ Fed Rio Grande Sul, ICBS, Ctr Memoria, BR-90035003 Porto Alegre, RS, Brazil. Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Santa Maria, CCNE, Dept Quim, BR-97119900 Santa Maria, RS, Brazil. RP Souza, DO (reprint author), Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, Rua Ramiro Barcelos 2600 Anexo, BR-90035003 Porto Alegre, RS, Brazil. RI Schmidt, Andre/E-4652-2012; Souza, Diogo/J-8894-2014; Coitinho, Adriana/A-4923-2015; OI Souza, Diogo/0000-0002-4322-0404; Rocha, Joao Batista Teixeira da/0000-0003-3829-0595 NR 30 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 13 PY 2002 VL 451 IS 2 BP 165 EP 169 AR PII S0014-2999(02)02221-5 DI 10.1016/S0014-2999(02)02221-5 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 597NL UT WOS:000178227600010 PM 12231387 ER PT J AU Kozak, L Gopal, G Yoon, JH Sauna, ZE Ambudkar, SV Thakurta, AG Dhar, R AF Kozak, L Gopal, G Yoon, JH Sauna, ZE Ambudkar, SV Thakurta, AG Dhar, R TI Elf1p, a member of the ABC class of ATPases, functions as a mRNA export factor in Schizosacchromyces pombe SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA EXPORT; SCHIZOSACCHAROMYCES-POMBE; NUCLEAR EXPORT; POLY(A)(+) RNA; FISSION YEAST; RAE1 GENE; TRANSPORT; MEX67P; INTERACTS; NUP116P AB Rae1p and Mex67p/Tap are conserved mRNA export factors. We have used synthetic lethal genetic screens in Schizosaccharomyces pombe to identify mutations in genes that are functionally linked to rae1 and mex67 in mRNA export. From these screens, we have isolated mutations in a putative S. pombe homologue of the Candida albicans elf1 gene. The elf1 of S. pombe is not an essential gene. When elt1 mutations are combined with rae1-167 mutation, growth and mRNA export is inhibited in the double mutants. This inhibition can be suppressed by the multicopy expression of mex67 suggesting that Mex67p can substitute for the loss of Elf1p function. Elf1p is a non-membrane member of the ATP-binding cassette (ABC) class of ATPase and the GFP-Elf1p fusion localizes to the cytoplasm. Elf1p, expressed and purified from Escherichia coli, binds and hydrolyzes ATP. A mutant Elf1p that carries a glycine to aspartic acid (G731D) mutation within the Walker A domain of the second ATP site retains the ATP binding but loses its ATPase activity in vitro. This mutant protein no longer functions in mRNA export. Taken together, our results show that Elf1p functions as a mRNA export factor along with Rae1p and Mex67p in S. pombe. C1 NCI, Canc Res Ctr, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP NCI, Canc Res Ctr, Basic Res Lab, NIH, Bldg 37,Rm 6138B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dharr@mail.nih.gov RI Ambudkar, Suresh/B-5964-2008 NR 36 TC 21 Z9 23 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 13 PY 2002 VL 277 IS 37 BP 33580 EP 33589 DI 10.1074/jbc.M205415200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100008 PM 12110682 ER PT J AU Lee, DK Kim, BC Brady, JN Jeang, KT Kim, SJ AF Lee, DK Kim, BC Brady, JN Jeang, KT Kim, SJ TI Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of smad proteins with smad-binding element SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID I TAX; TRANSCRIPTIONAL ACTIVATION; FUNCTIONAL INTERACTION; COACTIVATORS CBP/P300; POTENTIAL MECHANISM; TRANSACTIVATOR TAX; DNA-BINDING; LEUKEMIA; GENE; EXPRESSION AB The human T-cell lymphotropic virus type I (HTLV-1) oncoprotein Tax is implicated in various clinical manifestations associated with infection by HTLV-1, including an aggressive and fatal T-cell malignancy. Because many human HTLV-1-infected T-cell lines are resistant to the growth inhibitory activity of transforming growth factor beta (TGF-beta), we examined the possibility that the HTVL-1-Tax oncoprotein regulates TGF-beta signaling. We show that Tax significantly decreases transcriptional activity and growth inhibition in response to TGF-beta. Tax inhibits TGF-beta-induced plasminogen activator inhibitor-1 expression and Smad2 phosphorylation. Competitive interaction studies show that Tax inhibits TGF-beta signaling, in part, by disrupting the interaction of the Smads with the transcriptional co-activator p300. Tax directly interacts with Smad2, Smad3, and Smad4; the Smad MH2 domain binds to Tax. Furthermore, Tax inhibits Smad3.Smad4 complex formation and its DNA binding. These results suggest that suppression of Smad-mediated signaling by Tax may contribute to HTLV-1-associated leukemogenesis. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 54 TC 62 Z9 65 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 SEP 13 PY 2002 VL 277 IS 37 BP 33766 EP 33775 DI 10.1074/jbc.M200150200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100033 PM 12097320 ER PT J AU Welm, AL Timchenko, NA Ono, Y Sorimachi, H Radomska, HS Tenen, DG Lekstrom-Himes, J Darlington, GJ AF Welm, AL Timchenko, NA Ono, Y Sorimachi, H Radomska, HS Tenen, DG Lekstrom-Himes, J Darlington, GJ TI C/EBP alpha is required for proteolytic cleavage of cyclin a by calpain 3 in myeloid precursor cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLONY-STIMULATING FACTOR; MUSCLE-SPECIFIC CALPAIN; BINDING PROTEIN-ALPHA; GRANULOCYTIC DIFFERENTIATION; PHYSIOLOGICAL-FUNCTION; TRANSCRIPTION FACTORS; DEFICIENT MICE; BETA ISOFORMS; RAT LENS; GENE AB In this report, we present novel findings that implicate CCAAT/enhancer-binding protein (C/EBPalpha) in regulating the expression and activity of calpain 3 in vivo and data showing a new physiological substrate for calpain 3, cyclin A. Our results demonstrate that cleavage of cyclin A by calpain 3 occurs in mouse and human myeloid precursor cells. Calpain 3 cleaves cyclin A in vitro and in vivo, resulting in the production of a truncated product that lacks the N-terminal destruction box required for its degradation at the end of mitosis. The cleaved form of cyclin A retains the cyclin-dependent kinase (cdk) binding domain and forms active complexes with cdk2. Calpain 3-mediated cleavage of cyclin A is lacking in C/EBPalpha-/- mice, which are not able to produce mature granulocytes. Our data support a model in which calpain 3-mediated cleavage of cyclin A in dividing myeloid progenitor cells is important for the onset of differentiation. Deficits in this pathway in C/EBPalpha-/- mice might contribute to the failure of these mice to produce mature granulocytes. These data reveal a new pathway involving tightly controlled post-translational processing of cyclin A during differentiation of granulocytes. C1 Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Univ Tokyo, Grad Sch Agr & Life Sci, Dept Appl Biol Chem, Tokyo 1138657, Japan. Univ Arizona, Coll Med, Tucson, AZ 85724 USA. Harvard Univ, Sch Med, Inst Med, Div Hematol Oncol, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. RP Darlington, GJ (reprint author), Baylor Coll Med, Huffington Ctr Aging, N803,1 Baylor Plaza, Houston, TX 77030 USA. RI Sorimachi, Hiroyuki/C-6448-2009; OI Sorimachi, Hiroyuki/0000-0001-9509-6727; Tenen, Daniel/0000-0002-6423-3888 FU NIA NIH HHS [AG 00766]; NIDDK NIH HHS [DK 07696, R01 DK 53045]; NIGMS NIH HHS [GM 55188] NR 43 TC 29 Z9 30 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 13 PY 2002 VL 277 IS 37 BP 33848 EP 33856 DI 10.1074/jbc.M204096200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100043 PM 12105198 ER PT J AU Thompson, J Lichtenthaler, FW Peters, S Pikis, A AF Thompson, J Lichtenthaler, FW Peters, S Pikis, A TI beta-glucoside kinase (BglK) from Klebsiella pneumoniae - Purification, properties, and preparative synthesis of 6-phospho-beta-D-glucosides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID-SEQUENCE; FAMILY 4; PHOSPHOTRANSFERASE SYSTEM; FUSOBACTERIUM-MORTIFERUM; GLYCOSYL HYDROLASES; ALPHA-GLUCOSIDASE; ESCHERICHIA-COLI; D-FRUCTOSES; BACTERIA; PHOSPHORYLATION AB ATP-dependent beta-glucoside kinase (BgIK) has been purified from cellobiose-grown cells of Klebsiella pneumoniae. In solution, the enzyme (EC 2.7.1.85) exists as a homotetramer composed of non-covalently linked subunits of M-r similar to 33,000. Determination of the first 28 residues from the N terminus of the protein allowed the identification and cloning of bglK from genomic DNA of K pneumoniae. The open reading frame (ORF) of bglK encodes a 297-residue polypeptide of calculated Mr 32,697. A motif of 7 amino acids (AFD(7)IG(9)GT) near the N terminus may comprise the ATP-binding site, and residue changes D7G and G9A yielded catalytically inactive proteins. BglK was progressively inactivated (t(1/2) similar to 19 min) by N-ethylmaleimide, but ATP afforded considerable protection against the inhibitor. By the presence of a centrally located signature sequence, BgIK can be assigned to the ROK (Repressor, ORF, Kinase) family of proteins. Preparation of (His6)BglK by nickel-nitrilotriacetic acid-agarose chromatography provided high purity enzyme in quantity sufficient for the preparative synthesis (200-500 mg) of ten 6-phospho-beta-D-glucosides, including cellobiose-6'-P, gentiobiose-6'-P, cellobiitol-6-P, salicin-6-P, and arbutin-6-P. These (and other) derivatives are substrates for phospho-beta-glucosidase(s) belonging to Families 1 and 4 of the glycosylhydrolase superfamily. The structures, physicochemical properties, and phosphorylation site(s) of the 6-phospho-beta-D-glucosides have been determined by fast atom bombardment-negative ion spectrometry, thin-layer chromatography, and H-1 and C-13 NMR spectroscopy. The recently sequenced genomes of two Listeria species, L. monocytogenes EGD-e and L. innocua CLIP 11262, contain homologous genes (lmo2764 and lin2907, respectively) that encode a 294-residue polypeptide (M-r similar to 32,200) that exhibits similar to58% amino acid identity with BgIK. The protein encoded by the two genes exhibits beta-glucoside kinase activity and cross-reacts with polyclonal antibody to (His6)BglK from K pneumoniae. The location of lmo2764 and lin2907 within a beta-glucoside (cellobiose):phosphotransferase system operon, may presage both enzymatic (kinase) and regulatory functions for the BgIK homolog in Listeria species. C1 NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Tech Univ Darmstadt, Inst Organ Chem, D-64287 Darmstadt, Germany. RP Thompson, J (reprint author), NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 528,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. NR 39 TC 13 Z9 17 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 13 PY 2002 VL 277 IS 37 BP 34310 EP 34321 DI 10.1074/jbc.M206397200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100102 PM 12110692 ER PT J AU Botos, I O'Keefe, BR Shenoy, SR Cartner, LK Ratner, DM Seeberger, PH Boyd, MR Wlodawer, A AF Botos, I O'Keefe, BR Shenoy, SR Cartner, LK Ratner, DM Seeberger, PH Boyd, MR Wlodawer, A TI Structures of the complexes of a potent anti-HIV protein cyanovirin-N and high mannose oligosaccharides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN GP120; INACTIVATING PROTEIN; BINDING; TYPE-1; CRYSTAL; CYANOBACTERIUM; GLYCOSYLATION; AFFINITY; SYSTEM AB The development of anti-human immunodeficiency virus (HIV) microbicides for either topical or ex vivo use is of considerable interest, mainly due to the difficulties in creating a vaccine that would be active against multiple clades of HIV. Cyanovirin-N (CV-N), an 11-kDa protein from the cyanobacterium (blue-green algae) Nostoc ellipsosporum with potent virucidal activity, was identified in the search for such antiviral agents. The binding of CV-N to the heavily glycosylated HIV envelope protein gp120 is carbohydrate-dependent. Since previous CV-N-dimannose structures could not fully explain CVN-oligomannose binding, we determined the crystal structures of recombinant CV-N complexed to Man-9 and a synthetic hexamannoside, at 2.5- and 2.4-Angstrom resolution, respectively. CV-N is a three-dimensional domain-swapped dimer in the crystal structures with two primary sites near the hinge region and two secondary sites on the opposite ends of the dimer. The binding interface is constituted of three stacked alpha1-->2-linked mannose rings for Man-9 and two stacked mannose rings for hexamannoside with the rest of the saccharide molecules pointing to the solution. These structures show unequivocally the binding geometry of high mannose sugars to CV-N, permitting a better understanding of carbohydrate binding to this potential new lead for the design of drugs against AIDS. C1 NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. Univ S Alabama, Coll Med, USA, Canc Res Inst, Mobile, AL 36688 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, NIH, MCL Bldg 536,Rm 5, Frederick, MD 21702 USA. FU NCI NIH HHS [N01 CO 12400] NR 42 TC 125 Z9 130 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 13 PY 2002 VL 277 IS 37 BP 34336 EP 34342 DI 10.1074/jbc.M205909200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100105 PM 12110688 ER PT J AU Chu, X Cheung, JY Barber, DL Birnbaumer, L Rothblum, LI Conrad, K Abrasonis, V Chan, YM Stahl, R Carey, DJ Miller, BA AF Chu, X Cheung, JY Barber, DL Birnbaumer, L Rothblum, LI Conrad, K Abrasonis, V Chan, YM Stahl, R Carey, DJ Miller, BA TI Erythropoietin modulates calcium influx through TRPC2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTRACELLULAR-FREE CALCIUM; MURINE ERYTHROLEUKEMIA-CELLS; HUMAN ERYTHROID PRECURSORS; CAPACITATIVE CA2+ ENTRY; CENTRAL-NERVOUS-SYSTEM; MOLECULAR MECHANISMS; HUMAN ERYTHROBLASTS; CATION CHANNEL; RECEPTOR; DIFFERENTIATION AB Mammalian isoforms of calcium-permeable Drosophila transient receptor potential channels (TRPC) are involved in the sustained phase of calcium entry in non-excitable cells. Erythropoietin (Epo) stimulates a rise in intracellular calcium ([Ca](i)) via activation of voltage-independent calcium channel(s) in erythroid cells. Here, involvement of murine orthologs of classical TRPC in the Epo-modulated increase in [Ca](i) was examined. RTPCR of TRPC 1-6 revealed high expression of only TRPC2 in Epo-dependent cell lines HCD-57 and Ba/F3 Epo-R, in which Epo stimulates a rise in [Ca](i). Using RT-PCR, Western blotting, and immunolocalization, expression of the longest isoform of mTRPC2, clone 14, was demonstrated in HCD-57 cells, Ba/F3 Epo-R cells, and primary murine erythroblasts. To determine whether erythropoietin is capable of modulating calcium influx through TRPC2, CHO cells were cotransfected with Epo-R subcloned into pTracer-CMV and either murine TRPC2 clone 14 or TRPC6, a negative control, into pQBI50. Successful transfection of Epo-R was verified in single cells by detection of green fluorescent protein from pTracer-CMV using digital video imaging, and successful transfection of TRPC was confirmed by detection of blue fluorescent protein fused through a flexible linker to TRPC. [Ca](i) changes were simultaneously monitored in cells loaded with Rhod-2 or Fura Red. Epo stimulation of CHO cells cotransfected with Epo-R and TRPC2 resulted in a rise in [Ca](i) above base line (372 +/- 71%), which was significantly greater (p less than or equal to 0.0007) than that seen in cells transfected with TRPC6 or empty pQBI50 vector. This rise in [Ca](i) required Epo and extracellular calcium. These results identify a calcium-permeable channel, TRPC2, in erythroid cells and demonstrate modulation of calcium influx through this channel by erythropoietin. C1 Sigfried & Janet Weis Ctr Res, Geisinger Clin, Henry Hood Res Program, Danville, PA 17822 USA. Geisinger Med Clin, Dept Med, Danville, PA 17822 USA. Geisinger Med Clin, Dept Pediat, Danville, PA 17822 USA. Ontario Canc Inst, Div Cell & Mol Biol, Toronto, ON M5G 2M9, Canada. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, BA (reprint author), Sigfried & Janet Weis Ctr Res, Geisinger Clin, Henry Hood Res Program, 100 N Acad Ave, Danville, PA 17822 USA. FU NHLBI NIH HHS [HL 58672]; NIDDK NIH HHS [DK 46778]; NIGMS NIH HHS [GM 46991]; NINDS NIH HHS [NS 37716, NS 41363, NS 21925] NR 44 TC 45 Z9 47 U1 1 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 SEP 13 PY 2002 VL 277 IS 37 BP 34375 EP 34382 DI 10.1074/jbc.M205541200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100110 PM 12167663 ER PT J AU McHugh, L Hu, S Lee, BK Santora, K Kennedy, PE Berger, EA Pastan, I Hamer, DH AF McHugh, L Hu, S Lee, BK Santora, K Kennedy, PE Berger, EA Pastan, I Hamer, DH TI Increased affinity and stability of an anti-HIV-1 envelope immunotoxin by structure-based mutagenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; HAIRY-CELL LEUKEMIA; RECOMBINANT IMMUNOTOXIN; CD4-PSEUDOMONAS EXOTOXIN; HIV-INFECTION; TYPE-1; ERADICATION; RESERVOIRS; GLYCOPROTEIN AB HIV-infected cells are selectively killed by an immunotoxin in which a truncated form of Pseudomonas exotoxin A is joined to the variable region of a broadly neutralizing antibody (3B3) that recognizes the viral envelope glycoprotein (Env). To improve the efficacy of this molecule, we used three-dimensional structural information and phage selection data to design 23 single and multiple point mutations in the antibody variable region sequences that contact Env. Substituting an aromatic residue for an aspartate in the third complementarity-determining region of V-H increased the potency of the immunotoxin by similar to10-fold in a cell-killing assay. Detailed analysis of one such mutant, N31H/Q100eY, revealed both a higher affinity for monomeric and cell surface Env and an increased stability against aggregation compared with the starting immunotoxin. Conversion to a disulfide-linked two-chain format further stabilized the protein. N31H/Q100eY retained the ability to bind to Env from multiple viral isolates, to inhibit Env-mediated cell fusion, and to limit spreading viral infection in peripheral blood mononuclear cells. Such site-directed mutants may increase the utility of immunotoxins for reducing or eradicating persistent HIV-1 infection in humans. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hamer, DH (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 37,Rm 6002,37 Convent Dr, Bethesda, MD 20892 USA. NR 26 TC 29 Z9 29 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 SEP 13 PY 2002 VL 277 IS 37 BP 34383 EP 34390 DI 10.1074/jbc.M205456200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100111 PM 12119300 ER PT J AU Kruth, HS Huang, W Ishii, I Zhang, WY AF Kruth, HS Huang, W Ishii, I Zhang, WY TI Macrophage foam cell formation with native low density lipoprotein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCYTE-DERIVED MACROPHAGES; HUMAN ATHEROSCLEROTIC LESIONS; RECEPTOR-MEDIATED ENDOCYTOSIS; FAMILIAL HYPERCHOLESTEROLEMIC SUBJECTS; MOUSE PERITONEAL-MACROPHAGES; TISSUE FACTOR EXPRESSION; CULTURED-CELLS; LIPOPOLYSACCHARIDE STIMULATION; CHOLESTEROL DEPOSITION; HORSERADISH-PEROXIDASE AB This investigation has elucidated a mechanism for development of macrophage foam cells when macrophages are incubated with native low density lipoprotein (LDL). LDL is believed to be the main source of cholesterol that accumulates in monocyte-derived macrophages within atherosclerotic plaques, but native LDL has not previously been shown to cause substantial cholesterol accumulation when incubated with macrophages. We have found that activation of human monocyte-derived macrophages with phorbol 12-myristate 13-acetate (PMA) stimulates LDL uptake and degradation and acyl-CoAcholesterol acyltransferase-mediated esterification of LDL-derived cholesterol, resulting in massive macrophage cholesterol accumulation that could exceed 400 nmol/mg of cell protein. Cholesterol accumulation showed a biphasic linear LDL concentration dependence with LDL levels as high as 4 mg/ml, similar to LDL levels in artery intima. Protein kinase C mediated the PMA-stimulated macrophage uptake of LDL because the protein kinase C inhibitors, G66983 and GF109203X, inhibited cholesterol accumulation. LDL receptors did not mediate macrophage cholesterol accumulation because accumulation occurred with reductively methylated LDL and in the presence of an anti-LDL receptor-blocking monoclonal antibody. LDL-induced cholesterol accumulation was not inhibited by antioxidants, was not accompanied by increased LDL binding to macrophages, did not depend on the apoB component of LDL, and was not down-regulated by prior cholesterol enrichment of macrophages. We have shown that the mechanism of LDL uptake by macrophages was PAU-stimulated endocytosis of LDL taken up as part of the bulk phase fluid (i.e. fluid phase endocytosis). The amount of LDL taken up with the bulk phase fluid was measured with [H-3]sucrose and accounted for a minimum. of 83% of the LDL cholesterol delivery and accumulation in PMA-activated macrophages. This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage fluid phase endocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis. C1 NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10,Rm 5N-113,10 Ctr Dr,MSC 1422, Bethesda, MD 20892 USA. RI Huang, Wei/E-3270-2011 NR 57 TC 84 Z9 89 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 SEP 13 PY 2002 VL 277 IS 37 BP 34573 EP 34580 DI 10.1074/jbc.M205059200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 592WD UT WOS:000177959100131 PM 12118008 ER PT J AU Koenig, BW Kontaxis, G Mitchell, DC Louis, JM Litman, BJ Bax, A AF Koenig, BW Kontaxis, G Mitchell, DC Louis, JM Litman, BJ Bax, A TI Structure and orientation of a G protein fragment in the receptor bound state from residual dipolar couplings SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE NMR; membrane protein; rhodopsin; transferred dipolar couplings; transducin ID NUCLEAR-MAGNETIC-RESONANCE; LIGHT-ACTIVATED RHODOPSIN; EFFECT DIFFERENCE SPECTROSCOPY; AMBIGUOUS DISTANCE RESTRAINTS; LIQUID-CRYSTALLINE MEDIUM; HETEROTRIMERIC G-PROTEIN; COVALENT CROSS-LINKING; ORIENTED MACROMOLECULES; BOVINE RHODOPSIN; COUPLED RECEPTOR AB Residual dipolar couplings for a ligand that is in fast exchange between a free state and a state where it is bound to a macroscopically ordered membrane protein carry precise information on the structure and orientation of the bound ligand. The couplings originate in the bound state but can be detected on the free ligand using standard high resolution NMR. This approach is used to study an analog of the C-terminal undecapeptide of the alpha-subunit of the heterotrimeric G protein transducin when bound to photo-activated rhodopsin. Rhodopsin is the major constituent of disk-shaped membrane vesicles from rod outer segments of bovine retinas, which align spontaneously in the NMR magnet. Photo-activation of rhodopsin triggers transient binding of the peptide, resulting in measurable dipolar contributions to (1)J(NH) and (1)J(CH) splittings. These dipolar couplings report on the time-averaged orientation of bond vectors in the bound peptide relative to the magnetic field, i.e. relative to the membrane normal. Approximate distance restraints of the bound conformation were derived from transferred NOEs, as measured from the difference of NOESY spectra recorded prior to and after photo-activation. The N-terminal eight residues of the bound undecapeptide adopt a near-ideal alpha-helical conformation. The helix is terminated by an alpha(L) type C-cap, with Gly9 at the C' position in the center of the reverse turn. The angle between the helix axis and the membrane normal is 40degrees(+/- 4)degrees. Peptide protons that make close contact with the receptor are identified by analysis of the NOESY cross-relaxation pattern and include the hydrophobic C terminus of the peptide. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Res Ctr Julich, Struct Biol Inst, D-52425 Julich, Germany. NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. NIAAA, Lab Membrane Biophys & Biochem, NIH, Rockville, MD 20852 USA. RP Koenig, BW (reprint author), Res Ctr Julich, Struct Biol Inst, IBI-2, D-52425 Julich, Germany. RI Koenig, Bernd/B-4315-2008 OI Koenig, Bernd/0000-0002-5300-6276 NR 96 TC 91 Z9 92 U1 0 U2 7 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 SEP 13 PY 2002 VL 322 IS 2 BP 441 EP 461 DI 10.1016/S0022-2836(02)00745-3 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 597PT UT WOS:000178230500015 PM 12217702 ER PT J AU Brambila, E Liu, J Morgan, DL Beliles, RP Waalkes, MP AF Brambila, E Liu, J Morgan, DL Beliles, RP Waalkes, MP TI Effect of mercury vapor exposure on metallothionein and glutathione S-transferase gene expression in the kidney of nonpregnant, pregnant, and neonatal rats SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID PROXIMAL TUBULAR CELLS; INORGANIC MERCURY; NULL MICE; METHYL MERCURY; RENAL TOXICITY; CHLORIDE; METABOLISM; CADMIUM; LIVER; ZINC AB Elemental mercury (Hg-o) is a ubiquitous toxic pollutant. Exposure to Hg-o vapor typically is by inhalation, and the kidney is the primary target organ. Glutathione (GSH) and metallothionein (MT) appear to mitigate mercury toxicity. However, little is known about GSH or MT regulation after Hgo vapor exposure, particularly during pregnancy, a time of high sensitivity to most metals. Thus, this study sought to determine renal mercury accumulation and MT- and GSH-related gene expression following Hg-o vapor exposure in nonpregnant, pregnant, and neonatal rats exposed in utero. Groups (n = 5) of pregnant rats (Long-Evans) were exposed to Hg-o vapor (4 mg/m(3)) or air (control) for 2 h/d from gestational day (GD) 6 to 75, and kidneys from dams and pups were removed at various times during and after the onset of exposure. For comparative purposes, nonpregnant female rats were exposed to Hg-o for 10 d under the same conditions. Renal mercury, MT protein, and GST activity were assayed by standard analytical techniques. Western blot analysis was also performed using antibodies against MT and CST-pi. GSH-related gene expression was studied by cDNA microarray. Hg-o vapor exposure produced renal accumulation of mercury in nonpregnant, pregnant, and neonatal rats. However, the transplacentally exposed neonates accumulated approximately 1000-fold less mercury than adults. Hg-o vapor exposure produced a time-dependent increase in renal MT protein in nonpregnant and preg nant rats, but not in neonatal rats. Maximum MT increases were observed on d 10 (five-fold) in nonpregnant and CD 15 (threefold) in pregnant rats. Activation of the MT gene by Hg-o was confirmed at the translational level by Western blot analysis and at the transcriptional level by Northern blot analysis. Microarray analysis revealed a significant upregulation in the renal expression of the GST-pi, GST-Ya, and microsomal GST and GST5-5 genes in nonpregnant and pregnant rats. Western blot and enzyme assay confirmed the upregulation of GST genes after Hgo exposure. Thus, in response to Hg-o vapor exposure, the expression of the MT gene and various GST genes is activated in nonpregnant and pregnant rats. Activation of these genes could be part of a defensive response directed at decreasing renal mercury toxicity, and may help divert the metal away from the fetus. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. US EPA, NCEA DC, Oakton, VA USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, 111 alexander Dr,Bldg 101 SC MD-FO-09,RM F095, Res Triangle Pk, NC 27709 USA. NR 41 TC 22 Z9 23 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD SEP 13 PY 2002 VL 65 IS 17 BP 1273 EP 1288 DI 10.1080/00984100290071405 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 588CN UT WOS:000177683300005 PM 12167210 ER PT J AU Patterson, GH Lippincott-Schwartz, J AF Patterson, GH Lippincott-Schwartz, J TI A photoactivatable GFP for selective photolabeling of proteins and cells SO SCIENCE LA English DT Article ID GREEN-FLUORESCENT PROTEIN; LYSOSOMAL MEMBRANE; STRUCTURAL BASIS; LIVING CELLS; MUTATIONS; GLYCOPROTEINS; EXCITATION; DYNAMICS; MUTANTS AB We report a photoactivatable variant of the Aequorea victoria green fluorescent protein (GFP) that, after intense irradiation with 413-nanometer light, increases fluorescence 100 times when excited by 488-nanometer light and remains stable for days under aerobic conditions. These characteristics offer a new tool for exploring intracellular protein dynamics by tracking photoactivated molecules that are the only visible GFPs in the cell. Here, we use the photoactivatable GFP both as a free protein to measure protein diffusion across the nuclear envelope and as a chimera with a lysosomal membrane protein to demonstrate rapid interlysosomal membrane exchange. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NR 25 TC 957 Z9 979 U1 15 U2 140 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 13 PY 2002 VL 297 IS 5588 BP 1873 EP 1877 DI 10.1126/science.1074952 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 592UJ UT WOS:000177955000045 PM 12228718 ER PT J AU Jacobson, KA Jarvis, MF Williams, M AF Jacobson, KA Jarvis, MF Williams, M TI Purine and pyrimidine (P2) receptors as drug targets SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Review ID HUMAN P2Y(1) RECEPTOR; GATED ION-CHANNEL; PROTEIN-COUPLED RECEPTORS; PLATELET ADP RECEPTOR; RAT VAS-DEFERENS; RECOMBINANT P2X(2) RECEPTOR; NUCLEUS-TRACTUS-SOLITARIUS; SITE-DIRECTED MUTAGENESIS; PAROTID ACINAR-CELLS; DORSAL-ROOT GANGLION C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Abbott Labs, Abbott Pk, IL 60064 USA. Northwestern Univ, Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. RP Williams, M (reprint author), 1130 Walden Lane, Lake Forest, IL 60045 USA. EM ruerivoli@aol.com RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 449 TC 197 Z9 204 U1 0 U2 11 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 SEP 12 PY 2002 VL 45 IS 19 BP 4057 EP 4093 DI 10.1021/jm020046y PG 37 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592AA UT WOS:000177913500001 PM 12213051 ER PT J AU Houlihan, WJ Kelly, L Pankuch, J Koletar, J Brand, L Janowsky, A Kopajtic, TA AF Houlihan, WJ Kelly, L Pankuch, J Koletar, J Brand, L Janowsky, A Kopajtic, TA TI Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SUBSTITUTED 3-ALPHA-TROPANE ANALOGS; PIPERIDINE-BASED ANALOGS; ABUSE TREATMENT AGENTS; REUPTAKE INHIBITORS; NEURONAL DOPAMINE; PHARMACOLOGY; DERIVATIVES; ANTAGONISTS; GBR-12909; AFFINITY AB A series of mazindol. (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal. membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [I-125] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEk-hDAT cells. The 4',7,8-trichloro analogue (38) of mazindol was the I most potent and selective ligand. for HEK-hDAT cells (DAT K-i = 1.1 nM; SERT/DAT 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more, tightly at the DAT than the corresponding keto tautomers. C1 Drew Univ, Charles A Dana Res Inst, Madison, NJ 07940 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Dept Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Houlihan, WJ (reprint author), Drew Univ, Charles A Dana Res Inst, Hall Sci, Madison, NJ 07940 USA. FU NIDA NIH HHS [R01 DA 10533] NR 69 TC 23 Z9 23 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 12 PY 2002 VL 45 IS 19 BP 4097 EP 4109 DI 10.1021/jm010302r PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592AA UT WOS:000177913500003 PM 12213053 ER PT J AU Houlihan, WJ Ahmad, UF Koletar, J Kelly, L Brand, L Kopajtic, TA AF Houlihan, WJ Ahmad, UF Koletar, J Kelly, L Brand, L Kopajtic, TA TI Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AFFINITIES; MAZINDOL AB A series of mazindol (1), homomazindol (2), and bishomomazindol (3) derivatives with a benzo or cyclohexano ring fused At various sites were prepared as part of an SAR study to determine the effect of increased aliphatic and aromatic lipophilicity on selected in vitro assays used to identify potential cocaine-like and cocaine antagonism activity. Very good (IC50 = 2-3 nM) inhibition of [H-3] WIN 35,428 and [I-125] RTI-55 binding on rat or guinea pig striatal membranes and HEK cells expressing cDNA for the human dopamine transporter (HEK-hDAT) was shown by the 8,9-benzomazindol 25 and 9,10-benzohomomazindol 28. All new compounds were weaker inhibitors of [H-3] DA uptake in HEK-hDAT cells than 1 and 2. No improvement in the binding selectivity ratio (SERT/DAT and NET/DAT) was found when compared to 2. Compounds 25 and 28 showed a considerable increase versus 1 in uptake/binding discrimination ratios at the DAT (311.0 and 182.1 vs 0.9), SERT (33.6 and 127.3 vs 1.9), and NET (7.3 and 10.0 vs 0.3). C1 Drew Univ, Charles A Dana Res Inst, Madison, NJ 07940 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Houlihan, WJ (reprint author), Drew Univ, Charles A Dana Res Inst, Hall Sci, Madison, NJ 07940 USA. FU NIDA NIH HHS [R03 DA 08516-02, N01 DA 38303, R01 DA 10533-01] NR 23 TC 15 Z9 15 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 SEP 12 PY 2002 VL 45 IS 19 BP 4110 EP 4118 DI 10.1021/jm010301z PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592AA UT WOS:000177913500004 PM 12213054 ER PT J AU Kulkarni, SS Newman, AH Houlihan, WJ AF Kulkarni, SS Newman, AH Houlihan, WJ TI Three-dimensional quantitative structure-activity relationships of Mazindol analogues at the dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR-FIELD ANALYSIS; COCAINE BINDING-SITE; ACID METHYL-ESTERS; LIGAND-BINDING; PHOTOAFFINITY LIGANDS; POTENTIAL INHIBITORS; CLONING; COMFA; ABUSE; PHARMACOTHERAPIES AB A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of mazindol analogues using the comparative molecular field analysis (CoMFA) method with their corresponding binding affinities for the displacement of [H-3]WIN 35 428 from rat caudate putamen tissue. The cross-validated CoMFA models were derived from a training set of 50 compounds, and the predictive ability of the, resulting CoMFA models was evaluated against a test set of 21 compounds. A set of alignment rules was derived to superimpose these compounds onto a template structure, mazindol (1). These CoMFA models yielded significant cross-validated r(cv)(2) values. Inclusion of additional descriptors did not improve the significance of the CoMFA models; thus, steric and electrostatic fields are the relevant descriptors for these compounds. The best QSAR model was selected on the basis of the predictive ability of the activity on the external test set of compounds. The analysis of coefficient contour maps provided further insight into the binding interactions of mazindol analogues with the DAT. The aromatic rings C and D are involved in hydrophobic interactions in which ring D may bind in a large hydrophobic groove. The relative orientation of these two rings is also important for high binding affinity to the DAT. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Drew Univ, Charles A Dana Res Inst, Madison, NJ 07940 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [DA 10533] NR 45 TC 20 Z9 20 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 SEP 12 PY 2002 VL 45 IS 19 BP 4119 EP 4127 DI 10.1021/jm0102093 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592AA UT WOS:000177913500005 PM 12213055 ER PT J AU Prisinzano, T Greiner, E Johnson, EM Dersch, CM Marcus, J Partilla, JS Rothman, RB Jacobson, AE Rice, KC AF Prisinzano, T Greiner, E Johnson, EM Dersch, CM Marcus, J Partilla, JS Rothman, RB Jacobson, AE Rice, KC TI Piperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxylethyl]-4-(3-phenylpropyl)piperazine (GBR 12909): High affinity ligands for the dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COCAINE-ABUSE; 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; 4-<2-(DIPHENYLMETHOXY)ETHYL>-1-BENZYLPIPERIDINE DERIVATIVES; N-ANALOG; 1-<2-(DIPHENYLMETHOXY)ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES; PHARMACOLOGY; SELECTIVITY; DEPENDENCE; INHIBITORS; MONKEYS AB A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the norepinephrine transporter, and the serotonin transporter (SERT). In particular, the role of the N-substituent on affinity and selectivity for the DAT was probed. 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl-1-(2-naphthylmethyl)piperidine was found to possess subnanomolar affinity (K-i = 0.7 nM) and good selectivity for the DAT (SERT/DAT = 323). C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RI Prisinzano, Thomas/B-7877-2010 NR 36 TC 15 Z9 15 U1 3 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 SEP 12 PY 2002 VL 45 IS 19 BP 4371 EP 4374 DI 10.1021/jm020264r PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 592AA UT WOS:000177913500028 PM 12213078 ER PT J AU Xie, Q Guo, HS Dallman, G Fang, SY Weissman, AM Chua, NH AF Xie, Q Guo, HS Dallman, G Fang, SY Weissman, AM Chua, NH TI SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals SO NATURE LA English DT Article ID LATERAL ROOT DEVELOPMENT; ARABIDOPSIS-THALIANA; AUX/IAA PROTEINS; LIGASE; SIAH-1; PATHWAY; DOMAIN; P53; ABSENTIA; MUTATION AB The plant hormone indole-3 acetic acid (IAA or auxin) controls many aspects of plant development, including the production of lateral roots(1-3). Ubiquitin-mediated proteolysis has a central role in this process. The genes AXR1 and TIR1 aid the assembly of an active SCF (Skp1/Cullin/F-box) complex that probably promotes degradation of the AUX/IAA transcriptional repressors in response to auxin(4-8). The transcription activator NAC1, a member of the NAM/CUC family of transcription factors, functions downstream of TIR1 to transduce the auxin signal for lateral root development(9). Here we show that SINAT5, an Arabidopsis homologue of the RING-finger Drosophila protein SINA, has ubiquitin protein ligase activity and can ubiquitinate NAC1. This activity is abolished by mutations in the RING motif of SINAT5. Overexpressing SINAT5 produces fewer lateral roots, whereas overexpression of a dominant-negative Cys49 --> Ser mutant of SINAT5 develops more lateral roots. These lateral root phenotypes correlate with the expression of NAC1 observed in vivo. Low expression of NAC1 in roots can be increased by treatment with a proteasome inhibitor, which indicates that SINAT5 targets NAC1 for ubiquitin-mediated proteolysis to downregulate auxin signals in plant cells. C1 Rockefeller Univ, Plant Mol Biol Lab, New York, NY 10021 USA. NCI, Ctr Canc Res, Regulat Prot Funct Lab, Bethesda, MD 20892 USA. Natl Univ Singapore, Temasek Life Sci Lab, Mol Cell Biol Lab, Singapore 117604, Singapore. RP Chua, NH (reprint author), Rockefeller Univ, Plant Mol Biol Lab, 1230 York Ave, New York, NY 10021 USA. RI Fang, Shengyun/H-3802-2011; Dallmann, Geza/E-1630-2012 NR 28 TC 265 Z9 304 U1 8 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 12 PY 2002 VL 419 IS 6903 BP 167 EP 170 DI 10.1038/nature00998 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 592HK UT WOS:000177931200041 PM 12226665 ER PT J AU Hebert, JM Mishina, Y McConnell, SK AF Hebert, JM Mishina, Y McConnell, SK TI BMP signaling is required locally to pattern the dorsal telencephalic midline SO NEURON LA English DT Article ID BONE MORPHOGENETIC PROTEINS; CEREBRAL-CORTEX; MOUSE EMBRYOGENESIS; VENTRICULAR ZONE; EXPRESSION; MICE; RECEPTORS; FOREBRAIN; EYE; CRE AB BMPs have been proposed to pattern the medial-lateral axis of the telencephalon in a concentration-dependent manner, thus helping to subdivide the embryonic telencephalon into distinct forebrain regions. Using a CRE/1oxP genetic approach, we tested this hypothesis by disrupting the Bmpr1a gene in the telencephalon. In mutants, BMP signaling was compromised throughout the dorsal telencephalon, but only the most dorsalmedial derivative, the choroid plexus, failed to be specified or differentiate. Choroid plexus precursors remained proliferative and did not adopt the fate of their lateral telencephalic neighbors. These results demonstrate that BMP signaling is required for the formation of the most dorsal telencephalic derivative, the choroid plexus, and that BMP signaling plays an essential role in locally patterning the dorsal midline. Our data fall to support a more global, concentration-dependent role in specifying telencephalic cell fates. C1 Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP McConnell, SK (reprint author), Stanford Univ, Dept Biol Sci, 385 Serra Mall, Stanford, CA 94305 USA. FU NIMH NIH HHS [MH51864]; NINDS NIH HHS [NS12151] NR 37 TC 159 Z9 165 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 12 PY 2002 VL 35 IS 6 BP 1029 EP 1041 DI 10.1016/S0896-6273(02)00900-5 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 594GC UT WOS:000178040000005 PM 12354394 ER PT J AU Goldman, D Barr, CS AF Goldman, D Barr, CS TI Restoring the addicted brain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 NIAAA, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 5 TC 9 Z9 9 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 12 PY 2002 VL 347 IS 11 BP 843 EP 845 DI 10.1056/NEJMcibr021948 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 592DK UT WOS:000177921300012 PM 12226158 ER PT J AU Karimpour, S Lou, JY Lin, LL Rene, LM Lagunas, L Ma, XR Karra, S Bradbury, CM Markovina, S Goswami, P Spitz, DR Hirota, K Kalvakolanu, DV Yodoi, J Gius, D AF Karimpour, S Lou, JY Lin, LL Rene, LM Lagunas, L Ma, XR Karra, S Bradbury, CM Markovina, S Goswami, P Spitz, DR Hirota, K Kalvakolanu, DV Yodoi, J Gius, D TI Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation SO ONCOGENE LA English DT Article DE thioredoxin reductase; thioredoxin; AP-1; redox; ionizing radiation ID NF-KAPPA-B; DNA-BINDING ACTIVITY; TRANSCRIPTION FACTOR; REDOX REGULATION; GENE-EXPRESSION; RETINOID COMBINATION; OXIDATIVE STRESS; DRUG TARGET; CELL-LINES; ACTIVATION AB A recently identified class of signaling factors uses critical cysteine motif(s) that act as redox-sensitive 'sulfhydryl switches' to reversibly modulate specific signal transduction cascades regulating downstream proteins with similar redox-sensitive sites. For example, signaling factors such as redox factor-1 (Ref-1) and transcription factors such as the AP-1 complex both contain redox-sensitive cysteine motifs that regulate activity in response to oxidative stress. The mammalian thioredoxin reductase-1 (TR) is an oxidoreductase selenocysteine-containing flavoprotein that also appears to regulate multiple downstream intracellular redox-sensitive proteins. Since ionizing radiation (IR) induces oxidative stress as well as increases AP-1 DNA-binding activity via the activation of Ref-1, the potential roles of TR and thioredoxin (TRX) in the regulation of AP-1 activity in response to IR were investigated. Permanently transfected cell lines that overexpress wild type TR demonstrated constitutive increases in AP-1 DNA-binding activity as well as AP-1-dependent reporter gene expression, relative to vector control cells. In contrast, permanently transfected cell lines expressing a TR gene with the active site cysteine motif deleted were unable to induce AP-1 activity or reporter gene expression in response to IR. Transient genetic overexpression of either the TR wild type or dominant-negative genes demonstrated similar results using a transient assay system. One mechanism through which TR regulates AP-1 activity appears to involve TRX sub-cellular localization, with no change in the total TRX content of the cell. These results identify a novel function of the TR enzyme as a signaling factor in the regulation of AP-1 activity via a cysteine motif located in the protein. C1 NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Sect Canc Biol, Mallinckrodt Inst Radiol, St Louis, MO USA. Univ Maryland, Sch Med, Greenbaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA. Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiol, Iowa City, IA USA. Kyoto Univ Hosp, Dept Anesthesia, Kyoto 606, Japan. Kyoto Univ, Dept Biol Responses, Inst Virus Res, Kyoto, Japan. RP NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Canc Res Ctr,NIH, 9000 Rockville Pike,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM giusd@mail.nih.gov FU NCI NIH HHS [1 K08 CA72602-01, CA 71401, CA69593, R01 CA 78282]; NHLBI NIH HHS [R01 HL51469] NR 39 TC 88 Z9 94 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD SEP 12 PY 2002 VL 21 IS 41 BP 6317 EP 6327 DI 10.1038/sj.onc.1205749 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 590NM UT WOS:000177829000008 PM 12214272 ER PT J AU Vasan, RS Benjamin, EJ Larson, MG Leip, EP Wang, TJ Wilson, PWF Levy, D AF Vasan, RS Benjamin, EJ Larson, MG Leip, EP Wang, TJ Wilson, PWF Levy, D TI Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction - The Framingham Heart study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MYOCARDIAL-INFARCTION; DIAGNOSTIC-TEST; PRIMARY-CARE; ECHOCARDIOGRAPHY; POPULATION; ACCURACY; FAILURE; MARKER; MORTALITY; SURVIVAL AB Context Several reports have suggested the usefulness of plasma brain natriuretic peptide (BNP) as a screening test for left ventricular hypertrophy (LVH) and systolic dysfunction (LVSD). Prior studies were limited by small sample sizes and selection bias and none compared the diagnostic performance of these peptides in men and women. Objectives To examine the usefulness of natriuretic peptides for screening for elevated LV mass and LVSD in the community. Design, Setting, and Participants Community-based prospective cohort study of 3177 participants (1707 women) from the Framingham Study who attended a routine examination in 1995-1998. Main Outcome Measures Receiver operating characteristic (ROC) curves, test sensitivity, specificity, positive and negative predictive values, and likelihood ratios for identifying elevated LV mass (sex-specific 90th percentile or higher of LV mass/[height](2)), LVSD (ejection fraction less than or equal to 50% and/or fractional shortening <29%), and moderate to severe LVSD (ejection fraction less than or equal to40% and/or fractional shortening <22%) at different discrimination limits of plasma BNP and N-terminal proatrial natriuretic peptide (NT-ANP), with echocardiography as the criterion standard. Results The areas under the ROC curves for elevated LV mass or LVSD were at or below 0.75 for both peptides, were higher for men compared with women, and were similar for BNP and NT-ANP. The diagnostic performance of natriuretic peptides for LVSD improved in women but not in men when select high-risk subgroups were targeted. Discrimination limits based on high specificity (0.95) yielded better positive predictive values and likelihood ratios compared with age- and sex-specific reference limits yet only identified less than one third of participants who had elevated LV mass or LVSD. Conclusion In our large community-based sample, the performance of BNP and NT-ANP for detection of elevated LV mass and LVSD was suboptimal, suggesting limited usefulness of natriuretic peptides as mass screening tools. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Div Endocrinol, Boston, MA 02118 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01HL67288-01, K24 HL 04334-01A1, N01-HC-25195] NR 42 TC 299 Z9 313 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 11 PY 2002 VL 288 IS 10 BP 1252 EP 1259 DI 10.1001/jama.288.10.1252 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 592BW UT WOS:000177917700024 PM 12215132 ER PT J AU Korzhnev, DM Skrynnikov, NR Millet, O Torchia, DA Kay, LE AF Korzhnev, DM Skrynnikov, NR Millet, O Torchia, DA Kay, LE TI An NMR experiment for the accurate measurement of heteronuclear spin-lock relaxation rates SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PROTEIN SIDE-CHAINS; TIME-SCALE DYNAMICS; MODEL-FREE APPROACH; CHEMICAL-SHIFT; CROSS-CORRELATION; ROTATING-FRAME; STAPHYLOCOCCAL NUCLEASE; BACKBONE DYNAMICS; BINDING DOMAIN AB Rotating-frame relaxation rates, R-1rho, are often measured in NMR studies of protein dynamics. We show here that large systematic errors can be introduced into measured values of heteronuclear R-1rho rates using schemes which are usually employed to suppress cross-correlation between dipole-dipole and CSA relaxation mechanisms. For example, in a scalar-coupled two-spin X-H spin system the use of H-1 WALTZ16 decoupling or H-1 pulses applied at regularly spaced intervals leads to a significant overestimation of heteronuclear R-1rho values. The problem is studied experimentally and theoretically for N-15-H-1 and C-13-H-1 spin pairs, and simple schemes are described which eliminate the artifacts. The approaches suggested are essential replacements of existing methodology if accurate dynamics parameters are to be extracted from spin-lock relaxation data sets. C1 Univ Toronto, Prot Engn Network Ctr Excellence, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Med Genet, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Chem, Toronto, ON M5S 1A8, Canada. Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. RP Kay, LE (reprint author), Univ Toronto, Prot Engn Network Ctr Excellence, Toronto, ON M5S 1A8, Canada. RI Millet, Oscar/F-9696-2011 NR 54 TC 83 Z9 83 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 11 PY 2002 VL 124 IS 36 BP 10743 EP 10753 DI 10.1021/ja0204776 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 591GW UT WOS:000177872200031 PM 12207529 ER PT J AU Cristofaro, JV Rausch, JW Le Grice, SFJ DeStefano, JJ AF Cristofaro, JV Rausch, JW Le Grice, SFJ DeStefano, JJ TI Mutations in the ribonuclease H active site of HIV-RT reveal a role for this site in stabilizing enzyme-primer-template binding SO BIOCHEMISTRY LA English DT Article ID VIRUS REVERSE-TRANSCRIPTASE; DEPENDENT DNA-POLYMERASE; HUMAN-IMMUNODEFICIENCY; RNASE-H; AVIAN-MYELOBLASTOSIS; DOMAIN; ENDONUCLEASE; SPECIFICITY; MUTAGENESIS; CLEAVAGE AB The RNase H activity of HIV-RT is coordinated by a catalytic triad (E478, D443, D498) of acidic residues that bind divalent cations, We examined the effect of RNase H deficient E-478-->Q and D-549-->N mutations that do not alter polymerase activity on binding of enzyme to various nucleic acid substrates. Binding of the mutant and wild-type enzymes to various nucleic acid substrates was examined by determining dissociation rate constants (k(off)) by titrating both Mg2+ and salt concentrations. In agreement with the unaltered polymerase activity of the mutant, the k(off) values for the wild-type and mutant enzymes were essentially identical using DNA-DNA templates in the presence of 6 MM Mg2+. However, with lower concentrations of Mg2+ and in the absence of Mg2+, although both enzymes dissociated more rapidly, the mutant enzymes dissociated several-fold more slowly than the wild type. This was also observed on RNA-DNA templates. These results indicate that alterations in residues essential for Mg2+ binding have a pronounced positive effect on enzyme-template stability and that the negative residues in the RNase H region of the enzyme have a negative influence on binding in the absence of Mg2+. In this regard RT is similar to other nucleic acid cleaving enzymes that show enhanced binding upon mutation of active site residues. C1 Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. FCRDC, Natl Canc Inst, HIV Drug Resistance Program, Resistance Mech Lab, Ft Detrick, MD 21702 USA. RP DeStefano, JJ (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. FU NIGMS NIH HHS [R01 GM051140] NR 30 TC 29 Z9 31 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 10 PY 2002 VL 41 IS 36 BP 10968 EP 10975 DI 10.1021/bi025871v PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 590VA UT WOS:000177843600010 PM 12206668 ER PT J AU Yu, CA Wen, XL Xiao, KH Xia, D Yu, L AF Yu, CA Wen, XL Xiao, KH Xia, D Yu, L TI Inter- and intra-molecular electron transfer in the cytochrome bc(1) complex SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article; Proceedings Paper CT 12th European Bioenergetics Conference CY SEP 11-15, 2002 CL FRANCE SP Grp Francais Bioenerget DE cytochrome bc(1) complex; electron transfer rate; iron-sulfur protein ID IRON-SULFUR PROTEIN; DOMAIN MOVEMENT; RHODOBACTER-SPHAEROIDES; PROTON TRANSLOCATION; UBIQUINOL-OXIDATION; ENERGY TRANSDUCTION; BOVINE HEART; STEADY-STATE; BC1 COMPLEX; Q-CYCLE AB In this review, we compare the intra-molecular and inter-molecular electron transfer rate constants of the high-potential branch of the cytochrome bc(1) complex. Several methods such as the conventional stopped-flow spectroscopy, pH-induced electron transfer, photoactivated ruthenium complex induced electron transfer and photoreleaseable caged quinol, have been used to determine reaction rates between redox centers in an attempt to elucidate the reaction mechanism of this vital energy conserving complex. Since the most active pure cytochrome bc(1) complex has a turnover number of 800 s(-1), any step with a rate constant much larger than this will not be rate-limiting. The most likely rate-limiting step is the cytochrome b redox state governed movement of the head domain of iron-sulfur protein from its electron-accepting site ("fixed" or "b-state" position) to its electron donating site ("c(1)-state" position). (C) 2002 Published by Elsevier Science B.V. C1 Oklahoma State Univ, Dept Biochem & Mol Biol, OAES, Stillwater, OK 74078 USA. Natl Canc Inst, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Yu, CA (reprint author), Oklahoma State Univ, Dept Biochem & Mol Biol, OAES, NRC-255, Stillwater, OK 74078 USA. FU NIGMS NIH HHS [GM30721] NR 39 TC 24 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD SEP 10 PY 2002 VL 1555 IS 1-3 SI SI BP 65 EP 70 AR PII S0005-2728(02)00256-6 DI 10.1016/S0005-2728(02)00256-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 595BX UT WOS:000178087900011 PM 12206893 ER PT J AU Mahadev, K Raval, G Bharadwaj, S Willingham, MC Lange, EM Vonderhaar, B Salomon, D Prasad, GL AF Mahadev, K Raval, G Bharadwaj, S Willingham, MC Lange, EM Vonderhaar, B Salomon, D Prasad, GL TI Suppression of the transformed phenotype of breast cancer by tropomyosin-1 SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE tropomyosin; breast cancer; cytoskeleton; E-cadherin; beta-catenin; tumor suppression ID E-CADHERIN; BETA-CATENIN; EPITHELIAL-CELLS; RAS-TRANSFORMATION; ALPHA-CATENIN; GAMMA-CATENIN; EXPRESSION; PROTEIN; CDNA; CALDESMON AB Changes in the expression of microfilament-associated proteins, such as tropomyosins (TMs), are commonly found in malignantly transformed cells. Previous work from this laboratory has shown that tropomyosin-1 (TM1) expression is consistently abolished in human breast carcinoma cell lines, suggesting that the loss of TM1 could be a common biochemical event in the transformation of mammary epithelium. To investigate whether changes in TM1 expression are causally linked to mammary carcinogenesis, we have tested the hypothesis that TM1 is a tumor suppressor of breast cancer. MCF-7 cells, which lack TM1, were utilized as a model of human breast cancer and transduced to reexpress TMI. protein. Restoration of TMI expression in MCF-7 cells (MCF-7/T cells) resulted in a slower growth rate, but cells remained sensitive to growth control by estrogen. TMI. expression in MCF-7 cells resulted in the emergence of TM-containing microfilaments. More significantly, MCF-7/T cells failed to grow under anchorage-independent conditions. TM1 reexpression alters the interaction of the E-cadherin-catenin complex with the cytoskeleton, indicating that TM1-induced cytoskeleton could play a significant role in suppression of the malignant phenotype. Taken together with our previous work on transformed murine fibroblasts, the results presented in this communication indicate that in nonmuscle cells TM1. functions as a suppressor of transformation. (C) 2002 Elsevier Science (USA). C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Gen Surg, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. NCI, Ctr Canc Res, Basic Res Lab, Bethesda, MD 20892 USA. RP Prasad, GL (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Gen Surg, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. NR 47 TC 58 Z9 60 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2002 VL 279 IS 1 BP 40 EP 51 DI 10.1006/excr.2002.5583 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 593AJ UT WOS:000177968800005 PM 12213212 ER PT J AU Yang, YA Han, WF Morin, PJ Chrest, FJ Pizer, ES AF Yang, YA Han, WF Morin, PJ Chrest, FJ Pizer, ES TI Activation of fatty acid synthesis during neoplastic transformation: Role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE fatty acid synthase; mitogen-activated protein kinase; phosphatidylinositol 3-kinase; sterol regulatory element-binding proteins; neoplasia ID HUMAN BREAST-CANCER; ELEMENT-BINDING PROTEINS; GROWTH-FACTOR RECEPTOR; SYNTHASE EXPRESSION; EPITHELIAL-CELLS; COLORECTAL NEOPLASIA; TRANSCRIPTION FACTOR; RAS TRANSFORMATION; GENE-EXPRESSION; TUMOR-GROWTH AB Activation of fatty acid synthase (FAS) expression and fatty acid synthesis is a common event in tumor cells from a variety of human cancers and is closely linked to malignant transformation and to tumor virulence in population studies of human cancer. We now show that, in contrast to nutritional regulation of lipogenesis in liver or adipose tissue, changes in fatty acid metabolism during in vitro transformation of the human mammary epithelial cell line MCF-10a are driven by increases in epidermal growth factor signaling, acting in major part through the mitogen-activated protein (MAP) kinase and phosphatidylinositol. (PI) 3-kinase signaling cascades. H-ras transformation of MCF-10a cells resulted in upregulation of MAP kinase and PI 3-kinase signals, upregulation of sterol regulatory element binding protein 1 (SREBP-1) transcription factor levels, and upregulation of FAS expression and FA synthesis. Deletion of the major SREBP binding site from the FAS promoter abrogated transcription in transformed MCF-10a cells. Inhibitors of MAP and PI 3-kinases downregulated SREBP-1 levels and decreased transcription from the FAS promoter, reducing FAS expression and fatty acid synthesis in transformed MCF-10a cells and in MCF-7 and HCT116 carcinoma cells. H-ras transformation sensitized MCF-10a cells to the FAS inhibitors cerulenin and C-75. These results confirm an important role for SREBP-1 in neoplastic lipogenesis, and provide a likely basis for the linkage of upregulated fatty acid metabolism with neoplastic transformation and with tumor virulence, since MAP and PI 3-kinase signaling contributes to both. (C) 2002 Elsevier Science (USA). C1 Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21224 USA. NIA, Biol Chem Lab, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Pizer, ES (reprint author), Johns Bayview Med Ctr, Dept Pathol, AA154C,4940 Eastern Ave, Baltimore, MD 21224 USA. FU NCI NIH HHS [PC991429, R29CA75219] NR 47 TC 128 Z9 139 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2002 VL 279 IS 1 BP 80 EP 90 DI 10.1006/excr.2002.5600 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 593AJ UT WOS:000177968800009 PM 12213216 ER PT J AU Thompson, J AF Thompson, J TI Purification and some properties of phospho-beta-galactosidase from the Gram-negative oral bacterium Leptotrichia buccalis ATCC 14201 SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE phospho-beta-galactosidase; lactose; dental caries; Leptotrichia buccalis ID D-PHOSPHOGALACTOSIDE GALACTOHYDROLASE; NUCLEOTIDE-SEQUENCE; STRUCTURAL-ANALYSIS; ESCHERICHIA-COLI; FAMILY 4; GENE; PHOSPHOENOLPYRUVATE; METABOLISM; ASSIGNMENT; HYDROLASE AB Phospho-beta-galactosidase (P-beta-gal; EC 3.2.1.85) is induced during growth of Leptotrichia buccalis ATCC 14201 on lactose and lactulose. The enzyme has been purified to electrophoretic homogeneity (M-r similar to 53 kDa, pI similar to 4.8), and kinetic parameters have been determined using the chromogenic analog o-nitrophenyl-beta-D-galactopyranoside-6-phosphate as substrate. Both ATP and galactose-6-phosphate are inhibitors of P-beta-gal activity. Microsequence analysis has identified the first 32 residues from the N-terminus of the protein, and by comparative sequence alignment the enzyme can be assigned to Family 1 of the glycosylhydrolase superfamily. Polyclonal antibody against the enzyme permits the highly specific immuno-detection of P-beta-gal in cell-free extracts of L. buccalis. Although described previously in several Gram-positive species, this is the first reported purification of P-beta-gal from a Gram-negative organism. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NR 30 TC 1 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD SEP 10 PY 2002 VL 214 IS 2 BP 183 EP 188 AR PII S0378-1097(02)00877-7 DI 10.1016/S0378-1097(02)00877-7 PG 6 WC Microbiology SC Microbiology GA 601UV UT WOS:000178467500007 PM 12351228 ER PT J AU Jemal, A Kulldorff, M Devesa, SS Hayes, RB Fraumeni, JF AF Jemal, A Kulldorff, M Devesa, SS Hayes, RB Fraumeni, JF TI A geographic analysis of prostate cancer mortality in the United States, 1970-89 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; cluster analysis; geographic; demography; epidemiology ID TRANSURETHRAL RESECTION; RADICAL PROSTATECTOMY; SOCIOECONOMIC-STATUS; SEXUAL-BEHAVIOR; INCIDENCE RATES; TIME TRENDS; PATTERNS; SELENIUM; FARMERS; COUNTIES AB The recently published atlas of cancer mortality in the United States revealed that prostate cancer mortality rates were elevated among white men in the Northwest, the Rocky Mountain states, the north-central area, New England and the South Atlantic area, and among black men in the South Atlantic area. Here we determine whether the elevated regional rates were statistically different from rates in the rest of the country and whether the pattern can be explained by selected regional characteristics. A spatial scan statistic was applied to county-based mortality data from 1970 through 1989 to identify geographic clusters of the elevated rates for prostate cancer. Five clusters of elevated mortality were detected in white men (p < 0.005) and 3 in black men (p = 0.0001-0.056). For white men, the primary cluster was in the northwestern quadrant, followed by clusters in New England, the eastern part of the north-central area, the mid-Atlantic states and the South Atlantic area, whereas for black men the primary cluster was in the South Atlantic area, followed by clusters in Alabama and the eastern part of the north-central area. Further analyses of these clusters revealed several significant subclusters (p < 0.05). None of the selected demographic and socioeconomic factors, separately or collectively, accounted for the primary clusters in the U.S. white and black populations. The patterns observed could not be attributed to selected demographic or socioeconomic characteristics but should provide leads for further study into the risk factors and the medical or reporting practices that may contribute to geographic variation in mortality from prostate cancer. (C) 2002 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Connecticut, Sch Med, Div Biostat, Farmington, CT USA. RP Jemal, A (reprint author), Amer Canc Soc, 1599 Clifton Rd NE, Atlanta, GA 30329 USA. RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993; Hayes, Richard/0000-0002-0918-661X NR 38 TC 52 Z9 55 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 10 PY 2002 VL 101 IS 2 BP 168 EP 174 DI 10.1002/ijc.10594 PG 7 WC Oncology SC Oncology GA 587CH UT WOS:000177622600009 PM 12209994 ER PT J AU Rao, AB Richert, N Howard, T Lewis, BK Bash, CN McFarland, HF Frank, JA AF Rao, AB Richert, N Howard, T Lewis, BK Bash, CN McFarland, HF Frank, JA TI Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFN beta-1b SO NEUROLOGY LA English DT Article ID REMITTING MULTIPLE-SCLEROSIS; DOSE INTRAVENOUS METHYLPREDNISOLONE; RESONANCE-IMAGING LESIONS; INTERFERON-BETA; WHITE-MATTER; AXONAL LOSS; MRI; ATROPHY; STEROIDS; GUIDELINES AB Objective: To determine the effect of IV methylprednisolone (IVMP) on brain fraction volume (BFV), contrast-enhancing (CE) lesions, and white matter lesion load (WMLL) in patients with relapsing-remitting MS treated for acute exacerbations. Background: MRI metrics of MS disease activity are being used as outcome measures in early phase treatment trials, however the short-term effects of IVMP treatment on cerebral atrophy are unknown, Methods: Serial monthly MRI were performed in 26 patients enrolled in a baseline vs treatment trial with interferon beta-1b (IFNbeta-1b) who were followed for 3 months before and after IVMP. All 26 patients were evaluated while receiving IFNbeta-1b, and 12 patients were also studied during the baseline stage of the trial (NHx). Acute exacerbations were treated with IVMP (1 g/d) for 3 to 5 days. Precontrast and postcontrast T1-weighted and proton density T2-weighted fast spin-echo images were analyzed. Results: Fifty-six acute exacerbations were evaluated. For the 3 months before IVMP, there was no difference in WMLL or BFV compared to month IVMP was administered. There was a significant decrease in BFV at month 1 after IVMP in the IFNbeta-1b and NHx groups. Compared to the month IVMP was administered, there was a difference in the CE lesions for months -3 and -1 prior (p < 0.039) in NHx patients. Following IVMP, CE lesions decreased (p < 0.0004) for months 1, 2, and 3 in both groups, but there was no effect on WMLL, Conclusions: BFV and CE lesions were significantly decreased for 1 month (BFV) and 3 months (CE lesions) following IVMP. Therefore, MRI studies should be delayed by probably at least 2 months following IVMP to avoid a possible confounding steroid effect in a clinical trial. C1 NIH, Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. RP Frank, JA (reprint author), NIH, Ctr Clin, Lab Diagnost Radiol Res, Bldg 10 Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. NR 45 TC 47 Z9 47 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 SEP 10 PY 2002 VL 59 IS 5 BP 688 EP 694 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 591TU UT WOS:000177897000008 PM 12221158 ER PT J AU Metman, LV Morris, MJ Farmer, C Gillespie, M Mosby, K Wuu, J Chase, TN AF Metman, LV Morris, MJ Farmer, C Gillespie, M Mosby, K Wuu, J Chase, TN TI Huntington's disease - A randomized, controlled trial using the NMDA-antagonist amantadine SO NEUROLOGY LA English DT Article; Proceedings Paper CT 53rd Annual Meeting of the American-Academy-of-Neurology CY MAY 05-12, 2001 CL PHILADELPHIA, PENNSYLVANIA SP Amer Acad Neurol ID LEVODOPA-INDUCED DYSKINESIAS; STRIATAL PROJECTION NEURONS; D-ASPARTATE RECEPTORS; MOTOR FLUCTUATIONS; PARKINSONS-DISEASE; REMACEMIDE HYDROCHLORIDE; MUTANT HUNTINGTIN; MOUSE MODEL; CELL-DEATH; DEXTROMETHORPHAN AB Objective: To examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington's disease (HD). Background: Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD. Methods: To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms. Results: Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign. Conclusions: Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit. C1 Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Metman, LV (reprint author), Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, 1725 W Harrison St,Suite 755, Chicago, IL 60612 USA. NR 48 TC 61 Z9 63 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 SEP 10 PY 2002 VL 59 IS 5 BP 694 EP 699 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 591TU UT WOS:000177897000009 PM 12221159 ER PT J AU den Heijer, T Oudkerk, M Launer, LJ van Duijn, CM Hofman, A Breteler, MMB AF den Heijer, T Oudkerk, M Launer, LJ van Duijn, CM Hofman, A Breteler, MMB TI Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes SO NEUROLOGY LA English DT Article ID E EPSILON-4; ALZHEIMERS-DISEASE; DEMENTIA; ALLELE; ROTTERDAM; LOBE AB The epsilon4 allele of the APOE gene increases the risk for AD, whereas the epsilon2 allele may be protective. The authors assessed the impact of APOE genotype on hippocampal, amygdalar, and global brain atrophy as putative markers of preclinical AD in a nondemented population. Carriers Of epsilon4 had significantly more hippocampal and amygdalar atrophy than epsilon3epsilon3 subjects, but not more global brain atrophy. Carriers of epsilon2 did not have less brain atrophy than epsilon3epsilon3 subjects. C1 Erasmus MC, Dept Epidemiol & Biostat, NL-3000 DR Rotterdam, Netherlands. Univ Groningen, Univ Med Ctr Groningen, Acad Hosp Groningen, Dept Radiol, Groningen, Netherlands. NIA, NIH, Bethesda, MD 20892 USA. RP Breteler, MMB (reprint author), Erasmus MC, Dept Epidemiol & Biostat, POB 1738, NL-3000 DR Rotterdam, Netherlands. EM breteler@epib.fgg.eur.nl RI Breteler, Monique /J-5058-2014 FU NIMHD NIH HHS [MD817876] NR 10 TC 120 Z9 121 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 10 PY 2002 VL 59 IS 5 BP 746 EP 748 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 591TU UT WOS:000177897000019 PM 12221169 ER PT J AU Gutmann, DH Rasmussen, SA Wolkenstein, P MacCollin, MM Guha, A Inskip, PD North, KN Poyhonen, M Birch, PH Friedman, JM AF Gutmann, DH Rasmussen, SA Wolkenstein, P MacCollin, MM Guha, A Inskip, PD North, KN Poyhonen, M Birch, PH Friedman, JM TI Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1) SO NEUROLOGY LA English DT Article ID CHILDREN; TUMORS AB Children with neurofibromatosis 1 (NF1) often develop low-grade gliomas, but brain tumors are infrequently encountered in adults with NF1. The authors present evidence from two clinical series, one including patients known to have NF1 and another focusing on adults with new onset brain tumors, that suggests an association between NF1 and symptomatic gliomas in older individuals. They also summarize the clinical data on 17 adolescents or adults with NF1 and symptomatic gliomas. The findings suggest that individuals with NF1 are at increased risk of developing gliomas throughout their lives. C1 Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. Univ Paris 12, Hop Henri Mondor, AP HP, Dept Dermatol, F-94010 Creteil, France. Neurosci Ctr MGH E, Charlestown, MA USA. Univ Toronto, Dept Neurosurg, Toronto, ON, Canada. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Sydney, Dept Paediat & Child Hlth, Sydney, NSW 2006, Australia. Family Federat Finland, Dept Med Genet, Helsinki, Finland. Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada. RP Gutmann, DH (reprint author), Washington Univ, Sch Med, Dept Neurol, Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. RI North, Kathryn/K-6476-2012 OI North, Kathryn/0000-0003-0841-8009 FU NINDS NIH HHS [NS36996] NR 10 TC 61 Z9 61 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 10 PY 2002 VL 59 IS 5 BP 759 EP 761 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 591TU UT WOS:000177897000023 PM 12221173 ER PT J AU Ma, XY Forns, X Gutierrez, R Mushahwar, IK Wu, T Payette, PJ Bukh, J Purcell, RH Davis, HL AF Ma, XY Forns, X Gutierrez, R Mushahwar, IK Wu, T Payette, PJ Bukh, J Purcell, RH Davis, HL TI DNA-based vaccination against hepatitis C virus (HCV): effect of expressing different forms of HCV E2 protein and use of CpG-optimized vectors in mice SO VACCINE LA English DT Article DE DNA vaccine; hepatitis C; HCV E2; antigen localization; CpG motifs ID BLOOD MONONUCLEAR-CELLS; CYTOTOXIC T-LYMPHOCYTE; B SURFACE-ANTIGEN; HUMAN DENDRITIC CELLS; HERPES-SIMPLEX VIRUS; PERIPHERAL-BLOOD; IMMUNE-RESPONSE; PLASMID DNA; MEASLES-VIRUS; MEDIATED IMMUNIZATION AB DNA-based immunization may be of prophylactic and therapeutic value for hepatitis C virus (HCV) infection. In efforts to improve the immunogenicity of a plasmid expressing the second envelope protein (E2) of HCV, we evaluated in mice the role of the antigen localization and demonstrated that membrane-bound and secreted forms induced higher titers of E2-specific antibodies, as well as earlier and higher seroconversion rates, than the intracellular form, but all three forms induced strong CTL. We also investigated whether E2-specific antibody responses could be enhanced by CpG optimization of the plasmid backbone and showed that removal of neutralizing CpG dinucleotides did not have a significant effect but addition of 64 immunostimulatory CpG motifs significantly enhanced anti-E2 titers. These results may have implications for the design and development of HCV DNA vaccines. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Loeb Hlth Res Inst, Ottawa, ON K1Y 4E9, Canada. NIAID, LID, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. Abbott Labs, Virus Discovery Grp, N Chicago, IL 60064 USA. Coley Pharmaceut Grp, Ottawa, ON K1Y 4S1, Canada. RP Davis, HL (reprint author), Loeb Hlth Res Inst, 725 Parkdale Ave, Ottawa, ON K1Y 4E9, Canada. NR 82 TC 31 Z9 34 U1 0 U2 3 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 SEP 10 PY 2002 VL 20 IS 27-28 BP 3263 EP 3271 AR PII S0264-410X(02)00304-3 DI 10.1016/S0264-410X(02)00304-3 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 602CB UT WOS:000178486700005 PM 12213395 ER PT J AU Zhang, MD Emerson, SU Nguyen, H Engle, R Govindarajan, S Blackwelder, WC Gerin, J Purcell, RH AF Zhang, MD Emerson, SU Nguyen, H Engle, R Govindarajan, S Blackwelder, WC Gerin, J Purcell, RH TI Recombinant vaccine against hepatitis E: duration of protective immunity in rhesus macaques SO VACCINE LA English DT Article DE hepatitis E; recombinant vaccine; 56 kDa capsid protein; duration of protection; Macaques ID E VIRUS HEV; INSECT CELLS; FOLLOW-UP; PROTEIN; IDENTIFICATION; ANTIBODIES; CHALLENGE; MONKEYS AB Hepatitis E virus (HEV) is an enterically transmitted virus that causes acute hepatitis. A candidate vaccine containing recombinant HEV capsid protein (56 kDa) expressed in insect cells was shown previously to be highly immunogenic when administered in two doses to rhesus monkeys and to protect them from hepatitis E when challenged with a large intravenous dose of homologous or heterologous HEV. In the present study, the effect of a third dose of the same vaccine lot was evaluated and more importantly, the duration of protection following two doses was determined. Rhesus monkeys vaccinated twice with the 56 kDa capsid protein were challenged with homologous virus 6 or 12 months after the last vaccination: 3 of 4 monkeys challenged 6 or 12 months later, respectively were protected against viral hepatitis. Similarly, all four of the rhesus monkeys given a third dose of vaccine I month prior to challenge were protected against hepatitis. In contrast, all four monkeys given placebo developed hepatitis following challenge. In summary, two doses of HEV vaccine partially protected rhesus monkeys from hepatitis E following intravenous challenge 6 or 12 months after vaccination. Published by Elsevier Science Ltd. C1 NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, Mol Hepatitits Sect, NIH, Bethesda, MD 20892 USA. Univ So Calif, Rancho Los Amigos Hosp, Liver Res & Educ Fdn Inc, Downey, CA 90242 USA. Biol Consulting Grp, Bethesda, MD USA. Georgetown Univ, Dept Microbiol, Div Mol Virol & Immunol, Rockville, MD 20850 USA. RP Purcell, RH (reprint author), NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 16 TC 38 Z9 40 U1 0 U2 3 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 SEP 10 PY 2002 VL 20 IS 27-28 BP 3285 EP 3291 AR PII S0264-410X(02)00314-6 DI 10.1016/S0264-410X(02)00314-6 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 602CB UT WOS:000178486700008 PM 12213398 ER PT J AU Rao, MR Blackwelder, WC Troendle, JF Naficy, AB Clemens, JD AF Rao, MR Blackwelder, WC Troendle, JF Naficy, AB Clemens, JD TI Sample size determination for phase II studies of new vaccines SO VACCINE LA English DT Article DE sample size; vaccine; clinical trials ID CLINICAL-TRIALS; INTERVAL ESTIMATION; NULL HYPOTHESIS; DIFFERENCE; EQUIVALENCE; STATISTICS; CONFIDENCE; FORMULAS AB Prior to the evaluation of protective efficacy, experimental vaccines conventionally undergo phase II randomized controlled clinical trials to evaluate safety and immunogenicity. Typically, an experimental vaccine is compared to another vaccine or to a placebo with respect to adverse events or immune responses, or both. Various strategies and methods are available for design and analysis of such studies. A key aspect of design is the determination of sample size. Often a sample size is chosen that gives a high probability ("power") of finding a statistically significant difference in an outcome of interest, if a difference of a specified size exists. This approach is appropriate when the primary goal of the study is to demonstrate that a difference exists between two groups or treatments. It may not, however, give adequate assurance that a confidence interval around the observed difference will be narrow enough to exclude the possibility of an unacceptably low immune response or unacceptably high adverse event frequency in recipients of the experimental vaccine. In this paper, we apply the "non-inferiority" trial design to phase II vaccine studies; that is, we design the trial to rule out a difference between the vaccine and control in immunogenicity or reactogenicity that is considered unacceptable. We also consider a setting in which the desire is to show that the difference between immune response rates for vaccine and control is greater than a specified value. Published by Elsevier Science Ltd. C1 NICHHD, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Int Vaccine Inst, Seoul, South Korea. RP Rao, MR (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 15 TC 8 Z9 8 U1 1 U2 1 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 SEP 10 PY 2002 VL 20 IS 27-28 BP 3364 EP 3369 AR PII S0264-410X(02)00317-1 DI 10.1016/S0264-410X(02)00317-1 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 602CB UT WOS:000178486700016 PM 12213406 ER PT J AU Yuan, LJ Saif, LJ AF Yuan, LJ Saif, LJ TI Induction of mucosal immune responses and protection against enteric viruses: rotavirus infection of gnotobiotic pigs as a model SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 6th International Veterinary Immunology Symposium CY JUL, 2001 CL SWEDISH UNIV AGR SCI, UPPSALA, SWEDEN SP Int Union Immunol Soc, Vet Immunol Comm HO SWEDISH UNIV AGR SCI DE mucosal vaccines; enteric virus; adjuvants; gnotobiotic pigs; memory cells ID ANTIBODY-SECRETING CELLS; HEAT-LABILE TOXIN; WA HUMAN ROTAVIRUS; MEMORY T-CELLS; ORAL IMMUNIZATION; HOMING RECEPTOR; INTRAMUSCULAR IMMUNIZATION; INTRANASAL IMMUNIZATION; RESPIRATORY CORONAVIRUS; INDEPENDENT PROTECTION AB Enteric viruses are a major cause of diarrhea in animals and humans. Among them, rotaviruses are one of the most important causes of diarrhea in young animals and human infants. A lack of understanding of mechanisms to induce intestinal immunity and the correlates of protective immunity in neonates has impaired development of safe and effective vaccines against enteric viruses, Studies of candidate vaccines using an adult mouse model of subclinical enteric viral infections often do not predict vaccine efficacy against disease evaluated in neonatal large animals. A series of studies have been conducted using a neonatal gnotobiotic pig model of rotavirus infection and diarrhea to identify correlates of protective immunity and to evaluate traditional and novel vaccine approaches for the induction of mucosal immune responses and protection to enteric viruses. Gnotobiotic pigs recovered from infection with virulent Wa human rotavirus (HRV) (mimic natural infection) had high numbers of intestinal IgA rotavirus-specific primary antibody-secreting cells (ASCs) and memory B-cells (to recall antigen) measured by ELISPOT assay, which correlated with complete protection against rotavirus challenge. Most short-term IgA memory B-cells were resident in the ileum, the major site of rotavirus replication. Spleen, not the bone marrow, was the major resident site for longer-term IgG memory B-cells. Candidate rotavirus vaccines evaluated in pigs for their ability to induce intestinal or systemic ASC and protection against rotavirus infection and diarrhea included attenuated live vir-us, inactivated virus, and baculovirus-expressed double-layered rotavirus-like particles (2/6-VLPs). In combination with those candidate vaccines, various adjuvants, delivery systems, and immunization routes were tested, including incomplete Freund's adjuvant for i.m. immunization, and a mutant Escherichia coli heat labile enterotoxin R192G (mLT) for i.n. immunization. It was shown that orally administered replicating vaccines were most effective for priming for intestinal IgA ASC and memory B-cell responses, but i.n. administered non-replicating 2/6-VLPs plus mLT were effective as booster vaccines. We conclude that protective immunity depends on the magnitude, location, viral protein-specificity, and isotype of the antibody responses induced by vaccination. Therefore highly effective enteric viral vaccines should: (i) induce sufficient levels of intestinal IgA antibodies; (ii) include viral antigens that induce neutralizing antibodies; and (iii) require the use of effective mucosal adjuvants or antigen delivery systems for non-replicating oral or i.n. vaccines. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Ohio Agr Res & Dev Ctr, Dept Vet Prevent Med, Food Anim Hlth Res Program, Wooster, OH 44691 USA. RP Yuan, LJ (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Yuan, Lijuan/A-2468-2008 OI Yuan, Lijuan/0000-0003-0709-5228 NR 75 TC 63 Z9 69 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD SEP 10 PY 2002 VL 87 IS 3-4 SI SI BP 147 EP 160 AR PII S0165-2427(02)00046-6 DI 10.1016/S0165-2427(02)00046-6 PG 14 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 568JH UT WOS:000176538300006 PM 12072229 ER PT J AU van Hattum, AH Hoogsteen, IJ Schluper, HMM Maliepaard, M Scheffer, GL Scheper, RJ Kohlhagen, G Pommier, Y Pinedo, HM Boven, E AF van Hattum, AH Hoogsteen, IJ Schluper, HMM Maliepaard, M Scheffer, GL Scheper, RJ Kohlhagen, G Pommier, Y Pinedo, HM Boven, E TI Induction of breast cancer resistance protein by the camptothecin derivative DX-895 1f is associated with minor reduction of antitumour activity SO BRITISH JOURNAL OF CANCER LA English DT Article DE DX-895 1f; BCRP; camptothecins; multidrug resistance; GF1209I8; ovarian cancer xenografts ID MULTIDRUG-RESISTANCE; CELL-LINE; IN-VITRO; MITOXANTRONE-RESISTANT; HALF-TRANSPORTER; CROSS-RESISTANCE; NUDE-MICE; TOPOTECAN; EXPRESSION; GF120918 AB DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRPI, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951 f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-II was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-II/SN-38. (C) 2002 Cancer Research UK. C1 Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. Netherlands Canc Inst, Div Expt Therapy, NL-1066 CX Amsterdam, Netherlands. Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Boven, E (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. NR 30 TC 17 Z9 17 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 SEP 9 PY 2002 VL 87 IS 6 BP 665 EP 672 DI 10.1038/sj.bjc.6600508 PG 8 WC Oncology SC Oncology GA 597LG UT WOS:000178222600013 PM 12237778 ER PT J AU O'Connell, KF AF O'Connell, KF TI The ZYG-1 kinase, a mitotic and meiotic regulator of centriole replication SO ONCOGENE LA English DT Review DE centrosome duplication; centriole; ZYG-1; C. elegans; mitosis; meiosis ID CAENORHABDITIS-ELEGANS EMBRYOS; XENOPUS EGG EXTRACTS; HAMSTER OVARY CELLS; CENTROSOME DUPLICATION; PROTEIN-KINASE; GAMMA-TUBULIN; C-ELEGANS; REPRODUCTIVE CAPACITY; BODY DUPLICATION; SPINDLE POLES C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP O'Connell, KF (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 2A07, Bethesda, MD 20892 USA. NR 53 TC 10 Z9 10 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 SEP 9 PY 2002 VL 21 IS 40 BP 6201 EP 6208 DI 10.1038/sj.onc.1205776 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 590TZ UT WOS:000177840500009 PM 12214250 ER PT J AU Deng, CX AF Deng, CX TI Roles of BRCA1 in centrosome duplication SO ONCOGENE LA English DT Review DE BRCA1; GADD45; p53; centrosome amplification ID GENETIC INSTABILITY; CELL-CYCLE; TRANSCRIPTIONAL ACTIVATION; BREAST-CANCER; ESTROGEN-RECEPTOR; DNA-DAMAGE; P53; MICE; PHOSPHORYLATION; TUMORIGENESIS AB Centrosome duplication is under precise control and occurs only once in a normal mammalian cell cycle. Disruption of this process causes centrosome amplification, unequal segregation of chromosomes and, ultimately, tumorigenesis. Recent studies indicate that breast cancer suppressor gene 1 (BRCA1) plays an important role in regulating centrosome duplication. BRCA1 is located in the centrosome and binds to gamma-tubulin. It interacts with a variety of proteins that regulate centrosome duplication, including BRCA2, CDK2 - Cyclin A, CDK2 - Cyclin E, Gadd45, p21, p53 and Rb. Furthermore, targeted disruption of murine BRCA1 results in centrosome amplification, suggesting that BRCA1 serves as a negative regulator for centrosome duplication. This review will examine these data and discuss possible relationships between BRCA1 and its interacting proteins in centrosome duplication. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 62 TC 79 Z9 81 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 9 PY 2002 VL 21 IS 40 BP 6222 EP 6227 DI 10.1038/sj.onc.1205713 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 590TZ UT WOS:000177840500011 PM 12214252 ER PT J AU Hollander, MC Fornace, AJ AF Hollander, MC Fornace, AJ TI Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a SO ONCOGENE LA English DT Review DE Gadd45a; centrosome amplification; p53(-/-) ID DOUBLE-STRAND BREAKS; DNA-DAMAGING AGENTS; C-MYC GENE; ATAXIA-TELANGIECTASIA; SACCHAROMYCES-CEREVISIAE; ANAPHASE INHIBITOR; KINASE-ACTIVITY; DEFICIENT MICE; PROTEIN-KINASE; S-PHASE AB Genomic instability has been a recognized feature of many human tumors for decades. Until recently, however, there was little insight into potential mechanisms for this phenomenon. Recent work has shown first, that increased centrosome numbers (also referred to as centrosome amplification) often accompany genomic instability and second, that when centrosome numbers are increased, cells become genetically unstable. Deletion of Gadd45a leads to centrosome amplification and consequent abnormal mitosis and aneuploidy. Gadd45a is known to be involved in a G2 checkpoint and may be involved in the normal progression from G2 to M and its coordination with S phase events. Whether these functions contribute to prevention of centrosome amplification is being investigated. However, potential mechanisms can be proposed based on known protein associations with Gadd45a, as well as proteins that regulate Gadd45a transcription and are also required for efficient coordination of centrosome duplication and DNA synthesis. C1 NCI, Gene Response Sect, CCR, NIH, Bethesda, MD 20892 USA. RP Hollander, MC (reprint author), NCI, Gene Response Sect, CCR, NIH, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 67 TC 79 Z9 87 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 9 PY 2002 VL 21 IS 40 BP 6228 EP 6233 DI 10.1038/sj.onc.1205774 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 590TZ UT WOS:000177840500012 PM 12214253 ER PT J AU Zhou, WB Lin, Y Wersto, R Chrest, J Gabrielson, E AF Zhou, WB Lin, Y Wersto, R Chrest, J Gabrielson, E TI Staurosporine-induced G(1) arrest in cancer cells depends on an intact pRB but is independent of p16 status SO CANCER LETTERS LA English DT Article DE staurosporine; pRB protein; p16 ID HUMAN-BREAST-CARCINOMA; 7-HYDROXYSTAUROSPORINE UCN-01; INDUCED CYTOTOXICITY; RETINOBLASTOMA GENE; EPITHELIAL-CELLS; PROTEIN-KINASES; TUMOR-CELLS; G1 ARREST; INHIBITOR; ABROGATION AB Staurosporine and its derivative 7-hydroxystaurosporine are protein kinase inhibitors that are being considered for treatments of cancers. Several recent studies have shown that cells with defective pRB protein are resistant to the G, cell cycle-inhibiting effects of staurosporine compounds. In this study, we examined the effect of staurosporine on two breast cancer-derived and three lung cancer-derived cell lines characterized by deficiencies in the p16 tumor suppressor. All of these p16-deficient cell lines are highly sensitive to staurosporine-induced inhibition of pRB phosphorylation and induction of arrest in G(1). This response is similar to that seen in cultured normal human bronchial epithelial cells and normal mammary epithelial cells, but strikingly different than the staurosporine resistance seen in cancer cells with detective pRB. Interestingly, inhibition of pRB phosphorylation could be seen within 4 h of treatment, suggesting that this inhibition is a consequence of direct effects of staurosporine on protein kinase(s) rather than a result of induction of other cyclin-dependent kinase inhibitors. Our findings suggest that different types of cancer cells have vastly different responses to the staurosporine class of agents, and that evaluation of pRB and p16 will help predict the response of the cancer cells to these agents. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Dept Pathol, Baltimore, MD 21231 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Gabrielson, E (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Dept Pathol, 418 Bond St, Baltimore, MD 21231 USA. NR 26 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 8 PY 2002 VL 183 IS 1 BP 103 EP 107 AR PII S0304-3835(02)00101-5 DI 10.1016/S0304-3835(02)00101-5 PG 5 WC Oncology SC Oncology GA 577GQ UT WOS:000177053500013 PM 12049820 ER PT J AU Jackson, T Thomas, J Green, ED Noben-Trauth, K AF Jackson, T Thomas, J Green, ED Noben-Trauth, K TI Genetic and physical maps of jerker (Espn(je)) on mouse chromosome 4 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE deafness; jerker; Espin (Espn) ID INNER-EAR DEGENERATION; MOUSE; MUTAGENESIS; MUTATION; LINKAGE; GENOME AB The jerker mutation causes degeneration of cochlea and vestibular sensory hair cells in mice. A frame-shift mutation in the actin bundling gene Espin (Espn) leads to hair bundle defects by disrupting the actin filament assembly in stereocilia. Previously, jerker was mapped to distal mouse chromosome 4. Here, analyzing 2536 informative meioses derived from two intersubspecific intercrosses, we localize jerker to a 0.51+/-0.14 cM interval on chromosome 4. The following order and distances of genes and markers were determined: D4Mit180-0.44+/-0.13 cM-Hes2, Espn(je)-0.08+/-0.06 cM-D4Mit356-0.28+/-0.1 cM-D4Mit208. A 300kb physical bacterial artificial chromosome (BAC) contig was generated containing the Espn(je) locus. The human homologous region maps to 1p36.31. We present a detailed high-resolution genetic and physical map of markers located at distal chromosome 4 and demonstrate concordance of Espn with jerker. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD USA. RP Noben-Trauth, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. EM nobentk@nidcd.nih.gov FU NIDCD NIH HHS [DC00056-01] NR 17 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 6 PY 2002 VL 296 IS 5 BP 1143 EP 1147 AR PII S0006-291X(02)02023-5 DI 10.1016/S0006-291X(02)02023-5 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 593JK UT WOS:000177987600018 PM 12207892 ER PT J AU Stephen, AG Worthy, KM Towler, E Mikovits, JA Sei, S Roberts, P Yang, QE Akee, RK Klausmeyer, P McCloud, TG Henderson, L Rein, A Covell, DG Currens, M Shoemaker, RH Fisher, RJ AF Stephen, AG Worthy, KM Towler, E Mikovits, JA Sei, S Roberts, P Yang, QE Akee, RK Klausmeyer, P McCloud, TG Henderson, L Rein, A Covell, DG Currens, M Shoemaker, RH Fisher, RJ TI Identification of HIV-1 nucleocapsid protein: nucleic acid antagonists with cellular anti-HIV activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE nucleocapsid protein; HIV-1; stoichiometric inhibitor; xanthenyl ring; surface plasmon resonance spectroscopy ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMER BINDING-SITE; ZINC FINGERS; GENOMIC RNA; ANTIVIRAL ACTIVITY; CHAPERONE ACTIVITY; INHIBITOR BINDING; IN-VITRO; NCP7; FLUORESCEIN AB The crucial functions of HIV-1 nucleocapsid-p7 protein (NC-p7) at different stages of HIV replication are dependent on its nucleic acid binding properties. In this study, a search has been made to identify antagonists of the interaction between NC-p7 and d(TG)(4). A chemical library of similar to2000 small molecules (the NCI Diversity Set) was screened, of the 26 active inhibitors that were identified, five contained a xanthenyl ring structure. Further analysis of 63 structurally related compounds led to the identification of 2,3,4,5-tetrachloro-6-(4',5',6'-trihydroxy-3'-oxo-3H-xanthen-9'-yl)benzoic acid, which binds to NC-p7 stoichiometrically. This compound exerted a significant anti-HIV activity in vitro with an IC50 of 16.6 +/- 4.3 muM (means +/- SD). Synthetic variants lacking the two hydroxyls at positions 4' and 5' in the xanthenyl ring system failed to bind NC-p7 and showed significantly less protection against HIV infection. Molecular modeling predicts that these hydroxyl groups would bind to the amide nitrogen of Gly(35) with other contacts at the carbonyl oxygens of Gly(40) and Lys(33). (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI Frederick, Lab Antiviral Drug Mech, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI Frederick, Nat Prod Support Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI Frederick, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI Frederick, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Fisher, RJ (reprint author), NCI Frederick, Prot Chem Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. RI Fisher, Robert/B-1431-2009 FU NCI NIH HHS [N01-CO12400] NR 41 TC 34 Z9 36 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 6 PY 2002 VL 296 IS 5 BP 1228 EP 1237 AR PII S0006-291X(02)02063-6 DI 10.1016/S0006-291X(02)02063-6 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 593JK UT WOS:000177987600031 PM 12207905 ER PT J AU Pitcher, WH Huestis, WH AF Pitcher, WH Huestis, WH TI Preparation and analysis of small unilamellar phospholipid vesicles of a uniform size SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE lipid vesicles; hemoglobin; dynamic light scattering ID INTEGRAL-EQUATIONS; HEMOGLOBIN BINDING; DIFFUSION; MEMBRANE; SALT AB The interaction of carbonmonoxyhemoglobin and heme with small unilamellar phospholipid vesicles was studied using dynamic light scattering. Addition of carbonmonoxyhemoglobin to dimyristoylphosphatidylcholine:dimyristoylphosphatidylserine small unilamellar vesicles resulted in an increase of average vesicle size from 17.4 to 32.0 nm. Addition of heme to vesicles produced a smaller size increase, from 17.4 to 21.0 nm. Also reported is a method for preparing small unilamellar lipid vesicles of a uniform size, suitable for use in NMR spectroscopy. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Stanford Univ, Dept Chem, Stanford, CA 94305 USA. RP Pitcher, WH (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, MR-03,Box 12233, Res Triangle Pk, NC 27709 USA. NR 28 TC 11 Z9 11 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 6 PY 2002 VL 296 IS 5 BP 1352 EP 1355 AR PII S0006-291X(02)02092-2 DI 10.1016/S0006-291X(02)02092-2 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 593JK UT WOS:000177987600050 PM 12207924 ER PT J AU Esaki, T Itoh, Y Shimoji, K Cook, M Jehle, J Sokoloff, L AF Esaki, T Itoh, Y Shimoji, K Cook, M Jehle, J Sokoloff, L TI Blockade of K-ATP channels with glibenclamide does not alter functional activation of cerebral blood flow in the unanesthetized rat SO BRAIN RESEARCH LA English DT Article DE ATP-sensitive K(_)(+)channel; whisker-to-barrel cortex pathway; functional brain mapping ID SENSITIVE POTASSIUM CHANNELS; SMOOTH-MUSCLE; CORONARY VASODILATION; BASILAR ARTERY; TONE; AUTORADIOGRAPHY; STIMULATION; CROMAKALIM; RABBIT; BRAIN AB Possible involvement of ATP-sensitive K-divided by (K-ATP) channels in the cerebral blood flow (CBF) response to neuronal functional activation was investigated in unanesthetized rats. Glibenclamide (1, 2, or 10 mumol/1), a specific inhibitor of KIT, channels, was infused intracisternally continuously for 30 min prior to and during the 1-min period of measurement of CBF. Unilateral functional activation was maintained throughout the measurement of CBF by continuous stroking of the vibrissae on the left side of the face. Local CBF was determined bilaterally by the quantitative autoradiographic [C-14] iodoantipyrine method in four structures of the whisker-to-barrel cortex pathway and in 18 structures unrelated to the pathway. Glibenclamide tended to lower baseline CBF in almost all regions examined, statistically significantly (P<0.05) in the cerebellar lobules with all doses, in the cerebellar cortex with 10 mumol/1, in the Pontine nuclei with 2 and 10 mumol/1, and in the spinal trigeminal nucleus of the unstimulated side with all doses. Vibrissal stimulation increased CBF unilaterally in all the stations of the pathway, but the percent increases were not statistically significantly affected by the glibenclamide treatment, except in the spinal trigeminal nucleus where it was reduced statistically significantly (P<0.05) only by 2 μmol/1 glibenclamide. These results indicate that K-ATP channels may play a role in the tonic regulation of baseline CBF in some regions but provide no support for their role in the increases in CBF evoked by functional activation. Published by Elsevier Science B.V. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36,Rm 1A07,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 32 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 6 PY 2002 VL 948 IS 1-2 BP 56 EP 63 AR PII S0006-8993(02)02948-7 DI 10.1016/S0006-8993(02)02948-7 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 599BV UT WOS:000178315000007 PM 12383955 ER PT J AU Waheed, AA Jones, TLZ AF Waheed, AA Jones, TLZ TI Hsp90 interactions and acylation target the G protein G alpha(12) but not G alpha(13) to lipid rafts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRESS FIBER FORMATION; HETEROTRIMERIC G-PROTEINS; THROMBIN RECEPTOR; TRANSFORMING ACTIVITY; MEDIATES ACTIVATION; SIGNAL-TRANSDUCTION; MEMBRANE RAFTS; P115 RHOGEF; IN-VIVO; PALMITOYLATION AB The heterotrimeric G proteins, G(12) and G(13), are closely related in their sequences, signaling partners, and cellular effects such as oncogenic transformation and cytoskeletal reorganization. Yet G(12) and G(13) can act through different pathways, bind different proteins, and show opposing actions on some effectors. We investigated the compartmentalization of G(12) and G(13) at the membrane because other G proteins reside in lipid rafts, membrane microdomains enriched in cholesterol and sphingolipids. Lipid rafts were isolated after cold, nonionic detergent extraction of cells and gradient centrifugation. Galpha(12) was in the lipid raft fractions, whereas Galpha(13) was not associated with lipid rafts. Mutation of Cys-11 on Galpha(12), which prevents its palmitoylation, partially shifted Galpha(12) from the lipid rafts. Geldanamycin treatment, which specifically inhibits Hsp90, caused a partial loss of wild-type Galpha(12) and a complete loss of the Cys-11 mutant from the lipid rafts and the appearance of a higher molecular weight form of Galpha(12) in the soluble fractions. These results indicate that acylation and Hsp90 interactions localized Galpha(12) to lipid rafts. Hsp90 may act as both a scaffold and chaperone to maintain a functional Galpha(12) only in discrete membrane domains and thereby explain some of the nonoverlapping functions of G(12) and G(13) and control of these potent cell regulators. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jones, TLZ (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Rm 9C101, Bethesda, MD 20892 USA. NR 41 TC 63 Z9 63 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 SEP 6 PY 2002 VL 277 IS 36 BP 32409 EP 32412 DI 10.1074/jbc.C200383200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000002 PM 12117999 ER PT J AU Kim, HT Kim, BC Kim, IY Mamura, M Seong, DH Jang, JJ Kim, SJ AF Kim, HT Kim, BC Kim, IY Mamura, M Seong, DH Jang, JJ Kim, SJ TI Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BCL-X-L; RECEPTOR-BETA; ER-BETA; BH3 DOMAIN; POSTMENOPAUSAL WOMEN; EPITHELIAL-CELLS; SURVIVAL SIGNALS; CYTOCHROME-C; DEATH; PHOSPHORYLATION AB Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor P. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X-L following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Rm C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. RI Jang, JaJune/F-6647-2011; OI Mamura, Mizuko/0000-0003-4531-0144 NR 41 TC 41 Z9 42 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 SEP 6 PY 2002 VL 277 IS 36 BP 32510 EP 32515 DI 10.1074/jbc.M202852200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000017 PM 12084714 ER PT J AU Hu, QH Yu, ZX Ferrans, VJ Takeda, K Irani, K Ziegelstein, RC AF Hu, QH Yu, ZX Ferrans, VJ Takeda, K Irani, K Ziegelstein, RC TI Critical role of NADPH oxidase-derived reactive oxygen species in generating Ca2+ oscillations in human aortic endothelial cells stimulated by histamine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUPEROXIDE ANION RELEASE; INOSITOL 1,4,5-TRISPHOSPHATE; PERMEABILIZED HEPATOCYTES; CALCIUM OSCILLATIONS; SIGNAL-TRANSDUCTION; HYDROGEN-PEROXIDE; HYPERPOLARIZING FACTOR; OXIDIZED GLUTATHIONE; INTRACELLULAR CA2+; OXIDATIVE STRESS AB There is increasing evidence that intracellular reactive oxygen species (ROS) play a role in cell signaling and that the NADPH oxidase is a major source of ROS in endothelial cells. At low concentrations, agonist stimulation of membrane receptors generates intracellular ROS and repetitive oscillations of intracellular Ca2+ concentration ([Ca2+](i)) in human endothelial cells. The present study was performed to examine whether ROS are important in the generation or maintenance of [Ca2+](i) oscillations in human aortic endothelial cells (HAEC) stimulated by histamine. Histamine (1 mum) increased the fluorescence of 2',7'-dihydrodichlorofluorescin diacetate in HAEC, an indicator of ROS production. This was partially inhibited by the NADPH oxidase inhibitor diphenyleneiodonium (DPI, 10 pm), by the farnesyltransferase inhibitor H-Ampamb-Phe-Met-OH (2 mum), and in HAEC transiently expressing Rac1(N17), a dominant negative allele of the protein Rac1, which is essential for NADPH oxidase activity. In indo 1-loaded HAEC, 1 mum histamine triggered [Ca2+](i) oscillations that were blocked by DPI or H-Ampamb-Phe-Met-OH. Histamine-stimulated [Ca2+](i) oscillations were not observed in HAEC lacking functional Rac1 protein but were observed when transfected cells were simultaneously exposed to a low concentration of hydrogen peroxide (10 muM), which by itself did not alter either [Ca2+](i) or levels of inositol 1,4,5-trisphosphate (Ins-1,4,5-P-3). Thus, histamine generates ROS in HAEC at least partially via NADPH oxidase activation. NADPH oxidase-derived ROS are critical to the generation of [Ca2+](i) oscillations in HAEC during histamine stimulation, perhaps by increasing the sensitivity of the endoplasmic reticulum to Ins-1,4,5-P-3. C1 Johns Hopkins Univ, Dept Med, Div Cardiol, Johns Hopkins Bayview Med Ctr,Sch Med, Baltimore, MD 21224 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Hu, QH (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Johns Hopkins Bayview Med Ctr,Sch Med, 5501 Hopkins Bayview Circle 1A32, Baltimore, MD 21224 USA. OI Irani, Kaikobad/0000-0001-9194-7387 FU NHLBI NIH HHS [R01 HL63720] NR 57 TC 61 Z9 63 U1 0 U2 5 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 SEP 6 PY 2002 VL 277 IS 36 BP 32546 EP 32551 DI 10.1074/jbc.M201550200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000021 PM 12093794 ER PT J AU Hidaka, K Caffrey, JJ Hua, L Zhang, T Falck, JR Nickel, GC Carrel, L Barnes, LD Shears, SB AF Hidaka, K Caffrey, JJ Hua, L Zhang, T Falck, JR Nickel, GC Carrel, L Barnes, LD Shears, SB TI An adjacent pair of human NUDT genes on chromosome X are preferentially expressed in testis and encode two new isoforms of diphosphoinositol polyphosphate phosphohydrolase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INOSITOL HEXAKISPHOSPHATE KINASE; DIADENOSINE POLYPHOSPHATES; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; SCHIZOSACCHAROMYCES-POMBE; FAMILY; HYDROLASES; ENZYME; CELLS; PENTAKISPHOSPHATE AB Combinatorial expression of the various isoforms of diphosphoinositol synthases and phosphohydrolases determines the rates of phosphorylation/dephosphorylation cycles that have been functionally linked to vesicle trafficking, stress responses, DNA repair, and apoptosis. We now describe two new 19-kDa diphosphoinositol polyphosphate phosphohydrolases (DIPPs), named types 3alpha and 3beta, which possess the canonical Nudix-type catalytic motif flanked on either side by short Gly-rich sequences. The two enzymes differ only in that Pro-89 in the a form is replaced by Arg-89 in the 13 form, making the latter similar to2-fold more active in vitro. Another Nudix substrate, diadenosine hexaphosphate, was hydrolyzed less efficiently (k(cat)/K-m = 0.2 x 10(5) M-1 s(-1)) compared with diphosphoinositol polyphosphates (k(cat)/K-m = 2-40 x 10(5) M-1 s(-1)). Catalytic activity in vivo was established by individual overexpression of the human (h) DIPP3 isoforms in HEK293 cells, which reduced cellular levels of diphosphoinositol polyphosphates by 40-50%. The hDIPP3 mRNA is preferentially expressed in testis, accompanied by relatively weak expression in the brain, contrasting with hDIPP1 and hDIPP2 which are widely expressed. The hDIPP3 genes (NUDT10 encodes hDIPP3alpha; NUDT11 encodes hDIPP3beta) are only 152 kbp apart at p11.22 on chromosome X and probably arose by duplication. Transcription of both genes is inactivated on one of the X chromosomes of human females to maintain appropriate gene dosage. The hDIPP3 pair add tissue-specific diversity to the molecular mechanisms regulating diphosphoinositol polyphosphate turnover. C1 NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Falck, John/0000-0002-9219-7845 NR 38 TC 28 Z9 31 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 SEP 6 PY 2002 VL 277 IS 36 BP 32730 EP 32738 DI 10.1074/jbc.M205476200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000044 PM 12105228 ER PT J AU Lou, LG Urbani, J Ribeiro-Neto, F Altschuler, DL AF Lou, LG Urbani, J Ribeiro-Neto, F Altschuler, DL TI cAMP inhibition of Akt is mediated by activated and phosphorylated Rap1b SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; PLECKSTRIN HOMOLOGY DOMAIN; GLYCOGEN-SYNTHASE KINASE-3; CYCLIC-AMP; CELL-PROLIFERATION; PHOSPHOINOSITIDE-3-OH KINASE; SIGNAL-TRANSDUCTION; MITOGENIC PATHWAY; THYROID-CELLS; INSULIN AB Rap1b has been implicated in the transduction of the cAMP mitogenic signal. Rap1b is phosphorylated and activated by cAMP, and its expression in cells where cAMP is mitogenic leads to an increase in G(1)/S phase entry and tumor formation. The PCCL3 thyroid follicular cells represent a differentiated and physiologically relevant system that requires thyrotropin (TSH), acting via cAMP, for a full mitogenic response. In this model system, cAMP stimulation of DNA synthesis requires activation and phosphorylation of Rap1b by the cAMP-dependent protein kinase A (PKA). This scenario presents the challenge of identifying biochemical processes involved in the phosphorylation-dependent Rap1b mitogenic action. In thyroid cells, Akt has been implicated in the stimulation of cell proliferation by TSH and cAMP. However, the mechanism(s) by which cAMP regulates Akt activity remains unclear. In this study we show that in PCCL3 cells 1) TSH inhibits Akt activity via cAMP and PKA; 2) Rap1b is required for cAMP inhibition of Akt; and 3) transduction of the cAMP signal into Akt requires activation as well as phosphorylation of Rap1b by PKA. C1 Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Altschuler, DL (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. FU NCI NIH HHS [R29 CA71649] NR 62 TC 51 Z9 52 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 SEP 6 PY 2002 VL 277 IS 36 BP 32799 EP 32806 DI 10.1074/jbc.M201491200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000053 PM 12089143 ER PT J AU Ghosh, A Shieh, JJ Pan, CJ Sun, MS Chou, JY AF Ghosh, A Shieh, JJ Pan, CJ Sun, MS Chou, JY TI The catalytic center of glucose-6-phosphatase - HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DISEASE TYPE IA; ACTIVE-SITE; CURVULARIA-INAEQUALIS; MESSENGER-RNA; GENE; IDENTIFICATION; PHOSPHATASE; MUTATIONS; CHLOROPEROXIDASE; EXPRESSION AB Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum. by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170) and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. It was predicted that His(176) would be the amino acid that acts as a nucleophile forming a phosphohistidine-enzyme intermediate, and His(119) would be the amino acid that provides the proton needed to liberate the glucose moiety. However, the phosphate acceptor in G6Pase has eluded molecular characterization. To identify the His residue that covalently bound the phosphate moiety, we generated recombinant adenoviruses carrying G6Pase wild type and active site mutants. A 40-kDa [P-32]phosphate-G6Pase intermediate was identified after incubating [P-32]glucose 6-phosphate with microsomes expressing wild type but not with microsomes expressing either H119A or H176A mutant G6Pase. Human G6Pase contains five methionine residues at positions 1, 5, 121, 130, and 279. After cyanogen bromide cleavage, His' 19 is predicted to be within a 116-amino acid peptide of 13.5 kDa with an isoelectric point of 5.3 (residues 6-121), and His 176 is predicted to be within a 149-amino acid peptide of 16.8 kDa with an isoelectric point of 9.3 (residues 131-279). We show that after digestion of a non-glycosylated [P-32] phosphate-G6Pase intermediate by cyanogen bromide, the [P-32]phosphate remains bound to a peptide of 17 kDa with an isoelectric point above 9, demonstrating that His(176) is the phosphate acceptor in G6Pase. C1 NICHD, Heritable Disorders Branch, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHD, Heritable Disorders Branch, Sect Cellular Differentiat, NIH, Bldg 10,Rm 9S241, Bethesda, MD 20892 USA. NR 32 TC 46 Z9 49 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 6 PY 2002 VL 277 IS 36 BP 32837 EP 32842 DI 10.1074/jbc.M201853200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000058 PM 12093795 ER PT J AU Brown, LJ Koza, RA Everett, C Reitman, ML Marshall, L Fahien, LA Kozak, LP MacDonald, MJ AF Brown, LJ Koza, RA Everett, C Reitman, ML Marshall, L Fahien, LA Kozak, LP MacDonald, MJ TI Normal thyroid thermogenesis but reduced viability and adiposity in mice lacking the mitochondrial glycerol phosphate dehydrogenase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCEROL-3-PHOSPHATE DEHYDROGENASE; SN-GLYCEROL-3-PHOSPHATE DEHYDROGENASE; 3-PHOSPHATE DEHYDROGENASE; LACTATE-DEHYDROGENASE; PANCREATIC-ISLETS; METABOLISM; MILK; EXPRESSION; GLUCOSE; NADH AB The mitochondrial glycerol phosphate dehydrogenase (mGPD) is important for metabolism of glycerol phosphate for gluconeogenesis or energy production and has been implicated in thermogenesis induced by cold and thyroid hormone treatment. mGPD in combination with the cytosolic glycerol phosphate dehydrogenase (cGPD) is proposed to form the glycerol phosphate shuttle, catalyzing the interconversion of dihydroxyacetone phosphate and glycerol phosphate with net oxidation of cytosolic NADH. We made a targeted deletion in Gdm1 and produced mice lacking mGPD. On a C57BL/6J background these mice showed a 50% reduction in viability compared with wild-type littermates. Uncoupling protein-1 mRNA levels in brown adipose tissue did not differ between mGPD knockout and control pups, suggesting normal thermogenesis. Pups lacking mGPD had decreased liver ATP and slightly increased liver glycerol phosphate. In contrast, liver and muscle metabolites were normal in adult animals. Adult mGPD knockout animals had a normal cold tolerance, normal circadian rhythm in body temperature, and demonstrated a normal temperature increase in response to thyroid hormone. However, they were found to have a lower body mass index, a 40% reduction in the weight of white adipose tissue, and a slightly lower fasting blood glucose than controls. The phenotype may be secondary to consequences of the obligatory production of cytosolic NADH from glycerol metabolism in the mGPD knockout animal. We conclude that, although mGPD is not essential for thyroid thermogenesis, variations in its function affect viability and adiposity in mice. C1 Univ Wisconsin, Dept Pediat, Madison, WI 53706 USA. Univ Wisconsin, Dept Pharmacol, Madison, WI 53706 USA. Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Brown, LJ (reprint author), Univ Wisconsin, Dept Pediat, 3550 MSC,1300 Univ Ave, Madison, WI 53706 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU NICHD NIH HHS [HD008431]; NIDDK NIH HHS [DK 28348] NR 41 TC 42 Z9 42 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 6 PY 2002 VL 277 IS 36 BP 32892 EP 32898 DI 10.1074/jbc.M202408200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000066 PM 12093799 ER PT J AU Lacana, E Maceyka, M Milstein, S Spiegel, S AF Lacana, E Maceyka, M Milstein, S Spiegel, S TI Cloning and characterization of a protein kinase A anchoring protein (AKAP)-related protein that interacts with and regulates sphingosine kinase 1 activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRAMMED CELL-DEATH; GROWTH-FACTOR; INTRACELLULAR SPHINGOSINE-1-PHOSPHATE; FUNCTIONAL-CHARACTERIZATION; MOLECULAR-CLONING; 2ND MESSENGER; RECEPTOR; ACTIVATION; APOPTOSIS; 1-PHOSPHATE AB Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has novel dual actions. S1P is the ligand for a family of G protein-coupled receptors known as S1PRs that mediate various physiological functions. Growth factors rapidly activate sphingosine kinase type 1 (SPHK1) resulting in phosphorylation of sphingosine to form S1P, which plays important roles in cell growth regulation and protection from apoptosis. However, little is known of the mechanism(s) by which SPHK activity is regulated. Using a yeast two-hybrid screening approach, we cloned a 3-kb cDNA encoding a SPHK1-interacting protein (SKIP). BLAST analysis revealed that SKIP corresponded to the C-terminal region of a larger (similar to7 kb) cDNA that encoded a protein with a high degree of similarity to a family of protein kinase A anchor proteins (AKAP). In confirmation of the yeast two-hybrid assay, glutathione S-transferase (GST)-SPHK1 specifically pulled down SKIP, whereas GST did not. Moreover, immunoprecipitation of in vitro translated SPHK1 and SKIP revealed that SKIP and SPHK1 are tightly associated. Furthermore, SKIP overexpression in NIH 3T3 fibroblasts reduced SPHK1 activity and interfered with its biological functions. The apoptotic-sparing effect of SPHK1 against serum deprivation was reduced when co-transfected with SKIP. In addition, SPHK1-enhanced cell proliferation was also abolished by SKIP, with a corresponding decrease in activation of ERK. Taken together, these results indicate that SKIP is a novel protein likely to play a regulatory role in the modulation of SPHK1 activity. C1 Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. Georgetown Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Med Coll Virginia Campus, Richmond, VA 23298 USA. RI Maceyka, Michael/B-9277-2008 FU NCI NIH HHS [R01 CA61774] NR 59 TC 50 Z9 52 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 SEP 6 PY 2002 VL 277 IS 36 BP 32947 EP 32953 DI 10.1074/jbc.M202841200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000073 PM 12080051 ER PT J AU Geanacopoulos, M Adhya, S AF Geanacopoulos, M Adhya, S TI Genetic analysis of GalR tetramerization in DNA looping during repressosome assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; MUTAGENESIS; REPRESSION; HU AB The Gal repressosome is a nucleoprotein complex consisting of 2 GalR dimers, 1 HU, and 1 DNA loop, which represses the transcription of the gal operon. We have adopted a structure-based genetic approach to complement ongoing physical studies of the complex. Homology-based and subsequent alanine-scanning mutageneses suggest that five residues in the DNA-distal subdomain of GalR dimer are important for repressosome formation. A further analysis of these and intragenic suppressors of looping-defective GalR mutants as well as gain-of-function mutants that permit repressosome assembly in the absence of HU show that GalR dimers contact each other in the repressosome in a partially stacked configuration. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,MSC 4264,Rm 5138, Bethesda, MD 20892 USA. NR 15 TC 17 Z9 17 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 SEP 6 PY 2002 VL 277 IS 36 BP 33148 EP 33152 DI 10.1074/jbc.M202445200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000097 PM 12065579 ER PT J AU Pawliczak, R Han, C Huang, XL Demetris, AJ Shelhamer, JH Wu, T AF Pawliczak, R Han, C Huang, XL Demetris, AJ Shelhamer, JH Wu, T TI 85-kDa cytosolic phospholipase A(2) mediates peroxisome proliferator-activated receptor gamma activation in human lung epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARACHIDONIC-ACID METABOLISM; PPAR-GAMMA; NUCLEAR-ENVELOPE; GENE-EXPRESSION; MACROPHAGE ACTIVATION; DEPENDENT MECHANISM; SIGNAL-TRANSDUCTION; AIRWAY INFLAMMATION; GROWTH-FACTOR; DIFFERENTIATION AB The 85-kDa cytosolic phospholipase A(2) (cPLA(2)) plays an important role in the control of arachidonic acid metabolism. This study was designed to investigate the possible contributions of cPLA(2) and group IIA secretory phospholipase A2 (sPLA(2)) in the regulation of peroxisome proliferator-activated receptor (PPAR)-mediated gene transcription in human airway epithelial cells. Primary normal human bronchial epithelial cells and human lung epithelial cell lines BEAS 2B, A549, and NCI-H292 all express PPARgamma and -beta. Overexpression of cPLA(2) in BEAS 213 cells and primary bronchial epithelial cells resulted in a significant increase of PPARgamma-mediated reporter activity. In contrast, overexpression of group IIA sPLA(2), had no effect on PPARgamma activation. The PPARgamma activity in A549 cells was significantly inhibited by the cPLA(2) inhibitor arachidonyltrifluoromethyl ketone but not by the sPLA2 inhibitor LY311727 and the iPLA(2) inhibitor HELSS. Activation of cPLA(2) by the calcium ionophore, A23187, induced a dose-dependent increase of PPAR activity in normal human bronchial epithelial cells and in the A549 cells. Electrophoretic mobility shift assays show that the binding between PPAR isolated from A549 cells and peroxisome proliferator response element (PPRE) is enhanced by A23187 but partially blocked by the cPLA2 inhibitors arachidonyltrifluoromethyl ketone and methyl arachidonyl fluorophosphate. Finally, NS 398, a COX-2 inhibitor, partially blocked the A23187 effect on PPAR activity and binding to the PPRE suggesting involvement of COX-2 metabolites in PPRE activation. The above results demonstrate a novel function of cPLA, in the control of PPARgamma activation in human lung epithelial cells. C1 Univ Pittsburgh, Dept Pathol, Sch Med, Pittsburgh, PA 15213 USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. Med Univ Lodz, Dept Allergy & Clin Immunol, PL-92213 Lodz, Poland. RP Wu, T (reprint author), Univ Pittsburgh, Dept Pathol, Sch Med, Pittsburgh, PA 15213 USA. RI Pawliczak, Rafal/S-9649-2016; OI Pawliczak, Rafal/0000-0001-6784-453X NR 65 TC 58 Z9 60 U1 0 U2 5 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 SEP 6 PY 2002 VL 277 IS 36 BP 33153 EP 33163 DI 10.1074/jbc.M200246200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000098 PM 12077117 ER PT J AU Mood, K Friesel, R Daar, IO AF Mood, K Friesel, R Daar, IO TI SNT1/FRS2 mediates germinal vesicle breakdown induced by an activated FGF receptor1 in Xenopus oocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; SIGNAL-TRANSDUCTION PATHWAYS; CYCLIC-AMP PHOSPHODIESTERASE; MAP KINASE ACTIVATION; MOS PROTO-ONCOGENE; PHOSPHATIDYLINOSITOL 3-KINASE; MESODERM INDUCTION; TYROSINE KINASE; MEIOTIC MATURATION; ADENYLATE-CYCLASE AB The docking protein SNT1/FRS2 (fibroblast growth factor receptor substrate 2) is implicated in the transmission of extracellular signals from the fibroblast growth factor receptor (FGFR), which plays vital roles during embryogenesis. Activating FGFR mutations cause several craniosynostoses and dwarfism syndromes in humans. Here we show that the Xenopus homolog of mammalian FRS-2 (XFRS2) is essential for the induction of oocyte maturation by an XFGFR1 harboring an activating mutation (XFGFR1act). Using a dominant-negative form of kinase suppressor of Ras, we show the Mek activity is required for germinal vesicle breakdown (GVBD) induced by co-expression of XFGFR1act and XFRS2, but this activity is not required for progesterone-induced GVBD. Furthermore, Mek/MAPK activity is critical for the induction and/or maintenance of H1 kinase activity at metaphase of meiosis II in progesterone-treated oocytes. An activated XFGFR1 containing a mutation in the phospholipase Cgamma binding site (XFGFR1actY672F) displayed a reduced ability to induce cell-cycle progression in oocytes, suggesting phospholipase Cgamma may not be necessary but that it augments XFGFR signaling in this system. Oocytes co-expressing XFGFR1act and XFRS2 showed substantial H1 kinase activity, but this activity was blocked when the oocytes were treated with the phosphatidylinositol 3-kinase inhibitor LY294002. Although phosphatidylinositol 3-kinase activity is essential for XFGFR1act/XFRS2-induced oocyte maturation, this activity is not required for maturation induced by progesterone. Finally, ectopic expression of Xspry2, a negative regulator of XFGFR signaling, greatly reduced MAPK activation and GVBD induced by the expression of either XFGFR1act plus XFRS2 or activated Ras (H-RasV12). In contrast, Xspry2 did not prevent GVBD induced by an activated form of Raf1, suggesting that Xspry2 exerts its inhibitory function upstream or parallel to Raf and downstream of Ras. C1 NCI, Regulat Cell Growth Lab, NIH, Frederick, MD 21702 USA. Maine Med Ctr, Inst Res, Ctr Mol Med, Portland, ME 04106 USA. RP Daar, IO (reprint author), NCI, Regulat Cell Growth Lab, NIH, Bldg 560,Rm 22-3, Frederick, MD 21702 USA. OI Daar, Ira/0000-0003-2657-526X FU NCRR NIH HHS [RR15555]; NHLBI NIH HHS [HL65301]; NIDCR NIH HHS [DE13234] NR 86 TC 12 Z9 12 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 SEP 6 PY 2002 VL 277 IS 36 BP 33196 EP 33204 DI 10.1074/jbc.M203894200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000103 PM 12082104 ER PT J AU Zhang, M Liu, P Dwyer, NK Christenson, LK Fujimoto, T Martinez, F Comly, M Hanover, JA Blanchette-Mackie, EJ Strauss, JF AF Zhang, M Liu, P Dwyer, NK Christenson, LK Fujimoto, T Martinez, F Comly, M Hanover, JA Blanchette-Mackie, EJ Strauss, JF TI MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE REGULATORY PROTEIN; PICK C1 PROTEIN; LOW-DENSITY LIPOPROTEIN; BINDS CHOLESTEROL; DOMAIN; CELLS; TRAFFICKING; GENE; STAR; COMPARTMENT AB This study demonstrates that the steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing protein, MLN64, participates in intra. cellular cholesterol trafficking. Analysis of the intracellular itinerary of MLN64 and MLN64 mutants tagged with green fluorescent protein showed that the N-terminal transmembrane domains mediate endocytosis of MLN64 from the plasma membrane to late endocytic compartments. MLN64 constitutively traffics via dynamic NPC1-containing late endosomal tubules in normal cells; this dynamic movement was inhibited in cholesterol-loaded cells, and MLN64 is trapped at the periphery of cholesterol-laden lysosomes. The MLN64 START domain stimulated free cholesterol transfer from donor to acceptor mitochondrial membranes and enhanced steroidogenesis by placental mitochondria. Expression of a truncated form of MLN64 (DeltaSTART-AULN64), which contains N-terminal transmembrane domains but lacks the START domain, caused free cholesterol accumulation in lysosomes and inhibited late endocytic dynamics. The DeltaSTART-MLN64 dominant negative protein was located at the surface of the cholesterol-laden lysosomes. This dominant negative mutant suppressed steroidogenesis in COS cells expressing the mitochondrial cholesterol side chain cleavage system. We conclude that MLN64 participates in mobilization and utilization of lysosomal cholesterol by virtue of the START domain's role in cholesterol transport. C1 NIDDK, Lipid Cell Biol Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Cell Biochem Sect, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. Univ Penn, Med Ctr, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. RP Strauss, JF (reprint author), NIDDK, Lipid Cell Biol Sect, NIH, Bldg 8,Rm 427,MSC 0851,8 Ctr Dr, Bethesda, MD 20892 USA. RI Christenson, Lane/G-6435-2013 FU FIC NIH HHS [D43-TW-00671]; NICHD NIH HHS [HD06274] NR 26 TC 93 Z9 93 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 6 PY 2002 VL 277 IS 36 BP 33300 EP 33310 DI 10.1074/jbc.M200003200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000116 PM 12070139 ER PT J AU Zhang, Y Dufau, ML AF Zhang, Y Dufau, ML TI Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SP1 SITES; REGULATE TRANSCRIPTION; CHROMATIN STRUCTURE; TRICHOSTATIN-A; REPRESSION; ACTIVATION; PROMOTER; ACETYLATION; EXPRESSION; INHIBITOR AB Modification of chromatin structure by histone acetylases and deacetylases is an important mechanism in modulation of eukaryotic gene transcription. The present study investigated regulation of the human luteinizing hormone receptor (hLHR) gene by historic deacetylases. Inhibition of histone deacetylases (HDACs) by trichostatin A (TSA) increased hLHR promoter activity by 40-fold in JAR cells and markedly elevated endogenous hLHR mRNA levels. Acetylated histones H3 and H4 accumulated in TSA-treated cells and associated predominantly with the hLHR promoter. Furthermore, TSA significantly enhanced the recruitment of RNA polymerase 11 to the promoter. One of the two Sp1 sites essential for basal promoter activity was identified as critical for the TSA effect, but the binding of Sp1/Sp3 to this site remained unchanged in the absence or presence of TSA. A multiprotein complex was recruited to the hLHR promoter via interaction with Sp1 and Sp3, in which HDAC1 and HDAC2 were docked directly to Sp1-bound DNA and indirectly to Sp3-bound DNA through RbAp48, while mSin3A interacted with both HDACs. HDAC1 and HDAC2 were shown to potently repress the hLHR gene transcription, and mSin3A potentiated the inhibition mediated by HDAC1. Our studies have demonstrated that the HDAC-mSin3A complex has an important role in the regulation of hLHR gene transcription by interaction with Sp1/Sp3 and by region-specific changes in histone acetylation and polymerase 11 recruitment within the hLHR promoter. C1 NICHD, Endocrinol & Reprod Res Branch, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, Endocrinol & Reprod Res Branch, Sect Mol Endocrinol, NIH, Bldg 49,Rm 6A036,49 Convent Dr MSC 4510, Bethesda, MD 20892 USA. NR 49 TC 69 Z9 70 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 6 PY 2002 VL 277 IS 36 BP 33431 EP 33438 DI 10.1074/jbc.M204417200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000132 PM 12091390 ER PT J AU Welker, E Raymond, LD Scheraga, HA Caughey, B AF Welker, E Raymond, LD Scheraga, HA Caughey, B TI Intramolecular versus intermolecular disulfide bonds in prion proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PANCREATIC RIBONUCLEASE-A; SCRAPIE; CONVERSION; CONFORMATIONS; INFECTIVITY; DISEASES; STATE AB Prion protein (PrP) is the major component of the partially protease-resistant aggregate that accumulates in mammals with transmissible spongiform encephalopathies. The two cysteines of the scrapie form, PrPSc, were found to be in their oxidized (i.e. disulfide) form (Turk, E., Teplow, D. B., Hood, L. E., and Prusiner, S. B. (1988) Eur. J. Biochem. 176,21-30); however, uncertainty remains as to whether the disulfide bonds are intra- or intermolecular. It is demonstrated here that the monomers of PrPSc are not linked by intermolecular disulfide bonds. Furthermore, evidence is provided that PrPSc can induce the conversion of the oxidized, disulfide. intact form of the monomeric cellular prion protein to its protease-resistant form without the temporary breakage and subsequent re-formation of the disulfide bonds in cell-free reactions. C1 Cornell Univ, Baker Lab Chem & Chem Biol, Ithaca, NY 14853 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Scheraga, HA (reprint author), Cornell Univ, Baker Lab Chem & Chem Biol, Ithaca, NY 14853 USA. FU NIGMS NIH HHS [GM-24893] NR 32 TC 64 Z9 67 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 SEP 6 PY 2002 VL 277 IS 36 BP 33477 EP 33481 DI 10.1074/jbc.M204273200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 591BC UT WOS:000177859000137 PM 12082114 ER EF