FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Black, DM Ensrud, K Greenspan, S Bilezikian, J McGowan, J Lang, T Garnero, P Rosen, C AF Black, DM Ensrud, K Greenspan, S Bilezikian, J McGowan, J Lang, T Garnero, P Rosen, C TI The effects of PTH, alendronate alone or in combination on bone mass and turnover: 12 month results of the PATH trial SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Columbia Univ, Dept Med, New York, NY USA. Natl Inst Hlth, Bethesda, MD USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Synarc, Lyon, France. St Josephs Hosp, Maine Ctr Osteo Res & Educ, Bangor, ME USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S3 EP S3 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500008 ER PT J AU Boileau, C Martel-Pelletier, J Guevremont, M Pelletier, J Merlino, G Reboul, P AF Boileau, C Martel-Pelletier, J Guevremont, M Pelletier, J Merlino, G Reboul, P TI Hepatocyte growth factor (HGF) is responsible of a high degree of bone remodeling and some cartilage matrix modifications. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Montreal, Arthrit Unit, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S192 EP S192 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500752 ER PT J AU Carbone, LD Kritchevsky, SB Wildy, K Barrow, KD Visser, M Harris, F Harris, TB Wang, BWE Nevitt, MC AF Carbone, LD Kritchevsky, SB Wildy, K Barrow, KD Visser, M Harris, F Harris, TB Wang, BWE Nevitt, MC TI The relationship of antiresorptive drug use to osteoarthritis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIA, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. EMGO Inst, Amsterdam, Netherlands. Univ Pittsburgh, Pittsburgh, PA 15260 USA. UTHSC, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S193 EP S193 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500758 ER PT J AU Cauley, J Robbins, J Chen, Z Cummings, S Jackson, R LaCroix, A LeBoff, M Lewis, C McGowan, J Neuner, J Pettinger, M Stefanick, M Wactawski-Wende, J Watts, N Pitt, U AF Cauley, J Robbins, J Chen, Z Cummings, S Jackson, R LaCroix, A LeBoff, M Lewis, C McGowan, J Neuner, J Pettinger, M Stefanick, M Wactawski-Wende, J Watts, N Pitt, U TI The risk vs. benefit profile of estrogen plus progestin does not differ by underlying risk of osteoporosis. The women's health initiative SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Cincinnati, Cincinnati, OH USA. SUNY Buffalo, Buffalo, NY 14260 USA. Stanford Univ, Palo Alto, CA 94304 USA. FHCRC, Seattle, WA USA. Univ Wisconsin, Milwaukee, WI 53201 USA. NIAMS, Bethesda, MD USA. Univ Alabama, Birmingham, AL USA. Harvard Univ, Boston, MA 02115 USA. FHCPC, Seattle, WA USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Arizona, Tucson, AZ USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S32 EP S32 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500118 ER PT J AU Cauley, JA Zmuda, JM Newman, AB Pahor, M Tylavsky, F Cummings, SR Harris, T AF Cauley, JA Zmuda, JM Newman, AB Pahor, M Tylavsky, F Cummings, SR Harris, T TI Circulating levels of cytokine soluble receptors predict incident fractures in older men and women: The health aging and body composition study (HABC). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Tennessee, Memphis, TN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S84 EP S84 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500331 ER PT J AU Chen, D Qiao, M Story, B Zhao, M Jiang, Y Zhao, J Feng, J Xie, Y Huang, S Roberts, A Karsenty, G Mundy, G AF Chen, D Qiao, M Story, B Zhao, M Jiang, Y Zhao, J Feng, J Xie, Y Huang, S Roberts, A Karsenty, G Mundy, G TI BMP signaling through the Smad1 pathway is required for normal postnatal bone formation SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Missouri, Kansas City, MO 64110 USA. NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 6 Z9 7 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S6 EP S6 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500021 ER PT J AU Chen, X Bian, X Yang, L Teslovich, T Stephan, D AF Chen, X Bian, X Yang, L Teslovich, T Stephan, D TI Determining gene expression patterns in biglycan deficient pre-osteoblasts using oligonucleotide microarrays. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIDCR, Csdb, NIH, Bethesda, MD USA. NCI, Cer, NIH, Bethesda, MD 20892 USA. NIH, Cbel, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Rcgm, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S109 EP S109 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500426 ER PT J AU Chung, C Maruyama, T Manabe, T Miwa, T Mishina, Y Nishimori, K Noda, M AF Chung, C Maruyama, T Manabe, T Miwa, T Mishina, Y Nishimori, K Noda, M TI Conditional alk-3 deletion enhances cancellous bone mass in long bone and hypertelorism in the skull of adult mice. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Tokyo Med & Dent Univ, Tokyo, Japan. Tohoku Univ, Sendai, Miyagi 980, Japan. Osaka Univ, Genome Informat Res Ctr, Osaka, Japan. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S106 EP S106 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500414 ER PT J AU Cizza, G Eskandari, F Martinez, P Torvik, S Kotila, C Mistry, S Sebring, N Drinkard, B Ronsaville, D Reynolds, J Gold, PW AF Cizza, G Eskandari, F Martinez, P Torvik, S Kotila, C Mistry, S Sebring, N Drinkard, B Ronsaville, D Reynolds, J Gold, PW TI 21 to 45 year old premenopausal women suffering from major depression are at increased risk for osteoporosis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 2 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S87 EP S87 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500340 ER PT J AU Cummings, SR Harris, F Cauley, JA Black, D Kritchevsky, S Simonsick, E Nevitt, M Harris, T AF Cummings, SR Harris, F Cauley, JA Black, D Kritchevsky, S Simonsick, E Nevitt, M Harris, T TI Patients staying > 3 days in hospital may warrant evaluation and treatment to prevent fractures. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 SF Coordinating Ctr San Francisco, San Francisco, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Memphis, TN USA. NIA, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S359 EP S359 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501452 ER PT J AU Huang, H Ye, L Xie, Y Ko, S Harris, SE Bonewald, L Mishina, Y Feng, JO AF Huang, H Ye, L Xie, Y Ko, S Harris, SE Bonewald, L Mishina, Y Feng, JO TI Bone repair is dramatically delayed in dentin matrix protein-1 (Dmp1) deficient mice. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ Missouri, Sch Dent, Kansas City, MO USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S197 EP S197 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500778 ER PT J AU Karadag, A Fedarko, LS Fisher, LW AF Karadag, A Fedarko, LS Fisher, LW TI Bone sialoprotein promotes invasion through basement membrane by forming a complex with both MMP-2 and integrin-alpha(v)beta(3). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIH, Nider, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S111 EP S111 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500434 ER PT J AU LeBoff, MS Cauley, J Chen, Z LaCroix, A Pettinger, M Cummings, S Watts, NB Lewis, C McGowan, J Stefanick, M Wactawski-Wende, J Robbins, J Jackson, R Neuner, J AF LeBoff, MS Cauley, J Chen, Z LaCroix, A Pettinger, M Cummings, S Watts, NB Lewis, C McGowan, J Stefanick, M Wactawski-Wende, J Robbins, J Jackson, R Neuner, J TI The effects of estrogen plus progestin, on bone mineral density (BMD) in postmenopausal women of different ages and ethnic groups enrolled in the Women's Health Initiative (WHI). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Brigham & Womens Hosp, Endocrine Diabet Hypertens Div, Boston, MA 02115 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Arizona, Tucson, AZ 85721 USA. FHCPC, Seattle, WA USA. FHCRC, Seattle, WA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. UAB, Birmingham, AL USA. NIAMS, Bethesda, MD USA. SUNY Buffalo, Buffalo, NY 14260 USA. Univ Calif Davis, Sacramento, CA 95817 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Wisconsin, Milwaukee, WI 53201 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S94 EP S94 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500367 ER PT J AU Manen, D Bisello, A Pierroz, D Usdin, T Rizzoli, R Ferrari, SL AF Manen, D Bisello, A Pierroz, D Usdin, T Rizzoli, R Ferrari, SL TI Differential regulation of parathyroid hormone (PTH) activity at the PTH receptors type I and II. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Div Bone Dis, Geneva, Switzerland. Univ Pittsburgh, Dept Med, Div Endocrinol & Metab, Pittsburgh, PA USA. NIH, Cell Biol Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S290 EP S290 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501161 ER PT J AU Marini, JC Kozloff, KM Uveges, TE Ty, JM Gronowicz, G Ledgard, F Goldstein, SA AF Marini, JC Kozloff, KM Uveges, TE Ty, JM Gronowicz, G Ledgard, F Goldstein, SA TI Alendronate treatment of Brtl mouse model for osteogenesis imperfecta increases bone strength by increasing bone volume but fails to improve femoral brittleness or mineralization. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NICHD, Sect Connect Tiss Disd, NIH, Bethesda, MD USA. Univ Michigan, Ortho Res Labs, Ann Arbor, MI 48109 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. NR 0 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S287 EP S287 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501146 ER PT J AU Mello, MA Tuan, RS AF Mello, MA Tuan, RS TI Cartilage maturation in vitro is influenced by TGF-beta 1 and T3. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIAMS, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S300 EP S301 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501205 ER PT J AU Miura, M Chen, X Gronthos, S Bi, Y Allen, MR Lakhani, S Flavell, R Feng, X Robey, PG Young, M Shi, S AF Miura, M Chen, X Gronthos, S Bi, Y Allen, MR Lakhani, S Flavell, R Feng, X Robey, PG Young, M Shi, S TI Caspase-3 deficiency causes osteopenia by attenuating differentiation of osteoblast progenitors. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Baylor Coll Med, Houston, TX 77030 USA. Yale Univ, Sch Med, New Haven, CT USA. Texas A&M Univ, Galveston, TX USA. NIDCR, Csdb, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S47 EP S47 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500183 ER PT J AU Modarresi, R Roman-Blas, J Lafond, T Danielson, KG Tuan, RS Seghatoleslami, MR AF Modarresi, R Roman-Blas, J Lafond, T Danielson, KG Tuan, RS Seghatoleslami, MR TI N-cadherin-mediated distribution of stabilized p-catenin alters the effect of MAP kinase and BMP-2 signaling on gene expression during chondrogenesis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S195 EP S195 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500767 ER PT J AU Schwartz, A Sellmeyer, D Feingold, K Strotmeyer, E Tylavsky, F Resnick, H Shorr, R Black, D Cauley, J Cummings, S Harris, T AF Schwartz, A Sellmeyer, D Feingold, K Strotmeyer, E Tylavsky, F Resnick, H Shorr, R Black, D Cauley, J Cummings, S Harris, T TI Increased femoral neck bone loss in older black and white women, but not men, with diabetes. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Memphis, TN USA. MedStar Res Inst, Hyattsville, MD USA. NIA, Bethesda, MD 20892 USA. RI Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S354 EP S354 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501435 ER PT J AU Song, L Tuan, RS AF Song, L Tuan, RS TI Transdifferentiation potentials of human mesenchymal stem cells derived from bone marrow stroma. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S345 EP S345 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501396 ER PT J AU Strotmeyer, E Cauley, J Schwartz, A Resnick, HE Bauer, DC Tylavsky, F De Rekeneire, N Harris, T Newman, A AF Strotmeyer, E Cauley, J Schwartz, A Resnick, HE Bauer, DC Tylavsky, F De Rekeneire, N Harris, T Newman, A TI Type 2 diabetes and non-traumatic fractures in older white and black men and women. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. MedStar Res Inst, Hyattsville, MD USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. NIA, Bethesda, MD 20892 USA. RI Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S243 EP S243 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500970 ER PT J AU Wadhwa, S Chen, XD Young, MF AF Wadhwa, S Chen, XD Young, MF TI Biglycan mediates the WNT signaling pathway in osteoblastic cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S38 EP S38 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500146 ER PT J AU Wallace, JM Rajacher, RM Chen, X Shi, S Allen, MR Bloomfield, SA Robey, PG Young, MF AF Wallace, JM Rajacher, RM Chen, X Shi, S Allen, MR Bloomfield, SA Robey, PG Young, MF TI Rescuing the phenotype of biglycan-deficient mice via exercise. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Texas A&M Univ, College Stn, TX USA. Nidcr, NIH, Bethesda, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. RI Wallace, Joseph/G-7906-2012; Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S45 EP S45 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500173 ER PT J AU Yamagiwa, H Yamada, Y Bolander, ME Sarkar, G AF Yamagiwa, H Yamada, Y Bolander, ME Sarkar, G TI Oligonucleotide decoy mimicking aA-crystallin binding protein 1 binding site on col2a1 enhancer stimulates transcription from the adjacent col2a1 promoter in chondrogenic ATDC5 cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Mayo Clin, Rochester, MN USA. NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S302 EP S303 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501214 ER PT J AU Ye, L Huang, H Xie, Y Lu, Y Chen, D Dallas, SL Bonewald, LF Mishina, Y Feng, JQ AF Ye, L Huang, H Xie, Y Lu, Y Chen, D Dallas, SL Bonewald, LF Mishina, Y Feng, JQ TI Dentin matrix protein-1 (Dmp1) mice display multiple abnormalities during early and late skeletal development. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. UTHSCSA, San Antonio, TX USA. UMKC, Sch Dent, Kansas City, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S39 EP S39 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080500149 ER PT J AU Zmuda, JM Cauley, JA Newman, AB Tylavsky, FA Nevitt, MC Black, DM Rubin, SM Visser, M Harris, TB AF Zmuda, JM Cauley, JA Newman, AB Tylavsky, FA Nevitt, MC Black, DM Rubin, SM Visser, M Harris, TB TI Bone mineral density (BMD) and rate of decline in BMD with aging among older black and white men and women: The Health, Aging and Body Composition Study. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 19-23, 2003 CL MINNEAPOLIS, MINNESOTA SP Amer Soc Bone Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Memphis, TN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. VU Univ, Med Ctr, Amsterdam, Netherlands. NIA, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2003 VL 18 SU 2 BP S300 EP S300 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 734WG UT WOS:000186080501203 ER PT J AU McCabe, MS AF McCabe, MS TI Progress against cancer: The National Cancer Institute's role SO JOURNAL OF CANCER EDUCATION LA English DT Editorial Material C1 NCI, Off Educ & Special Initiat, Off Director, NIH, Bethesda, MD 20892 USA. RP McCabe, MS (reprint author), NCI, Off Educ & Special Initiat, Off Director, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD FAL PY 2003 VL 18 IS 3 BP 161 EP 163 DI 10.1207/S15430154JCE1803_10 PG 3 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 776MV UT WOS:000189120500010 PM 14512264 ER PT J AU Topol, L Jiang, XY Choi, H Garrett-Beal, L Carolan, PJ Yang, YZ AF Topol, L Jiang, XY Choi, H Garrett-Beal, L Carolan, PJ Yang, YZ TI Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation SO JOURNAL OF CELL BIOLOGY LA English DT Article DE limb; chondrogenesis; cancer; Siah2; APC ID PROTEIN-KINASE-II; ENDOCHONDRAL BONE-DEVELOPMENT; SIGNALING PATHWAY; FRIZZLED HOMOLOGS; COLON-CARCINOMA; JOINT FORMATION; IN-VIVO; EXPRESSION; TRANSCRIPTION; ACTIVATION AB Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Writ as it does not signal by stabilizing beta-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Writ pathway by promoting the degradation of beta-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and beta-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote beta-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Yang, YZ (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,Room 4A68, Bethesda, MD 20892 USA. NR 60 TC 455 Z9 469 U1 2 U2 9 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 1 PY 2003 VL 162 IS 5 BP 899 EP 908 DI 10.1083/job.200303158 PG 10 WC Cell Biology SC Cell Biology GA 718KT UT WOS:000185145100016 PM 12952940 ER PT J AU Chen, XL Al-Hasani, H Olausson, T Wenthzel, AM Smith, U Cushman, SW AF Chen, XL Al-Hasani, H Olausson, T Wenthzel, AM Smith, U Cushman, SW TI Activity, phosphorylation state and subcellular distribution of GLUT4-targeted Akt2 in rat adipose cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE PKB/Akt; GLUT4; translocation; phosphorylation ID PROTEIN-KINASE-B; INSULIN-STIMULATED TRANSLOCATION; GLUCOSE-TRANSPORTER GLUT4; PHOSPHATIDYLINOSITOL 3-KINASE; GLUT4-CONTAINING VESICLES; PLASMA-MEMBRANE; ADIPOCYTES; ACTIVATION; TRAFFICKING; GLUCOSE-TRANSPORTER-4 AB In this study, fusion of the kinase domain of Akt2 to the cytosolic C terminus of exofacially-HA-tagged GLUT4 is used to investigate the activity, phosphorylation state and subcellular localization of Akt2 specifically targeted to the GLUT4-trafficking pathway in rat adipose cells. Fusion of wild-type (wt) Akt2, but not a kinase-dead (KD) mutant results in constitutive targeting of the HA-GLUT4 fusion protein to the cell surface to a level similar to that of HA-GLUT4 itself in the insulin-stimulated state. Insulin does not further enhance the cell-surface level of HA-GLUT4-Akt2-wt, but does stimulate the translocation of HA-GLUT4-Akt2-KD. Cell-surface HA-GLUT4-Akt2-wt is found to be phosphorylated on Ser(474) in both the absence and presence of insulin, and mutation of Ser(474) to Ala reduces the increased basal cell-surface localization of the fusion protein. While Ser(474) phosphorylation of HA-GLUT4-Akt2-KD is detected only in the insulin-stimulated state, trapping this fusion protein on the cell surface by coexpression of a dominant negative mutant dynamin does not induce Ser474 phosphorylation. Phosphorylation on Thr(309) is not detectable in either HA-GLUT4-Akt2-wt or HA-GLUT4-Akt2-KD, in either the basal or insulin-stimulated state, and mutation of Thr(309) to Ala does not influence the insulin-independent increases in cell-surface localization and Ser(474) phosphorylation. Expression of HA-GLUT4-Akt2-wt stimulates the translocation of co-transfected myc-GLUT4 to a level similar to that in the insulin-stimulated state; this increase is moderately reduced by mutation of Ser(474) to Ala and absent with the kinase-dead mutant. These results demonstrate that targeting Akt2 to the GLUT4-trafficking pathway induces Akt2 activation and GLUT4 translocation. Ser(474) phosphorylation is an autocatalytic reaction requiring an active kinase, and kinase activity is associated with a plasma membrane localization. Fusion of Akt2 to the C terminus of GLUT4 appears to substitute for Thr(309) phosphorylation in activating the autocatalytic process. C1 NIDDK, EDMNS DB, NIH, Bethesda, MD 20892 USA. German Inst Human Nutr, D-14558 Bergholz Rehbrucke, Germany. Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, Lundberg Lab Diabet Res, SE-41345 Gothenburg, Sweden. RP Cushman, SW (reprint author), NIDDK, EDMNS DB, NIH, 8 Ctr Dr,MSC 0842, Bethesda, MD 20892 USA. NR 33 TC 17 Z9 19 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 1 PY 2003 VL 116 IS 17 BP 3511 EP 3518 DI 10.1242/jcs.00675 PG 8 WC Cell Biology SC Cell Biology GA 755GJ UT WOS:000187394900007 PM 12876218 ER PT J AU Ichise, M Liow, JS Lu, JQ Takano, T Model, K Toyama, H Suhara, T Suzuki, T Innis, RB Carson, TE AF Ichise, M Liow, JS Lu, JQ Takano, T Model, K Toyama, H Suhara, T Suzuki, T Innis, RB Carson, TE TI Linearized reference tissue parametric Imaging methods: Application to [C-11]DASB positron emission tomography studies of the serotonin transporter in human brain SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE positron emission tomography; parametric imaging; linerarized reference tissue model; noise-induced bias; serotonin transporters; [C-11]DASB ID GRAPHICAL ANALYSIS; BINDING-SITES; H-3 PAROXETINE; IN-VITRO; PET; MODEL; NEURORECEPTOR; QUANTIFICATION; RADIOTRACERS; -DASB AB The authors developed and applied two new linearized reference tissue models for parametric images of binding potential (BP) and relative delivery (R-1) for [C-11]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate (k'(2)) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k'(2). The resulting BP and R-1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [C-11]DASB data. MRTM gave k'(2) estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and ITKA, reducing BP bias markedly over MRTMO from 12-70% to 1-4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R-1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [C-11]DASB positron emission tomography studies. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Natl Inst Radiol Sci, Brain Imaging Project, Chiba 260, Japan. Natl Inst Hlth, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD USA. RP Ichise, M (reprint author), NIMH, Mol Imaging Branch, Bldg 1 B3-10,1 Ctr Dr,MSC0135, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 29 TC 337 Z9 339 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD SEP PY 2003 VL 23 IS 9 BP 1096 EP 1112 PG 17 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 718KQ UT WOS:000185144800011 PM 12973026 ER PT J AU Sporn, A Gogtay, N Ortiz-Aguayo, R Alfaro, C Tossell, J Lenane, M Gochman, P Rapoport, JL AF Sporn, A Gogtay, N Ortiz-Aguayo, R Alfaro, C Tossell, J Lenane, M Gochman, P Rapoport, JL TI Clozapine-induced neutropenia in children: Management with lithium carbonate SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID FACTOR G-CSF; INDUCED AGRANULOCYTOSIS; SCHIZOPHRENIA AB Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 mug/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. Natl Inst Hlth Clin Ctr Pharm Dept, Bethesda, MD USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N 202, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 19 TC 33 Z9 33 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FAL PY 2003 VL 13 IS 3 BP 401 EP 404 DI 10.1089/104454603322572697 PG 4 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 737NL UT WOS:000186238600019 PM 14642024 ER PT J AU Hudson, LD AF Hudson, LD TI Pelizaeus-Merzbacher disease and spastic paraplegia type 2: Two faces of myelin loss from mutations in the same gene SO JOURNAL OF CHILD NEUROLOGY LA English DT Article; Proceedings Paper CT Meeting of the Child-Neurology-Society CY OCT, 2002 CL WASHINGTON, D.C. SP Child Neurol Soc ID PROTEOLIPID PROTEIN GENE; CENTRAL-NERVOUS-SYSTEM; CNS MYELIN; MAJOR CAUSE; PRENATAL-DIAGNOSIS; NONSENSE MUTATION; MEMBRANE DOMAINS; POINT MUTATIONS; INTERPHASE FISH; SCHWANN-CELLS AB Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 are two sides of the same coin. Both arise from mutations in the gene encoding myelin proteolipid protein. The disease spectrum for Pelizaeus-Merzbacher disease and spastic paraplegia type 2 is extraordinarily broad, ranging from a spastic gait in the pure form of spastic paraplegia type 2 to a severely disabling form of Pelizaeus-Merzbacher disease featuring hypotonia, respiratory distress, stridor, nystagmus, and profound myelin loss. The diverse disease spectrum is mirrored by the underlying pathogenesis, in which a blockade at any stage of myelin proteolipid protein synthesis and assembly into myelin spawns a unique phenotype. The continuing definition of pathogenetic mechanisms operative in Pelizaeus-Merzbacher disease and spastic paraplegia type 2, together with advances in neural cell transplant therapy, augurs well for future treatment of the severe forms of Pelizaeus-Merzbacher disease. C1 NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Hudson, LD (reprint author), NINDS, Sect Dev Genet, NIH, Bldg 36,Room 5D06,36 Convent Dr,MSC 4160, Bethesda, MD 20892 USA. NR 79 TC 28 Z9 28 U1 0 U2 3 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD SEP PY 2003 VL 18 IS 9 BP 616 EP 624 DI 10.1177/08830738030180090801 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 725JC UT WOS:000185539500007 PM 14572140 ER PT J AU Ilias, I Yu, J Carrasquillo, JA Chen, CC Eisenhofer, G Whatley, M McElroy, B Pacak, K AF Ilias, I Yu, J Carrasquillo, JA Chen, CC Eisenhofer, G Whatley, M McElroy, B Pacak, K TI Superiority of 6-[(18)F]-fluorodopamine positron emission tomography versus [(131)I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID I-131 METAIODOBENZYLGUANIDINE SCINTIGRAPHY; MALIGNANT PHEOCHROMOCYTOMA; MAGNETIC-RESONANCE; MIBG SCINTIGRAPHY; EVOLVING CONCEPTS; DIAGNOSIS; PET; OCTREOTIDE; MEDICINE; TUMORS AB The purpose of the study was to assess the diagnostic utility of 6-[(18)F]-fluorodopamine ([(18)F]-DA) positron emission tomography scanning ( PET) vs. [(131)I]-metaiodobenzylguanidine ( MIBG) scintigraphy in patients with metastatic pheochromocytoma (PHEO). We studied 10 men and six women ( mean age 38.2 +/- 11.5 yr) referred to our institution for metastatic PHEO; two patients were studied twice within a 2-yr interval. Imaging modalities included computed tomography (CT), magnetic resonance imaging (MRI), [(131)I]-MIBG scintigraphy, and [(18)F]-DA PET. Fifteen of 16 patients had positive findings on CT and/or MRI consistent with the presence of pheochromocytoma. [(18)F]-DAPETwas positive in all patients, but seven patients had negative [(131)I]- MIBG scans. Thirty-eight foci of uptake were shown by both [(18)F]- DA PET and [(131)I]- MIBG scintigraphy, 90 only by [(18)F]- DA PET, and 10 only by [(131)I]MIBG; most lesions were also visible on CT/ MRI. In this initial series of patients with metastatic pheochromocytoma, [(18)F]DA PET localized PHEO in all patients and showed a large number of foci that were not imaged with [(131)I]- MIBG scintigraphy. Thus, [(18)F]- DA PET was found to be a superior imaging method in patients with metastatic PHEO, in which correct detection of disease extension often determines the most appropriate therapeutic plan and future follow-up. C1 NICHD, Unit Clin Neuroendocrinol, PREB, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHD, Unit Clin Neuroendocrinol, PREB, NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 40 TC 150 Z9 163 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2003 VL 88 IS 9 BP 4083 EP 4087 DI 10.1210/jc.2003-030235 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720JY UT WOS:000185258700009 PM 12970267 ER PT J AU Winer, KK Ko, CW Reynolds, JC Dowdy, K Keil, M Peterson, D Gerber, LH McGarvey, C Cutler, GB AF Winer, KK Ko, CW Reynolds, JC Dowdy, K Keil, M Peterson, D Gerber, LH McGarvey, C Cutler, GB TI Long-term treatment of hypoparathyroidism: A randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; PHOSPHATE-METABOLISM; VITAMIN-D; OSTEOPOROSIS; TRIAL; 1,25-DIHYDROXYVITAMIN-D3; CHILDREN; THERAPY; PARATHYROID-HORMONE-1-34 AB Hypoparathyroidism is one of the few remaining hormonal insufficiency states for which replacement therapy is unavailable. Previous short-term controlled trials have shown PTH to be a safe and effective treatment of hypoparathyroidism. In this randomized, parallel group, open-label trial, we compared synthetic human PTH-(1-34) (PTH) with conventional therapy, calcitriol and calcium, over a 3-yr period. Twenty-seven patients with confirmed hypoparathyroidism, aged 18-70 yr, were randomized to either twice daily sc PTH or oral calcitriol and calcium. The primary end points were calcium levels in serum and urine. Secondary end points were creatinine clearance, markers of bone turnover, and bone mineral density. Throughout the 3-yr study period, serum calcium levels were similar in both treatment groups within or just below the normal range. Mean urinary calcium excretion was within the normal range from 1-3 yr in PTH- treated patients, but remained above normal in the calcitriol group. Bone mineral content and bone mineral density showed no significant between-group differences over the 3-yr study period. We conclude that treatment with twice daily sc PTH provides a safe and effective alternative to calcitriol therapy and is able to maintain normal serum calcium levels without hypercalciuria for at least 3 yr in patients with hypoparathyroidism. C1 NICHHD, Pediat & Reprod Endocrinol Branch, Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Winer, KK (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, Natl Inst Deafness & Other Commun Disorders, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. EM winerk@mail.nih.gov NR 29 TC 109 Z9 119 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 SEP PY 2003 VL 88 IS 9 BP 4214 EP 4220 DI 10.1210/jc.2002-021736 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720JY UT WOS:000185258700032 PM 12970289 ER PT J AU Liu, J Erlichman, B Weinstein, LS AF Liu, J Erlichman, B Weinstein, LS TI The stimulatory G protein alpha-subunit G(s)alpha is imprinted in human thyroid glands: Implications for thyroid function in pseudohypoparathyroidism types 1A and 1B SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ALBRIGHT-HEREDITARY-OSTEODYSTROPHY; NUCLEOTIDE-BINDING PROTEIN; CYCLASE COUPLING PROTEIN; HUMAN GNAS1 GENE; PARENTAL ORIGIN; MATERNAL TRANSMISSION; MUTATIONAL ANALYSIS; ADENYLATE-CYCLASE; CHROMOSOME 20Q; RECEPTOR AB The stimulatory G protein alpha-subunit G(s)alpha couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous G(s)alpha null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of G(s)alpha in specific hormone targets could explain this observation. Using hot-stop PCR analysis on total RNA from six normal human thyroid specimens, we showed that the majority of the G(s)alpha mRNA (72 +/- 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal G(s)alpha null mutations (PHP1A) and the absence of TSH resistance in patients with paternal G(s)alpha mutations (pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the G(s)alpha gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific G(s)alpha deficiency. We found evidence of borderline TSH resistance in 10 of 22 PHP1B patients. This study provides further evidence for tissue-specific imprinting of G(s)alpha in humans and provides a potential mechanism for mild to moderate TSH resistance in PHP1A and borderline resistance in some patients with PHP1B. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Weinstein, LS (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. EM leew@amb.niddk.nih.gov NR 47 TC 105 Z9 107 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2003 VL 88 IS 9 BP 4336 EP 4341 DI 10.1210/jc.2003-030393 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720JY UT WOS:000185258700050 PM 12970307 ER PT J AU Collins, MT Sarlis, NJ Merino, MJ Monroe, J Crawford, SE Krakoff, JA Guthrie, LC Bonat, S Robey, PG Shenker, A AF Collins, MT Sarlis, NJ Merino, MJ Monroe, J Crawford, SE Krakoff, JA Guthrie, LC Bonat, S Robey, PG Shenker, A TI Thyroid carcinoma in the McCune-Albright syndrome: Contributory role of activating G(s)alpha mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 82nd Annual Meeting of the Endocrine-Society CY JUN 21-24, 2000 CL TORONTO, CANADA SP Endocrine Soc ID STIMULATORY G-PROTEIN; HUMAN ENDOCRINE TUMORS; LEYDIG-CELL TUMORS; GS-ALPHA GENE; FIBROUS DYSPLASIA; TRANSGENIC MICE; THYROTROPIN RECEPTOR; FOLLICULAR CARCINOMA; CONGENITAL GOITER; ONCOGENE AB McCune-Albright syndrome (MAS) is defined by the triad of cafe-au-lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, such as precocious puberty, hyperthyroidism, GH excess, and Cushing's syndrome. This disorder is caused by sporadic, postzygotic activating mutations in the GNAS1 gene, which codes for the G(s)alpha protein in the cAMP signaling cascade. Nodular and diffuse goiters (with and without hyperthyroidism), as well as benign thyroid nodules, have been reported in association with MAS. Herein we report two cases of thyroid carcinoma in patients with MAS. The first is a case of papillary thyroid cancer detected incidentally during a hemithyroidectomy for hyperthyroidism in a 14-yr-old girl. The second is one of a 41-yr-old woman with long-standing MAS and an enlarging thyroid nodule, which was diagnosed as a clear cell thyroid carcinoma, a rare variant of thyroid cancer. Molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg(201) in the GNAS1 gene. These findings suggest that the infrequent development of thyroid carcinoma in MAS patients involves additional mutational or epigenetic events. C1 Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, CSDB, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Div Intramural Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, CSDB, NIH,Dept Hlth & Human Serv, Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov; njsarlis@mdanderson.org RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NCI NIH HHS [CA-78436] NR 41 TC 53 Z9 56 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 SEP PY 2003 VL 88 IS 9 BP 4413 EP 4417 DI 10.1210/jc.2002-021642 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720JY UT WOS:000185258700061 PM 12970318 ER PT J AU Porta, M Fernandez, E Alguacil, J AF Porta, M Fernandez, E Alguacil, J TI Serniology, proteomics, and the early detection of symptomatic cancer SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Editorial Material DE lung cancer; diagnosis; treatment; survival; delay; symptoms; signs; semiology; proteomics; genomics ID CELL LUNG-CANCER; PHASE-III TRIALS; COLORECTAL-CANCER; DIGESTIVE-TRACT; STAGING SYSTEM; OVARIAN-CANCER; BREAST-CANCER; SURVIVAL; SERUM; PROGNOSIS AB "Diagnostic delay," the duration of symptoms or the symptom to diagnosis interval (SDI), are highly complex variables that reflect the behavior of the patient and the attending physician, tumor biology and host-tumor interactions, the functioning of the health care system, and sociocultural norms. In addition to tumor stage, other variables mediate the relationship between duration of symptoms and survival; clinical and epidemiologic procedures to measure them must be improved. Largely at odds with clinical and common wisdom, decades of research have shown that often SDI is not associated with tumor stage and/or with survival from cancer. It would be relevant to increase evidence in support of the notion that, for each type of tumor, there is a positive relationship between the length of the presymptomatic and the symptomatic phases. SDI could then be used to classify tumors according to their likelihood of being detected early when still asymptomatic. Also, tumors could be classified according to the ratio of the median SDI to the median survival (SDI to survival ratio, SSR), which may estimate the relative likelihood for clinical lead-time bias. If adhering to rigorous methodologic standards, proteomic analyses of early-stage cancers might provide new insights into changes that occur in early phases of tumorigenesis. More real examples are needed of uses of pathologic and genomic data to study mechanisms through which SDI influences-or fails to influence-prognosis. The degree of correlation between proteomic patterns and classic semiology constitutes an area of interest in itself; their respective correlations with cancer prognosis should be assessed in properly designed epidemiologic studies. (C) 2003 Elsevier Inc. All rights reserved. C1 Inst Municipal Invest Med, E-08003 Barcelona, Spain. Univ Autonoma Barcelona, E-08193 Barcelona, Spain. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Inst Catala Oncol, E-08907 Barcelona, Spain. Univ Barcelona, E-08007 Barcelona, Spain. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Porta, M (reprint author), Inst Municipal Invest Med, Carrer del Dr Aiguader 80, E-08003 Barcelona, Spain. RI Porta, Miquel/B-5787-2008; Fernandez, Esteve/A-9750-2008 OI Porta, Miquel/0000-0003-1684-7428; Fernandez, Esteve/0000-0003-4239-723X NR 50 TC 14 Z9 14 U1 0 U2 0 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 SEP PY 2003 VL 56 IS 9 BP 815 EP 819 DI 10.1016/S0895-4356(03)00165-3 PG 5 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 728PU UT WOS:000185726200001 PM 14505764 ER PT J AU Chambless, LE Folsom, AR Sharrett, AR Sorlie, P Couper, D Szklo, M Nieto, FJ AF Chambless, LE Folsom, AR Sharrett, AR Sorlie, P Couper, D Szklo, M Nieto, FJ TI Coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC) study SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE coronary heart disease; prediction; risk factors; subclinical disease; population attributable risk; ROC curves ID IMPROVED LIPOLYTIC EFFICIENCY; PHYSICAL-ACTIVITY; ENZYMATIC DETERMINATION; HEMOSTATIC FACTORS; SERUM-CHOLESTEROL; WALL THICKNESS; ARTERIAL-WALL; SHORT-TERM; VARIABILITY; EXPERIENCE AB Risk prediction functions for incident coronary heart disease (CHD) were estimated using data from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective study of CHD in 15,792 persons recruited in 1987-1989 from four U.S. communities, with follow-up through 1998. Predictivity of which individuals had incident CHD was assessed by increase in area under ROC curves resulting from adding nontraditional risk factors and markers of subclinical disease to a basic model containing only traditional risk factors. We also assessed the increase in population attributable risk. The additional factors were body mass index; waist-hip ratio; sport activity index; forced expiratory volume; plasma fibrinogen, factor VIII, von Willebrand factor, and Lp(a); heart rate; Keys score; pack-years smoking; and subclinical disease marker carotid intima-media thickness. These factors substantially improved prediction of future CHD for men, less for women, and also increased attributable risks. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Dept Biostat, Bank Amer Ctr, Chapel Hill, NC 27514 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55454 USA. NHLBI, NIH, Rockledge Ctr 2, Bethesda, MD 20892 USA. Johns Hopkins Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. Univ Wisconsin, Sch Med, Dept Populat Hlth Sci, Madison, WI 53705 USA. RP Chambless, LE (reprint author), Univ N Carolina, Dept Biostat, Bank Amer Ctr, CB 8300,137 E Franklin St,Suite 400, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 53 TC 175 Z9 182 U1 0 U2 5 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 SEP PY 2003 VL 56 IS 9 BP 880 EP 890 DI 10.1016/S0895-4356(03)00055-6 PG 11 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 728PU UT WOS:000185726200011 PM 14505774 ER PT J AU Moayeri, M Haines, D Young, HA Leppla, SH AF Moayeri, M Haines, D Young, HA Leppla, SH TI Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MOUSE STRAIN DIFFERENCES; INHALATIONAL ANTHRAX; NITRIC-OXIDE; BIOTERRORISM EXPOSURE; PROTECTIVE ANTIGEN; MURINE MACROPHAGES; FACTOR CLEAVES; KINASE-KINASE; FAS LIGAND AB Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and CS7BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than CS7BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1beta. No changes in TNF-alpha occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-alpha-independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin. C1 NIAID, NIH, Bethesda, MD 20892 USA. NCI, Vet Pathol Sect, Pathol & Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21701 USA. NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21701 USA. RP Leppla, SH (reprint author), NIAID, NIH, Bldg 30,Room 303, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01CO12400]; PHS HHS [N01-C0-12400] NR 75 TC 224 Z9 231 U1 1 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2003 VL 112 IS 5 BP 670 EP 682 DI 10.1172/JC1200317991 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 719NN UT WOS:000185209900011 PM 12952916 ER PT J AU Riminucci, M Collins, MT Fedarko, NS Cherman, N Corsi, A White, KE Waguespack, S Gupta, A Hannon, T Econs, MJ Bianco, P Robey, PG AF Riminucci, M Collins, MT Fedarko, NS Cherman, N Corsi, A White, KE Waguespack, S Gupta, A Hannon, T Econs, MJ Bianco, P Robey, PG TI FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TUMOR-INDUCED OSTEOMALACIA; DOMINANT HYPOPHOSPHATEMIC RICKETS; X-LINKED HYPOPHOSPHATEMIA; MCCUNE-ALBRIGHT SYNDROME; ONCOGENIC OSTEOMALACIA; IN-VIVO; GENE; MUTATIONS; REABSORPTION; FGF23 AB FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified "fibrous" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS. C1 Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Parco Sci Biomed San Raffaele, Rome, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. Johns Hopkins Univ, Dept Med, Div Geriatr, Baltimore, MD USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. Univ Texas, MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Viale Regina Elena 324, I-00161 Rome, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NIA NIH HHS [AG-18397, P01 AG018397]; NIAMS NIH HHS [AR-02095, AR-42228, AR-47866, R01 AR042228, R01 AR047866]; NIDDK NIH HHS [DK-063934, R01 DK063934]; Telethon [E.1029] NR 39 TC 322 Z9 334 U1 0 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2003 VL 112 IS 5 BP 683 EP 692 DI 10.1172/JC120031899 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 719NN UT WOS:000185209900012 PM 12952917 ER PT J AU Castle, PE Lorincz, AT Scott, DR Sherman, ME Glass, AG Rush, BB Wacholder, S Burk, RD Manos, MM Schussler, JE Macomber, P Schiffman, M AF Castle, PE Lorincz, AT Scott, DR Sherman, ME Glass, AG Rush, BB Wacholder, S Burk, RD Manos, MM Schussler, JE Macomber, P Schiffman, M TI Comparison between prototype Hybrid Capture 3 and Hybrid Capture 2 human papillomavirus DNA assays for detection of high-grade cervical intraepithelial neoplasia and cancer SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID COSTA-RICA; STRATEGIES; WOMEN; RISK; MANAGEMENT; INFECTION; WORLDWIDE; CYTOLOGY; LESIONS; PCR AB We compared the performance of a prototype version of the Hybrid Capture 3 (HC3) human papillomavirus (HPV) DNA assay to the current generation Hybrid Capture 2 (HC2) assay, both of which target 13 oncogenic HPV types, for the detection of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) with cervico-vaginal lavage specimens collected at enrollment into a 10-year cohort study at Kaiser Permanente (Portland, Oreg.). HC3 results for a risk-stratified sample (n = 4,364) were compared to HC2 results for the entire cohort (n = 20,810) with receiver operating characteristics curves, and the optimal cut points for both tests (relative light units [RLU]/positive control [PC]) for the detection of CIN3+ were determined. Specimens were also tested for HPV16 and HPV18 with separate HC3 type-specific probes. The optimal cut point for detecting CIN3 + was 1.0 RLU/PC for HC2, as previously shown, and was 0.6 RLU/PC for HC3. At the optimal cut points, HC3 and HC2 had similar screening performance characteristics for CIN3+ diagnosed at the enrollment visit. In analyses that included cases CIN3+ at enrollment and those diagnosed during early follow-up, HC3 had nonsignificantly higher sensitivity and equal specificity for the detection of CIN3+ compared to HC2; this increase in sensitivity was primarily the result of increased detection of CIN3+ in women who were 30 years of age or older and were cytologically negative (P = 0.006). We also compared the performance of the hybrid capture tests to MY09/11 L1 consensus primer PCR results (n = 1,247). HC3 was less likely than HC2 to test positive for specimens that tested positive by PCR for any untargeted types (P < 0.001). HC3 was less likely than HC2 to test positive for untargeted PCR-detected single infections with HPV53 (P = 0.001) and HPV66 (P = 0.01). There was good agreement between test positivity by PCR and by single type-specific HC3 probes for HPV16 (kappa = 0.76; 95% confidence interval [CI] = 0.71 to 0.82) and for HPV18 (kappa = 0.73; 95% CI = 0.68 to 0.79). In conclusion, we suggest that HC3 (greater than or equal to0.6 RLU/PC) may be slightly more sensitive than and equally specific test as HC2 (greater than or equal to1.0 RLU/PC) for the detection of CIN3+ over the duration of typical screening intervals. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Digene, Gaithersburg, MD USA. Kaiser Permanente, Portland, OR USA. Albert Einstein Coll Med, Canc Res Ctr, Bronx, NY 10467 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7074,MSC 7234, Bethesda, MD 20892 USA. NR 20 TC 36 Z9 40 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD SEP PY 2003 VL 41 IS 9 BP 4022 EP 4030 DI 10.1128/JCM.41.9.4022-4030.2003 PG 9 WC Microbiology SC Microbiology GA 720DT UT WOS:000185246800003 PM 12958220 ER PT J AU Packer, RJ Gurney, JG Punyko, JA Donaldson, SS Inskip, PD Stovall, M Yasui, Y Mertens, AC Sklar, CA Nicholson, HS Zeltzer, LK Neglia, JP Robison, LL AF Packer, RJ Gurney, JG Punyko, JA Donaldson, SS Inskip, PD Stovall, M Yasui, Y Mertens, AC Sklar, CA Nicholson, HS Zeltzer, LK Neglia, JP Robison, LL TI Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: Childhood cancer survivor study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; RADIATION-THERAPY; ADJUVANT CHEMOTHERAPY; YOUNG-CHILDREN; THYROID-FUNCTION; POSTERIOR-FOSSA; MEDULLOBLASTOMA; TRANSPLANTATION; BRACHYTHERAPY; RADIOTHERAPY AB Purpose : To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. Patients and Methods: Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. Results: Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. Conclusion: Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored. (C) 2003 by American Society of Clinical Oncology. C1 Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Dept Neurol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Dept Pediat, Washington, DC 20010 USA. George Washington Univ, Dept Neurol, Washington, DC USA. George Washington Univ, Dept Pediat, Washington, DC 20052 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Stanford Univ, Med Ctr, Dept Radiat Oncol, Stanford, CA 94305 USA. Univ Calif Los Angeles, David Gelfen Sch Med, Dept Pediat, Los Angeles, CA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. Oregon Hlth Sci Univ, Div Pediat Hematol Oncol, Portland, OR 97201 USA. RP Packer, RJ (reprint author), Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. RI Yasui, Yutaka/E-2564-2015 OI Yasui, Yutaka/0000-0002-7717-8638 FU NCI NIH HHS [U24 CA 55727] NR 33 TC 169 Z9 169 U1 0 U2 4 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 1 PY 2003 VL 21 IS 17 BP 3255 EP 3261 DI 10.1200/JCO.2003.01.202 PG 7 WC Oncology SC Oncology GA 717LT UT WOS:000185091300014 PM 12947060 ER PT J AU Moore, MJ Hamm, J Dancey, J Eisenberg, PD Dagenais, M Fields, A Hagan, K Greenberg, B Colwell, B Zee, B Tu, D Ottaway, J Humphrey, R Seymour, L AF Moore, MJ Hamm, J Dancey, J Eisenberg, PD Dagenais, M Fields, A Hagan, K Greenberg, B Colwell, B Zee, B Tu, D Ottaway, J Humphrey, R Seymour, L TI Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 19-23, 2000 CL NEW ORLEANS, LOUISIANA SP Amer Soc Clin Oncol ID MULTIPLE TESTING PROCEDURE; ADVANCED SOLID TUMORS; FIRST-LINE THERAPY; RANDOMIZED TRIAL; CARCINOMA; MARIMASTAT; ONCOLOGY AB Purpose : To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer. Methods: Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m(2) administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. he planned sample size of the study was 350 patients. Two formal interim analyses were planned. Results: The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the SAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P < .001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P < .001). Quality-of-life analysis also favored gemcitabine. Conclusion: Gemcitabine is significantly superior to. BAY 12-9566 in advanced pancreatic cancer. (C) 2003 by American Society of Clinical Oncology. C1 Univ Toronto, Princess Margaret Hosp, Hlth Network, Toronto, ON, Canada. NCI, Canada Clin Trials Grp, Kingston, ON, Canada. CHU Montreal Pavillon St Luc, Montreal, PQ, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Nova Scotia Canc Ctr, Halifax, NS, Canada. Alliant Hlth Syst, Louisville, KY USA. Sutter Hlth Canc Res Ctr, Greenbrae, CA USA. Hematol & Oncol Associates Virginia, Richmond, VA USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. RP Moore, MJ (reprint author), Princess Margaret Hosp, Dept Med Oncol, 5-206,610 Univ Ave, Toronto, ON M5G 2M9, Canada. OI Zee, Benny Chung-Ying/0000-0002-7238-845X NR 20 TC 224 Z9 240 U1 0 U2 2 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 1 PY 2003 VL 21 IS 17 BP 3296 EP 3302 DI 10.1200/JCO.2003.02.098 PG 7 WC Oncology SC Oncology GA 717LT UT WOS:000185091300019 PM 12947065 ER PT J AU Padmanabhan, H Ehrlich, LD Quazedo, M Fojo, T Louie, A Walther, M Pacak, K AF Padmanabhan, H Ehrlich, LD Quazedo, M Fojo, T Louie, A Walther, M Pacak, K TI Case 2. Metastatic pheochromocytoma to the colon SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MALIGNANT PHEOCHROMOCYTOMA C1 NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. RP Padmanabhan, H (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 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 1 PY 2003 VL 21 IS 17 BP 3369 EP 3371 DI 10.1200/JCO.2003.09.100 PG 3 WC Oncology SC Oncology GA 717LT UT WOS:000185091300030 PM 12947075 ER PT J AU Reed, MD Findling, RL Capparelli, EV O'Riordan, MA Blumer, JL AF Reed, MD Findling, RL Capparelli, EV O'Riordan, MA Blumer, JL TI A population pharmacokinetic (pop-PK) model of steady-state (SS) paroxetine (PXT) in depressed children (C) and adolescents (A). SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-College-of-Clinical-Pharmacology CY SEP 21-23, 2003 CL TAMPA, FLORIDA SP Amer Coll Clin Pharmacol C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NICHD, PPRU Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2003 VL 43 IS 9 MA 60 BP 1028 EP 1028 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 714PA UT WOS:000184921600056 ER PT J AU Khatami, M AF Khatami, M TI Inflammation-induced lymphoid hyperplasia: Inflammatory responses as ideal biomarkers of early detection or therapy of tumor/cancer. SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-College-of-Clinical-Pharmacology CY SEP 21-23, 2003 CL TAMPA, FLORIDA SP Amer Coll Clin Pharmacol C1 Univ PA, NCI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2003 VL 43 IS 9 MA 106 BP 1039 EP 1039 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 714PA UT WOS:000184921600100 ER PT J AU Comanor, L Elkin, C Leung, K Krajden, M Kronquist, K Nicolas, K Horansky, E deMedina, M Kittichai, P Sablon, E Ziermann, R Sherlock, C AF Comanor, L Elkin, C Leung, K Krajden, M Kronquist, K Nicolas, K Horansky, E deMedina, M Kittichai, P Sablon, E Ziermann, R Sherlock, C TI Successful HCV genotyping of previously failed and low viral load specimens using an HCV RNA qualitative assay based on transcription-mediated amplification in conjunction with the line probe assay SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE HCV genotype; transcription-mediated amplification; line probe assay; TMA-LiPA ID HEPATITIS-C VIRUS; PERFORMANCE-CHARACTERISTICS; MANAGEMENT; SEQUENCE; REGION AB Background: Hepatitis C virus (HCV) genotyping is a critical part of the diagnostic work-up for chronic hepatitis C. The VERSANT((R)) HCV line probe assay (LiPA) marketed by Bayer Corporation requires PCR-derived amplicons for genotyping usually obtained from commercial assays, including Amplicor((R)) HCV 2.0 (Amplicor 2.0), Amplicor HCV Monitor((R)) 2.0, or SuperQuant((R)). Occasionally, PCR-based methods in conjunction with LiPA fail to give a genotyping result. Although most genotyping failures occur among low viral load specimens, some occur in specimens with relatively high viral loads. The Bayer HCV RNA Qualitative assay (HCV TMA), with a limit of detection of approximately 5-10 IU/ml, is more sensitive than other commercial assays. Objectives: An HCV genotyping protocol using HCV TMA linked with LiPA (TMA-LiPA) was developed and tested for ability to genotype samples that had previously failed genotyping by PCR-based methods in conjunction with LiPA. Study design: Clinical specimens were obtained from eight independent laboratories in Canada and the US and tested with TMA-LiPA at the Bayer Reference Testing Laboratory. Specimens included those that failed to produce a genotype result when a PCR-based assay was used in conjunction with LiPA and specimens for which genotyping was not attempted because the viral load was below the validated cut-off determined in the laboratory of origin. Results and conclusions: TMA-LiPA successfully genotyped 68 of 75 (90.7%) specimens that had failed genotyping by PCR-based methods used in conjunction with LiPA and 36 of 40 (90.0'Yo) specimens that were rejected for genotyping due to low viral load. Moreover, TMA-LiPA assigned subtype for 79 of 107 (73.8%) specimens. Our TMA-LiPA results reflected the distribution of HCV genotypes found in North America, and were 100% concordant with those of Amplicor 2.0 in conjunction with LiPA for control specimens genotyped by both assays. TMA-LiPA may prove useful both in optimizing LiPA performance and genotyping patient specimens. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Bayer Reference Testing Lab, Berkeley, CA USA. British Columbia Ctr Dis Control, Vancouver, BC, Canada. Univ Colorado Hosp, Denver, CO USA. Ontario Minist Hlth, Toronto, ON M5W 1R5, Canada. Long Beach Vet Adm Hosp, Long Beach, CA USA. Univ Miami, Miami, FL 33152 USA. NIDDK, NIH, Bethesda, MD USA. Innogenet, Ghent, Belgium. Bayer Corp, Div Diagnost, Berkeley, CA USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Comanor, L (reprint author), 180 Waverley St, Palo Alto, CA 94301 USA. NR 23 TC 18 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD SEP PY 2003 VL 28 IS 1 BP 14 EP 26 AR PII S1386-6532(02)00234-2 DI 10.1016/S1386-6532(02)00234-2 PG 13 WC Virology SC Virology GA 721EW UT WOS:000185304900002 PM 12927747 ER PT J AU Nemukhin, AV Grigorenko, BL Topol, IA Burt, SK AF Nemukhin, AV Grigorenko, BL Topol, IA Burt, SK TI Flexible effective fragment QM/MM method: Validation through the challenging tests SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE QM/MM methods; potentials of internal rotation ID MOLECULAR MECHANICAL METHODS; POTENTIAL-ENERGY SURFACE; OVOMUCOID 3RD DOMAIN; AB-INITIO; CHORISMATE MUTASE; CLAISEN REARRANGEMENT; COMBINED QUANTUM; HYBRID QM/MM; ACTIVE-SITE; SYSTEMS AB A new version of the QM/MM method, which is based on the effective fragment potential (EFP) methodology [Gordon, M. et al., J Phys Chem A 2001, 105, 293] but allows flexible fragments, is verified through calculations of model molecular systems suggested by different authors as challenging tests for QM/MM approaches. For each example, the results of QM/MM calculations for a partitioned system are compared to the results of an all-electron ab initio quantum chemical study of the entire system. In each case we were able to achieve approximately similar or better accuracy of the QM/MM results compared to those described in original publications. In all calculations we kept the same set of parameters of our QM/MM scheme. A new test example is considered when calculating the potential of internal rotation in the histidine dipeptide around the C-alpha-C-beta side chain bond. (C) 2003 Wiley Periodicals, Inc. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. NCI, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Topol, IA (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RI Nemukhin, Alexander/P-9662-2015 NR 42 TC 46 Z9 50 U1 0 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD SEP PY 2003 VL 24 IS 12 BP 1410 EP 1420 DI 10.1002/jcc.10309 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 707MX UT WOS:000184515400006 PM 12868106 ER PT J AU Beauchemin, S Hesterberg, D Chou, J Beauchemin, M Simard, RR Sayers, DE AF Beauchemin, S Hesterberg, D Chou, J Beauchemin, M Simard, RR Sayers, DE TI Speciation of phosphorus in phosphorus-enriched agricultural soils using X-ray absorption near-edge structure spectroscopy and chemical fractionation SO JOURNAL OF ENVIRONMENTAL QUALITY LA English DT Article ID P K-EDGE; XANES SPECTRA; PHOSPHATE; SORPTION; FORMS; CRYSTALLIZATION; MANAGEMENT; ADSORPTION; MOVEMENT; ALUMINUM AB Knowledge of phosphorus (P) species in P-rich soils is useful for assessing P mobility and potential transfer to ground water and surface waters. Soil P was studied using synchrotron X-ray absorption near-edge structure (XANES) spectroscopy (a nondestructive chemical-speciation technique) and sequential chemical fractionation. The objective was to determine the chemical speciation of P in long-term-fertilized, P-rich soils differing in pH, clay, and organic matter contents. Samples of three slightly acidic (pH 5.5-6.2) and two slightly alkaline (pH 7.4-7.6) soils were collected from A or B horizons in two distinct agrosystems in the province of Quebec, Canada. The soils contained between 800 and 2100 mg total P kg(-1). Distinct XANES features for Ca-phosphate mineral standards and for standards of adsorbed phosphate made it possible to differentiate these forms of P in the soil samples. The XANES results indicated that phosphate adsorbed on Fe- or Al-oxide minerals was present in all soils, with a higher proportion in acidic than in slightly alkaline samples. Calcium phosphate also occurred in all soils, regardless of pH. In agreement with chemical fractionation results, XANES data showed that Ca-phosphates were the dominant P forms in one acidic (pH 5.5) and in the two slightly alkaline (pH 7.4-7.6) soil samples. X-ray absorption near-edge structure spectroscopy directly identified certain forms of soil P, while chemical fractionation provided indirect supporting data and gave insights on additional forms of P such as organic pools that were not accounted for by the XANES analyses. C1 Nat Resources Canada, CANMET, Off 332A, Ottawa, ON K1A 0G1, Canada. N Carolina State Univ, Dept Soil Sci, Raleigh, NC 27695 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Canada Ctr Remote Sensing, Ottawa, ON K1A 0Y7, Canada. N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. RP Beauchemin, S (reprint author), Nat Resources Canada, CANMET, Off 332A, 555 Booth St, Ottawa, ON K1A 0G1, Canada. NR 63 TC 140 Z9 147 U1 6 U2 75 PU AMER SOC AGRONOMY PI MADISON PA 677 S SEGOE RD, MADISON, WI 53711 USA SN 0047-2425 J9 J ENVIRON QUAL JI J. Environ. Qual. PD SEP-OCT PY 2003 VL 32 IS 5 BP 1809 EP 1819 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA 723AD UT WOS:000185409500027 PM 14535324 ER PT J AU Doi, Y Inoue, Y Minowa, M Uchiyama, M Okawa, M AF Doi, Y Inoue, Y Minowa, M Uchiyama, M Okawa, M TI Periodic leg movements during sleep in Japanese community-dwelling adults based on the assessments of their bed partners SO JOURNAL OF EPIDEMIOLOGY LA English DT Article DE epidemiology; periodic limb movements; periodic leg movements during sleep; sleep ID NOCTURNAL MYOCLONUS; LIMB MOVEMENTS; APNEA; DISORDER; POPULATION; SYMPTOMS AB BACKGROUND: There is little known about epiderniologic evidence on periodic leg movements during sleep (PLMS) for the Japanese. The present study was a cross-sectional epidemiologic study to estimate the prevalence of PLMS and examine the associated factors of PLMS in Japanese community-dwelling adults. METHODS: The subjects were 884 with bed partners or bedroom mates of 1,889 Japanese adults aged 20 years and over randomly selected from the general population. The case ascertainment of PLMS was based on the assessments of their bed partners or bedroom mates using the Pittsburgh Sleep Quality Index. Multiple logistic regression analyses were used for investigating the associated factors. RESULTS: The age-adjusted prevalences (95% confidence interval) were 5.8% (4.7-6.8%) and 1.3% (0.8-1.9%) for 1 to 2-times, and 3-times or greater of PLMS per week during the preceding month, respectively. Those with PLMS were more likely to experience difficulty in initiating sleep, snore during sleep, be depressed, and suffer from peptic ulcer. Sex, age, difficulty in maintaining sleep, excessive daytime sleepiness, medication use to aid sleep, and any psychoactive substances (tobacco, alcohol, and caffeine) were not identified as significant associated factors of PLMS. CONCLUSIONS: The results suggest that the prevalence of PLMS in Japanese community-dwelling adults is not so high as those reported from Western countries, and that PLMS is correlated with some sleep and health disturbances. C1 Natl Publ Hlth Inst, Dept Epidemiol, Wako, Saitama 3510197, Japan. NIMH, Dept Psychophysiol, Bethesda, MD USA. Shiga Univ Med Sci, Dept Psychiat, Shiga, Japan. RP Doi, Y (reprint author), Natl Publ Hlth Inst, Dept Epidemiol, 2-3-6 Minami, Wako, Saitama 3510197, Japan. NR 34 TC 3 Z9 3 U1 0 U2 1 PU JAPAN EPIDEMIOLOGICAL ASSOC PI TOCHIGI PA JICHI MEDICAL SCHOOL, DEPT PUBLIC HEALTH, 3311-1 YAKUSHIJI, MINAMIKAWACH, TOCHIGI, 329-0498, JAPAN SN 0917-5040 J9 J EPIDEMIOL JI J. Epidemiol. PD SEP PY 2003 VL 13 IS 5 BP 259 EP 265 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 736EG UT WOS:000186157800004 PM 14604221 ER PT J AU Lee, HJ Chang, JH Kim, YS Kim, SJ Yang, HK AF Lee, HJ Chang, JH Kim, YS Kim, SJ Yang, HK TI Effect of Ets-related transcription factor (ERT) on transforming growth factor (TGF)-beta type II receptor gene expression in human cancer cell lines SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article DE transforming growth factor-beta (TGF-beta); Ets-related transcription factor (ERT); antisense; transcriptional repression; MFG-based retroviral vector ID BETA TGF-BETA; INACTIVATION; REPRESSION; INHIBITION; MECHANISMS AB Transcriptional repression of the TGF-beta type II receptor (RII) is one of the mechanisms leading to TGF-beta resistance. The newly identified epithelium-specific ets transcription factor ERT/ESX/ESE-1 binds to the TGF-beta RII promoter and induces promoter activity. This study aims to investigate the mechanisms underlying development of ERT-mediated TGF-beta resistance using antisense ERT oligonucleotide. We performed Northern blot analysis of TGF-beta RII expression in human colon cancer cell line, RKO, after transfecting these cells with MFG-antisense-ERT retroviral construct. The plasmid containing the chloramphenicol acetyltransferase (CAT) gene alone was used as the control. The amount of TGF-P RII mRNA appears to be poor in RKO cells expressing antisense ERT compared with both parental RKO and control cells. In conclusion, transfection of MFG-antisense-ERT construct into the colon cancer cell line could result in lower levels of TGF-beta RII mRNA expression, which means that ERT mediates the expression of TGF-beta RII and the transcriptional inhibition of ERT could be a one of the mechanisms of colonic carcinogenesis. More in vitro and in vivo studies should be required to evaluate this treatment in clinical setting. C1 Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110744, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. Hanyang Univ, Coll Med, Dept Biochem, Seoul 133791, South Korea. RP Yang, HK (reprint author), Seoul Natl Univ, Coll Med, Dept Surg, 28 Yongon Dong, Seoul 110744, South Korea. RI Yang, Han-Kwang/J-2767-2012; Lee, Hyuk-Joon/J-2782-2012 NR 19 TC 9 Z9 9 U1 0 U2 1 PU APSIT ASSOC PROM STUD IMMUNOL TUMOR PI ROME PA VIALE REGINA ELENA 291, 00161 ROME, ITALY SN 0392-9078 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD SEP PY 2003 VL 22 IS 3 BP 477 EP 480 PG 4 WC Oncology SC Oncology GA 731KC UT WOS:000185882000019 PM 14582709 ER PT J AU Eltzschig, HK Ibla, JC Furuta, GT Leonard, MO Jacobson, KA Enjyoji, K Robson, SC Colgan, SP AF Eltzschig, HK Ibla, JC Furuta, GT Leonard, MO Jacobson, KA Enjyoji, K Robson, SC Colgan, SP TI Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A(2B) receptors SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE adenosine; ectonucleotidase; endothelium; neutrophil; inflammation ID TRANSENDOTHELIAL MIGRATION; BARRIER FUNCTION; ECTO-5'-NUCLEOTIDASE CD73; EPITHELIAL PERMEABILITY; CELL LINE; HYPOXIA; ATP; EXPRESSION; ACTIVATION; DIPHOSPHOHYDROLASE AB Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (>60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (>20-and >12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A(2B) receptor (AdoRA(2B)) is selectively up-regulated by hypoxia (>5-fold increase in mRNA), and that AdoRA(2B) antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Anesthesiol Perioperat, Ctr Expt Therpeut & Reperfus Injury, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02115 USA. Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. NIH, Mol Recognit Sect, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Transplantat Ctr, Boston, MA 02115 USA. Univ Tubingen, Dept Anesthesiol & Intens Care Med, D-72076 Tubingen, Germany. RP Colgan, SP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Anesthesiol Perioperat, Ctr Expt Therpeut & Reperfus Injury, Thorn Bldg 704,75 Francis St, Boston, MA 02115 USA. RI Jacobson, Kenneth/A-1530-2009; Colgan, Sean/B-4573-2009 OI Jacobson, Kenneth/0000-0001-8104-1493; FU Intramural NIH HHS [Z01 DK031116-20]; NHLBI NIH HHS [HL 60569, R01 HL060569]; NIDCR NIH HHS [DE 13499, P01 DE013499]; NIDDK NIH HHS [DK 50189, R01 DK050189, R29 DK050189, R37 DK050189] NR 47 TC 301 Z9 310 U1 0 U2 10 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 1 PY 2003 VL 198 IS 5 BP 783 EP 796 DI 10.1084/jem.20030891 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 718PK UT WOS:000185155500010 PM 12939345 ER PT J AU Saitoh, S Odom, S Gomez, G Sommers, CL Young, HA Rivera, J Samelson, LE AF Saitoh, S Odom, S Gomez, G Sommers, CL Young, HA Rivera, J Samelson, LE TI The four distal tyrosines are required for LAT-dependent signaling in Fc epsilon RI-mediated mast cell activation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE signal transduction; adapter molecules; phosphorylation; Fc epsilon receptor; anaphylaxis ID AFFINITY IGE RECEPTOR; BASOPHILIC LEUKEMIA-CELLS; T-CELLS; PHOSPHOLIPASE C-GAMMA-1; ADAPTER PROTEIN; KINASE; SLP-76; GRB2; RAS; PHOSPHORYLATION AB The linker for activation of T cells (LAT) is an adaptor protein critical for FcepsilonRI-mediated mast cell activation. LAT is a substrate of the tyrosine kinases activated after TCR and FcepsilonRI engagement. After phosphorylation of the cytosolic domain of LAT, multiple signaling molecules such as phospholipase C-gamma1, Grb2, and Gads associate with phosphorylated LAT via their SH2 domains. The essential role of the four distal tyrosines in TCR-mediated signaling and T cell development has been demonstrated by experiments using LAT-deficient cell lines and genetically modified mice. To investigate the role of these four tyrosines of LAT in FcepsilonRI-mediated mast cell activation, bone marrow-derived mast cells from LAT-deficient mice were infected with retroviral vectors designed to express wild-type or mutant LAT. Examination of bone marrow-derived mast cells expressing various tyrosine to phenylalanine mutants in LAT demonstrates a differential requirement for these different binding sites. In these studies, assays of biochemical pathways, degranulation, and cytokine and chemokine release were performed. Finally, the role of these tyrosines was also evaluated in vivo using genetically modified animals. Deletion of all four distal tyrosines, and in particular, loss of the primary phospholipase C-gamma-binding tyrosine had a significant effect on antigen-induced histamine release. C1 NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. NIAMSD, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Samelson, LE (reprint author), NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. NR 39 TC 65 Z9 66 U1 0 U2 0 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 1 PY 2003 VL 198 IS 5 BP 831 EP 843 DI 10.1084/jem.20030574 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 718PK UT WOS:000185155500014 PM 12953098 ER PT J AU Dolensky, B Narayanan, J Kirk, KL AF Dolensky, B Narayanan, J Kirk, KL TI Preparation of beta-fluoro- and beta,beta-difluoro-histidinols SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE "FBr" addition; imidazole analogues; histidine biosynthesis; solvent effects on halogen mobility ID FLUOROUROCANIC ACIDS; BUILDING-BLOCKS; DERIVATIVES AB Nucleophilic attack of azide on 2-bromo-3-fluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1a) in aprotic solvent occurs on the 2-position to give the 2-azido derivative (2a). Reduction of azide and removal of the trityl group produces beta-fluorohistidinol (6a). Elimination of HBr from 1a followed by "FBr" addition to the resulting double bond gives 2-bromo-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1b). Nucleophilic attack of azide followed by reduction and removal of the trityl group, as for the preparation of 6a, gives beta,beta-difluorohistidinol (6b). Initial attempts, under a variety of conditions, to oxidize the fluorinated histidinol precursors to carboxylic acids have not been successful. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov NR 12 TC 5 Z9 5 U1 1 U2 5 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD SEP 1 PY 2003 VL 123 IS 1 BP 95 EP 99 DI 10.1016/S0022-1139(03)00096-4 PG 5 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 725BM UT WOS:000185522800015 ER PT J AU Yesavage, JA Friedman, L Ancoli-Israel, S Bliwise, D Singer, C Vitiello, MV Monjan, AA Lebowitz, B AF Yesavage, JA Friedman, L Ancoli-Israel, S Bliwise, D Singer, C Vitiello, MV Monjan, AA Lebowitz, B TI Development of diagnostic criteria for defining sleep disturbance in Alzheimer's disease SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article DE sleep; Alzheimer's disease; diagnosis ID NURSING-HOME PATIENTS; CIRCADIAN REST-ACTIVITY; BRIGHT LIGHT THERAPY; LONG-TERM-CARE; PHYSICAL-ACTIVITY; ENVIRONMENTAL INTERVENTION; SUPRACHIASMATIC NUCLEUS; NIGHTTIME ENVIRONMENT; ACTIGRAPHIC MEASURES; RHYTHM DISTURBANCES AB This article proposes new standards for identifying, defining, and naming sleep/wake cycle disturbances associated with Alzheimer's disease (AD) to aid in more effective research, including the development and testing of potential treatments. Many AD patients develop sleep/wake cycle disturbances associated with distress, depression, and sleep disturbances in the caregiver, as well as early nursing home placement for the patient. The Food and Drug Administration Psychopharmacological Drugs Advisory Committee has emphasized the need for a comprehensive diagnostic system. A key point made by the committee was that behavioral problems associated with dementia (including sleep and chrono-biological disturbances) are scientifically and clinically valid targets of pharmacologic treatment. However, current diagnostic criteria preclude development of FDA-acceptable studies of pharmacological interventions because they do not include the required specific indications for treatment. This article attempts to develop better-defined provisional criteria with the goal of promoting epidemiological, physiological, and, especially, pharmacological research on sleep/wake disturbances. C1 Palo Alto VA Hlth Care Syst, Sierra Pacific Mental Illness Res Educ, Palo Alto, CA 94304 USA. Palo Alto VA Hlth Care Syst, Ctr Clin, Palo Alto, CA 94304 USA. Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Palo Alto, CA 94304 USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. San Diego Vet Affairs Healthcare Syst, San Diego, CA USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Washington, Seattle, WA 98195 USA. NIA, Neurosci & Neuropsychol Aging Program, Bethesda, MD 20892 USA. NIMH, Adult & Geriatr Treatment & Prevent Intervent Res, Bethesda, MD 20892 USA. RP Yesavage, JA (reprint author), Palo Alto VA Hlth Care Syst, Sierra Pacific Mental Illness Res Educ, Palo Alto, CA 94304 USA. EM yesavage@stanford.edu OI Vitiello, Michael/0000-0002-9776-0473 FU NIA NIH HHS [AG10643, AG08415, AG15301, AG17824]; NIMH NIH HHS [KO2 MH01158, MH53575] NR 89 TC 63 Z9 64 U1 3 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0891-9887 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD SEP PY 2003 VL 16 IS 3 BP 131 EP 139 DI 10.1177/0891988703255684 PG 9 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA 847GJ UT WOS:000223380400001 PM 12967054 ER PT J AU Kuznetsov, SB Matveeva, NM Murphy, WJ O'Brien, SJ Serov, OL AF Kuznetsov, SB Matveeva, NM Murphy, WJ O'Brien, SJ Serov, OL TI Mapping of 53 loci in american mink (Mustela vison) SO JOURNAL OF HEREDITY LA English DT Article ID CHROMOSOMAL LOCALIZATION; CLONE PANEL; MOUSE; REARRANGEMENTS; ASSIGNMENT; CARNIVORA; HYBRIDS; MAMMALS; GENOME AB Fifty-three genes were mapped in the American mink genome using polymerase chain reaction (PCR)-based analysis of a Chinese hamster-American mink somatic cell hybrid panel. Heterologous primers designed for cat gene mapping were used in this study. Forty-nine of these loci were localized into expected chromosome regions according to Zoo-FISH data, whereas four loci-ALPL, CDC20, ERF-2, and Fc(Mv)23617-were mapped out of expected conserved regions. PCR products amplified with primers corresponding to these four markers were partly sequenced and verified using BLAST. The results showed the homology to be more than 90% between mink and human or cat counterparts. At present, the gene map of American mink has expanded to 127 loci. C1 Inst Cytol & Genet, Lab Dev Genet, Novosibirsk 90, Russia. NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Fed Rio de Janeiro, Inst Biophys, Rio De Janeiro, Brazil. RP Serov, OL (reprint author), Inst Cytol & Genet, Lab Dev Genet, Novosibirsk 90, Russia. NR 22 TC 6 Z9 6 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD SEP PY 2003 VL 94 IS 5 BP 386 EP 391 DI 10.1093/jhered/esg084 PG 6 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 733RA UT WOS:000186013400004 PM 14557391 ER PT J AU Schmidt, J Metselaar, JM Gold, R AF Schmidt, J Metselaar, JM Gold, R TI Intravenous liposomal prednisolone downregulates in situ TNF-alpha production by T-cells in experimental autoimmune encephalomyelitis SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE glucocorticosteroids; drug targeting; long-circulating liposomes; multiple sclerosis; EAE; neuroinflammation; autoimmunity; immunohistochemical double labeling ID MULTIPLE-SCLEROSIS; THERAPY; METHYLPREDNISOLONE; DEMYELINATION; PATHOGENESIS; MS AB Multiple sclerosis (MS) relapses are treated with high-dose IV glucocorticosteroids. Here we investigated mechanisms of long-circulating polyethylene glycol-coated liposomes encapsulating prednisolone (PL) in adoptive transfer experimental autoimmune encephalomyelitis. Rats received IV 10 mg/kg PL 6, 18, or 42 hr before sacrifice at disease maximum. In formalin-fixed, paraffin-embedded spinal cord we employed a nonfluorescent immunohistochemical (IHC) double labeling. We stained for tumor necrosis factor-alpha (TNF-alpha) in combination with a T-cell antigen. Compared with PBS-containing liposomes, PL at 18 hr, and more at 42 hr, significantly reduced the rate of TNF-alpha double-labeled T-cells. This correlated with an ameliorated disease score at day 5 after PL 42 hr. Our results help to further understand mechanisms of action of drug targeting by liposomal steroids, with possible implications for treatment of autoimmune disorders such as MS. C1 Univ Wurzburg, Dept Neurol, D-8700 Wurzburg, Germany. Univ Utrecht, Dept Pharmaceut, Utrecht, Netherlands. RP Schmidt, J (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N 252,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. RI Schmidt, Jens/B-5791-2013 NR 12 TC 16 Z9 16 U1 0 U2 0 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 SEP PY 2003 VL 51 IS 9 BP 1241 EP 1244 PG 4 WC Cell Biology SC Cell Biology GA 716NB UT WOS:000185034200015 PM 12923250 ER PT J AU Nagata, S Salvatore, G Pastan, I AF Nagata, S Salvatore, G Pastan, I TI DNA immunization followed by a single boost with cells: a protein-free immunization protocol for production of monoclonal antibodies against the native form of membrane proteins SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE hybridoma; monoclonal antibody; DNA immunization; ret; CD30; immunotherapy ID DIRECT GENE-TRANSFER; PHAGE DISPLAY; INTRASPLENIC IMMUNIZATION; RECOMBINANT IMMUNOTOXINS; HODGKINS-DISEASE; MUSCLE INVIVO; RET RECEPTOR; PLASMID DNA; CD30; GENERATION AB Recent advancements in antibody-based therapies require the development of an efficient method for generation of monoclonal antibodies (MAbs) against the native form of membrane proteins. We examined DNA immunization followed by a single boost with cells as a protein-free immunization protocol for production of MAbs. Mice immunized with plasmid cDNAs encoding human CD30 or Ret tyrosine kinase were given a single boost with cells expressing the corresponding antigen prior to cell fusion. A total of nine cell fusion experiments revealed that the cell boost is necessary for efficient generation of hybridomas and the DNA-cell boost method gave good yields of specific MAbs (5-59 MAbs from one mouse). All IgG isotypes except IgG3 were generated, although IgG2a was the dominant isotype. All the MAbs reacted with native antigens expressed on cells in a fluorescence-activated cell sorter (FACS) analysis as well as with recombinant CD30 or Ret protein genetically fused with human Fc in an enzyme-linked immunosorbent assay (ELISA). The affinities of the anti-CD30 MAbs to CD30-Fc protein ranged from 0.9 to 12.4 nM K(d)s, which were comparable to existing MAbs to these proteins, which range from 3.0 to 13.0 nM. Western blot analysis and topographical epitope mapping experiments based on the mutual competition of pairs of the anti-CD30 MAbs revealed that about 40% of the epitopes were linear epitopes and that each epitope was topographically classified into one of six groups. The large number of MAbs that react with high affinities to a variety of epitopes on the native form of antigens indicates that the method presented in this paper could be generally useful for generating MAbs to other membrane proteins. Published by Elsevier B.V. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Rm 5106, Bethesda, MD 20892 USA. NR 53 TC 33 Z9 38 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD SEP PY 2003 VL 280 IS 1-2 BP 59 EP 72 DI 10.1016/S0022-1759(03)00192-3 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 725LB UT WOS:000185543700006 PM 12972188 ER PT J AU Martin, MP Bashirova, A Traherne, J Trowsdale, J Carrington, M AF Martin, MP Bashirova, A Traherne, J Trowsdale, J Carrington, M TI Cutting edge: Expansion of the KIR locus by unequal crossing over SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL INHIBITORY RECEPTORS; GENE CONTENT; ALLELIC POLYMORPHISM; HAPLOTYPES CONTAIN; DIVERSITY; EVOLUTION; ARTHRITIS; FAMILIES; MHC AB The killer Ig-like receptor (KIR) genes have high sequence similarity and are organized in a head-to-tail fashion. These properties may enhance misalignment of homologous chromosomes during synapsis preceding meiotic recombination, resulting in unequal crossing over. We have identified an extended KIR haplotype that contains a novel hybrid gene and two copies of each of two previously described KIR genes. A parsimonious mechanism for the derivation of this haplotype invokes unequal crossing over between two known ancestral KIR haplotypes. These data raise the possibility that unequal crossing over may be responsible in part for the expansion/contraction of KIR haplotypes as well as other homologous gene families that map in tandem. C1 NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Univ Cambridge, Dept Pathol, Div Immunol, Cambridge CB2 1QP, England. RP Carrington, M (reprint author), NCI, Basic Res Program, Sci Applicat Int Corp, POB B, Frederick, MD 21702 USA. FU Medical Research Council [G9800943]; NCI NIH HHS [N01 CO 12400] NR 22 TC 94 Z9 95 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2003 VL 171 IS 5 BP 2192 EP 2195 PG 4 WC Immunology SC Immunology GA 715KM UT WOS:000184970900003 PM 12928362 ER PT J AU Salazar-Fontana, LI Barr, V Samelson, LE Bierer, BE AF Salazar-Fontana, LI Barr, V Samelson, LE Bierer, BE TI CD28 engagement promotes actin polymerization through the activation of the small Rho GTPase Cdc42 in human T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; SIGNAL-TRANSDUCTION; ADHESION MOLECULES; ARP2/3 COMPLEX; TCR LIGATION; CYTOSKELETON; LYMPHOCYTES; PROTEINS; PHOSPHORYLATION; REORGANIZATION AB Engagement of the costimulatory molecule CD28 is an important step in the optimal activation of T cells. Nevertheless, the specific role of CD28 in the formation of the immunological synapse and cytoskeletal changes that occur upon TCR/CD3 complex engagement is still poorly understood. Using Ab-coated surfaces, we show that CD28 engagement in the absence of any other signal induced the formation of cytoplasmic elongations enriched in filamentous actin (F-actin), in this work called filopodia or micro-spikes. Such structures were specific for engagement of CD28 on mAb-coated surfaces because they could not be observed in surfaces coated with either poly(L-lySine) or anti-CD3 mAb. The signaling pathway coupling CD28 to cytoskeletal rearrangements required Src-related kinase activity and promoted Vav phosphorylation and Cdc42 activation independently of the zeta-chain-associated kinase (ZAP-70). CD28-induced filopodia required Cdc42 GTPase activity, but not the related Rho GTPase Rac1. Moreover, Cdc42 colocalized to areas of increased F-actin. Our results support a specific role for the activation of the small Rho GTPase Cdc42 in the actin reorganization mediated by CD28 in human T cells. C1 NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bierer, BE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 33 TC 53 Z9 56 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 1 PY 2003 VL 171 IS 5 BP 2225 EP 2232 PG 8 WC Immunology SC Immunology GA 715KM UT WOS:000184970900007 PM 12928366 ER PT J AU Gagnon, SJ Wang, ZC Turner, R Damirjian, M Biddison, WE AF Gagnon, SJ Wang, ZC Turner, R Damirjian, M Biddison, WE TI MHC recognition by hapten-specific HLA-A2-restricted CD8(+) CTL SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; CLASS-I; CELL-RECEPTORS; STRUCTURAL BASIS; HTLV-1 TAX; PEPTIDES; COMPLEX; ANTIGEN; IDENTIFICATION; EPITOPES AB T cell recognition by peptide-specific alphabeta TCRs involves not only recognition of the peptide, but also recognition of multiple molecular features on the surface of the MHC molecule to which the peptide has been bound. We have Previously shown that TCRs that are specific for five different peptides presented by HLA-A2 recognize similar molecular features on the surface of the alpha1 and alpha2 helices of the HLA-A2 molecule. We next asked whether these same molecular features of the HLA-A2 molecule would be recognized by hapten-specific HLA-A2-restricted TCRs, given that hapten-specific T cells frequently show reduced MHC dependence/restriction. The results show that a panel of CD8(+) CTL that are specific for the hapten DNP bound to two different peptides presented by HLA-A2 do the following: 1) show stringent MHC restriction, and 2) are largely affected by the same mutations on the HLA-A2 molecule that affected recognition by peptide-specific CTL. A small subset of this panel of CD8(+) CTL can recognize a mutant HLA-A2 molecule in the absence of hapten. These data suggest that TCR recognition of a divergent repertoire of ligands presented by HLA-A2 is largely dependent upon common structural elements in the central portion of the peptide-binding site. C1 NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Biddison, WE (reprint author), NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. NR 35 TC 5 Z9 6 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2003 VL 171 IS 5 BP 2233 EP 2241 PG 9 WC Immunology SC Immunology GA 715KM UT WOS:000184970900008 PM 12928367 ER PT J AU Su, SB Silver, PB Wang, P Chan, CC Caspi, RR AF Su, SB Silver, PB Wang, P Chan, CC Caspi, RR TI Dissociating the enhancing and inhibitory effects of pertussis toxin on autoimmune disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CARBOHYDRATE RECOGNITION DOMAINS; B-OLIGOMER; HUMAN MACROPHAGES; T-CELLS; ENCEPHALOMYELITIS; PROTEIN; EXPRESSION; INDUCTION; RESPONSES; MICE AB Pertussis toxin (PT) has both enhancing and inhibitory effects on experimental autoimmune disease, depending on its. time of administration relative to immunization. The inhibitory effect is due to blocking of G(i)-coupled receptors by the enzymatic A subunit. In this study, we attribute the enhancing effect of PT to the cell-binding B subunit (PT-B). C57BL/6 mice, a strain that requires PT to develop experimental uveitis, were immunized with a retinal Ag and were injected with whole PT, PT-B, or vehicle. Disease and associated immunological responses were evaluated. The results showed that PT-B, determined to be free of biologically significant contamination with whole PT or with endotoxin, was able to mimic all the effects of PT with respect to disease induction, enhancement of delayed-type hypersensitivity, enhancement of lymphocyte proliferation, induction of an innate IL-12 response, and promotion of an adaptive IFN-gamma response to the uveitogenic Ag. Our results suggest that PT-B is largely responsible for the disease-enhancing properties of PT. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N222, Bethesda, MD 20892 USA. NR 32 TC 9 Z9 10 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 1 PY 2003 VL 171 IS 5 BP 2314 EP 2319 PG 6 WC Immunology SC Immunology GA 715KM UT WOS:000184970900017 PM 12928376 ER PT J AU Caldwell, SA Ryan, MH McDuffie, E Abrams, SI AF Caldwell, SA Ryan, MH McDuffie, E Abrams, SI TI The Fas/Fas ligand pathway is important for optimal tumor regression in a mouse model of CTL adoptive immunotherapy of experimental CMS4 lung metastases SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE-MEDIATED CYTOTOXICITY; FLICE-INHIBITORY PROTEIN; RENAL-CANCER CELLS; IN-VIVO; PULMONARY METASTASES; CD8(+) CTL; T-CELLS; FAS; PERFORIN; ANTIGEN AB The mechanisms of CTL-mediated tumor regression in vivo remain to be fully understood. If CTL do mediate tumor regression in vivo by direct cytotoxicity, this may occur via two major effector mechanisms involving the secretion of perforin/granzymes and/or engagement of Fas by Fas ligand (FasL) expressed by the activated CTL. Although the perforin pathway has been considered the dominant player, it is unclear whether Fas-mediated cytotoxicity is additionally required for optimal tumor rejection. Previously, we produced H-2L(d)-restricted CTL reactive against the CMS4 sarcoma, which expresses a naturally occurring rejection Ag recognized by these CTL and harbors a cytokine (IFN-gamma plus TNF)-inducible, Fas-responsive phenotype. The adoptive transfer of these CTL to syngeneic BALB/c mice with minimal (day 3 established) or extensive (day 10 established) experimental pulmonary metastases resulted in strong antitumor responses. Here we investigated whether a FasL-dependent CTL effector mechanism was important for optimal tumor regression in this adoptive immunotherapy model. The approach taken was to compare the therapeutic efficacy of wild-type to FasL-deficient (gld) CTL clones by adoptive transfer. In comparison with wild-type CTL, gld-CTL efficiently mediated tumor cytolysis and produced comparable amounts of IFN-gamma, after tumor-specific stimulation, as in vitro assessments of Ag recognition. Moreover, gld-CTL mediated comparably potent antitumor effects in a minimal disease setting, but were significantly less effective under conditions of an extensive tumor burden. Overall, under conditions of extensive lung metastases, these data revealed for the first time an important role for a FasL-dependent CTL effector mechanism in optimal tumor regression. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10,Room 5B46,10 Ctr Dr, Bethesda, MD 20892 USA. NR 38 TC 53 Z9 58 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2003 VL 171 IS 5 BP 2402 EP 2412 PG 11 WC Immunology SC Immunology GA 715KM UT WOS:000184970900028 PM 12928387 ER PT J AU Yano, S Ghosh, P Kusaba, H Buchholz, M Longo, DL AF Yano, S Ghosh, P Kusaba, H Buchholz, M Longo, DL TI Effect of promoter methylation on the regulation of IFN-gamma gene during in vitro differentiation of human peripheral blood T cells into a Th2 population SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-3; HISTONE ACETYLATION; LINEAGE COMMITMENT; CHROMATIN-STRUCTURE; CYTOKINE RESPONSES; EXPRESSION; MICE; IL-4; DNA; BET AB The carefully orchestrated. events that result in a protective immune response are coordinated to a large extent by cytokines produced by Th1 and Th2 cell subsets. Th1 cells preferentially produce IL-2 and IFN-gamma, resulting in a cellular response that helps to eliminate infected cells. In contrast, Th2 cells produce IL-4, IL-5, IL-6, and IL-10, stimulating an Ab response that attacks extracellular pathogens, thereby preventing the cells from becoming infected. To elucidate the mechanisms of differential regulation of cytokine genes by these two different subsets of T cells, we established an in vitro differentiation model of freshly isolated human peripheral blood T cells in which IFN-gamma was used as an index gene to study the transcriptional regulation. The data presented here demonstrate that the IFN-gamma promoter undergoes differential methylation during in vitro differentiation: the promoter becomes hypermethylated in Th2 cells, whereas it is hypomethylated in Th1 cells. Hypermethylation in Th2 cells results in chromatin condensation and exclusion of CREB proteins from the IFN-gamma promoter. Treatment with 5-azacytidine, a demethylating agent, causes Th2 cells to reverse histone condensation and enables CREB recruitment to the hypomethylated promoter. This results in the increased production of IFN-gamma. These data indicate the importance of promoter methylation in the regulation of the IFN-gamma gene during differentiation. C1 NIA, Lymphocyte Cell Biol Sect, Immunol Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Longo, DL (reprint author), NIA, Lymphocyte Cell Biol Sect, Immunol Lab, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 31 TC 71 Z9 80 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 1 PY 2003 VL 171 IS 5 BP 2510 EP 2516 PG 7 WC Immunology SC Immunology GA 715KM UT WOS:000184970900041 PM 12928400 ER PT J AU Tritel, M Stoddard, AM Flynn, BJ Darrah, PA Wu, CY Wille, U Shah, JA Huang, Y Xu, L Betts, MR Nabel, GJ Seder, RA AF Tritel, M Stoddard, AM Flynn, BJ Darrah, PA Wu, CY Wille, U Shah, JA Huang, Y Xu, L Betts, MR Nabel, GJ Seder, RA TI Prime-boost vaccination with HIV-1 Gag protein and cytosine phosphate guanosine oligodeoxynucleotide, followed by adenovirus, induces sustained and robust humoral and cellular immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VACCINIA VIRUS ANKARA; CD8(+) T-CELLS; HUMAN DENDRITIC CELLS; BACTERIAL CPG-DNA; IN-VIVO; RECOMBINANT ADENOVIRUS; RHESUS MACAQUES; ANTIGEN PRESENTATION; PROTECTIVE EFFICACY; LYMPHOCYTE ACTIVITY AB A prophylactic vaccine for HIV-1 will probably require the induction and maintenance of both humoral and cellular immunity. One current strategy to achieve such long term immune responses is a prime-boost vaccination approach using a DNA priming inoculation, followed by recombinant viral boost. In this report we use a novel prime-boost approach in which the priming injections consist of recombinant HIV-1 Gag protein mixed with cytosine phosphate guanosine oligodeoxynucleotide (CpG ODN), followed by recombinant adenoviral boost expressing HIV-1 Gag. Analysis of the immune responses indicates that HIV-1 Gag protein plus CpG ODN immunization alone induces potent humoral as well as Th1 and CD8(+) T cell responses. Boosting with recombinant adenovirus strikingly enhances CD8(+), but not Th1, T cell responses, resulting in CD8(+) T cell responses far greater in magnitude than Th1 responses. Furthermore, the Th1 and CD8(+) T cell responses following prime-boost immunization were seen in both lymphoid and peripheral mucosal organs and were sustained over several months. Together, these data suggest a new immunization approach for elicitation of long term humoral and cellular immune responses. C1 NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Vector Core, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 40-3512, Bethesda, MD 20892 USA. NR 65 TC 62 Z9 63 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2003 VL 171 IS 5 BP 2538 EP 2547 PG 10 WC Immunology SC Immunology GA 715KM UT WOS:000184970900045 PM 12928404 ER PT J AU Okazaki, T Pendleton, CD Lemonnier, F Berzofsky, JA AF Okazaki, T Pendleton, CD Lemonnier, F Berzofsky, JA TI Epitope-enhanced conserved HIV-1 peptide protects HLA-A2-transgenic mice against virus expressing HIV-1 antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; TRANSGENIC MICE; CELL RESPONSES; CTL RESPONSES; IMMUNOGENICITY; HLA-A2.1; COMPLEX; IDENTIFICATION; INFECTION AB HIV epitopes may have developed to be poor immunogens. As a counterapproach HIV vaccine strategy, we used epitope enhancement of a conserved HIV reverse transcriptase (RT) epitope for induction of antiviral protection in HLA-A2-transgenic mice mediated by human HLA-A2-restricted CTLs. We designed two epitope-enhanced peptides based on affinity for HLA-A2, one substituted in anchor residues (RT-2L9V) and the other also with tyrosine at position 1 (RT-1Y2L9V), and examined the balance between HLA binding and T cell recognition. CTL lines and bulk cultures in two HLA-A2-transgenic mouse strains showed that RT-2L9V was more effective in inducing CTL reactive with wild-type Ag than RT-1Y2L9V, despite the higher affinity of the latter, because the 1Y substitution unexpectedly altered T cell recognition. Accordingly, RT-2L9V afforded the greatest protection in vivo against a surrogate virus expressing HIV-1 RT mediated by HLA-A2-restricted CTL in a mouse in which all CTL are restricted to only the human HLA molecule. Such antiviral protection has not been previously achieved with an HLA epitope-enhanced vaccine. These findings define a critical balance between MHC affinity and receptor cross-reactivity required for effective epitope enhancement and also demonstrate construction and efficacy of such a component of a new generation vaccine. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. Inst Pasteur, Unite Immunite Cellulaire Antivirale, Paris, France. RP Berzofsky, JA (reprint author), St Marianna Univ, Div Rheumatol, Dept Internal Med, Sch Med,Miyamae Ku, 2-16-1 Sugao, Kawasaki, Kanagawa 2168512, Japan. NR 38 TC 30 Z9 31 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 1 PY 2003 VL 171 IS 5 BP 2548 EP 2555 PG 8 WC Immunology SC Immunology GA 715KM UT WOS:000184970900046 PM 12928405 ER PT J AU Cataisson, C Joseloff, E Murillas, R Wang, A Atwell, C Torgerson, S Gerdes, M Subleski, J Gao, JL Murphy, PM Wiltrout, RH Vinson, C Yuspa, SH AF Cataisson, C Joseloff, E Murillas, R Wang, A Atwell, C Torgerson, S Gerdes, M Subleski, J Gao, JL Murphy, PM Wiltrout, RH Vinson, C Yuspa, SH TI Activation of cutaneous protein kinase C alpha induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SKIN TUMOR-PROMOTION; TRANSGENIC MICE; DIFFERENTIAL EXPRESSION; MOUSE KERATINOCYTES; GENE-EXPRESSION; IN-VIVO; NEOPLASTIC KERATINOCYTES; TRANSCRIPTIONAL ACTIVITY; EPIDERMAL-KERATINOCYTES; TRANSDUCTION PATHWAYS AB Skin keratinocytes are major mediators of host immune responses. The skin is also a target for immunologically based inflammation in many pathological states. Activation of protein kinase C (PKC) can induce cutaneous inflammation, but the precise role of each of six cutaneous PKC isoforms (alpha, delta, epsilon, eta, zeta, mu) that regulate normal skin homeostasis or contribute to skin pathology has not been clarified. We generated transgenic mice that overexpress PKCalpha in the basal layer of the epidermis and the outer root sheath of hair follicles under the regulation of the bovine keratin 5 promoter. K5-PKCalpha transgenic mice exhibit severe intraepidermal neutrophilic inflammation and disruption of the epidermis and upper hair follicles when treated topically with 12-O-tetradecanoylphorbol-13-acetate (TPA). Both TPA and UVB cause apoptosis in transgenic skin, but only TPA evokes intraepidermal inflammation. TPA also induces apoptosis in cultured transgenic keratinocytes, and this is prevented by an AP-1 dominant-negative construct. However, inhibiting AP-1 in vivo does not abrogate intraepidermal inflammation. Transcripts for specific cytokines and chemokines are elevated in TPA-treated cultured transgenic keratinocytes, and conditioned culture medium from these cells promotes neutrophil migration in vitro. Chemokine expression and neutrophil migration are not diminished by inhibiting AP-1. Thus, PKCalpha activation induces keratinocyte apoptosis via an AP-1-dependent pathway and mediates chemokine induction and intraepidermal inflammation independently. This model system will be useful to define specific chemokines regulated by PKCalpha that promote intraepidermal neutrophilic inflammation, a condition that characterizes several human cutaneous diseases such as pustular psoriasis and acute generalized exanthematous pustulosis. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Lab Metab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, 37 Convent Dr,MSC 4255,Bldg 37,Room 4068, Bethesda, MD 20892 USA. NR 63 TC 53 Z9 56 U1 0 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 1 PY 2003 VL 171 IS 5 BP 2703 EP 2713 PG 11 WC Immunology SC Immunology GA 715KM UT WOS:000184970900065 PM 12928424 ER PT J AU Rosenberg, SA Yang, JC Robbins, PF Wunderlich, JR Hwu, P Sherry, RM Schwartzentruber, DJ Topalian, SL Restifo, NP Filie, A Chang, R Dudley, ME AF Rosenberg, SA Yang, JC Robbins, PF Wunderlich, JR Hwu, P Sherry, RM Schwartzentruber, DJ Topalian, SL Restifo, NP Filie, A Chang, R Dudley, ME TI Cell transfer therapy for cancer: Lessons from sequential treatments of a patient with metastatic melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; cancer; melanoma ID TUMOR-INFILTRATING LYMPHOCYTES; ADOPTIVE TRANSFER; T-LYMPHOCYTES; INTERLEUKIN-2; IMMUNOTHERAPY; PHENOTYPES; REGRESSION; CLONES AB The development of effective autologous cell transfer therapies for the treatment of patients with cancer has been difficult, in part because the cells used to treat each patient are different, as are the patient's tumor and immune status. Much can thus be learned by sequential treatments of the same patient with the same cells, making single modifications in the treatments to determine which factors are critical. The authors have treated a single patient with five sequential administrations of the same cells with minor modifications in the mode of administration and the immune status of the patient. The treatment of this patient strongly suggested that 1) the highly avid recognition of tumor antigens in vitro by a tratisferred lymphocyte population does not necessarily predict in vivo antitumor activity; 2) the administration of highly avid antitumor autologous lymphocyte populations can be far more active in mediating tumor regression in vivo when administered after nonmyeloablative chemotherapy than when administered without this prior chemotherapy; 3) intra-arterial administration of highly avid antitumor autologous lymphocytes into the blood supply of the tumor can be more effective in mediating tumor regression than the intravenous administration of these same tumor infiltrating lymphocytes; 4) one mechanism of tumor escape from immunotherapy is loss of class I MHC antigen expression by the tumor due to mutation of the beta-2 microglobulin gene. C1 NCI, Canc Res Ctr, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Canc Res Ctr, Surg Branch, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 17 TC 37 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD SEP-OCT PY 2003 VL 26 IS 5 BP 385 EP 393 DI 10.1097/00002371-200309000-00001 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 718KR UT WOS:000185144900001 PM 12973027 ER PT J AU Fischl, MA Ribaudo, HJ Collier, AC Erice, A Giuliano, M Dehlinger, M Eron, JJ Saag, MS Hammer, SM Vella, S Morse, GD Feinberg, JE AF Fischl, MA Ribaudo, HJ Collier, AC Erice, A Giuliano, M Dehlinger, M Eron, JJ Saag, MS Hammer, SM Vella, S Morse, GD Feinberg, JE CA Adult AIDS Clin Trials Grp 388 Stu TI A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th Conference on Retroviruses and Opportunistic Infection CY FEB 24-28, 2002 CL SEATTLE, WASHINGTON ID HIV-INFECTED ADULTS; PROTEASE INHIBITOR; REVERSE-TRANSCRIPTASE; HIV-1-INFECTED PATIENTS; COMBINATION THERAPY; CLINICAL-TRIALS; PLUS INDINAVIR; NAIVE PATIENTS; DOUBLE-BLIND; ZIDOVUDINE AB To compare long-term virologic benefits of antiretroviral regimens in persons with advanced human immunodeficiency virus (HIV) disease, a randomized, open-label study was conducted of 517 subjects with no or limited previous experience with antiretroviral therapy. Subjects received lamivudine plus zidovudine and indinavir (indinavir group), efavirenz plus indinavir (efavirenz + indinavir group), or nelfinavir plus indinavir (nelfinavir + indinavir group) and were monitored for 2.1 years. Virologic failure was lower in the efavirenz + indinavir group (P = .04) and higher in the nelfinavir + indinavir group (P = .006), compared with that in the indinavir group. No difference in grade 3 or 4 adverse event rates in the efavirenz + indinavir group (P = .97) and a trend toward an increased rate in the nelfinavir + indinavir group (P = .07), compared with the indinavir group, were noted. A 4-drug regimen containing efavirenz plus indinavir resulted in a superior virologic response, whereas one containing nelfinavir plus indinavir resulted in an inferior response and a greater likelihood of toxicity. C1 Univ Miami, Sch Med, AIDS Clin Res Unit R60A, Dept Med, Miami, FL 33101 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Univ Washington, Sch Med, Div Infect Dis, Seattle, WA USA. Univ Minnesota, Med Ctr, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. Univ Alabama, Div Infect Dis, Birmingham, AL USA. Columbia Univ, Coll Phys & Surg, Div Infect Dis, New York, NY USA. Univ Buffalo, Div Infect Dis, Amherst, NY USA. Inst Super Sanita, Rome, Italy. Univ Cincinnati, Div Infect Dis, Cincinnati, OH 45221 USA. RP Fischl, MA (reprint author), Univ Miami, Sch Med, AIDS Clin Res Unit R60A, Dept Med, POB 016960, Miami, FL 33101 USA. RI Vella, Stefano/D-4912-2015 OI Vella, Stefano/0000-0003-2347-5984 FU NCRR NIH HHS [RR00046]; NIAID NIH HHS [AI38855, AI25987, AI27661, AI27664, AI27675, AI32775, AI38858, AI42848, AI46386, AI98013] NR 40 TC 57 Z9 57 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 1 PY 2003 VL 188 IS 5 BP 625 EP 634 DI 10.1086/377311 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 718ED UT WOS:000185131400001 PM 12934177 ER PT J AU Priola, SA Raines, A Caughey, W AF Priola, SA Raines, A Caughey, W TI Prophylactic and therapeutic effects of phthalocyanine tetrasulfonate in scrapie-infected mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN; INCUBATION PERIOD; BLOOD-TRANSFUSION; DEXTRAN SULFATE; HAMSTERS; TRANSMISSION; EXPRESSION; POLYANIONS; PORPHYRIN AB The transmissible spongiform encephalopathy (TSE) diseases are rare, neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy, and Creutzfeldt-Jakob disease in humans. There are no effective treatments available for clinical use in humans. We now demonstrate that, in 2 different rodent models of scrapie, multiple pretreatments with the cyclic tetrapyrrole phthalocyanine tetrasulfonate (PcTS) were as effective at delaying disease as multiple treatments starting at the time of infection. At low doses of scrapie infectivity, PcTS also protected some mice from peripheral scrapie infection, even if treatment was initiated several weeks after infection. Furthermore, PcTS completely inactivated low levels of scrapie infectivity when incubated with the infectious inoculum. Thus, PcTS has a broad range of antiscrapie activities. These findings suggest that cyclic tetrapyrroles may be useful both prophylactically and therapeutically against TSE diseases in vivo, as well as for inactivation of TSE infectivity suspended in solution. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 24 TC 29 Z9 32 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2003 VL 188 IS 5 BP 699 EP 705 DI 10.1086/377310 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 718ED UT WOS:000185131400010 PM 12934186 ER PT J AU Vuong, C Gerke, C Somerville, GA Fischer, ER Otto, M AF Vuong, C Gerke, C Somerville, GA Fischer, ER Otto, M TI Quorum-sensing control of biofilm factors in Staphylococcus epidermidis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POLYSACCHARIDE INTERCELLULAR ADHESIN; GRAM-POSITIVE BACTERIA; AGR SYSTEM; AUREUS; VIRULENCE; IDENTIFICATION; SEQUENCE; GENE; ADHERENCE; SURFACES AB Staphylococcus epidermidis is the most frequent cause of nosocomial sepsis and catheter-related infections, in which biofilm formation is considered to be the main virulence mechanism. Quorum-sensing systems have been recognized as important regulators of virulence and biofilm formation in many bacteria. There is a single quorum-sensing system in S. epidermidis encoded by the agr operon. To investigate quorum-sensing control of biofilm formation, we constructed an agr deletion mutant, assayed for the different stages of biofilm formation, and determined agr-dependent regulation of biofilm factors. The agr mutant showed increased biofilm formation, primary attachment, and expression of the autolysin AtlE, but lacked delta-toxin production. However, the level of polysaccharide intercellular adhesin expression was equivalent to the isogenic wild-type strain. In contrast to AtlE, which is known to influence primary attachment, delta-toxin appeared to exert its effect on attachment to polystyrene during later stages of biofilm formation. Importantly, addition of cross-inhibiting pheromones mimicked an agr mutation and significantly enhanced biofilm formation, which suggests that care should be used when treating S. epidermidis infections with cross-inhibiting peptides. Our data demonstrate the importance of quorum sensing in the establishment of a biofilm in this critical human pathogen. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Tubingen, Tubingen, Germany. RP Otto, M (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Somerville, Greg/B-1326-2013; OI Somerville, Greg/0000-0002-0991-8737; Otto, Michael/0000-0002-2222-4115 NR 49 TC 173 Z9 197 U1 2 U2 21 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 1 PY 2003 VL 188 IS 5 BP 706 EP 718 DI 10.1086/377239 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 718ED UT WOS:000185131400011 PM 12934187 ER PT J AU DiGiovanna, JJ AF DiGiovanna, JJ TI Peter M. Steinert, 1945-2003 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item C1 Brown Med Sch, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02903 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP DiGiovanna, JJ (reprint author), Brown Med Sch, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02903 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2003 VL 121 IS 3 BP IV EP IV DI 10.1046/j.1523-1747.2003.12457.x PG 1 WC Dermatology SC Dermatology GA 717EV UT WOS:000185073800001 ER PT J AU Kass, NE Natowicz, MR Hull, RC Faden, RR Plantinga, L Gostin, LO Slutsman, J AF Kass, NE Natowicz, MR Hull, RC Faden, RR Plantinga, L Gostin, LO Slutsman, J TI The use of medical records in research: What do patients want? SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article C1 Johns Hopkins Bioeth Inst, Baltimore, MD USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. NHGRI, Bioeth Res Sect, NIH, Bethesda, MD USA. Johns Hopkins Univ, Phobe R Berman Bioeth Inst, Baltimore, MD 21218 USA. Georgetown Univ, Washington, DC 20057 USA. NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Kass, NE (reprint author), Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. FU Intramural NIH HHS [Z99 HG999999] NR 12 TC 35 Z9 35 U1 0 U2 4 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD FAL PY 2003 VL 31 IS 3 BP 429 EP 433 DI 10.1111/j.1748-720X.2003.tb00105.x PG 5 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 735ZC UT WOS:000186143900009 PM 14626550 ER PT J AU Berlin, I Gorelick, DA AF Berlin, I Gorelick, DA TI The French law on "Protection of persons undergoing biomedical research": Implications for the US SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID CLINICAL-TRIALS; RESEARCH ETHICS C1 Univ Paris 06, Pitie Salpetriee Med Sch, Paris, France. NIDA, Clin Pharmacol Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Berlin, I (reprint author), Univ Paris 06, Pitie Salpetriee Med Sch, Paris, France. NR 19 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD FAL PY 2003 VL 31 IS 3 BP 434 EP 441 DI 10.1111/j.1748-720X.2003.tb00106.x PG 8 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 735ZC UT WOS:000186143900010 PM 14626551 ER PT J AU Kobayashi, SD Voyich, JM Somerville, GA Musser, JM Malech, HL DeLeo, FR AF Kobayashi, SD Voyich, JM Somerville, GA Musser, JM Malech, HL DeLeo, FR TI Response to the letter submitted by R. Brooks Robey SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Letter ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; INFLAMMATION C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Somerville, Greg/B-1326-2013 OI Somerville, Greg/0000-0002-0991-8737 NR 4 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2003 VL 74 IS 3 BP 309 EP 310 DI 10.1189/jlb.0503225 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 755FD UT WOS:000187392100002 ER PT J AU Yang, D Chen, Q Hoover, DM Staley, P Tucker, KD Lubkowski, J Oppenheim, JJ AF Yang, D Chen, Q Hoover, DM Staley, P Tucker, KD Lubkowski, J Oppenheim, JJ TI Many chemokines including CCL20/MIP-3 alpha display antimicrobial activity SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE defensin; macrophage-inflammatory protein; colony-forming assay ID IMMATURE DENDRITIC CELLS; CXC CHEMOKINES; INFLAMMATORY PROTEIN-3-ALPHA/CCL20; BETA-DEFENSINS; EXPRESSION; IMMUNITY; PEPTIDES; RECEPTOR; PROTEIN; INNATE AB Previous studies have demonstrated that beta-defensins exhibit chemotactic activity by sharing the chemokine receptor CCR6 with the CC chemokine ligand CCL20/macrophage-inflammatory protein-3alpha (MIP-3alpha). Structural analysis of CCL20/3HP-3alpha revealed that most of the positively charged residues are concentrated at one area of its topological surface, a characteristic considered to be important for the antimicrobial activity of defensins. Here, we report that similar to defensins, CCL20/MIP-3alpha has antimicrobial effects on Escherichia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, Streptococcus pyogenes, Enterococcus faecium, Staphylococcus aureus, and Candida albicans. Additionally, by screening a total of 30 human chemokines, we have identified an additional 17 human chemokines, which exhibit antimicrobial activity in vitro. Collectively, about two-thirds of the chemokines investigated so far has the capacity to kill microorganisms in vitro, suggesting that antimicrobial activity may be another host-defense function for certain chemokines. Comparison of the structural characteristics between antimicrobial and nonantimicrobial chemokines suggests that topological formation of a large, positively charged electrostatic patch on the surface of the molecule is likely to be a common structural feature of antimicrobial chemokines. C1 NCI, LMI, CCR, Frederick, MD 21702 USA. Sci Applicat Int Corp Inc, Basic Res Program, Frederick, MD USA. Sci Applicat Int Corp Inc, Macromol Crystallog Labs, Frederick, MD USA. Sci Applicat Int Corp Inc, Opportunist Infect Labs, Div Canc Treatment, Frederick, MD USA. Sci Applicat Int Corp Inc, Diag Dev Therapeut Program, Frederick, MD USA. RP Oppenheim, JJ (reprint author), NCI, LMI, CCR, Bldg 560,Room 21-89, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 40 TC 259 Z9 272 U1 2 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2003 VL 74 IS 3 BP 448 EP 455 DI 10.1189/jlb.0103024 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 755FD UT WOS:000187392100017 PM 12949249 ER PT J AU Lipsitz, RS Tjandra, N AF Lipsitz, RS Tjandra, N TI N-15 chemical shift anisotropy in protein structure refinement and comparison with NH residual dipolar couplings SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE chemical shift anisotropy; residual dipolar coupling; protein structure refinement ID RELAXATION INTERFERENCE; HUMAN UBIQUITIN; NMR STRUCTURES; PROTON; MACROMOLECULES; BIOMOLECULES; ORIENTATION; ALIGNMENT; NITROGEN; DYNAMICS AB Recent methods of aligning proteins which were developed in order to measure residual dipolar couplings (RDCs) in solution can also be used for additional applications such as measuring the N-15 CSA in the form of chemical shift differences, Deltadelta. A new XPLORNIH module has been developed and implemented for NMR structure refinement using the N-15 Deltadelta data as restraints. The results of this refinement are shown using the protein Bax. This method should be amenable to any protein which can be studied by NMR. An analysis comparing the structural information provided by NH RDCs and the N-15 Deltadelta is included. Published by Elsevier Science (USA). C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3503, Bethesda, MD 20892 USA. NR 27 TC 32 Z9 32 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD SEP PY 2003 VL 164 IS 1 BP 171 EP 176 DI 10.1016/S1090-7807(03)00176-9 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 717NC UT WOS:000185095200022 PM 12932470 ER PT J AU Kovacik, V Patoprsty, V Oksman, P Mistrik, R Kovac, P AF Kovacik, V Patoprsty, V Oksman, P Mistrik, R Kovac, P TI Electron ionization mass spectrometric study of monomeric models of O-polysaccharides of Vibrio cholerae O : 1, serotypes Ogawa and Inaba SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE electron ionization mass spectra; high-resolution measurements; parent ions; collision-induced dissociation measurements; Mass Frontier software; Vibrio cholerae; O-polysaccharides ID METHYL ALPHA-GLYCOSIDE; VIBRIO-CHOLERAE O-1; LIPOPOLYSACCHARIDE; DETERMINANTS; ANALOGS AB Fragmentation mechanisms of electron ionization (EI) mass spectrometry of the title compounds have been elucidated by high-resolution (HR) mass spectrometric measurements of the elemental composition and measurements of the metastable transitions (B-2/E, CID). The experimental results were interpreted with the help of Mass Frontier 3.0 software, which aided the elucidation of fragmentation mechanisms and helped to deduce structures of the ions formed. Characteristic under the conditions of EI-MS measurement was the production of protonated adducts. Three distinct pathways observed include the formation of oxonium type ions, the conjugated transfer of electrons in the pyranose ring, and cleavage of the acylamide side chains. By applying the results obtained, the molecular mass, as well as the structures of both the saccharide and acylamide side chain involved in related substances, can be determined. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Slovak Acad Sci, Inst Chem, SK-84538 Bratislava, Slovakia. Univ Oulu, Dept Chem, FIN-90014 Oulu, Finland. High Chem Ltd, Bratislava 84105, Slovakia. NIDDK, NIH, Bethesda, MD 20892 USA. RP Kovacik, V (reprint author), Slovak Acad Sci, Inst Chem, Dubravska Cesta 9, SK-84538 Bratislava, Slovakia. NR 11 TC 6 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD SEP PY 2003 VL 38 IS 9 BP 924 EP 930 DI 10.1002/jms.506 PG 7 WC Biophysics; Chemistry, Organic; Spectroscopy SC Biophysics; Chemistry; Spectroscopy GA 719YF UT WOS:000185232100002 PM 14505319 ER PT J AU Lehmann, A Kannouche, P Coull, B Wing, J Woodgate, R AF Lehmann, A Kannouche, P Coull, B Wing, J Woodgate, R TI Xeroderma pigmentosum variant: replication of damage, new DNA polymerases and cancer avoidance SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 15-17, 2003 CL UNIV YORK, YORK, ENGLAND HO UNIV YORK C1 Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1468-6244 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2003 VL 40 SU 1 BP S31 EP S31 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 737LP UT WOS:000186232100058 ER PT J AU Frattali, C Bayles, K Beeson, P Kennedy, MRT Wambaugh, J Yorkston, KM AF Frattali, C Bayles, K Beeson, P Kennedy, MRT Wambaugh, J Yorkston, KM TI Development of evidence-based practice guidelines: Committee update SO JOURNAL OF MEDICAL SPEECH-LANGUAGE PATHOLOGY LA English DT Article AB The Academy of Neurologic Communication Disorders and Sciences (ANCDS), by way of the mission, purposes, and activities of its Ad Hoc Practice Guidelines Coordinating Committee and respective Writing Committees, has embarked on a 5-year project to develop a range of evidence-based practice guidelines for specific neurologically impaired patient populations (i.e., dysarthria, dementia, acquired apraxia of speech, developmental apraxia of speech, aphasia, cognitive-communication disorders after traumatic brain injury, and cognitive and communication disorders after right-hemisphere brain damage). The project embraces a philosophy that quality of care is best supported by scientific evidence of treatment efficacy. This article, which details and updates the proceedings from the Committee's presentation at the ANCDS annual educational and scientific meeting in 2002 in Atlanta, Georgia, summarizes the progress to date by the various Writing Committees responsible for developing these evidence-based practice guidelines. C1 NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Arizona, Dept Hearing & Speech Sci, Tucson, AZ USA. Univ Minnesota, Dept Commun, Minneapolis, MN USA. Univ Utah, Salt Lake City, UT USA. Univ Washington, Seattle, WA 98195 USA. RP Frattali, C (reprint author), NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 6S 235,MSC 1604, Bethesda, MD 20892 USA. EM carol_frattali@nih.gov NR 15 TC 9 Z9 9 U1 0 U2 2 PU DELMAR CENGAGE LEARNING PI FLORENCE PA PO BOX 6904, FLORENCE, KY 41022-6904 USA SN 1065-1438 J9 J MED SPEECH-LANG PA JI J. Med. Speech-Lang. Pathol. PD SEP PY 2003 VL 11 IS 3 BP IX EP XVII PG 9 WC Audiology & Speech-Language Pathology; Clinical Neurology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology GA 722PH UT WOS:000185384900002 ER PT J AU Graff, J Emerson, SU AF Graff, J Emerson, SU TI Importance of amino acid 216 in nonstructural protein 2B for replication of hepatitis A virus in cell culture and in vivo SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HAV; 213; viral replication; in vivo; cell culture; transcomplementation ID COMPLETE NUCLEOTIDE-SEQUENCE; VIRAL-RNA SYNTHESIS; INTRACELLULAR MEMBRANE REARRANGEMENTS; WILD-TYPE VIRUS; MONOCLONAL-ANTIBODIES; POLIOVIRUS 2C; ENDOPLASMIC-RETICULUM; CDNA-CLONE; STRAIN GBM; ADAPTATION AB Clinical isolates of hepatitis A virus (HAV) replicate inefficiently in cell culture unless mutations are acquired throughout the genome. An Ala-to-Val substitution in the nonstructural protein 2B (2B-216) was known to have a major impact on replication in cell culture. Analysis of chimeric viruses confirmed that the 2B-A[216]V change was critical for efficient replication and that Leu or lle could substitute for Val. Viruses containing Val, lle, or Leu at 2B-216 all replicated with similar kinetics in cell culture, whereas the virus containing Ala at this position grew 10- to 20-fold less efficiently. In contrast, in vivo, virus with either Ala or Val at 2B-216 replicated equally efficiently when tested in a chimpanzee and in tamarins, and each amino acid was stably maintained. Attempts to complement wild-type 2B in trans with adapted 2B provided by co-infection with a second viable HAV mutant failed to enhance replication of the virus containing the wild-type 2B sequence. (C) 2003 Wiley-Liss, Inc.(dagger) C1 NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Graff, J (reprint author), NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bldg 50,Room 6535,50 S Dr,MSC 8009, Bethesda, MD 20892 USA. NR 52 TC 9 Z9 9 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2003 VL 71 IS 1 BP 7 EP 17 DI 10.1002/jmv.10457 PG 11 WC Virology SC Virology GA 705JZ UT WOS:000184393100002 PM 12858403 ER PT J AU Manigold, T Bocker, U Chen, JS Gundt, J Traber, P Singer, MV Rossol, S AF Manigold, T Bocker, U Chen, JS Gundt, J Traber, P Singer, MV Rossol, S TI Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HBV infection; HBcAg; IL-18; ELISA; quantitative RT-PCR ID IFN-GAMMA PRODUCTION; VIRUS CORE; T-CELLS; CYTOKINE PRODUCTION; ESCHERICHIA-COLI; TRANSGENIC MICE; IL-18; DNA; EXPRESSION; RECEPTOR AB Clearance of hepatitis B virus infection (HBV) infection implies a polyclonal vigorous T-helper 1 (Th1) and cytotoxic T-lymphocyte (CTL) response. Interleukin-18 (IL-18), a monokine that shares functional abilities with IL-12, is a potent inductor of interferon-gamma (IFN-gamma) by Th1 and natural killer (NK) cells. However, the role and regulation in HBV infection of IFN-gamma have not been defined. This study therefore sought to determine hepatitis B core antigen (HBcAg)-mediated regulation of IL-18 production in peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and patients with chronic hepatitis B (CHB) or acute hepatitis B (AHB); 31 HC, 27 patients with CHB and 8 patients with AHB infection were included in the study. HBcAg-mediated induction of IL-18 was determined by quantitative reverse transcription-polymerase chain reaction (RTPCR) and specific enzyme-linked immunosorbent assay (ELISA). HBcAg induced IL-18 gene transcription and dose-dependent secretion of mature IL-18 protein in HC, CHB, and AHB. HBcAg-dependent IL-18 levels were abrogated by inhibition of Caspase-1, but not by blockade of CD40-CD154 interaction. Serum levels of IFN-gamma correlated inversely with viremia in patients with CHB (p = -0.54, P < 0.05), but not with serum levels of IL-12 or IL-18. Interestingly, in PBMCs of HBeAg-negative patients, HBcAg induced significantly higher amounts of IL-18 than in those of HBeAg-positive patients. A variant, lacking the histone-like arginine-rich domain, did not induce IL-18 in either HC or CHB in vitro. Taken together, these results indicate that HBcAg induces IL-18 secretion by induction of Caspase-1. Differential regulation in HBeAg-negative and positive patients suggests an important role of IL-18 in CHB infection. (C) 2003 Wiley-Liss, Inc. C1 Univ Hosp Mannheim, Dept Med 2, Mannheim, Germany. RP Manigold, T (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. NR 47 TC 22 Z9 24 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2003 VL 71 IS 1 BP 31 EP 40 DI 10.1002/jmv.10445 PG 10 WC Virology SC Virology GA 705JZ UT WOS:000184393100005 PM 12858406 ER PT J AU Watanabe, H Saito, T Shinzawa, H Okumoto, K Hattori, E Adachi, T Takeda, T Sugahara, K Ito, JI Saito, K Togashi, H Suzuki, R Hayashi, M Miyamura, T Matsuura, Y Kawata, S AF Watanabe, H Saito, T Shinzawa, H Okumoto, K Hattori, E Adachi, T Takeda, T Sugahara, K Ito, JI Saito, K Togashi, H Suzuki, R Hayashi, M Miyamura, T Matsuura, Y Kawata, S TI Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: A population-based cohort study SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE hepatitis C; epidemiology; chronic hepatitis; neutralization of binding; NOB antibody ID POLYMERASE CHAIN-REACTION; INFECTION; ANTIBODY; TRANSFUSION; DISEASES; ENVELOPE; VIREMIA; BINDING; CELLS; AREA AB The natural course of hepatitis C virus (HCV) infection has not been fully elucidated. To investigate whether HCV is spontaneously eliminated in chronic carriers, a long-term population-based cohort study was conducted on 435 chronic HCV carriers. Individual characteristics, serum HCV RNA, and liver function tests were analyzed, and ultra sonography (US) was performed in all subjects. Subjects were followed up for 7.2 +/- 2.4 years (mean +/- SD). Serum HCV RNA was spontaneously eliminated in 16/435 (3.7%) individuals during this period; thus, the incidence of spontaneous elimination of serum HCV RNA was 0.5%/year/person. Multivariate analysis revealed that both a low value of ZTT and no US finding of chronic liver disease were associated with spontaneous viral elimination in HCV carriers. Three of these 16 individuals had chronic hepatitis, and 13 of them had normal ALT levels. When the neutralization of binding (NOB) assay that evaluates inhibition of the HCV envelope-2 protein binding to human cells was examined using sera from these 16 individuals, the NOB antibody was detected in only 3 cases with chronic hepatitis. These results suggest that serum HCV RNA is spontaneously eliminated in chronic HCV carriers in a population, and that the development of NOB antibody is associated with a natural resolution of chronic hepatitis in the minority of them. (C) 2003 Wiley-Liss, Inc. C1 Yamagata Univ, Sch Med, Dept Internal Med 2, Yamagata 9909585, Japan. NIAID, Dept Virol 2, Tokyo, Japan. Osaka Univ, Microbial Dis Res Inst, Res Ctr Emerging Infect Dis, Osaka, Japan. RP Saito, T (reprint author), Yamagata Univ, Sch Med, Dept Internal Med 2, Iida 2-2-2, Yamagata 9909585, Japan. NR 19 TC 41 Z9 41 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2003 VL 71 IS 1 BP 56 EP 61 DI 10.1002/jmv.10448 PG 6 WC Virology SC Virology GA 705JZ UT WOS:000184393100008 PM 12858409 ER PT J AU Snyder, DS Garon, CF AF Snyder, DS Garon, CF TI Decreased uptake of bodipy-labelled compounds in the presence of the nuclear stain, DRAQ5 SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article DE bodipy; boron dipyrromethane; DRAQ5; fluorescent microscopy; fluorescence resonance energy transfer (FRET); lysotracker ID FLOW-CYTOMETRY; CELL-PERMEANT; DNA-PROBE AB We have found the nuclear stain DRAQ5 to decrease the cellular uptake of a series of boron dipyrromethane (bodipy)-labelled compounds. This phenomenon is consistent between Lysotracker Green DND 26, Lysotracker Red DND 99 and bodipy-labelled mycolactone. Although DRAQ5 uptake was not prevented, DRAQ5 was in significant excess in each case. As the effect is consistent among two cell types, RAW 264.7 monocyte/macrophages and Bend 3 endothelial cells, we hypothesize that it may be a result of the two dyes complexing in solution into a form that is not taken up by the cells. This hypothesis is confirmed by fluorescence resonance energy transfer analysis in solution. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Snyder, DS (reprint author), Baylor Coll Med, 1 Baylor Plaza, Houston, TX 77030 USA. NR 8 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.-Oxf. PD SEP PY 2003 VL 211 BP 208 EP 211 PN 3 PG 4 WC Microscopy SC Microscopy GA 717WJ UT WOS:000185113500002 PM 12950469 ER PT J AU Tokumasu, F Dvorak, J AF Tokumasu, F Dvorak, J TI Development and application of quantum dots for immunocytochemistry of human erythrocytes SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article DE erythrocytes; fixation; fluorescent probes; malaria; quantum dots ID BAND-3 PROTEIN; HEINZ BODIES; MEMBRANE; BINDING; RAFTS; CHOLESTEROL; ANTIBODIES; FIXATION; TISSUE AB Recent developments in quantum dot technology have resulted in the introduction of new fluorescence immunocytochemical probes. In contrast to organic fluorophores, which are not photostable, the high quantum yield and remarkable photostability of quantum dots solve major problems associated with immunocytochemical studies of erythrocytes. We report here the first application of quantum dots to immunocytochemical studies of human erythrocytes capable of being used in high-magnification, three-dimensional erythrocyte reconstruction techniques. The procedure consists of stabilizing human erythrocytes with a homofunctional imidoester cross-linker to minimize fixative-induced autofluorescence followed by reacting with a quantum dot-monoclonal antibody complex to label band 3 protein. Our new procedure clearly showed a non-homogeneous, raft-like distribution of band 3 protein in the erythrocyte membrane. We also demonstrate the applicability of our technique to studies of erythrocyte membrane modifications occurring during the invasion of a malaria parasite. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Dvorak, J (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bldg 4 Room B2-11,MSC 0425,4 Ctr Dr, Bethesda, MD 20892 USA. OI Tokumasu, Fuyuki/0000-0003-2790-1071 NR 28 TC 82 Z9 84 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.-Oxf. PD SEP PY 2003 VL 211 BP 256 EP 261 PN 3 PG 6 WC Microscopy SC Microscopy GA 717WJ UT WOS:000185113500007 PM 12950474 ER PT J AU Murphy, E Tong, HY Steenbergen, C AF Murphy, E Tong, HY Steenbergen, C TI Preconditioning: is the Akt-ion in the PI3K pathway? SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1; K-ATP CHANNELS; S6 KINASE; PHOSPHATIDYLINOSITOL 3'-KINASE; MYOCARDIAL PROTECTION; CELL-SURVIVAL; ACTIVATED AKT; MUSCLE-CELLS; IN-VIVO; PHOSPHORYLATION C1 NIEHS, DHHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Murphy, E (reprint author), NIEHS, DHHS, Lab Signal Transduct, NIH, MD-D2-03,Maildrop F2-07,Box 12233, Res Triangle Pk, NC 27709 USA. EM murphy1@niehs.nih.gov FU NHLBI NIH HHS [R01 HL039752] NR 28 TC 13 Z9 14 U1 0 U2 1 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 SEP PY 2003 VL 35 IS 9 BP 1021 EP 1025 DI 10.1016/S0022-2828(03)00233-5 PG 5 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 724NZ UT WOS:000185494800005 PM 12967624 ER PT J AU Wu, JF Huang, KP Huang, FL AF Wu, JF Huang, KP Huang, FL TI Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+-Ca2+/calmodulin-dependent neuronal signaling in the hippocampus SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE hippocampus; learning and memory; neurogranin; NMDA; signaling transduction ID PROTEIN-KINASE-C; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; GLUTAMATE RECEPTORS; NITRIC-OXIDE; LATE-PHASE; AREA CA1; MEMORY; LTP; PKC AB Neurogranin/RC3 (Ng) is a postsynaptic protein kinase C (PKC) substrate and calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by Ca2+, phosphorylation and oxidation. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity. Previously, we showed a severe deficit of spatial memory in Ng knockout (KO) mice. Activation of the NMDA receptor and its downstream signaling molecules are known to be involved in long-term memory formation. In the present study, using mouse hippocampal slices, we demonstrated that NMDA induced a rapid and transient phosphorylation and oxidation of Ng. NMDA also caused activation of PKC as evidenced by their phosphorylations, whereas, such activations were greatly reduced in the KO mice. A higher degree of phosphorylation of Ca2+/CaM-dependent kinase II and activation of cyclic AMP-dependent protein kinase were also evident in the WT compared to those of the KO mice. Phosphorylation of downstream targets, including mitogen-activated protein kinases and cAMP response element-binding protein, were significantly attenuated in the KO mice. These results suggest that by its Ca2+-sensitive CaM-binding feature, and through its phosphorylation and oxidation, Ng regulates the Ca2+- and Ca2+/CaM-dependent signaling pathways subsequent to the stimulation of NMDA receptor. These findings support the hypothesis that the derangement of hippocampal signal transduction cascades in Ng KO mice causes the deficits in synaptic plasticity, learning and memory that occur in these mice. C1 NICHHD, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Huang, FL (reprint author), NICHHD, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM fhuang@helix.nih.gov NR 36 TC 32 Z9 38 U1 0 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 SEP PY 2003 VL 86 IS 6 BP 1524 EP 1533 DI 10.1046/j.1471-4159.2003.01963.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 764ZQ UT WOS:000188241400021 PM 12950461 ER PT J AU Moncek, F Aguilera, G Jezova, D AF Moncek, F Aguilera, G Jezova, D TI Insufficient activation of adrenocortical but not adrenomedullary hormones during stress in rats subjected to repeated immune challenge SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE LPS; stress; inflammation; aldosterone; catecholamines ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING-FACTOR; PROOPIOMELANOCORTIN MESSENGER-RNA; TUMOR NECROSIS FACTOR; HYPERRENINEMIC HYPOALDOSTERONISM; SYMPATHETIC-ADRENOMEDULLARY; CORTICOSTERONE RESPONSES; PLASMA-CATECHOLAMINES; ALDOSTERONE SECRETION; MEDULLARY RESPONSES AB We have tested the hypothesis that chronic inflammatory stress results in changes in sympathoadrenal and renin-angiotensin-aldosterone responses to novel stressors. Repeated treatment of rats with increasing doses of lipopolysaccharide (LPS) resulted in a decrease of plasma adrenaline and aldosterone as well as in renin activity (angiotensin 1) responses compared to those after acute administration. Repeated LPS administration was associated with decreased plasma aldosterone responses to a different stressor (immobilization) in spite of preserved or even elevated responses of plasma renin activity and catecholamines. These alterations may contribute to the development of cardiovascular complications during chronic inflammatory states. (C) 2003 Elsevier B.V. All rights reserved. C1 Slovak Acad Sci, Inst Expt Endocrinol, SK-83306 Bratislava, Slovakia. Natl Inst Child Hlth & Human Dev, Dev Envdocrinol Branch, Sect Endocrine Physiol, NIH, Bethesda, MD USA. RP Jezova, D (reprint author), Slovak Acad Sci, Inst Expt Endocrinol, Vlarska 3, SK-83306 Bratislava, Slovakia. NR 47 TC 15 Z9 15 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP PY 2003 VL 142 IS 1-2 BP 86 EP 92 DI 10.1016/S0165-5728(03)00268-6 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 732WE UT WOS:000185967900009 PM 14512167 ER PT J AU Edelman, JA Goldberg, ME AF Edelman, JA Goldberg, ME TI Saccade-related activity in the primate superior colliculus depends on the presence of local landmarks at the saccade endpoint SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID EYE-MOVEMENTS; VISUAL-ATTENTION; MONKEY; TARGETS; NEURONS; CORTEX; CELLS; REPRESENTATIONS; DISSOCIATION; ORGANIZATION AB Saccade-related discharge in the superior colliculus is greater for saccades made to a spot of light than for saccades in complete darkness. However, it is unclear whether this enhancement is due to the discontinuity of the spot or due to its being a new object of fixation. In these experiments, we examined the saccade-related activity of intermediate-layer neurons in the primate superior colliculus during delayed saccades to the center or corner of a large, bright square, as well as for visual and memory-guided movements to small spots in isolation. The saccade-related discharge for movements made to a local visual landmark present at the time of the saccade, be it a corner of a square or a small spot, was higher than that for saccades made to the center of a square that contained no local visual landmarks within. Moreover, discharge for movements to the center of a square were very similar to that for saccades to blank, dark space. Saccade velocity was similarly dependent on the presence of such a landmark, though less dramatically. The endpoints of saccades directed toward a square's corner were slightly displaced toward the center of the square. Across all neurons, discharge and velocity for saccades to the center of a square increased as the square size was decreased, but were never greater than those for saccades to a small spot of light. These results suggest that both saccade-related discharge in the superior colliculus and saccade metrics are enhanced for movements directed to parts of the visual scene with high contrast, while shifting fixation to a new object is not itself sufficient to elevate discharge and metrics above those of saccades to blank space. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Edelman, JA (reprint author), CUNY City Coll, Dept Biol, J526,Marshak Sci Bldg, New York, NY 10031 USA. FU NEI NIH HHS [R01 EY017039] NR 36 TC 12 Z9 12 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2003 VL 90 IS 3 BP 1728 EP 1736 DI 10.1152/jn.00016.2003 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 719RG UT WOS:000185217700035 PM 12736233 ER PT J AU Port, NL Wurtz, RH AF Port, NL Wurtz, RH TI Sequential activity of simultaneously recorded neurons in the superior colliculus during curved saccades SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID INTERMEDIATE GRAY LAYER; MOTOR CORTICAL ACTIVITY; DOUBLE-STEP STIMULI; EYE-MOVEMENTS; TARGET SELECTION; VISUAL-SEARCH; MONKEY; REPRESENTATION; TASK; GENERATION AB The visual world presents multiple potential targets that can be brought to the fovea by saccadic eye movements. These targets produce activity at multiple sites on a movement map in the superior colliculus (SC), an area of the brain related to saccade generation. The saccade made must result from competition between the populations of neurons representing these many saccadic goals, and in the present experiments we used multiple moveable microelectrodes to follow this competition. We recorded simultaneously from two sites on the SC map where each site was related to a different saccade target. The two targets appeared in rapid sequence, and the monkey was rewarded for making a saccade toward the one appearing first. Our study concentrated on trials in which the monkey made strongly curved saccades that were directed first toward one target and then toward the other. These curved saccades activated both sites on the SC map as they veered from one target to the other. The major finding was that the strongly curved saccades were preceded by sequential activity in the two neurons as indicated by three observations: the firing rate for the neuron related to the first target reached its peak earlier than did the rate of the neuron for the second target; the timing of the peak activity of the two neurons was related to the beginning and end of the saccade curvature; a weighted vector-average model based on the activity of the two neurons predicted the timing of saccade curvature. Straight averaging saccades ended between the targets so that they did not go to either target, and they were accompanied by simultaneous rather than sequential activation of the two neurons. Thus when multiple populations of neurons are active on the SC movement map, the resulting saccade is determined by the relative timing of the activity in the populations as well as their magnitude. In contrast, SC activity at the two sites did not predict the final direction of the saccade, and several control experiments found insufficient activity at other sites on the SC map to account for that final direction. We conclude that the SC neuronal activity predicts the timing of the saccade curvature, but not the final direction of the trajectory. These observations are consistent with SC activity being critical in selecting the goal of the saccade, but not in determining the exact trajectory. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Port, NL (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20982 USA. NR 61 TC 84 Z9 84 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2003 VL 90 IS 3 BP 1887 EP 1903 DI 10.1152/jn.01151.2002 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 719RG UT WOS:000185217700048 PM 12966180 ER PT J AU Korytko, PJ Rodvold, KA Crowell, JA Stacewicz-Sapuntzakis, M Diwadkar-Navsariwala, V Bowen, PE Schalch, W Levine, BS AF Korytko, PJ Rodvold, KA Crowell, JA Stacewicz-Sapuntzakis, M Diwadkar-Navsariwala, V Bowen, PE Schalch, W Levine, BS TI Pharmacokinetics and tissue distribution of orally administered lycopene in male dogs SO JOURNAL OF NUTRITION LA English DT Article DE carotenoid; prostate; cancer; chemoprevention; canine ID PROSTATE-CANCER; TOMATO SAUCE; INTRAEPITHELIAL NEOPLASIA; TRANS-LYCOPENE; HUMAN SERUM; RISK; CAROTENOIDS; RETINOL; ISOMERS; SUPPLEMENTATION AB Consumption of lycopene, the predominant carotenoid in tomatoes and tomato products, is associated with reduced prostate cancer risk. The purpose of this study was to measure the pharmacokinetics and tissue distribution of lycopene after oral administration to male dogs. After single doses of 10, 30 and 50 mg/kg body weight (BW) lycopene to 2 dogs/dose, the mean half-life was 36 h and the plasma systemic exposure levels AUC(O-infinity), area under the curve) after the 30 and 50 mg/kg BW doses were similar. In a repeat dose study, 30 mg/(kg BW (.) d) administered orally to six dogs for 28 d resulted in steady-state plasma concentrations between 785 and 997 nmol/L lycopene. Apparent clearance, volume of distribution and apparent elimination half-life were 2.29 U(h (.) kg), 96 L/kg and 30.5 h, respectively. Dogs were killed 1 or 5 d after the last dose and 23 tissues were collected for lycopene analysis. Lycopene concentrations were highest in liver, adrenals, spleen, lymph nodes and intestinal tissues. Liver lycopene concentrations were 66 and 91 nmol/g 1 and 5 d after cessation of treatment, respectively. Prostate lycopene concentrations were < 0.2 nmol/g both 1 and 5 d after dosing ceased (<0.4% of liver concentrations). Although 70% trans-lycopene was used in the dosing material, most of the lycopene identified in plasma-and tissues was cis-lycopene. C1 Univ Illinois, Toxicol Res Lab, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL USA. NCI, Rockville, MD USA. Roche Vitamins Inc, Basel, Switzerland. RP Korytko, PJ (reprint author), Univ Illinois, Toxicol Res Lab, Chicago, IL 60612 USA. NR 22 TC 15 Z9 16 U1 1 U2 3 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD SEP PY 2003 VL 133 IS 9 BP 2788 EP 2792 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 720KC UT WOS:000185259100016 PM 12949366 ER PT J AU Bartali, B Salvini, S Turrini, A Lauretani, F Russo, CR Corsi, AM Bandinelli, S D'Amicis, A Palli, D Guralnik, JM Ferrucci, L AF Bartali, B Salvini, S Turrini, A Lauretani, F Russo, CR Corsi, AM Bandinelli, S D'Amicis, A Palli, D Guralnik, JM Ferrucci, L TI Age and disability affect dietary intake SO JOURNAL OF NUTRITION LA English DT Article DE InCHIANTI; aging; nutrient intake; food consumption; disability ID NUTRITIONAL-STATUS; OLDER-PEOPLE; ELDERLY POPULATION; FOOD SOURCES; NUTRIENTS; ITALIANS; PATTERNS; ABILITY; STATE AB The purpose of the study was to provide information on dietary intake in the InCHIANTI study population, a representative sample (n = 1453) of persons living in two towns of Tuscany (Italy), including a large number of old and very old individuals (79.5% >65 y old). We also investigated whether difficulties in nutrition-related activities were associated with inadequate intake of selected nutrients. The percentage of persons with an inadequate intake of nutrients according to Italian Recommended Nutrients Levels (LARN) was higher in the older age groups. Older persons tended to adapt their diets in response to individual functional difficulties, often leading to monotonous food consumption and, as a consequence, to inadequate nutrient intakes. Multiple logistic models were used to evaluate whether inadequate intake of selected nutrients could be predicted by nutrition-related difficulties. Reporting difficulties in three or more nutrition-related activities (chewing, self-feeding, shopping for basic necessities, carrying a shopping bag, cooking a warm meal, using fingers to grasp or handle) significantly increased the risk of inadequate intake of energy [odds ratio (OR) = 3.8, 95% Cl = 1.9-7.8) and vitamin C (OR = 2.2, 95% Cl = 1.2-4.2, after adjustment for energy intake). More attention to functional problems in the elderly population and the provision of formal or informal help to those who have difficulty in purchasing, processing and eating food may reduce, at least in part, the percentage of older persons with poor nutrition. C1 NIA, Gerontol Res Ctr, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. Natl Inst Res & Care Aging, Lab Clin Epidemiol, Dept Geriatr, Florence, Italy. Sci Inst Tuscany, Mol & Nutr Epidemiol Unit, Canc Study & Prevent Ctr, CSPO, Florence, Italy. Natl Inst Res Food & Nutr, INRAN, Rome, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), NIA, Gerontol Res Ctr, Longitudinal Studies Sect, NIH, 4940 Eastern Ave, Baltimore, MD 21224 USA. RI Turrini, Aida/K-5353-2016; Lauretani, Fulvio/K-5115-2016; OI Turrini, Aida/0000-0002-2188-9406; Lauretani, Fulvio/0000-0002-5287-9972; PALLI, Domenico/0000-0002-5558-2437 FU NIMHD NIH HHS [263-MD-821336, 263-MD-9164-13] NR 28 TC 41 Z9 46 U1 0 U2 8 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD SEP PY 2003 VL 133 IS 9 BP 2868 EP 2873 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 720KC UT WOS:000185259100029 PM 12949379 ER PT J AU Dionne, RA Gordon, SM Rowan, J Kent, A Brahim, JS AF Dionne, RA Gordon, SM Rowan, J Kent, A Brahim, JS TI Dexamethasone suppresses peripheral prostanoid levels without analgesia in a clinical model of acute inflammation SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTAGLANDIN E-2; CYCLOOXYGENASE-2 COX-2; GLUCOCORTICOIDS; INHIBITION; RAT; EXPRESSION; IBUPROFEN; KETOROLAC; TISSUE AB Purpose: The therapeutic effects of glucocorticoids are generally attributed to suppression of multiple signaling pathways involved in the inflammatory response leading to decreased levels of inflammatory mediators at the site of injury. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after dexamethasone administration in a clinical model of tissue injury. Methods: Subjects were administered dexamethasone 4 mg or placebo 12 hours and 1 hour before the removal of 2 mandibular third molars. A microdialysis probe was implanted at each surgical site for measurement of immunoreactive prostaglandin E2 (PGE(2)) or immunoreactive thromboxane B-2 (TxB(2)), and pain was measured concurrently. Subjects received either ketorolac 30 mg intravenously or placebo at pain onset. Results: PGE(2) was detectable in the first postoperative sample, decreased over the next hour and then increased coincident with the onset of postoperative pain. Administration of dexamethasone suppressed PGE(2) levels in samples collected at pain onset in comparison to placebo and significantly suppressed TxB(2) at the surgical site but without any effect on pain report. Subsequent administration of ketorolac significantly reduced pain while decreasing both PGE(2) and TxB(2) levels at the surgical site. Conclusion: The lack of an analgesic effect for dexamethasone while reducing both PGE(2) and TxB(2) at the site of injury in comparison to ketorolac analgesia accompanied by greater reductions in levels of these prostanoids suggests that glucocorticoids at this dose do not suppress PGE(2) release sufficiently to attenuate peripheral sensitization of nociceptors after tissue injury. Published by Elsevier on behalf of the American Association of Oral and Maxillofacial Surgeons. C1 NIDCR, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NIDCR, Pain & Neurosensory Mech Branch, NIH, 10 Ctr Dr,Room 1N-103, Bethesda, MD 20892 USA. NR 36 TC 38 Z9 41 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD SEP PY 2003 VL 61 IS 9 BP 997 EP 1003 DI 10.1016/S0278-2391(03)00310-0 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 716UA UT WOS:000185046500004 PM 12966473 ER PT J AU Kim, CJ Yoon, BH Jun, JK Park, JO Cho, SY Romero, R Kim, YM Yu, ES AF Kim, CJ Yoon, BH Jun, JK Park, JO Cho, SY Romero, R Kim, YM Yu, ES TI Promyelocytic leukaemia (PML) protein expression in human placenta and choriocarcinoma SO JOURNAL OF PATHOLOGY LA English DT Article DE PML; placenta; choriocarcinoma ID NEOPLASTIC HUMAN TISSUES; EARLY HUMAN-PREGNANCY; TROPHOBLASTIC INVASION; T(15-17) TRANSLOCATION; ALTERED EXPRESSION; GROWTH-SUPPRESSOR; CANCER CELLS; GENE; APOPTOSIS; RAR AB Promyelocytic leukaemia (PML) protein, the product of the pml gene, is heterogeneously expressed in various normal and neoplastic tissues, and the fusion of the pml gene with retinoic acid receptor-alpha is believed to be a central mechanism in acute PML tumourigenesis. As PML is important for controlling major cellular processes, such as growth and differentiation, it is believed that it plays an important role during human gestation. The human placenta is a critical organ for the maintenance of gestation, but the expression pattern and functional significance of PML in the placenta have not been documented. The present study has therefore investigated the expression of PML in the human placenta and in choriocarcinoma, and has observed the biological effects following the overexpression of PML in choriocarcinoma cell lines (BeWo and JEG-3). In the human placenta, PML expression was readily found in villous stromal fibroblasts, capillary endothelial cells, Hofbauer cells, and occasionally in amnion cells. Moreover, immunoblotting of placental lysates demonstrated increased PML expression with increasing gestation. Interestingly, PML expression was confined to intermediate trophoblasts and syncytiotrophoblastic giant cells at the placental site (placental site giant cells) in the trophoblastic cell population. Intermediate trophoblasts at non-placental sites, and villous cytotrophoblasts and syncytiotrophoblasts consistently did not express PML. Further screening of PML expression in hydatidiform moles (n = 4) and choriocarcinomas (n = 7) also revealed selective PML expression in intermediate trophoblastic cells and syncytiotrophoblastic cells, but not in the cytotrophoblastic populations, which corresponds well with observations in the placental bed. Adenoviral transduction of PML resulted in a marked reduction in cell growth in both choriocarcinoma cell lines, which was associated with increased apoptosis. The findings of the present study strongly suggest that PML plays an important role in human placental development and growth, and in the pathobiology of trophoblasts and trophoblastic neoplasia. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Seoul Natl Univ, Coll Med, Dept Pathol, Chongno Gu, Seoul 110799, South Korea. Seoul Natl Univ Hosp, Clin Res Inst, Lab Fetal Med Res, Seoul 110744, South Korea. Natl Inst Child Hlth & Human Dev, Perinatol Res Branch, Bethesda, MD USA. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Diagnost Pathol, Seoul, South Korea. RP Kim, CJ (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, Chongno Gu, 28 Yongon Dong, Seoul 110799, South Korea. EM cjkim@plaza.snu.ac.kr RI Seoul National University, Pathology/B-6702-2012; Yoon, Bo Hyun/H-6344-2011; Jun, Jong Kwan/D-5776-2012 OI Jun, Jong Kwan/0000-0002-0242-1736 NR 35 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD SEP PY 2003 VL 201 IS 1 BP 83 EP 89 DI 10.1002/path.1382 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 721XV UT WOS:000185344500010 PM 12950020 ER PT J AU Goldstein, DS Li, ST Holmes, C Bankiewicz, K AF Goldstein, DS Li, ST Holmes, C Bankiewicz, K TI Sympathetic innervation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MULTIPLE SYSTEM ATROPHY; I-123 MIBG UPTAKE; ORTHOSTATIC HYPOTENSION; AUTONOMIC FAILURE; DIAGNOSTIC-VALUE; NERVE ACTIVITY; CARDIAC UPTAKE; DENERVATION; MPTP; HUMANS AB Cardiac sympathetic denervation occurs commonly in Parkinson's disease. This study explored whether analogous denervation occurs in primates with Parkinsonism from systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 6-[F-18]Fluorodopamine positron emission tomographic scanning and plasma levels of catecholamines and their deaminated metabolites were used to assess sympathetic and adrenomedullary function in rhesus monkeys, in the untreated state (n = 3), 2 weeks after a series of four MPTP injections, before establishment of Parkinsonism (acute phase, n = 1); a month later, after four more MPTP doses, associated with severe Parkinsonism (subacute phase, n = 1); or more than 2 years from the last dose (remote phase, n = 3), with persistent severe Parkinsonism. A positive control received i.v. 6-hydroxydopamine 1 week before 6-[F-18]fluorodopamine scanning. Acute MPTP treatment increased cardiac 6-[F-18]fluorodopamine-derived radioactivity, whereas 6-hydroxydopamine markedly decreased cardiac radioactivity, despite similarly low plasma levels of catecholamines and metabolites after either treatment. Subacutely, plasma catecholamines remained decreased, but now with myocardial 6-[F-18]fluorodopamine-derived radioactivity also decreased. Remotely, MPTP-treated monkeys had lower plasma catecholamines and higher myocardial 6-[F-18]fluorodopamine-derived radioactivity than did untreated animals. The results indicate that in nonhuman primates, systemic MPTP administration produces multiphasic effects on peripheral catecholamine systems, with nearly complete recovery by 2 years. MPTP- and 6-hydroxydopamine-induced changes differ markedly, probably from ganglionic or preganglionic neurotoxicity with the former and more severe cardiac sympathetic neurotoxicity with the latter. Because of multiphasic sympathetic and adrenomedullary effects, without cardioselective sympathetic denervation at any time, the primate MPTP model does not mimic the changes in peripheral catecholamine systems that characterize the human disease. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. NR 40 TC 12 Z9 13 U1 0 U2 0 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 SEP PY 2003 VL 306 IS 3 BP 855 EP 860 DI 10.1124/jpet.103.051714 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 712UU UT WOS:000184817400005 PM 12805479 ER PT J AU Tosaka, T Casimiro, MC Rong, Q Tella, S Oh, M Katchman, AN Pezzullo, JC Pfeifer, K Ebert, SN AF Tosaka, T Casimiro, MC Rong, Q Tella, S Oh, M Katchman, AN Pezzullo, JC Pfeifer, K Ebert, SN TI Nicotine induces a long QT phenotype in Kcnq1-deficient mouse hearts SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GUINEA-PIG HEART; HUMAN VENTRICULAR MYOCYTES; LANGE-NIELSEN-SYNDROME; TORSADE-DE-POINTES; POTASSIUM CHANNEL; I-KS; CARDIAC-ARRHYTHMIAS; TARGETED DISRUPTION; ADRENERGIC NEURONS; FEMALE GENDER AB We have previously shown that targeted disruption of the mouse Kcnq1 gene produces a long QT phenotype in vivo that requires extracardiac factors for manifestation (Casimiro et al., 2001). In the present study, we explore the hypothesis that autonomic neuroeffector transmission represents the "extracardiac" stimulus that induces a long QT phenotype in mouse hearts lacking Kcnq1. Using the isolated perfused (Langendorff) mouse heart preparation, we challenged wild-type (Kcnq1(+/+)) and mutant (Kcnq1(-/-)) mouse hearts with nicotine, an autonomic stimulant. ECGs were recorded continuously, and QT intervals were compared at baseline and peak nicotine-induced heart rates. No significant differences in QT or any other ECG parameters were observed in Kcnq1(+/+) versus Kcnq1(-/-) hearts at baseline. In the presence of nicotine, however, the JT, QT, and rate-corrected QT (QTc) intervals were significantly prolonged in Kcnq1(-/-) hearts relative to Kcnq1(+/+) hearts (e.g., QTc = 92 +/- 11 ms versus 66 +/- 2 ms, respectively, p < 0.01). Similar findings were obtained when the hearts were challenged with either epinephrine or isoproterenol (0.1 μM each), thereby suggesting that sympathetic stimulation drives the long QT phenotype in Kcnq1-deficient hearts. This idea is supported by in vivo ECG data obtained from unrestrained conscious mice using radiotelemetry recording techniques. Again, no significant ECG differences were observed in Kcnq1(-/-) versus Kcnq1(+/+) mice at baseline, but handling/injection stress led to significant QTc increases in Kcnq1(-/-) mice relative to wild-type controls (11 +/- 3 versus -1 +/- 1%, respectively, p < 0.05). These data suggest that sympathetic stimulation induces a long QT phenotype in Kcnq1-deficient mouse hearts. C1 Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20057 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Drug Enforcement Adm, Drug & Chem Evaluat Sect, Off Divers Control, Washington, DC USA. RP Ebert, SN (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. OI Pfeifer, Karl/0000-0002-0254-682X FU NHLBI NIH HHS [HL58743]; NIDDK NIH HHS [DK56920] NR 46 TC 17 Z9 18 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2003 VL 306 IS 3 BP 980 EP 987 DI 10.1124/jpet.103.053017 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 712UU UT WOS:000184817400019 PM 12766260 ER PT J AU Oz, M Ravindran, A Diaz-Ruiz, O Zhang, L Morales, M AF Oz, M Ravindran, A Diaz-Ruiz, O Zhang, L Morales, M TI The endogenous cannabinoid anandamide inhibits alpha(7) nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID METABOTROPIC GLUTAMATE; SYNAPTIC TRANSMISSION; BRAIN CONSTITUENT; ARACHIDONIC-ACID; LAEVIS OOCYTES; CHANNELS; MODULATION; CALCIUM; NEURONS; DELTA-9-TETRAHYDROCANNABINOL AB The effect of the endogenous cannabinoid ligand anandamide on the function of the cloned alpha(7) subunit of the nicotinic acetylcholine (ACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Anandamide reversibly inhibited nicotine (10 muM) induced-currents in a concentration-dependent manner (10 nM to 30 muM), with an IC50 value of 229.7 +/- 20.4 nM. The effect of anandamide was neither dependent on the membrane potential nor meditated by endogenous Ca2+ dependent Cl- channels since it was unaffected by intracellularly injected BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Anandamide decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on nicotinic acetylcholine (nACh) alpha(7) receptors. This effect was not mediated by CB 1 or CB 2 receptors, as neither the selective CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) nor CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528) reduced the inhibition by anandamide. In addition, inhibition of nicotinic responses by anandamide was not sensitive to either pertussis toxin treatment or to the membrane permeable cAMP analog 8-Br-cAMP (0.2 mM). Inhibitors of enzymes involved in anandamide metabolism including phenylmethylsulfonyl fluoride, superoxide dismutase, and indomethacin, or the anandamide transport inhibitor AM404 did not prevent anandamide inhibition of nicotinic responses, suggesting that anandamide itself acted on nicotinic receptors. In conclusion, these results demonstrate that the endogenous cannabinoid anandamide inhibits the function of nACh alpha(7) receptors expressed in Xenopus oocytes in a cannabinoid receptor-independent and noncompetitive manner. C1 NIDA, NIH, Dept Hlth & Human Serv, Intramural Res Program,Cellular Neurobiol Sect, Baltimore, MD 21224 USA. NIDA, NIH, Dept Hlth & Human Serv, Intramural Res Program,Cellular Neurophysiol Sect, Baltimore, MD USA. NIAAA, NIH, Dept Hlth & Human Serv, Mol & Cellular Neurobiol Lab, Bethesda, MD USA. RP Oz, M (reprint author), NIDA, NIH, Dept Hlth & Human Serv, Intramural Res Program,Cellular Neurobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Diaz-Ruiz, Oscar/F-3162-2010; Oz, Murat/E-2148-2012 NR 48 TC 42 Z9 44 U1 0 U2 0 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 SEP PY 2003 VL 306 IS 3 BP 1003 EP 1010 DI 10.1124/jpet.103.049981 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 712UU UT WOS:000184817400022 PM 12766252 ER PT J AU Drevets, WC AF Drevets, WC TI Application of functional neuroimaging to investigations of the neuropharmacological correlates of mood disorders SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT Summer Meeting of the British-Association-for-Psychopharmacology CY JUL 20-23, 2003 CL CAMBRIDGE, ENGLAND SP British Assoc Psychopharmacol C1 NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD SEP PY 2003 VL 17 IS 3 SU S BP A4 EP A4 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 726WC UT WOS:000185623500016 ER PT J AU Law, AJ Weickert, SC Hyde, TM Kleinman, JE Harrison, PJ AF Law, AJ Weickert, SC Hyde, TM Kleinman, JE Harrison, PJ TI Spinophilin and MAP2 gene expression in schizophrenia, mood disorder and following neuroleptic treatment in the rat SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT Summer Meeting of the British-Association-for-Psychopharmacology CY JUL 20-23, 2003 CL CAMBRIDGE, ENGLAND SP British Assoc Psychopharmacol C1 Univ Oxford, Dept Psychiat, Oxford OX1 2JD, England. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RI Law, Amanda/G-6372-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD SEP PY 2003 VL 17 IS 3 SU S BP A47 EP A47 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 726WC UT WOS:000185623500185 ER PT J AU O'Sullivan, GJ Tighe, O Croke, DT Kinsella, A Sibley, DR Waddington, JL AF O'Sullivan, GJ Tighe, O Croke, DT Kinsella, A Sibley, DR Waddington, JL TI Topographical evaluation of spontaneous and agonist-induced behavioural phenotype in mice with congenic dopamine D-5 receptor knockout SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT Summer Meeting of the British-Association-for-Psychopharmacology CY JUL 20-23, 2003 CL CAMBRIDGE, ENGLAND SP British Assoc Psychopharmacol C1 Royal Coll Surgeons Ireland, Dept Clin Pharmacol, Dublin 2, Ireland. Royal Coll Surgeons Ireland, Dept Biochem, Dublin 2, Ireland. Dublin Inst Technol, Sch Math, Dublin 8, Ireland. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD SEP PY 2003 VL 17 IS 3 SU S BP A26 EP A26 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 726WC UT WOS:000185623500102 ER PT J AU Tohen, M Ketter, TA Zarate, CA Suppes, T Frye, M Altshuler, L Zajecka, Y Schuh, LM Risser, RC Brown, E McGee, D Baker, RW AF Tohen, M Ketter, TA Zarate, CA Suppes, T Frye, M Altshuler, L Zajecka, Y Schuh, LM Risser, RC Brown, E McGee, D Baker, RW TI Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT Summer Meeting of the British-Association-for-Psychopharmacology CY JUL 20-23, 2003 CL CAMBRIDGE, ENGLAND SP British Assoc Psychopharmacol C1 Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Belmont, MA USA. Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA. NIMH, Bethesda, MD 20892 USA. Univ Texas, Dallas, TX 75230 USA. Univ Calif Los Angeles, Los Angeles, CA USA. St Lukes Hosp, Chicago, IL USA. Eli Lilly & Co, Basingstoke, Hants, England. RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD SEP PY 2003 VL 17 IS 3 SU S BP A23 EP A23 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 726WC UT WOS:000185623500093 ER PT J AU Goodwin, RD Wamboldt, MZ Pine, DS AF Goodwin, RD Wamboldt, MZ Pine, DS TI Lung disease and internalizing disorders - Is childhood abuse a shared etiologic factor? SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE lung disease; respiratory illness; epidemiology; anxiety; childhood abuse ID NATIONAL-COMORBIDITY-SURVEY; PHYSICAL ABUSE; ANXIETY DISORDERS; MAJOR DEPRESSION; PANIC DISORDER; T-CELLS; ASTHMA; CHILDREN; PREVALENCE; FIBROMYALGIA AB Objective: To investigate the role of childhood abuse in the relationship between panic attack, depression and lung disease among adults in the population. Methods: Data were drawn from the National Comorbidity Survey (n=5877), a representative sample of adults age 15-54 in the United States. Multiple logistic regression analyses were used to determine the association between childhood abuse and lung disease, and to determine whether childhood abuse is an independent predictor of the co-occurrence of lung disease, panic attack and depression. Results: Childhood abuse was associated with significantly increased odds of panic attacks (OR=2.2 (1.5, 3.1)) and depression (OR=1.6 (1.1, 2.3)). Childhood abuse increased likelihood of lung disease (OR=1.5 (1.1, 2.2)). Childhood abuse independently predicted the co-occurrence of lung disease, panic attack and depression (OR=10.7 (2.2, 51.5)). Conclusion: These data are preliminary, but if replicated, suggest that childhood abuse may be associated with increased risk of lung disease during adulthood, and further may reflect a shared vulnerability for the co-occurrence of lung disease, panic attack and depression in the community. Future studies are needed to further explore the mechanism of this association. (C) 2003 Elsevier Inc. All rights reserved. C1 Columbia Univ, New York, NY USA. Natl Jewish Med & Res Ctr, Denver, CO USA. NIMH, Bethesda, MD 20892 USA. RP Goodwin, RD (reprint author), 1051 Riverside Dr,Unit 43, New York, NY 10032 USA. NR 37 TC 18 Z9 18 U1 2 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 SEP PY 2003 VL 55 IS 3 BP 215 EP 219 DI 10.1016/S0022-3999(02)00497-X PG 5 WC Psychiatry SC Psychiatry GA 716NA UT WOS:000185034100006 PM 12932794 ER PT J AU Poggi, SH Ghidini, A Allen, RH Pezzullo, JC Rosenbaum, TC Spong, CY AF Poggi, SH Ghidini, A Allen, RH Pezzullo, JC Rosenbaum, TC Spong, CY TI Effect of operative vaginal delivery on the outcome of permanent brachial plexus injury SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 14-19, 2002 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med DE delivery; brachial plexus; dystocia ID SHOULDER DYSTOCIA; RISK-FACTORS; FETAL MACROSOMIA; FORCEPS; PALSY AB OBJECTIVE: To evaluate whether operative vaginal delivery worsens the extent and/or, degree of permanent brachial plexus injury. STUDY DESIGN. We utilized a dataset (n = 104) of vaginal deliveries resulting in permanent brachial plexus injury that ultimately underwent litigation. We excluded patients on whom neonatal injury information was incomplete (n = 5). Patients who had an operative vaginal delivery (n = 33) were compared with those who did not. (n = 66) in regard to neonatal outcome and the location and extent of neurologic injury. RESULTS: The 2 classes were similar in demographic and obstetric variables. There were no differences in rates of 5-minute Apgar scores <7 (17.9%, or 5/28, vs. 5.2%, or 3/57, P = .1), complete neurologic injury to the brachial plexus (C5-T1) (39%, or 13/33, vs. 38%, or 25/66; P = 1.0) or avulsion of the nerve roots (44%, or 12/27, vs. 36%, or 18/50; P = .5) between those with operative or spontaneous vaginal delivery. CONCLUSION: Operative vaginal delivery did not increase the severity of impairment in a dataset of deliveries, resulting in permanent brachial plexus injury. C1 Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20057 USA. Georgetown Univ Hosp, Dept Pharmacol, Washington, DC 20057 USA. Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. Davidson Associates, Res Div, Baltimore, MD USA. Natl Inst Child Hlth & Dev, Ctr Res Mothers & Children, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. RP Poggi, SH (reprint author), 3800 Reservoir Rd 3PHC, Washington, DC 20007 USA. RI Allen, Robert/A-3731-2010 NR 21 TC 15 Z9 16 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD SEP PY 2003 VL 48 IS 9 BP 692 EP 696 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 723YU UT WOS:000185459800006 PM 14562633 ER PT J AU Pianta, RC AF Pianta, RC TI Untitled SO JOURNAL OF SCHOOL PSYCHOLOGY LA English DT Editorial Material C1 Univ Virginia, NICHD Study Early Child Care, Charlottesville, VA 22908 USA. RP Pianta, RC (reprint author), Univ Virginia, NICHD Study Early Child Care, POB 800784, Charlottesville, VA 22908 USA. OI Pianta, Robert/0000-0002-6280-8051 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-4405 J9 J SCHOOL PSYCHOL JI J. Sch. Psychol. PD SEP-OCT PY 2003 VL 41 IS 5 BP 311 EP 312 DI 10.1016/S0022-4405(03)00083-9 PG 2 WC Psychology, Educational SC Psychology GA 723FD UT WOS:000185421000001 ER PT J AU Korach, KS Emmen, JMA Walker, VR Hewitt, SC Yates, M Hall, JM Swope, DL Harrell, JC Couse, JF AF Korach, KS Emmen, JMA Walker, VR Hewitt, SC Yates, M Hall, JM Swope, DL Harrell, JC Couse, JF TI Update on animal models developed for analyses of estrogen receptor biological activity SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 6th International Aromatase Conference CY OCT 26-30, 2002 CL KYOTO, JAPAN DE estrogen receptor; knock-out mice; phenotypes; reproductive tract ID ALPHA KNOCKOUT MICE; MAMMARY-GLAND DEVELOPMENT; BETA ER-BETA; TARGETED DISRUPTION; REPRODUCTIVE PHENOTYPES; TISSUE DISTRIBUTION; SIGNALING PATHWAYS; OVARIAN PHENOTYPE; GROWTH-FACTOR; MOUSE AB Targeted disruption of the different ER genes has generated experimental animal models that are very useful in evaluating the distinct and cooperative roles of the two estrogen receptors, ERalpha and ERbeta, in reproductive but also non-reproductive tissues of both sexes. Phenotypic analysis has provided definitive experimental findings for estrogen receptor mediated physiological actions, involving ERalpha in uterine, mammary gland and neuroendocrine sites. ERbeta is involved most dramatically in the ovary as is ERalpha. More detailed studies in combination with tissue specific or inducible ER knock outs will be important for future research. (C) 2003 Published by Elsevier Ltd. C1 NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Sect, NIH, POB 12233,111 Alexander Dr,MD B3-02, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 39 TC 55 Z9 59 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 SEP PY 2003 VL 86 IS 3-5 BP 387 EP 391 DI 10.1016/S0960-0760(03)00348-0 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 749GX UT WOS:000186912500023 PM 14623535 ER PT J AU Yue, W Santen, RJ Wang, JP Li, Y Verderame, MF Bocchinfuso, WR Korach, KS Devanesan, P Todorovic, R Rogan, EG Cavalieri, EL AF Yue, W Santen, RJ Wang, JP Li, Y Verderame, MF Bocchinfuso, WR Korach, KS Devanesan, P Todorovic, R Rogan, EG Cavalieri, EL TI Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 6th International Aromatase Conference CY OCT 26-30, 2002 CL KYOTO, JAPAN DE breast cancer; catechol estrogen; estrogen receptor; carcinogenesis ID CATECHOL-O-METHYLTRANSFERASE; ESTROGEN-RECEPTOR-ALPHA; MAMMARY-GLAND HYPERPLASIA; CANCER RISK; POSTMENOPAUSAL WOMEN; EPITHELIAL-CELLS; GENE; MICE; POLYMORPHISM; INITIATION AB Long term exposure to estradiol increases the risk of breast cancer in a variety of animal species, as well as in women. The mechanisms responsible for this effect have not been firmly established. The prevailing theory proposes that estrogens increase the rate of cell proliferation by stimulating estrogen receptor-mediated transcription and thereby the number of errors occurring during DNA replication. An alternative hypothesis proposes that estradiol can be metabolized to quinone derivatives which can react with DNA and then remove bases from DNA through a process called depurination. Error prone DNA repair then results in point mutations. We postulate that these two processes, increased cell proliferation and genotoxic metabolite formation, act in an additive or synergistic fashion to induce cancer. If correct, aromatase inhibitors would block both processes whereas anti-estrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than use of anti-estrogens. Our studies initially demonstrated that catechol estrogen (CE) quinone metabolites are formed in MCF-7 human breast cancer cells in culture. Measurement of estrogen metabolites and conjugates involved utilization of an HPLC separation coupled with an electrochemical detector. We then utilized an animal model that allows dissociation of estrogen receptor-mediated function from that of the effects of estradiol metabolites. Wnt-1 transgenic mice harboring a knock-out of ERalpha provides a means of examining the effect of estrogen deprivation in the absence of the ER in animals with a high incidence of breast tumors. ERbeta was shown to be absent in the breast tissue of these animals by RNase protection assay. In the breast tissue of these estrogen receptor alpha knock-out (ERKO)Wnt-1 transgenic mice, we demonstrated formation of genotoxic estradiol metabolites. The ERKO/Wnt-1 breast extracts contained picomole amounts of the 4-catechol estrogens, but not their methoxy conjugates nor the 2-CE or their methoxy conjugates. The 4-CE conjugates with glutathione or its hydrolytic products (cysteine and N-acetylcysteine) were detected in picomole amounts in both tumors and hyperplastic mammary tissue, demonstrating the formation of CE-3,4-quinones. These results are consistent with the hypothesis that mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones, which may react with DNA to induce oncogenic mutations. The next set of experiments examined the incidence of tumors formed in Wnt-1 transgenic mice bearing wild type ERalpha (ER+/+), the heterozygous combination of genes (ER+/ER-) or ERalpha knock-out (ER-/-). To assess the effect of estrogens in the absence of ER, half of the animals were oophorectomized on day 15 and the other half were sham operated. Castration reduced the incidence of breast tumors in all animal groups and demonstrated the dependence of tumor formation upon estrogens. A trend toward reduction in tumor number (not statistically significant at this interim analysis) occurred in the absence of functional ER since the number of tumors was markedly reduced in ERKO animals which were castrated early in life. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER mediated mechanisms to induce breast cancer. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Virginia, Hlth Sci Syst, Dept Internal Med, Charlottesville, VA 22903 USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Med, Hershey, PA 17033 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Nebraska, Med Ctr, Eppley Canc Inst, Omaha, NE 68198 USA. RP Yue, W (reprint author), Univ Virginia, Hlth Sci Syst, Dept Internal Med, POB 801416, Charlottesville, VA 22903 USA. OI Verderame, Michael F./0000-0001-7046-0879; Korach, Kenneth/0000-0002-7765-418X NR 42 TC 144 Z9 153 U1 3 U2 14 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 SEP PY 2003 VL 86 IS 3-5 BP 477 EP 486 DI 10.1016/S0960-0760(03)00377-7 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 749GX UT WOS:000186912500035 PM 14623547 ER PT J AU Najavits, LM Runkel, R Neuner, C Frank, AF Thase, ME Crits-Christoph, P Blaine, J AF Najavits, LM Runkel, R Neuner, C Frank, AF Thase, ME Crits-Christoph, P Blaine, J TI Rates and symptoms of PTSD among cocaine-dependent patients SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; NATIONAL-INSTITUTE; ABUSE; COMORBIDITY; WOMEN AB Objective: This study evaluated lifetime traumatic events and current posttraumatic stress disorder (PTSD) symptoms in a substance abuse sample. Method: Participants in the study consisted of 558 (75.1% male) cocaine-dependent individuals who completed self-report measures of trauma and PTSD symptoms prior to entry into treatment. Results: Results showed a high number of lifetime traumatic events, even among those without PTSD. General disaster was the most prevalent. Current PTSD was found in 10.9% of the participants, with a significantly higher rate among women (21.6%) than among men (7.2%). For those with PTSD, the most prominent PTSD symptom cluster was arousal, and the most common symptoms were restricted affect, detachment and irritability. Participants with PTSD endorsed a large number of symptoms, almost double that needed to meet diagnostic criteria; however. neither number of traumas nor type of trauma was associated with their level of PTSD symptoms. Even among those not meeting PTSD criteria, subthreshold symptoms were found, with avoidance the most prominent cluster. Sociodemographic and recent cocaine use variables did not differentiate the PTSD from non-PTSD groups. Conclusions: PTSD is present in a sizeable percentage of cocaine-dependent treatment-seeking patients, particularly women. Clinicians might address arousal symptoms in particular, which were the most prominent symptom cluster, and which may be exacerbated by cocaine use. Even among those without PTSD, lifetime trauma is substantial and subthreshold PTSD symptoms are common. Vulnerability to PTSD needs further study, as sociodemographic and cocaine use variables did not distinguish between PTSD and non-PTSD groups. C1 McLean Hosp, Belmont, MA 02478 USA. Univ Heidelberg, Dept Psychol, Heidelberg, Germany. Boston Coll, Boston, MA USA. Brookside Hosp, Nashua, NH USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. NIDA, Rockville, MD USA. RP Najavits, LM (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. FU NIAAA NIH HHS [R21 AA12181]; NIDA NIH HHS [U18-DA07673, R01 DA012249, U18 DA007090, U18-DA07085, K02 DA00400, U18-DA07693, U18-DA07090, U18-DA07663] NR 26 TC 40 Z9 41 U1 4 U2 5 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD SEP PY 2003 VL 64 IS 5 BP 601 EP 606 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 725ZH UT WOS:000185572200001 PM 14572180 ER PT J AU Warner, EE Mulshine, JL AF Warner, EE Mulshine, JL TI Surgical considerations with lung cancer screening SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Editorial Material ID ASSISTED THORACIC-SURGERY; HELICAL COMPUTED-TOMOGRAPHY; SMALL PULMONARY NODULES; LYMPH-NODE DISSECTION; RANDOMIZED TRIAL; ACTION PROJECT; RESECTION; LOBECTOMY; CARCINOMA; THORACOSCOPY C1 NCI, Intervent Sect,Cell & Canc Biol Branch, Upper Aerodigest Chemoprevent Fac, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Dept Surg, Div Gen Surg, Washington, DC 20007 USA. Dept Hlth & Human Serv, Bethesda, MD USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect,Cell & Canc Biol Branch, Upper Aerodigest Chemoprevent Fac, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 47 TC 10 Z9 10 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD SEP PY 2003 VL 84 IS 1 BP 1 EP 6 DI 10.1002/jso.10280 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 718AY UT WOS:000185124000001 PM 12949983 ER PT J AU Isenberg, JS AF Isenberg, JS TI Inhibition of nitric oxide synthase (NOS) conversion of L-arginine to nitric oxide (NO) decreases low density mononuclear cell (LD MNC) trans-endothelial migration and cytokine output SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE l-arginine; nitric oxide; endothelium; cellular migration; wound healing ID STRESS STIMULATES PHOSPHORYLATION; INDUCED MICROVASCULAR DYSFUNCTION; ISCHEMIA-REPERFUSION INJURY; FREE-TISSUE TRANSFER; PROTEIN-KINASE-A; MYOCUTANEOUS FLAPS; IMMUNE-COMPLEXES; SKELETAL-MUSCLE; SKIN FLAPS; MICROCIRCULATION AB Background. Biochemical, molecular, and cellular events at the micro-vascular endothelial interface determine the integrity of the vascular system. Disruption of these events has been described to occur in accordance with ischemic/reperfusion injury leading to inflammation, cell adhesion, and endothelial permeability changes. It has also been suggested that nitric oxide (NO) participates in these events. However, the manner in which it does is debated. The purpose of this study was to investigate the effects of exogenous L-arginine, an NO precursor, and L-N (G) nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, upon inflammatory events at the endothelial interface. Materials and methods. Fresh cultures of human umbilical vein endothelial cells were established and used to seed Transwell chemotaxic chambers, and then grown to confluence. Whole blood was obtained from the same healthy volunteer and processed for light density mononuclear cells. Following per-stimulation of the endothelial monolayer with IL-1beta or antigen-antibody complex, known numbers of mononuclear cells were seeded to the endothelium. Incubation with and without exogenous L-arginine or L-NAME for 48 h was done. Lower chamber supernatant was then collected, cell numbers and viability determined and levels of inflammatory cytokines TNF-alpha and INF-lambda determined via ELISA assay. Results. Tran-endothelial cellular migration was nil lacking pre-stimulation, regardless of the addition of exogenous L-arginine. With pre-stimulation trans-endothelial migration increased significantly, a response that was greatly enhanced by L-arginine. With the further addition of L-NAME cellular migration decreased substantially. Pro-inflammatory cytokine levels of TNF-alpha and INF-lambda followed levels of cellular migration. Conclusions. In vitro there was little to no trans-endothelial migration of inflammatory cells across an unstimulated monolayer of vascular endothelium. Pre-stimulation of the same endothelial monolayer with either a cytokine or antigen-antibody complex resulted in a significant trans-endothelial migration of inflammatory cells. This latter response was associated with a concurrent increase in the secretion of the pro-inflammatory cytokines TNF-alpha and INF-gamma. The presence of the NO precursor L-arginine greatly enhanced the observed inflammatory response. Conversely, L-NAME, an inhibitor of NOS, depressed the inflammatory response. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Oklahoma, Dept Oral & Maxillofacial Surg, Oklahoma City, OK USA. RP Isenberg, JS (reprint author), NCI, NIH, 10 Ctr Dr Bldg 10,Room 2A29, Bethesda, MD 20892 USA. NR 36 TC 11 Z9 11 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2003 VL 114 IS 1 BP 100 EP 106 DI 10.1016/S0022-4804(03)00310-X PG 7 WC Surgery SC Surgery GA 721FM UT WOS:000185306400015 PM 13678705 ER PT J AU Schlom, J Canter, D Zeytin, H Greiner, J AF Schlom, J Canter, D Zeytin, H Greiner, J TI Evaluation of recombinant murine interferon-alpha and interferon-gamma as cancer vaccine immunoadjuvants SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 89th Annual Clinical Congress of the American-College-of-Surgeons CY OCT 19-23, 2003 CL CHICAGO, ILLINOIS SP Amer Coll Surg C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2003 VL 197 IS 3 SU S BP S74 EP S74 PG 1 WC Surgery SC Surgery GA 720EH UT WOS:000185248100183 ER PT J AU Payette, H Roubenoff, R Jacques, PF Dinarello, CA Wilson, PWF Abad, LW Harris, T AF Payette, H Roubenoff, R Jacques, PF Dinarello, CA Wilson, PWF Abad, LW Harris, T TI Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: The Framingham Heart Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE sarcopenia; predictors; growth hormone; cytokine; population-based ID SKELETAL-MUSCLE MASS; FAT-FREE MASS; BODY-COMPOSITION; ELDERLY-MEN; CYTOKINE PRODUCTION; ASSOCIATION; HORMONE; DISABILITY; WEIGHT; HEALTH AB OBJECTIVES: To assess the prognostic role of the inflammatory cytokine, interleukin 6 (IL-6), and insulin-like growth factor-1 (IGF-1) in predicting 2-year changes in fat-free mass (FFM) while controlling for potential confounders. DESIGN: Population-based cohort, the Framingham Heart Study, examined in 1992-93 and 1994-95. SETTING: General community. PARTICIPANTS: Two hundred thirty-two men and 326 women aged 72 to 92. MEASUREMENTS: IGF-1 was measured using radioimmunoassay and cellular IL-6 production using non-crossreacting radioimmunoassays. FFM was estimated using population-specific equations for predicting FFM from bioelectrical impedance analysis developed separately for men and women. RESULTS: Higher IGF-1 predicted smaller loss of FFM in men than lower IGF-1 did (P = .002), after adjusting for age, baseline FFM, fat mass, and 2-year weight changes, whereas cellular IL-6 was a significant predictor of sarcopenia in women (P = .02). Weight change was a strong determinant of change in FFM in both sexes (P < .0001). CONCLUSION: Predictors of sarcopenia include body composition characteristics that are common to men and women and sex-specific metabolic predictors. Sarcopenia appears to reflect a withdrawal of anabolic stimuli, such as growth hormone, in men but an increase in catabolic stimuli, such as cellular IL-6, in women. C1 Tufts Univ, Nutr Exercise Physiol & Sarcopenia Lab, Boston, MA 02111 USA. Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Univ Colorado, Med Ctr, Denver, CO 80202 USA. Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NIA, Geriatr Epidemiol Off, Bethesda, MD 20892 USA. RP Payette, H (reprint author), Sherbrooke Geriatr Univ Inst, Res Ctr Aging, 1036 Belvedere St, Sherbrooke, PQ J1H 4C4, Canada. FU NHLBI NIH HHS [N01-HC-Z5195]; NIA NIH HHS [Y01-AG-4-0245, AG15797]; NIDDK NIH HHS [DK02120] NR 51 TC 111 Z9 113 U1 1 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2003 VL 51 IS 9 BP 1237 EP 1243 DI 10.1046/j.1532-5415.2003.51407.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 721NF UT WOS:000185321900006 PM 12919235 ER PT J AU Ammenwerth, E Wolff, AC Knaup, P Ulmer, H Skonetzki, S van Bemmel, JH McCray, AT Haux, R Kulikowski, C AF Ammenwerth, E Wolff, AC Knaup, P Ulmer, H Skonetzki, S van Bemmel, JH McCray, AT Haux, R Kulikowski, C TI Developing and evaluating criteria to help reviewers of biomedical informatics manuscripts SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID MEDICAL INFORMATICS; JOURNALS; GUIDELINES AB Peer-reviewed publication of scientific research results represents the most important means of their communication. The authors have annually reviewed a large heterogeneous set of papers to produce the International Medical Informatics Association (IMIA) Yearbook of Medical Informatics. To support an objective and high-quality review process, the authors attempted to provide reviewers with a set of refined quality criteria, comprised of 80 general criteria and an additional 60 criteria for specific types of manuscripts. Authors conducted a randomized controlled trial, with 18 reviewers, to evaluate application of the refined criteria on review outcomes. Whereas the trial found that reviewers applying the criteria graded papers more strictly (lower overall scores), and that junior reviewers appreciated the availability of the criteria, there was no overall change in the interrater variability in reviewing the manuscripts. The authors describe their experience as a "case report" and provide a reference to the refined quality review criteria without claiming that the criteria represent a validated instrument for quantitative quality measurement. C1 Univ Hlth Informat & Technol Tyrol, Res Grp Assessment Hlth Informat Syst, A-6020 Innsbruck, Austria. Univ Heidelberg, Dept Med Informat, Heidelberg, Germany. Univ Innsbruck, Inst Biostat & Documentat, A-6020 Innsbruck, Austria. Erasmus Univ, Rotterdam, Netherlands. Erasmus Univ, Bethesda, MD USA. Natl Lib Med, Bethesda, MD USA. Univ Hlth Informat & Technol, Inst Hlth Informat Syst, Innsbruck, Austria. Rutgers State Univ, Dept Comp Sci, New Brunswick, NJ 08903 USA. RP Ammenwerth, E (reprint author), Univ Hlth Informat & Technol Tyrol, Res Grp Assessment Hlth Informat Syst, Innrain 98, A-6020 Innsbruck, Austria. EM elske.ammenwerth@umit.at RI Ammenwerth, Elske/F-5430-2010; Ulmer, Hanno/C-3488-2011 OI Ulmer, Hanno/0000-0001-5911-1002 NR 16 TC 13 Z9 13 U1 2 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP-OCT PY 2003 VL 10 IS 5 BP 512 EP 514 DI 10.1197/jamia.M1062 PG 3 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 722ZY UT WOS:000185409000014 PM 12807814 ER PT J AU Abbott, KC Yuan, CM Taylor, AJ Cruess, DF Agodoa, LYC AF Abbott, KC Yuan, CM Taylor, AJ Cruess, DF Agodoa, LYC TI Early renal insufficiency and hospitalized heart disease after renal transplantation in the era of modern immunosuppression SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE CORONARY SYNDROMES; ACUTE MYOCARDIAL-INFARCTION; UNITED-STATES; CARDIOVASCULAR-DISEASE; SERUM CREATININE; ESRD PATIENTS; RISK-FACTORS; RECIPIENTS; SURVIVAL; MORTALITY AB Renal insufficiency has been identified as a risk factor for graft loss and death after renal transplantation but has not been consistently linked to early, nonfatal, hospitalized heart disease (HHD). With the United States Renal Data System database, 29,597 patients who received a kidney transplant between January 1, 1996, and July 31, 2000, with Medicare as the primary payer, and were monitored until December 31, 2000, were studied. Cox proportional-hazards regression models were used to calculate the association of recipient estimated GFR (eGFR) at 1 yr after renal transplantation, as determined with the Modification of Diet in Renal Disease formula, with hospitalization for treatment of acute coronary syndromes (ACS) (International Classification of Diseases, version 9, code 410.x or 411.x) or congestive heart failure (CHF) (code 428.x) 1 to 3 yr after renal transplantation. Rates of ACS and CHF were 2.2 and 4.9%, respectively, for patients with eGFR of <44.8 ml/min per 1.73 m(2), compared with 1.2 and 1.4% for patients with eGFR of >69.7 ml/min per 1.73 m(2). Reduced eGFR (<44.8 ml/min per 1.73 m(2), compared with >69.7 ml/min per 1.73 m(2)) at the end of the first 1 yr after transplantation was independently associated with increased risks of both ACS (adjusted hazard ratio, 2.16; 95% confidence interval, 1.39 to 3.35) and CHF (adjusted hazard ratio, 2.95; 95% confidence interval, 2.24 to 3.90). It was concluded that early renal insufficiency (approximately stage 3 chronic kidney disease) was associated with higher rates of HHD I to 3 yr after kidney transplantation. Preservation of renal function after renal transplantation may reduce the rates of HHD, and renal transplant recipients with reduced eGFR should be considered at high risk of developing cardiovascular disease. 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. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 43 TC 42 Z9 46 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2003 VL 14 IS 9 BP 2358 EP 2365 DI 10.1097/01.ASN.0000083008.25305.67 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 716JR UT WOS:000185025500018 PM 12937314 ER PT J AU Hostetter, TH Ibrahim, HN AF Hostetter, TH Ibrahim, HN TI Aldosterone in chronic kidney and cardiac disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CONVERTING ENZYME-INHIBITORS; PLASMINOGEN-ACTIVATOR INHIBITOR-1; DIETARY-PROTEIN INTAKE; CHRONIC RENAL-FAILURE; II RECEPTOR BLOCKADE; SMOOTH-MUSCLE-CELLS; HEART-FAILURE; MINERALOCORTICOID RECEPTORS; MYOCARDIAL-INFARCTION; DIABETIC-NEPHROPATHY C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Div Renal Dis & Hypertens, Minneapolis, MN 55455 USA. RP Hostetter, TH (reprint author), NIDDKD, NIH, 6707 Democracy Blvd,Room 625, Bethesda, MD 20892 USA. NR 68 TC 74 Z9 75 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2003 VL 14 IS 9 BP 2395 EP 2401 DI 10.1097/01.ASN.0000086472.65806.73 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 716JR UT WOS:000185025500023 PM 12937319 ER PT J AU Dunson, DB AF Dunson, DB TI Dynamic latent trait models for multidimensional longitudinal data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Bayesian analysis; latent variables; mixed-effects model; multiple discrete and continuous outcomes; multivariate count data; repeated measure; transition model ID GENERALIZED LINEAR-MODELS; VARIABLE MODELS; POLYTOMOUS DATA; LIKELIHOOD; OUTCOMES AB This article presents a new approach for analysis of multidimensional longitudinal data, motivated by studies using an item response battery to measure traits of an individual repeatedly over time. A general modeling framework is proposed that allows mixtures of count, categorical, and continuous response variables. Each response is related to age-specific latent traits through a generalized linear model that accommodates item-specific measurement errors. A transition model allows the latent traits at a given age to depend on observed predictors and on previous latent traits for that individual. Following a Bayesian approach to inference, a Markov chain Monte Carlo algorithm is proposed for posterior computation. The methods are applied to data from a neurotoxicity study of the pesticide methoxychlor, and evidence of a dose-dependent increase in motor activity is presented. C1 Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. NR 28 TC 63 Z9 64 U1 0 U2 5 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD SEP PY 2003 VL 98 IS 463 BP 555 EP 563 DI 10.1198/016214503000000387 PG 9 WC Statistics & Probability SC Mathematics GA 733HK UT WOS:000185993900006 ER PT J AU Wu, CO Huang, JHZ AF Wu, CO Huang, JHZ TI Wavelet-based nonparametric modeling of hierarchical functions in colon carcinogenesis - Comment SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Editorial Material C1 NHLBI, Off Biostat Res, DECA, Bethesda, MD 20892 USA. Univ Penn, Dept Stat, Philadelphia, PA 19104 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat Res, DECA, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD SEP PY 2003 VL 98 IS 463 BP 588 EP 591 DI 10.1198/016214503000000486 PG 4 WC Statistics & Probability SC Mathematics GA 733HK UT WOS:000185993900011 ER PT J AU Sant, GR Propert, KJ Hanno, PM Burks, D Culkin, D Diokno, AC Hardy, C Landis, JR Mayer, R Madigan, R Messing, EM Peters, K Theoharides, TC Warren, J Wein, AJ Steers, W Kusek, JW Nyberg, LM AF Sant, GR Propert, KJ Hanno, PM Burks, D Culkin, D Diokno, AC Hardy, C Landis, JR Mayer, R Madigan, R Messing, EM Peters, K Theoharides, TC Warren, J Wein, AJ Steers, W Kusek, JW Nyberg, LM CA Interstitial Cystitis Clinical Tri TI A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis SO JOURNAL OF UROLOGY LA English DT Article DE clinical trial, hydroxyzine; cystitis, interstitial; pentosan polysulfate sodium ID SYMPTOM-INDEX; SODIUM; PENTOSANPOLYSULFATE; THERAPY AB Purpose: This pilot study was designed to evaluate the feasibility of a multicenter, randomized, clinical trial in interstitial cystitis (IC). Secondary objectives were to evaluate the safety and efficacy of oral pentosan polysulfate sodium (PPS), hydroxyzine, and the combination to consider their use in a larger randomized clinical trial. Materials and Methods: A 2 X 2 factorial study design was used to evaluate PPS and hydroxyzine. Participants met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency for a minimum of 6 months before study entry. The primary end point was a patient reported global response assessment. Secondary end points included validated symptom indexes and patient reports of pain, urgency and frequency. The target sample size was 136 participants recruited during 10 months. Results: A total of 121 (89% of goal) participants were randomized over 18 months and 79% provided complete followup data. The response rate for hydroxyzine was 31% for those treated and 20% for those not treated (p = 0.26). A nonsignificant trend was seen in the PPS treatment groups (34%) as compared to no PPS (18%, p = 0.064). There were no treatment differences for any of the secondary end points. Adverse events were mostly minor and similar to those in previous reports. Conclusions: The low global response rates for PPS and hydroxyzine suggest that neither provided benefit for the-majority of patients with IC. This trial demonstrated the feasibility of conducting a multicenter randomized clinical trial in IC using uniform procedures and outcomes. However, slow recruitment underscored the difficulties of evaluating commonly available IC drugs. C1 Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Henry Ford Hosp, Detroit, MI 48202 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Univ Rochester, Rochester, NY 14627 USA. Univ Maryland, Baltimore, MD 21201 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA USA. RP Propert, KJ (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, Blockley Hall,6th Floor,423 Guardian Dr, Philadelphia, PA 19104 USA. RI Landis, J. Richard/A-9330-2010; Theoharides, Theoharis/E-5596-2010 FU NIDDK NIH HHS [U01 DK 54138, U01 DK 54108, U01 DK 54125, U01 DK 54127, U01 DK 54133, U01 DK 54158] NR 19 TC 112 Z9 115 U1 0 U2 2 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 SEP PY 2003 VL 170 IS 3 BP 810 EP 815 DI 10.1097/01.ju.0000083020.06212.3d PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 712TN UT WOS:000184813400028 PM 12913705 ER PT J AU Gravitt, PE Peyton, C Wheeler, C Apple, R Higuchi, R Shah, KV AF Gravitt, PE Peyton, C Wheeler, C Apple, R Higuchi, R Shah, KV TI Reproducibility of HPV 16 and HPV 18 viral load quantitation using TaqMan real-time PCR assays SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE human papillomavirus; viral load; real-time PCR; quantitation; reproducibility ID HUMAN-PAPILLOMAVIRUS DNA; CARCINOMA IN-SITU; CERVICAL DISEASE; WOMEN; GRADE; HYBRIDIZATION; TYPE-16; LESIONS; RISK AB A reproducibility study was designed to assess within-assay, between-day, and interlaboratory variability of three real-time PCR assays targeting HPV 16, HPV 18, and the human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) pseudogenes. Fifteen HPV 16 and fifteen HPV 18 cervical swab samples were amplified in triplicate by GAPDH and HPV 16 and by GAPDH and HPV 18 assays, respectively. All samples were amplified undiluted and at a 1: 10 dilution on 2 separate days in the same laboratory, and the same samples were amplified in a separate laboratory. HPV 16 and HPV 18 normalized viral load is reported as the number of HPV genomes per 20 000 GAPDH copies. The analytic specificity of the HPV 16 and 18 assays was 100 and 97%, respectively. The intraclass correlation coefficients (ICC) were 0.99, 0.97, and 0.98 for HPV 16, HPV 18, and GAPDH, respectively, indicating that the variability due to experimental error was very low. Ten-fold differences in viral load could be readily discriminated across a six order of magnitude dynamic range (ca. 5-5 x 10(6) Copies). Power of discrimination was increased at higher target concentrations ( > 5000 copies). The correlation of normalized HPV 16 and 18 viral load was high between the two laboratories (Spearman rho (rho) = 0.96 and 0.87, respectively). These HPV 16 and HPV 18 quantitative PCR assays with GAPDH normalization are reproducibly quantitative over a broad linear dynamic range allowing for application in epidemiologic studies for measurement of viral load. (C) 2003 Elsevier B.V. All rights reserved. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM USA. Roche Mol Syst, Dept Human Genet, Alameda, CA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Gravitt, PE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Room E6014, Baltimore, MD 21205 USA. RI apple, raymond/I-4506-2012 OI apple, raymond/0000-0002-8007-0345 NR 23 TC 72 Z9 78 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD SEP PY 2003 VL 112 IS 1-2 BP 23 EP 33 DI 10.1016/S0166-0934(03)00186-1 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 723HL UT WOS:000185426900003 PM 12951209 ER PT J AU Kotelkin, A Prikhod'ko, EA Cohen, JI Collins, PL Bukreyev, A AF Kotelkin, A Prikhod'ko, EA Cohen, JI Collins, PL Bukreyev, A TI Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand SO JOURNAL OF VIROLOGY LA English DT Article ID NF-KAPPA-B; TRAIL-INDUCED APOPTOSIS; HUMAN DENDRITIC CELLS; BCL-2 ANTISENSE OLIGONUCLEOTIDES; NUCLEAR FACTOR (NF)-KAPPA-B; EPITHELIAL-CELLS; GENE-EXPRESSION; ENDOPLASMIC-RETICULUM; INHIBITS APOPTOSIS; INTERLEUKIN-8 GENE AB Respiratory syncytial virus (RSV) is an important cause of respiratory tract disease worldwide, especially in the pediatric population. For viruses in general, apoptotic death of infected cells is a mechanism for reducing virus replication. Apoptosis can also be an important factor in augmenting antigen presentation and the host immune response. We examined apoptosis in response to RSV infection of primary small airway cells, primary tracheal-bronchial cells, and A549 and HEp-2 cell lines. The primary cells and the A549 cell line gave generally similar responses, indicating their appropriateness as models in contrast to HEp-2 cells. With the use of RNase protection assays with probes representing 33 common apoptosis factors, we found strong transcriptional activation of both pro- and antiapoptotic factors in response to RSV infection, which were further studied at the protein level and by functional assays. In particular, RSV infection strongly up-regulated the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its functional receptors death receptor 4 (DR4) and DR5. Furthermore, RSV-infected cells became highly sensitive to apoptosis induced by exogenous TRAIL. These findings suggest that RSV-infected cells in vivo are susceptible to killing through the TRAIL pathway by immune cells such as natural killer and CD4(+) cells that bear membrane-bound TRAIL. RSV infection also induced several proapoptotic factors of the Bcl-2 family and caspases 3, 6, 7, 8, 9, and 10, representing both the death receptor- and mitochondrion-dependent apoptotic pathways. RSV also mediated the strong induction of antiapoptotic factors of the Bcl-2 family, especially Mcl-1, which might account for the delayed induction of apoptosis in RSV-infected cells in the absence of exogenous induction of the TRAIL pathway. C1 NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, 50 South Dr,Rm 6505, Bethesda, MD 20892 USA. NR 80 TC 83 Z9 89 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2003 VL 77 IS 17 BP 9156 EP 9172 DI 10.1128/JVI.77.17.9156-9172.2003 PG 17 WC Virology SC Virology GA 712BR UT WOS:000184776800006 PM 12915532 ER PT J AU Sullivan, N Yang, ZY Nabel, GJ AF Sullivan, N Yang, ZY Nabel, GJ TI Ebola virus pathogenesis: Implications for vaccines and therapies SO JOURNAL OF VIROLOGY LA English DT Review ID HEMORRHAGIC-FEVER; VIRION GLYCOPROTEINS; NONHUMAN-PRIMATES; PASSIVE TRANSFER; CELLULAR ENTRY; DNA VACCINES; DC-SIGN; INFECTION; VACCINATION; ANTIBODY C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. NR 51 TC 54 Z9 63 U1 5 U2 55 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 SEP PY 2003 VL 77 IS 18 BP 9733 EP 9737 DI 10.1128/JVI.77.18.9733-9737.2003 PG 5 WC Virology SC Virology GA 716TX UT WOS:000185046200001 PM 12941881 ER PT J AU Lemiale, F Kong, WP Akyurek, LM Ling, X Huang, Y Chakrabarti, BK Eckhaus, M Nabel, GJ AF Lemiale, F Kong, WP Akyurek, LM Ling, X Huang, Y Chakrabarti, BK Eckhaus, M Nabel, GJ TI Enhanced mucosal immunoglobulin A response of intranasal adenoviral vector human immunodeficiency virus vaccine and localization in the central nervous system SO JOURNAL OF VIROLOGY LA English DT Article ID INFLAMMATORY RESPONSE; PROTECTIVE EFFICACY; REPRODUCTIVE-TRACT; IMMUNE-RESPONSES; LANGERHANS CELLS; DENDRITIC CELLS; RHESUS MACAQUES; DNA VACCINATION; GENE-EXPRESSION; LYMPHOID-TISSUE AB Replication-defective adenovirus (ADV) vectors represent a promising potential platform for the development of a vaccine for AIDS. Although this vector is typically administered intramuscularly, it would be desirable to induce mucosal immunity by delivery through alternative routes. In this study, the immune response and biodistribution of ADV vectors delivered by different routes were evaluated. ADV vectors expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env were delivered intramuscularly or intranasally into mice. Intranasal immunization induced greater HIV-specific immunoglobulin A (IgA) responses in mucosal secretions and sera than in animals with intramuscular injection, which showed stronger systemic cellular and IgG responses. Administration of the vaccine through an intranasal route failed to overcome prior ADV immunity. Animals exposed to ADV prior to vaccination displayed substantially reduced cellular and humoral immune responses to HIV antigens in both groups, though the reduction was greater in animals immunized intranasally. This inhibition was partially overcome by priming with a DNA expression vector expressing HIV-1 Gag, Pol, and Env before boosting with the viral vector. Biodistribution of recombinant adenovirus (rADV) vectors administered intranasally revealed infection of the central nervous system, specifically in the olfactory bulb, possibly via retrograde transport by olfactory neurons in the nasal epithelium, which may limit the utility of this route of delivery of ADV vector-based vaccines. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Vasc Biol Branch, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Inst Pathol Sect, Off Res Serv, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. NR 53 TC 103 Z9 105 U1 0 U2 3 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 SEP PY 2003 VL 77 IS 18 BP 10078 EP 10087 DI 10.1128/JVI.77.18.10078-10087.2003 PG 10 WC Virology SC Virology GA 716TX UT WOS:000185046200037 PM 12941918 ER PT J AU Grim, KC Van der Merwe, E Sullivan, M Parsons, N McCutchan, TF Cranfield, M AF Grim, KC Van der Merwe, E Sullivan, M Parsons, N McCutchan, TF Cranfield, M TI Plasmodium juxtanucleare associated with mortality in black-footed penguins (Spheniscus demersus) admitted to a rehabilitation center SO JOURNAL OF ZOO AND WILDLIFE MEDICINE LA English DT Article DE avian malaria; Plasmodium juxtanucleare; black-footed penguin; Spheniscus demersus; polymerase chain reaction ID AVIAN MALARIA INFECTIONS; RIBOSOMAL-RNA; DIAGNOSIS; IDENTIFICATION; FALCIPARUM; ANTIBODIES; TARGET AB Five black-footed penguins (Spheniscus demersus) admitted to the Southern African Foundation for the Conservation of Coastal Birds, in Cape Town, South Africa, died from malaria infection. Evidence for malaria as the cause of death included antemortem clinical signs, parasitemia. splenomegaly, pulmonary edema, and the presence of histologically visible schizonts in the reticuloendothelial system. A portion of the malarial small subunit ribosomal ribonucleic acid gene was detected by polymerase chain reaction from postmortem blood samples from all the birds. A species-specific variable region of this gene was compared with the same region on genes from other known avian malarial organisms, establishing that Plasmodium juxtanucleare was involved. C1 Balimore Zoo, Dept Med, Baltimore, MD 21217 USA. So African Fdn Conservat Coastal Birds, ZA-7443 Cape Town, South Africa. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Div Comp Applicat, Baltimore, MD 21205 USA. RP Grim, KC (reprint author), NIAID, NIH, 4 Ctr Dr,Room BT-28, Bethesda, MD 20892 USA. NR 35 TC 29 Z9 29 U1 0 U2 12 PU AMER ASSOC ZOO VETERINARIANS PI MEDIA PA 6 NORTH PENNELL ROAD, MEDIA, PA 19063 USA SN 1042-7260 J9 J ZOO WILDLIFE MED JI J. Zoo Wildl. Med. PD SEP PY 2003 VL 34 IS 3 BP 250 EP 255 DI 10.1638/02-070 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 729EL UT WOS:000185759600004 PM 14582786 ER PT J AU Chapman, AB Guay-Woodford, LM Grantham, JJ Torres, VE Bae, KT Baumgarten, DA Kenney, PJ King, BF Glockner, JF Wetzel, LH Brummer, ME O'Neill, WC Robbin, ML Bennett, WM Klahr, S Hirschman, GH Kimmel, PL Thompson, PA Miller, JP AF Chapman, AB Guay-Woodford, LM Grantham, JJ Torres, VE Bae, KT Baumgarten, DA Kenney, PJ King, BF Glockner, JF Wetzel, LH Brummer, ME O'Neill, WC Robbin, ML Bennett, WM Klahr, S Hirschman, GH Kimmel, PL Thompson, PA Miller, JP TI Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Nephrology CY OCT 30-NOV 06, 2002 CL PHILADELPHIA, PA SP Amer Soc Nephrol DE autosomal-dominant polycystic kidney disease; magnetic resonance imaging; renal volume; cyst volume; renal function ID MAGNETIC-RESONANCE; COMPUTED-TOMOGRAPHY; PROGRESSION; VOLUME; STEREOLOGY; SIZE AB Background. Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. Methods. Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. Results. Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. Conclusion. MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function. C1 Emory Univ, Sch Med, Atlanta, GA 30322 USA. Univ Alabama Birmingham, Dept Med, Div Renal, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Radiol, Birmingham, AL 35294 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Washington Univ, Div Biostat, St Louis, MO USA. NW Renal Clin, Portland, OR USA. NIDDK, NIH, Bethesda, MD USA. RP Emory Univ, Sch Med, 1639 Pierce Dr,WMB 338, Atlanta, GA 30322 USA. EM arlene_chapman@emory.org OI Miller, J Philip/0000-0003-4568-6846 FU NCRR NIH HHS [M01-RR00039, M01-RR00052, M01-RR00585]; NIDDK NIH HHS [U01-DK56956] NR 26 TC 178 Z9 182 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2003 VL 64 IS 3 BP 1035 EP 1045 DI 10.1046/j.1523-1755.2003.00185.x PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 711GY UT WOS:000184732300029 PM 12911554 ER PT J AU Daugirdas, JT Greene, T Depner, TA Chumlea, C Rocco, MJ Chertow, GM AF Daugirdas, JT Greene, T Depner, TA Chumlea, C Rocco, MJ Chertow, GM CA HEMO Study Grp TI Anthropometrically estimated total body water volumes are larger than modeled urea volume in chronic hemodialysis patients: Effects of age, race, and gender SO KIDNEY INTERNATIONAL LA English DT Article DE total body water volume; hemodialysis; urea ID BIOELECTRICAL-IMPEDANCE; KINETIC-MODELS; EQUATIONS; REMOVAL; KT/V; MASS; POOL; HEMO AB Background. The modeled volume of urea distribution (Vm) in intermittently hemodialyzed patients is often compared with total body water (TBW) volume predicted from population studies of patient anthropometrics (Vant). Methods. Using data from the HEMO Study, we compared Vm determined by both blood-side and dialysate-side urea kinetic models with Vant as calculated by the Watson, Hume-Weyers, and Chertow anthropometric equations. Results. Median levels of dialysate-based Vm and blood-based Vm agreed (43% and 44% of body weight, respectively). These volumes were lower than anthropometric estimates of TBW, which had median values of 52% to 55% of body weight for the three formulas evaluated. The difference between the Watson equation for TBW and modeled urea volume was greater in Caucasians (19%) than in African Americans (13%). Correlations between Vm and Vant determined by each of the three anthropometric estimation equations were similar; but Vant derived from the Watson formula had a slightly higher correlation with Vm. The difference between Vm and the anthropometric formulas was greatest with the Chertow equation, less with the Hume-Weyers formula, and least with the Watson estimate. The age term in the Watson equation for men that adjusts Vant downward with increasing age reduced an age effect on the difference between Vant and Vm in men. Conclusion. The findings show that kinetically derived values for V from blood-side and dialysate-side modeling are similar, and that these modeled urea volumes are lower by a substantial amount than anthropometric estimates of TBW. The higher values for anthropometry-derived TBW in hemodialyzed patients could be due to measurement errors. However, the possibility exists that TBW space is contracted in patients with end-stage renal disease (ESRD) or that the TBW space and the urea distribution space are not identical. C1 NIDDK, NIH, Bethesda, MD USA. RP Daugirdas, JT (reprint author), 15W560 89th St, Burr Ridge, IL 60527 USA. NR 32 TC 46 Z9 46 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2003 VL 64 IS 3 BP 1108 EP 1119 DI 10.1046/j.1523-1755.2003.00179.x PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 711GY UT WOS:000184732300039 PM 12911564 ER PT J AU Garrett-Beal, LJ Hoogstraten-Miller, SL AF Garrett-Beal, LJ Hoogstraten-Miller, SL TI Managing a Mouse Mutant Resource Center... this is not your father's transgenic Core SO LAB ANIMAL LA English DT Article ID MUTAGENESIS AB Genetically engineered mice are making an increasingly valuable contribution to biomedical research, and many institutions have begun to assemble dedicated facilities for the development of transgenic animals. The authors describe the structure, function, and management of the transgenic core at NHGRI. C1 NHGRI, Embryon Stem Cell & Transgen Core Facil, Anim Program, Bethesda, MD USA. RP Garrett-Beal, LJ (reprint author), NIH, Room 4A52,Bldg 49,49 Convent Dr, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD SEP PY 2003 VL 32 IS 8 BP 31 EP 37 DI 10.1038/laban0903-31 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 717KD UT WOS:000185086900008 PM 12966446 ER PT J AU Debelenko, LV Arthur, DC Pack, SD Helman, LJ Schrump, DS Tsokos, M AF Debelenko, LV Arthur, DC Pack, SD Helman, LJ Schrump, DS Tsokos, M TI Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor SO LABORATORY INVESTIGATION LA English DT Review ID LARGE-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; TRANSFER-RNA SYNTHETASE; KINASE GENE; PSEUDOTUMOR; TRANSLOCATION; EXPRESSION; FIBROSARCOMA; TPM3-ALK; NPM AB Inflammatory myofibroblastic tumor (IMT) is a rare childhood neoplasm. The natural history of this disease is poorly understood. Recently chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene have been implicated in this tumor. We have studied a case of ALK-positive soft tissue IMT showing clinical and morphologic features of malignancy. Interphase fluorescence in situ hybridization demonstrated ALK rearrangements in both primary and metastatic lesions. Rapid amplification of cDNA ends (5'RACE) identified cysteinyl-tRNA synthetase (CARS) gene fused to ALK, which predicts an in-frame chimeric protein with the preserved functional catalytic domain of ALK at the C terminus. Amplification and sequencing of tumor DNA confirmed the breakpoint at the genomic level. Restriction analysis of DNA from primary soft tissue and recurrent lung tumors showed identical patterns, indicating the same clonal origin of both lesions. Western blot analysis with C-terminus ALK antibody showed expression of an aberrantly sized chimeric protein of approximately 130 kd in tumor tissue. This is the second case of IMT demonstrating CARS as the ALK fusion partner, which confirms the recurring involvement of ALK in IMT by a common genetic mechanism. Moreover, identical clonality of separate lesions involving different sites supports metastasis in IMT. C1 NCI, Pathol Lab, NIH, Bethesda, MD USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD USA. NCI, Thorac Oncol Sect, Surg Branch, NIH, Bethesda, MD USA. NIAID, NIH, Rockville, MD USA. RP Debelenko, LV (reprint author), Childrens Hosp, Dept Pathol, 300 Longwood Ave, Boston, MA 02115 USA. RI Pack, Svetlana/C-2020-2014 NR 46 TC 66 Z9 73 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD SEP PY 2003 VL 83 IS 9 BP 1255 EP 1265 DI 10.1097/01.LAB.0000088856.49388.EA PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 724PV UT WOS:000185496700001 PM 13679433 ER PT J AU Stone, HB Coleman, CN Anscher, MS McBride, WH AF Stone, HB Coleman, CN Anscher, MS McBride, WH TI Effects of radiation on normal tissue: consequences and mechanisms SO LANCET ONCOLOGY LA English DT Review ID INDUCED PULMONARY FIBROSIS; CONVERTING ENZYME-INHIBITORS; GROWTH-FACTOR BETA-1; INDUCED LUNG INJURY; PROSTATE-CANCER; GASTROINTESTINAL-TRACT; CONFORMAL RADIOTHERAPY; THERAPY; DAMAGE; APOPTOSIS AB The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. As a result, patients may experience symptoms associated with damage to normal tissue during the course of therapy for a few weeks after therapy or months or years later. Symptoms may be due to cell death or wound healing initiated within irradiated tissue, and may be precipitated by exposure to further injury or trauma. Many factors contribute to risk and severity of normal tissue reactions; these factors are site specific and vary with time after treatment. Treatments that reduce the risk or severity of damage to normal tissue or that facilitate the healing of radiation injury are being developed. These could greatly improve the quality of life of patients treated for cancer. C1 NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH,Radiat Oncol Sci Program, Bethesda, MD 20892 USA. Duke Univ, Ctr Med, Dept Radiat Oncol, Durham, NC 27706 USA. Univ Calif Los Angeles, Ctr Med, Res Lab, Dept Expt Radiat Oncol, Los Angeles, CA 90024 USA. RP Stone, HB (reprint author), NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH,Radiat Oncol Sci Program, 6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. NR 89 TC 347 Z9 359 U1 1 U2 28 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2003 VL 4 IS 9 BP 529 EP 536 DI 10.1016/S1470-2045(03)01191-4 PG 8 WC Oncology SC Oncology GA 721YZ UT WOS:000185347200015 PM 12965273 ER PT J AU Kim, SJ Letterio, J AF Kim, SJ Letterio, J TI Transforming growth factor-beta signaling in normal and malignant hematopoiesis SO LEUKEMIA LA English DT Review DE transforming growth factor-beta (TGF-beta); TGF-beta receptors; Smad; leukemogenesis; hematopoiesis; CDK inhibitors; human T-cell lymphotropic virus type I (HTLV-I) ID CELL-CYCLE ARREST; VIRUS TYPE-1 TAX; ACUTE LYMPHOBLASTIC-LEUKEMIA; COLONY-STIMULATING FACTOR; TGF-BETA; II RECEPTOR; C-MYC; EPITHELIAL-CELLS; MYELOID-LEUKEMIA; MESSENGER-RNA AB Transforming growth factor-beta (TGF-beta) is perhaps the most potent endogenous negative regulator of hematopoiesis. The intracellular signaling events mediating the effects of TGF-beta are multiple, involving extensive crosstalk between Smad-dependent and MAP-kinase-dependent pathways. We are only beginning to understand the importance of the balance between these cascades as a determinant of the response to TGF-beta, and have yet to determine the roles that disruption in TGF-beta signaling pathways might play in leukemogenesis. This review summarizes current knowledge regarding the function of TGF-beta in normal and malignant hematopoiesis. The principal observations made by gene targeting studies in mice are reviewed, with an emphasis on how a disruption of this pathway in vivo can affect blood cell development and immune homeostasis. We overview genetic alterations that lead to impaired TGF-beta signaling in hematopoietic neoplasms, including the suppression of Smad-dependent transcriptional responses by onco-proteins such as Tax and Evi-1, and fusion proteins such as AML1/ETO. We also consider mutations in genes encoding components of the core cell cycle machinery, such as p27(Kip1) and p15(INK4A), and emphasize their impact on the ability of TGF-beta to induce G1 arrest. The implications of these observations are discussed, and opinions regarding important directions for future research on TGF-beta in hematopoiesis are provided. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD 20892 USA. NR 104 TC 85 Z9 96 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2003 VL 17 IS 9 BP 1731 EP 1737 DI 10.1038/sj.leu.2403069 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 721UE UT WOS:000185335600008 PM 12970772 ER PT J AU Tchinda, J Volpert, S McNeil, N Neumann, T Kennerknecht, I Ried, T Buchner, T Serve, H Berdel, WE Horst, J Hilgenfeld, E AF Tchinda, J Volpert, S McNeil, N Neumann, T Kennerknecht, I Ried, T Buchner, T Serve, H Berdel, WE Horst, J Hilgenfeld, E TI Multicolor karyotyping in acute myeloid leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE M-FISH; SKY; AML; MDS ID IN-SITU HYBRIDIZATION; ACUTE PROMYELOCYTIC LEUKEMIA; COMPLEX ABERRANT KARYOTYPE; FISH M-FISH; CHROMOSOMAL-ABERRATIONS; MYELODYSPLASTIC SYNDROME; TRANSGENIC MICE; HEMATOLOGICAL MALIGNANCIES; MOUSE CHROMOSOMES; 24-COLOR FISH AB Cytogenetic data have significantly contributed to our understanding of the heterogeneity of acute myeloid leukemia (AML). In AML, numerous recurrent chromosomal aberrations have been identified, and several of them, e.g. t(8;21)(q22;q22), t(15;17)(q22;q11-12), inv(16)(p13q22), are specific for distinct subgroups. Furthermore, chromosomal aberrations have proved to be of paramount prognostic importance for remission induction and survival. Chromosome analysis using classical cytogenetic banding techniques often fails to completely resolve complex karyotypes and cryptic translocations not identifiable by these techniques have been detected using molecular cytogenetic methods. While fluorescence in situ hybridization (FISH) has become an indispensable tool for screening and follow-up of known aberrations, the techniques of spectral karyotyping (SKY) and multiplex-fluorescence in situ hybridization (M-FISH) allow for the simultaneous visualization of all chromosomes of a metaphase in a single hybridization step, and thereby enable screening for the aberrations present without their prior knowledge. Therefore, with the introduction of these techniques in 1996 the comprehensive analysis of complex karyotypes and the identification of new, hitherto cryptic translocations and, ultimately, the identification of new disease subgroups seemed possible. Since, more than 600 cases of AML and MDS have been analyzed. Herein, we attempt to summarize the data published and discuss what has been achieved towards realization of these goals. C1 Univ Klinikum Munster, Inst Humangenet, D-48129 Munster, Germany. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Klinikum Munster, Med Klin & Poliklin A, Munster, Germany. RP Tchinda, J (reprint author), Univ Klinikum Munster, Inst Humangenet, Vesaliusweg 12-14, D-48129 Munster, Germany. NR 69 TC 11 Z9 14 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2003 VL 44 IS 11 BP 1843 EP 1853 DI 10.1080/10428190310001603605 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 726RJ UT WOS:000185612700001 PM 14738135 ER PT J AU Broun, K AF Broun, K TI Integrating Internet content SO LIBRARY JOURNAL LA English DT Article C1 NCI, Elect Informat Serv, Commun Serv Branch, Bethesda, MD 20892 USA. NCI, Lib Serv, Commun Serv Branch, Bethesda, MD 20892 USA. RP Broun, K (reprint author), NCI, Elect Informat Serv, Commun Serv Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BOWKER MAGAZINE GROUP CAHNERS MAGAZINE DIVISION PI NEW YORK PA 249 W 17TH ST, NEW YORK, NY 10011 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD FAL PY 2003 BP 20 EP 23 PG 4 WC Information Science & Library Science SC Information Science & Library Science GA 730KB UT WOS:000185829000008 ER PT J AU Tsai, YY McGlynn, KA Hu, Y Cassidy, AB Arnold, J Engstrom, PF Buetow, KH AF Tsai, YY McGlynn, KA Hu, Y Cassidy, AB Arnold, J Engstrom, PF Buetow, KH TI Genetic susceptibility and dietary patterns in lung cancer SO LUNG CANCER LA English DT Article DE dietary patterns; lung cancer; genetic polymorphism; detoxification enzymes; cluster analysis ID GLUTATHIONE-S-TRANSFERASE; MICROSOMAL EPOXIDE HYDROLASE; DNA ADDUCT LEVELS; CLUSTER-ANALYSIS; VEGETABLE CONSUMPTION; RISK; POLYMORPHISMS; ENZYMES; GENOTYPES; SMOKING AB Cigarette smoking is the dominant risk factor for lung cancer, but only a minority of smokers ever develops tumors. Though genetic susceptibility is likely to explain some of the variability in risk, results from previous studies of genetic polymorphisms have been inconclusive. As diet may also affect the risk of lung cancer, it is possible that the degree of risk produced by smoking and genetic susceptibility varies, depending on diet. To assess this hypothesis, we conducted a case-control study to examine the effect of cigarette smoking, dietary patterns and variation in genes involved in phase II metabolism. A total of 254 individuals with lung cancer and 184 healthy controls were recruited for the study. To identify persons with similar dietary patterns, cluster analysis was performed using nutrient densities of four major dietary constituents: protein, carbohydrate, animal fat, and dietary fiber. Two groups of individuals were identified with distinct dietary patterns: (1) a group (n = 2241) with a high intake of animal fat and protein and a low intake of carbohydrates and dietary fiber (the 'healthy' pattern) (2) a group (n = 197) with a high intake of fiber and carbohydrate and a tow intake of protein and animal fat (the 'unhealthy' pattern). On stratified analysis, several genotype/dietary pattern combinations were found to affect risk of lung cancer. Smokers who were not homozygous for the most common GSTP1 allele and had a healthy dietary pattern were at significantly lower risk than smokers who were homozygous for the GSTP1 common allele and who had an unhealthy dietary pattern (OR = 0.16, 95%Cl: 0.04-0.57). Among smokers who were GSTM1 null, persons with a healthy dietary pattern were at lower risk than persons with an unhealthy dietary pattern (OR: 0.46, 95%Cl: 0.21-1.01). Among smokers with an unhealthy dietary patterns, persons with a His/His genotype in the exon 3 polymorphism of EPHX1 were at significantly lower risk that persons who were not homozygous. These data suggest that dietary factors may affect the risk imposed by genetic susceptibility at detoxification loci. Adjustments using dietary pattern may be useful in elucidating the effects of polymorphisms in genes responsible for carcinogen metabolism. Published by Elsevier Science Ireland Ltd. C1 NCI, Lab Populat Genet, Ctr Canc Res, DHHS,NIH, Bethesda, MD 20814 USA. NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20814 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. RP Buetow, KH (reprint author), NCI, Lab Populat Genet, Ctr Bioinformat, NIH, 6116 Execut Blvd,Suite 403,Room 4001, Bethesda, MD 20814 USA. NR 52 TC 32 Z9 34 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD SEP PY 2003 VL 41 IS 3 BP 269 EP 281 DI 10.1016/S0169-5002(03)00238-1 PG 13 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 721ZD UT WOS:000185347600003 PM 12928118 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Calcium induced volume transition in polyelectrolyte gels SO MACROMOLECULAR SYMPOSIA LA English DT Article; Proceedings Paper CT 16th Polymer-Networks-Group Meeting (Polymer Networks 2002) CY SEP 02-06, 2002 CL AUTRANS, FRANCE SP Polymer Net Grp DE gels; neutron scattering; osmotic pressure; polyacrylate hydrogel; volume transition ID PHYSIOLOGICAL SALT-SOLUTIONS; IONIC GELS; POLYACRYLATE HYDROGELS; LENGTH AB The osmotic properties and the small angle neutron scattering (SANS) behaviour of fully neutralized sodium polyacrylate gels are investigated in the presence of calcium ions. Analysis of the SANS response displays three characteristic length scales, two of which are of thermodynamic origin, while the third, associated with the frozen-in structural inhomogeneities, is static. The SANS results are consistent with direct osmotic observations which indicate that the thermodynamic properties cannot be adequately described by a single correlation length. The concentration dependence of the osmotic pressure displays a power law behaviour with an exponent that decreases with increasing calcium concentration. C1 NIH, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS UMR 5588, Spectrometrie Phys Lab, F-38402 St Martin Dheres, France. RP Horkay, F (reprint author), NIH, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, Bldg 10, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 17 TC 1 Z9 1 U1 0 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1022-1360 J9 MACROMOL SYMP JI Macromol. Symp. PD SEP PY 2003 VL 200 BP 21 EP 30 DI 10.1002/masy.200351003 PG 10 WC Polymer Science SC Polymer Science GA 742JG UT WOS:000186513200004 ER PT J AU Morfin, I Horkay, F Basser, PJ Bley, F Ehrburger-Dolle, F Hecht, AM Rochas, C Geissler, E AF Morfin, I Horkay, F Basser, PJ Bley, F Ehrburger-Dolle, F Hecht, AM Rochas, C Geissler, E TI Ion condensation in a polyelectrolyte gel SO MACROMOLECULAR SYMPOSIA LA English DT Article; Proceedings Paper CT 16th Polymer-Networks-Group Meeting (Polymer Networks 2002) CY SEP 02-06, 2002 CL AUTRANS, FRANCE SP Polymer Net Grp DE anomalous; gel; polyelectrolyte; scattering; volume transition AB Anomalous small angle X-ray scattering is used to determine the distribution of divalent ions in a neutralized polyelectrolyte gel of sodium polyacrylate in the vicinity of the volume transition. At the five different energies of the incident beam used to vary the contrast, the scattering curves have similar shapes, and are separated only by constant multiplying factors. This result, in conjunction with SANS results from the same sample, indicates that the divalent ion (strontium) is confined on the polymer backbone. C1 Univ Grenoble 1, Spectrometrie Phys Lab, CNRS, UMR 5588, F-38402 St Martin Dheres, France. NICHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Inst Natl Polytech Grenoble, Thermodynam & Physicochim Met Lab, CNRS, UMR 5614, F-38402 St Martin Dheres, France. RP Morfin, I (reprint author), Univ Grenoble 1, Spectrometrie Phys Lab, CNRS, UMR 5588, BP 87, F-38402 St Martin Dheres, France. EM isabelle.morfin@ujf-grenoble.fr RI Basser, Peter/H-5477-2011; d2am, beamline/I-6445-2015 NR 7 TC 4 Z9 4 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1022-1360 J9 MACROMOL SYMP JI Macromol. Symp. PD SEP PY 2003 VL 200 BP 227 EP 233 DI 10.1002/masy.200351023 PG 7 WC Polymer Science SC Polymer Science GA 742JG UT WOS:000186513200024 ER PT J AU Callot, V Bennett, E Decking, UKM Balaban, RS Wen, H AF Callot, V Bennett, E Decking, UKM Balaban, RS Wen, H TI In vivo study of microcirculation in canine myocardium using the IVIM method SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE morphology; anisotropy; perfusion; MRI; capillaries ID REGIONAL BLOOD-VOLUME; MAGNETIC-RESONANCE; APPARENT DIFFUSION; CLASSICAL PERFUSION; CAPILLARY NETWORK; WATER DIFFUSION; RAT-BRAIN; FLOW; HEART; HETEROGENEITY AB The intravoxel incoherent motion (IVIM) method was implemented in closed-chest dogs to obtain measurements on microcirculation in the left ventricular wall in vivo. Specifically, it enabled us to measure the mean microflow velocity (400 +/- 40 mum/s) and the vascular volume fraction (VVF) (11.1% +/- 2.2%), and observe the directional preference of capillary orientation. The apparent diffusion coefficients (ADCs) of water along and perpendicular to myofibers were also measured. With vasodilatation by adenosine infusion, a 25% increase in the VVF and a 7% increase in the mean microflow velocity were observed, while no change in the ADC was detected. A 28.5% decrease of the ADC was observed postmortem. Published 2003 Wiley-Liss, Inc.(dagger). C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Univ Dusseldorf, Dept Cardiac Physiol, D-4000 Dusseldorf, Germany. RP Wen, H (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Bldg 10,B1D416, Bethesda, MD 20892 USA. RI Balaban, Robert/A-7459-2009; Wen, Han/G-3081-2010 OI Balaban, Robert/0000-0003-4086-0948; Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [ZIA HL004606-13] NR 40 TC 50 Z9 50 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2003 VL 50 IS 3 BP 531 EP 540 DI 10.1002/nhlbi.nih.gov PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 718YP UT WOS:000185174500012 PM 12939761 ER PT J AU Bammer, R Markl, M Barnett, A Acar, B Alley, MT Pelc, NJ Glover, GH Moseley, ME AF Bammer, R Markl, M Barnett, A Acar, B Alley, MT Pelc, NJ Glover, GH Moseley, ME TI Analysis and generalized correction of the effect of spatial gradient field distortions in diffusion-weighted imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion-weighted imaging; diffusion tensor imaging; magnetic field gradients; data correction; MRI; fiber tracking ID MRI AB Nonuniformities of magnetic field gradients can cause serious artifacts in diffusion imaging. While it is well known that nonlinearities of the imaging gradients lead to image warping, those imperfections can also cause spatially dependent errors in the direction and magnitude of the diffusion encoding. This study shows that the potential errors in diffusion imaging are considerable. Further, we show that retrospective corrections can be applied to reduce these errors. A general mathematical framework was formulated to characterize the contribution of gradient nonuniformities to diffusion experiments. The gradient field was approximated using spherical harmonic expansion, and this approximation was employed (after geometric distortions were eliminated) to predict and correct the errors in diffusion encoding. Before the corrections were made, the experiments clearly revealed marked deviations of the calculated diffusivity for fields of view (FOVs) generally used in diffusion experiments. These deviations were most significant farther away from the magnet's isocenter. For an FOV of 25 cm, the resultant errors in absolute diffusivity ranged from approximately -10% to +20%. Within the same FOV, the diffusion-encoding direction and the orientation of the calculated eigenvectors can be significantly altered if the perturbations by the gradient nonuniformities are not considered. With the proposed correction scheme, most of the errors introduced by gradient nonuniformities can be removed. (C) 2003 Wiley-Liss, Inc. C1 Stanford Univ, Dept Radiol, Richard Lucas MRSI Ctr, Radiol Sci Lab, Stanford, CA 94305 USA. NIMH, Clin Brain Disorders Branch, CBDB, Bethesda, MD 20892 USA. RP Bammer, R (reprint author), Stanford Univ, Dept Radiol, Richard Lucas MRSI Ctr, Radiol Sci Lab, 1201 Welch Rd, Stanford, CA 94305 USA. RI Acar, Burak/C-7904-2009; Markl, Michael/F-7436-2011 OI Acar, Burak/0000-0003-4818-9378; FU NCRR NIH HHS [P41 RR09784]; NHLBI NIH HHS [1R01HL46347]; NINDS NIH HHS [1R01NS35959] NR 20 TC 38 Z9 39 U1 3 U2 11 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 SEP PY 2003 VL 50 IS 3 BP 560 EP 569 DI 10.1002/mrm.10545 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 718YP UT WOS:000185174500015 PM 12939764 ER PT J AU Ennis, DB Epstein, FH Kellman, P Fananapazir, L McVeigh, ER Arai, AE AF Ennis, DB Epstein, FH Kellman, P Fananapazir, L McVeigh, ER Arai, AE TI Assessment of regional systolic and diastolic dysfunction in familial hypertrophic cardiomyopathy using MR tagging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE hypertrophy; cardiomyopathy; diastole; tagging; regional ID HUMAN LEFT-VENTRICLE; IMAGES; MOTION; PHASE AB Diastolic and systolic left ventricular (LV) dysfunction often significantly contribute to disabling symptoms in familial hypertrophic cardiomyopathy (FHC). This study compares regional LV function (midwall circumferential strain) during systole and diastole in eight FHC patients and six normal volunteers (NVs) using MR tagging. A prospectively-gated fast gradient-echo sequence with an echotrain readout was modified to support complementary spatial modulation of magnetization (CSPAMM) tagging and full cardiac cycle data acquisition using the cardiac phase to order reconstruction (CAPTOR), thus providing tag persistence and data acquisition during the entire cardiac cycle. Total systolic strains in FHC patients were significantly reduced in septal and inferior regions (both P < 0.01). Early-diastolic strain rates were reduced in all regions of the FHC group (all P < 0.03). The combination of CSPAMM and CAPTOR allows regional indices of myocardial function to be quantified throughout the cardiac cycle. This technique reveals regional differences in systolic and diastolic impairment in FHC patients. Published 2003 Wiley-Liss, Inc. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. Univ Virginia, Dept Radiol, Charlottesville, VA USA. RP Ennis, DB (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-416, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL004608-08] NR 20 TC 65 Z9 71 U1 0 U2 1 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 SEP PY 2003 VL 50 IS 3 BP 638 EP 642 DI 10.1002/mrm.10543 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 718YP UT WOS:000185174500025 PM 12939774 ER PT J AU Saul, A AF Saul, A TI Zooprophylaxis or zoopotentiation: the outcome of introducing animals on vector transmission is highly dependent on the mosquito mortality while searching SO MALARIA JOURNAL LA English DT Article ID CATTLE OWNERSHIP; INFECTION-RATES; MALARIA; DIPTERA; MODEL; POPULATIONS; CULICIDAE; CAPACITY; PAKISTAN; STRATEGY AB Background: Zooprophylaxis, the diversion of disease carrying insects from humans to animals, may reduce transmission of diseases such as malaria. However, as the number of animals increases, improved availability of blood meals may increase mosquito survival, thereby countering the impact of diverting feeds. Methods: Computer simulation was used to examine the effects of animals on the transmission of human diseases by mosquitoes. Three scenarios were modelled: ( 1) endemic transmission, where the animals cannot be infected, eg. malaria; ( 2) epidemic transmission, where the animals cannot be infected but humans remain susceptible, e. g. malaria; ( 3) epidemic disease, where both humans and animals can be infected, but develop sterile immunity, eg. Japanese encephalitis B. For each, the passive impact of animals as well as the use of animals as bait to attract mosquitoes to insecticide was examined. The computer programmes are available from the author. A teaching model accompanies this article. Results: For endemic and epidemic malaria with significant searching-associated vector mortality, changing animal numbers and accessibility had little impact. Changing the accessibility of the humans had a much greater effect. For diseases with an animal amplification cycle, the most critical factor was the proximity of the animals to the mosquito breeding sites. Conclusion: Estimates of searching-associated vector mortality are essential before the effects of changing animal husbandry practices can be predicted. With realistic values of searching-associated vector mortality rates, zooprophylaxis may be ineffective. However, use of animals as bait to attract mosquitoes to insecticide is predicted to be a promising strategy. C1 NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. RP Saul, A (reprint author), NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. EM ASaul@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 23 TC 74 Z9 76 U1 6 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD SEP PY 2003 VL 2 AR 32 DI 10.1186/1475-2875-2-32 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 739QV UT WOS:000186358700001 PM 14565850 ER PT J AU Warren, JL Harlan, LC AF Warren, JL Harlan, LC TI Can cancer registry data be used to study cancer treatment? SO MEDICAL CARE LA English DT Editorial Material ID BREAST-CANCER; MEDICARE CLAIMS; THERAPY; STAGE; CARCINOMA; SURVIVAL C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. RP Warren, JL (reprint author), NCI, Appl Res Program, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. NR 12 TC 25 Z9 25 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2003 VL 41 IS 9 BP 1003 EP 1005 DI 10.1097/01.MLR.0000086827.00805.B5 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 716DZ UT WOS:000185014700001 PM 12972839 ER PT J AU Styner, M Gerig, G Lieberman, J Jones, D Weinberger, D AF Styner, M Gerig, G Lieberman, J Jones, D Weinberger, D TI Statistical shape analysis of neuroanatomical structures based on medial models SO MEDICAL IMAGE ANALYSIS LA English DT Article DE medical image analysis; shape analysis; Voronoi skeleton; medial shape description; brain morphometry ID SEGMENTATION; SCHIZOPHRENIA; PATTERNS; SIZE AB Knowledge about the biological variability of anatomical objects is essential for statistical shape analysis and discrimination between healthy and pathological structures. This paper describes a novel approach that incorporates the variability of an object population into the generation of a characteristic 3D shape model. The proposed shape representation is a coarse-scale sampled medial description derived from a fine-scale spherical harmonics (SPHARM) boundary description. This medial description is composed of a net of medial samples (m-rep) with fixed graph properties. The medial model is computed automatically from a predefined shape space using pruned 3D Voronoi skeletons. A new method determines the stable medial branching topology from the shape space. An intrinsic coordinate system and an implicit correspondence between shapes is defined on the medial manifold. Several studies of biological structures clearly demonstrate that the novel representation has the promise to describe shape changes in a natural and intuitive way. A new medial shape similarity study of group differences between monozygotic and dizygotic twins in lateral ventricle shape demonstrates the meaningful and powerful representation of local and global form. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. EM martin_styner@ieee.org FU NCI NIH HHS [CA 47982]; NIMH NIH HHS [P30-MH33127] NR 35 TC 112 Z9 112 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD SEP PY 2003 VL 7 IS 3 BP 207 EP 220 DI 10.1016/S1361-8415(02)00110-X PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 723MC UT WOS:000185435300001 PM 12946464 ER PT J AU Stark, KD Park, EJ Holub, BJ AF Stark, KD Park, EJ Holub, BJ TI Fatty acid composition of serum phospholipid of premenopausal women and postmenopausal women receiving and not receiving hormone replacement therapy SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE omega-3 fatty acids; cardiovascular disease; hormone therapy; postmenopausal; premenopausal ID ESTROGEN PLUS PROGESTIN; CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; NORMAL-PREGNANCY; LIPIDS; PLASMA; TRIAL; INFLAMMATION; CHOLESTEROL; COAGULATION AB Objective: To compare the fatty acid composition of serum phospholipid of premenopausal women with that of postmenopausal women receiving and not receiving hormone replacement therapy (HRT). Design: Women between the ages of 43 and 70 were recruited for two separate case-comparison studies. Participants were grouped as either premenopausal, postmenopausal receiving HRT, or postmenopausal not receiving HRT. All participants were required to complete a 3-day dietary record before providing a 12-h fasting blood sample. Fatty acid composition of phospholipids and lipid concentrations was determined from serum samples. Results: The postmenopausal women receiving HRT had significantly higher concentrations of palmitic acid (16:0), palmitoleic acid (16: 1), and di-homo-gamma-linolenic (20:3n-6) and significantly lower levels of docosapentaenoic acid (22:5n-3) than the other groups in both studies. In addition, the postmenopausal women receiving HRT had lower levels of behenic (22:0), lignoceric (24:0), and nervonic acid (24: 1) in comparison with the postmenopausal women not receiving HRT. Conclusion: The results of this study indicate that the fatty acid composition of serum phospholipids in women is influenced by menopausal status and hormone use. These results are of interest because high levels of 20:3n-6 and low levels of docosapentaenoic acid have been associated with increased myocardial infarction plus stroke mortality from cardiovascular disease. C1 NIAAA, DICBR, LMBB, Bethesda, MD 20892 USA. NIAAA, Div Intramural Clin & Biol Res, Lab Membrane Biochem & Biophys, Sect Nutr Neurosci,NIH, Rockville, MD 20852 USA. Univ Alberta, Dept Agr Food & Nutr Sci, Edmonton, AB, Canada. Univ Guelph, Dept Human Biol & Nutr Sci, Guelph, ON N1G 2W1, Canada. RP Stark, KD (reprint author), NIAAA, DICBR, LMBB, Pk 5 Bldg,12420 Parklawn Dr MSC 8115, Bethesda, MD 20892 USA. RI Stark, Ken/I-1347-2016 OI Stark, Ken/0000-0001-7828-4072 NR 37 TC 18 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP-OCT PY 2003 VL 10 IS 5 BP 448 EP 455 DI 10.1097/01.GME.0000059861.93639.1A PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 721XE UT WOS:000185343100012 PM 14501607 ER PT J AU Wu, YT Marsh, JW AF Wu, YT Marsh, JW TI Gene transcription in HIV infection SO MICROBES AND INFECTION LA English DT Review DE HIV; transcription; Tat; Rev; LTR ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEAR-LOCALIZATION SIGNAL; LONG TERMINAL REPEAT; T-CELL-ACTIVATION; VIRAL PROTEIN EXPRESSION; NF-KAPPA-B; TYPE-1 INTEGRASE; MESSENGER-RNA; IMPORTIN-BETA; IN-VIVO AB Transcription from the HIV genome is regulated by the 5' long-terminal-repeat viral promoter as well as regulatory proteins, especially Tat and Rev. Both the promoter activity and the function of regulatory proteins require the activity of cellular components, thus the virus remains highly dependent on the metabolic state of the cell. HIV also possesses the unusual capacity to transcribe from non-integrated DNA. Published by Editions scientifiques et medicales Elsevier SAS. C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, Mol Biol Lab, 36 Convent Dr, Bethesda, MD 20892 USA. NR 59 TC 24 Z9 25 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD SEP PY 2003 VL 5 IS 11 BP 1023 EP 1027 DI 10.1016/S1286-4579(03)00187-4 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 728DM UT WOS:000185700000012 PM 12941394 ER PT J AU Bour, S Strebel, K AF Bour, S Strebel, K TI The HIV-1 Vpu protein: a multifunctional enhancer of viral particle release SO MICROBES AND INFECTION LA English DT Review DE HIV; Vpu; accessory genes ID HUMAN-IMMUNODEFICIENCY-VIRUS; I-KAPPA-B; PIG-TAILED MACAQUES; AMINO-ACID SUBSTITUTIONS; TYPE-1 VPU; CYTOPLASMIC DOMAIN; U VPU; ENVELOPE GLYCOPROTEIN; ENDOPLASMIC-RETICULUM; TRANSMEMBRANE DOMAIN AB HIV accessory genes are expressed throughout the viral life cycle and regulate wide-ranging aspects of virus replication including viral infectivity (Vif and Nef), viral gene expression (Vpr) and progeny virion production (Vpu). While in many cases the molecular basis of accessory protein function is not fully understood, a consensus is emerging that these viral products are generally devoid of enzymatic activity and instead act as multifunctional adapters, subverting normal cellular processes to serve the needs of the virus. This review focuses on presenting our current knowledge of the HIV-1-specific Vpu protein and its essential role in regulating viral particle release, viral load and expression of the CD4 receptor. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 NIAID, Mol Microbiol Lab, Bioinformat Core Facil, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Bour, S (reprint author), NIAID, Mol Microbiol Lab, Bioinformat Core Facil, NIH, 4,Ctr Dr,Room 337, Bethesda, MD 20892 USA. NR 96 TC 75 Z9 80 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD SEP PY 2003 VL 5 IS 11 BP 1029 EP 1039 DI 10.1016/S1286-4579(03)00191-6 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 728DM UT WOS:000185700000013 PM 12941395 ER PT J AU Aberle, CJ Bethards, KJ Orsega, SM Ricciardi, R AF Aberle, CJ Bethards, KJ Orsega, SM Ricciardi, R TI Designing a Medical Humanitarian Assistance Course for advanced practice nurses in the uniformed services SO MILITARY MEDICINE LA English DT Article ID MISSIONS AB The U.S. uniformed services frequently respond to natural and man-made disasters worldwide. Disaster management and humanitarian assistance has been a major focus of military medicine for well over a decade. Training for these missions is a priority for the U.S. military, specifically as a result of the Gulf War. The Medical Humanitarian Assistance Course for advanced practice nurses is a course available to train advanced practice nurses in disaster management and humanitarian assistance. This article will describe the evolution, design, format, and implementation of the Medical Humanitarian Assistance Course. C1 Brooke Army Med Ctr, Family Med Serv, Ft Sam Houston, TX 78234 USA. Raymond W Bliss Hlth Ctr, Dept Mil Med, Ft Huachuca, AZ 85613 USA. NIH, Ctr Clin, Serv Nursing Dept, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Kimbrough Army Community Hosp, Ft George G Meade, MD 20755 USA. RP Aberle, CJ (reprint author), Brooke Army Med Ctr, Family Med Serv, 3851 Roger Brooke Dr, Ft Sam Houston, TX 78234 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD SEP PY 2003 VL 168 IS 9 BP 729 EP 732 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 740LH UT WOS:000186403500010 PM 14529248 ER PT J AU Crabtree, JS Scacheri, PC Ward, JM McNally, SR Swain, GP Montagna, C Hager, JH Hanahan, D Edlund, H Magnuson, MA Garrett-Beal, L Burns, AL Ried, T Chandrasekharappa, SC Marx, SJ Spiegel, AM Collins, FS AF Crabtree, JS Scacheri, PC Ward, JM McNally, SR Swain, GP Montagna, C Hager, JH Hanahan, D Edlund, H Magnuson, MA Garrett-Beal, L Burns, AL Ried, T Chandrasekharappa, SC Marx, SJ Spiegel, AM Collins, FS TI Of mice and MEN1: Insulinomas in a conditional mouse knockout SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; TUMOR-SUPPRESSOR GENE; CELL CARCINOGENESIS; PARATHYROID TUMORS; MUTATIONS; INTERACTS; PROTEIN; TYPE-1; EXPRESSION; PRODUCT AB Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by IoxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NCI, NIH, Frederick, MD 21702 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Dept Biochem, San Francisco, CA 94143 USA. Umea Univ, Dept Microbiol, S-90187 Umea, Sweden. Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bldg 31,Rm 4B09, Bethesda, MD 20892 USA. RI Magnuson, Mark/B-1335-2009 OI Magnuson, Mark/0000-0002-8824-6499 FU NIDDK NIH HHS [P30 DK050306, P30 DK50306] NR 34 TC 127 Z9 129 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2003 VL 23 IS 17 BP 6075 EP 6085 DI 10.1128/MCB.23.17.6075-6085.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713FP UT WOS:000184846700011 PM 12917331 ER PT J AU Hsiao, PW Fryer, CJ Trotter, KW Wang, WD Archer, TK AF Hsiao, PW Fryer, CJ Trotter, KW Wang, WD Archer, TK TI BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HUMAN BREAST-CANCER; GLUCOCORTICOID-RECEPTOR; ESTROGEN-RECEPTOR; TRANSCRIPTIONAL ENHANCEMENT; HORMONE-RECEPTORS; SWI/SNF SUBUNITS; DNA-BINDING; ACTIVATION; NUCLEOSOME; PROTEINS AB Nuclear hormone receptors are ligand-dependent transcriptional regulators that modulate chromatin structure. However, the precise molecular mechanisms by which receptors recruit chromatin-remodeling activity are not fully elucidated. We show that in the absence of its ligand-binding domain, the glucocorticoid receptor (GR) is able to interact with both nuclear receptor coactivators and the BRG1 chromatin-remodeling complex in vivo. Individually, the GR makes direct interactions with BRG1-associated factor 60a (BAF60a) and BAF57, but not with BRG1, BAF155, or BAF170. Further, BAF60a possesses at least two interaction surfaces, one for GR and BRG1 and a second for BAF155 and BAF170. A GR mutant, GR(R488Q), that fails to interact with BAF60a in vitro has reduced chromatin-remodeling activity and reduced transcriptional activity from the promoter assembled as chromatin in vivo. Stable expression of a BAF60a truncation mutant, BAF60a4-140, caused chromatin-specific loss of GR functions in vivo. In the presence of the BAF60a mutant, the GR fails to interact with the BRG1 complex and consequently is also deficient in its ability to activate transcription from chromatin. Thus, in addition to previously identified BAF250, BAF60a may provide another critical and direct link between nuclear receptors and the BRG1 complex that is required for promoter recruitment and subsequent chromatin remodeling. C1 NIEHS, Mol Carcinogenesis Lab, Chromatin & Gene Express Sect, NIH, Res Triangle Pk, NC 27709 USA. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Archer, TK (reprint author), NIEHS, Mol Carcinogenesis Lab, Chromatin & Gene Express Sect, NIH, POB 12233,111 Alexander Dr,MD E4-6, Res Triangle Pk, NC 27709 USA. OI Hsiao, Pei-Wen/0000-0002-3589-6754 NR 49 TC 110 Z9 121 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2003 VL 23 IS 17 BP 6210 EP 6220 DI 10.1128/MCB.23.17.6210-6220.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713FP UT WOS:000184846700022 PM 12917342 ER PT J AU Stebbins, CC Watzl, C Billadeau, DD Leibson, PJ Burshtyn, DN Long, EO AF Stebbins, CC Watzl, C Billadeau, DD Leibson, PJ Burshtyn, DN Long, EO TI Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; COMPLEX CLASS-I; T-CELL; ACTIN CYTOSKELETON; NK CELLS; SIGNAL-TRANSDUCTION; STRUCTURAL BASIS; IMMUNE SYNAPSE; KINASE ACTIVATION; CUTTING EDGE AB Here, we present data suggesting a novel mechanism for regulation of natural killer (NK) cell cytotoxicity through inhibitory receptors. Interaction of activation receptors with their ligands on target cells induces cytotoxicity by NK cells. This activation is under negative control by inhibitory receptors that recruit tyrosine phosphatase SHP-1 upon binding major histocompatibility class I on target cells. How SHP-1 blocks the activation pathway is not known. To identify SHP-1 substrates, an HLA-C-specific inhibitory receptor fused to a substrate-trapping mutant of SHP-1 was expressed in NK cells. Phosphorylated Vav1, a regulator of actin cytoskeleton, was the only protein detectably associated with the catalytic site of SHP-1 during NK cell contact with target cells expressing HLA-C. Vav1 trapping was independent of actin polymerization, suggesting that inhibition of cellular cytotoxicity occurs through an early dephosphorylation of Vav1 by SHP-1, which blocks actin-dependent activation signals. Such a mechanism explains how inhibitory receptors can block activating signals induced by different receptors. C1 NIAID, LIG, NIH, Rockville, MD 20852 USA. Mayo Clin & Mayo Fdn, Dept Immunol, Rochester, MN 55905 USA. Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB T6G 2S2, Canada. RP Long, EO (reprint author), NIAID, LIG, NIH, Twinbrook 2,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Watzl, Carsten/B-4911-2013; Long, Eric/G-5475-2011 OI Watzl, Carsten/0000-0001-5195-0995; Long, Eric/0000-0002-7793-3728 NR 63 TC 149 Z9 151 U1 1 U2 5 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 SEP PY 2003 VL 23 IS 17 BP 6291 EP 6299 DI 10.1128/MCB.23.17.6291-6299.2003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713FP UT WOS:000184846700029 PM 12917349 ER PT J AU Cheng, WH von Kobbe, C Opresko, PL Fields, KM Ren, J Kufe, D Bohr, VA AF Cheng, WH von Kobbe, C Opresko, PL Fields, KM Ren, J Kufe, D Bohr, VA TI Werner syndrome protein phosphorylation by Abl tyrosine kinase regulates its activity and distribution SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DNA-DAMAGING AGENTS; C-ABL; FUNCTIONAL INTERACTION; APOPTOTIC RESPONSE; IONIZING-RADIATION; INDUCE APOPTOSIS; NUCLEAR FOCI; HELICASE; COMPLEX; CELLS AB The Werner syndrome protein (WRN) is a caretaker of the human genome, and the Abl kinase is a regulator of the DNA damage response. Aberrant DNA repair has been linked to the development of cancer. Here, we have identified a direct binding between WRN and c-Abl in vitro via the N-terminal and central regions of WRN and the Src homology domain 3 of c-Abl. After bleomycin treatment in culture, WRN and c-Abl are dissociated and followed by an Abl kinase-dependent WRN relocalization to the nucleoplasm. WRN is a substrate of c-Abl in vitro and in vivo. WRN is tyrosine phosphorylated either transiently by treatment of HeLa cells with bleomycin or constitutively in cells from chronic myeloid leukemia (CML) patients, and these phosphorylations are prevented by treatment with the Abl kinase inhibitor STI-571. Tyrosine phosphorylation of WRN results in inhibition of both WRN exonuclease and helicase activities. Furthermore, anti-WRN immunoprecipitates from CML cells treated with STI-571 show increased 3'-->5' exonuclease activity. These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Opresko, Patricia/0000-0002-6470-2189 FU NCI NIH HHS [CA 29431, R01 CA029431] NR 57 TC 52 Z9 53 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 SEP PY 2003 VL 23 IS 18 BP 6385 EP 6395 DI 10.1128/MCB.23.18.6385-6395.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 717RM UT WOS:000185103900005 PM 12944467 ER PT J AU Kerscher, O Crotti, LB Basrai, MA AF Kerscher, O Crotti, LB Basrai, MA TI Recognizing chromosomes in trouble: Association of the spindle checkpoint protein Bub3p with altered kinetochores and a unique defective centromere SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLE BODY DUPLICATION; CELL-CYCLE ARREST; BUDDING YEAST; SACCHAROMYCES-CEREVISIAE; MITOTIC CHECKPOINT; ASSEMBLY CHECKPOINT; FISSION YEAST; UNATTACHED KINETOCHORES; CHROMATID COHESION; GENE MPS1 AB Spindle checkpoint proteins monitor the interaction of the spindle apparatus with the kinetochores, halting anaphase even if the microtubule attachment of only a single chromosome is altered. In this study, we show that Bub3p of Saccharomyces cerevisiae, an evolutionarily conserved spindle checkpoint protein, exhibits distinct interactions with an altered or defective kinetochore(s). We show for the first time that green fluorescent protein-tagged S. cerevisiae Bub3p (Bub3-GFP) exhibits not only a diffuse nuclear localization pattern but also forms distinct nuclear foci in unperturbed growing and G(2)/M-arrested cells. As Bub3-GFP foci overlap only a subset of kinetochores, we tested a model in which alterations or defects in kinetochore or spindle integrity lead to the distinct enrichment of Bub3p at these structures. In support of our model, kinetochore-associated Bub3-GFP is enriched upon activation of the spindle checkpoint due to nocodazole-induced spindle disassembly, overexpression of the checkpoint kinase Mps1p, or the presence of a defective centromere (CEN). Most importantly, using a novel approach with the chromatin immunoprecipitation (ChIP) technique and genetically engineered defective CEN [CF/CEN6(Delta31)], we determined that Bub3-GFP can associate with a single defective kinetochore. Our studies represent the first comprehensive molecular analysis of spindle checkpoint protein function in the context of a wild-type or defective kinetochore(s) by use of live-cell imaging and the ChIP technique in S. cerevisiae. C1 NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20889 USA. RP Basrai, MA (reprint author), NNMC, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 55 TC 18 Z9 18 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 SEP PY 2003 VL 23 IS 18 BP 6406 EP 6418 DI 10.1128/MCB.23.18.6406-6418.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 717RM UT WOS:000185103900007 PM 12944469 ER PT J AU Zolotukhin, AS Michalowski, D Bear, J Smulevitch, SV Traish, AM Peng, R Patton, J Shatsky, IN Felber, BK AF Zolotukhin, AS Michalowski, D Bear, J Smulevitch, SV Traish, AM Peng, R Patton, J Shatsky, IN Felber, BK TI PSF acts through the human immunodeficiency virus type 1 mRNA instability elements to regulate virus expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SPLICING FACTOR PSF; TRACT-BINDING-PROTEIN; REV PROTEIN; NUCLEAR-LOCALIZATION; CRS ELEMENTS; VIRAL-RNA; HNRNP A1; EXPORT; GAG; IDENTIFICATION AB Human immunodeficiency virus type 1 (HIV) gag/pol and env mRNAs contain cis-acting regulatory elements (INS) that impair stability, nucleocytoplasmic transport, and translation by unknown mechanisms. This downregulation can be counteracted by the viral Rev protein, resulting in efficient export and expression of these mRNAs. Here, we show that the INS region in HIV-1 gag mRNA is a high-affinity ligand of p54nrb/PSF, a heterodimeric transcription/splicing factor. Both subunits bound INS RNA in vitro with similar affinity and specificity. Using an INS-containing subgenomic gag mRNA, we show that it specifically associated with p54nrb in vivo and that PSF inhibited its expression, acting via INS. Studying the authentic HIV-1 mRNAs produced from an infectious molecular clone, we found that PSF affected specifically the INS-containing, Rev-dependent transcripts encoding Gag-Pol and Env. Both subunits contained nuclear export and nuclear retention signals, Whereas p54nrb was continuously exported from the nucleus and associated with INS-containing mRNA in the cytoplasm, suggesting its additional role at late steps of mRNA metabolism. Thus, p54nrb and PSF have properties of key factors mediating INS function and likely define a novel mRNA regulatory pathway that is hijacked by HIV-1. C1 NCI, Human Retrovirus Pathogenesis Sect, Basic Res Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Vanderbilt Univ, Dept Mol Biol, Nashville, TN 37235 USA. Moscow MV Lomonosov State Univ, An Belozersky Inst, Moscow, Russia. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Basic Res Lab, Frederick Canc Res & Dev Ctr, Bldg 535,Rm 110, Frederick, MD 21702 USA. RI Shatsky, Ivan/A-5331-2012 FU NCI NIH HHS [CA 33572, P30 CA033572] NR 67 TC 74 Z9 78 U1 1 U2 4 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 SEP PY 2003 VL 23 IS 18 BP 6618 EP 6630 DI 10.1128/MCB.23.18.6618-6630.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 717RM UT WOS:000185103900025 PM 12944487 ER PT J AU Youn, YH Feng, J Tessarollo, L Ito, K Sieber-Blum, M AF Youn, YH Feng, J Tessarollo, L Ito, K Sieber-Blum, M TI Neural crest stem cell and cardiac endothelium defects in the TrkC null mouse SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID INVITRO CLONAL ANALYSIS; SMOOTH-MUSCLE-CELLS; III BETA-TUBULIN; NERVOUS-SYSTEM; HEART DEVELOPMENT; OUTFLOW TRACT; MESSENGER-RNA; RAT TRKC; IN-VITRO; NEUROTROPHIN-3 AB TrkC null mice have multiple cardiac malformations. Since neural crest cells participate in cardiac outflow tract septation, the aim of this study was to determine at the cellular level the putative neural crest defect. We have identified three types of progenitor cells: stem cells that undergo self-renewal and can generate many cell types, cells that are restricted in their developmental potentials, and cells that are committed to the smooth muscle cell lineage. In TrkC null mice, there is a greater than 50% decrease in stem cell numbers and an equivalent increase in fate-restricted cells. The outflow tract wall is thickened and the endothelial tube is disorganized. We conclude that deletion of the TrkC gene causes precocious fate restrictions of the neural crest stem cell and a defect of the outflow tract endothelium, both of which may contribute to the outflow tract malformations that occur in TrkC null mice. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. NCI, FCRDC, Neural Dev Grp, ABL Basic Res Program, Frederick, MD 21702 USA. Osaka Univ, Grad Sch Sci, Dept Biol, Toyonaka, Osaka 5600043, Japan. RP Sieber-Blum, M (reprint author), Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NINDS NIH HHS [NS 38500] NR 55 TC 34 Z9 34 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD SEP PY 2003 VL 24 IS 1 BP 160 EP 170 DI 10.1016/S1044-7431(03)00125-8 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 729VV UT WOS:000185796500014 PM 14550777 ER PT J AU Krauss, J AF Krauss, J TI Recombinant antibodies for the diagnosis and treatment of cancer SO MOLECULAR BIOTECHNOLOGY LA English DT Review DE cancer diagnosis and therapy; clinical trial; recombinant antibodies ID SINGLE-CHAIN FV; ANTI-CD20 MONOCLONAL-ANTIBODY; METASTATIC BREAST-CANCER; NON-HODGKINS-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMA; COMPLEMENTARITY-DETERMINING REGIONS; AFFINITY HUMAN-ANTIBODIES; HUMAN-TUMOR GROWTH; PHASE-II TRIAL AB The advent of recombinant antibody technology led to an enormous revival in the use of antibodies as diagnostic and therapeutic tools for fighting cancer. This review provides a brief historical sketch of the development of recombinant antibodies for the diagnosis and immunotherapy of cancer and summarizes the most significant clinical data for the best established reagents to date. It also discusses clinically relevant aspects of the use of recombinant antibodies in cancer patients. C1 Natl Canc Inst, SAIC Frederick, Frederick, MD 21702 USA. RP Krauss, J (reprint author), Natl Canc Inst, SAIC Frederick, Bldg 320,Rm 8, Frederick, MD 21702 USA. EM jkrauss@ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 203 TC 10 Z9 10 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 EI 1559-0305 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD SEP PY 2003 VL 25 IS 1 BP 1 EP 17 DI 10.1385/MB:25:1:1 PG 17 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 716VQ UT WOS:000185050600001 PM 13679630 ER PT J AU Diaz, M Watson, NB Turkington, G Verkoczy, LK Klinman, NR McGregor, WG AF Diaz, M Watson, NB Turkington, G Verkoczy, LK Klinman, NR McGregor, WG TI Decreased frequency and highly aberrant spectrum of ultraviolet-induced mutations in the hprt gene of mouse fibroblasts expressing antisense RNA to DNA polymerase zeta SO MOLECULAR CANCER RESEARCH LA English DT Article ID XERODERMA-PIGMENTOSUM VARIANT; ESCHERICHIA-COLI DINB; SACCHAROMYCES-CEREVISIAE GENE; DAMAGE-INDUCED MUTAGENESIS; UV-INDUCED MUTATIONS; ERROR-PRONE BYPASS; TRANSLESION SYNTHESIS; POSTREPLICATION REPAIR; EMBRYONIC LETHALITY; CATALYTIC SUBUNIT AB In the budding yeast Saccharomyces cerevisiae, DNA polymerase zeta (pol zeta) is responsible for the great majority of mutations generated during error-prone translesion replication of DNA that contains UV-induced lesions. The catalytic subunit of pol zeta is encoded by the Rev3 gene. The orthologue of Rev3 has been cloned from higher eukaryotic cells, including human, but its role in mutagenesis and carcinogenesis remains obscure. Investigation into the cellular function of pol zeta has been hindered by the fact that Rev3 knockout mice do not survive beyond midgestation, and embryonic stem cells used to derive these mice are not genetically stable. We have generated a transgenic mouse that expresses antisense RNA transcripts to mRev3 endogeneous RNA. These mice are viable, have greatly reduced levels of Rev3 transcript, and have reduced levels of B cells and impaired development of high-affinity memory B cells. Here, we report that exposure of fibroblasts derived from these mice to UV resulted in a 4-5-fold reduction in mutant frequency at the hprt locus at every dose examined, and the mutation spectrum was highly aberrant compared with the control cells. In the control cells, 80% of the mutations were transitions and similar to75% of these arose from photoproducts in the putative leading strand template. Strikingly, in transgenic cells, most of the mutations were transversions and there was a complete loss of strand bias. This mutation spectrum is highly aberrant and is similar to that induced by UV in human xeroderma pigmentosum variant cells, which lack polymerase eta. These data indicate that most UV-induced mutations are dependent on DNA pol zeta, a function that has been conserved from yeast to higher eukaryotic cells. However, in mammalian cells, other DNA polymerase(s) may accomplish error-prone translesion replication and are responsible for residual UV mutagenesis observed in the absence of pol zeta. Further, these data support a central role for DNA polymerase eta in the error-free bypass of UV photoproducts. The antisense Rev3 mice should. be a useful model to study mutagenic lesion bypass by pol zeta in mammalian cells and to investigate the role this polymerase plays in carcinogenesis. C1 NIEHS, Mol Genet Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. Univ Louisville, JG Brown Canc Ctr, Dept Med Hematol & Med Oncol, Mol Targets Program, Louisville, KY 40292 USA. Univ Louisville, JG Brown Canc Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA USA. RP Diaz, M (reprint author), NIEHS, Mol Genet Lab, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA-73964]; NIAID NIH HHS [AI-15797, AI50055] NR 56 TC 47 Z9 49 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2003 VL 1 IS 11 BP 836 EP 847 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 724RG UT WOS:000185500100006 PM 14517346 ER PT J AU Cooper, SJ MacGowan, J Ranger-Moore, J Young, MR Colburn, NH Bowden, GT AF Cooper, SJ MacGowan, J Ranger-Moore, J Young, MR Colburn, NH Bowden, GT TI Expression of dominant negative c-jun inhibits ultraviolet B-induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model SO MOLECULAR CANCER RESEARCH LA English DT Article ID SKIN TUMOR-DEVELOPMENT; NF-KAPPA-B; CYCLIN D1; INDUCED TRANSFORMATION; TRANSCRIPTION FACTORS; DELETION MUTANT; EPIDERMAL-CELLS; TRANSGENIC MICE; TARGET GENES; IN-VIVO AB UVB radiation is a complete carcinogen able to initiate, promote, and progress keratinocyte cells toward carcinogenesis. Exposure to UVB leads to the propagation of a number of signal transduction pathways resulting in increased DNA binding of transcription factors, including activator protein-1 (AP-1), and subsequent gene expression. To test the hypothesis that AP-1 activation plays a role in the promotion of UVB-induced skin tumors, a dominant negative c-jun (TAM67) mutant transgene was expressed in the epidermis of SKH-1 hairless mice and bred with mice expressing an AP-1 luciferase reporter gene. Single UVB exposure experiments showed a significant decrease in AP-1 activity, as measured by luciferase levels, in mice expressing TAM67 72 h postexposure. Transgenic and nontransgenic littermates were placed into a chronic UVB exposure experiment, three exposures per week for 25 weeks. Expression of TAM67 reduced the number of tumors per mouse by 58% and tumor sizes were 79% smaller than the tumors present in the nontransgenic study group. These tumors were histologically identified as squamous cell carcinomas. TAM67 had no effect on UVB-induced hyperplasia because comparable epidermal thickening was observed in both study groups over a 5-day period post-UVB exposure. immunohistochemical analysis showed a reduction in the number of cyclin D-1-expressing cells in squamous cell carcinoma samples removed from the TAM67 study group. These data show that TAM67 can inhibit UVB-induced squamous cell carcinoma formation, suggesting that AP-1 is a good candidate target for the development of new chemo-prevention strategies to prevent sunlight-induced skin cancers. C1 Arizona Canc Ctr, Dept Radiat Oncol, Tucson, AZ 85724 USA. Univ Arizona, Coll Publ Hlth, Dept Epidemiol & Biostat, Tucson, AZ USA. NCI, Basic Res Lab, Frederick, MD USA. RP Bowden, GT (reprint author), Arizona Canc Ctr, Dept Radiat Oncol, Room 4999,1515 N Campbell Ave, Tucson, AZ 85724 USA. FU NCI NIH HHS [CA27502] NR 32 TC 77 Z9 77 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2003 VL 1 IS 11 BP 848 EP 854 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 724RG UT WOS:000185500100007 PM 14517347 ER PT J AU Macpherson, GR Ng, SSW Forbes, SL Melillo, G Karpova, T McNally, J Conrads, TP Veenstra, TD Martinez, A Cuttitta, F Price, DK Figg, WD AF Macpherson, GR Ng, SSW Forbes, SL Melillo, G Karpova, T McNally, J Conrads, TP Veenstra, TD Martinez, A Cuttitta, F Price, DK Figg, WD TI Anti-angiogenic activity of human endostatin is HIF-1-independent in vitro and sensitive to timing of treatment in a human saphenous vein assay SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; INHIBITOR ENDOSTATIN; ENDOTHELIAL-CELLS; TUMOR-GROWTH; ACTIVATION; CANCER; PROTEINS; DEGRADATION; HIF-1-ALPHA; INDUCTION AB Endostatin is a 20-kDa endogenous angiogenesis inhibitor that has recently been shown to inhibit the expression of vascular endothelial growth factor (VEGF), an angiogenic growth factor that is up-regulated by hypoxia via the HIF-1 transcription factor complex. To determine if the anti-angiogenic activity of endostatin involves a modulation of the HIF-1/VEGF pathway in cancer cells, experiments were conducted to establish what effect endostatin has on HIF-1 activity, HIF-1alpha protein production, and cellular localization in prostate cancer cells and endothelial cells. Endothelial cell tube formation was inhibited by endostatin purchased from Calbiochem (San Diego, CA) but not endostatin obtained from EntreMed (Rockville, MD). Subsequent experiments using Calbiochem endostatin showed that it did not alter HIF-1alpha protein production or cellular localization in any of the cell lines tested, nor did it alter HIF-1 transactivational activity in hypoxia. Whether or not this is also true in vivo remains to be determined. Nevertheless, these data suggest that the anti-angiogenic activity of endostatin is independent of the HIF-1/VEGF pathway. Immunocytochemical staining results do not indicate a decreased production of VEGF in Calbiochem endostatin-treated LNCaP or human umbilical vein endothelial cells (HUVEC). Treatment of rat aortic cross sections with human endostatin from Calbiochem resulted in a dose-dependent inhibition of microvessel outgrowth. Importantly, inhibition of vessel outgrowth by Calbiochem endostatin in a human saphenous vein angiogenesis assay required early treatment. In view of this in vitro data, we suggest that clinical trials involving endostatin treatment of late-stage disease may not adequately represent the efficacy of this drug in early-stage cancer. C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Cell Canc Biol Branch, Bethesda, MD 20892 USA. NCI, Vasc Biol Fac, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI, Frederick, MD USA. DTP Tumor Hypoxia Lab, Frederick, MD USA. RP Figg, WD (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10,Rm 5A01, Bethesda, MD 20892 USA. RI Martinez, Alfredo/A-3077-2013; Figg Sr, William/M-2411-2016 OI Martinez, Alfredo/0000-0003-4882-4044; FU NCI NIH HHS [N01-CO-12400] NR 36 TC 20 Z9 24 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2003 VL 2 IS 9 BP 845 EP 854 PG 10 WC Oncology SC Oncology GA 723PH UT WOS:000185440400003 PM 14555703 ER PT J AU Liu, SH Leppla, SH AF Liu, SH Leppla, SH TI Retroviral insertional mutagenesis identifies a small protein required for synthesis of diphthamide, the target of bacterial ADP-ribosylating toxins SO MOLECULAR CELL LA English DT Article ID HAMSTER OVARY CELLS; DENSITY-LIPOPROTEIN RECEPTOR; PSEUDOMONAS EXOTOXIN-A; ELONGATION FACTOR-II; DIPHTHERIA-TOXIN; SACCHAROMYCES-CEREVISIAE; ANTHRAX TOXIN; RESISTANT MUTANTS; CROSS-RESISTANT; LETHAL FACTOR AB Retroviral insertional mutagenesis was used to produce a mutant Chinese hamster ovary cell line that is completely resistant to several different bacterial ADP-ribosylating toxins. The gene responsible for toxin resistance, termed diphtheria toxin (DT) and Pseudomonas exotoxin A (ETA) sensitivity required gene 1 (DESR1), encodes two small protein isoforms of 82 and 57 residues. DESR1 is evolutionally conserved and ubiquitously expressed. Only the longer isoform is functional because the mutant cell line can be complemented by transfection with the long but not the short isoform. We demonstrate that DESR1 is required for the first step in the posttranslational modification of elongation factor-2 at His(715) that yields diphthamide, the target site for ADP ribosylation by DT and ETA. KTI11, the analog of DESR1 in yeast, which was originally identified as a gene regulating the sensitivity of yeast to zymocin, is also required for diphthamide biosynthesis, implicating DESR1/KTI11 in multiple biological processes. C1 NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 33 TC 42 Z9 45 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 SEP PY 2003 VL 12 IS 3 BP 603 EP 613 DI 10.1016/j.molcel.2003.08.003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 726RV UT WOS:000185613800010 PM 14527407 ER PT J AU Lento, GM Baker, CS David, V Yuhki, N Gales, NJ O'Brien, SJ AF Lento, GM Baker, CS David, V Yuhki, N Gales, NJ O'Brien, SJ TI Automated single-strand conformation polymorphism reveals low diversity of a Major Histocompatibility Complex Class II gene in the threatened New Zealand sea lion SO MOLECULAR ECOLOGY NOTES LA English DT Article DE ABI; DQB; genetic diversity; major histocompatibility complex; new Zealand sea lion; population genetics; SSCP ID POPULATION BIOLOGY; MUTATIONS; EVOLUTION; LOCUS AB Single-strand conformation polymorphism (SSCP) analysis of the second exon of the DQB gene in the endemic New Zealand sea lion (Phocarctos hookeri) was automated using fluorescently-labelled PCR primers and a capillary sequencer. SSCP mobility profiles (n = 61 individuals) were confirmed by direct sequencing of genomic polymerase chain reaction (PCR) products (n = 39). We found only two alleles defined by changes at a single codon of this apparently functional locus. SSCP at a constant temperature above ambient allowed consistent and rapid genotyping. By comparison, sequence-based genotyping was highly dependent on the threshold used to identify secondary peaks indicative of a heterozygote. C1 Univ Auckland, Sch Biol Sci, Populat Genet & Evolut Res Grp, Auckland 1, New Zealand. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Genom Divers, Frederick, MD 21702 USA. Australian Antarctic Div, Kingston, Tas 7050, Australia. RP Baker, CS (reprint author), Univ Auckland, Sch Biol Sci, Populat Genet & Evolut Res Grp, Private Bag 92019, Auckland 1, New Zealand. NR 13 TC 18 Z9 18 U1 0 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1471-8278 J9 MOL ECOL NOTES JI Mol. Ecol. Notes PD SEP PY 2003 VL 3 IS 3 BP 346 EP 349 DI 10.1046/j.1471-8286.2003.00445.x PG 4 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 719VG UT WOS:000185225300006 ER PT J AU Navarro, CE Saeed, SA Murdock, C Martinez-Fuentes, AJ Arora, KK Krsmanovic, LZ Catt, KJ AF Navarro, CE Saeed, SA Murdock, C Martinez-Fuentes, AJ Arora, KK Krsmanovic, LZ Catt, KJ TI Regulation of cyclic adenosine 3 ',5 '-monophosphate signaling and pulsatile neurosecretion by G(i)-coupled plasma membrane estrogen receptors in immortalized gonadotropin-releasing hormone neurons SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID KAINATE-INDUCED CURRENTS; MESSENGER-RIBONUCLEIC-ACID; FEMALE RAT; HYPOTHALAMIC NEURONS; HIPPOCAMPAL-NEURONS; BINDING-SITES; GNRH NEURONS; BETA-IMMUNOREACTIVITY; OVARIECTOMIZED RAT; EXPRESSING NEURONS AB Immortalized GnRH neurons (GT1-7) express receptors for estrogen [estrogen receptor-alpha and -beta(ERalpha and ERbeta)] and progesterone (progesterone receptor A) and exhibit positive immunostaining for both intracellular and plasma membrane ERs. Exposure of GT1-7 cells to picomolar estradiol concentrations for 5-60 min caused rapid, sustained, and dose-dependent inhibition of cAMP production. In contrast, treatment with nanomolar estradiol concentrations for 60 min increased cAMP production. The inhibitory and stimulatory actions of estradiol on cAMP formation were abolished by the ER antagonist, ICI 182,780. The estradiol-induced inhibition of cAMP production was prevented by treatment with pertussis toxin, consistent with coupling of the plasma membrane ER to an inhibitory G protein. Coimmunoprecipitation studies demonstrated an estradiol-regulated stimulatory interaction between ERalpha and G(alphai3) that was prevented by the ER antagonist, ICI 182,780. Exposure of perifused GT1-7 cells and hypothalamic neurons to picomolar estradiol levels increased the GnRH peak interval, shortened peak duration, and increased peak amplitude. These findings indicate that occupancy of the plasma membrane-associated ERs expressed in GT1-7 neurons by physiological estradiol levels causes activation of a G(i) protein and modulates cAMP signaling and neuropeptide secretion. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36, Bethesda, MD 20892 USA. NR 69 TC 76 Z9 79 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2003 VL 17 IS 9 BP 1792 EP 1804 DI 10.1210/me.2003-0040 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716EC UT WOS:000185015000010 PM 12819297 ER PT J AU Dhanvantari, S Shen, FS Adams, T Snell, CR Zhang, CF Mackin, RB Morris, SJ Loh, YP AF Dhanvantari, S Shen, FS Adams, T Snell, CR Zhang, CF Mackin, RB Morris, SJ Loh, YP TI Disruption of a receptor-mediated mechanism for intracellular sorting of proinsulin in familial hyperproinsulinemia SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID REGULATED SECRETORY PATHWAY; CARBOXYPEPTIDASE-E; MESSENGER-RNA; CPE(FAT)/CPE(FAT) MICE; PANCREATIC-ISLETS; INSULIN CRYSTALS; POINT MUTATION; CELLS; IDENTIFICATION; PROTEIN AB In familial hyperproinsulinemia, specific mutations in the proinsulin gene are linked with a profound increase in circulating plasma proinsulin levels. However, the molecular and cellular basis for this disease remains uncharacterized. Here we investigated how these mutations may disrupt the sorting signal required to target proinsulin to the secretory granules of the regulated secretory pathway, resulting in the unregulated release of proinsulin. Using a combination of molecular modeling and site-directed mutagenesis, we have identified structural molecular motifs in proinsulin that are necessary for correct sorting into secretory granules of endocrine cells. We show that membrane carboxypeptidase E (CPE), previously identified as a prohormone-sorting receptor, is essential for proinsulin sorting. This was demonstrated through short interfering RNA-mediated depletion of CPE and transfection with a dominant negative mutant of CPE in a beta-cell line. Mutant proinsulins found in familial hyperproinsulinemia failed to bind to CPE and were not sorted efficiently. These findings provide evidence that the elevation of plasma proinsulin levels found in patients with familial hyperproinsulinemia is caused by the disruption of CPE-mediated sorting of mutant proinsulins to the regulated secretory pathway. C1 NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Medivir UK Ltd, Cambridge CB1 9PT, England. Creighton Univ, Sch Med, Omaha, NE 68178 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38,MSC 4480, Bethesda, MD 20892 USA. RI Dhanvantari, Savita/B-5362-2015 NR 40 TC 27 Z9 29 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2003 VL 17 IS 9 BP 1856 EP 1867 DI 10.1210/me.2002-0380 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716EC UT WOS:000185015000016 PM 12829804 ER PT J AU Raben, N Danon, M Gilbert, AL Dwivedi, S Collins, B Thurberg, BL Mattaliano, RJ Nagaraju, K Plotz, PH AF Raben, N Danon, M Gilbert, AL Dwivedi, S Collins, B Thurberg, BL Mattaliano, RJ Nagaraju, K Plotz, PH TI Enzyme replacement therapy in the mouse model of Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Pompe disease; lysosomal storage; enzyme replacement therapy; glycogen accumulation; acid alpha-glucosidase ID ACID-ALPHA-GLUCOSIDASE; MANNOSE 6-PHOSPHATE RECEPTORS; GENERALIZED GLYCOGEN-STORAGE; HIGH-LEVEL PRODUCTION; RABBIT MILK; LONG-TERM; MAMMALIAN-CELLS; KNOCKOUT MICE; GENE-THERAPY; DEFICIENCY AB Deficiency of acid alpha-glucosidase (GAA) results in widespread cellular deposition of lysosomal glycogen manifesting as myopathy and cardiomyopathy. When GAA-/- mice were treated with rhGAA (20 mg/kg/week for up to 5 months), skeletal muscle cells took up little enzyme compared to liver and heart. Glycogen reduction was less than 50%, and some fibers showed little or no glycogen clearance. A dose of 100 mg/kg/week resulted in similar to75% glycogen clearance in skeletal muscle. The enzyme reduced cardiac glycogen to undetectable levels at either dose. Skeletal muscle fibers with residual glycogen showed immunoreactivity for LAMP-1/LAMP-2, indicating that undigested glycogen remained in proliferating lysosomes. Glycogen clearance was more pronounced in type I fibers, and histochemical analysis suggested an increased mannose-6-phosphate receptor immunoreactivity in these fibers. Differential transport of enzyme into lysosomes may explain the strikingly uneven pattern of glycogen removal. Autophagic vacuoles, a feature of both the mouse model and the human disease, persisted despite glycogen clearance. In some groups a modest glycogen reduction was accompanied by improved muscle strength. These studies suggest that enzyme replacement therapy, although at much higher doses than in other lysosomal diseases, has the potential to reverse cardiac pathology and to reduce the glycogen level in skeletal muscle. (C) 2003 Elsevier Inc. All rights reserved. C1 NIAMS, Arthrit & Rheumatism Branch, NIH, US HHS, Bethesda, MD 20892 USA. Univ Minnesota, Hennepin Med Ctr, Minneapolis, MN 55404 USA. Genzyme Corp, Cell & Prot Therapeut R&D, Framingham, MA 01701 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21205 USA. RP Raben, N (reprint author), NIAMS, Arthrit & Rheumatism Branch, NIH, US HHS, 9000 Rockville Pike,Bld 10-9N244, Bethesda, MD 20892 USA. NR 50 TC 116 Z9 117 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2003 VL 80 IS 1-2 BP 159 EP 169 DI 10.1016/j.ymgme.2003.08.022 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 738TU UT WOS:000186304600013 PM 14567965 ER PT J AU Keelan, JA Wang, K Chaiworapongsa, T Romero, R Mitchell, MD Sato, TA Brown, DA Fairlie, WD Breit, SN AF Keelan, JA Wang, K Chaiworapongsa, T Romero, R Mitchell, MD Sato, TA Brown, DA Fairlie, WD Breit, SN TI Macrophage inhibitory cytokine 1 in fetal membranes and amniotic fluid from pregnancies with and without preterm labour and premature rupture of membranes SO MOLECULAR HUMAN REPRODUCTION LA English DT Article DE amniotic fluid; MIC-1; pregnancy; premature rupture of membranes; preterm birth ID GROWTH-FACTOR-BETA; PRO-INFLAMMATORY CYTOKINES; NECROSIS-FACTOR-ALPHA; BACTERIAL LIPOPOLYSACCHARIDE; GESTATIONAL TISSUES; IN-VITRO; SUPERFAMILY; CELLS; MIC-1; IMMUNOMODULATORS AB The placenta and fetal membranes are the site of expression of macrophage inhibitory cytokine (MIC-1), a member of the transforming growth factor (TGF)-beta superfamily. We hypothesized that MIC-1 may act as an immune regulator in pregnancy complications associated with intrauterine inflammation. Decidual cells, chorionic trophoblasts and amnion epithelial cells were identified by immunohistochemistry as the predominant MIC-1-containing cell type in term membranes. Amnion and choriodecidual explants all produced MIC-1 in culture, the latter having the greatest production rate (206 +/- 74.5 pg/mg tissue/24 h, n = 6; mean +/- SEM). Production was not responsive to stimulation by pro-inflammatory cytokines. MIC-1 was detectable in 217 transabdominal amniotic fluid (AF) samples taken from 15 to 41 weeks gestation, concentrations ranging from 0.9-51.1 ng/ml. AF MIC-1 concentrations in pregnancies with premature rupture of membranes (PROM) or preterm labour, either with or without microbial invasion of the amniotic cavity, were not significantly different from those delivered at term either with or without labour. Treatment with MIC-1 (0.25-25 ng/ml) did not alter production of interleukin-6 or -8 by amnion or choriodecidual cells in vitro. We conclude that AF MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or PROM. C1 Univ Auckland, Liggins Inst, Dept Pharmacol & Clin Pharmacol, Fac Med & Hlth Sci, Auckland 1, New Zealand. Univ Auckland, Dept Obstet & Gynecol, Fac Med & Hlth Sci, Auckland 1, New Zealand. NICHHD, Perinatol Res Branch, DHHS, NIH, Detroit, MI USA. NICHHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD 20892 USA. St Vincents Hosp, Ctr Immunol, Sydney, NSW 2010, Australia. Univ New S Wales, Sydney, NSW 2010, Australia. RP Keelan, JA (reprint author), Univ Auckland, Liggins Inst, Dept Pharmacol & Clin Pharmacol, Fac Med & Hlth Sci, 2-6 Park Ave, Auckland 1, New Zealand. RI Mitchell, Murray/A-8639-2010; Keelan, Jeffrey/G-2170-2011; Fairlie, Walter/M-8401-2015 OI Mitchell, Murray/0000-0002-6167-7176; Keelan, Jeffrey/0000-0002-5403-6266; Fairlie, Walter/0000-0002-2498-1160 NR 22 TC 14 Z9 15 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD SEP 1 PY 2003 VL 9 IS 9 BP 535 EP 540 DI 10.1093/molehr/gag068 PG 6 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 710ME UT WOS:000184683300005 PM 12900512 ER PT J AU Diaz, M Ray, M Wheeler, LJ Verkoczy, LK Mathews, CK AF Diaz, M Ray, M Wheeler, LJ Verkoczy, LK Mathews, CK TI Mutagenesis by AID, a molecule critical to immunoglobulin hypermutation, is not caused by an alteration of the precursor nucleotide pool SO MOLECULAR IMMUNOLOGY LA English DT Article DE AID; hypermutation; immunoglobulin; nucleotide pools; mutagenesis ID CYTIDINE DEAMINASE AID; DEOXYRIBONUCLEOSIDE TRIPHOSPHATE POOLS; CLASS-SWITCH RECOMBINATION; ANTIBODY DIVERSIFICATION; DNA DEAMINATION; PROTEIN; ENZYME; CELLS; RNA; TRANSCRIPTION AB The novel cytidine deaminase, AID, plays a critical role in immunoglobulin (Ig) hypermutation. Its possible modes of action include deamination of an RNA transcript that encodes a molecule involved in these processes, deamination of the DNA encoding the variable regions of immunoglobulin genes, or deamination of monomeric cytidine or deoxycytidine (dC) nucleotide generating a mutagenic imbalanced nucleotide pool. We transformed AID into Escherichia coli cells and measured the nucleotide pools at 2 and 6 h following induction of expression. Although the majority of the cells expressed AID at the relevant time points, the nucleotide pools were unaltered. In addition, mutagenesis by AID expression in E. coli was not synergistically enhanced in a bacterial strain defective in dUTPase, an enzyme that prevents accumulation of dUTP in the nucleotide pool. Finally, while some AID-GFP fused molecules localized to nucleoids, and a significant portion appears to be distributed throughout the bacterial cell, the highest concentration seemed to localize to the cell poles. Chloramphenicol treatment, which detaches the nucleoids from the membrane, caused a further disassociation of AID-GFP from nucleoids suggesting that AID does not intrinsically bind DNA. These results strongly argue against a role for AID in mutagenesis by deamination of cytosine in the nucleotide pool, and suggest that while AID probably acts by deaminating cytosine in the DNA, it requires a protein partner for efficient localization to DNA. (C) 2003 Elsevier Ltd. All rights reserved. C1 NIEHS, Mol Genet Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. RP Diaz, M (reprint author), NIEHS, Mol Genet Lab, Dept Hlth & Human Serv, NIH, Mail Drop D3-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [P3O ES00210] NR 24 TC 8 Z9 8 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 SEP PY 2003 VL 40 IS 5 BP 261 EP 268 DI 10.1016/S0161-5890(03)00113-5 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 720QV UT WOS:000185272200004 PM 12943798 ER PT J AU Baxevanis, AD AF Baxevanis, AD TI Using genomic databases for sequence-based biological discovery SO MOLECULAR MEDICINE LA English DT Article AB The inherent potential underlying the sequence data produced by the International Human Genome Sequencing Consortium and other systematic sequencing projects is, obviously, tremendous. As such, it becomes increasingly important that all biologists have the ability to navigate through and cull important information from key publicly available databases. The continued rapid rise in available sequence information, particularly as model organism data is generated at breakneck speed, also underscores the necessity for all biologists to learn how to effectively make their way through the expanding "sequence information space." This review discusses some of the more commonly used tools for sequence discovery; tools have been developed for the effective and efficient mining of sequence information. These include LocusLink, which provides a gene-centric view of sequence-based information, as well as the 3 major genome browsers: the National Center for Biotechnology Information Map Viewer, the University of California Santa Cruz Genome Browser, and the European Bioinformatics Institute's Ensembl system. An overview of the types of information available through each of these front-ends is given, as well as information on tutorials and other documentation intended to increase the reader's familiarity with these tools. C1 NHGRI, Genome Technol Branch, NIH, Rockville, MD 20852 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, NIH, Bldg 50,Room 5222, Rockville, MD 20852 USA. EM andy@nhgri.nih.gov NR 13 TC 11 Z9 11 U1 0 U2 0 PU NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE PI MANHASSET PA 350 COMMUNITY DRIVE, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD SEP-DEC PY 2003 VL 9 IS 9-12 BP 185 EP 192 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 833JP UT WOS:000222333900001 PM 15208739 ER PT J AU Wood, H Fehlner-Gardner, C Berry, J Fischer, E Graham, B Hackstadt, T Roshick, C McClarty, G AF Wood, H Fehlner-Gardner, C Berry, J Fischer, E Graham, B Hackstadt, T Roshick, C McClarty, G TI Regulation of tryptophan synthase gene expression in Chlamydia trachomatis SO MOLECULAR MICROBIOLOGY LA English DT Article ID OBLIGATE INTRACELLULAR PATHOGEN; OUTER-MEMBRANE PROTEIN; INFECTION IN-VITRO; ESCHERICHIA-COLI; INTERFERON-GAMMA; TRP APOREPRESSOR; TRANSCRIPTION; IDENTIFICATION; PERSISTENCE; PNEUMONIAE AB We previously reported that Chlamydia trachomatis expresses the genes encoding tryptophan synthase (trpA and trpB). The results presented here indicate that C. trachomatis also expresses the tryptophan repressor gene (trpR). The complement of genes regulated by tryptophan levels in C. trachomatis is limited to trpBA and trpR. trp gene expression was repressed if chlamydiae-infected HeLa cells were cultured the presence of tryptophan and induced if grown in tryptophan-depleted medium or in the presence of IFN-gamma. Furthermore, expression of the trp genes in strains which encode a functional tryptophan synthase is repressed when infected cells are cultured in the presence of the tryptophan precursor indole. Results from experiments with cycloheximide, an inhibitor of eukaryotic protein synthesis, indicate that in addition to the absolute size of the intracellular tryptophan pool, host competition for available tryptophan plays a key role in regulating expression of the trp genes. The tryptophan analogue, 5-fluorotryptophan, repressed trp gene expression and induced the formation of aberrant organisms of C. trachomatis. The growth-inhibitory properties of 5-fluorotryptophan could be reversed with exogenous tryptophan but not indole. In total, our results indicate that the ability to regulate trp gene expression in response to tryptophan availability is advantageous for the intracellular survival of this organism. Furthermore, the fact that C. trachomatis has retained the capacity to respond to tryptophan limitation supports the view that the in vivo antichlamydial effect of IFN-gamma is via the induction of the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase. C1 Hlth Canada, Natl Microbiol Lab, Winnipeg, MB R3T 2N2, Canada. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0W3, Canada. Canadian Food Inspect Agcy, Winnipeg, MB R3T 2N2, Canada. NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP McClarty, G (reprint author), Hlth Canada, Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB R3T 2N2, Canada. RI Berry, Jody/C-3184-2013 NR 44 TC 30 Z9 31 U1 0 U2 7 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 SEP PY 2003 VL 49 IS 5 BP 1347 EP 1359 DI 10.1046/j.1365-2958.2003.03638.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 717UX UT WOS:000185110100016 PM 12940992 ER PT J AU Marchand, C Johnson, AA Karki, RG Pais, GCG Zhang, XC Cowansage, K Patel, TA Nicklaus, MC Burke, TR Pommier, Y AF Marchand, C Johnson, AA Karki, RG Pais, GCG Zhang, XC Cowansage, K Patel, TA Nicklaus, MC Burke, TR Pommier, Y TI Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S) SO MOLECULAR PHARMACOLOGY LA English DT Article ID VIRUS TYPE-1 INTEGRASE; VIRAL-DNA BINDING; ACTIVE-SITE; IN-VITRO; CATALYTIC DOMAIN; CRYSTAL-STRUCTURE; TERMINAL DOMAINS; SMALL-MOLECULE; FORCE-FIELD; PROTEIN AB The beta-diketo acids (DKAs) represent a major advance for anti HIV-1 integrase drug development. We compared the inhibition of HIV-1 integrase by six DKA derivatives using the wild-type enzyme or the double-mutant F185K/C280S, which has been previously used for crystal structure determinations. With the wild-type enzyme, we found that DKAs could be classified into two groups: those similarly potent in the presence of magnesium and manganese and those potent in manganese and relatively ineffective in the presence of magnesium. Both the aromatic and the carboxylic or tetrazole functions of DKAs determined their metal selectivity. The F185K/C280S enzyme was markedly more active in the presence of manganese than magnesium. The F185K/C280S integrase was also relatively resistant to the same group of DKAs that were potent in the presence of magnesium with the wild-type enzyme. Resistance was caused by a synergistic effect from both the F185K and C280S mutations. Molecular modeling and docking suggested metal-dependent differences for binding of DKAs. Molecular modeling also indicated that the tetrazole or the azido groups of some derivatives could directly chelate magnesium or manganese in the integrase catalytic site. Together, these experiments suggest that DKAs recognize conformational differences between wild-type and the double-mutant HIV-1 integrase, because they chelate the magnesium or manganese in the enzyme active site and compete for DNA binding. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. RI Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; Marchand, Christophe/D-8559-2016 NR 59 TC 112 Z9 121 U1 0 U2 6 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 SEP PY 2003 VL 64 IS 3 BP 600 EP 609 DI 10.1124/mol.64.3.600 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 711WP UT WOS:000184764300009 PM 12920196 ER PT J AU Rambau, RV Robinson, TJ Stanyon, R AF Rambau, RV Robinson, TJ Stanyon, R TI Molecular genetics of Rhabdomys pumilio subspecies boundaries: mtDNA phylogeography and karyotypic analysis by fluorescence in situ hybridization SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE cytochrome b; fluorescence in situ hybridization; phylogeography; Rhabdomys pumilio ID CYTOCHROME-B GENE; SPECIES GROUP RODENTIA; NAMIB DESERT RODENTS; CHROMOSOMAL EVOLUTION; REPRODUCTIVE ISOLATION; AFRICAN RODENTS; SOUTHERN-AFRICA; DNA-SEQUENCES; SMALL MAMMALS; MURIDAE AB The phylogeography of the African four-striped mouse, Rhabdomys pumilio, was investigated using complete sequences of the mtDNA cytochrome b gene (1140 bp) and a combination of fluorescence in situ hybridization (FISH) and conventional cytogenetic banding techniques (G- and C-banding). Two cytotypes (2n = 46 and 2n = 48) were identified by cytogenetic analysis. There is no evidence of diploid number variation within populations, difference in gross chromosome morphology or of subtle interchromosomal rearrangements at levels detected by ZOO-FISH. Analysis of the mtDNA cytochrome b resulted in two major lineages that correspond roughly to the xeric and mesic biotic zones of southern Africa. One mtDNA clade comprises specimens with 2n = 48 and the other representatives of two cytotypes (2n = 48 and 2n = 46). The mean sequence divergence (12%, range 8.3-15.6%) separating the two mtDNA clades is comparable to among-species variation within murid genera suggesting their recognition as distinct species, the prior names for which would be R. dilectus and R. pumilio. Low sequence divergences and the diploid number dichotomy within the mesic lineage support the recognition of two subspecies corresponding to R. d. dilectus (2n = 46) and R. d. chakae (2n = 48). Our data do not support subspecific delimitation within the nominate, R. pumilio. Molecular dating places cladogenesis of the two putative species at less than five million years, a period characterised by extensive climatic oscillations which are thought to have resulted in habitat fragmentation throughout much of the species range. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Stellenbosch, Dept Zool, ZA-76021 Matieland, South Africa. NCI, Genet Branch, Frederick, MD 21702 USA. RP Robinson, TJ (reprint author), Univ Stellenbosch, Dept Zool, Private Bag 11, ZA-76021 Matieland, South Africa. EM tjr@sun.ac.za OI Stanyon, Roscoe/0000-0002-7229-1092 NR 89 TC 45 Z9 46 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 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD SEP PY 2003 VL 28 IS 3 BP 564 EP 575 DI 10.1016/S1055-7903(03)00058-7 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 715LY UT WOS:000184974800015 PM 12927139 ER PT J AU Huttemann, M Jaradat, S Grossman, LI AF Huttemann, M Jaradat, S Grossman, LI TI Cytochrome c oxidase of mammals contains a testes-specific isoform of subunit VIb - the counterpart to testes-specific cytochrome c? SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE COX; mitochondria; cDNA; energy; evolution ID SPERM; MOUSE; PHOSPHORYLATION; TRANSCRIPTION; LOCALIZATION; EXPRESSION; SEARCH; GENES; STATE; STEP AB Sperm motility is highly dependent on aerobic energy metabolism, of which the apparent rate-limiting step of the mitochondrial respiratory chain is catalyzed by cytochrome c oxidase (COX). COX is the only electron transport chain complex to display isoforms, consistent with its suggested rate-limiting role. Isoforms were previously described for four of the 13 subunits. We now report the discovery that COX subunit VIb displays a testes-specific isoform in human, bull, rat, and mouse (COX VIb-2). Analysis of a variety of rat and mouse tissues, including ovaries, demonstrates exclusive expression of VIb-2 in testes, whereas VIb-1 transcripts are absent in rodent testes, even at early developmental stages. In contrast, both isoforms are transcribed in human testes. In situ hybridizations with human, rat, and mouse testes sections reveal VIb-2 transcripts in all testicular cell types. Within the seminiferous tubules, VIb-1 shows stronger signals in the periphery than in the lumen. Previously, cytochrome c was the only component of the mitochondrial respiratory chain known to express a testes-specific isoform in mammals. COX subunit VIb connects the two COX monomers into the physiological dimeric form, and is the only COX subunit that, like cytochrome c, is solely located in the inter-membrane space. Significant differences between the isoform sequences, in particular changes in charged amino acids, suggest interactions with cytochrome c and sperm-specific energy requirements. (C) 2003 Wiley-Liss, Inc. C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Wayne State Univ, Sch Med, Ctr Mol Med & Genet, 540 E Canfield Ave, Detroit, MI 48201 USA. EM l.grossman@wayne.edu FU NIGMS NIH HHS [GM48517] NR 36 TC 62 Z9 66 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1040-452X EI 1098-2795 J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD SEP PY 2003 VL 66 IS 1 BP 8 EP 16 DI 10.1002/mrd.10327 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 707VC UT WOS:000184529700002 PM 12874793 ER PT J AU Zeuner, KE Hallett, M AF Zeuner, KE Hallett, M TI Sensory training as treatment for focal hand dystonia: A 1-year follow-up SO MOVEMENT DISORDERS LA English DT Article DE focal dystonia; sensory training; tactile spatial acuity ID TACTILE SPATIAL-RESOLUTION; DISCRIMINATION AB In a prior study, 10 patients with focal hand dystonia learned braille reading as sensory training for 8 weeks. Practice time was 30 to 60 minutes daily. They improved both their spatial acuity using the Grating Orientation Discrimination Task (GOT) and their dystonia using the Fahn scale. Three patients continued training for 1 year. Patients showed further improvement in the GOT, writing a standard paragraph, and self-rating scales. Sensory training lasting longer than 8 weeks may lead to continued improvement. (C) 2003 Movement Disorder Society. C1 NINDS, HMCS, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, HMCS, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC1428, Bethesda, MD 20892 USA. NR 10 TC 41 Z9 43 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2003 VL 18 IS 9 BP 1044 EP 1047 DI 10.1002/mds.10490 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 723PF UT WOS:000185440200011 PM 14502673 ER PT J AU Rogozin, IB Pavlov, YI AF Rogozin, IB Pavlov, YI TI Theoretical analysis of mutation hotspots and their DNA sequence context specificity SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE DNA sequence context; classification analysis; mutable motif; microsatellite; hotspot; direct repeat; palindrome; oligonucleotides; mutation spectra ID DOUBLE-STRAND BREAKS; IMMUNOGLOBULIN VARIABLE GENES; HUMAN MITOCHONDRIAL-DNA; BASE-PAIR SUBSTITUTION; ALLOW RAPID DETECTION; MTDNA 9-BP DELETION; HUMAN HPRT GENE; SOMATIC HYPERMUTATION; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE AB Mutation frequencies vary significantly along nuclectide sequences such that mutations often concentrate at certain positions called hotspots. Mutation hotspots in DNA reflect intrinsic properties of the mutation process, such as sequence specificity, that manifests itself at the level of interaction between mutagens, DNA, and the action of the repair and replication machineries. The hotspots might also reflect structural and functional features of the respective DNA sequences. When mutations in a gene are identified using a particular experimental system, resulting hotspots could reflect the properties of the gene product and the mutant selection scheme. Analysis of the nucleotide sequence context of hotspots can provide information on the molecular mechanisms of mutagenesis. However, the determinants of mutation frequency and specificity are complex, and there are many analytical methods for their study. Here we review computational approaches for analyzing mutation spectra (distribution of mutations along the target genes) that include many mutable (detectable) positions. The following methods are reviewed: derivation of a consensus sequence, application of regression approaches to correlate nucleotide sequence features with mutation frequency, mutation hotspot prediction, analysis of oligonucleotide composition of regions containing mutations, pairwise comparison of mutation spectra, analysis of multiple spectra, and analysis of "context-free" characteristics. The advantages and pitfalls of these methods are discussed and illustrated by examples from the literature. The most reliable analyses were obtained when several methods were combined and information from theoretical analysis and experimental observations was considered simultaneously. Simple, robust approaches should be used with small samples of mutations, whereas combinations of simple and complex approaches may be required for large samples. We discuss several well-documented studies where analysis of mutation spectra has substantially contributed to the current understanding of molecular mechanisms of mutagenesis. The nucleotide sequence context of mutational hotspots is a fingerprint of interactions between DNA and DNA repair, replication, and modification enzymes, and the analysis of hotspot context provides evidence of such interactions. Published by Elsevier B.V. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. RP Pavlov, YI (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM pavlov@niehs.nih.gov NR 169 TC 84 Z9 88 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 EI 1388-2139 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD SEP PY 2003 VL 544 IS 1 BP 65 EP 85 DI 10.1016/S1383-5742(03)00032-2 PG 21 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 718PX UT WOS:000185156600004 PM 12888108 ER PT J AU Robinson, WH Fontoura, P Lee, BJ de Vegvar, HEN Tom, J Pedotti, R DiGennaro, CD Mitchell, DJ Fong, D Ho, PPK Ruiz, PJ Maverakis, E Stevens, DB Bernard, CCA Martin, R Kuchroo, VK van Noort, JM Genain, CP Amor, S Olsson, T Utz, PJ Garren, H Steinman, L AF Robinson, WH Fontoura, P Lee, BJ de Vegvar, HEN Tom, J Pedotti, R DiGennaro, CD Mitchell, DJ Fong, D Ho, PPK Ruiz, PJ Maverakis, E Stevens, DB Bernard, CCA Martin, R Kuchroo, VK van Noort, JM Genain, CP Amor, S Olsson, T Utz, PJ Garren, H Steinman, L TI Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis SO NATURE BIOTECHNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; ORIGINAL ANTIGENIC SIN; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; SELF-PEPTIDE; PLASMID DNA; DISEASE; MICE; IMMUNIZATION; EPITOPE AB The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines. C1 Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA. GRECC, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. Bayhill Therapeut Inc, Palo Alto, CA 94303 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Vet Affairs Med Ctr, Portland, OR 97239 USA. La Trobe Univ, Neuroimmunol Lab, Bundoora, Vic 3083, Australia. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. TNO Prevent & Hlth, Div Infect Dis & Immunol, NL-2301 CE Leiden, Netherlands. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Biomed Primate Res Ctr, NL-2280 GH Rijswijk, Netherlands. Karolinska Hosp, Neuroimmunol Unit, Ctr Mol Med, S-17176 Stockholm, Sweden. RP Robinson, WH (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. RI Fontoura, Paulo/A-2315-2010; Maverakis, Emanual/E-1185-2013; OI van Noort, Johannes/0000-0002-9060-5921; Maverakis, Emanual/0000-0002-6294-6294 FU NHLBI NIH HHS [N01 HV 28183]; NIAID NIH HHS [AI50864, AI50865, AI51614]; NIAMS NIH HHS [AR49328, K08 AR02133]; NIDDK NIH HHS [DK61934, U19 DK61934]; NINDS NIH HHS [5R01NS18235] NR 41 TC 170 Z9 178 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD SEP PY 2003 VL 21 IS 9 BP 1033 EP 1039 DI 10.1038/nbt859 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 716VV UT WOS:000185051000035 PM 12910246 ER PT J AU Lippincott-Schwartz, J Altan-Bonnet, N Patterson, GH AF Lippincott-Schwartz, J Altan-Bonnet, N Patterson, GH TI Photobleaching and photoactivation: following protein dynamics in living cells SO NATURE CELL BIOLOGY LA English DT Review ID GREEN FLUORESCENT PROTEIN; ENDOPLASMIC-RETICULUM; IN-VIVO; LATERAL DIFFUSION; MEMBRANE-TRANSPORT; PLASMA-MEMBRANE; MITOCHONDRIAL MATRIX; MAMMALIAN-CELLS; GENE-EXPRESSION; MOBILITY AB Cell biology is being transformed by the use of fluorescent proteins as fusion tags to track protein behaviour in living cells. Here, we discuss the techniques of photobleaching and photoactivation, which can reveal the location and movement of proteins, Widespread applications of these fIuorescent-based methods are revealing new aspects of protein dynamics and the biological processes that they regulate. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov NR 87 TC 6 Z9 6 U1 6 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2003 SU S BP S7 EP S14 DI 10.1038/ncb1032 PG 8 WC Cell Biology SC Cell Biology GA 720KM UT WOS:000185260000003 ER PT J AU Noben-Trauth, K Zheng, QY Johnson, KR AF Noben-Trauth, K Zheng, QY Johnson, KR TI Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss SO NATURE GENETICS LA English DT Article ID SYNDROME TYPE 1D; INBRED STRAINS; MICE; LOCUS; SUSCEPTIBILITY; STEREOCILIA; MUTATIONS; HARMONIN; MODEL; MOUSE AB Age-related hearing loss (AHL) in common inbred mouse strains is a genetically complex quantitative trait. We found a synonymous single-nucleotide polymorphism in exon 7 of Cdh23 that shows significant association with AHL and the deafness modifier mdfw (modifer of deafwaddler). The hypomorphic Cdh23(753A) allele causes in-frame skipping of exon 7. Altered adhesion or reduced stability of CDH23 may confer susceptibility to AHL. Homozygosity at Cdh23(753A) or in combination with heterogeneous secondary factors is a primary determinant of AHL in mice. C1 Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, NIH, Rockville, MD 20850 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Noben-Trauth, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, NIH, 5 Res Court, Rockville, MD 20850 USA. RI Zheng, Qing/C-1731-2012 FU NIDCD NIH HHS [R01 DC004301-05, R01 DC004301, R01 DC005827, R01 DC005827-03, R01 DC009246, R03 DC004376, R03 DC004376-01A1, R21 DC005846, R21 DC005846-01A1] NR 15 TC 211 Z9 224 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2003 VL 35 IS 1 BP 21 EP 23 DI 10.1038/ng1226 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 716FQ UT WOS:000185018500006 PM 12910270 ER PT J AU Li, W Zhang, Q Oiso, N Novak, EK Gautam, R O'Brien, EP Tinsley, CL Blake, DJ Spritz, RA Copeland, NG Jenkins, NA Amato, D Roe, BA Starcevic, M Dell'Angelica, EC Elliott, RW Mishra, V Kingsmore, SF Paylor, RE Swank, RT AF Li, W Zhang, Q Oiso, N Novak, EK Gautam, R O'Brien, EP Tinsley, CL Blake, DJ Spritz, RA Copeland, NG Jenkins, NA Amato, D Roe, BA Starcevic, M Dell'Angelica, EC Elliott, RW Mishra, V Kingsmore, SF Paylor, RE Swank, RT TI Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) SO NATURE GENETICS LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; STORAGE POOL DEFICIENCY; PLATELET-DENSE GRANULES; GENETIC-VARIATION; MOUSE MODEL; 6P22.3 GENE; MUTATION; PROTEIN; HOMOLOG; TRAFFICKING AB Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules(1-3). In mice, at least 16 loci are associated with HPS4-6, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells(8). We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1. C1 Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA. Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Toronto, Dept Med, Div Hematol & Med Oncol, Toronto, ON M5G 1X5, Canada. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. Univ Florida, Dept Med, Gainesville, FL 32610 USA. Mol Staging, New Haven, CT 06511 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Swank, RT (reprint author), Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. RI turton, miranda/F-4682-2011; OI kingsmore, stephen/0000-0002-3758-4631 FU NHLBI NIH HHS [R01 HL068117]; NIAID NIH HHS [P01 AI039824, P01 AI039824-050002]; NICHD NIH HHS [U19 HD077693] NR 30 TC 273 Z9 284 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2003 VL 35 IS 1 BP 84 EP 89 DI 10.1038/ng1229 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 716FQ UT WOS:000185018500015 PM 12923531 ER PT J AU Seder, RA Ahmed, R AF Seder, RA Ahmed, R TI Similarities and differences in CD4(+) and CD8(+) effector and memory T cell generation SO NATURE IMMUNOLOGY LA English DT Review ID CYTOKINE GENE-EXPRESSION; IN-VIVO; INTERFERON-GAMMA; CUTTING EDGE; CLONAL EXPANSION; LYMPHOCYTE RESPONSES; LINEAGE COMMITMENT; CD8-T-CELL MEMORY; LEISHMANIA-MAJOR; CD4-T-CELL HELP AB Naive CD4(+) and CD8(+) T cells undergo unique developmental programs after activation, resulting in the generation of effector and long-lived memory T cells. Recent evidence indicates that both cell-intrinsic and cell-extrinsic factors regulate memory T cell differentiation. This review compares and contrasts how naive CD4(+) and CD8(+) T cells make the transition to effector and/or memory cells and discusses the implications of these findings for vaccine development. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 75 TC 508 Z9 531 U1 4 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2003 VL 4 IS 9 BP 835 EP 842 DI 10.1038/ni969 PG 8 WC Immunology SC Immunology GA 715YN UT WOS:000185002200009 PM 12942084 ER PT J AU Steeg, PS AF Steeg, PS TI Angiogenesis inhibitors and hypoxia - Reply SO NATURE MEDICINE LA English DT Letter ID ANTIANGIOGENIC THERAPY; TUMOR-GROWTH; INTERFERON-ALPHA; CELL CARCINOMA; METASTASIS; APOPTOSIS; RECEPTOR; CANCER; MICE C1 NCI, Pathol Lab, Womens Canc Sect, NIH, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Pathol Lab, Womens Canc Sect, NIH, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2003 VL 9 IS 9 BP 1104 EP 1105 DI 10.1038/nm0903-1104b PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 716ZX UT WOS:000185061600012 ER PT J AU Mattson, MP Perry, T Greig, NH AF Mattson, MP Perry, T Greig, NH TI Learning from the gut SO NATURE MEDICINE LA English DT Editorial Material ID GLUCAGON-LIKE PEPTIDE-1; METABOLISM; EXENDIN-4; RECEPTOR; GLP-1; CELL C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 12 TC 21 Z9 23 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2003 VL 9 IS 9 BP 1113 EP 1115 DI 10.1038/0903-1113 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 716ZX UT WOS:000185061600016 PM 12949521 ER PT J AU Dudley, ME Rosenberg, SA AF Dudley, ME Rosenberg, SA TI Adoptive-cell-transfer therapy for the treatment of patients with cancer SO NATURE REVIEWS CANCER LA English DT Review ID TUMOR-INFILTRATING LYMPHOCYTES; EPSTEIN-BARR-VIRUS; CYTOTOXIC T-CELLS; COLONY-STIMULATING FACTOR; PERIPHERAL-BLOOD LYMPHOCYTES; INTERFERON-GAMMA SECRETION; VACCINE-PRIMED LYMPHOCYTES; HIGH-DOSE INTERLEUKIN-2; LYMPH-NODE LYMPHOCYTES; ACTIVATED KILLER-CELLS AB Adoptive immunotherapy - the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration - is a promising approach to inducing antitumour immune responses. The molecular identification of tumour antigens and the ability to monitor the persistence and transport of transferred cells has provided new insights into the mechanisms of tumour immunotherapy. Recent studies have shown the effectiveness of cell-transfer therapies for the treatment of patients with selected metastatic cancers. These studies provide a blueprint for the wider application of adoptive-cell-transfer therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, Bldg 10,Room 2B-34,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-32] NR 97 TC 396 Z9 406 U1 4 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD SEP PY 2003 VL 3 IS 9 BP 666 EP U2 DI 10.1038/nrc1167 PG 11 WC Oncology SC Oncology GA 717JE UT WOS:000185084700015 PM 12951585 ER PT J AU Helman, LJ Meltzer, P AF Helman, LJ Meltzer, P TI Mechanisms of sarcoma development SO NATURE REVIEWS CANCER LA English DT Review ID SOFT-TISSUE TUMORS; GASTROINTESTINAL STROMAL TUMORS; GROWTH-FACTOR-II; TYROSINE KINASE INHIBITOR; GIANT-CELL FIBROBLASTOMA; MOLECULAR-GENETICS; DERMATOFIBROSARCOMA PROTUBERANS; SYNOVIAL SARCOMA; ALVEOLAR RHABDOMYOSARCOMA; EWINGS-SARCOMA AB Sarcomas are a rare and diverse group of tumours that are derived from connective tissues, including bone, muscle and cartilage. Although there are instances of hereditary predisposition to sarcomas, the overwhelming majority of such tumours are sporadic. In the past decade, we have gained much insight into the genetic abnormalities that seem to underlie the pathogenesis of these tumours. This information has already led to new classification of many sarcomas, as well as to successful therapies that are targeted at specific genetic abnormalities. It is likely that this approach will lead to continued refinements in classification and treatment of these tumours. C1 NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Helman, LJ (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 13N240,MSC 1928, Bethesda, MD 20892 USA. NR 93 TC 239 Z9 244 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD SEP PY 2003 VL 3 IS 9 BP 685 EP 694 DI 10.1038/nrc1168 PG 10 WC Oncology SC Oncology GA 717JE UT WOS:000185084700017 PM 12951587 ER PT J AU Larsen, M Tremblay, ML Yamada, KM AF Larsen, M Tremblay, ML Yamada, KM TI Phosphatases in cell-matrix adhesion and migration SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID PROTEIN-TYROSINE-PHOSPHATASE; TUMOR-SUPPRESSOR PTEN; 2A CATALYTIC SUBUNIT; MYOSIN LIGHT-CHAIN; SRC FAMILY KINASES; FOCAL-ADHESION; BETA-CATENIN; P21-ACTIVATED KINASE; LIM-KINASE; PTP-PEST AB Many proteins that have been implicated in cell-matrix adhesion and cell migration are phosphorylated, which regulates their folding, enzymatic activities and protein-protein interactions. Although modulation of cell motility by kinases is well known, increasing evidence confirms that phosphatases are essential at each stage of the migration process. Phosphatases can control the formation and maintenance of the actin cytoskeleton, regulate small GTPase molecular switches, and modulate the dynamics of matrix-adhesion interaction, actin contraction, rear release and migratory directionality. C1 McGill Univ, Ctr Canc, Montreal, PQ H3G 1Y6, Canada. McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Larsen, M (reprint author), McGill Univ, Ctr Canc, Montreal, PQ H3G 1Y6, Canada. EM mlarsen@mail.nih.gov; kyamada@mail.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805; Larsen, Melinda/0000-0002-5026-2012 NR 133 TC 85 Z9 88 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD SEP PY 2003 VL 4 IS 9 BP 700 EP 711 DI 10.1038/nrm1199 PG 12 WC Cell Biology SC Cell Biology GA 716ZW UT WOS:000185061500013 PM 14506473 ER PT J AU Hall, TMT AF Hall, TMT TI SAM breaks its stereotype SO NATURE STRUCTURAL BIOLOGY LA English DT Editorial Material ID PUMILIO-HOMOLOGY DOMAIN; NANOS MESSENGER-RNA; CRYSTAL-STRUCTURE; CRYSTALLOGRAPHIC ANALYSIS; KARYOPHERIN-ALPHA; JUNCTION COMPLEX; BETA-CATENIN; RECOGNITION; PROTEIN; DROSOPHILA AB Don't prejudge the function of a domain based on its sequence. Two recent studies drive home this message and add the sterile-alpha-motif (SAM) to the growing list of domains that are able to interact with both proteins and nucleic acids. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 29 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD SEP PY 2003 VL 10 IS 9 BP 677 EP 679 DI 10.1038/nsb0903-677 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 715KK UT WOS:000184970700005 PM 12942139 ER PT J AU Breinig, S Kervinen, J Stith, L Wasson, AS Fairman, R Wlodawer, A Zdanov, A Jaffe, EK AF Breinig, S Kervinen, J Stith, L Wasson, AS Fairman, R Wlodawer, A Zdanov, A Jaffe, EK TI Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID 5-AMINOLEVULINIC ACID DEHYDRATASE; X-RAY-STRUCTURE; DELTA-AMINOLEVULINATE DEHYDRATASE; PSEUDOMONAS-AERUGINOSA; CRYSTAL-STRUCTURE; ARTIFICIAL GENE; BINDING-SITES; PURIFICATION; INHIBITORS/; RESOLUTION AB Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of tetrapyrroles ( such as heme and chlorophyll). Although the predominant oligomeric form of this enzyme, as inferred from many crystal structures, is that of a homo-octamer, a rare human PBGS allele, F12L, reveals the presence of a hexameric form. Rearrangement of an N-terminal arm is responsible for this oligomeric switch, which results in profound changes in kinetic behavior. The structural transition between octamer and hexamer must proceed through an unparalleled equilibrium containing two different dimer structures. The allosteric magnesium, present in most PBGS, has a binding site in the octamer but not in the hexamer. The unprecedented structural rearrangement reported here relates to the allosteric regulation of PBGS and suggests that alternative PBGS oligomers may function in a magnesium-dependent regulation of tetrapyrrole biosynthesis in plants and some bacteria. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. 3 Dimens Pharmaceut Inc, Exton, PA 19341 USA. Haverford Coll, Dept Biol, Haverford, PA 19041 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Jaffe, EK (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. NR 36 TC 66 Z9 71 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD SEP PY 2003 VL 10 IS 9 BP 757 EP 763 DI 10.1038/nsb963 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 715KK UT WOS:000184970700019 PM 12897770 ER PT J AU Zimonjic, DB Durkin, ME Keck-Waggoner, CL Park, SW Thorgeirsson, SS Popescu, NC AF Zimonjic, DB Durkin, ME Keck-Waggoner, CL Park, SW Thorgeirsson, SS Popescu, NC TI SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma SO NEOPLASIA LA English DT Article DE SMAD5; gene expression; chromosome rearrangements; gene amplification; fragile sites ID CELL-LINES; CHROMOSOME TRANSLOCATIONS; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; FHIT GENE; GROWTH; TUMORIGENICITY; LOCALIZATION; IMBALANCES; BREAKAGE AB Signaling by the transforming growth factor (TGF)family members is transduced from the cell surface to the nucleus by the Smad group of intracellular proteins. Because we detected alterations on the long arm of chromosome 5, we examined the status of the SMAD5 gene in human hepatocellular carcinoma (HCC) cell lines and primary HCC. In 16 cell lines, chromosome alterations of chromosome 5 were observed in nine cell lines by fluorescence in situ hybridization (FISH), and an increase in SMAD5 gene copy number relative to the ploidy level was found in eight lines. The breakpoints in unbalanced translocations. and deletions frequently occurred near the SMAD5 locus, but apparently did not cause loss of SMAD5. In one cell line, where comparative genomic hybridization showed DNA copy number gain confined to the region 5q31, we detected by FISH high-level amplification of the SMAD5 gene located within the fragile site FRA5C. Semiquantitative polymerase chain reaction did not reveal changes in SMAD5 DNA levels in 15 of 17 primary HCC specimens. In 17 HCC cell lines, SMAD5 mRNA levels were either maintained or upregulated by an increase in gene dosage or another mechanism. Collectively, our results show that SMAD5 undergoes copy number gain and increased expression, rather than loss of expression, and therefore suggest that this gene does not act as a tumor-suppressor gene in HCC. The Hep-40 HCC cell line with high-level amplification and significant overexpression of SMAD5 may be useful in studying the interaction of SMAD5 with other genes. C1 NCI, Ctr Canc Res, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), 37 Convent Dr MSC,4262 Bldg 37,Room 4128B, Bethesda, MD 20892 USA. NR 36 TC 18 Z9 18 U1 0 U2 0 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP-OCT PY 2003 VL 5 IS 5 BP 390 EP 396 PG 7 WC Oncology SC Oncology GA 745ZW UT WOS:000186722400002 PM 14670176 ER PT J AU Skotheim, RI Abeler, VM Nesland, JM Fossa, SD Holm, R Wagner, U Florenes, VA Aass, N Kallioniemi, OP Lothe, RA AF Skotheim, RI Abeler, VM Nesland, JM Fossa, SD Holm, R Wagner, U Florenes, VA Aass, N Kallioniemi, OP Lothe, RA TI Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays SO NEOPLASIA LA English DT Article DE candidate genes; molecular tumorigenesis; protein expression; testicular germ cell tumor; tissue microarray ID GERM-CELL TUMORS; FOCAL ADHESION KINASE; CYTOGENETIC ANALYSIS; FACTOR-RECEPTOR; BREAST-CANCER; D2 EXPRESSION; CYCLIN D2; GRB7; ASSOCIATION; CARCINOMA AB By the use of high-throughput molecular technologies, the number of genes and proteins potentially relevant to testicular germ cell tumor (TGCT) and other diseases will increase rapidly. In a recent transcriptional profiling, we demonstrated the overexpression of GRB7 and JUP in TGCTs, and confirmed the reported overexpression of CCND2. We also have recent evidences for frequent genetic alterations of FHIT and epigenetic alterations of MGMT. To evaluate whether the expression of these genes is related to any clinicopathological variables, we constructed a tissue microarray with 510 testicular tissue cores from 279 patients diagnosed with TGCT, covering various histological subgroups and clinical stages. By immunohistochemistry, we found that JUP, GRB7, and CCND2 proteins were rarely present in normal testis, but frequently expressed at high levels in TGCT. Additionally, all premalignant intratubular germ cell neoplaslas were JUP-immunopositive. MGMT and FHIT were expressed by normal testicular tissues, but at significantly lower frequencies in TGCT. Except for CCND2, the expressions of all markers were significantly associated with various TGCT subtypes. In summary, we have developed a high-throughput tool for the evaluation of TGCT markers, and utilized this to validate five candidate genes whose protein expressions were indeed deregulated in TGCT. C1 Norwegian Radium Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. Norwegian Radium Hosp, Dept Med Oncol & Radiotherapy, N-0310 Oslo, Norway. Univ Basel, Inst Pathol, Basel, Switzerland. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. VTT Tech Res Ctr Finland, Med Biotechnol Grp, Turku, Finland. Univ Turku, Turku, Finland. RP Lothe, RA (reprint author), Norwegian Radium Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 44 TC 33 Z9 33 U1 0 U2 0 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP-OCT PY 2003 VL 5 IS 5 BP 397 EP 404 PG 8 WC Oncology SC Oncology GA 745ZW UT WOS:000186722400003 PM 14670177 ER PT J AU Turner, JA Anderson, KC Siegel, RM AF Turner, JA Anderson, KC Siegel, RM TI Cell responsiveness in macaque superior temporal polysensory area measured by temporal discriminants SO NEURAL COMPUTATION LA English DT Article ID TWO-DIMENSIONAL PATTERNS; SINGLE UNITS; OPTIC FLOW; CORTICAL-NEURONS; VISUAL-CORTEX; MONKEY; MOTION AB The firing-rate data from 341 cells from two macaques' superion temporal polysensory area (STPa) were subjected to three different analyses to determine the temporal firing-rate patterns in response to visual optic flow patterns. The data were collected while the monkey viewed four types of optic flow and responded to the change in the display. The mean firing rate NFR) analysis considered the mean change in firing rate for 500 ms after stimulus onset; the discriminant (DIS) analysis and the principal components (PCA+DIS) analysis considered the change in time-binned firing rate over 1000 ms after stimulus presentation, using bin sizes of 30 to 500 ms. The DIS analysis used a step-down discriminant analysis to find temporal windows in which the cell's firing rate could discriminate among the stimuli; the PCA+DlS analysis extracted the principal components of the cell's firing rates without regard for the stimulus type and then applied a step-down discriminant analysis to the PCA scores to determine whether any of the principal components could discriminate among the stimuli. The two temporal analyses found cells sensitive to the optic flows that the MFR analysis missed. A small proportion of cells showed multiple selectivities under the temporal analyses. Thus, the temporal analyses give a more complete representation of the information encoded by the firing properties of STPa neurons. Finally, this approach incorporates temporal approaches with classical statistical techniques in order to select tuned neurons from a population in an unbiased manner. C1 Long Beach VA Med Ctr, Neuroimaging Res Lab, Long Beach, CA 90822 USA. NIMH, Bethesda, MD 20892 USA. Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. RP Turner, JA (reprint author), Long Beach VA Med Ctr, Neuroimaging Res Lab, Long Beach, CA 90822 USA. RI Turner, Jessica/H-7282-2015 OI Turner, Jessica/0000-0003-0076-8434 FU NCRR NIH HHS [1S10RR12873]; NEI NIH HHS [EY06738, EY09223] NR 19 TC 0 Z9 0 U1 0 U2 0 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD SEP PY 2003 VL 15 IS 9 BP 2067 EP 2090 DI 10.1162/089976603322297296 PG 24 WC Computer Science, Artificial Intelligence SC Computer Science GA 704CB UT WOS:000184319200004 PM 12959666 ER PT J AU Lee, SS Kim, YM Junn, E Lee, G Park, KH Tanaka, M Ronchetti, RD Quezado, MM Mouradian, MM AF Lee, SS Kim, YM Junn, E Lee, G Park, KH Tanaka, M Ronchetti, RD Quezado, MM Mouradian, MM TI Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies SO NEUROBIOLOGY OF AGING LA English DT Article DE alpha-synuclein; Parkinson; proliferation; MAPK; cell cycle; synucleinopathy; Alzheimer; PC12 cells ID ACTIVATED PROTEIN-KINASE; MULTIPLE SYSTEM ATROPHY; ALZHEIMERS-DISEASE BRAIN; PARKINSONS-DISEASE; NEURONAL DEATH; PRESYNAPTIC PROTEIN; DNA-REPLICATION; NEURODEGENERATIVE DISORDERS; DIFFERENTIAL ACTIVATION; CYTOPLASMIC INCLUSIONS AB alpha-Synuclein is a presynaptic protein that accumulates abnormally in Lewy bodies of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Its physiological function and role in neuronal death remain poorly understood. Recent immunohistochemical studies suggest that cell cycle-related phenomena may play a role in the pathogenesis of Alzheimer's disease and perhaps other neurodegenerative disorders. In this investigation, we examined the effects of alpha-synuclein expression levels on cell cycle indices in PC12 cells engineered to conditionally induce alpha-synuclein expression upon withdrawal of doxycycline. Over-expression of alpha-synuclein resulted in enhanced proliferation rate and enrichment of cells in the S phase of the cell cycle. This was associated with increased accumulation of the mitotic factor cyclin B and down-regulation of the tumor suppressor retinoblastoma 2. Additionally, ERK1/2, key molecules in proliferation signaling, were highly phosphorylated. Immunohistochemical studies on postmortem brains revealed intense cyclin B immunoreactivity in Lewy bodies in cases with DLB and to a lesser extent in PD. We propose that elevated expression of alpha-synuclein causes changes in cell cycle regulators through ERK activation leading to apoptosis of postmitotic neurons. These changes in cell cycle proteins are also associated with ectopic expression of cyclin B in Lewy bodies. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, 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 82 TC 41 Z9 45 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2003 VL 24 IS 5 BP 687 EP 696 AR PII S0197-4580(02)00196-3 DI 10.1016/S0197-4580(02)00196-3 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 709PA UT WOS:000184632500007 PM 12885576 ER PT J AU Contoreggi, C Herning, RI Koeppl, B Simpson, PM Negro, PJ Fortner-Burton, C Hess, J AF Contoreggi, C Herning, RI Koeppl, B Simpson, PM Negro, PJ Fortner-Burton, C Hess, J TI Treatment-seeking inpatient cocaine abusers show hypothalamic dysregulation of both basal prolactin and cortisol secretion SO NEUROENDOCRINOLOGY LA English DT Article DE cocaine; stress; abstinence; cortisol; prolactin; corticotropin-releasing hormone; adrenal steroids; clinical neuroendocrinology ID CORTICOTROPIN-RELEASING HORMONE; AFTERNOON PLASMA-CORTISOL; PITUITARY-ADRENAL AXIS; STRESS-INDUCED RELAPSE; INTRAVENOUS COCAINE; ANTERIOR-PITUITARY; ANOREXIA-NERVOSA; SERUM CORTISOL; DEPRESSION; ABSTINENCE AB Cocaine causes neuroendocrine aberrations in cocaine abusers with pituitary stress hormone secretion providing a window to the stress system in the brain. Substance abusers and control participants were hormonally profiled for 3 weeks. Abusers showed significant basal elevations in prolactin in week 1 with normalization over the 3 weeks. No differences in prolactin secretion were seen with either thyrotropin-releasing hormone stimulation or L-dopa suppression testing. Basal afternoon cortisol secretion was significantly elevated during weeks 1 and 2 comparing abusers to controls. Elevated afternoon cortisol secretion is a sensitive indicator of central stress activation. These results point to the hypothalamus, not the pituitary gland, as being primarily altered in cocaine withdrawal. The data demonstrate that both the dopamine-prolactin and hypothalamic-pituitary-adrenal (HPA) axes are affected during cocaine cessation. As medications are developed to modulate activation of a dysfunctional stress system, future therapeutic studies of substance abuse, withdrawal, craving and relapse should employ more sophisticated tests of hypothalamic pituitary function, especially the HPA axis, as this information may be a guide in the diagnosis and predict clinical responses. Copyright (C) 2003 S. Karger AG, Basel. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Arkansas, Arkansas Childrens Hosp, Med Ctr, Dept Pediat, Little Rock, AR 72204 USA. Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. United Network Organ Sharing, Richmond, VA USA. RP Contoreggi, C (reprint author), NIDA, Intramural Res Program, POB 5180, Baltimore, MD 21224 USA. NR 51 TC 22 Z9 22 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD SEP PY 2003 VL 78 IS 3 BP 154 EP 162 DI 10.1159/000072797 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 731KQ UT WOS:000185883300004 PM 14512708 ER PT J AU Ding, JZ Nieto, FJ Beauchamp, NJ Longstreth, WT Manolio, TA Hetmanski, JB Fried, LP AF Ding, JZ Nieto, FJ Beauchamp, NJ Longstreth, WT Manolio, TA Hetmanski, JB Fried, LP TI A prospective analysis of risk factors for white matter disease in the brain stem SO NEUROEPIDEMIOLOGY LA English DT Article DE brain stem; cerebrovascular disorders; epidemiology; hypertension; magnetic resonance imaging ID MODERATE ALCOHOL-CONSUMPTION; PONTINE ISCHEMIC RAREFACTION; CARDIOVASCULAR HEALTH; OLDER ADULTS; FOLLOW-UP; STROKE; LESIONS; ATHEROSCLEROSIS; MRI; ABNORMALITIES AB Background and Purpose: White matter disease (WMD) in the brain stem may be a predictor of poor clinical outcome, independent of WMD in the periventricular and subcortical areas of the brain. Many cardiovascular risk factors such as older age, hypertension, and smoking have been suggested as risk factors for WMD in the periventricular and subcortical areas of the brain. However, no epidemiologic study has examined the associations between cardiovascular risk factors and WMD in the brain stem. Methods: A total of 789 participants, aged 65 years or older, from the Cardiovascular Health Study constituted the present study population. WMD, defined as hyperintensive lesions on magnetic resonance imaging (MRI), in the brain stem was measured in 1992/1993 and 1997/1998. Results: Of the 789 participants, 212 (26.9%) had WMD in the brain stem in 1997/1998. In multivariate logistic regression analysis, the presence of WMD in the brain stem in 1997/1998 was significantly associated with several variables measured in 1992/1993: an increase by 5 years of age (OR = 1.51, 95% CI: 1.25-1.83), a 10-pack-years increase in smoking (OR = 1.12, 95% CI: 1.04-1.21), a 0.1-liter increase in first-second forced expiratory volume (OR = 0.95, 95% CI: 0.920.99), a 1 mumol/I increase in fibrinogen level (OR = 1.13, 95% CI: 1.03-1.23), and MRI infarction (OR = 2.58, 95% CI: 1.78- 3.74). Excluding those (n = 167) with WMD in the brain stem in 1992/1993, the pattern remained. Hypertension was not associated with WMD in the brain stem. Conclusions: Increased age, smoking, lower forced expiratory volume, increased fibrinogen level, and MRI infarction, but not hypertension, may be independent risk factors for WMD in the brain stem in older adults. Copyright (C) 2003 S. Karger AG, Basel. C1 Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Univ Wisconsin, Sch Med, Dept Populat Hlth Sci, Madison, WI USA. Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Ding, JZ (reprint author), Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, 615 N Wolfe St,Room W6009, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [N01 HC 85085, N01 HC 85084, N01 HC 85080, N01 HC 85082, N01 HC 85081, N01 HC 85083, N01 HC 85079, N01 HC 15103, N01 HC 85086, N01 HC 35129] NR 31 TC 18 Z9 18 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-5350 J9 NEUROEPIDEMIOLOGY JI Neuroepidemiology PD SEP-OCT PY 2003 VL 22 IS 5 BP 275 EP 282 DI 10.1159/000071190 PG 8 WC Public, Environmental & Occupational Health; Clinical Neurology SC Public, Environmental & Occupational Health; Neurosciences & Neurology GA 712RA UT WOS:000184809600002 PM 12902622 ER PT J AU Monk, CS McClure, EB Nelson, EE Zarahn, E Bilder, RM Leibenluft, E Charney, DS Ernst, M Pine, DS AF Monk, CS McClure, EB Nelson, EE Zarahn, E Bilder, RM Leibenluft, E Charney, DS Ernst, M Pine, DS TI Adolescent immaturity in attention-related brain engagement to emotional facial expressions SO NEUROIMAGE LA English DT Article ID HUMAN AMYGDALA; NEURAL MECHANISMS; RESPONSES; CHILDREN; FACES; HABITUATION; ACTIVATION; DISORDERS; COGNITION; FEARFUL AB Selective attention, particularly during the processing of emotionally evocative events, is a crucial component of adolescent development. We used functional magnetic resonance imagining (fMRI) with adolescents and adults to examine developmental differences in activation in a paradigm that involved selective attention during the viewing of emotionally engaging face stimuli. We evaluated developmental differences in neural activation for three comparisons: (1) directing attention to subjective responses to fearful facial expressions relative to directing attention to a nonemotional aspect (nose width) of fearful faces, (2) viewing fearful relative to neutral faces while attending to a nonemotional aspect of the face, and (3) viewing fearful relative to neutral faces while attention was unconstrained (passive viewing). The comparison of activation across attention tasks revealed greater activation in the orbital frontal cortex in adults than in adolescents. Conversely, when subjects attended to a nonemotional feature, fearful relative to neutral faces influenced activation in the anterior cingulate more in adolescents than in adults. When attention was unconstrained, adolescents relative to adults showed greater activation in the anterior cingulate, bilateral orbitofrontal cortex, and right amygdala in response to the fearful relative to neutral faces. These findings suggest that adults show greater modulation of activity in relevant brain structures based on attentional demands, whereas adolescents exhibit greater modulation based on emotional content. (C) 2003 Elsevier Inc. All rights reserved. C1 NIMH, Sect Dev & Affect Neurosci, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY 10032 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Monk, CS (reprint author), 15K North Dr,Room 204,MSC 2670, Bethesda, MD 20892 USA. RI Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014; Bilder, Robert/A-8894-2008 OI Nelson, Eric/0000-0002-3376-2453; Bilder, Robert/0000-0001-5085-7852 NR 38 TC 270 Z9 272 U1 7 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2003 VL 20 IS 1 BP 420 EP 428 DI 10.1016/S1053-8119(03)00355-0 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 728ZN UT WOS:000185746400038 PM 14527602 ER PT J AU Goebel, HH Goldfarb, L Laing, N AF Goebel, HH Goldfarb, L Laing, N TI Protein aggregate myopathies, a subgroup in congenital myopathies - an update and review SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 8th International Congress of the World-Muscle-Society CY SEP 03-06, 2003 CL SZEGED, HUNGARY SP World Muscle Soc C1 Univ Mainz, D-55131 Mainz, Germany. NIH, Bethesda, MD 20892 USA. Queen Elizabeth II Med Ctr, Mol Neurogenet Lab, Nedlands, WA, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD SEP PY 2003 VL 13 IS 7-8 BP 616 EP 616 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 716AX UT WOS:000185007600014 ER PT J AU Piercy, RJ Pombo, A Stewart, CL Muntoni, F Brown, SC AF Piercy, RJ Pombo, A Stewart, CL Muntoni, F Brown, SC TI Does an association of nuclear replication and transcription sites with the nuclear matrix underlie the pathogenesis of the laminopathies? SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 8th International Congress of the World-Muscle-Society CY SEP 03-06, 2003 CL SZEGED, HUNGARY SP World Muscle Soc C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dubowitz Neuromuscular Unit, London W12 0NN, England. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, MRC, Ctr Clin Sci, London W12 0NN, England. NCI, FCRDC, Lab Canc Div Biol, Ft Detrick, MD 21702 USA. RI Nicholas, Janet/C-6674-2008; Pombo, Ana/A-1045-2010 OI Pombo, Ana/0000-0002-7493-6288 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD SEP PY 2003 VL 13 IS 7-8 BP 658 EP 658 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 716AX UT WOS:000185007600167 ER PT J AU Matveeva, OV Mathews, DH Tsodikov, AD Shabalina, SA Gesteland, RF Atkins, JF Freier, SM AF Matveeva, OV Mathews, DH Tsodikov, AD Shabalina, SA Gesteland, RF Atkins, JF Freier, SM TI Thermodynamic criteria for high hit rate antisense oligonucleotide design SO NUCLEIC ACIDS RESEARCH LA English DT Article ID THEORETICAL APPROACH; RNA; PARAMETERS; DNA; PREDICTION; STABILITY; DUPLEXES; PROBES AB Antisense oligonucleotides are used for therapeutic applications and in functional genomic studies. In practice, however, many of the oligonucleotides complementary to an mRNA have little or no antisense activity. Theoretical strategies to improve the 'hit rate' in antisense screens will reduce the cost of discovery and may lead to identification of antisense oligonucleotides with increased potency. Statistical analysis performed on data collected from more than 1000 experiments with phosphorothioate-modified oligonucleotides revealed that the oligo-probes, which form stable duplexes with RNA (DeltaG(37)(o) less than or equal to -30 kcal/mol) and have small self-interaction potential, are more frequently efficient than molecules that form less stable oligonucleotide-RNA hybrids or more stable self-structures. To achieve optimal statistical preference, the values for self-interaction should be (DeltaG(37)(o)) greater than or equal to -8 kcal/mol for inter-oligonucleotide pairing and (DeltaG(37)(o)) greater than or equal to -1.1 kcal/mol for intra-molecular pairing. Selection of oligonucleotides with these thermodynamic values in the analyzed experiments would have increased the 'hit rate' by as much as 6-fold. C1 Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. Ctr Human Genet, Rochester, NY 14642 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. ISIS Pharmaceut, Carlsbad, CA 92008 USA. RP Matveeva, OV (reprint author), Univ Utah, Dept Human Genet, 15N 2030E Room 7410, Salt Lake City, UT 84112 USA. RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU NIGMS NIH HHS [R01-GM61200, GM48152, R01 GM048152] NR 15 TC 46 Z9 51 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 1 PY 2003 VL 31 IS 17 BP 4989 EP 4994 DI 10.1093/nar/gkg710 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718LU UT WOS:000185148300012 PM 12930948 ER PT J AU De Roos, AJ Zahm, SH Cantor, KP Weisenburger, DD Holmes, FF Burmeister, LF Blair, A AF De Roos, AJ Zahm, SH Cantor, KP Weisenburger, DD Holmes, FF Burmeister, LF Blair, A TI Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID SOFT-TISSUE SARCOMA; UNITED-STATES; AGRICULTURAL USE; ORGANOPHOSPHATE PESTICIDES; HIERARCHICAL REGRESSION; TIME TRENDS; EXPOSURE; FARMERS; CANCER; WORKERS AB Background: An increased rate of non-Hodgkin's lymphoma (NHL) has been repeatedly observed among farmers, but identification of specific exposures that explain this observation has proven difficult. Methods: During the 1980s, the National Cancer Institute conducted three case-control studies of NHL in the midwestern United States. These pooled data were used to examine pesticide exposures in farming as risk factors for NHL in men. The large sample size (n = 3417) allowed analysis of 47 pesticides simultaneously, controlling for potential confounding by other pesticides in the model, and adjusting the estimates based on a prespecified variance to make them more stable. Results: Reported use of several individual pesticides was associated with increased NHL incidence, including organophosphate insecticides coumaphos, diazinon, and fonofos, insecticides chlordane, dieldrin, and copper acetoarsenite, and herbicides atrazine, glyphosate, and sodium chlorate. A subanalysis of these " potentially carcinogenic" pesticides suggested a positive trend of risk with exposure to increasing numbers. Conclusion: Consideration of multiple exposures is important in accurately estimating specific effects and in evaluating realistic exposure scenarios. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Omaha, NE USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Univ Iowa, Coll Med, Iowa City, IA USA. RP De Roos, AJ (reprint author), 1100 Fairview Ave N,MP-474,POB 19024, Seattle, WA 98109 USA. RI Zahm, Shelia/B-5025-2015 NR 55 TC 103 Z9 104 U1 5 U2 36 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2003 VL 60 IS 9 AR e11 DI 10.1136/oem.60.9.e11 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 714GH UT WOS:000184904000029 PM 12937207 ER PT J AU Amundson, SA Bittner, M Fornace, AJ AF Amundson, SA Bittner, M Fornace, AJ TI Functional genomics as a window on radiation stress signaling SO ONCOGENE LA English DT Article DE gene induction; cDNA microarray; cancer cells ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; IONIZING-RADIATION; GENE-EXPRESSION; DNA-DAMAGE; TARGET GENES; CHROMATIN IMMUNOPRECIPITATION; MALIGNANT-MELANOMA; GENOTOXIC STRESS; GAMMA-RADIATION AB Exposure to ionizing radiation, as well as other stresses, results in the activation of complex signal transduction pathways, which eventually shape the response of cells and organisms. Some of the important pathways responding to radiation include the ATM/P53 pathway, MAPK cascades and NF-kappaB activation, as well as signaling events initiated at the cell membrane and within the cytoplasm. Alterations in gene expression play roles both as intermediaries in signaling and as downstream effector genes. Differences in cell type, interindividual genetic differences and crosstalk occurring between signaling pathways may help to channel radiation stress signals between cell cycle delay, enhanced DNA repair, and apoptosis. These differences may in turn help determine the likelihood of late effects of radiation exposure, including carcinogenesis and fibrosis. The tools of the postgenomic era enable high-throughput studies of the multiple changes resulting from the interplay of radiation signaling pathways. Gene expression profiling, in particular shows great promise, both in terms of insight into basic molecular mechanisms and for the future hope of biomarker development and individual tailoring of cancer therapy. C1 NCI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, NIH, 37 Convent Dr,Bldg 37,Room 6144, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 52 TC 71 Z9 73 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 1 PY 2003 VL 22 IS 37 BP 5828 EP 5833 DI 10.1038/sj.onc.1206681 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 717JV UT WOS:000185086100009 PM 12947389 ER PT J AU Wan, XS Zhou, ZZ Steele, V Kopelovich, L Kennedy, AR AF Wan, XS Zhou, ZZ Steele, V Kopelovich, L Kennedy, AR TI Establishment and characterization of sublines of LNCaP human prostate cancer cells SO ONCOLOGY REPORTS LA English DT Article DE LNCaP cells; cloning; prostate cancer ID NUDE-MICE; MULTISTAGE CARCINOGENESIS; ANDROGEN DEPRIVATION; GENE-EXPRESSION; CARCINOMA; ANTIGEN; MODEL; GROWTH; LINE; TUMORIGENICITY AB The present study was undertaken to develop a panel of human prostate cancer. cell sublines that represent a phenotypic continuum of prostate carcinogenesis. We cloned and established more than two dozen LNCaP sublines from parental LNCaP cells by the limiting dilution method, akin to a fluctuation analysis, in vitro. The newly established LNCaP sublines differ in hormone-sensitivity, anchorage-independent growth ability and rate of PSA production. These LNCaP sublines may represent the naturally occurring heterogeneity in human prostate cancer and, therefore, could be useful for studying the effects of anticarcinogenic agents on cell clones that are derived from the same parental cell population. C1 Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19083 USA. NCI, DCP, CADRG, Bethesda, MD 20892 USA. RP Kennedy, AR (reprint author), Univ Penn, 195 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. FU NCI NIH HHS [N01-CN-95105] NR 43 TC 7 Z9 7 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD SEP-OCT PY 2003 VL 10 IS 5 BP 1569 EP 1575 PG 7 WC Oncology SC Oncology GA 706QA UT WOS:000184463500084 PM 12883743 ER PT J AU Wilkinson, CP Ferris, FL Klein, RE Lee, PP Agardh, CD Davis, M Dills, D Kampik, A Pararajasegaram, R Verdaguer, JT AF Wilkinson, CP Ferris, FL Klein, RE Lee, PP Agardh, CD Davis, M Dills, D Kampik, A Pararajasegaram, R Verdaguer, JT CA Gobal Diabetic Retinopathy Project TI Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY OCT 22, 2002 CL ORLANDO, FLORIDA SP Amer Acad Ophthalmol ID 4-YEAR INCIDENCE; PROGRESSION; DIAGNOSIS; AGE AB Purpose: To develop consensus regarding clinical disease severity classification systems for diabetic retinopathy and diabetic macular edema that can be used around the world, and to improve communication and coordination of care among physicians who care for patients with diabetes. Design: Report regarding the development of clinical diabetic retinopathy disease severity scales. Participants: A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialties, endocrinology, and epidemiology. Methods: An initial clinical classification system, based on the Early Treatment Diabetic Retinopathy Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy publications, was circulated to the group in advance of a workshop. Each member reviewed this using e-mail, and a modified Delphi system was used to stratify responses. At a later workshop, separate systems for diabetic retinopathy and macular edema were developed. These were then reevaluated by group members, and the modified Delphi system was again used to measure degrees' of agreement. Main Outcome Measures: Consensus regarding specific classification systems was achieved. Results: A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent. If training and equipment allow the screener to make a valid decision, macular edema is further categorized as a function of its distance from the central macula. Conclusions: There seems to be a genuine need for consistent international clinical classification systems for diabetic retinopathy and diabetic macular edema that are supported with solid evidence. The proposed clinical classification systems provide a means of appropriately categorizing diabetic retinopathy and macular edema. It is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients. (C) 2003 by the American Academy of Ophthalmology. C1 Greater Baltimore Med Ctr, Baltimore, MD 21204 USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Madison, WI USA. Duke Univ, Durham, NC USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Univ Munich, Munich, Germany. World Hlth Org, Geneva, Switzerland. Univ Chile, Santiago, Chile. RP Wilkinson, CP (reprint author), Amer Acad Ophthalmol, 655 Beach St,POB 7424, San Francisco, CA 94120 USA. OI Klein, Ronald/0000-0002-4428-6237; Lee, Paul/0000-0002-3338-136X NR 11 TC 686 Z9 793 U1 6 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2003 VL 110 IS 9 BP 1677 EP 1682 DI 10.1016/S0161-6420(03)00475-5 PG 6 WC Ophthalmology SC Ophthalmology GA 715BG UT WOS:000184950200002 PM 13129861 ER PT J AU Chew, EY Ferris, FL Csaky, KG Murphy, RP Agron, E Thompson, DJS Reed, GF Schachat, AP AF Chew, EY Ferris, FL Csaky, KG Murphy, RP Agron, E Thompson, DJS Reed, GF Schachat, AP TI The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy - The early treatment diabetic retinopathy follow-up study SO OPHTHALMOLOGY LA English DT Article ID PROGNOSIS AB Objectives: To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. Design: Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. Methods: Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). Main Outcome Measures: The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. Results: Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. Conclusions: As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high. (C) 2003 by the American Academy of Ophthalmology. C1 NEI, NIH, Div Epidemiol & Clin Res, Bethesda, MD USA. NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD 21205 USA. RP Chew, EY (reprint author), NEI, Div Biometry & Epidemiol, NIH, Bldg 31,Room 6A52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 EY999999] NR 16 TC 62 Z9 67 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2003 VL 110 IS 9 BP 1683 EP 1689 DI 10.1016/S0161-6420(03)00579-7 PG 7 WC Ophthalmology SC Ophthalmology GA 715BG UT WOS:000184950200003 PM 13129862 ER PT J AU Sen, HN Suhler, EB Al-Khatib, SQ Djalilian, AR Nussenblatt, RB Buggage, RR AF Sen, HN Suhler, EB Al-Khatib, SQ Djalilian, AR Nussenblatt, RB Buggage, RR TI Mycophenolate mofetil for the treatment of scleritis SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Meeting of the American-Uveitis-Society CY MAY 04, 2002 CL FT LAUDERDALE, FLORIDA SP Amer Uveitis Soc ID ACUTE REJECTION; RENAL-TRANSPLANTATION; THERAPY; PREVENTION; EPISCLERITIS; CYCLOSPORINE; DISEASE AB Purpose: To evaluate the usefulness of mycophenolate mofetil (MMF) (CellCept, Roche, Nutley, NJ), an antimetabolite immunosuppressant with a selective anti proliferative effect on T and B lymphocytes, for the treatment of scleritis. Design: Retrospective, noncomparative case series. Participants: Eight patients with scleritis treated with MMF in a tertiary referral center. Methods: Review of the clinical records of patients evaluated at the National Eye Institute and prescribed MMF for the treatment of scleritis. Main Outcome Measures: Control of scleral inflammation, the ability to taper prednisone or other immunosuppressive medications, and adverse events were recorded for each patient. Mycophenolate mofetil was determined to be an effective steroid-sparing agent if the daily prednisone dosage could be reduced by 50% or more and was determined to be an effective adjunctive immunosuppressive agent if the scleral inflammation was controlled in patients with active scleritis. Results: Four patients with diffuse anterior scleritis, two with necrotizing scleritis with inflammation, one with nodular anterior scleritis, and one with nodular anterior and posterior scleritis, were identified. Mycophenolate mofetil administration was initiated as a steroid-sparing agent in 4 patients with controlled scleritis and as an additional immunosuppressive agent in 4 patients with active scleritis receiving concomitant treatment with prednisone and cyclosporine or methotrexate. In 3 of the 4 patients started on MMF as a steroid-sparing agent, the scleritis remained controlled while the prednisone dosage was tapered by more than 50%. One of the patients started on MMF as a steroid-sparing agent had recurrent scleritis, and each of the patients with active scleritis continued to have persistent scleral inflammation requiring additional immunosuppressive therapy. Adverse effects recorded in 4 of the 8 patients included a rash, gastrointestinal symptoms, paresthesias, and laboratory evidence of hepatotoxicity and renal toxicity. Conclusions: Although MMF maybe be useful as a steroid-sparing agent, it was not effective as an adjunctive immunosuppressive agent in patients with active scleritis in our small, tertiary referral series. The adverse effects encountered with the use of MMF in this study cannot be attributed conclusively to MMF and are more likely complications of the multiagent systemic immunosuppressive therapy required for the treatment of recalcitrant scleritis. (C) 2003 by the American Academy of Ophthalmology. C1 NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Buggage, RR (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 22 TC 27 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2003 VL 110 IS 9 BP 1750 EP 1755 DI 10.1016/S0161-6420(03)00570-0 PG 6 WC Ophthalmology SC Ophthalmology GA 715BG UT WOS:000184950200015 PM 13129873 ER PT J AU Robinson, MR Lee, SS Sneller, MC Lerner, R Langford, CA Talar-Williams, C Cox, TA Chan, CC Smith, JA AF Robinson, MR Lee, SS Sneller, MC Lerner, R Langford, CA Talar-Williams, C Cox, TA Chan, CC Smith, JA TI Tarsal-conjunctival disease associated with Wegener's granulomatosis SO OPHTHALMOLOGY LA English DT Article ID OCULAR MANIFESTATIONS; OBSTRUCTION; MANAGEMENT; BIOPSIES; STENOSIS AB Objective: To describe the clinical characteristics of tarsal-conjunctival disease in a cohort of patients with Wegener's granulomatosis (WG). Design: Retrospective, case-controlled study. Participants: The medical records of 82 consecutive WG patients who underwent an eye examination between January 1996 and June 2002 at the National Institutes of Health were reviewed. Methods: Details of the ophthalmic examination, results of medical therapy, and histopathologic analysis results were recorded. Tarsal- conjunctival disease was defined by (1) conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva, or (2) evidence of inactive fibrovascular scar. The association of tarsal-conjunctival disease with major organ system involvement was assessed using Bayesian methods. Main Outcome Measures: The occurrence and clinical characteristics of tarsal-conjunctival disease in a cohort of patients with WG and associations with major organ system involvement. Results: Tarsal- conjunctival disease occurred in 13 of 82 patients (16%) with WG examined over a 6.5-year period. The palpebral surface of the upper lid was involved most commonly, showing conjunctival hyperemia in seven patients, granulomatous lesions in three patients, tarsal-conjunctival necrosis in four patients, active fibrovascular proliferation in six patients, and inactive fibrous scar tissue in seven patients. Histopathologic analysis of eyelid biopsy specimens showed granulomatous inflammation, focal necrosis, and areas of occlusive vasculitis in the tarsus and conjunctiva. In reviewing the patterns of organ involvement in patients with and without tarsal-conjunctival disease, the association of subglottic stenosis and nasolacrimal duct obstruction with tarsal-conjunctival disease showed a high probability of clinical significance. Conclusions: Tarsal- conjunctival disease, a previously uncommon finding in patients with WG, was characterized by inflammation of the palpebral conjunctiva and tarsus followed by a fibrovascular proliferation and scar formation. Because of the important association of tarsal-conjunctival disease with subglottic stenosis, which can progress and lead to laryngeal obstruction and respiratory failure, patients with tarsal-conjunctival disease should be referred to an otolaryngologist for evaluation. C1 NEI, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10S229,10 Ctr Dr MSC 1863, Bethesda, MD 20892 USA. NR 32 TC 22 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2003 VL 110 IS 9 BP 1770 EP 1780 DI 10.1016/S0161-6420(03)00616-X PG 11 WC Ophthalmology SC Ophthalmology GA 715BG UT WOS:000184950200018 PM 13129876 ER PT J CA Vision Preschoolers VIP Study Grp TI Visual acuity results in school-aged children and adults: Lea symbols chart versus Bailey-Lovie chart SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE visual acuity; interocular acuity difference; Lea Symbols distance acuity chart; Bailey-Lovie distance acuity chart; method comparison AB Purpose. To compare visual acuity results obtained using the Lea Symbols chart with visual acuity results obtained with the Bailey-Lovie chart in school-aged children and adults using a within-subjects comparison of monocular acuity results. Methods. Subjects were 62 individuals between 4.5 and 60 years of age, recruited from patients seen in five optometry clinics. Each subject had acuity of the right eye and the left eye tested with the Lea Symbols chart and the Bailey-Lovie chart, with order of testing varied across subjects. Outcome measures were monocular logarithm of the minimum angle of resolution (logMAR) visual acuity and inter-eye acuity difference in logMAR units for each test. Results. Correlation between acuity results obtained with the two charts was high. There was no difference in absolute inter-eye acuity difference measured with the two acuity charts. However, on average, Lea Symbols acuity scores were one logMAR line better than Bailey-Lovie acuity scores, and this difference increased with worse visual acuity. Conclusions. The Lea Symbols chart provides a measure of inter-eye difference that is similar to that obtained with the Bailey-Lovie chart. However, the monocular acuity results obtained with the Lea Symbols chart differ from those obtained with the Bailey-Lovie chart, and the difference is dependent on the individual's absolute level of visual acuity. C1 Northeastern State Univ, Tahlequah, OK USA. Univ Arizona, Dept Anthropol, Tucson, AZ 85721 USA. Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. New England Coll Optometry, Boston, MA USA. Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. Childrens Hosp Philadelphia, Div Pediat Ophthalmol, Philadelphia, PA 19104 USA. NEI, Bethesda, MD 20892 USA. Univ Maryland, Univ Coll, Adelphi, MD USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. NR 10 TC 0 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD SEP PY 2003 VL 80 IS 9 BP 650 EP 654 PG 5 WC Ophthalmology SC Ophthalmology GA 723NR UT WOS:000185438900006 ER PT J AU Akintoye, SO Lee, JS Feimster, T Booher, S Brahim, J Kingman, A Riminucci, M Robey, PG Collins, MT AF Akintoye, SO Lee, JS Feimster, T Booher, S Brahim, J Kingman, A Riminucci, M Robey, PG Collins, MT TI Dental characteristics of fibrous dysplasia and McCune-Albright syndrome SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article; Proceedings Paper CT Meeting of the International-Association-for-Dental-Research/American-Association-for-D ental-Research CY MAR 06-09, 2002 CL SAN DIEGO, CALIFORNIA SP Int Assoc Dent Res, Amer Assoc Dent Res ID STIMULATORY G-PROTEIN; ACTIVATING MUTATIONS; CLINICAL IMPLICATIONS; GENETIC-DEFECTS; MOLECULAR-BASIS; UNITED-STATES; BONE; TAURODONTISM; ABNORMALITIES; DENTITION AB Objective. Fibrous dysplasia (FD) is a skeletal disorder often associated with McCune-Albright syndrome, a rare multisystem disorder caused by GNAS1 gene mutation. FD frequently affects the craniofacial bones, including the maxilla and the mandible; nevertheless, its effects on dental tissues and the implications for dental care remain unclear. The aim of this study was to characterize the dental features associated with FD and the reaction of affected bones to routine dental therapy. Study design. Thirty-two patients with FD underwent dental evaluation and endocrine testing as part of the diagnosis of FD/McCune-Albright syndrome. Any dental anomalies were recorded, and the associations between endocrinopathies and dental anomalies were analyzed statistically by means of the paired t test. Results. Eighty-four percent had FD in the maxilla and/or mandible; endocrine dysfunction; and/or renal phosphate wasting. The caries index scores were 2.9 (ages 4-17 years) and 9.6 (ages 18-50 years). Malocclusion (81%) and other prevalent dental anomalies (41%) included tooth rotation, oligodontia, and taurodontism. The expansion of the maxilla or mandible by FD did not distort the dental arch curvature, and routine dental therapies such as extractions, restorations, and orthodontic treatment did not exacerbate FD lesions. Conclusion. Maxillomandibular FD was associated with higher rates of caries and malocclusion than were present in healthy patients. Furthermore, patients with FD did not require special dental management and were able to undergo routine dental care without an exacerbation of FD lesions. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIDCR, Div Populat & Hlth Promot Sci Biostat Core, NIH, Bethesda, MD USA. Univ Aquila, Dipartimento Med Sperimentale, Rome, Italy. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 32 TC 31 Z9 33 U1 1 U2 8 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD SEP PY 2003 VL 96 IS 3 BP 275 EP 282 DI 10.1016/S1079-2104(03)00225-7 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 722LY UT WOS:000185377300008 PM 12973283 ER PT J AU Radfar, L Shea, Y Fischer, SH Sankar, V Leakan, RA Baum, BJ Pillemer, SR AF Radfar, L Shea, Y Fischer, SH Sankar, V Leakan, RA Baum, BJ Pillemer, SR TI Fungal load and candidiasis in Sjogren's syndrome SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID ORAL CANDIDIASIS; PREVALENCE; MANIFESTATIONS; ALBICANS; SALIVARY AB Objective. We sought to investigate the prevalence of Candida carriage and the relationships between salivary flow rates and oral Candida load in patients with Sjogren's syndrome (SS). Methods. The oral Candida load of patients with SS was evaluated by culturing oral rinse (swish and spit) samples. Culture, Gram stain, and wet-mount test results were reported. Results. One hundred three patients (96 women) met European criteria for SS (91 with primary SS and 12 with secondary SS). The mean age (95% confidence interval) was 55 years (range, 51-57 years). Oral rinse cultures were positive in 77% of subjects. The total stimulated salivary flow rate was inversely correlated with oral Candida load (r = -0.47; P less than or equal to .0001). The oral rinse samples yielded gram-positive results in 38% of patients with SS, and the Fungi-Fluor assay (wet mount) results were positive in 49%. Conclusions. The prevalence of Candida carriage varies according to the methods used to determine the presence of the organism and is similar to that reported in the literature. A low stimulated salivary flow rate-not a low unstimulated flow rate-was associated with Candida carriage. C1 NIDCR, GTTB, NIH, Bethesda, MD USA. NIH, Warren Grant Magnuson Clin Ctr, DLM, Bethesda, MD 20892 USA. NIH, CC, DLM, Bethesda, MD 20892 USA. NIDCR, Sjogrens Syndrome Clin, GTTB, NIH, Bethesda, MD 20892 USA. RP Radfar, L (reprint author), SUNY Buffalo, Sch Dent Med, 355 Squire Hall,3435 Main St, Buffalo, NY 14214 USA. NR 32 TC 27 Z9 29 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD SEP PY 2003 VL 96 IS 3 BP 283 EP 287 DI 10.1016/S1079-2104(03)00224-5 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 722LY UT WOS:000185377300009 PM 12973284 ER PT J AU Begley, DA Mohiddin, SA Tripodi, D Winkler, JB Fananapazir, L AF Begley, DA Mohiddin, SA Tripodi, D Winkler, JB Fananapazir, L TI Efficacy of implantable cardioverter defibrillator therapy for primary and secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Review DE cardiomyopathy; genetics; sudden death; prognosis ID LEFT-VENTRICULAR HYPERTROPHY; BLOOD-PRESSURE RESPONSE; ALPHA-TROPOMYOSIN; YOUNG-PATIENTS; PROGNOSIS; ARREST; MUTATIONS; CHILDREN; RISK; ELECTROPHYSIOLOGY AB Risk stratification and effectiveness of implantable cardioverter-defibrillator (ICD) therapy are unresolved issues in hypertrophic cardiomyopathy (HCM), a cardiac disease that is associated with arrhythmias and sudden death. We assessed ICD therapy in 132 patients with HCM: age at implantation was 34 +/- 17 years, and 44 (33%) patients were aged less than or equal to 20 years. Indications were sustained ventricular tachycardia (VT) or cardiac arrest (secondary prevention) in 47 (36%) patients, and clinical features associated with increased risk for sudden death (primary prevention) in 85 (64%) patients. There were 6 deaths and 55 appropriate interventions in 27 (20%) patients during a mean follow-up period of 4.8 +/- 4.2 years: 5-year survival and event-free rates were 96% +/- 2% and 75% +/- 5%, respectively. ICD intervention-free rates were significantly less for secondary than for primary prevention: 64% +/- 7% versus 84% +/- 6% at 5 years, P = 0.02. Notably, 59 of 67 events (cardiac arrest and therapeutic ICD interventions), or 88%, occurred during sedentary or noncompetitive activity. Incidence of therapeutic shocks was related to age but not to other reported risk factors, including severity of cardiac hypertrophy, nonsustained VT during Holter monitoring, and abnormal blood pressure response to exercise. ICD related complications occurred in 38 (29%) patients, including 60 inappropriate ICD interventions in 30 (23%) patients. However, 8 (27%) of the patients with inappropriate shocks also had therapeutic interventions. ICD is effective for secondary prevention of sudden death in HCM. However, selection of patients for primary prevention of sudden death, and prevention of device related complications require further refinement. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Fananapazir, L (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,Room 7B-15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. NR 49 TC 66 Z9 68 U1 2 U2 3 PU BLACKWELL FUTURA PUBLISHING, INC PI MALDEN PA 350 MAIN STREET, MALDEN, MA 01248-5018 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD SEP PY 2003 VL 26 IS 9 BP 1887 EP 1896 DI 10.1046/j.1460-9592.2003.00285.x PG 10 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 722ZT UT WOS:000185408500015 PM 12930505 ER PT J AU Siegel, RM Kiely, M Bien, JP Joseph, EC Davis, JB Mendel, SG Pestian, JP DeWitt, TG AF Siegel, RM Kiely, M Bien, JP Joseph, EC Davis, JB Mendel, SG Pestian, JP DeWitt, TG TI Treatment of otitis media with observation and a safety-net antibiotic prescription SO PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY MAY 04-07, 2002 CL BALTIMORE, MARYLAND SP Pediat Acad Soc DE acute otitis media; safety-net antibiotic prescription; practice-based research network; observation ID RESISTANT STREPTOCOCCUS-PNEUMONIAE; ACUTE MASTOIDITIS; PRESCRIBING PATTERNS; ANTIMICROBIAL USE; CHILDREN; MANAGEMENT; METAANALYSIS; DIAGNOSIS; TRIAL AB Objective. Several studies have demonstrated that acute otitis media (AOM) in children can be managed without antibiotics. Because children with AOM have traditionally been treated with antibiotics in the United States, there are concerns that parents may not be comfortable with their children being treated with pain control alone. Recently, Cates in England showed that antibiotic usage for AOM could be decreased by prescribing a safety-net antibiotic prescription ( SNAP) to be filled if symptoms do not resolve with observation after 48 hours. It is not clear whether a SNAP will be acceptable to parents in other settings such as the United States. The objective of our study was to determine whether parents in the United States find a SNAP for AOM acceptable and whether antibiotic usage could be decreased by its use. Methods. A pediatric practice-based research network in a midwestern community of 1.8 million was the setting for this study. The Cincinnati Pediatric Research Group ( CPRG) includes practices in Ohio, Kentucky, and Indiana. Children who were between 1 and 12 years of age and presented to the offices of the CPRG with uncomplicated AOM were eligible for the study. Children were excluded when they had temperature > 101.5degreesF, had an ear infection in the past 3 months, showed signs of another bacterial infection, or were toxic appearing. Families were given acetaminophen, ibuprofen, or topical otic anesthetic drops for pain control. They were also given a prescription for an antibiotic and instructed not to fill it unless symptoms either increased or did not resolve after 48 hours. The data were entered directly by investigators via an Internet site. Results. A total of 194 children were enrolled in 11 offices over 12 months; 175 ( 90%) completed the follow-up interview. The average child's age was 5.0 years. Only 55 (31%) of the 175 who were contacted for follow-up had filled their antibiotic prescription. Compared with their previous experience, parents were overwhelmingly willing to treat AOM with pain medication alone (chi(2) = 111). Seventy-eight percent (95% confidence interval: 71% - 84%) of parents reported that the pain medication was effective. Sixty-three percent ( 95% confidence interval: 55% - 70%) of parents reported that they would be willing to treat future AOM episodes without antibiotics and with pain medication alone. Conclusions. A subset of parents find a safety-net prescription and pain control acceptable in the treatment of AOM, and antibiotic usage can be lowered with this strategy. C1 Childrens Hosp, Med Ctr, Cincinnati Pediat Res Grp, Div Gen & Community Pediat, Cincinnati, OH 45229 USA. NICHHD, Div Epidemiol Stat & Prevent Res, US Dept HHS, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Med Ctr, Div Informat Serv, Cincinnati, OH 45229 USA. RP Siegel, RM (reprint author), Childrens Hosp, Med Ctr, Cincinnati Pediat Res Grp, Div Gen & Community Pediat, Cincinnati, OH 45229 USA. NR 26 TC 73 Z9 75 U1 0 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 SEP PY 2003 VL 112 IS 3 BP 527 EP 531 DI 10.1542/peds.112.3.527 PG 5 WC Pediatrics SC Pediatrics GA 716NL UT WOS:000185035100022 PM 12949278 ER PT J AU Benjamin, DK DeLong, ER Steinbach, WJ Cotton, CM Walsh, TJ Clark, RH AF Benjamin, DK DeLong, ER Steinbach, WJ Cotton, CM Walsh, TJ Clark, RH TI Empirical therapy for neonatal candidemia in very low birth weight infants SO PEDIATRICS LA English DT Article DE invasive candidiasis; prophylaxis; positive predictive value ID INTENSIVE-CARE UNIT; SYSTEMIC CANDIDIASIS; RISK-FACTORS; INVASIVE CANDIDIASIS; BLOOD CULTURES; INFECTION; EPIDEMIOLOGY; COLONIZATION; FLUCONAZOLE; PROPHYLAXIS AB Objective. Neonatal candidemia is often fatal. Empirical antifungal therapy is associated with improved survival in neonates and patients with fever and neutropenia. Although guidelines for empirical therapy exist for patients with fever and neutropenia, these do not exist for neonates. Methods. A multicenter, retrospective, cohort study was conducted of neonatal intensive care unit patients (N=6172) who had a blood culture (N=21233) after day of life 3 and whose birth weight was less than or equal to1250 g. We performed multivariable conditional logistic regression of risk factors for candidemia. From the regression modeling coefficients, we developed a candidemia score. Results. In multivariable modeling, thrombocytopenia (odds ratio [OR]: 3.56; 95% confidence interval [CI]: 2.68-4.74) and cephalosporin or carbapenem use in the 7 days before obtaining the blood culture (OR: 1.77; 95% CI: 1.33-2.29) were risk factors for subsequent candidemia. Children who were 25 to 27 weeks' estimated gestational age (OR: 2.02; 95% CI: 1.52-3.05) and children who were born at <25 weeks (OR: 4.15; 95% CI: 3.12-6.29) were at higher risk of developing candidemia than were children who were born at &GE;28 weeks. We developed a candidemia score on the basis of the ORs from the multivariable model. Children with a candidemia score &GE;2 points were classified as having a "positive" score, and a score of &GE;2 points had a sensitivity of 85% and a specificity of 47%. Conclusions. We developed a clinical predictive model for neonatal candidemia with high sensitivity and moderate specificity for candidemia. On the basis of our model, when a physician obtains a blood culture, the physician should consider providing antifungal therapy to neonates who are <25 weeks' estimated gestational age and to neonates who have thrombocytopenia at the time of blood culture. In addition, if a physician obtains a blood culture from a child who is 25 to 27 weeks' estimated gestational age and is not thrombocytopenic but has a history of third-generation cephalosporin or carbapenem exposure in the 7 days before the blood culture, then the physician should consider administration of empirical antifungal therapy. C1 Duke Univ, Clin Res Inst, Durham, NC 27715 USA. Duke Univ, Dept Pediat, Durham, NC 27706 USA. Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27706 USA. Duke Univ, Mycol Res Unit, Durham, NC USA. NCI, Bethesda, MD 20892 USA. Pediatrix Med Grp Inc, Jacksonville, FL USA. RP Benjamin, DK (reprint author), Duke Univ, Clin Res Inst, Box 17969, Durham, NC 27715 USA. FU NICHD NIH HHS [R03HD42940-01] NR 25 TC 86 Z9 96 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 J9 PEDIATRICS JI Pediatrics PD SEP PY 2003 VL 112 IS 3 BP 543 EP 547 DI 10.1542/peds.112.3.543 PG 5 WC Pediatrics SC Pediatrics GA 716NL UT WOS:000185035100025 PM 12949281 ER PT J AU Benjamin, DK Poole, C Steinbach, WJ Rowen, JL Walsh, TJ AF Benjamin, DK Poole, C Steinbach, WJ Rowen, JL Walsh, TJ TI Neonatal candidemia and end-organ damage: A critical appraisal of the literature using meta-analytic techniques SO PEDIATRICS LA English DT Review DE invasive candidiasis; deep tissue ID BIRTH-WEIGHT INFANTS; INTENSIVE-CARE UNIT; LATE-ONSET SEPSIS; SYSTEMIC CANDIDIASIS; AMPHOTERICIN-B; RISK-FACTORS; FUNGAL COLONIZATION; RESEARCH NETWORK; INFECTION; ASSOCIATION AB Objective. Neonatal candidemia is an increasing cause of infant morbidity and mortality. We evaluated the current medical literature in an effort to critique the literature and to document the reported prevalences of end-organ damage after neonatal candidemia. Methods. We analyzed all peer-reviewed articles of neonatal candidemia published in the English language; inclusion criteria included a cohort limited to all neonatal intensive care unit admissions or all episodes of candidemia in neonates. Articles that also incorporated older patients, did not define a numerator and a denominator for at least 1 form of end-organ damage, included patients from other reports, or did not include all episodes of candidemia in the source population were excluded from the analysis. Results. Thirty-four articles reported episodes of candidemia and mortality; 21 articles reported prevalence for at least 1 form of end-organ damage. Only 4 (19%) of 21 articles reported prevalence for >4 forms of end-organ damage from the following list: endophthalmitis, meningitis, brain parenchyma invasion, endocarditis, renal abscesses, positive cultures from other normally sterile body fluids, or hepatosplenic abscesses. The median reported prevalence of endophthalmitis was 3% (interquartile range [IQR]: 0%-17%), of meningitis was 15% (IQR: 3%-23%), of brain abscess or ventriculitis was 4% (IQR: 3%-21%), of endocarditis was 5% (IQR: 0%-13%), of positive renal ultrasound was 5% (IQR: 0%-14%), and of positive urine culture was 61% (IQR: 40%-76%). The medical literature concerning end-organ evaluation after episodes of neonatal candidemia is heterogeneous and consists largely of single-center retrospective studies. Year that the data were collected and prevalence of neonates infected with Candida albicans were associated with observed heterogeneity. Conclusions. Given the heterogeneity of the medical literature, precise estimates of the frequencies of end-organ damage are not possible and a prospective multi-center trial is warranted, but the data from the published literature suggest that the prevalence of neonates with end-organ damage not only is greater than 0 but also is high enough that until such a prospective trial is completed, end-organ studies should be considered before the conclusion of antifungal therapy. C1 Duke Univ, Clin Res Inst, Durham, NC 27715 USA. Duke Univ, Dept Pediat, Durham, NC 27706 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Duke Univ, Mycol Res Unit, Durham, NC USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Benjamin, DK (reprint author), Duke Univ, Clin Res Inst, Box 17969, Durham, NC 27715 USA. FU NICHD NIH HHS [R03HD42940-01] NR 51 TC 111 Z9 120 U1 0 U2 3 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 SEP PY 2003 VL 112 IS 3 BP 634 EP 640 DI 10.1542/peds.112.3.634 PG 7 WC Pediatrics SC Pediatrics GA 716NL UT WOS:000185035100039 PM 12949295 ER PT J AU Tamula, MAT Wolters, PL Walsek, C Zeichner, S AF Tamula, MAT Wolters, PL Walsek, C Zeichner, S TI Cognitive decline with immunologic and virologic stability in four children with human immunodeficiency virus disease SO PEDIATRICS LA English DT Article DE HIV; HAART ID CENTRAL-NERVOUS-SYSTEM; SYMPTOMATIC HIV DISEASE; AIDS DEMENTIA COMPLEX; ANTIRETROVIRAL DRUGS; WISC-R; INFECTION; ENCEPHALOPATHY; ZIDOVUDINE; THERAPY; PROGRESSION AB This case series describes 4 children with vertically acquired human immunodeficiency virus (HIV) infection who exhibited immunologic, virologic, and clinical stability while on a protease inhibitor-containing highly active antiretroviral therapy (HAART) regimen, yet demonstrated significant cognitive decline as measured by standardized intelligence tests. A retrospective review of 107 patient records of children with HIV infection on HAART treatment protocols was conducted. Four patients were identified who responded to protease inhibitor-containing HAART therapy with sustained viral load suppression, and stable immunologic and medical parameters, yet demonstrated significant cognitive decline. Such discordance between biological and clinical markers previously has been reported in adults with HIV disease but not in children. This observed decline in neurocognitive functioning despite stable medical parameters suggests that HAART regimens that are effective for systemic disease may not be as effective for the central nervous system (CNS), perhaps because the antiretrovirals do not penetrate adequately into the CNS. Of note, 3 of these 4 patients did not have zidovudine (ZDV) included in their HAART regimen. The only patient who was treated with ZDV containing regimen received 90 mg/m(2) every 6 hours, which is at the lower end of the recommended ZDV pediatric full-dose range (90 mg/m(2) to 120 mg/m(2)). Two of the 4 patients began ZDV at 120 mg/m(2) every 6 hours following the decline in their cognitive test scores and subsequently showed improved or stable functioning as evidenced by the results of follow-up psychometric testing. Long-term prospective studies using both systemic and CNS measures are necessary to further investigate the effects of HAART in children with HIV disease. Longitudinal cognitive assessments of children receiving HAART appear indicated to identify cognitive decline and to provide appropriate therapeutic intervention when manifestations of HIV-related CNS disease progression occur. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Med Illness Counseling Ctr, Chevy Chase, MD 20815 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Tamula, MAT (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Rm 10S255,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-SC-07006] NR 38 TC 22 Z9 25 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 SEP PY 2003 VL 112 IS 3 BP 679 EP 684 DI 10.1542/peds.112.3.679 PG 7 WC Pediatrics SC Pediatrics GA 716NL UT WOS:000185035100047 PM 12949303 ER PT J AU Ashur-Fabian, O Segal-Ruder, Y Skutelsky, E Brenneman, DE Steingart, RA Giladi, E Gozes, I AF Ashur-Fabian, O Segal-Ruder, Y Skutelsky, E Brenneman, DE Steingart, RA Giladi, E Gozes, I TI The neuroprotective peptide NAP inhibits the aggregation of the beta-amyloid peptide SO PEPTIDES LA English DT Article DE A beta aggregation; activity-dependent neuroprotective protein; Alzheimer's disease; brain-cortical cultures; vasoactive intestinal peptide; NAP ID SHEET BREAKER PEPTIDES; FORMATION IN-VITRO; ALZHEIMERS-DISEASE; FIBRIL FORMATION; A-BETA; CULTURED ASTROCYTES; FATTY NEUROPEPTIDE; PRECURSOR PROTEIN; OXIDATIVE STRESS; APOLIPOPROTEIN-E AB Alzheimer's disease (AD) is characterized by brain plaques containing the beta-amyloid peptide (Abeta). One approach for treating AD is by blocking Abeta aggregation. Activity-dependant neuroprotective protein contains a peptide, NAP that protects neurons in culture against Abeta toxicity. Here, NAP was shown to inhibit Abeta aggregation using: (1) fluorimetry; (2) electron microscopy; (3) high-throughput screening of Abeta deposition onto a synthetic template (synthaloid); and (4) Congo Red staining of neurons. Further assays showed biotin-NAP binding to Abeta. These results suggest that part of the neuroprotective mechanism exerted by NAP is through modulation of toxic protein folding in the extracellular milieu. (C) 2003 Elsevier Inc. All rights reserved. C1 Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Dept Pathol, IL-69978 Tel Aviv, Israel. NICHD, LDN, SDMP, NIH, Bethesda, MD 20892 USA. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. EM igozes@post.tau.ac.il NR 56 TC 54 Z9 54 U1 2 U2 4 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 SEP PY 2003 VL 24 IS 9 BP 1413 EP 1423 DI 10.1016/j.peptides.2003.08.005 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 764WC UT WOS:000188228100014 PM 14706557 ER PT J AU Rosenberg, L Rao, RS Palmer, JR AF Rosenberg, L Rao, RS Palmer, JR TI A case-control study of acetaminophen use in relation to the risk of first myocardial infarction in men SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE acetaminophen; aspirin; case-control; men; myocardial infarction ID LDL; PREVENTION; OXIDATION; ISCHEMIA AB Purpose Experimental evidence raises the possibility that acetaminophen use could reduce the risk of myocardial infarction (MI). We assessed the relation of acetaminophen use, and also of aspirin use, to first MI in a case-control study. Methods Data on analgesic use and other factors were collected in a hospital-based case-control study of first MI in men under 55 years of age conducted from 1980 to 1983. We compared 2035 men with first MIs to 2656 control men admitted for conditions unrelated to analgesic use. Odds ratios (ORs) for acetaminophen use relative to nonuse were estimated with logistic regression analysis, controlling for major MI risk factors. Results The OR was 0.9 (95% confidence interval (CI): 0.6-1.3) for acetaminophen use at least once a week for at least 3 months, 0.7 (95%CI: 0.4-1.1) for daily use for at least 3 months, and 0.5 (95%CI: 0.2-1.6) for daily use for at least 5 years. In analyses of aspirin use, the OR was 0.9 (95%CI: 0.7-1.2) for use at least once a week for at least 3 moths, 0.9 (95%CI: 0.6-1.2) for daily use lasting at least 3 months, 0.6 (95%CI: 0.4-1.1) for daily use for at least 5 years, and 0.4 (95%CI: 0.2-1.0) for daily use for at least 10 years. Conclusions While our results raise the possibility of a protective effect of long-term regular acetaminophen use against first MI, they are compatible with no effect. The data suggest a potential protective effect of long-term regular aspirin use. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. NCI, Div Canc Epidemiol, Bethesda, MD USA. RP Rosenberg, L (reprint author), Boston Univ, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. OI Palmer, Julie/0000-0002-6534-335X FU NICHD NIH HHS [N01-HD-0-2810] NR 16 TC 10 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2003 VL 12 IS 6 BP 459 EP 465 DI 10.1002/pds.867 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 718MG UT WOS:000185150100003 PM 14513659 ER PT J AU Abernethy, DR Altman, R Long, RM AF Abernethy, DR Altman, R Long, RM TI PharmGKB and Pharmacological Reviews SO PHARMACOLOGICAL REVIEWS LA English DT Editorial Material C1 NIGMS, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2003 VL 55 IS 3 BP 397 EP 397 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 711HK UT WOS:000184733400001 ER PT J AU Agnati, LF Ferre, S Lluis, C Franco, R Fuxe, K AF Agnati, LF Ferre, S Lluis, C Franco, R Fuxe, K TI Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons SO PHARMACOLOGICAL REVIEWS LA English DT Review ID ADENOSINE A(2A) RECEPTORS; CENTRAL-NERVOUS-SYSTEM; METABOTROPIC GLUTAMATE RECEPTORS; PROTEIN-COUPLED RECEPTORS; NUCLEUS-TRACTUS-SOLITARII; DOPAMINE D-1 RECEPTORS; C-FOS EXPRESSION; COTRANSFECTED FIBROBLAST CELLS; RAT NEOSTRIATAL MEMBRANES; RESONANCE ENERGY-TRANSFER AB The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABA(B) heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as delta/kappa opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR5/dopamine D-2 and adenosine A(1)/dopamine D-1 heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABA(A)/dopamine D-5 receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson's disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Univ Modena, I-41100 Modena, Italy. NIDA, NIA, US Dept HHS, Baltimore, MD USA. Univ Barcelona, Barcelona, Spain. RP Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. EM Kjell.Fuxe@neuro.ki.se RI Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; OI Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Fuxe, Kjell/0000-0001-8491-4288 NR 425 TC 245 Z9 252 U1 2 U2 12 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2003 VL 55 IS 3 BP 509 EP 550 DI 10.1124/pr.55.3.2 PG 42 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 711HK UT WOS:000184733400006 PM 12869660 ER PT J AU Reeves, R Thiruchelvam, M Richfield, EK Cory-Slechta, DA AF Reeves, R Thiruchelvam, M Richfield, EK Cory-Slechta, DA TI Behavioral sensitization and long-term neurochemical alterations associated with the fungicide triadimefon SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE triadimefon; behavioral sensitization; neurotoxicity; pesticides ID VENTRAL TEGMENTAL AREA; DOPAMINE TRANSPORTER BINDING; MEDIAL PREFRONTAL CORTEX; RAT NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; REPEATED COCAINE; RECEPTOR ANTAGONIST; TRIAZOLE FUNGICIDE; D-AMPHETAMINE; REPEATED INJECTIONS AB Triadimefon (TDF), a widely used triazole fungicide, blocks reuptake of the neurotransmitter dopamine (DA), similarly to cocaine. Preliminary studies show that intermittent intraperitoneal injections of TDF increase ambulatory and vertical activity across repeated injections [Neurotoxicology (in press)] leading to the hypothesis tested here, that exposure to TDF may influence the development and expression of behavioral sensitization, a model of psychostimulant-induced psychosis. Exposure of adult male C57BL/6 mice to 75 mg/kg ip TDF (TDF75) twice a week for 7 weeks increased vertical activity at each injection. Following a 2-week withdrawal period, a TDF challenge to test for expression of behavioral sensitization revealed further increases in vertical activity levels relative to all other conditions. TDF induction/expression of behavioral sensitization was associated with long-term, perhaps permanent modulation of dopaminergic function that included increases in striatal dihydroxyphenylacetic acid (DOPAC) and DA turnover, increases in medial prefrontal cortex (mPFC) dopamine transporter (DAT) binding, as well as decreases in DA D1 and increases in DA D2 and DAY receptor binding that appeared to target the nucleus accumbens shell (NAs) subregion. Thus, TDF exposure may serve as an environmental risk factor for DA system dysfunctions. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Rochester, Dept Environm Med, Sch Med & Dent, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, NIEHS, Environm Hlth Sci Ctr, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY 14642 USA. RP Cory-Slechta, DA (reprint author), Univ Rochester, Dept Environm Med, Sch Med & Dent, 575 Elmwood Ave,Box EHSC, Rochester, NY 14642 USA. FU NIEHS NIH HHS [ES01247, T32ES07026, ES10791] NR 55 TC 18 Z9 21 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD SEP PY 2003 VL 76 IS 2 BP 315 EP 326 DI 10.1016/j.pbb.2003.08.003 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 743AL UT WOS:000186550200013 PM 14592684 ER PT J AU Gallinat, J Bajbouj, M Sander, T Xu, K Goldman, D Winterer, G AF Gallinat, J Bajbouj, M Sander, T Xu, K Goldman, D Winterer, G TI Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing SO PHARMACOPSYCHIATRY LA English DT Meeting Abstract CT 23rd Symposium of the Arbeitsgemeinschaft-Neuropsychopharmakologie-und-Pharmakopsychiatrie (AGNP) CY OCT 08-10, 2003 CL MUNICH, GERMANY SP Arbeits Gemeinsch Neuropsychopharmakologie & Pharmakopsychiatr C1 Humboldt Univ, Univ Clin Charite, Clin Psychiat & Psychotherapy, D-1086 Berlin, Germany. Free Univ Berlin, Dept Psychiat, D-1000 Berlin, Germany. Max Delbruck Ctr Mol Med, Gene Mapping Ctr, D-1000 Berlin, Germany. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RI Bajbouj, Malek/B-3579-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2003 VL 36 IS 5 MA 81 BP 226 EP 226 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 737ZT UT WOS:000186262800090 ER PT J AU Teipel, SJ Alexander, GE Schapiro, MB Moller, HJ Rapoport, SI Hampel, H AF Teipel, SJ Alexander, GE Schapiro, MB Moller, HJ Rapoport, SI Hampel, H TI Age-related cortical gray matter reductions in non-demented adults with Down's syndrome determined by magnetic resonance imaging with optimized voxel-based morphometry SO PHARMACOPSYCHIATRY LA English DT Meeting Abstract CT 23rd Symposium of the Arbeitsgemeinschaft-Neuropsychopharmakologie-und-Pharmakopsychiatrie (AGNP) CY OCT 08-10, 2003 CL MUNICH, GERMANY SP Arbeits Gemeinsch Neuropsychopharmakologie & Pharmakopsychiatr C1 Univ Munich, Dept Psychiat, D-8000 Munich, Germany. Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. Childrens Hosp, Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2003 VL 36 IS 5 MA 285 BP 267 EP 267 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 737ZT UT WOS:000186262800294 ER PT J AU Koller, EA Cross, JT Doraiswamy, PM Malozowski, SN AF Koller, EA Cross, JT Doraiswamy, PM Malozowski, SN TI Pancreatitis associated with atypical antipsychotics: From the Food and Drug Administration's MedWatch surveillance system and published reports SO PHARMACOTHERAPY LA English DT Review ID CLOZAPINE; OLANZAPINE; SEVERITY AB Study Objective. To investigate the relative numbers and clinical characteristics of pancreatitis in patients treated with the atypical antipsychotic agents, clozapine, olanzapine, and risperidone, versus the conventional neuroleptic, haloperidol. Design. Pharmacovigilance study of pooled, spontaneously reported adverse events. Setting. Government-affiliated drug evaluation center. Patients. One hundred ninety-two patients who developed pancreatitis during treatment with one or more antipsychotic agents. Intervention. Patients were identified with the Food and Drug Administration's MedWatch surveillance program and a MEDLINE search. Measurements and Main Results. Most cases of pancreatitis occurred within 6 months after the start of therapy with one or more antipsychotic agents. Of the reports of pancreatitis occurring in conjunction with these drugs, 40%, 33%, 16%, and 12% were in patients receiving treatment with clozapine, olanzapine, risperidone, and haloperidol, respectively In 50% of the patients receiving haloperidol, an atypical antipsychotic was listed as a concomitant drug. Valproate was administered concomitantly in 23% of patients. Hyperglycemia and acidosis, although uncommon, developed with all the drugs except haloperidol. Twenty-two patients died. In contrast to patients who developed pancreatitis while receiving an atypical antipsychotic, those who developed the disease while receiving haloperidol were women and tended to be older. Conclusion. The number of reports involving the three atypical antipsychotic agents and the relative paucity of reports involving haloperidol, despite its more extensive patient exposure, suggest that atypical antipsychotics may precipitate pancreatitis. However, the risk may not be the same with all agents; pancreatitis was reported most frequently with clozapine, followed by olanzapine, and then risperidone. The temporal relationship of the onset of pancreatitis with the start of drug therapy further supports a cause-and-effect relationship. C1 Ctr Drug Evaluat & Review Food & Drug Adm, Div Metab & Endocrine Drug Prod, Rockville, MD USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. Natl Inst Diabet & Digest Dis, Clin Trials & Diabet Translat, NIH, Bethesda, MD USA. RP Doraiswamy, PM (reprint author), Duke Univ, Med Ctr, Dept Psychiat, Box 3018, Durham, NC 27710 USA. NR 32 TC 43 Z9 44 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 SEP PY 2003 VL 23 IS 9 BP 1123 EP 1130 DI 10.1592/phco.23.10.1123.32759 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 718KL UT WOS:000185144200006 PM 14524644 ER PT J AU Shrader, JA Siegel, KL AF Shrader, JA Siegel, KL TI Nonoperative management of functional hallux limitus in a patient with rheumatoid arthritis SO PHYSICAL THERAPY LA English DT Article; Proceedings Paper CT Combined Sections Meeting of the American-Physical-Therapy-Association CY FEB 02-06, 2000 CL NEW ORLEANS, LA SP American Phys Therapy Assoc DE case report; foot orthoses; gait disturbance; in-shoe plantar pressure measurement; physical therapy; shoe modifications; windlass mechanism ID METATARSOPHALANGEAL JOINT; WINDLASS MECHANISM; NAVICULAR DROP; RELIABILITY; FOOT; SUBTALAR; HINDFOOT; SHOE; PAIN; GAIT AB Background and Purpose. Functional hallux limitus (FHL) is a condition that affects motion at the first metatarsophalangeal joint and may lead to abnormal forefoot plantar pressures, pain, and difficulty with ambulation. The purpose of this case report is to describe a patient with rheumatoid arthritis (RA) and FHL who was managed with foot orthoses, footwear, shoe modifications, and patient education. Case Description. The patient was a 55-year-old woman diagnosed with seropositive RA 10 years previously. Her chief complaint was bilateral foot pain, particularly under the left great toe. Her foot pain had been present for several years, but during the past 5 months it had intensified and interfered with her work performance, activities of daily living, and social life. Outcomes. Following 4 sessions of physical therapy over a 6-week time period, the patient reported complete relief of forefoot pain despite no change in medication use or RA disease pathophysiology. She was able to continuously walk for up to 4 hours. Left hallux peak plantar pressures were reduced from 43 N/cm(2) to 18 N/cm(2) with the foot orthoses. Discussion. Patients with RA who develop FHL may benefit from physical therapist management using semirigid foot,orthoses, footwear, shoe modifications, and patient education. C1 Warren Grant Magnuson Clin Ctr, Dept Rehabil Med, Phys Therapy Sect, US Dept HHS,NIH, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Rehabil Med, Phys Disabil Branch, US Dept HHS,NIH, Bethesda, MD 20892 USA. RP Shrader, JA (reprint author), Warren Grant Magnuson Clin Ctr, Dept Rehabil Med, Phys Therapy Sect, US Dept HHS,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM joseph_shrader@nih.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 NR 45 TC 19 Z9 19 U1 0 U2 1 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD SEP PY 2003 VL 83 IS 9 BP 831 EP 843 PG 13 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 805XO UT WOS:000220399200005 PM 12940769 ER PT J AU Daniels, DM Stoddart, CW Martin-Iverson, MT Lai, CM Redmond, TM Rakoczy, PE AF Daniels, DM Stoddart, CW Martin-Iverson, MT Lai, CM Redmond, TM Rakoczy, PE TI Entrainment of circadian rhythm to a photoperiod reversal shows retinal dystrophy in RPE65(-/-) mice SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE circadian rhythm; RPE65(-/-); retinal degeneration; entrainment; locomotor activity ID GENE-THERAPY; SUPRACHIASMATIC NUCLEUS; CONGENITAL AMAUROSIS; CHILDHOOD BLINDNESS; MOUSE MODEL; PHOTORECEPTORS; MELATONIN; LIGHT; SYSTEM; CLOCK AB Light entrainment of circadian rhythms is mediated by classical "visual" photoreceptors (rods and cones) as well as "nonvisual" photoreceptive elements (light-detecting cells that do not contribute to classical "vision"). This paper aimed to assess whether light entrainment of locomotor circadian rhythms in mice with impaired rods and cones differs from normal controls and whether this technique, alongside existing techniques, could be used to assess visual function. The study was primarily interested in differences between the entrainment of circadian rhythms of normal-sighted C57BI/6J mouse and the C57B1/RPE65 knockout mouse (RPE65(-/-)), although C3H/HeJ (rd/rd) mice were included as a preexisting model of retinal degeneration. Circadian rhythms of motor activity before and after a 12-h light reversal were assessed in custom-built cages that continuously monitored movement. The controls showed a significantly higher mesor and amplitude when compared to the RPE65(-/-) and rd/rd mice. Despite the loss of rods and cones, the RPE65(-/-) and rd/rd maintained a 24-h circadian rhythm entrained to light similar to controls and were capable of circadian reentrainment to a 12-h light reversal. Importantly, this light reentrainment of the circadian phase occurred at a significantly slower rate in the retinal degenerate models than in the controls. The RPE65(-/-) model demonstrates a retinal degenerate reentrainment phenotype when compared to the rd/rd model. It is suggested that these retinal degenerate mice retain the ability to detect light for the purposes of circadian rhythm entrainment. However, alterations of specific parameters of the circadian rhythm with loss of rods and cones may provide measures of loss of visual function (sight). (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Vis Sci, Nedlands, WA 6009, Australia. Univ Western Australia, Dept Pharmacol, Nedlands, WA 6009, Australia. Univ Western Australia, Dept Psychiat & Behav Sci, Nedlands, WA 6009, Australia. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. RP Daniels, DM (reprint author), Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Vis Sci, 2 Verdun St, Nedlands, WA 6009, Australia. OI Redmond, T. Michael/0000-0002-1813-5291 NR 38 TC 4 Z9 4 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD SEP PY 2003 VL 79 IS 4-5 BP 701 EP 711 DI 10.1016/S0031-9384(03)00202-6 PG 11 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 722JZ UT WOS:000185373100020 PM 12954412 ER PT J AU Mierzejewski, P Koros, E Goldberg, SR Kostowski, W Stefanski, R AF Mierzejewski, P Koros, E Goldberg, SR Kostowski, W Stefanski, R TI Intravenous self-administration of morphine and cocaine: A comparative study SO POLISH JOURNAL OF PHARMACOLOGY LA English DT Article DE morphine; cocaine; setf-administration; reinforcement ID RHESUS-MONKEYS; DOPAMINERGIC SYSTEM; FIXED-RATIO; METHAMPHETAMINE; INJECTION; SCHEDULES; SQUIRREL; ABUSE; DRUGS AB The aim of the present study was to estimate differences between patterns of morphine and cocaine use in Sprague-Dawley rats. This was done by first developing a set of conditions under which both drugs would be consistently self-administered over time. Subsequently rats were studied in groups of three, with only one rat actively self-administering morphine or cocaine while others two receiving yoked injections of either the drug or saline. With the exception of the 0.056, 0.1, 0.3 and 1.0 mg/kg/inj. training-dose regimens, intravenous (iv) self-administration of morphine was acquired at the dose of 0.56 mg/kg/inj. and subsequently maintained by rats. In contrast to morphine self-administration, rats rapidly acquired cocaine self-administration behavior at either the 0.3 or 0.56 injection dose and showed typical inverted U-shaped dose-response curves with maximal responding occurring at the injection dose of 0.3 mg/kg. With the "yoked" pairs of subjects, the rate of responding of the animal actually self-administering the drug was significantly higher than that of a paired animal which passively received injection whenever the first animal self-administered the drug. Thus, both morphine and cocaine served as a positive reinforcer of self-administration behavior under the fixed ratio 5 schedule of reinforcement. However, the 0.56 mg/kg injection dose of morphine resulted in an acquisition curve that was markedly, temporally delayed relative to the injection dose of cocaine. Finally, cocaine maintained higher rates of responding for its delivery than morphine. These differences between self-administration patterns of morphine and cocaine may provide significant information about the nature of drug reinforcement and dependence. C1 Inst Psychiat & Neurol, Dept Pharmacol & Physiol Nervous Syst, PL-02957 Warsaw, Poland. Warsaw Acad Med & Hosp, Dept Expt & Clin Pharmacol, PL-00927 Warsaw, Poland. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Stefanski, R (reprint author), Inst Psychiat & Neurol, Dept Pharmacol & Physiol Nervous Syst, Sobieskiego 9, PL-02957 Warsaw, Poland. NR 26 TC 15 Z9 16 U1 4 U2 8 PU POLISH ACAD SCIENCES INST PHARMACOLOGY PI KRAKOW PA SMETNA 12, 31-343 KRAKOW, POLAND SN 1230-6002 J9 POL J PHARMACOL JI Pol. J. Pharmacol. PD SEP-OCT PY 2003 VL 55 IS 5 BP 713 EP 726 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 755GE UT WOS:000187394500007 PM 14704467 ER PT J AU Bachrach, C McNicoll, G AF Bachrach, C McNicoll, G TI Causal analysis in the population sciences: A symposium - Introduction SO POPULATION AND DEVELOPMENT REVIEW LA English DT Editorial Material C1 NICHHD, Demog & Behav Sci Branch, Bethesda, MD 20892 USA. Populat Council, Policy Res Div, New York, NY USA. RP Bachrach, C (reprint author), NICHHD, Demog & Behav Sci Branch, Bethesda, MD 20892 USA. NR 5 TC 4 Z9 4 U1 0 U2 0 PU POPULATION COUNCIL PI NEW YORK PA ONE DAG HAMMARSKJOLD PLAZA, NEW YORK, NY 10017 USA SN 0098-7921 J9 POPUL DEV REV JI Popul. Dev. Rev. PD SEP PY 2003 VL 29 IS 3 BP 443 EP 447 DI 10.1111/j.1728-4457.2003.00443.x PG 5 WC Demography; Sociology SC Demography; Sociology GA 806OM UT WOS:000220443200005 ER PT J AU Mazza, V Ottolenghi, C Di Monte, I Baldassari, F Rivasi, F Volpe, A Forabosco, A AF Mazza, V Ottolenghi, C Di Monte, I Baldassari, F Rivasi, F Volpe, A Forabosco, A TI Early prenatal diagnosis of recurrent 46,XY partial gonadal dysgenesis SO PRENATAL DIAGNOSIS LA English DT Article DE XY partial gonadal dysgenesis; recurrence; fetal gender; prenatal diagnosis; sonography ID TESTICULAR REGRESSION SYNDROME; GERM-CELL TUMORS; SEX-REVERSAL; FETAL GENDER; GENE; DIFFERENTIATION; ULTRASOUND; FEMALES; 9P; PSEUDOHERMAPHRODITISM AB Objectives We present a case of early prenatal diagnosis of recurrent 46,XY partial gonadal dysgenesis, by combining early genetic and sonographic evaluations. Methods The conceptus of a mother with a first child affected by 46,XY gonadal dysgenesis was sonographically evaluated at 21- and 23-mm BPD (12(+2) and 12(+6) LMP-based age) and the female genitalia were observed. Karyotype analyses was performed on amniotic fluid and it revealed a 46,XY complement without mosaicism. SRY was amplified by PCR for molecular analyses. Results We observed a discordance between female phenotype detected at 21 and 23 mm of biparietal diameter (12(+2) and 12(+6) LMP-based age) and male karyotype. In the child and the fetus, seminiferous cords were not recognisable, whereas rare Leydig cells and no germ cells could be identified. Internal and external genitalia were sexually ambiguous in the child and feminized in the fetus. Conclusion This is the first case of early prenatal diagnosis of recurrent 46,XY partial gonadal dysgenesis and it points to the importance of combining early analyses of genetic sex with sonography in the management of anomalies of sexual development, with particular regard to syndromes for which the risk of recurrence is little understood. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Univ Modena, Dept Mother & Child, Obstet & Gynecol Unit, I-41100 Modena, Italy. NIA, NIH, IRP, Genet Lab, Baltimore, MD 21224 USA. Univ Modena, Dept Mother & Child, Med Genet Unit, I-41100 Modena, Italy. Univ Modena, Dept Anat Pathol & Forens Sci, I-41100 Modena, Italy. RP Mazza, V (reprint author), Univ Modena, Dipartimento Sci Ostet Ginecol & Pediat, Sez Ginecol & Ostet, Via Pozzo 71, I-41100 Modena, Italy. NR 39 TC 3 Z9 4 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD SEP PY 2003 VL 23 IS 9 BP 716 EP 721 DI 10.1002/pd.673 PG 6 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 725ZB UT WOS:000185571400004 PM 12975780 ER PT J AU Canto, MT Drury, TF Horowitz, AM AF Canto, MT Drury, TF Horowitz, AM TI Use of skin and oral cancer examinations in the United States, 1998 SO PREVENTIVE MEDICINE LA English DT Article ID KNOWLEDGE; MELANOMA; RISK; PREVENTION AB Background. Findings from previous surveys suggest low utilization of oral cancer examinations, even though this examination is noninvasive. The purpose of this analysis is to compare the use of an oral cancer examination (OCE) and a skin cancer examination (SCE) in the past 12 months within the United States. Both exams are noninvasive and include a visual component. Methods. Weighted data from the Adult Prevention Supplement of the 1998 National Health Interview Survey (NHIS) for adults 40 years of age or older were analyzed using SAS and SUDAAN. A ratio compared the percentage reporting an OCE (%OCE) with the percentage reporting a SCE (%SCE). Results. The percentage having an OCE in the past year (13.8%) was very similar to the percentage having a SCE (13.5%) during that same period. With increasing age group, the %OCE/%SCE ratio varied inversely from 1.60 (C.I. 1.42-1.78) among persons 40-49 years to 0.62 (C.I. 0.55-0.69) among persons 70+ years. The ratio was similar in whites and blacks, males and females, and Hispanics and non-Hispanics. There was a positive gradient in the ratio by education and family income. Conclusions. Overall, less than 15% of the population is receiving either of these examinations, although the American Cancer Society recommends both of them on an annual basis for individuals 40 years of age and older. To increase detection of these cancers at early stages, extensive educational and media campaigns for the public and providers identifying risk factors and the availability of and the need for these examinations are required. (C) 2003 American Health Foundation and Elsevier Inc. All rights reserved. C1 NIDCR, Div Hlth Promot & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Canto, MT (reprint author), NIDCR, Div Hlth Promot & Populat Sci, NIH, 45 Ctr Dr,Bldg 45,Room 4AS43B, Bethesda, MD 20892 USA. NR 17 TC 7 Z9 7 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 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2003 VL 37 IS 3 BP 278 EP 282 DI 10.1016/S0091-7435(03)00124-5 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 711VG UT WOS:000184761300012 PM 12914834 ER PT J AU Jiang, GH Skorvaga, M Van Houten, B States, JC AF Jiang, GH Skorvaga, M Van Houten, B States, JC TI Reduced sulfhydryls maintain specific incision of BPDE-DNA adducts by recombinant thermoresistant Bacillus caldotenax UvrABC endonuclease SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE DNA damage; benzo[a]pyrene-diol-epoxide; DNA repair; UvrABC endonuclease ID NUCLEOTIDE EXCISION-REPAIR; BENZOPYRENE DIOL EPOXIDE; ESCHERICHIA-COLI; CROSS-LINKS; (A)BC EXCINUCLEASE; P53 GENE; NUCLEASE; COMPLEX; DAMAGE; UVRB AB Prokaryotic DNA repair nucleases are useful reagents for detecting DNA lesions. Escherichia coli UvrABC endonuclease can incise DNA containing UV photoproducts and bulky chemical adducts. The limited stability of the E coli UvrABC subunits leads to difficulty in estimating incision efficiency and quantitative adduct detection. To develop a more stable enzyme with greater utility for the detection of DNA adducts, thermoresistant UvrABC endonuclease was cloned from the eubacterium Bacillus caldotenax (Bca) and individual recombinant protein subunits were overexpressed in and purified from E coli. Here, we show that Bea UvrC that had lost activity or specificity could be restored by dialysis against buffer containing 500 mM KCl and 20 mM dithiothreitol. Our data indicate that UvrC solubility depended on high salt concentrations and UvrC nuclease activity and the specificity of incisions depended on the presence of reduced sulfhydryls. Optimal conditions for BCA UvrABC-specific cleavage of plasmid DNAs treated with [H-3](+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) (1-5 lesions/plasmid) were developed. Preincubation of substrates with UvrA and UvrB enhanced incision efficiency on damaged substrates and decreased nonspecific nuclease activity on undamaged substrates. Under optimal conditions for damaged plasmid incision, similar to70% of adducts were incised in I nM plasmid DNA (2 BPDE adducts/5.4 kbp plasmid) with UvrA at 2.5 nM, UvrB at 62.5 nM, and UvrC at 25 nM. These results demonstrate the potential usefulness of the Bea UvrABC for monitoring the distribution of chemical carcinogen-induced lesions in DNA. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP States, JC (reprint author), Univ Louisville, Dept Pharmacol & Toxicol, 570 S Preston St,Suite 221, Louisville, KY 40202 USA. RI States, J./H-4246-2011 FU NIEHS NIH HHS [1R01-ES06460] NR 34 TC 8 Z9 8 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD SEP PY 2003 VL 31 IS 1 BP 88 EP 98 DI 10.1016/S1046-5928(03)00137-2 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 725QM UT WOS:000185553900011 PM 12963345 ER PT J AU Ma, BY Nussinov, R AF Ma, BY Nussinov, R TI Energy landscape and dynamics of the beta-hairpin G peptide and its isomers: Topology and sequences SO PROTEIN SCIENCE LA English DT Article DE protein folding; side-chain interaction; hydrogen bonding; hydrophobic interactions; beta-peptide; beta-hairpin ID PROTEIN SECONDARY STRUCTURE; MOLECULAR-DYNAMICS; EXPLICIT SOLVENT; SHEET PROTEIN; SIDE-CHAIN; SIMULATIONS; FRAGMENT; MODEL; KINETICS; THERMODYNAMICS AB We have investigated free energy landscape [MM/PBSA + normal modes entropy] of permutations in the G peptide (41-56) from the protein G 131 domain by studying six isomers corresponding to moving the hydrophobic cluster along the beta-strands (toward the turn: T1, AGEWTYDDKTFTVTET; T2, GEDTWDYATFrVTKTE; T3, GEDDWTYATFFVTKTE; toward the end: E1, WTYDDAGETKTFTVT; E2, WEYTGDDATKTETFTV; E3, WTYEGDDATKTETFTV). The free energy terms include molecular mechanics energy, Poisson-Boltzmann electrostatic solvation energy, surface area solvation energy, and conformational entropy estimated by using normal mode analysis. From the wild type to T1, then T3, and finally T2, we see a progressively changing energy landscape, toward a less stable beta-hairpin structure. Moving the hydrophobic cluster outside toward the end region causes a greater change in the energy landscape. alpha-Helical instead of a beta-hairpin structure was the most stable form for the E2 isomer. However, no matter how much the sequence changes, for all variants studied, ideal "native" beta-hairpin topologies remain as minima (regardless of whether global or local) in the energy landscape. In general, we find that the energy landscape is dependent on the hydrophobic cluster topology and on the sequence. Our present study indicates that the key is the relative conformational energies of the different conformations. Changes in the sequence strongly modulate the relative stabilities of topologically similar regions in the energy landscape, rather than redefine the topology space. This finding is consistent with a population redistribution in the process of protein folding. The limited variation of topological space, compared with the number of possible sequence changes, may relate to the observation that the number of known protein folds are far less than the sequential allowance. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, FCRF, 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 [N01CO12400]; PHS HHS [N01-C0-12400] NR 55 TC 26 Z9 26 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2003 VL 12 IS 9 BP 1882 EP 1893 DI 10.1110/ps.0306103 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 715MK UT WOS:000184976100008 PM 12930988 ER PT J AU Dimitrova, MN Peterkofsky, A Ginsburg, A AF Dimitrova, MN Peterkofsky, A Ginsburg, A TI Opposing effects of phosphoenolpyruvate and pyruvate with Mg2+ on the conformational stability and dimerization of phosphotransferase enzyme I from Escherichia coli SO PROTEIN SCIENCE LA English DT Article DE enzyme I; E. coli phosphoenolpyruvate : sugar phosphotransferase system; active-site mutant (EI[H189A]); phosphoenolpyruvate; pyruvate; Mg2+; phosphonopyruvate; differential scanning calorimetry; Trp fluorescence; sedimentation equilibrium; dimerization; isothermal titration calorimetry ID DIFFERENTIAL SCANNING CALORIMETRY; DODECAMERIC GLUTAMINE-SYNTHETASE; AMINO-TERMINAL DOMAIN; BACTERIAL PHOSPHOENOLPYRUVATE; SALMONELLA-TYPHIMURIUM; SYSTEM; PHOSPHORYLATION; PROTEIN; TRANSPORT; SITE AB The activity of enzyme I (EI), the first protein in the bacterial PEP:sugar phosphotransferase system, is regulated by a monomer-dimer equilibrium where a Mg2+-dependent autophosphorylation by PEP requires the homodimer. Using inactive EI(HI89A), in which alanine is substituted for the active-site His189, substrate-binding effects can be separated from those of phosphorylation. Whereas 1 mM PEP (with 2 mM Mg2+) strongly promotes dimerization of EI(HI89A) at pH 7.5 and 20degreesC, 5 mM pyruvate (with 2 mM Mg2+) has the opposite effect. A correlation between the coupling of N- and C-terminal domain unfolding, measured by differential scanning calorimetry, and the dimerization constant for EI, determined by sedimentation equilibrium, is observed. That is, when the coupling between N- and C-terminal domain unfolding produced by 0.2 or 1.0 mM PEP and 2 mM Mg2+ is inhibited by 5 mM pyruvate, the dimerization constant for EI(H189A) decreases from > 10(8) to < 5 x 10(5) or 3 x 10(7) M-1, respectively. Incubation of the wild-type, dephospho-enzyme I with the transition-state analog phosphonopyruvate and 2 mM Mg2+ also increases domain coupling and the dimerization constant &SIM;42-fold. With 2 mM Mg2+ at 15-25&DEG;C and pH 7.5, PEP has been found to bind to one site/monomer of EI(HI89A) with K-A' &AP; 106 M-1 (&UDelta;G' = -8.05 &PLUSMN; 0.05 kcal/mole and &UDelta;H = +3.9 kcal/mole at 20&DEG;C); &UDelta;C-p = -0.33 kcal K-1 mole(-1). The binding of PEP to EI(HI89A) is synergistic with that of Mg2+. Thus, physiological concentrations of PEP and Mg2+ increase, whereas pyruvate and Mg2+ decrease the amount of dimeric, active, dephospho-enzyme I. C1 NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ginsburg, A (reprint author), NHLBI, Sect Prot Chem, Biochem Lab, NIH, 50 South Dr,Room 2339, Bethesda, MD 20892 USA. NR 33 TC 11 Z9 11 U1 2 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2003 VL 12 IS 9 BP 2047 EP 2056 DI 10.1110/ps.0352103 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 715MK UT WOS:000184976100022 PM 12931002 ER PT J AU Sluis-Cremer, N Kempner, E Parniak, MA AF Sluis-Cremer, N Kempner, E Parniak, MA TI Structure-activity relationships in HIV-1 reverse transcriptase revealed by radiation target analysis SO PROTEIN SCIENCE LA English DT Article DE HIV-1; reverse transcriptase; radiation inactivation; dimer; monomer ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNASE-H ACTIVITY; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; MOLECULAR-WEIGHT; WILD-TYPE; INACTIVATION; SIZE; POLYMERIZATION; PURIFICATION AB Radiation target analysis is a powerful technique that can be used to determine both the structural and functional sizes of macromolecules. We have used this technique to probe the structure-function relationships of the recombinant forms of HIV-1 reverse transcriptase (RT). For the p66/p51 and p66/p66 dimeric forms of HIV-1 RT, both the structural and functional target sizes corresponded to that of the dimeric protein, indicating that a primary ionization in one subunit of the HIV-1 RT enzyme results in the concomitant polymer scission of both subunits. In contrast to p66/p51 and p66/p66 RT, the individually isolated p51 subunit of HIV-1 RT inactivated as a monomer. However, in the presence of a DNA template/primer substrate, the radiation inactivation analyses of p51 yielded a structural target size corresponding to that of a dimeric protein. This would indicate that the DNA substrate acted as a scaffold or template for p51 RT homodimer formation. In light of this observation, radiation inactivation studies can readily be applied to other DNA polymerase enzymes, such as the murine leukemia virus RT, for which the functional form of the enzyme has yet to be determined. C1 Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Univ Pittsburgh, Dept Med, Div Infect Dis, Scaife Hall S808,3550 Terrace St, Pittsburgh, PA 15261 USA. EM CremerN@msx.dept-med.pitt.edu; ParniakM@msx.dept-med.pitt.edu FU NIGMS NIH HHS [1R01 GM068406-01 A1, R01 GM068406] NR 30 TC 6 Z9 6 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2003 VL 12 IS 9 BP 2081 EP 2086 DI 10.1110/ps.03130503 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 715MK UT WOS:000184976100026 PM 12931006 ER PT J AU Bujnicki, JM Prigge, ST Caridha, D Chiang, PK AF Bujnicki, JM Prigge, ST Caridha, D Chiang, PK TI Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE malaria; protein-ligand interactions; homology modeling; molecular phylogenetics ID ADENOSYLHOMOCYSTEINE HYDROLASE; CRYSTAL-STRUCTURE; RAT-LIVER; SEQUENCE; ADENOSYLMETHIONINE; METHYLATION; GENERATION; GENOME; ENZYME; GENE AB S-adenosylhomocysteine hydrolase (SAHH) is a key regulator of S-adenosylmethionine-dependent methylation reactions and an interesting pharmacologic target. We cloned the SAHH gene from Plasmodium falciparum (PfSAHH), with an amino acid sequence agreeing with that of the PlasmoDB genomic database. Even though the expressed recombinant enzyme, PfSAHH, could use 3-deaza-adenosine (DZA) as an alternative substrate in contrast to the human SAHH, it has a unique inability to substitute 3-deaza-(+/-)aristeromycin (DZAri) for adenosine. Among the analogs of DZA, including neplanocin A, DZAri was the most potent inhibitor of the PfSAHH enzyme activity, with a K-i of about 150nM, whether Ado or DZA was used as a substrate. When the same DZA analogs were tested for their antimalarial activity, they also inhibited the in vitro growth of P. falciparum parasites potently. Homology-modeling analysis revealed that a single substitution (Thr60-Cys59) between the human and malarial PfSAHH, in an otherwise similar SAH-binding pocket, might account for the differential interactions with the nucleoside analogs. This subtle difference in the active site may be exploited in the development of novel drugs that selectively inhibit PfSAHH. We performed a comprehensive phylogenetic analysis of the SAHH superfamily and inferred that SAHH evolved in the common ancestor of Archaea and Eukaryota, and was subsequently horizontally transferred to Bacteria. Additionally, an analysis of the unusual and uncharacterized AHCYL1 family of the SAHH paralogs extant only in animals reveals striking divergence of its SAH-binding pocket and the loss of key conserved residues, thus suggesting an evolution of novel function(s). (C) 2003 Wiley-Liss, Inc. C1 Int Inst Mol & Cell Biol, Bioinformat Lab, PL-02109 Warsaw, Poland. Walter Reed Army Inst Res, Silver Spring, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Baltimore, MD USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Bujnicki, JM (reprint author), Int Inst Mol & Cell Biol, Bioinformat Lab, PL-02109 Warsaw, Poland. NR 27 TC 26 Z9 27 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD SEP 1 PY 2003 VL 52 IS 4 BP 624 EP 632 DI 10.1002/prot.10446 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 715AC UT WOS:000184947400013 PM 12910461 ER PT J AU Herrmann, PC Gillespie, JW Charboneau, L Bichsel, VE Paweletz, CP Calvert, VS Kohn, EC Emmert-Buck, MR Liotta, LA Petricoin, EF AF Herrmann, PC Gillespie, JW Charboneau, L Bichsel, VE Paweletz, CP Calvert, VS Kohn, EC Emmert-Buck, MR Liotta, LA Petricoin, EF TI Mitochondrial proteome: Altered cytochrome c oxidase subunit levels in prostate cancer SO PROTEOMICS LA English DT Article DE cancer; cytochrome c oxidase; mitochondrial proteome; oxidative phosphorylation; prostate ID CELLS; ASSIGNMENT; SEQUENCE; TISSUE; GENES; RESPIRATION; PROGRESSION; EXPRESSION; METABOLISM AB to quantitatively analyze the ratios of mitochondrial encoded cytochrome c oxidase subunits to nuclear encoded cytochrome c oxidase subunits, and to correlate the ratios with malignant progression in human prostate tissue specimens. Cytochrome c oxidase subunits I-III comprise the catalytic core of the enzyme and are all synthesized from mitochondrial DNA. The remaining subunits (IV-VIII) are synthesized from cellular nuclear DNA. A significant (P < 0.001, 30/30 prostate cases) shift in the relative concentrations of nuclear encoded cytochrome c oxidase subunits IV, Vb, and Vic compared to mitochondrial encoded cytochrome c oxidase subunits I and II was noted during the progression of prostate cancer from normal epithelium through premalignant lesions to invasive carcinoma. Significantly, this shift was discovered to begin even in the premalignant stage. Reverse phase protein lysate array-based observations were corroborated with immunohistochemistry, and extended to a few human carcinomas in addition to prostate. This analysis points to a role for nuclear DNA encoded mitochondrial proteins in carcinogenesis; underscoring their potential as targets for therapy while highlighting the need for full characterization of the mitochondrial proteome. C1 NCI, US FDA, Clin Prote Program, Lab Pathol,NIH, Bethesda, MD 20892 USA. NCI, US FDA, Clin Prote Program, Div Therapeut Prod, Bethesda, MD 20892 USA. RP Herrmann, PC (reprint author), NCI, US FDA, Clin Prote Program, Lab Pathol,NIH, 10 Ctr Dr,Bldg 10,Room 2N212, Bethesda, MD 20892 USA. NR 32 TC 95 Z9 107 U1 0 U2 10 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD SEP PY 2003 VL 3 IS 9 BP 1801 EP 1810 DI 10.1002/pmic.200300461 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 722YB UT WOS:000185404700020 PM 12973739 ER PT J AU Blehar, MC AF Blehar, MC TI Public health context of women's mental health research SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL-COMORBIDITY-SURVEY; MAJOR DEPRESSIVE DISORDER; PRIMARY-CARE PATIENTS; PSYCHIATRIC-DISORDERS; SEX-DIFFERENCES; POSTPARTUM DEPRESSION; MATERNAL DEPRESSION; SUBSTANCE USE; COST-EFFECTIVENESS AB This article considers mental illness in women from a public health perspective. Epidemiology and clinical research are viewed from the perspective of their implications for designing interventions and services. This article argues that mental disorders in US women are a major public health problem because of their scope, course, and functional impact. Programs to identify affected women and provide interventions in real-world settings could have a significant impact on the health status of women and their families. It is important to measure the benefits and costs of these strategies along with the costs of illness. Such knowledge is essential to health policy makers and managers in allocating behavioral health care resources. C1 NIMH, DHHS, NIH, Bethesda, MD 20892 USA. RP Blehar, MC (reprint author), NIMH, DHHS, NIH, 6001 Execut Blvd,Suite 8125,MSC9659, Bethesda, MD 20892 USA. NR 86 TC 7 Z9 7 U1 2 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2003 VL 26 IS 3 BP 781 EP + DI 10.1016/S0193-953X(03)00039-X PG 20 WC Psychiatry SC Psychiatry GA 726NP UT WOS:000185606000015 PM 14563109 ER PT J AU Bonne, O Lahat, S Kfir, R Berry, E Katz, M Bachar, E AF Bonne, O Lahat, S Kfir, R Berry, E Katz, M Bachar, E TI Parent-daughter discrepancies in perception of family function in bulimia nervosa SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Article ID EATING-DISORDERS; BONDING INSTRUMENT; ANOREXIA-NERVOSA; WOMEN; CHILDHOOD; ENVIRONMENT; VALIDATION AB EATING disorders have traditionally been associated with disturbed family function. Most empirical data regarding this issue, however, were gathered from eating disorders patients. Attitudes, function, and inter-personal relationships were examined within 16 families with a member suffering from bulimia nervosa (BN) and compared to 16 matched healthy families. Perception of family function was significantly more derogatory in bulimic subjects than in their parents, while in control subjects and parents, perception was largely congruent. Subjects suffering from BN perceived their families as less cohesive, adaptable, and supportive than did healthy subjects. No such difference in perception of family function was observed between parents of respective groups. This preliminary study shows that parent-daughter discrepancy in perception of family function may prove more characteristic of eating disorder families than any particular deficit. Future research should aim to replicate these findings, incorporate them into treatment paradigms, and employ them to monitor treatment outcome. C1 NIMH, Mood & Anxiety Disorders Programs, Bethesda, MD 20892 USA. Hadassah Univ Hosp, Dept Psychiat, Outpatient Clin, IL-91120 Jerusalem, Israel. Sourasky Med Ctr, Tel Aviv, Israel. Hebrew Univ Jerusalem, Hadassah Hosp, Sch Med, Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Hosp, Sch Med, Dept Psychiat, Jerusalem, Israel. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Programs, 15K N Dr,Room 200, Bethesda, MD 20892 USA. NR 38 TC 7 Z9 8 U1 4 U2 8 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD FAL PY 2003 VL 66 IS 3 BP 244 EP 254 DI 10.1521/psyc.66.3.244.25154 PG 11 WC Psychiatry SC Psychiatry GA 735HU UT WOS:000186107900007 PM 14587361 ER PT J AU Robin, RW Greene, RL Albaugh, B Caldwell, A Goldman, D AF Robin, RW Greene, RL Albaugh, B Caldwell, A Goldman, D TI Use of the MMPI-2 in American Indians: I. Comparability of the MMPI-2 between two tribes and with the MMPI-2 normative group SO PSYCHOLOGICAL ASSESSMENT LA English DT Article ID NATIVE-AMERICAN; PSYCHOLOGICAL-ASSESSMENT; PERSONALITY-ASSESSMENT; ALCOHOL DEPENDENCE; PERFORMANCE; POPULATION; DISORDERS; VALIDITY; SCORES; MEN AB The comparability of the. MMPI-2 in American Indians with the MMPI-2 normative group was investigated in a sample of 535 Southwestern and 297 Plains American Indian tribal members with contrasting sociocultural and historical origins. Both American Indian tribal groups had clinically significant higher T scores (>5 T points) on 5 validity and clinical scales, 6 content scales, and 2 supplementary scales than did the MMPI-2 normative group. There were no significant differences between the 2 tribal groups on any of the MMPI-2 clinical, content, or supplementary scales. Matching members of both tribes with persons in the MMPI-2 normative group on the basis of age, gender, and education reduced the magnitude of the differences between the 2 groups on all of these scales, although the differences in T scores still exceeded 5 T points. It appears likely that the MMPI-2 differences of these 2 American Indian groups from the normative group may reflect their adverse historical, social, and economic conditions. C1 Yale Univ, Sch Med, Dept Psychiat, Sitka, AK 99835 USA. Ctr Nat Amer Dev, Weatherford, OK USA. Caldwell Report, Dept Psychiat, Los Angeles, CA USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Robin, RW (reprint author), Yale Univ, Sch Med, Dept Psychiat, POB 617, Sitka, AK 99835 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 52 TC 14 Z9 14 U1 0 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD SEP PY 2003 VL 15 IS 3 BP 351 EP 359 DI 10.1037/1040-3590.15.3.351 PG 9 WC Psychology, Clinical SC Psychology GA 734NF UT WOS:000186061800012 PM 14593835 ER PT J AU Greene, RL Robin, RW Albaugh, B Caldwell, A Goldman, D AF Greene, RL Robin, RW Albaugh, B Caldwell, A Goldman, D TI Use of the MMPI-2 in American Indians: II. Empirical correlates SO PSYCHOLOGICAL ASSESSMENT LA English DT Article ID DIFFERENTIAL MISDIAGNOSIS; DIAGNOSTIC INTERVIEW; AFFECTIVE-DISORDERS; BLACK; VALIDITY; SCALE; SCHIZOPHRENIA; INPATIENTS; SCHEDULE; SAMPLE AB R. W. Robin, R. L. Greene, B. Albaugh, A. Caldwell, and D. Goldman (2003) reported that members of 2 American Indian tribal groups had statistically significant higher T scores on several MMPI-2 clinical, content, and supplementary scales than did the MMPI-2 normative group. The present study investigated the empirical correlates of the MMPI-2 scales in these American Indian tribal members. There were a large number of significant correlates reflecting antisocial symptoms with Scales 4 (Psychopathic Deviate), 9 (Hypomania), Anger, and Antisocial Practices. There were even a larger number of significant correlates reflecting generalized distress and negative affect with Scales 7 (Psychosthenia), 8 (Schizophrenia), Anxiety, Obsessions, Depression, and Welsh Anxiety. The rationally derived MMPI-2 content scales generally had larger correlations with these constructs than the clinical scales. Thus, the differences reported by R. W. Robin et al. (2003), appear to reflect behaviors and symptoms that American Indians participants were experiencing rather than test bias. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Ctr Nat Amer Dev, Weatherford, OK USA. Caldwell Report, Dept Psychiat, Los Angeles, CA USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Greene, RL (reprint author), 2401 New Castle Circle, Plano, TX 75075 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 40 TC 8 Z9 8 U1 0 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD SEP PY 2003 VL 15 IS 3 BP 360 EP 369 DI 10.1037/1040-3590.15.3.360 PG 10 WC Psychology, Clinical SC Psychology GA 734NF UT WOS:000186061800013 PM 14593836 ER PT J AU Schulz, R Belle, SH Czaja, SJ Gitlin, LN Wisniewski, SR Ory, MG AF Schulz, R Belle, SH Czaja, SJ Gitlin, LN Wisniewski, SR Ory, MG CA REACH Investigators TI Introduction to the special section on Resources for enhancing Alzheimer's Caregiver Health (REACH) SO PSYCHOLOGY AND AGING LA English DT Article AB This article provides background information and an overview on Resources for Enhancing Alzheimer's Caregiver Health (REACH) a multisite intervention trial for caregivers of persons with Alzheimer's disease designed to reduce caregiver burden and depression. REACH is the largest randomized controlled clinical trial to date, involving 1,222 caregiver and care recipient dyads recruited from 6 different sites in the United States. The authors describe the design of the study, summarize the interventions implemented at each site, and provide an overview of the 4 articles in this special section. C1 Univ Pittsburgh, Ctr Social & Urban Res, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Miami Univ, Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. Thomas Jefferson Univ, Community Homecare Res Div, Philadelphia, PA 19107 USA. NCI, Behav & Social Sci Program, Bethesda, MD 20892 USA. RP Schulz, R (reprint author), Univ Pittsburgh, Ctr Social & Urban Res, 121 Univ Pl, Pittsburgh, PA 15260 USA. OI Wisniewski, Stephen/0000-0002-3877-9860 FU NIA NIH HHS [U01-AG13255, U01-AG13265, U01-AG13289, U01-AG13297, U01-AG13305, U01-AG13313]; NINR NIH HHS [U01-NR13269] NR 13 TC 41 Z9 42 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2003 VL 18 IS 3 BP 357 EP 360 DI 10.1037/0882-7974.18.3.357 PG 4 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 723EP UT WOS:000185419700001 PM 14518799 ER PT J AU Gitlin, LN Belle, SH Burgio, LD Czaja, SJ Mahoney, D Gallagher-Thompson, D Burns, R Hauck, WW Zhang, S Schulz, R Ory, MG AF Gitlin, LN Belle, SH Burgio, LD Czaja, SJ Mahoney, D Gallagher-Thompson, D Burns, R Hauck, WW Zhang, S Schulz, R Ory, MG CA REACH TI Effect of multicomponent interventions on caregiver burden and depression: The REACH multisite initiative at 6-month follow-up SO PSYCHOLOGY AND AGING LA English DT Article ID FAMILY CAREGIVERS; ALZHEIMERS-DISEASE; DEMENTIA CAREGIVERS; AFRICAN-AMERICAN; PSYCHOSOCIAL INTERVENTIONS; TREATMENT IMPLEMENTATION; CULTURAL-DIFFERENCES; GENDER-DIFFERENCES; SPOUSE-CAREGIVERS; WHITE CAREGIVERS AB Meta-analysis was used to examine pooled parameter estimates of 9 active compared with 6 control conditions of the Resources for Enhancing Alzheimer's Caregiver Health (REACH) project at 6 months on caregiver burden and depressive symptoms. Associations of caregiver characteristics and outcomes were examined. For burden, active interventions were superior to control conditions (p = .022). Also, active interventions were superior to control conditions for women versus men and for caregivers with lower education versus those with higher education. For depressive symptoms, a statistically significant association of group assignment was found for Miami's family therapy and computer technology intervention (p = .034). Also, active interventions were superior to control conditions for Hispanics, nonspouses, and caregivers with lower education. Results suggest interventions should be multicomponent and tailored. C1 Thomas Jefferson Univ, Community & Homecare Res Div, Philadelphia, PA 19107 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Alabama, Appl Gerontol Program, Tuscaloosa, AL USA. Miami Univ, Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Stanford Univ, Sch Med, Vet Affairs Med Ctr, Stanford, CA 94305 USA. Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. Univ Tennessee, Knoxville, TN 37996 USA. Thomas Jefferson Univ, Dept Clin Pharmacol, Philadelphia, PA 19107 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Social & Urban Res, Pittsburgh, PA USA. NIA, Behav & Social Sci Program, Bethesda, MD 20892 USA. RP Gitlin, LN (reprint author), Thomas Jefferson Univ, Community & Homecare Res Div, 130 S 9th St,Suite 513, Philadelphia, PA 19107 USA. OI Mahoney, Diane/0000-0002-6415-475X FU NIA NIH HHS [U01 AG013289, U01-AG13313, U01 AG013305, U01 AG013313, U01-AG13265, U01-AG13289, U01-AG13255, U01 AG013265, U01-AG13297, U01 AG013255, U01-AG13305]; NINR NIH HHS [U01 NR004261-07, U01 NR004261, U01-NR13269] NR 70 TC 154 Z9 155 U1 3 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2003 VL 18 IS 3 BP 361 EP 374 DI 10.1037//0882-7974.18.3.361 PG 14 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 723EP UT WOS:000185419700002 PM 14518800 ER PT J AU Wisniewski, SR Belle, SH Coon, DW Marcus, SM Ory, MG Burgio, LD Burns, R Schulz, R AF Wisniewski, SR Belle, SH Coon, DW Marcus, SM Ory, MG Burgio, LD Burns, R Schulz, R CA REACH TI The resources for enhancing Alzheimer's caregiver health (REACH): Project design and baseline characteristics SO PSYCHOLOGY AND AGING LA English DT Article ID PSYCHOSOCIAL INTERVENTIONS; SOCIAL SUPPORT; OLDER ADULTS; DEMENTIA; PEOPLE; STRESS; PREVALENCE; CARERS AB The Resources for Enhancing Alzheimer's Cargiver Health (REACH) project was designed to test promising interventions for enhancing family caregiving for persons with dementia. The purpose of this article is to describe the research design, interventions, and outcome measures used in REACH and to characterize the sample recruited for the study. Nine interventions and 2 control conditions were implemented at 6 sites; 1,222 dyads were randomly assigned to an intervention or a control condition. The caregiver sample was 18.6% male with an average age of 62.3 years (56% Caucasian, 24% Black, and 19% Hispanic). Caregivers reported high levels of depressive symptoms and moderate burden. Care recipients were older, with a mean age of 79, and were moderately to severely impaired with mean Mini-Mental State Exam scores of 13/30. C1 Univ Pittsburgh, Epidemiol Data Ctr, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NIA, Behav & Social Sci Program, Bethesda, MD 20892 USA. Univ Alabama, Appl Gerontol Program, Tuscaloosa, AL USA. Univ Tennessee, Reg Med Ctr Prevent Med, Knoxville, TN 37996 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Social & Urban Res, Pittsburgh, PA 15260 USA. RP Wisniewski, SR (reprint author), Univ Pittsburgh, Epidemiol Data Ctr, Dept Epidemiol, Pittsburgh, PA 15261 USA. OI Wisniewski, Stephen/0000-0002-3877-9860 FU NIA NIH HHS [AG13255, AG13265, AG13289, AG13297, AG13305, AG13313, U01 AG013265, U01 AG013289, U01 AG013305, U01 AG013313]; NINR NIH HHS [NR13269, U01 NR004261, U01 NR004261-07] NR 38 TC 110 Z9 113 U1 1 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2003 VL 18 IS 3 BP 375 EP 384 DI 10.1037/0882-7974.18.3.375 PG 10 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 723EP UT WOS:000185419700003 PM 14518801 ER PT J AU Belle, SH Czaja, SJ Schulz, R Zhang, S Burgio, LD Gitlin, LN Jones, R Mendelsohn, AB Ory, MG AF Belle, SH Czaja, SJ Schulz, R Zhang, S Burgio, LD Gitlin, LN Jones, R Mendelsohn, AB Ory, MG CA REACH TI Using a new taxonomy to combine the uncombinable: Integrating results across diverse interventions SO PSYCHOLOGY AND AGING LA English DT Article ID CAREGIVERS; DEMENTIA; METAANALYSIS AB Researchers have examined numerous psychosocial and behavioral interventions intended to alleviate distress among family caregivers of persons with dementia. Many of these interventions are complex, combining numerous treatment components. Although some multicomponent interventions have been successful in reducing caregiver distress, the impact of specific elements of these interventions on outcomes is not known. The article presents results of an analytic approach that allows researchers to describe the individual elements of multicomponent interventions and to examine the relationships between those components and outcomes. This approach is successfully applied to interventions being evaluated in the Resources for Enhancing Alzheimer's Caregiver Health (REACH) program. The results indicate that actively targeting caregiver behavior is effective in achieving positive outcomes with respect to care giver depression. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Coral Gables, FL 33124 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Social & Urban Res, Pittsburgh, PA 15260 USA. Univ Alabama, Appl Gerontol Program, Tuscaloosa, AL USA. Thomas Jefferson Univ, Community & Homecare Res Div, Philadelphia, PA 19107 USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. NIA, Behav & Social Sci Program, Bethesda, MD 20892 USA. RP Belle, SH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 504 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Jones, Richard/J-3488-2013 OI Jones, Richard/0000-0002-1049-218X FU NIA NIH HHS [U01 AG013265, U01 AG013289, U01 AG013305, U01 AG013313, U01-AG13255, U01-AG13265, U01-AG13289, U01-AG13297, U01-AG13305, U01-AG13313]; NINR NIH HHS [U01 NR004261-07, U01 NR004261, U01-NR13269] NR 32 TC 32 Z9 32 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2003 VL 18 IS 3 BP 396 EP 405 DI 10.1037/0882-7974.18.3.396 PG 10 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 723EP UT WOS:000185419700005 PM 14518803 ER PT J AU Caplan, LJ Schooler, C AF Caplan, LJ Schooler, C TI The roles of fatalism, self-confidence, and intellectual resources in the disablement process in older adults SO PSYCHOLOGY AND AGING LA English DT Article ID MINI-MENTAL-STATE; PSYCHOLOGICAL ATTRIBUTES; FUNCTIONAL LIMITATIONS; SOCIOECONOMIC-STATUS; ALLOSTATIC LOAD; DISABILITY; HEALTH; AGE; IMPACT; MACARTHUR AB In this study, the authors examined the relations between 3 psychological variables-fatalism, self-confidence, and intellectual resources-and the subsequent development of illness and disability 20 years later in an adult sample. Results indicated that greater fatalism, assessed in 1974, predicted greater difficulty in everyday cognitive tasks as well as illness in 1994. Higher self-confidence in 1974 was associated with lesser degrees of cognitive and fine motor difficulty in 1994. Greater intellectual resources in 1974 (a combination of intellectual flexibility and education) predicted less cognitive and gross motor difficulty as well as lesser degrees of illness in 1994. Some of these relations were stronger for older than for middle-aged individuals. Results are discussed in the context of models of the disablement process. C1 NIMH, Sect Socioenvironm Studies, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Caplan, LJ (reprint author), NIMH, Sect Socioenvironm Studies, US Dept HHS, NIH, 6006 Execut Blvd,Room 321,MSC 7055, Bethesda, MD 20892 USA. FU NIA NIH HHS [Y02 AG-1-0168] NR 57 TC 41 Z9 42 U1 2 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2003 VL 18 IS 3 BP 551 EP 561 DI 10.1037/0882.7974.18.3.551 PG 11 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 723EP UT WOS:000185419700017 PM 14526765 ER PT J AU Tanda, G Goldberg, SR AF Tanda, G Goldberg, SR TI Cannabinoids: reward, dependence, and underlying neurochemical mechanisms - a review of recent preclinical data SO PSYCHOPHARMACOLOGY LA English DT Review DE THC; marijuana; drug self-administration; conditioned place preference; drug discrimination; cannabinoid dependence; in vivo microdialysis; opioid-cannabinoid interactions ID CONDITIONED PLACE PREFERENCE; FREELY-MOVING RATS; RECEPTOR KNOCKOUT MICE; MESOLIMBIC DOPAMINE TRANSMISSION; INCREASE EXTRACELLULAR DOPAMINE; BRAIN-STIMULATION REWARD; MESSENGER-RNA LEVELS; CHRONIC DELTA(9)-TETRAHYDROCANNABINOL TREATMENT; DISCRIMINATIVE STIMULUS PROPERTIES; CORTICOTROPIN-RELEASING-FACTOR AB Background and rationale. Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, Delta(9)-tetrahydrocannabinol (THC).Objectives. The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids. Results and conclusions. Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program,US DHHS, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, Med Discovery Res Branch, NIH,Intramural Res Program,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program,US DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Tanda, Gianluigi/B-3318-2009 OI Tanda, Gianluigi/0000-0001-9526-9878 NR 224 TC 163 Z9 167 U1 7 U2 25 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2003 VL 169 IS 2 BP 115 EP 134 DI 10.1007/s00213-003-1485-z PG 20 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 717MP UT WOS:000185093800001 PM 12827346 ER PT J AU Justinova, Z Tanda, G Redhi, GH Goldberg, SR AF Justinova, Z Tanda, G Redhi, GH Goldberg, SR TI Self-administration of Delta(9)-tetrahydrocannabinol (THC) by drug naive squirrel monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE cannabis; Delta(9); -tetrahydrocannabinol (THC); drug self-administration; squirrel monkeys; marijuana ID RECEPTOR AGONIST WIN-55,212-2; CONDITIONED PLACE PREFERENCE; RHESUS-MONKEYS; CANNABINOID RECEPTOR; FIXED-RATIO; DELTA-9-TETRAHYDROCANNABINOL; BEHAVIOR; COCAINE; INJECTION; SYSTEM AB Rationale. Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of Delta(9)-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC. Objectives. To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys. Methods. Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11-34 sessions. Dose of THC was then varied from 1 to 16 mug/kg per injection with vehicle extinction following each dose of THC. Results. THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 mug/kg per injection, with maximal rates of responding at 4 mug/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration. Conclusions. THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,US DHHS, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, Med Discovery Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,US DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Tanda, Gianluigi/B-3318-2009; Justinova, Zuzana/A-9109-2011 OI Tanda, Gianluigi/0000-0001-9526-9878; Justinova, Zuzana/0000-0001-5793-7484 NR 40 TC 105 Z9 113 U1 1 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2003 VL 169 IS 2 BP 135 EP 140 DI 10.1007/s00213-003-1484-0 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 717MP UT WOS:000185093800002 PM 12827345 ER PT J AU Elliot, EE Sibley, DR Katz, JL AF Elliot, EE Sibley, DR Katz, JL TI Locomotor and discriminative-stimulus effects of cocaine in dopamine D-5 receptor knockout mice SO PSYCHOPHARMACOLOGY LA English DT Article DE dopamine; D-5; knockout; cocaine; SCH 39166; locomotor activity; drug discrimination ID RAT-BRAIN; MUTANT MICE; D1; ANTAGONISTS; MEDIATION; MONKEYS; NUCLEUS; SYSTEM AB Rationale. Dopamine D-1-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D-1 and D-5 receptors, the specific roles of the subtypes have not been determined. Objectives. Dopamine D-5 receptor knockout (DA D5R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D-5 dopamine receptors in the effects of cocaine. In addition, effects of the D-1-like antagonist, SCH 39166 were also studied to further clarify the roles of D-1 and D-5 dopamine receptors in the discriminative-stimulus effects of cocaine. Methods. DA D5R KO, HET and WT mice were treated with cocaine (3-30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0-10 mg/kg) were administered 5 min before 15-min test-sessions. Results. Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D5R WT mice. Both DA D5R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01-0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. Conclusions. The present data suggest an involvement of DA D5R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D5R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D-1 receptor in the behavioral effects of cocaine. C1 NIDA, Psychobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Adelaide, Dept Publ Hlth, Adelaide, SA 5005, Australia. NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, NIH, Bethesda, MD 20892 USA. NR 23 TC 40 Z9 40 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2003 VL 169 IS 2 BP 161 EP 168 DI 10.1007/s00213-003-1494-y PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 717MP UT WOS:000185093800005 PM 12768268 ER PT J AU Fenton, WS Stover, EL Insel, TR AF Fenton, WS Stover, EL Insel, TR TI Breaking the log-jam in treatment development for cognition in schizophrenia: NIMH perspective SO PSYCHOPHARMACOLOGY LA English DT Editorial Material C1 NIMH, NIH, US Dept HHS, Bethesda, MD 20892 USA. NIMH, Div Mental Disorders Behav Res & AIDS, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Fenton, WS (reprint author), NIMH, NIH, US Dept HHS, Room 6216,6001 Execut Blvd,MSC 9621, Bethesda, MD 20892 USA. NR 5 TC 26 Z9 26 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 SEP PY 2003 VL 169 IS 3-4 BP 365 EP 366 DI 10.1007/s00213-003-1564-1 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 732RH UT WOS:000185959000014 PM 12955292 ER PT J AU Siegler, IC Costa, PT Brummett, BH Helms, MJ Barefoot, JC Williams, RD Dahlstrom, WG Kaplan, BH Vitaliano, PP Nichaman, MZ Day, RS Rimer, BK AF Siegler, IC Costa, PT Brummett, BH Helms, MJ Barefoot, JC Williams, RD Dahlstrom, WG Kaplan, BH Vitaliano, PP Nichaman, MZ Day, RS Rimer, BK TI Patterns of change in hostility from college to midlife in the UNC alumni heart study predict high-risk status SO PSYCHOSOMATIC MEDICINE LA English DT Article DE hostility; age; patterns of change; health risk; risk trajectories ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY DISEASE; TOTAL MORTALITY; CARDIOVASCULAR-DISEASE; PSYCHOLOGICAL RISK; METABOLIC SYNDROME; AGE-DIFFERENCES; CHD INCIDENCE; YOUNG-ADULTS; LIFE-SPAN AB Objective: To examine hostility measured in college and patterns of change in hostility from college to midlife as predictors of high health-related risk later in midlife. Methods: Logistic regression models were used to test hostility/risk associations. Results: College hostility predicted being a current smoker, consuming more than two drinks of alcohol, low social support, achieving less than expected in career and in relationships, risk for depression, and appraisal of life changing for the worse in terms of family events at midlife. Change in hostility did not predict smoking and drinking; however, it did significantly predict social isolation, lower income (only for women), obesity, avoidance of exercise, high-fat diet, and negative changes in economic life, work life, and physical health events-all risk indicators measured during the next decade. Appraisals of social support, lowered expectations, risk for depression, and reports of family life changing for the worse were predicted at both time periods. When change in hostility was modeled with college hostility, all risk indicators were significantly predicted by college hostility. Conclusions: High hostility in college and change in hostility from college to midlife predicts a full range of health risk indicators. When compared with the average population decline in hostility, gains in hostility at midlife are related to increased risk while declines in hostility are related to reduced risk. Higher midlife hostility is associated with increased odds of being in the higher risk group. Future research should focus on developing interventions to reduce hostility. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Behav Med Res Ctr, Durham, NC 27710 USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NIA, Gerontol Res Ctr, Intramural Res Program, Lab Personal & Cognit, Baltimore, MD 21224 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Texas, Sch Publ Hlth, Ctr Human Nutr, Houston, TX 77225 USA. Univ N Carolina, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. RP Siegler, IC (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. OI Costa, Paul/0000-0003-4375-1712 FU NCI NIH HHS [P01 CA72099]; NHLBI NIH HHS [P01 HL36578, R01 HL055356, R01 HL54780, R01 HL55356]; NIA NIH HHS [R01 AG12458]; NIMH NIH HHS [R01 MH 57663] NR 68 TC 49 Z9 49 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2003 VL 65 IS 5 BP 738 EP 745 DI 10.1097/01.PSY.0000088583.25140.9C PG 8 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 727QQ UT WOS:000185670300003 PM 14508014 ER PT J AU Heinloth, AN Shackelford, RE Innes, CL Bennett, L Li, LP Amin, RP Sieber, SO Flores, KG Bushel, PR Paules, RS AF Heinloth, AN Shackelford, RE Innes, CL Bennett, L Li, LP Amin, RP Sieber, SO Flores, KG Bushel, PR Paules, RS TI ATM-dependent and -independent gene expression changes in response to oxidative stress, gamma irradiation, and UV irradiation SO RADIATION RESEARCH LA English DT Article ID ATAXIA-TELANGIECTASIA GENE; G(2) CHECKPOINT FUNCTION; DNA MICROARRAY ANALYSIS; S-PHASE CHECKPOINT; KAPPA-B-ALPHA; CANCER; RADIATION; DAMAGE; P53; PHOSPHORYLATION AB Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, immunodeficiencies, telangiectasias, sensitivity to ionizing radiation, and high predisposition for malignancies. The ataxia telangiectasia mutated (ATM) gene encodes a protein (ATM) with serine/threonine kinase activity. DNA-double strand breaks are known to increase its kinase activity. While cells from individuals with AT are attenuated in their G(1)-, S- and G(2)-phase cell cycle checkpoint functions in response to gamma irradiation and oxidative stress, their response to UV irradiation appears to be equivalent to that of wild-type cells. In this study, we investigated changes in gene expression in response to gamma irradiation, oxidative stress, and UV irradiation, focusing on the dependence on ATM. Doses for all three treatments were selected that resulted in roughly an equivalent induction of a G(1) checkpoint response and inhibition of progression through S phase. To investigate gene expression changes, logarithmically growing wild-type and AT dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 muM t-butyl-hydroperoxide), or UV radiation (7.5 J/m(2)), and RNA was harvested 6 h after treatment. Gene expression analysis was performed using the NIEHS Human ToxChip 2.0 with approximately 1900 cDNA clones representing known genes and ESTs. All three treatments resulted in distinct patterns of gene expression changes, as shown previously. ATM-dependent and ATM-independent components were detected within these patterns, as were novel indications of involvement of ATM in regulation of transcription factors such as SP1, AP1 and MTF1. (C) 2003 by Radiation Research Society. C1 NIEHS, Growth Control & Canc Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), NIEHS, Growth Control & Canc Grp, Mail Drop D2-03,111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 46 Z9 46 U1 0 U2 6 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 SEP PY 2003 VL 160 IS 3 BP 273 EP 290 DI 10.1667/RR3047 PG 18 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 716LB UT WOS:000185029000003 PM 12926986 ER PT J AU Choyke, PL AF Choyke, PL TI Imaging of hereditary renal cancer SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; PARENCHYMAL SPARING SURGERY; VONHIPPEL-LINDAU DISEASE; SICKLE-CELL-DISEASE; TUBEROUS SCLEROSIS; MEDULLARY CARCINOMA; LAPAROSCOPIC CRYOABLATION; EPITHELIAL NEOPLASMS; GERMLINE MUTATIONS AB The major hereditary renal cancer syndromes are von Hippel-Lindau disease, hereditary papillary renal cancer, hereditary leiomyoma renal cell carcinoma, Birt-Hogg-Dube syndrome, and tuberous sclerosis. Patients with these syndromes require careful screening with imaging. In addition to hepheron sparing surgery, hereditary renal tumors can be treated with minimally invasive techniques, such as radiofrequency ablation and cryotherapy. C1 Imaging Sci Program, Dept Radiol, NIH, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), Imaging Sci Program, Dept Radiol, NIH, NIH Bldg 10,Rm 1C660, Bethesda, MD 20892 USA. NR 71 TC 18 Z9 18 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 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2003 VL 41 IS 5 BP 1037 EP + DI 10.1016/S0033-8389(03)00068-X PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 723DV UT WOS:000185417900011 PM 14521208 ER PT J AU Summers, RM AF Summers, RM TI Science to practice - Detection of active colonic hemorrhage with use of helical CT: Findings in a swine model SO RADIOLOGY LA English DT Editorial Material C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, 10 Ctr Dr,MSC 1182,Bldg 10,Rm 1C660, Bethesda, MD 20892 USA. NR 2 TC 2 Z9 2 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 SEP PY 2003 VL 228 IS 3 BP 599 EP 600 DI 10.1148/radiol.2283030680 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 715HT UT WOS:000184966400001 PM 12954883 ER PT J AU Susil, RC Krieger, A Derbyshire, JA Tanacs, A Whitcomb, LL Fichtinger, G Atalar, E AF Susil, RC Krieger, A Derbyshire, JA Tanacs, A Whitcomb, LL Fichtinger, G Atalar, E TI System for MR image-guided prostate interventions: Canine study SO RADIOLOGY LA English DT Article DE magnetic resonance (MR), experimental studies; magnetic resonance (MR), guidance; prostate neoplasms; prostate neoplasms, MR; prostate neoplasms, therapeutic radiology ID MAGNETIC-RESONANCE; CANCER; BRACHYTHERAPY; BIOPSY; EXPERIENCE; ANTIGEN; THERAPY; GRADE AB The purpose of this study was to demonstrate the use of a transrectal system that enables precise magnetic resonance (MR) image guidance and monitoring of prostate interventions. The system used a closed-bore 1.5-T MR imaging unit and enables one to take advantage of the higher signal-to-noise ratio achieved with traditional magnet designs, which is crucial for accurate targeting and monitoring of prostate interventions. In the first of the four canine studies, reliable needle placement, with all needles placed within 2 mm of the desired target site, was achieved. In two other studies, MR imaging was used to monitor distribution of injected contrast agent solution (gadopentetate dimeglumine mixed with trypan blue dye) in and around the prostate, thereby confirming that solution had been delivered to the desired tissue and also detecting faulty injections. In the final study, accurate placement and MR imaging of brachytherapy seeds in the prostate were demonstrated. The described system provides a flexible platform for a variety of minimally invasive MR image-guided therapeutic and diagnostic prostate interventions. C1 Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Mech Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Comp Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. Bilkent Univ, Dept Elect Engn, Ankara, Turkey. RP Atalar, E (reprint author), Johns Hopkins Univ, Sch Med, Dept Biomed Engn, 720 Rutland Ave,Taylor Bldg 330, Baltimore, MD 21205 USA. RI Atalar, Ergin/D-3184-2012 OI Atalar, Ergin/0000-0002-6874-6103 FU NHLBI NIH HHS [R01 HL057483, R01 HL57483, R01 HL61672, R01 HL061672]; NIBIB NIH HHS [R01 EB002963, R01 EB002963-05] NR 30 TC 59 Z9 59 U1 0 U2 9 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 SEP PY 2003 VL 228 IS 3 BP 886 EP 894 DI 10.1148/radiol.2283020911 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 715HT UT WOS:000184966400041 PM 12954903 ER PT J AU Monika, GBA Stahl, RL Gerstenberger, SL Tripoli, V Hutz, RJ AF Monika, GBA Stahl, RL Gerstenberger, SL Tripoli, V Hutz, RJ TI Modulation of ovarian follicle maturation in Long-Evans rats exposed to polychlorinated biphenyls (PCBs) in-utero and lactationally SO REPRODUCTIVE TOXICOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 28-31, 2002 CL BALTIMORE, MARYLAND SP Soc Study Reproduct DE apoptosis; aroclor 1016; follicle; ovary; thyroid hormones; PCBs ID FEMALE REPRODUCTIVE-SYSTEM; THYROID-HORMONE LEVELS; MINK MUSTELA-VISON; GRANULOSA-CELLS; AROCLOR 1254; METABOLITES; VITRO; CONGENERS; ESTROGEN; TOXICITY AB Polychlorinated biphenyls (PCBs) are ubiquitous man-made toxicants capable of endocrine disruption. Studies in several species have shown that exposure to PCBs and their hydroxylated metabolites reduces fecundity and decreases circulating concentrations of thyroid hormones, causing serious reproductive and developmental defects. Thyroid hormones modulate both follicular development and steroidogenesis, and affect estrogen metabolism and the regulation of estrogen receptor. This study was designed (1) to determine whether exposure to a commercially prepared PCB mixture (Aroclor 1016) exerts detrimental effects on follicle maturation in the Long-Evans hooded rat; and (2) to determine whether the modulatory effects of Aroclor can be attenuated by levo-thyroxine sodium (T-4) supplementation. Animals were treated on gestation days 7-13 with a single daily intraperitoneal injection (2.5 mg/kg per day) of Aroclor. Half of the Aroclor-treated dams were also given T-4 supplements (2.89 mug/kg per day) via drinking water. Female pups were sacrificed on postnatal days 24/25, and the ovaries were excised, fixed for histology and analyzed. The analysis included a count, measurement and classification of healthy and atretic preantral and antral follicles in the greatest cross-sectional area. The results indicated that treatment with Aroclor significantly reduced the number of preantral follicles <50,000 mum(2) and the total number of antral follicles in the 50-100,000 and >100,000 mum(2) size classes. T-4 circumvented the Aroclor effect on the number of preantral follicles <50,000 mum(2); however, a significant reduction in the antral follicle number persisted in the 50-100,000 and >100,000 mum(2) size classes. In addition, we observed a significant increase in atresia in the Aroclor-treated ovaries in the antral <50,000 mum(2) size class, which was not present in ovaries exposed to both Aroclor and T-4. These data support the hypothesis that Aroclor reduces the number of preantral and antral follicles of certain size classes in rats exposed during the critical period of development, and that supplementation with T-4 can attenuate the effects of Aroclor on small, but not medium or large antral follicles. Atresia of small, antral follicles may constitute one of the underlying mechanisms by which folliculogenesis is modulated by Aroclor 1016. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. Univ Nevada, Dept Environm Studies, Las Vegas, NV 89154 USA. Univ Wisconsin, NIEHS, Biomed Sci Ctr, Milwaukee, WI 53204 USA. RP Hutz, RJ (reprint author), Univ Wisconsin, Dept Biol Sci, 3209 N Maryland Ave, Milwaukee, WI 53211 USA. NR 53 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2003 VL 17 IS 5 BP 567 EP 573 DI 10.1016/S0890-6238(03)00095-9 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 741FK UT WOS:000186447900008 ER PT J AU Zdanov, AS Phan, J Evdokimov, AG Tropea, JE Peters, HK Kapust, RB Li, M Wlodawer, A Waugh, AS AF Zdanov, AS Phan, J Evdokimov, AG Tropea, JE Peters, HK Kapust, RB Li, M Wlodawer, A Waugh, AS TI Tobacco etch virus protease: Crystal structure of the active enzyme and its inactive mutant SO RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY LA English DT Article DE autolysis; crystal structure; cysteine proteases; TEV protease; tobacco etch virus ID NLA PROTEINASE; DESIGN AB Tobacco Etch Virus Protease (TEV protease) is widely used as a tool for separation of recombinant target proteins from their fusion partners. The crystal structures of two mutants of TEV protease, the active autolysis-resistant mutant TEV-S219D in complex with the proteolysis product, and the inactive mutant TEV-C151A in complex with a substrate, have been determined at 1.8 and 2.2 Angstrom resolution, respectively. The active sites of both mutants, including their oxyanion holes, have identical structures. The C-terminal residues 217-221 of the enzyme are involved in formation of the binding pockets S-3-S-6. This indicates that the autolysis of the peptide bond Met218-Ser219 exerts a strong effect on the fine-tuning of the substrate in the enzyme active site, which results in a considerable decrease n the enzymatic activity. C1 NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Zdanov, AS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. NR 18 TC 0 Z9 0 U1 1 U2 6 PU MAIK NAUKA/INTERPERIODICA PI NEW YORK PA C/O KLUWER ACADEMIC-PLENUM PUBLISHERS, 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1068-1620 J9 RUSS J BIOORG CHEM+ JI Russ. J. Bioorg. Chem. PD SEP-OCT PY 2003 VL 29 IS 5 BP 415 EP 417 DI 10.1023/A:1026041223534 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 735QA UT WOS:000186125000003 ER PT J AU Markov, AV Zakharov, AA Galkin, AP Strunnikov, AV Smirnov, AF AF Markov, AV Zakharov, AA Galkin, AP Strunnikov, AV Smirnov, AF TI Cohesin complexes in polytene chromosomes of Drosophila melanogaster are located in interbands SO RUSSIAN JOURNAL OF GENETICS LA English DT Article ID SISTER-CHROMATID COHESION; MOLECULAR-GENETIC-ANALYSIS; FISSION YEAST; S-PHASE; DNA; PROTEINS; CONDENSATION; ORGANIZATION; MAINTENANCE; MUTATIONS AB The distribution of cohesin complex in polytene chromosomes of Drosophila melanogaster was studied. Cohesin is a complicated protein complex which is regulated by the DRAD21 subunit. Using immunostaining for DRAD21p, the cohesins were shown to be preferentially located in the interband regions. This specificity was not characteristic for puffs, where uniform staining was observed. The presence of a few brightly fluorescent regions (five to ten per chromosome arm) enriched with cohesin complexes was shown. Some of these regions had permanent location, and the others, variable location. No antibody binding was detected in the chromocenter. Immunostaining of interphase nuclei of neuroblasts revealed large cohesin formations. On the polytene chromosomes of D. melanogaster, the Drad21 gene was mapped to the chromocentric region (81) of the L arm of chromosome 3. C1 St Petersburg State Univ, St Petersburg 199034, Russia. NICHD, NIH, Unit Chromosome Struct & Funct, Bethesda, MD USA. RP Markov, AV (reprint author), St Petersburg State Univ, St Petersburg 199034, Russia. RI Galkin, Alexey/K-2968-2013; OI Galkin, Alexey/0000-0002-7362-8857; Strunnikov, Alexander/0000-0002-9058-2256 NR 33 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 1022-7954 J9 RUSS J GENET+ JI Russ. J. Genet. PD SEP PY 2003 VL 39 IS 9 BP 1013 EP 1020 DI 10.1023/A:1025770900683 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 721VT UT WOS:000185339700006 ER PT J AU Apud, JA Egan, MF Wyatt, RJ AF Apud, JA Egan, MF Wyatt, RJ TI Neuroleptic withdrawal in treatment-resistant patients with schizophrenia: tardive dyskinesia is not associated with supersensitive psychosis SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; tardive dyskinesia; antipsychotic; neuroleptics; drug withdrawal; coded inactive medication ID SUPER-SENSITIVITY PSYCHOSIS; LONG-TERM; DOPAMINE; RELAPSE; DRUGS; NEUROTOXICITY; HALOPERIDOL; SCALE; RATS AB The objective of this retrospective study was to determine whether tardive dyskinesia (TD) represents a risk factor for supersensitive psychosis (SS) by assessing the effect of medication withdrawal on ratings of psychopathology for 30 days following discontinuation of antipsychotic medication in patients with and without TD. The subjects were 101 treatment-resistant patients with schizophrenia who had been admitted to the inpatient service of Neuroscience Research Hospital (NRH), National Institute of Mental Health, between 1982 and 1994 to undergo studies involving discontinuation of antipsychotic medication. Patients were rated independently on a daily basis on the 22-item Psychiatric Symptom Assessment Scale (PSAS), an extended version of the Brief Psychiatric Rating Scale (BPRS). The overall frequency of TD was 35.6%. Tardive dyskinesia patients were older (p<0.0006) and had suffered from schizophrenia for a longer time (p<0.003) than No-TD patients. Repeated measure ANOVA revealed a "time" effect for all subgroups studied. The interaction TD X time, however, was not statistically significant for any of the clusters. Within-group analysis revealed significant differences against baseline for measures of positive symptoms, negative symptoms and abnormal involuntary movements in the No-TD group 3 and 4 weeks after antipsychotic withdrawal. In the TD group, however, the changes were observed only at 4 weeks following antipsychotic discontinuation in just two of the positive symptoms cluster. Between-group analyses revealed that, at baseline, the Mannerisms cluster (abnormal involuntary movements) was significantly higher in the TD group (p<0.05). No significant differences were observed between any of the remaining clusters at baseline or at different times following drug withdrawal. In conclusion, the relationship between SS and TD could not be confirmed in a cohort of patients with treatment-resistant schizophrenia. In the present study, patients with no TD seemed to deteriorate faster than patients with TD in terms of psychopathology and abnormal involuntary movements. It is possible that both group of patients may undergo supersensitive receptor changes, and that these changes may be more pronounced but potentially reversible in the group without TD. Published by Elsevier Science B.V. C1 NIMH, Neuropsychiat Branch, NIH, Bethesda, MD 20892 USA. RP Apud, JA (reprint author), Clin Brain Disorders Branch, 10 Ctr Dr,Bldg 10 4S241, Bethesda, MD 20892 USA. NR 42 TC 4 Z9 4 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 SEP 1 PY 2003 VL 63 IS 1-2 BP 151 EP 160 DI 10.1016/S0920-9964(02)00338-9 PG 10 WC Psychiatry SC Psychiatry GA 711MQ UT WOS:000184746000017 PM 12892869 ER PT J AU Arora, NK AF Arora, NK TI Interacting with cancer patients: the significance of physicians' communication behavior SO SOCIAL SCIENCE & MEDICINE LA English DT Review DE patient-physician interaction; patient participation; cancer; health outcomes; quality of life ID EARLY BREAST-CANCER; QUALITY-OF-LIFE; ANALYSIS SYSTEM RIAS; DECISION-MAKING; PROVIDER COMMUNICATION; MEDICAL CONSULTATIONS; HEALTH OUTCOMES; PATIENTS PERCEPTIONS; PATIENTS PREFERENCES; CONSENSUS STATEMENT AB A diagnosis of cancer typically results in patients experiencing uncertainty about and loss of control over their situation, which in turn has a negative influence on their health outcomes. Cancer treatment further disrupts patients' quality of life. Throughout their cancer journey patients often rely on their physicians to provide them with social/interpersonal, informational, and decisional support. A growing body of research shows that physicians' communication behavior does indeed have a positive impact on patient health outcomes. Thus, the patient-physician interaction assumes great significance in the cancer care delivery process. It is encouraging to note that research in this area, largely dominated by studies conducted in primary care, is attracting the attention of cancer researchers. In an attempt to encourage and aid future research on patient-physician communication in cancer care, this paper presents a critical evaluation of existing literature on key elements of physicians' communication behavior (i.e., interpersonal communication, information exchange, and facilitation of patient involvement in decision-making). Different approaches to assessing physician behavior are discussed followed by a review of key findings linking physician behavior with cancer patient health outcomes. Finally, potential limitations of existing research are highlighted and areas for future research are identified. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control Control & Populat Sci, Bethesda, MD 20892 USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. NR 128 TC 240 Z9 246 U1 2 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD SEP PY 2003 VL 57 IS 5 BP 791 EP 806 AR PII S0277-9536(02)00449-5 DI 10.1016/S0277-9536(02)00449-5 PG 16 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 703DY UT WOS:000184265800004 PM 12850107 ER PT J AU Soran, A AF Soran, A TI Lightning injuries SO SOUTHERN MEDICAL JOURNAL LA English DT Letter C1 Univ Pittsburgh, Inst Canc, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15260 USA. RP Soran, A (reprint author), Univ Pittsburgh, Inst Canc, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15260 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD SEP PY 2003 VL 96 IS 9 BP 942 EP 942 DI 10.1097/01.SMJ.0000086762.59141.2F PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 831CO UT WOS:000222170700028 PM 14514000 ER PT J AU Majeed, S Ofek, G Belachew, A Huang, CC Zhou, TQ Kwong, PD AF Majeed, S Ofek, G Belachew, A Huang, CC Zhou, TQ Kwong, PD TI Enhancing protein crystallization through precipitant synergy SO STRUCTURE LA English DT Article ID EGG-WHITE LYSOZYME; X-RAY DATA; ENVELOPE GLYCOPROTEIN; POLYETHYLENE-GLYCOL; HUMAN CD4; CRYSTALS; CRYSTALLOGRAPHY; MACROMOLECULES; DESIGN; HIV-1 AB Suitable conditions for protein crystallization are commonly identified by screening combinations of independent factors that affect crystal formation. Because precipitating agents are prime determinants of crystallization, we investigated whether a systematic exploration of combinations of mechanistically distinct precipitants would enhance crystallization. A crystallization screen containing 64 precipitant mixtures was devised. Tests with ten HIV envelope-related proteins demonstrated that use of precipitant mixtures significantly enhanced both the probability of crystallization as well as the quality of optimized crystals. Tests with hen egg white lysozyme generated a novel C2 crystal from a salt/organic solvent mixture; structure solution at 2 Angstrom resolution revealed a lattice held together by both hydrophobic and electrostatic dyad interactions. The results indicate that mechanistically distinct precipitants can synergize, with precipitant combinations adding unique dimensions to protein crystallization. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Kwong, PD (reprint author), NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010; Ofek, Gilad/A-6965-2010 OI Zhou, Tongqing/0000-0002-3935-4637; NR 45 TC 43 Z9 45 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP PY 2003 VL 11 IS 9 BP 1061 EP 1070 DI 10.1016/S0969-2126(03)00185-0 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 721EF UT WOS:000185303500004 PM 12962625 ER PT J AU Cohen, RM Podruchny, TA Bokde, ALW Carson, RE Herscovitch, P Kiesewetter, DO Eckelman, WC Sunderland, T AF Cohen, RM Podruchny, TA Bokde, ALW Carson, RE Herscovitch, P Kiesewetter, DO Eckelman, WC Sunderland, T TI Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon 4 allele SO SYNAPSE LA English DT Article DE PET; brain imaging; cholinergic ID POSITRON-EMISSION-TOMOGRAPHY; CHOLINE-ACETYLTRANSFERASE ACTIVITY; ALZHEIMERS-DISEASE; EPSILON-4 ALLELE; ACETYLCHOLINESTERASE ACTIVITY; DEMENTED PATIENTS; SENILE DEMENTIA; E GENOTYPE; E4 ALLELE; BRAIN AB The apolipoprotein E-is an element of4 allele confers an increased susceptibility to age-related memory problems and Alzheimer's disease. Abnormalities in the cholinergic system are also likely contributors to memory deficits associated with aging and AD. To determine the effect of the APOE-is an element of4 allele on the muscarinic component of the cholinergic system of aging subjects, 10 healthy subjects with APOE-is an element of4 alleles (APOE-is an element of4+) and 10 without (APOE-is an element of4-), ranging in age from 52 to 75 years, were tomographically scanned with the F-18-labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[F-18]Flouro-propyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([F-18]FP-TZTP). The distribution volumes (V-T) of [F-18]FP-TZTP were determined by compartmental modeling of partial volume and free fraction corrected PET scans. Regional cerebral blood flow (rCBF) measurements with (H2O)-O-15 were also performed. Global Gray V-T (840 +/- 155 ml plasma/ml tissue) was greater in APOE-is an element of4+ subjects than APOE-is an element of4-subjects (660 +/- 113 ml plasma/ml tissue, P = 0.01), and previously studied younger subjects. There were no significant differences between the groups with respect to rCBF, but within the APOE-is an element of4+ group there was a trend for subjects with the higher Global Gray V(T)s to have lower Global Gray CBFs (r = -0.65, P < 0.06). A lower concentration of acetylcholine in the synapse of APOE-is an element of4+ older individuals is a likely explanation for the greater [F-18]FP-TZTP distribution volumes. Published 2003 Wiley-Liss, Inc. C1 NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, Munich, Germany. Univ Munich, Dementia & Neuroimaging Res Sect, Alzheimers Mem Ctr, Munich, Germany. NIH, Warren G Magnuson Clin Ctr, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. RP Cohen, RM (reprint author), NIMH, Geriatr Psychiat Branch, NIH, Bldg 10,Rm 3N228,MSC 1274,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 50 TC 38 Z9 39 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP 1 PY 2003 VL 49 IS 3 BP 150 EP 156 DI 10.1002/syn.10225 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 702HG UT WOS:000184218000002 PM 12774299 ER PT J AU Haseman, JK AF Haseman, JK TI An alternative perspective: A critical evaluation of the Waddell threshold extrapolation model in chemical carcinogenesis SO TOXICOLOGIC PATHOLOGY LA English DT Editorial Material DE carcinogenesis; thresholds; extrapolation; risk assessment AB In a recent Perspective article (Toxicologic Pathology 31: 260-262, 2003) Waddell asserts that he has developed a log linear extrapolation model that can demonstrate a threshold and resolve for once and for all the uncertainies associated with low dose cancer risk extrapolation. However, his method essentially forces, rather than demonstrates, a threshold, and has many serious flaws that result in significant under-estimation of low dose risk. It would be a serious mistake for the scientific community to adopt Waddell's log linear extrapolation model for chemical carcinogenesis risk assessment. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Haseman, JK (reprint author), NIEHS, Biostat Branch, III Alexander Dr,MD A3-03, Res Triangle Pk, NC 27709 USA. NR 8 TC 8 Z9 8 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2003 VL 31 IS 5 BP 468 EP 470 DI 10.1080/01926230390228940 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA 712GG UT WOS:000184789300001 PM 14692613 ER PT J AU Calderon-Garciduenas, L Maronpot, RR Torres-Jardon, R Henriquez-Roldan, C Schoonhoven, R Acuna-Ayala, H Villarreal-Calderon, A Nakamura, J Fernando, R Reed, W Azzarelli, B Swenberg, JA AF Calderon-Garciduenas, L Maronpot, RR Torres-Jardon, R Henriquez-Roldan, C Schoonhoven, R Acuna-Ayala, H Villarreal-Calderon, A Nakamura, J Fernando, R Reed, W Azzarelli, B Swenberg, JA TI DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration SO TOXICOLOGIC PATHOLOGY LA English DT Review DE urban pollution; Alzheimer's disease; ozone; ultrafine particulate matter; brain inflammation; combustion metals; nasal and olfactory pathology; blood-brain barrier; DNA oxidative damage ID AMYLOID PRECURSOR PROTEIN; NF-KAPPA-B; APURINIC APYRIMIDINIC SITES; ASSESSING CHRONIC EXPOSURES; AGE-RELATED-CHANGES; ALZHEIMERS-DISEASE; RAT-BRAIN; OXIDATIVE DAMAGE; MEXICO-CITY; NITRIC-OXIDE AB Acute, subchronic, or chronic exposures to particulate matter (PM) and pollutant gases affect people in urban areas and those exposed to fires, disasters, and wars. Respiratory tract inflammation, production of mediators of inflammation capable of reaching the brain, systemic circulation of PM, and disruption of the nasal respiratory and olfactory barriers are likely in these populations. DNA damage is crucial in aging and in age-associated diseases such as Alzheimer's disease. We evaluated apurinic/apyrimidinic (AP) sites in nasal and brain genomic DNA, and explored by immunohistochemistry the expression of nuclear factor NFkappaB p65, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), metallothionein I and II, apolipoprotein E, amyloid precursor protein (APP), and beta-amyloid(1-42) in healthy dogs naturally exposed to urban pollution in Mexico City. Nickel (Ni) and vanadium (V) were measured by inductively coupled plasma mass spectrometry (ICP-MS). Forty mongrel dogs, ages 7 days-10 years were studied (14 controls from Tlaxcala and 26 exposed to urban pollution in South West Metropolitan Mexico City (SWMMC)). Nasal respiratory and olfactory epithelium were found to be early pollutant targets. Olfactory bulb and hippocampal AP sites were significantly higher in exposed than in control age matched animals. Ni and V were present in a gradient from olfactory mucosa > olfactory bulb > frontal cortex. Exposed dogs had (a) nuclear neuronal NFkappaB p65, (b) endothelial, glial and neuronal iNOS, (c) endothelial and glial COX2, (d) ApoE in neuronal, glial and vascular cells, and (e) APP and beta amyloid(1-42) in neurons, diffuse plaques (the earliest at age 11 months), and in subarachnoid blood vessels. Increased AP sites and the inflammatory and stress protein brain responses were early and significant in dogs exposed to urban pollution. Oil combustion PM-associated metals Ni and V were detected in the brain. There was an acceleration of Alzheimer's-type pathology in dogs chronically exposed to air pollutants. Respiratory tract inflammation and deteriorating olfactory and respiratory barriers may play a role in the observed neuropathology. These data suggest that Alzheimer's disease may be the sequela of air pollutant exposures and the resulting systemic inflammation. C1 Univ N Carolina, Environm Pathol Program, Chapel Hill, NC 27599 USA. Inst Nacl Pediat, Mexico City 14410, DF, Mexico. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Nacl Autonoma Mexico, Ctr Ciencias Atmosfera, Mexico City 04510, DF, Mexico. Univ Valparaiso, Dept Estadist, Valparaiso, Chile. Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. Univ Nacl Autonoma Mexico, NUCE, Fac Med, Mexico City 04510, DF, Mexico. RTI Int, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA. Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. Indiana Univ, Dept Pathol, Indianapolis, IN 46202 USA. RP Calderon-Garciduenas, L (reprint author), Univ N Carolina, Environm Pathol Program, 348 Rosenau Hall CB 7431, Chapel Hill, NC 27599 USA. EM liliancalderon888@hotmail.com FU NCI NIH HHS [P-30-CA 16086]; NIEHS NIH HHS [T-32 ES07017, P30-ES10126] NR 113 TC 108 Z9 111 U1 4 U2 21 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2003 VL 31 IS 5 BP 524 EP 538 DI 10.1080/01926230390226645 PG 15 WC Pathology; Toxicology SC Pathology; Toxicology GA 712GG UT WOS:000184789300009 PM 14692621 ER PT J AU Rapaka, RS Weber, SG AF Rapaka, RS Weber, SG TI Understanding illicit drug use SO TRAC-TRENDS IN ANALYTICAL CHEMISTRY LA English DT Editorial Material C1 NIDA, Div Neurosci & Behav Res, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. RP Rapaka, RS (reprint author), NIDA, Div Neurosci & Behav Res, 6001 Execut Blvd,Rm 4282,MSC 9555, Bethesda, MD 20892 USA. OI Weber, Stephen/0000-0002-7970-2632 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-9936 J9 TRAC-TREND ANAL CHEM JI Trac-Trends Anal. Chem. PD SEP PY 2003 VL 22 IS 9 BP XIV EP XIV DI 10.1016/S0165-9936(03)00911-7 PG 1 WC Chemistry, Analytical SC Chemistry GA 726BP UT WOS:000185578400012 ER PT J AU Knodler, LA Steele-Mortimer, O AF Knodler, LA Steele-Mortimer, O TI Taking possession: Biogenesis of the Salmonella-containing vacuole SO TRAFFIC LA English DT Review DE effector; endocytosis; intracellular pathogen; phagosome; translocation; type III secretion ID ENTERICA SEROVAR TYPHIMURIUM; LYSOSOMAL MEMBRANE-GLYCOPROTEINS; III SECRETION SYSTEM; NUCLEOTIDE EXCHANGE FACTOR; LATE ENDOCYTIC COMPARTMENTS; NITRIC-OXIDE SYNTHASE; EPITHELIAL-CELLS; PATHOGENICITY ISLAND; ACTIN CYTOSKELETON; HOST-CELL AB The Gram-negative pathogen Salmonella enterica can survive and replicate within a variety of mammalian cells. Regardless of the cell type, internalized bacteria survive and replicate within the Salmonella -containing vacuole, the biogenesis of which is dependent on bacterially encoded virulence factors. In particular, Type III secretion systems translocate bacterial effector proteins into the eukaryotic cell where they can specifically interact with a variety of targets. Salmonella has two distinct Type III secretion systems that are believed to have completely different functions. The SPI2 system is induced intracellularly and is required for intracellular survival in macrophages; it plays no role in invasion but is categorized as being required for Salmonella -containing vacuole biogenesis. In contrast, the SPI1 Type III secretion system is induced extracellularly and is essential for invasion of nonphagocytic cells. Its role in post-invasion processes has not been well studied. Recent studies indicate that Salmonella -containing vacuole biogenesis may be more dependent on SPI1 than previously believed. Other non-SPI2 virulence factors and the host cell itself may play critical roles in determining the intracellular environment of this facultative intracellular pathogen. In this review we discuss the recent advances in determining the mechanisms by which Salmonella regulate Salmonella -containing vacuole biogenesis and the implications of these findings. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 119 TC 116 Z9 118 U1 1 U2 11 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD SEP PY 2003 VL 4 IS 9 BP 587 EP 599 DI 10.1034/j.1600-0854.2003.00118.x PG 13 WC Cell Biology SC Cell Biology GA 711HE UT WOS:000184732900002 PM 12911813 ER PT J AU Fairhurst, RM Sadou, B Guindo, A Diallo, DA Doumbo, OK Wellems, TE AF Fairhurst, RM Sadou, B Guindo, A Diallo, DA Doumbo, OK Wellems, TE TI Case report: life-threatening hypoglycaemia associated with sulfadoxine-pyrimethamine, a commonly used antimalarial drug SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE malaria; hypoglycaemia; chemotherapy; sulfadoxine-pyrimethamine; Mali ID FALCIPARUM-MALARIA; CHILDREN AB Due to chloroquine resistance, several African countries have changed their first-line malaria treatment to sulfadoxine-pyrimethamine (SP). In this report, we present a case of hypoglycaemic coma associated with SP, an adverse reaction that is likely to be underreported and expected to occur with greater frequency as the use of SP increases. C1 NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Mali, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, Bldg 4,Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. EM rfairhurst@niaid.nih.gov NR 6 TC 4 Z9 4 U1 0 U2 0 PU ROYAL SOC TROPICAL MEDICINE PI LONDON PA MANSON HOUSE 26 PORTLAND PLACE, LONDON W1N 1EY, ENGLAND SN 0035-9203 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD SEP-OCT PY 2003 VL 97 IS 5 BP 595 EP 596 DI 10.1016/S0035-9203(03)80041-X PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 844RE UT WOS:000223176500029 PM 15307435 ER PT J AU Bolan, CD Yau, YY Nambiar, A Haddad, S Leitman, SF AF Bolan, CD Yau, YY Nambiar, A Haddad, S Leitman, SF TI Inadvertent hypercalcemia during intravenous calcium prophylaxis for large volume leukapheresis (LVL) SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 28A EP 28A PG 1 WC Hematology SC Hematology GA 716TT UT WOS:000185045700094 ER PT J AU Kolf, CM Bolan, CD Wesley, RA Browning, JN Leitman, SF AF Kolf, CM Bolan, CD Wesley, RA Browning, JN Leitman, SF TI Sustained decreases in lymphocyte counts in serial long-term leukapheresis donors SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 28A EP 29A PG 2 WC Hematology SC Hematology GA 716TT UT WOS:000185045700095 ER PT J AU Busch, MP Hirschkorn, DF Herring, BL Delwart, EL McAuley, J Murthy, KK Alter, HJ AF Busch, MP Hirschkorn, DF Herring, BL Delwart, EL McAuley, J Murthy, KK Alter, HJ TI Defining the minimal infectious dose and infectious window period for HCV using plasma donor panels and the chimpanzee transfusion model SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 Blood Syst Inc, Blood Ctr Pacific, San Francisco, CA USA. Univ Calif San Francisco, Blood Ctr Pacific, San Francisco, CA USA. Blood Syst Lab, Tempe, AZ USA. SW Fdn Biomed Res, San Antonio, TX 78284 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RI Herring, Belinda/M-7252-2015 NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 32A EP 32A PG 1 WC Hematology SC Hematology GA 716TT UT WOS:000185045700108 ER PT J AU Stroncek, DF Byrne, KM Leitman, SF AF Stroncek, DF Byrne, KM Leitman, SF TI Storage of sickle trait donor blood in oxygen permeable bags with a large surface area allows effective leukocyte reduction by filtration SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 42A EP 42A PG 1 WC Hematology SC Hematology GA 716TT UT WOS:000185045700140 ER PT J AU Lazo, A Tassello, J Ohagen, A Aytay, S Lunderville, D Wong, S Brown, K AF Lazo, A Tassello, J Ohagen, A Aytay, S Lunderville, D Wong, S Brown, K TI Inactivation of human parvovirus B19 by INACTINE (TM) PEN110 SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 VI Technol Inc, Watertown, MA USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 86A EP 86A PG 1 WC Hematology SC Hematology GA 716TT UT WOS:000185045700290 ER PT J AU Loy, DA AF Loy, DA TI Use of hospital wide occurrence reporting system aids in reducing labeling errors SO TRANSFUSION LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-of-Blood-Banks CY NOV 01-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Blood Banks C1 NIH, CC, DTM, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 SU S BP 163A EP 164A PG 2 WC Hematology SC Hematology GA 716TT UT WOS:000185045700552 ER PT J AU Pellett, PE Wright, DJ Engels, EA Ablashi, DV Dollard, SC Forghani, B Glynn, SA Goedert, JJ Jenkins, FJ Lee, TH Neipel, F Todd, DS Whitby, D Nemo, GJ Busch, MP AF Pellett, PE Wright, DJ Engels, EA Ablashi, DV Dollard, SC Forghani, B Glynn, SA Goedert, JJ Jenkins, FJ Lee, TH Neipel, F Todd, DS Whitby, D Nemo, GJ Busch, MP CA Retrovirus Epidemiology Donor Stud TI Multicenter comparison of serologic assays and estimation of human herpesvirus 8 seroprevalence among US blood donors SO TRANSFUSION LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; LATENT CLASS ANALYSIS; KAPOSIS-SARCOMA; DIAGNOSTIC-ACCURACY; RISK-FACTORS; ANTIBODIES; INFECTION; TRANSMISSION; PREVALENCE; AFRICA AB BACKGROUND: As part of assessing the possibility of transfusion transmission of human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus), HHV-8 seroprevalence was estimated among US blood donors, the performance of HHV-8 serologic tests was compared, and the presence of HHV-8 DNA was tested for in donated blood. STUDY DESIGN AND METHODS: Replicate panels of 1040 plasma specimens prepared from 1000 US blood donors (collected in 1994 and 1995) and 21 Kaposi's sarcoma patients were tested for antibodies to HHV-8 in six laboratories. HHV-8 PCR was performed on blood samples from 138 donors, including all 33 who tested seropositive in at least two laboratories and 22 who tested positive in at least one. RESULTS: The estimated HHV-8 seroprevalence among US blood donors was 3.5 percent (95% Cl, 1.2%-9.8%) by a conditional dependence latent-class model, 3.0 percent (95% Cl, 2.0%-4.6%) by a conditional independence latent-class model, and 3.3 percent (95% Cl, 2.3%-4.6%) by use of a consensus-derived gold standard (specimens positive in two or more laboratories); the conditional dependence model best fit the data. In this model, laboratory specificities ranged from 96.6 to 100 percent. Sensitivities ranged widely, but with overlapping 95 percent CIs. HHV-8 DNA was detected in blood from none of 138 donors evaluated. CONCLUSIONS: Medical and behavioral screening does not eliminate HHV-8-seropositive persons from the US blood donor pool, but no viral DNA was found in donor blood. Further studies of much larger numbers of seropositive individuals will be required to more completely assess the rate of viremia and possibility of HHV-8 transfusion transmission. Current data do not indicate a need to screen US blood donors for HHV-8. C1 Ctr Dis Control & Prevent, Atlanta, GA USA. Westat Corp, Rockville, MD USA. NCI, NIH, Frederick, MD 21701 USA. NCI, NIH, Rockville, MD USA. ABI, Columbia, MD USA. Calif Dept Hlth Serv, Viral & Rickettsial Dis Lab, Richmond, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. Blood Ctr Pacific, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Erlangen Nurnberg, Inst Virol, Erlangen, Germany. NHLBI, REDS, NIH, Bethesda, MD 20892 USA. RP Pellett, PE (reprint author), Lerner Res Inst, Dept Virol, NN10,9500 Euclid Ave, Cleveland, OH 44195 USA. RI Jenkins, Frank/A-8529-2009 FU NHLBI NIH HHS [N01-HB-97082, N01-HB-97080, N01-HB-97079, N01-HB-97077, N01-HB-47114, N01-HB-97078, N01-HB-97081] NR 41 TC 97 Z9 109 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2003 VL 43 IS 9 BP 1260 EP 1268 DI 10.1046/j.1537-2995.2003.00490.x PG 9 WC Hematology SC Hematology GA 713KD UT WOS:000184855900012 PM 12919429 ER PT J AU Yen, PM AF Yen, PM TI Molecular basis of resistance to thyroid hormone SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID DOMINANT-NEGATIVE ACTIVITY; RECEPTOR-BETA GENE; LIGAND-BINDING DOMAIN; GENERALIZED RESISTANCE; TR-BETA; TARGETED MUTATION; CO-REPRESSOR; IN-VIVO; MICE; COACTIVATOR AB Resistance to thyroid hormone (RTH) is a syndrome in which patients have raised serum thyroid hormone (TH) levels and raised or inappropriately normal thyrotropin (TSH) levels. In general, patients exhibit TH resistance in the pituitary and peripheral tissues. Novel techniques and genetically engineered mouse model systems have increased our understanding of thyroid hormone receptor (TR) action, and shed new light on the underlying molecular mechanisms for RTH. In particular, we are learning how mutant TRs from RTH patients can block wild-type TR function, with consequent effects in various tissues and cells. This dominant-negative activity has important implications for other hormone-resistant conditions and in hormone-sensitive tumors. This article examines the molecular basis of RTH. C1 NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Yen, PM (reprint author), NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 66 TC 85 Z9 92 U1 2 U2 2 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 SEP PY 2003 VL 14 IS 7 BP 327 EP 333 DI 10.1016/S1043-2760(03)00114-0 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 721HX UT WOS:000185311900005 PM 12946875 ER PT J AU Leapman, R AF Leapman, R TI SALSA '02 - Proceedings of the International Workshop on Strategies and Advances in Atomic Level Spectroscopy and Analysis - Guadeloupe, French West Indies, 5-9 May 2002 - Part 1: Techniques and instrumentation - Foreword SO ULTRAMICROSCOPY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Leapman, R (reprint author), NIH, Bldg 13,3N17, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD SEP PY 2003 VL 96 IS 3-4 BP V EP VI DI 10.1016/S0304-3991(03)00089-5 PG 2 WC Microscopy SC Microscopy GA 705NX UT WOS:000184402100001 ER PT J AU Koch, M Pancera, M Kwong, PD Kolchinsky, P Grundner, C Wang, LP Hendrickson, WA Sodroski, J Wyatt, R AF Koch, M Pancera, M Kwong, PD Kolchinsky, P Grundner, C Wang, LP Hendrickson, WA Sodroski, J Wyatt, R TI Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition SO VIROLOGY LA English DT Article DE HIV-1; exterior envelope glycoprotein; structure; deglycosylation; neutralization; antibody binding; correlation ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 ENVELOPE GLYCOPROTEIN; N-LINKED OLIGOSACCHARIDE; SOLUBLE CD4 BINDING; MONOCLONAL-ANTIBODIES; V3 LOOP; CHEMOKINE RECEPTORS; ATOMIC-STRUCTURE; VARIABLE LOOPS; RESISTANCE AB The human immunodeficiency virus (HIV-1) exterior envelope glycoprotein, gpl20, mediates receptor binding and is the major target for neutralizing antibodies. Primary HIV-1 isolates are characteristically more resistant to broadly neutralizing antibodies, although the structural basis for this resistance remains obscure. Most broadly neutralizing antibodies are directed against functionally conserved gp120 regions involved in binding to either the primary virus receptor, CD4, or the viral coreceptor molecules that normally function as chemokine receptors. These antibodies are known as CD4 binding site (CD4BS) and CD4-induced (CD4i) antibodies, respectively. Inspection of the gp120 crystal structure reveals that although the receptor-binding regions lack glycosylation, sugar moieties lie proximal to both receptor-binding sites on gp120 and thus in proximity to both the CD4BS and the CD4i epitopes. In this study, guided by the X-ray crystal structure of gp 120, we deleted four N-linked glycosylation sites that flank the receptor-binding regions. We examined the effects of selected changes on the sensitivity of two prototypic HIV-1 primary isolates to neutralization by antibodies. Surprisingly, removal of a single N-linked glycosylation site at the base of the gp120 third variable region (V3 loop) increased the sensitivity of the primary viruses to neutralization by CD4BS antibodies. Envelope glycoprotein oligomers on the cell surface derived from the V3 glycan-deficient virus were better recognized by a CD4BS antibody and a V3 loop antibody than were the wild-type glycoproteins. Absence of all four glycosylation sites rendered a primary isolate sensitive to CD4i antibody-mediated neutralization. Thus, carbohydrates that flank receptor-binding regions on gp120 protect primary HIV-1 isolates from antibody-mediated neutralization. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIH, Vaccine Res Ctr, Virol Lab, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Wyatt, R (reprint author), NIH, Vaccine Res Ctr, Virol Lab, Bldg 40,Room 4512, Bethesda, MD 20892 USA. FU NIAID NIH HHS [1 R21 AI-44328-02, 5 R21 AI-44328-02] NR 63 TC 135 Z9 139 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 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2003 VL 313 IS 2 BP 387 EP 400 DI 10.1016/S0042-6822(03)00294-0 PG 14 WC Virology SC Virology GA 720LC UT WOS:000185261400006 PM 12954207 ER PT J AU Zheng, CY O'Connell, BC Baum, BJ AF Zheng, CY O'Connell, BC Baum, BJ TI Inclusion of Moloney murine leukemia virus elements upstream of the transgene cassette in an El-deleted adenovirus leads to an unusual genomic integration in epithelial cells SO VIROLOGY LA English DT Article DE adenovirus; retroviral elements; genomic integration; nonhomologous recombination; hybrid vector ID VIRAL-DNA SEQUENCES; RETROVIRUS DNA; POL GENE; INFECTION; TRANSFORMATION; EXPRESSION; VECTOR; FRAGMENTS; LINE; DEPENDENCE AB Classically, the 5' and 3' long terminal repeats (LTRs) are considered necessary but not sufficient for retroviral integration. Recently, we reported that inclusion of these and additional elements from Moloney murine leukemia virus (MoMLV) facilitated transgene integration, without retroviral integrase, when placed in an adenoviral context (AdLTR-luc vector) (Nat. Biotech. 18 (2000), 176; Biochem. Biophys. Res. Commun. 300 (2003), 115). To help understand this nonhomologous DNA recombination event, we constructed another vector, AdELP-luc, with 2.7 kb of MoMLV elements identically placed into an El-deleted adenovirus type 5 backbone upstream of a luciferase cDNA reporter gene. Unlike AdLTR-luc, no MoMLV elements were placed downstream of the expression cassette. AdELP-luc readily infected epithelial cells in vitro. Southern hybridizations with DNA from cloned cells showed that disruption of the MoMLV sequences occurred. One cell clone, grown in vitro without any special selection medium for 9 months, exhibited stable vector integration and luciferase activity. Importantly, both Southern hybridization and FISH analyses showed that in addition to the MoMLV elements and expression cassette, substantial adenoviral sequence downstream of the luciferase cDNA was genomically integrated. These results suggest that the 2.7 kb of MoMLV sequence included in AdELP-luc have cis-acting functions and mediates an unusual integration event. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1N113,MSC-1190,10 Ctr Dr, Bethesda, MD 20892 USA. NR 32 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2003 VL 313 IS 2 BP 460 EP 472 DI 10.1016/S0042-6822(03)00374-X PG 13 WC Virology SC Virology GA 720LC UT WOS:000185261400012 PM 12954213 ER PT J AU Ahvazi, B Steinert, PM AF Ahvazi, B Steinert, PM TI A model for the reaction mechanism of the transglutaminase 3 enzyme SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE calcium ions; protein structure; residue specificity; TGase; TGase mechanism; X-ray crystallography ID COAGULATION FACTOR-XIII; CELL-ENVELOPE PROTEINS; CIS PEPTIDE-BONDS; CROSS-LINKING; 3-DIMENSIONAL STRUCTURE; MOLECULAR-CLONING; CALCIUM-IONS; BINDING; ACTIVATION; IDENTIFICATION AB Transglutaminase enzymes (TGases) catalyze the calcium dependent formation of an isopeptide bond between protein-bound glutamine and lysine substrates. Previously we have shown that activated TGase 3 acquires two additional calcium ions at site two and three. The calcium ion at site three results in the opening of a channel. At this site, the channel opening and closing could modulate, depending on which metal is bound. Here we propose that the front of the channel could be used by the two substrates for enzyme reaction. We propose that the glutamine substrate is directed from Trp236 into the enzyme, shown by molecular docking. Then a lysine substrate approaches the opened active site to engage Trp327, leading to formation of the isopeptide bond. Further, direct comparisons of the structures of TGase 3 with other TGases have allowed us to identify several residues that might potentially be involved in generic and specific recognition of the glutamine and lysine substrates. C1 NIAMSD, Off Sci & Technol, Lab Xray Crystallog Facil, NIH, Bethesda, MD 20892 USA. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ahvazi, B (reprint author), NIAMSD, Off Sci & Technol, Lab Xray Crystallog Facil, NIH, Bethesda, MD 20892 USA. NR 36 TC 23 Z9 23 U1 0 U2 2 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD AUG 31 PY 2003 VL 35 IS 4 BP 228 EP 242 PG 15 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 724WR UT WOS:000185510100002 PM 14508061 ER PT J AU Buydens-Branchey, L Branchey, M McMakin, DL Hibbeln, JR AF Buydens-Branchey, L Branchey, M McMakin, DL Hibbeln, JR TI Polyunsaturated fatty acid status and relapse vulnerability in cocaine addicts SO PSYCHIATRY RESEARCH LA English DT Article DE PUFAs; cocaine abuse; recurrence ID HUMAN DOPAMINE TRANSPORTER; RAT FRONTAL-CORTEX; ARACHIDONIC-ACID; SEROTONINERGIC NEUROTRANSMISSION; DOCOSAHEXAENOIC ACID; BEHAVIOR AB There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of depressive and aggressive disorders, including homicides. There is also evidence derived mostly from the animal literature that PUFAs could play a role in the abuse of substances through their action on central serotonergic and dopaminergic systems that are both known to play a role in reward mechanisms. In this study, we explored the possibility that the relapse rates of cocaine addicts discharged after a period of detoxification on an inpatient unit would be associated with their PUFA status. Thirty-eight patients were enrolled in the study. PUFA status was assessed only at baseline, shortly after admission. Resumption of substance use was assessed 3 months, 6 months and I year following discharge. Thirty-two patients remained available for follow-up for the duration of the study. Subjects who relapsed at 3 months had significantly lower baseline levels of total n-6 PUFAs, linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) and total n-3 PUFAs when compared to non-relapsers by ANCOVAs with age and weight as covariates. Lower baseline total n-6 PUFAs, LA and AA continued to predict relapse 6 months and 12 months following discharge. Age, marital status, educational level, cocaine use parameters or psychopathology did not differ between relapsers and non-relapsers. In conclusion, low PUFA status at baseline was a better predictor of relapse than cocaine use, sociodemographic or clinical parameters. These data suggest, but do not prove, the existence of a causal relationship between n-6 or n-3 status and relapse vulnerability in cocaine addicts, and provide a rationale for the exploration of possible relationships between relapse to addictive disorders and PUFA status in observational and interventional trials. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 SUNY Hlth Sci Ctr, Dept Psychiat, Brooklyn, NY 11209 USA. Vet Affairs New York Harbor Healthcare Syst, Brooklyn, NY 11209 USA. NIAAA, Rockville, MD 20852 USA. RP Buydens-Branchey, L (reprint author), SUNY Hlth Sci Ctr, Dept Psychiat, Brooklyn Campus 11S-BK,800 Poly Pl, Brooklyn, NY 11209 USA. NR 22 TC 18 Z9 19 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 AUG 30 PY 2003 VL 120 IS 1 BP 29 EP 35 DI 10.1016/S0165-1781(03)00168-9 PG 7 WC Psychiatry SC Psychiatry GA 728GR UT WOS:000185709900003 PM 14500111 ER PT J AU Zheng, G AF Zheng, G TI Use of max and min scores for trend tests for association when the genetic model is unknown SO STATISTICS IN MEDICINE LA English DT Article DE family of genetic models; candidate-gene associations; case-control study; choice of scores; Cochran-Armitage trend test ID EFFICIENCY ROBUST-TESTS; CONTINGENCY-TABLES; SAMPLE-SIZE; ORDERED TABLES; INDEPENDENCE; PROPORTIONS; MARKERS; ATOPY; POWER AB In case-control studies, the Cochran-Armitage (CA) trend test is powerful for detection of an association between a risk allele and a marker. To apply this test, a score should be assigned to the genotypes based on the genetic model. When the underlying genetic model is unknown, the trend test statistic is a function of the score. In this paper, simple procedures are given to obtain two scores (max and min), which respectively maximize and minimize the CA trend test statistics for genetic associations. These two scores can be used to examine the effect of the choice of scores on the test of no association. When the CA trend test statistic with the max (or min) score is less (or greater) than a prespecified value, the conclusion is clear: we will accept (or reject) the null hypothesis of no association for any scores used. When this value is less than the CA trend test statistic with the max score but greater than the one with the min score, the decision of whether or not to reject the null hypothesis depends on the choice of scores. In this situation, the CA trend test with a prespecified score cannot be used without careful scientific justification of the choice of scores. The use of max and min scoring schemes is applied to a real data set. Published in 2003 by John Wiley Sons, Ltd. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Room 8223,Rockledge 2,6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 18 TC 14 Z9 15 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2003 VL 22 IS 16 BP 2657 EP 2666 DI 10.1002/sim.1474 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 708BJ UT WOS:000184546400008 PM 12898550 ER PT J AU Lee, KB Kim, UK AF Lee, KB Kim, UK TI Angiotensinogen and angiotensin II type 1 receptor gene polymorphism in patients with autosomal dominant polycystic kidney disease: Effect on hypertension and ESRD SO YONSEI MEDICAL JOURNAL LA English DT Article DE polycystic kidney; autosomal dominant; angiotensin; angiotensinogen; polymorphism ID RENAL-DISEASE; PROGRESSION; RENIN; RISK; IDENTIFICATION; ASSOCIATION; VARIANT; SYSTEM; JAPAN AB Autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease, is characterized by the development of hypertension and end stage renal disease. An increase in the activity of the renin-angiotensin system, due to a renal ischemia caused by cyst expansion, contributes to the development of hypertension and renal failure in ADPKD. Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease. We, hypothesized that the AGT M235T and ATR A1166C polymorphisms could account for some of the variability in the progression of ADPKD. Genotyping was performed in 108 adult patients with ADPKD, and 105 normotensive healthy controls, using PCR and restriction digestion. We analyzed the effects of the AGT M235T and ATR A1166C polymorphisms on hypertension and age at the end stage renal disease (ESRD). Of the 108 patients with ADPKD, 64 (59%) had hypertension and 24 (22%) reached the ESRD. The prevalence of hypertension were; [MM+MT], [TT] genotypes, 60%, 59% (p=1.00); [AA], [AC+CC] genotypes, 60%, 50% respectively (p=0.54). The ages at the onset of ESRD were; [MM+MT], [TT] genotypes, 50+/-9 years, 56+/-8 years (p=0.07); [AA], [AC+CC] genotypes, 54+/-8 years, 52+/-14 years, respectively (p=0.07). There were no differences in the prevalence of hypertension and the ages at the ESRD in relation to the AGT M235T and ATR A1166C polymorphisms. We suggest that the AGT and ATR gene polymorphisms would not have an effect on hypertension or the ESRD in ADPKD. C1 Sungkyunkwan Univ Sch Med, Kangbuck Samsung Hosp, Dept Internal Med, Seoul 110746, South Korea. Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD USA. RP Lee, KB (reprint author), Sungkyunkwan Univ Sch Med, Kangbuck Samsung Hosp, Dept Internal Med, 108 Pyung Dong, Seoul 110746, South Korea. NR 25 TC 10 Z9 10 U1 2 U2 6 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA C/O KYUN0-IL IM, M.D., PH.D, SHINCHON DONG 134, SEODAEMOON KU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD AUG 30 PY 2003 VL 44 IS 4 BP 641 EP 647 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 720ZQ UT WOS:000185292900012 PM 12950120 ER PT J AU Castro, AF Rebhun, JF Clark, GJ Quilliam, LA AF Castro, AF Rebhun, JF Clark, GJ Quilliam, LA TI Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTORS; TUMOR-SUPPRESSOR PROTEINS; TUBEROUS-SCLEROSIS; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; CELL-GROWTH; FARNESYLTRANSFERASE INHIBITORS; SCHIZOSACCHAROMYCES-POMBE; 3-KINASE/AKT PATHWAY; FISSION YEAST; GENE-PRODUCT AB Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug. C1 Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN 46202 USA. NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. RP Castro, AF (reprint author), Indiana Univ, Sch Med, Dept Biochem & Mol Biol, 35 barnhill Dr,MS-4053, Indianapolis, IN 46202 USA. RI Quilliam, Lawrence/B-6447-2015 NR 45 TC 244 Z9 250 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 AUG 29 PY 2003 VL 278 IS 35 BP 32493 EP 32496 DI 10.1074/jbc.C300226200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714FN UT WOS:000184901800003 PM 12842888 ER PT J AU Tortorici, MA Broering, TJ Nibert, ML Patton, JT AF Tortorici, MA Broering, TJ Nibert, ML Patton, JT TI Template recognition and formation of initiation complexes by the replicase of a segmented double-stranded RNA virus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ROTAVIRUS MESSENGER-RNA; GENOME REPLICATION; CONSENSUS SEQUENCE; OPEN CORES; IN-VITRO; POLYMERASE; IDENTIFICATION; PARTICLES; MECHANISM; PROMOTER AB Replication of the segmented double-stranded (ds) RNA genome of viruses belonging to the Reoviridae family requires the RNA-dependent RNA polymerase (RdRP) to use 10-12 different mRNAs as templates for (-) strand synthesis. Rotavirus serves as a model system for study of this process, since its RdRP (VP1) is catalytically active and can specifically recognize template mRNAs in vitro. Here, we have analyzed the requirements for template recognition by the rotavirus RdRP and compared those to the requirements for formation of (-) strand initiation complexes. The results show that multiple functionally independent recognition signals are present at the 3'-end of viral mRNAs, some positioned in nonconserved regions upstream of the highly conserved 3'-terminal consensus sequence. We also found that RdRP recognition signals are distinct from cis-acting signals that promote (-) strand synthesis, because deletions of portions of the 3'-consensus sequence that caused viral mRNAs to be poorly replicated in vitro did not necessarily prevent efficient recognition of the RNA by the RdRP. Although the RdRP alone can specifically bind to viral mRNAs, our analysis reveals that this interaction is not sufficient to generate initiation complexes, even in the presence of nucleotides and divalent cations. Rather, the formation of initiation complexes also requires the core lattice protein (VP2), a virion component that forms a T=1 icosahedral shell that encapsidates the segmented dsRNA genome. The essential role that the core lattice protein has in (-) strand initiation provides a mechanism for the coordination of genome replication and virion assembly. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,MSC 8026,Rm 6314, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 29 TC 44 Z9 50 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 AUG 29 PY 2003 VL 278 IS 35 BP 32673 EP 32682 DI 10.1074/jbc.M305358200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714FN UT WOS:000184901800025 PM 12788926 ER PT J AU Park, JH Wolff, EC Folk, JE Park, MH AF Park, JH Wolff, EC Folk, JE Park, MH TI Reversal of the deoxyhypusine synthesis reaction - Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION-FACTOR 5A; YEAST SACCHAROMYCES-CEREVISIAE; PYRROLIZIDINE ALKALOID BIOSYNTHESIS; PATHWAY-SPECIFIC ENZYME; CELL VIABILITY; INTERMEDIATE FORMATION; SUBSTRATE-SPECIFICITY; HAMSTER EPIDIDYMIS; HYPUSINE DEPLETION; PROTEIN SUBSTRATE AB Deoxyhypusine synthase catalyzes the first step in hypusine (N-epsilon-(4-amino-2-hydroxybutyl) lysine) synthesis in a single cellular protein, eIF5A precursor. The synthesis of deoxyhypusine catalyzed by this enzyme involves transfer of the 4-aminobutyl moiety of spermidine to a specific lysine residue in the eIF5A precursor protein to form a deoxyhypusine-containing eIF5A intermediate, eIF5A(Dhp). We recently discovered the efficient reversal of deoxyhypusine synthesis. When eIF5A([H-3]Dhp), radiolabeled in the 4-aminobutyl portion of its deoxyhypusine residue, was incubated with human deoxyhypusine synthase, NAD, and 1,3-diaminopropane, [H-3] spermidine was formed by a rapid transfer of the radiolabeled 4-aminobutyl side chain of the [H-3] deoxyhypusine residue to 1,3-diaminopropane. No reversal was observed with [H-3] hypusine protein, suggesting that hydroxylation at the 4-aminobutyl side chain of the deoxyhypusine residue prevents deoxyhypusine synthase-mediated reversal of the modification. Purified human deoxyhypusine synthase also exhibited homospermidine synthesis activity when incubated with spermidine, NAD, and putrescine. Thus it was found that [C-14] putrescine can replace eIF5A precursor protein as an acceptor of the 4-aminobutyl moiety of spermidine to form radiolabeled homospermidine. The K-m value for putrescine (1.12 mM) as a 4-aminobutyl acceptor, however, is much higher than that for eIF5A precursor (1.5 muM). Using [C-14] putrescine as an acceptor, various spermidine analogs were evaluated as donor substrates for human deoxyhypusine synthase. Comparison of spermidine analogs as inhibitors of deoxyhypusine synthesis, as donor substrates for synthesis of deoxyhypusine (or its analog), and for synthesis of homospermidine (or its analog) provides new insights into the intricate specificity of this enzyme and versatility of the deoxyhypusine synthase reaction. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Park, MH (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Dept Hlth & Human Serv, Bldg 30,Rm 211, Bethesda, MD 20892 USA. NR 42 TC 30 Z9 31 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 AUG 29 PY 2003 VL 278 IS 35 BP 32683 EP 32691 DI 10.1074/jbc.M304247200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714FN UT WOS:000184901800026 PM 12788913 ER PT J AU Wang, Q Song, CC Yang, XY Li, CCH AF Wang, Q Song, CC Yang, XY Li, CCH TI D1 ring is stable and nucleotide-independent, whereas D2 ring undergoes major conformational changes during the ATPase cycle of p97-VCP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SENSITIVE FUSION PROTEIN; VALOSIN-CONTAINING PROTEIN; AAA-ATPASE; MEMBRANE-FUSION; BINDING-SITES; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; CLPAP PROTEASE AB The 97-kDa valosin-containing protein (p97-VCP) belongs to the AAA ( ATPases associated with various cellular activities) family and acts as a molecular chaperone in diverse cellular events, including ubiquitin-proteasome-mediated degradation. We previously showed that VCP contains a substrate-binding domain, N, and two conserved ATPase domains, D1 and D2, of which D2 is responsible for the major enzyme activity. VCP has a barrel-like structure containing two stacked homo-hexameric rings made of the D1 and D2 domains, and this structure is essential for its biological functions. During ATPase cycles, VCP undergoes conformational changes that presumably apply tensions to the bound substrate, leading to the disassembly of protein complexes or unfolding of the substrate. How ATPase activity is coupled with the conformational changes in VCP complex and the D1 and D2 rings is not clear. In this report, we took biochemical approaches to study the structure of VCP in different nucleotide conditions to depict the conformational changes in the ATPase cycles. In contrast to many AAA chaperones that require ATP/ADP to form oligomers, both wild type VCP and ATP-binding site mutants can form hexamers without the addition of nucleotide. This nucleotide-independent hexamerization requires an intact D1 and the downstream linker sequence of VCP. Tryptophan fluorescence and trypsin digestion analyses showed that ATP/ ADP binding induces dramatic conformational changes in VCP. These changes do not require the presence of an intact ATP-binding site in D1 and is thus mainly attributed to the D2 domain. We propose a model whereby D1, although undergoing minor conformational changes, remains as a relatively trypsin-resistant hexameric ring throughout the ATPase cycle, whereas D2 only does so when it binds to ATP or ADP. After ADP is released at the end of the ATP hydrolysis, D2 ring is destabilized and adopts a relatively flexible and open structure. C1 NCI, Basic Res Program, Sci Applicat Int Corp, NIH, Frederick, MD 21702 USA. NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. RP Li, CCH (reprint author), NCI, Basic Res Program, Sci Applicat Int Corp, NIH, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 41 TC 58 Z9 59 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 29 PY 2003 VL 278 IS 35 BP 32784 EP 32793 DI 10.1074/jbc.M303869200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714FN UT WOS:000184901800038 PM 12807884 ER PT J AU Storey, NM Gomez-Angelats, M Bortner, CD Armstrong, DL Cidlowski, JA AF Storey, NM Gomez-Angelats, M Bortner, CD Armstrong, DL Cidlowski, JA TI Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED CELL-DEATH; CYTOCHROME-C; KINASE-C; SIGNALING COMPLEX; VOLUME REGULATION; K+ CHANNELS; CASPASE ACTIVATION; MEDIATED APOPTOSIS; FAS; SHRINKAGE AB The loss of intracellular potassium is a pivotal step in the induction of apoptosis but the mechanisms underlying this response are poorly understood. Here we report caspase-dependent stimulation of potassium channels by the Fas receptor in a human Jurkat T cell line. Receptor activation with Fas ligand for 30 min increased the amplitude of voltage-activated potassium currents 2-fold on average. This produces a sustained outward current, similar to 10 pA, at physiological membrane potentials during Fas ligand-induced apoptosis. Both basal and Fas ligand-induced currents were blocked completely by toxins that selectively inhibit Kv1.3 potassium channels. Kv1.3 stimulation required the expression of Fas-associated death domain protein and activation of caspase 8, but did not require activation of caspase 3 or protein synthesis. Furthermore, Kv1.3 stimulation by Fas ligand was prevented by chronic stimulation of protein kinase C with 20 nM phorbol 12-myristate 13-acetate during Fas ligand treatment, which also blocks apoptosis. Thus, Fas ligand increases Kv1.3 channel activity through the same canonical apoptotic signaling cascade that is required for potassium efflux, cell shrinkage, and apoptosis. C1 NIEHS, Membrane Signaling Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Membrane Signaling Grp, Res Triangle Pk, NC 27709 USA. NR 43 TC 60 Z9 65 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 AUG 29 PY 2003 VL 278 IS 35 BP 33319 EP 33326 DI 10.1074/jbc.M300443200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714FN UT WOS:000184901800102 PM 12807917 ER PT J AU Snijder, EJ Bredenbeek, PJ Dobbe, JC Thiel, V Ziebuhr, J Poon, LLM Guan, Y Rozanov, M Spaan, WJM Gorbalenya, AE AF Snijder, EJ Bredenbeek, PJ Dobbe, JC Thiel, V Ziebuhr, J Poon, LLM Guan, Y Rozanov, M Spaan, WJM Gorbalenya, AE TI Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE nidovirus; genome organization; subgenomic mRNA synthesis; replicase; RNA processing ID ACUTE RESPIRATORY SYNDROME; MOUSE HEPATITIS-VIRUS; INFECTIOUS-BRONCHITIS-VIRUS; MULTIPLE SEQUENCE ALIGNMENT; MESSENGER-RNA SYNTHESIS; CYSTEINE PROTEINASE; BOVINE CORONAVIRUS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; ACTIVE-SITE AB The genome organization and expression strategy of the newly identified severe acute respiratory syndrome coronavirus (SARS-CoV) were predicted using recently published genome sequences. Fourteen putative open reading frames were identified, 12 of which were predicted to be expressed from a nested set of eight subgenomic mRNAs. The synthesis of these mRNAs in SARS-CoV-infected cells was confirmed experimentally. The 4382- and 7073 amino acid residue SARS-CoV replicase poly-proteins are predicted to be cleaved into 16 subunits by two viral proteinases (bringing the total number of SARS-CoV proteins to 28). A phylogenetic analysis of the replicase gene, using a distantly related torovirus as an outgroup, demonstrated that, despite a number of unique features, SARS-CoV is most closely related to group 2 coronaviruses. Distant homologs of cellular RNA processing enzymes were identified in group 2 coronaviruses, with four of them being conserved in SARS-CoV. These newly recognized viral enzymes place the mechanism of coronavirus RNA synthesis in a completely new perspective. Furthermore, together with previously described viral enzymes, they will be important targets for the design of antiviral strategies aimed at controlling the further spread of SARS-CoV. (C) 2003 Elsevier Ltd. All rights reserved. C1 Leiden Univ, Med Ctr, Dept Med Microbiol, Mol Virol Lab, NL-2300 RC Leiden, Netherlands. Univ Wurzburg, Inst Immunol & Virol, Wurzburg, Germany. Univ Hong Kong, Queen Mary Hosp, Dept Microbiol & Pathol, Hong Kong, Hong Kong, Peoples R China. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Snijder, EJ (reprint author), Leiden Univ, Med Ctr, Dept Med Microbiol, Mol Virol Lab, Room L4-34,Albinusdreef 2,POB 9600, NL-2300 RC Leiden, Netherlands. RI Poon, Leo/C-4382-2009; Gorbalenya, Alexander/J-4818-2012 OI Poon, Leo/0000-0002-9101-7953; Gorbalenya, Alexander/0000-0002-4967-7341 NR 78 TC 636 Z9 680 U1 4 U2 30 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 AUG 29 PY 2003 VL 331 IS 5 BP 991 EP 1004 DI 10.1016/S0022-2836(03)00865-9 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716NZ UT WOS:000185036400004 PM 12927536 ER PT J AU Ramasamy, V Ramakrishnan, B Boeggeman, E Qasba, PK AF Ramasamy, V Ramakrishnan, B Boeggeman, E Qasba, PK TI The role of tryptophan 314 in the conformational changes of beta 1,4-galactosyltransferase-I SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta 1,4-galactosyltransferase-I tryptophan mutant; flexible loop conformation; protease digestion; substrate binding; catalytic mechanism ID ALPHA-LACTALBUMIN LA; CRYSTAL-STRUCTURE; N-ACETYLGLUCOSAMINE; CATALYTIC MECHANISM; LACTOSE SYNTHASE; BINDING-SITES; UDP-GLUCOSE; PROTEIN; GLYCOSYLTRANSFERASES; COMPLEX AB beta1,4-Galactosyltransferase-I (beta4Gal-T1) undergoes critical conformational changes upon substrate binding from an open conformation (conf-I) to the closed conformation (conf-II). This change involves two flexible loops: the small (residues 313-316) and the long loop (residues 345-365). Upon substrate binding, Trp314 in the small flexible loop moves towards the catalytic pocket and interacts with the donor and the acceptor substrates. For a better understanding of the role played by Trp314 in the conformational changes of beta4Gal-T1, we mutated it to Ala and carried out substrate-binding, proteolytic and crystallographic studies. The W314A mutation reduces the enzymatic activity binding to substrates and to the modifier protein, alpha-lactalbumin (LA), by over 99%. The limited proteolysis with Glu-C or Lys-C proteases shows differences in the rate of cleavage of the long loop of the wild-type and mutant W314A, indicating conformational differences in the region between the two proteins. Without substrate, the mutant crystallizes in a conformation (conf-I') (1.9 Angstrom resolution crystal structure), that is not identical with, but close to an open conformation (conf-I), whereas its complex with the substrates and alpha-lactalbumin, crystallizes in a conformation (2.3 Angstrom resolution crystal structure) that is identical with the closed conformation (conf-II). This study shows the crucial role Trp314 plays in the conformational state of the long loop, in the binding of substrates and in the catalytic mechanism of the enzyme. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Struct Glycobiol Sect, LECB, CCR, Frederick, MD 21702 USA. NCI, Basic Res Program, LECB, CCR, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, LECB, CCR, Bldg 469,Room 221, Frederick, MD 21702 USA. FU PHS HHS [N01-C0-12400] NR 36 TC 21 Z9 24 U1 1 U2 3 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 AUG 29 PY 2003 VL 331 IS 5 BP 1065 EP 1076 DI 10.1016/S0022-2836(03)00790-3 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716NZ UT WOS:000185036400010 PM 12927542 ER PT J AU Lipman, EA Schuler, B Bakajin, O Eaton, WA AF Lipman, EA Schuler, B Bakajin, O Eaton, WA TI Single-molecule measurement of protein folding kinetics SO SCIENCE LA English DT Article ID RESONANCE ENERGY-TRANSFER; TRANSFER CONFOCAL MICROSCOPY; FLUORESCENCE SPECTROSCOPY; DYNAMICS; PEPTIDES; TIME AB In order to investigate the behavior of single molecules under conditions far from equilibrium, we have coupled a microfabricated laminar-flow mixer to a confocal optical system. This combination enables time-resolved measurement of Forster resonance energy transfer after an abrupt change in solution conditions. Observations of a small protein show the evolution of the intramolecular distance distribution as folding progresses. This technique can expose subpopulations, such as unfolded protein under conditions favoring the native structure, that would be obscured in equilibrium experiments. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Lawrence Livermore Natl Lab, Biosecur Nanosci Lab, Livermore, CA 94550 USA. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 104, Bethesda, MD 20892 USA. RI Bakajin, Olgica/A-9745-2008; Lipman, Everett/D-1696-2009; Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 NR 21 TC 280 Z9 289 U1 2 U2 54 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 AUG 29 PY 2003 VL 301 IS 5637 BP 1233 EP 1235 DI 10.1126/science.1085399 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 715ZC UT WOS:000185003500041 PM 12947198 ER PT J AU Spath, GF Lye, LF Segawa, H Sacks, DL Turco, SJ Beverley, SM AF Spath, GF Lye, LF Segawa, H Sacks, DL Turco, SJ Beverley, SM TI Persistence without pathology in phosphoglycan-deficient Leishmania major SO SCIENCE LA English DT Article ID MURINE CUTANEOUS LEISHMANIASIS; LATENT LEISHMANIASIS; VIRULENCE FACTOR; LIPOPHOSPHOGLYCAN; MICE; PARASITES; HOST; PROMASTIGOTES; REACTIVATION; IMMUNITY AB Leishmania infections involve an acute phase of replication within macrophages, typically associated with pathology. After recovery parasites persist for long periods, which can lead to severe disease upon reactivation. Unlike the role of host factors, parasite factors affecting persistence are poorly understood. Leishmania major lacking phosphoglycans (lpg2(-)) were unable to survive in sand flies and macrophages, but retained the ability to persist indefinitely in the mammalian host without inducing disease. The L. major lpg2(-) thus provides a platform for probing parasite factors implicated in persistence and its role in disease and immunity. C1 Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA. Univ Kentucky, Dept Biochem, Lexington, KY 40536 USA. NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Beverley, SM (reprint author), Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA. RI Spaeth, Gerald/B-1393-2014; OI Beverley, Stephen/0000-0001-5319-0811 FU NIAID NIH HHS [AI31078] NR 30 TC 116 Z9 122 U1 2 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 29 PY 2003 VL 301 IS 5637 BP 1241 EP 1243 DI 10.1126/science.1087499 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 715ZC UT WOS:000185003500044 PM 12947201 ER PT J AU Pombo, I Rivera, J Blank, U AF Pombo, I Rivera, J Blank, U TI Munc18-2/syntaxin3 complexes are spatially separated from syntaxin3-containing SNARE complexes SO FEBS LETTERS LA English DT Article DE SNARE; munic18; raft; membrane fusion ID FC-EPSILON-RI; GLYCOSPHINGOLIPID-ENRICHED MICRODOMAINS; MAST-CELL DEGRANULATION; MEMBRANE-FUSION; LIPID RAFTS; 3T3-L1 ADIPOCYTES; EXOCYTOSIS; ACTIVATION; CHOLESTEROL; RECEPTORS AB Exocytosis of mast cell granules requires a vesicular-and plasma membrane-associated fusion machinery. We examined the distribution of SNARE membrane fusion and Munc18 accessory proteins in lipid rafts of RBL mast cells. SNAREs were found either excluded (syntaxin2), equally distributed between raft and non-raft fractions (syntaxin4, VAMP-8, VAMP-2), or selectively enriched in rafts (syntaxin3, SNAP-23). Syntaxin4-binding Munc18-3 was absent, whereas small amounts of the syntaxin3-interacting partner Munc18-2 consistently distributed into rafts. Cognate SNARE complexes of syntaxin3 with SNAP-23 and VAMP-8 were enriched in rafts, whereas Munc18-2/syntaxin3 complexes were excluded. This demonstrates a spatial separation between these two types of complexes and suggests that Munc18-2 acts in a step different from SNARE complex formation and fusion. (C) 2003 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Inst Pasteur, Unite Immunoallergie, F-75724 Paris, France. NIAMSD, Mol Inflammat Sect, NIH, Bethesda, MD 20892 USA. RP Blank, U (reprint author), Fac Med X, INSERM, E 0225, 16 Rue Henri Huchard,POB 416, F-75870 Paris 18, France. NR 42 TC 37 Z9 40 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 28 PY 2003 VL 550 IS 1-3 BP 144 EP 148 DI 10.1016/S0014-5793(03)00864-0 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 716XM UT WOS:000185055000026 PM 12935901 ER PT J AU Jeong, LS Jin, DZ Kim, HO Shin, DH Moon, HR Gunaga, P Chun, MW Kim, YC Melman, N Gao, ZG Jacobson, KA AF Jeong, LS Jin, DZ Kim, HO Shin, DH Moon, HR Gunaga, P Chun, MW Kim, YC Melman, N Gao, ZG Jacobson, KA TI N-6-substituted D-4 '-thioadenosine-5 '-methyluronamides: Potent and selective agonists at the human A(3) adenosine receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MAST-CELLS; LIGANDS; DERIVATIVES; PURINE AB 4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K-i = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from D-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K-i = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively. C1 Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. Kwangju Inst Sci & Technol, Dept Life Sci, Gwangju 500712, South Korea. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 19 TC 62 Z9 63 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 AUG 28 PY 2003 VL 46 IS 18 BP 3775 EP 3777 DI 10.1021/jm034098e PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 714YL UT WOS:000184942500002 PM 12930138 ER PT J AU Luzzio, FA Mayorov, AV Ng, SSW Kruger, EA Figg, WD AF Luzzio, FA Mayorov, AV Ng, SSW Kruger, EA Figg, WD TI Thalidomide metabolites and analogues. 3. Synthesis and antiangiogenic activity of the teratogenic and TNF alpha-modulatory thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MARMOSET MONKEY; IN-VITRO; ANGIOGENESIS; DERIVATIVES; ENANTIOMERS; INHIBITORS; EM-12; ACID AB Versatile synthesis of the teratogenic, TNFalpha-modulatory, and antiangiogenic thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine (1) and its direct antiangiogenic properties are described. With thalidomide or thalidomide derivatives as precursors, the synthesis involved either carbonyl reduction/thiation-desulfurization or carbonyl reduction/acyliminium ion reduction protocols. Compared to earlier studies with thalidomide, which was only active with microsomal treatment, I exhibited marginal inhibitory activity in the rat aortic ring assay, thereby demonstrating the requirement for metabolic activation. C1 Univ Louisville, Dept Chem, Louisville, KY 40292 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RP Luzzio, FA (reprint author), Univ Louisville, Dept Chem, 2320 S Brook St, Louisville, KY 40292 USA. EM faluzz01@athena.louisville.edu RI Mayorov, Alexander/G-5204-2014; Figg Sr, William/M-2411-2016 OI Mayorov, Alexander/0000-0002-0899-7138; NR 25 TC 33 Z9 35 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 28 PY 2003 VL 46 IS 18 BP 3793 EP 3799 DI 10.1021/jm020079d PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 714YL UT WOS:000184942500006 PM 12930142 ER PT J AU Rockwood, LD Nussenzweig, A Janz, S AF Rockwood, LD Nussenzweig, A Janz, S TI Paradoxical decrease in mutant frequencies and chromosomal rearrangements in a transgenic lacZ reporter gene in Ku80 null mice deficient in DNA double strand break repair SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE genomic instability; Ku80 deficiency; in vivo mutant frequency; transgenic shuttle vector-based mutagenesis assay ID END-JOINING PATHWAY; IONIZING-RADIATION; MAMMALIAN-CELLS; GENOME REARRANGEMENTS; V(D)J RECOMBINATION; SOMATIC MUTATIONS; TRANSLOCATIONS; AMPLIFICATION; ACCUMULATION; MUTAGENESIS AB Repair of DNA double strand breaks (DSB), either by homologous recombination (HR) or nonhomologous end-joining (NHEJ), is essential to maintain genomic stability. To examine the impact of NHEJ deficiency on genomic integrity in Ku80null (Ku(-)) mice, the chromosomally integrated shuttle vector pUR288, which includes a lacZ reporter gene, was used to measure mutations in vivo. Unexpectedly, a significant decrease was found in mutant frequencies of Ku(-) liver (5.04 x 10(-5)) and brain (4.55 x 10(-5)) compared to tissues obtained from normal (Ku(+)) littermates (7.92 x 10(-5) and 7.30 x 10(-5), respectively). No significant difference was found in mutant frequencies in spleen from Ku(-) (7.21 X 10(-5)) and Ku(+) mice (8.16 x 10(-5)). The determination of the mutant spectrum in lacZ revealed the almost complete absence of chromosomal rearrangements (R) in Ku(-) tissues (0.5%, 3/616), a notable distinction from Ku(+) controls (16.7%, 104/621). These findings suggest that accurate repair of DSB by HR and elimination of cells with unrepaired DNA damage by apoptosis are capable of maintaining genomic stability of the lacZ reporter in Ku(-) mice. (C) 2003 Elsevier B.V. All rights reserved. C1 NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Room 2B10,Bldg 37, Bethesda, MD 20892 USA. NR 33 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 28 PY 2003 VL 529 IS 1-2 BP 51 EP 58 DI 10.1016/S0027-5107(03)00108-8 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 720ED UT WOS:000185247800005 PM 12943919 ER PT J AU Ling, H Boudsocq, F Plosky, BS Woodgate, R Yang, W AF Ling, H Boudsocq, F Plosky, BS Woodgate, R Yang, W TI Replication of a cis-syn thymine dimer at atomic resolution SO NATURE LA English DT Article ID DNA-POLYMERASE-ETA; CRYSTAL-STRUCTURE; SULFOLOBUS-SOLFATARICUS; XERODERMA-PIGMENTOSUM; EXCISION-REPAIR; ERROR-PRONE; DAMAGED DNA; Y-FAMILY; BYPASS; MUTATIONS AB Ultraviolet light damages DNA by catalysing covalent bond formation between adjacent pyrimidines, generating cis-syn cyclobutane pyrimidine dimers (CPDs) as the most common lesion(1). CPDs block DNA replication by high-fidelity DNA polymerases, but they can be efficiently bypassed by the Y-family DNA polymerase pol eta(2,3). Mutations in POLH encoding pol h are implicated in nearly 20% of xeroderma pigmentosum, a human disease characterized by extreme sensitivity to sunlight and predisposition to skin cancer(4-6). Here we have determined two crystal structures of Dpo4, an archaeal pol eta homologue, complexed with CPD-containing DNA, where the 3' and 5' thymine of the CPD separately serves as a templating base. The 3' thymine of the CPD forms a Watson-Crick base pair with the incoming dideoxyATP, but the 5' thymine forms a Hoogsteen base pair with the dideoxyATP in syn conformation. Dpo4 retains a similar tertiary structure, but each unusual DNA structure is individually fitted into the active site for catalysis. A model of the pol eta-CPD complex built from the crystal structures of Saccharomyces cerevisiae apo-pol eta and the Dpo4-CPD complex suggests unique features that allow pol eta to efficiently bypass CPDs. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Ling, Hong/E-3729-2010; Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 30 TC 157 Z9 158 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 28 PY 2003 VL 424 IS 6952 BP 1083 EP 1087 DI 10.1038/nature01919 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 715QR UT WOS:000184984200050 PM 12904819 ER PT J AU Lu, B AF Lu, B TI Pro-region of neurotrophins: Role in synaptic modulation SO NEURON LA English DT Review ID REGULATED SECRETORY PATHWAY; NERVE GROWTH-FACTOR; LONG-TERM POTENTIATION; HIPPOCAMPAL-NEURONS; FACTOR RECEPTORS; BDNF; MECHANISM; CELLS; TRKB; NEUROENDOCRINE AB Neurotrophins are synthesized first as precursors, followed by maturation through proteolytic removal of the "pro" region. Since pro- and mature neurotrophins elicit opposite functional effects by differential interactions with Trks and p75 receptors, extracellular cleavage represents a new way to control the synaptic functions of neurotrophins. A single nucleotide mutation in the pro-region appears to affect synaptic targeting and activity-dependent secretion of BDNF in hippocampal neurons. These results demonstrate new mechanisms by which neurotrophins regulate synaptic plasticity and memory function. C1 NICHHD, Sect Neurol Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Sect Neurol Dev & Plast, NIH, Bethesda, MD 20892 USA. NR 23 TC 145 Z9 149 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 28 PY 2003 VL 39 IS 5 BP 735 EP 738 DI 10.1016/S0896-6273(03)00538-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 717GN UT WOS:000185079300004 PM 12948441 ER PT J AU Lawrence, J Mayers, DL Hullsiek, KH Collins, G Abrams, DI Reisler, RB Crane, LR Schmetter, BS Dionne, TJ Saldanha, JM Jones, MC Baxter, JD AF Lawrence, J Mayers, DL Hullsiek, KH Collins, G Abrams, DI Reisler, RB Crane, LR Schmetter, BS Dionne, TJ Saldanha, JM Jones, MC Baxter, JD CA 064 Study Team Terry Beirn TI Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIROLOGICAL FAILURE; THERAPY; MUTATIONS; HIV-1; EVOLUTION; REGIMENS; VIREMIA; IMPACT AB BACKGROUND: We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV). METHODS: Patients with multidrug-resistant HIV and HIV RNA levels of more than 5000 copies per milliliter were randomly assigned to a four-month structured interruption of treatment followed by a change in antiretroviral regimen (treatment-interruption group) or to an immediate change in regimen (control group). Genotypic and phenotypic resistance testing was performed. Disease progression, death, and changes in genotypic resistance, CD4 cell counts, HIV RNA levels, and quality of life were assessed. RESULTS: After a median follow-up of 11.6 months, disease progression or death occurred in 22 of the 138 patients in the treatment-interruption group and in 12 of the 132 patients in the control group (P=0.01), with a hazard ratio of 2.57 (95 percent confidence interval, 1.2 to 5.5) for the treatment-interruption group. There were eight deaths in each group. In the treatment-interruption group, the mutant HIV populations completely or partially reverted to wild type by four months in 64.0 percent of patients. As compared with the control group, the treatment-interruption group had a mean CD4 cell count that was 85 cells per cubic millimeter lower from months 0 through 4 (P<0.001), 47 cells per cubic millimeter lower from months 5 through 8 (P<0.001), and 31 cells per cubic millimeter lower after eight months (P=0.11). The mean HIV RNA levels were 1.2 log copies per milliliter higher (on a base-10 scale) in the treatment-interruption group during months 0 through 4 (P<0.001), but they were not significantly different from those in the control group after month 4. The overall quality of life was similar in the two groups. CONCLUSIONS: In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life. C1 Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Posit Hlth Program, San Francisco, CA 94110 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. NIAID, NIH, Div AIDS, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. Social & Sci Syst, Silver Spring, MD USA. Washington Reg AIDS Program, Washington, DC USA. Denver Publ Hlth Dept, Denver, CO USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cooper Hosp, Dept Med, Camden, NJ 08103 USA. RP Lawrence, J (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Posit Hlth Program, 3180 18th St,Suite 305, San Francisco, CA 94110 USA. FU NIAID NIH HHS [5U01AI042170-10, 5U01AI046362-03] NR 23 TC 174 Z9 177 U1 1 U2 11 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 AUG 28 PY 2003 VL 349 IS 9 BP 837 EP 846 DI 10.1056/NEJMoa035103 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 715JM UT WOS:000184968400004 PM 12944569 ER PT J AU Lenfant, C AF Lenfant, C TI Shattuck Lecture: Clinical research to clinical practice - Lost in translation? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Massachusetts-Medical-Society CY MAY 03, 2003 CL BOSTON, MASSACHUSETTS SP Massachusetts Med Soc ID ACUTE MYOCARDIAL-INFARCTION; PRACTICE GUIDELINES COMMITTEE; CORONARY HEART-DISEASE; ASSOCIATION TASK-FORCE; ACC/AHA GUIDELINES; HEALTH-CARE; RISK; MEDICATION; AMERICAN; POLYMORPHISMS C1 NHLBI, NIH, Bethesda, MD 20892 USA. Dept Hlth & Human Serv, Washington, DC USA. RP Lenfant, C (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 31,Room 5A52, Bethesda, MD 20892 USA. NR 29 TC 463 Z9 477 U1 5 U2 17 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 28 PY 2003 VL 349 IS 9 BP 868 EP 874 DI 10.1056/NEJMsa035507 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 715JM UT WOS:000184968400009 PM 12944573 ER PT J AU Leaner, VD Kinoshita, I Birrer, MJ AF Leaner, VD Kinoshita, I Birrer, MJ TI AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a fibroblasts and share transcriptional targets SO ONCOGENE LA English DT Article DE cJun; JunB; JunD; transcriptional targets ID ANCHORAGE-INDEPENDENT GROWTH; BREAST-CANCER CELLS; C-JUN; PROTEIN-KINASE; V-JUN; RAT-1A CELLS; EXPRESSION; CAVEOLIN-1; FOS; GENE AB To investigate the role of individual Jun proteins in cell growth and transformation, we have used a doxycycline-inducible retroviral vector to regulate their expression in rat fibroblasts. AP-1 complexes enriched with cJun and JunB result in morphological alterations and anchorage-independent cell growth consistent with a transformation-like phenotype, whereas complexes enriched with JunD had an antiproliferative effect. These results suggest that genes regulated by both cJun and JunB are potentially involved in transformation and that they can be distinguished from those regulated by AP-1 complexes containing JunD. To identify genes regulated by cJun and JunB that may have a role in anchorage-independent growth, we investigated differential gene expression by each of the Jun family members using the Affymetrix Rat oligonucleotide microarray, RG_U34A containing approximately 8000 genes. Differentially regulated genes were identified and grouped for correlation with regulation by the different Jun proteins. A total of 33 candidate genes were found to be differentially regulated by both cJun and JunB and not by JunD. These genes have roles in cell metabolism, growth, signal transduction, migration and adhesion. We validated the differential regulation by cJun and JunB of 10 candidate genes by Northern blot analysis. Of these, eight were further characterized as potential direct targets of AP-1 regulation based on Northern blot results showing differential regulation that correlate with cJun expression. Our results show that inducible cJun and JunB expression result in anchorage-independent growth of Rat1a cells, distinct from JunD-expressing cells. This model system and a functional genomic approach enabled us to differentiate AP-1-regulated genes involved in transformation from AP-1-regulated genes known as bystander genes. This approach significantly reduces the number of bystanders and allows for the targeting of genes specifically involved in transformation. C1 NCI, Cell & Canc Biol Dept, NIH, Rockville, MD 20850 USA. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Dept, NIH, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. NR 55 TC 38 Z9 38 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 AUG 28 PY 2003 VL 22 IS 36 BP 5619 EP 5629 DI 10.1038/sj.onc.1206644 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 713NY UT WOS:000184865900011 PM 12944910 ER PT J AU Vastag, B Lenfant, C AF Vastag, B Lenfant, C TI Claude Lenfant, MD - Retiring NHLBI director looks ahead SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 27 PY 2003 VL 290 IS 8 BP 1017 EP 1018 DI 10.1001/jama.290.8.1017 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 715FA UT WOS:000184958900004 ER PT J AU Wang, TJ Massaro, JM Levy, D Vasan, RS Wolf, PA D'Agostino, RB Larson, MG Kannel, WB Benjamin, EJ AF Wang, TJ Massaro, JM Levy, D Vasan, RS Wolf, PA D'Agostino, RB Larson, MG Kannel, WB Benjamin, EJ TI A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community - The Framingham Heart Study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CONTROLLED TRIALS; LEFT-VENTRICULAR HYPERTROPHY; ANTITHROMBOTIC THERAPY; ELDERLY POPULATION; CLINICAL-TRIALS; ISCHEMIC STROKE; ASPIRIN THERAPY; ANTICOAGULATION; PREVENTION; THROMBOEMBOLISM AB Context Prior risk stratification schemes for atrial fibrillation (AF) have been based on randomized trial cohorts or Medicare administrative databases, have included patients with established AF, and have focused on stroke as the principal outcome. Objective To derive risk scores for stroke alone and stroke or death in community-based individuals with new-onset AF. Design, Setting, and Participants Prospective, community-based, observational cohort in Framingham, Mass. We identified 868 participants with new-onset AF, 705 of whom were not treated with warfarin at baseline. Risk scores for stroke (ischemic or hemorrhagic) and stroke or death were developed with censoring when warfarin initiation occurred during follow-up. Event rates were examined in low-risk individuals, as defined by the risk score and 4 previously published risk schemes. Main Outcome Measures Stroke and the combination of stroke or death. Results During a mean follow-up of 4.0 years free of warfarin use, stroke alone occurred in 83 participants and stroke or death occurred in 382 participants. A risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes. With the risk score, 14.3% of the cohort had a predicted 5-year stroke rate less than or equal to7.5% (average annual rate less than or equal to1.5%), and 30.6% of the cohort had a predicted 5-year stroke rate less than or equal to10% (average annual rate less than or equal to2%). Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk schemes classified 6.4% to 17.3% of subjects as low risk, with actual stroke rates of 0.9 to 2.3 per 100 person-years. A risk score for stroke or death is also presented. Conclusion These risk scores can be used to estimate the absolute risk of an adverse event in individuals with AF, which may be helpful in counseling patients and making treatment decisions. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiol, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. RP Benjamin, EJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1K24-HL-04334, K23 HL074077-01, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 44 TC 401 Z9 411 U1 0 U2 15 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 AUG 27 PY 2003 VL 290 IS 8 BP 1049 EP 1056 DI 10.1001/jama.290.8.1049 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 715FA UT WOS:000184958900023 PM 12941677 ER PT J AU Agrawal, M Emanuel, EJ AF Agrawal, M Emanuel, EJ TI Ethics of phase 1 oncology studies - Reexamining the arguments and data SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID I CLINICAL-TRIALS; QUALITY-OF-LIFE; RENAL-CELL CARCINOMA; ABL TYROSINE KINASE; INFORMED CONSENT; CANCER-PATIENTS; THERAPEUTIC RESPONSE; ANTICANCER AGENTS; FUNCTIONAL STATUS; DESIGN AB Phase 1 oncology trials are critical to improving the treatment of cancer. Critics have raised 2 fundamental ethical challenges about phase 1 cancer research: the paucity of benefits with substantial risks and poor-quality informed consent. Despite 3 decades of controversy about phase 1 oncology research, there is little critical analysis of the arguments or of the data relevant to these questions. Existing but old data reveal that about 5% of patients in phase 1 trials experience shrinkage of their tumor, with a 0.5% mortality rate. In some notable cases, patients in phase 1 trials have been cured or sustained long-term remissions. Limited data suggest that patients in phase 1 trials may have better quality of life than comparable patients receiving supportive care. More important, the risks and benefits of phase 1 trials are not clearly worse than risk-benefit ratios used by the US Food and Drug Administration to approve chemotherapeutic agents for clinical use. The objections based on informed consent are deficiencies of disclosure, understanding, and voluntariness. The available data do not support the claim that disclosure is deficient. Although studies evaluating patient understanding have substantial methodological problems, they demonstrate that more than 70% of patients understand that they may not directly benefit even when they hope they will personally benefit. Finally, a closer look at issues of voluntariness reveals that patients with advanced cancer who participate in phase 1 research may have a different set of values than do critics and are not coerced. Overall, it appears that phase 1 oncology trials satisfy the requirement for a favorable risk-benefit ratio and that patients who enroll provide adequate informed consent. C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Agrawal, M (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bldg 10,Room 1C118,10 Ctr Dr, Bethesda, MD 20892 USA. NR 66 TC 108 Z9 109 U1 1 U2 10 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 AUG 27 PY 2003 VL 290 IS 8 BP 1075 EP 1082 DI 10.1001/jama.290.8.1075 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 715FA UT WOS:000184958900027 PM 12941681 ER PT J AU Fields, RL House, SB Gainer, H AF Fields, RL House, SB Gainer, H TI Regulatory domains in the intergenic region of the oxytocin and vasopressin genes that control their hypothalamus specific expression in vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article DE hypothalamus; organotypic culture; biolistics; gene expression; vasopressin; oxytocin ID CILIARY NEUROTROPHIC FACTOR; CELL-SPECIFIC EXPRESSION; MAGNOCELLULAR NEURONS; ORGANOTYPIC CULTURES; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; NEUROHYPOPHYSEAL SYSTEM; PARAVENTRICULAR NUCLEUS; TRANSGENIC MICE; RAT; NEUROPHYSIN AB Previous studies of oxytocin (OT) and vasopressin (VP) cell-specific gene expression in the hypothalamus using transgenic mouse and rat models focused attention on the intergenic region (IGR) as the site of critical enhancer elements. In this study, we used organotypic slice-explant cultures of rat hypothalamus as in vitro models, and particle-mediated gene transfer (biolistics) transfection methods to identify critical DNA sequences in the IGR between the OT and VP genes responsible for hypothalamic-specific gene expression. Reducing the 5' flanking region in the mouse VP gene from 3.5 kbp to 288 bp did not alter the efficacy of its expression in hypothalamic slices. All subsequent VP constructs were based on this 288 bp VP gene construct with changes made only to the IGR. These studies, which used various constructs with OT and VP promoters driving enhanced green fluorescent protein reporter gene expression, demonstrated that the IGR is necessary for OT and VP gene expression in hypothalamic slices in vitro. The DNA sequences in the IGR responsible for both OT and VP gene expression were located in a 178 bp domain immediately downstream of exon 3 of the VP gene. In addition, another domain in the IGR, 430 bp immediately downstream of exon 3 of the OT gene, contained a positive regulatory element for OT gene expression in the hypothalamus. Alignment of the DNA sequences in the 178 and 430 bp domains reveals four common sequences (motifs) that may be candidates for the putative enhancers in the IGR that regulate OT and VP gene hypothalamic-specific expression. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D-04, Bethesda, MD 20892 USA. NR 53 TC 23 Z9 23 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 AUG 27 PY 2003 VL 23 IS 21 BP 7801 EP 7809 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 715YH UT WOS:000185001700011 PM 12944509 ER PT J AU Wang, Y Chang, CF Morales, M Chiang, YH Harvey, BK Su, TP Tsao, LI Chen, SY Thiemermann, C AF Wang, Y Chang, CF Morales, M Chiang, YH Harvey, BK Su, TP Tsao, LI Chen, SY Thiemermann, C TI Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ischemia; stroke; Parkinson's disease; repair; protection; diadenosine tetraphosphate; apoptosis ID CEREBRAL-ARTERY OCCLUSION; POLYPHOSPHATES; TRANSPLANTATION; SYNAPTOSOMES; RECEPTOR; BINDING; ATP; DISTINCT; PATHWAY; STROKE AB Diadenosine tetraphosphate (AP(4)A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP(4)A in rodent models of stroke and Parkinson's disease. AP(4)A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP(4)A also induced protection when given early after MCA ligation. AP(4)A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling ( TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P-2/P-4 antagonist di-inosine pentaphosphate or P-1-receptor antagonist sulfonylphenyl theophylline, but not the P-2-receptor antagonist suramin, antagonized the effect of AP(4)A, suggesting that the observed protection is mediated through an antiapoptotic mechanism and the activation of P-1- and P-4-purinergic receptors. AP(4)A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP(4)A. In addition, AP(4)A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP(4)A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP(4)A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease. C1 NIDA, NIH, Baltimore, MD 21224 USA. Natl Def Med Ctr, Triserv Gen Hosp, Taipei 114, Taiwan. Queen Mary Univ, William Harvey Res Inst, London EC1M 6BQ, England. RP Wang, Y (reprint author), NIDA, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 25 TC 47 Z9 49 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 27 PY 2003 VL 23 IS 21 BP 7958 EP 7965 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 715YH UT WOS:000185001700029 PM 12944527 ER PT J AU Hering, BJ Anand, R Close, N Eggerman, T AF Hering, BJ Anand, R Close, N Eggerman, T CA CITR Res Grp TI NIH-supported Collaborative Islet Transplant Registry SO TRANSPLANTATION LA English DT Meeting Abstract CT 9th Congress of the International-Pancreas-and-Islet-Transplant-Association CY JUL 08-11, 2003 CL DUBLIN, IRELAND SP Int Pancreas & Islet Transplant Assoc C1 Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. EMMES Corp, Rockville, MD USA. Natl Inst Diabet & Kidney Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2003 VL 76 IS 4 SU S MA 66 BP S40 EP S40 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 718FV UT WOS:000185135200066 ER PT J AU Spragg, DD Leclercq, C Loghmani, M Faris, OP Tunin, RS DiSilvestre, D McVeigh, ER Tomaselli, GF Kass, DA AF Spragg, DD Leclercq, C Loghmani, M Faris, OP Tunin, RS DiSilvestre, D McVeigh, ER Tomaselli, GF Kass, DA TI Regional alterations in protein expression in the dyssynchronous failing heart SO CIRCULATION LA English DT Article DE heart failure; pacing; molecular biology; sarcoplasmic reticulum ID BUNDLE-BRANCH BLOCK; DILATED CARDIOMYOPATHY; VENTRICULAR WALL; CONNEXIN43; FAILURE; ACTIVATION; GENE; MORTALITY; SUDDEN AB Background - Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results - Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression ( with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial - paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions - LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility. C1 Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Kass, DA (reprint author), Johns Hopkins Univ Hosp, Halsted 500,600 N Wolfe St, Baltimore, MD 21287 USA. FU NHLBI NIH HHS [P50-HL52307] NR 19 TC 161 Z9 175 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 AUG 26 PY 2003 VL 108 IS 8 BP 929 EP 932 DI 10.1161/01.CIR.0000088782.99568.CA PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 715DH UT WOS:000184954900007 PM 12925451 ER PT J AU Wang, TJ Evans, JC Benjamin, EJ Levy, D LeRoy, EC Vasan, RS AF Wang, TJ Evans, JC Benjamin, EJ Levy, D LeRoy, EC Vasan, RS TI Natural history of asymptomatic left ventricular systolic dysfunction in the community SO CIRCULATION LA English DT Article DE heart failure; ventricular dysfunction; echocardiography ID CONGESTIVE-HEART-FAILURE; MYOCARDIAL-INFARCTION; EJECTION FRACTION; CLINICAL IMPLICATIONS; URBAN-POPULATION; MORTALITY; SURVIVAL; DISEASE AB Background - Information is limited regarding the rates of progression to congestive heart failure (CHF) and death in individuals with asymptomatic left ventricular systolic dysfunction (ALVD). We sought to characterize the natural history of ALVD, by studying unselected individuals with this condition in the community. Methods and Results - We studied 4257 participants ( 1860 men) from the Framingham Study who underwent routine echocardiography. The prevalence of ALVD ( visually estimated ejection fraction [EF] less than or equal to 50% without a history of CHF) was 6.0% in men and 0.8% in women. During up to 12 years of follow-up, rates of CHF among subjects with normal left ventricular systolic function ( EF > 50%, n = 4128) and ALVD ( n = 129) were 0.7 and 5.8 per 100 person-years, respectively. After adjustment for cardiovascular disease risk factors, ALVD was associated with a hazards ratio (HR) for CHF of 4.7 (95% CI 2.7 to 8.1), compared with individuals without ALVD. An elevated risk of CHF after ALVD was observed even in individuals without prior myocardial infarction or valvular disease, with an adjusted HR of 6.5 ( CI 3.1 to 13.5). Mild ALVD ( EF 40% to 50%, n = 78) and moderate-to-severe ALVD ( EF < 40%, n = 51) were associated with adjusted HRs for CHF of 3.3 ( CI 1.7 to 6.6) and 7.8 ( CI 3.9 to 15.6), respectively. ALVD was also associated with an increased mortality risk ( adjusted HR 1.6, CI 1.1 to 2.4). The median survival of ALVD subjects was 7.1 years. Conclusion - Individuals with ALVD in the community are at high risk of CHF and death, even when only mild impairment of EF is present. Additional studies are needed to define optimal therapy for mild ALVD. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston Med Ctr, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston Med Ctr, Dept Med, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23 HL-074077-01, K24 HL-04334-01A1, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 21 TC 255 Z9 261 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 AUG 26 PY 2003 VL 108 IS 8 BP 977 EP 982 DI 10.1161/01.CIR.0000085166.44904.79 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 715DH UT WOS:000184954900015 PM 12912813 ER PT J AU Hill, JM Dick, AJ Raman, VK Thompson, RB Yu, ZX Hinds, KA Pessanha, BSS Guttman, MA Varney, TR Martin, BJ Dunbar, CE McVeigh, ER Lederman, RJ AF Hill, JM Dick, AJ Raman, VK Thompson, RB Yu, ZX Hinds, KA Pessanha, BSS Guttman, MA Varney, TR Martin, BJ Dunbar, CE McVeigh, ER Lederman, RJ TI Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells SO CIRCULATION LA English DT Article DE cells; magnetic resonance imaging; myocardial infarction; contrast media ID MARROW STROMAL CELLS; IN-VIVO TRACKING; TRANSPLANTATION; RECOVERY; MARKING; MODEL; HEART AB Background - Delivery and tracking of endomyocardial stem cells are limited by the inability to image transplanted cells noninvasively in the beating heart. We hypothesized that mesenchymal stem cells (MSCs) could be labeled with a iron fluorophore particle (IFP) to provide MRI contrast in vivo to assess immediate and long-term localization. Methods and Results - MSCs were isolated from swine. Short-term incubation of MSCs with IFP resulted in dose-dependent and efficient labeling. Labeled cells remained viable for multiple passages and retained in vitro proliferation and differentiation capacity. Labeled MSCs (10(4) to 10(6) cells/150 muL) were injected percutaneously into normal and freshly infarcted myocardium in swine. One, 3, and 1 animals underwent serial cardiac MRI ( 1.5T) for 4, 8, and 21 days, respectively. MRI contrast properties were measured both in vivo and in vitro for cells embedded in agar. Injection sites containing as few as 10(5) MSCs could be detected and contained intact IFP-bearing MSCs on histology. Conclusions - IFP labeling of MSCs imparts useful MRI contrast, enabling ready detection in the beating heart on a conventional cardiac MR scanner after transplantation into normal and infarcted myocardium. The dual-labeled MSCs can be identified at locations corresponding to injection sites, both ex vivo using fluorescence microscopy and in vivo using susceptibility contrast on MRI. This technology may permit effective in vivo study of stem cell retention, engraftment, and migration. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Osiris Therapeut, Baltimore, MD USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. RI Thompson, Richard/E-9821-2011 FU Intramural NIH HHS [Z01 HL004608-08] NR 20 TC 305 Z9 356 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 26 PY 2003 VL 108 IS 8 BP 1009 EP 1014 DI 10.1161/01.CIR.0000084537.66419.7A PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 715DH UT WOS:000184954900020 PM 12912822 ER PT J AU Maraini, G Hejtmancik, JF Shiels, A Mackay, DS Aldigeri, R Jiao, XD Williams, SL Sperduto, RD Reed, G AF Maraini, G Hejtmancik, JF Shiels, A Mackay, DS Aldigeri, R Jiao, XD Williams, SL Sperduto, RD Reed, G TI Galactokinase gene mutations and age-related cataract. Lack of association in an Italian population SO MOLECULAR VISION LA English DT Article ID DEFICIENCY; IDENTIFICATION AB Purpose: To investigate possible associations between sequence changes in the galactokinase gene (GALK1) and age-related cataract in a European population. METHODS: Persons without lens opacities and persons with clinically significant age-related cataract were selected from those participating in the Collaborative Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract or from those attending the Section of Ophthalmology of the University of Parma for cataract surgery. Type and severity of the opacities were assessed by slit-lamp and retro-illumination lens photographs. Mutations in GALK1 were identified by PCR amplification of individual exons and flanking sequences and sequencing using fluorescent terminator technology in an ABI 377 Prism or 3100 automated DNA sequencer. Results: DNA samples were obtained from 115 individuals with clear lenses and from 185 individuals with cataract (106 with any nuclear, 88 with any cortical, and 25 with any posterior sub capsular cataract). 157 of the 185 patients with cataract (85%) were age-matched with a control within an age range of plus or minus 1 year. SNPs causing amino acid changes in the galactokinase protein were identified in exon 4; I184M, 1/115 control versus 0/185 cataractous individuals, p=0.38, exon 6; G274D, 0/115 control versus 1/185 cataractous individuals, p>0.99, and exon 7; V338A, 0/115 control versus 1/185 cataractous individuals, p>0.99. Thus, there were no significant differences in the distribution of sequence alterations resulting in amino acid changes between control and cataractous individuals. Eighty samples showed a C to T transition 43 bases into intron 7 (46 cataracts and 34 controls). Testing the distribution of the intron 7 findings showed Hardy-Weinberg equilibrium for both cases (p=0.73) and controls (p=0.51). There was no difference in C/T distribution between cases and controls (p=0.27). Conclusions: In this northern Italian population age-related cataract does not appear to be associated with GALK1 alleles. Since this is due to a lack of sequence changes in both affected and control individuals, this study cannot rule out the possibility of an association in other populations. C1 Univ Parma, I-43100 Parma, Italy. NEI, NIH, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. RP Maraini, G (reprint author), Univ Parma, Via Gramsci 14, I-43100 Parma, Italy. OI Aldigeri, Raffaella/0000-0003-2350-1222 FU NEI NIH HHS [EY12284] NR 11 TC 10 Z9 11 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD AUG 26 PY 2003 VL 9 IS 51 BP 397 EP 400 PG 4 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 715LL UT WOS:000184973500001 PM 12942049 ER PT J AU Zeuner, KE Shoge, RO Goldstein, SR Dambrosia, JM Hallett, M AF Zeuner, KE Shoge, RO Goldstein, SR Dambrosia, JM Hallett, M TI Accelerometry to distinguish psychogenic from essential or parkinsonian tremor SO NEUROLOGY LA English DT Article ID MOVEMENT-DISORDERS; FREQUENCY; TIME AB The authors measured postural wrist tremor with accelerometry in patients with psychogenic (n = 6), essential ( n = 11), and parkinsonian ( n = 12) tremor. Tremor was measured in one hand, while the other hand either rested or tapped to an auditory stimulus at 3 and 4 or 5 Hz. Psychogenic tremors showed larger tremor frequency changes and higher intraindividual variability while tapping. Accelerometry may differentiate psychogenic from essential and parkinsonian tremor. C1 NINDS, NIH, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. NINDS, Biostat Branch, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, NIH, Human Motor Control Sect, Med Neurol Branch, 10 Ctr Dr,Bldg 10,Rm 5N226,MSC1428, Bethesda, MD 20892 USA. NR 10 TC 50 Z9 52 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 26 PY 2003 VL 61 IS 4 BP 548 EP 550 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 715CX UT WOS:000184953900026 PM 12939436 ER PT J AU Wright, V Horvath, R Baird, AE AF Wright, V Horvath, R Baird, AE TI Aortic dissection presenting as acute ischemic stroke SO NEUROLOGY LA English DT Editorial Material C1 NINDS, Stroke Neurosci Unit, NIH, Bethesda, MD 20892 USA. RP Baird, AE (reprint author), NINDS, Stroke Neurosci Unit, NIH, 10 Ctr Dr,MSC 1294,Rm 3N258, Bethesda, MD 20892 USA. NR 7 TC 21 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 26 PY 2003 VL 61 IS 4 BP 581 EP 582 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 715CX UT WOS:000184953900042 PM 12939452 ER PT J AU Levin, I Leapman, RD Kovler, M Roizin, Y AF Levin, I Leapman, RD Kovler, M Roizin, Y TI Radiation-induced nitrogen segregation during electron energy loss spectroscopy of silicon oxide-nitride-oxide stacks SO APPLIED PHYSICS LETTERS LA English DT Article AB Electron energy loss spectroscopy (EELS) in both fixed-probe transmission electron microscopy (TEM) and scanning TEM (STEM) was used to measure elemental profiles of Si, O, and N in the SiOx/SixNy/SiOx/poly-Si stacks deposited on silicon. The results revealed radiation-induced nitrogen segregation to both the Si/SiOx and SiOx/poly-Si interfaces; the extent of nitrogen segregation increased visibly with increasing the radiation dose. The nitrogen diffusion through the oxide layers apparently was accompanied by the diffusion of oxygen into the nitride. Low-noise artifact-free nitrogen profiles across the Si/SiOx interfaces were obtained in STEM by scanning the beam parallel to the layers. These measurements indicated lack of detectable nitrogen segregation to the interfaces. (C) 2003 American Institute of Physics. C1 Natl Inst Stand & Technol, Div Ceram, Gaithersburg, MD 20899 USA. NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. Tower Semicond Ltd, IL-23105 Migdal Haemeq, Israel. RP Levin, I (reprint author), Natl Inst Stand & Technol, Div Ceram, Gaithersburg, MD 20899 USA. EM igor.levin@nist.gov RI Levin, Igor/F-8588-2010 NR 8 TC 8 Z9 8 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0003-6951 EI 1077-3118 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD AUG 25 PY 2003 VL 83 IS 8 BP 1548 EP 1550 DI 10.1063/1.1604182 PG 3 WC Physics, Applied SC Physics GA 713EN UT WOS:000184844100018 ER PT J AU Rosas, MER Patel, S Wainer, IW AF Rosas, MER Patel, S Wainer, IW TI Determination of the enantiomers of ketamine and norketamine in human plasma by enantioselective liquid chromatography-mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE enantiomer separation; ketamine; norketamine ID SURGICAL PATIENTS; PHARMACOKINETICS; PHARMACOLOGY; RAT; VOLUNTEERS; PERCEPTION; RECEPTORS; ISOMERS AB A sensitive enantioselective liquid chromatographic assay with mass spectrometric detection has been developed and validated for the simultaneous determination of plasma concentrations of (R)- and (S)-ketamine, and (R)- and (S)-norketamine. The compounds were extracted from human plasma using solid-phase extraction and then directly injected into the LC-MS system for detection and quantification. Enantioselective separations were achieved on a liquid chromatographic chiral stationary phase based upon immobilized alpha(1)-acid glycoprotein (the Chiral AGP column). The separations were achieved using a mobile phase composed of 2-propanol-ammonium acetate buffer (10 mM, pH 7.6) (6:94, v/v), a flow-rate of 0.5 ml/min and a temperature of 25 degreesC. Under these conditions, the analysis time was 20 min. Detection of the ketamine, norketamine and bromoketamine (internal standard) enantiomers was achieved using selected ion monitoring at m/z 238.1, 224.1 and 284.0. respectively. Extracted calibration curves were linear from 1 to 125 ng/ml per enantiomer for each analyte with correlation coefficients better than 0.9993 and intra- and inter-day RSDs of less than 8.0%. The method was applied to samples from a clinical study of ketamine in pain management. (C) 2003 Elsevier B.V. All rights reserved. C1 NIA, Bioanalyt & Drug Discovery Unit, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 25 TC 24 Z9 24 U1 1 U2 9 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 AUG 25 PY 2003 VL 794 IS 1 BP 99 EP 108 DI 10.1016/S1570-0232(03)00420-3 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 707TM UT WOS:000184526000011 ER PT J AU Axelrod, J AF Axelrod, J TI Plan your research to build a career SO SCIENTIST LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Axelrod, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD AUG 25 PY 2003 VL 17 IS 16 BP 57 EP 57 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 715KU UT WOS:000184971600040 ER PT J AU Myers, G Cox, C Davidson, PW Huang, LS Clarkson, TW AF Myers, G Cox, C Davidson, PW Huang, LS Clarkson, TW TI Prenatal methylmercury exposure in the Seychelles - Reply SO LANCET LA English DT Letter C1 Univ Rochester, Med Ctr, Div Pediat Neurol, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Biostat, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Environm Hlth, Rochester, NY 14642 USA. NICHD, BMSB, DESPR, NIH, Bethesda, MD USA. RP Myers, G (reprint author), Univ Rochester, Med Ctr, Div Pediat Neurol, 601 Elmwood Ave, Rochester, NY 14642 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 23 PY 2003 VL 362 IS 9384 BP 665 EP 665 DI 10.1016/S0140-6736(03)14167-0 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 714GJ UT WOS:000184904100032 ER PT J AU Takeda, K Kishi, H Ma, XF Yu, ZX Adelstein, RS AF Takeda, K Kishi, H Ma, XF Yu, ZX Adelstein, RS TI Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis SO CIRCULATION RESEARCH LA English DT Article DE cell cycle; heart development; immunohistochemistry; myocyte enlargement; bromodeoxyuridine labeling index ID CELLS; BRAIN; HEART AB We have identified a novel form of cardiac myocyte enlargement in nonmuscle myosin heavy chain II-B (NMHC II-B) ablated mice, based on a partial failure in cytokinesis. In contrast to most cells, cardiac myocytes lack NMHC II-A, and ablation of NMHC II-B results in a heart with 70% fewer myocytes at embryonic day 14.5 (E14.5) than control mice (B+/B- and B+/B+). In addition, B-/B- cardiac myocytes show a marked increase in binucleation at E12.5, reflecting the occurrence of karyokinesis in the absence of cytokinesis. An increase in binucleation and cell size is also found in hypomorphic, homozygous mice harboring a single amino acid mutation (R709C) in the gene encoding NMHC II-B. The nonmyocytes in B-/B- hearts and homozygous mutant hearts, all of which contain NMHC II-A, do not show either of these abnormalities. B-/B- cardiac myocytes at E14.5 show a decreased bromodeoxyuridine (BrdU) labeling index compared with controls, consistent with the decrease in myocyte proliferation. This decreased BrdU labeling is not seen in nonmyocyte cells in the heart. In addition to these changes, both B-/B- mice as well as homozygous mutated mice show an increase in cyclin D2 and D3 reflecting an abnormality in earlier steps in the cell cycle. Whereas cardiac myocytes completely ablated for NMHC II-B show enlargement and binucleation, mice expressing as little as 6% of the normal amount of wild-type NMHC II-B in the heart do not show these abnormalities. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. Yamaguchi Univ, Sch Med, Dept Mol Physiol, Yamaguchi, Japan. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Room 8N202,10 Ctr Dr MSC 1762, Bethesda, MD 20892 USA. OI Adelstein, Robert/0000-0002-8683-2144 NR 20 TC 47 Z9 49 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 22 PY 2003 VL 93 IS 4 BP 330 EP 337 DI 10.1161/01.RES.0000089256.00309.CB PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 713XA UT WOS:000184882200009 PM 12893741 ER PT J AU Roda, RH Balakrishnan, M Hanson, MN Wohr, BM Le Grice, SFJ Roques, BP Gorelick, RJ Bambara, RA AF Roda, RH Balakrishnan, M Hanson, MN Wohr, BM Le Grice, SFJ Roques, BP Gorelick, RJ Bambara, RA TI Role of the reverse transcriptase, nucleocapsid protein, and template structure in the two-step transfer mechanism in retroviral recombination SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; INFECTIOUS-ANEMIA VIRUS; STRAND TRANSFER-REACTIONS; RNASE-H ACTIVITY; HIGH NEGATIVE INTERFERENCE; SINGLE REPLICATION CYCLE; DEPENDENT DNA POLYMERASE; PRIMER BINDING-SITE; GENETIC-RECOMBINATION AB Template switching during reverse transcription promotes recombination in retroviruses. Efficient switches have been measured in vitro on hairpin-containing RNA templates by a two-step mechanism. Pausing of the reverse transcriptase (RT) at the hairpin base allowed enhanced cleavage of the initial donor RNA template, exposing regions of the cDNA and allowing the acceptor to base pair with the cDNA. This defines the first or docking step. The primer continued synthesis on the donor, transferring or locking in a second step. Here we determine the enzyme-dependent factors that influence template switching by comparing the RTs from human immunodeficiency virus, type 1 (HIV-1), and equine infectious anemia virus (EIAV). HIV-1 RT promoted transfers with higher efficiency than EIAV RT. We found that both RTs paused strongly at the base of the hairpin. While stalled, HIV-1 RT made closely spaced cuts, whereas EIAV RT made only a single cut. Docking occurred efficiently at the multiply cut but not at the singly cut site. HIV-1 nucleocapsid (NC) protein stimulated strand transfers. It improved RNase H activity of both RTs. It allowed the EIAV RT to make a distribution of cuts, greatly stimulating docking at the base of the hairpin. Most likely, it also promoted strand exchange, allowing transfers to be initiated from sites throughout the hairpin. Minor pause sites beyond the base of the hairpin correlated with the locking sites. The strand exchange properties of NC likely promote this step. We present a model that explains the roles of RNase H specificity, template structure, and properties of NC in the two-step transfer reaction. C1 Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. Max Planck Inst Mol Physiol, Phys Biochem Abt, D-44227 Dortmund, Germany. NCI Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI Frederick, AIDS Vaccine Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Dept Pharmacochem Mol & Struct, INSERM, U266, CNRS,UMR 8600, F-75270 Paris 06, France. RP Bambara, RA (reprint author), Univ Rochester, Med Ctr, Dept Biochem & Biophys, 601 Elmwood Ave,Box 712, Rochester, NY 14642 USA. FU NCI NIH HHS [N01-CO-12400, T32-CA09363]; NIGMS NIH HHS [F31 GM20911-02, GM49573, T32-GM07356] NR 96 TC 60 Z9 63 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 AUG 22 PY 2003 VL 278 IS 34 BP 31536 EP 31546 DI 10.1074/jbc.M304608200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 712DP UT WOS:000184782100013 PM 12801926 ER PT J AU Haan, S Ferguson, P Sommer, U Hiremath, M McVicar, DW Heinrich, PC Johnston, JA Cacalano, NA AF Haan, S Ferguson, P Sommer, U Hiremath, M McVicar, DW Heinrich, PC Johnston, JA Cacalano, NA TI Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOKINE SIGNALING-3; MEDIATED DEGRADATION; PROTEIN INTERACTS; UBIQUITIN LIGASE; MOLECULAR-BASIS; KINASE-ACTIVITY; BOX MOTIF; SUPPRESSOR; RECEPTOR; VHL AB The suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor-induced signal transduction. The C-terminal SOCS box region is thought to regulate SOCS protein stability most likely via an elongin C interaction. In the present study, we have found that phosphorylation of SOCS3 at two tyrosine residues in the conserved SOCS box, Tyr(204) and Tyr(221), can inhibit the SOCS3-elongin C interaction and activate proteasome-mediated SOCS3 degradation. Jak-mediated phosphorylation of SOCS3 decreased SOCS3 protein half-life, and phosphorylation of both Tyr(204) and Tyr(221) was required to fully destabilize SOCS3. In contrast, a phosphorylation-deficient mutant of SOCS3, Y204F, Y221F, remained stable in the presence of activated Jak2 and receptor tyrosine kinases. SOCS3 stability correlated with the relative amount that bound elongin C, because in vitro phosphorylation of a SOCS3-glutathione S-transferase fusion protein abolished its ability to interact with elongin C. In addition, a SOCS3/SOCS1 chimera that co-precipitates with markedly increased elongin C, was significantly more stable than wild-type SOCS3. The data suggest that interaction with elongin C stabilizes SOCS3 protein expression and that phosphorylation of SOCS box tyrosine residues disrupts the complex and enhances proteasome-mediated degradation of SOCS3. C1 Queens Univ Belfast, Dept Immunol, Belfast BT9 7BL, Antrim, North Ireland. Rhein Westfal TH Aachen, Inst Biochem, D-52074 Aachen, Germany. NCI, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Radiat Oncol, Los Angeles, CA 90095 USA. RP Johnston, JA (reprint author), Queens Univ Belfast, Sch Med, Dept Microbiol & Immunol, Rm 226,Whitla Med Bldg,97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. RI McVicar, Daniel/G-1970-2015 NR 53 TC 74 Z9 80 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 AUG 22 PY 2003 VL 278 IS 34 BP 31972 EP 31979 DI 10.1074/jbc.M303170200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 712DP UT WOS:000184782100066 PM 12783885 ER PT J AU Brewer, HB AF Brewer, HB TI A symposium: Charting the universe in dyslipidemia management - Introduction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Editorial Material ID C-REACTIVE PROTEIN; CARDIOVASCULAR EVENTS; ROSUVASTATIN; HYPERCHOLESTEROLEMIA; ATORVASTATIN; EFFICACY; TRIAL; SIMVASTATIN; PRAVASTATIN; DISEASE C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20814 USA. RP Brewer, HB (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Magnuson CC,Room 7N115,10 Ctr Dr, Bethesda, MD 20814 USA. NR 12 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 AUG 21 PY 2003 VL 92 IS 4B BP 1K EP 2K DI 10.1016/S0002-9149(03)00767-7 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 717NM UT WOS:000185096200001 ER PT J AU Brewer, HB Santamarina-Fojo, S AF Brewer, HB Santamarina-Fojo, S TI Clinical significance of high-density lipoproteins and the development of atherosclerosis: Focus on the role of the adenosine triphosphate-binding cassette protein A1 transporter SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Satellite Symposium on Charting the Universe in Dyslipidemia Management CY NOV 16, 2002 CL CHICAGO, ILLINOIS ID CORONARY-HEART-DISEASE; HUMAN ABCA1 GENE; TANGIER-DISEASE; CHOLESTEROL EFFLUX; TRANSGENIC MICE; CONTROLLED TRIAL; X-RECEPTOR; SIMVASTATIN; PRAVASTATIN; PREVENTION AB Low levels of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary artery disease, and there is evidence that increasing HDL cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is at least as common in patients hospitalized for cardiovascular disease as is hypercholesterolemia, and it is characteristic of diabetes and the metabolic syndrome, conditions associated with increased cardiovascular risk. Recent studies have elucidated mechanisms by which HDL acts to reduce cardiovascular risk, bolstering the rationale for targeting of HDL in lipid-modifying therapy. In particular, HDL (1) carries excess cholesterol from peripheral cells to the liver for removal in the process termed reverse cholesterol transport, (2) reduces oxidative modification of low-density lipoproteins (LDL), and (3) inhibits cytokine-induced expression of cellular adhesion molecules on endothelial cells. Studies of the newly described adenosine triphosphate-binding cassette protein A1 (ABCA1) transporter have established a crucial role for this transporter in modulating the levels of plasma HDL and intracellular cholesterol in the liver as well as in peripheral cells. Elevated levels of intracellular cholesterol stimulate the liver X receptor pathway, enhancing the expression of ABCA1, which increases intracellular trafficking of excess cholesterol to the cell surface for interaction with lipid-poor apolipoprotein A-1 to form nascent HDL. Nascent HDL facilitates the removal of additional excess cellular cholesterol, which is esterified by lecithin-cholesterol acyltransferase with conversion of the nascent HDL to mature spherical HDL. Overexpression of ABCA1 in mice on a regular chow or Western diet results in a marked increase in plasma HDL, increased LDL, and increased transport of cholesterol to the liver. On a high cholesterol/cholate diet, transgenic mice overexpressing ABCA1 have increased HDL, reduced LDL, increased HDL-mediated cholesterol flux to the liver, and reduced atherosclerosis. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of atherosclerosis will provide several new targets for the development of drugs to decrease the risk of atherosclerosis. (C) 2003 by Excerpta Medica, Inc. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20894 USA. RP Brewer, HB (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Maguson CC,Room 7N115,10 Ctr Dr, Bethesda, MD 20894 USA. RI 应, 宁宁/G-9472-2011 NR 43 TC 30 Z9 32 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 AUG 21 PY 2003 VL 92 IS 4B BP 10K EP 16K DI 10.1016/S0002-9149(03)00769-0 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 717NM UT WOS:000185096200003 PM 12948871 ER PT J AU Brewer, HB AF Brewer, HB TI Benefit-risk assessment of rosuvastatin 10 to 40 milligrams SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Satellite Symposium on Charting the Universe in Dyslipidemia Management CY NOV 16, 2002 CL CHICAGO, ILLINOIS ID DENSITY-LIPOPROTEIN CHOLESTEROL; COA REDUCTASE INHIBITOR; HIGH BLOOD CHOLESTEROL; NCEP EXPERT PANEL; HYPERCHOLESTEROLEMIC PATIENTS; HEALTHY-VOLUNTEERS; DOUBLE-BLIND; PHARMACOKINETICS; ATORVASTATIN; TRIAL AB The aim of this article is to examine the benefit-risk profile of rosuvastatin at doses of 10 to 40 mg. In dyslipidemic patients, rosuvastatin produced markedly greater reductions in low-density lipoprotein (LDL) cholesterol and equivalent or greater improvements in various lipid measures, including high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and triglycerides when compared with atorvastatin, simvastatin, and pravastatin. In addition, rosuvastatin is more effective than these statins in allowing patients to reach National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and Joint European Societies LDL cholesterol goals. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg. In controlled trials, rosuvastatin 10 to 40 mg demonstrated a similar adverse event profile to those for atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg. Myopathy (defined as muscle symptoms plus serum creatine kinase levels > 10 times the upper limit of normal) attributed to rosuvastatin occurred in less than or equal to 0.03% of patients receiving rosuvastatin 10 to 40 mg. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. Clinically significant alanine aminotransferase elevations occurred in 0.2% of patients receiving rosuvastatin and those receiving atorvastatin, simvastatin, and provastatin. Compared with other widely used statins, the benefit-risk profile of rosuvastatin 10 to 40 mg appears to be very favorable. (C) 2003 by Excerpta Medica, Inc. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20894 USA. RP Brewer, HB (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Magnuson CC,Room 7N115,10 Ctr Dr, Bethesda, MD 20894 USA. NR 41 TC 51 Z9 59 U1 1 U2 4 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 AUG 21 PY 2003 VL 92 IS 4B BP 23K EP 29K DI 10.1016/S0002-9149(03)00779-3 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 717NM UT WOS:000185096200005 PM 12948873 ER PT J AU Stierum, R Gaspari, M Dommels, Y Ouatas, T Pluk, H Jespersen, S Vogels, J Verhoeckx, K Groten, J van Ommen, B AF Stierum, R Gaspari, M Dommels, Y Ouatas, T Pluk, H Jespersen, S Vogels, J Verhoeckx, K Groten, J van Ommen, B TI Proteome analysis reveals novel proteins associated with proliferation and differentiation of the colorectal cancer cell line Caco-2 SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE Caco-2; differentiation; proteome analysis; two-dimensional gel electrophoresis; mass spectrometry ID CREATINE-KINASE BB; GLUTATHIONE S-TRANSFERASES; ALZHEIMERS-DISEASE BRAIN; NITRIC-OXIDE SYNTHASE; ACID-BINDING-PROTEIN; HUMAN COLON-CANCER; DOWN-REGULATION; 1,25-DIHYDROXYVITAMIN D-3; GENE-EXPRESSION; ACTIN DYNAMICS AB Here, we describe a proteomics approach to study protein expression changes in differentiating Caco-2 cells. Caco-2 is a colorectal carcinoma cell line, which upon differentiation loses its tumorigenic phenotype and displays characteristics of mature enterocytes, including brush borders with microvilli. Cells were grown in culture flasks and harvested at different stages of differentiation (days post-confluence: - 3, 0, 3, 7, 10, 14, and 18). Two-dimensional gel electrophoresis was used to analyse proteome changes. Approximately 1400 protein spots were detected within the Caco-2 proteome, within the pH 4-7 range. Two-dimensional gel electrophoresis allowed for the detection of 18 proteins from which the levels of expression were found to be associated with differentiation. Of these proteins, 11 were identified by means of MALDI-TOF or NANO-ESI-MS/MS mass spectrometry and include liver fatty acid binding protein (FABL), three forms of alpha-enolase (ENOA), nucleoside diphosphate kinase A (NDKA), cofilin-1 (COF1), translationally controlled tumour protein (TCTP), mitochondrial 60-kDa heat shock protein (CH60), probable protein disulfide isomerase (ER60), creatine kinase B (KCRB), and glutathione S-transferase alpha (GTA1). Thus, proteomics revealed that the differentiation-related change in phenotype of Caco-2 involves changes in a variety of distinct biochemical pathways. Some of these proteins have not been shown before to be associated with Caco-2 differentiation (ER60; COF1; CH60; NDKA; TCTP and ENOA). Therefore, processes related to protein folding and disulfide bridge formation, cytoskeleton formation and maintenance, nucleotide metabolism, glycolysis as well as tumorigenesis-associated proteins may be involved in Caco-2 differentiation. Changes in the expression of CH60, TCTP, GTA1, NDKA, and FABL have also been reported to be associated with in vivo colon carcinogenesis. These findings illustrate that a combination of proteomics and cell culture is a useful approach to find markers for Caco-2 differentiation, which could contribute to the comprehension of the process of colon carcinogenesis. (C) 2003 Elsevier B.V. All rights reserved. C1 TNO Nutr & Food Res, Dept Biomol Sci, NL-3700 AJ Zeist, Netherlands. Univ Wageningen & Res Ctr, Ctr Food Toxicol, Wageningen, Netherlands. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. UMC St Radboud, NCMLS, Dept Cell Biol, Nijmegen, Netherlands. RP Stierum, R (reprint author), TNO Nutr & Food Res, Dept Biomol Sci, POB 360, NL-3700 AJ Zeist, Netherlands. RI Gaspari, Marco/C-2756-2009 OI Gaspari, Marco/0000-0002-5411-8800 NR 67 TC 87 Z9 104 U1 0 U2 18 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 AUG 21 PY 2003 VL 1650 IS 1-2 BP 73 EP 91 DI 10.1016/S1570-9639(03)00204-8 PG 19 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 715NH UT WOS:000184978300009 PM 12922171 ER PT J AU Yamada, KM AF Yamada, KM TI Cell biology - Tumour jailbreak SO NATURE LA English DT Editorial Material ID MATRIX C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 10 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 21 PY 2003 VL 424 IS 6951 BP 889 EP 890 DI 10.1038/424889a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 713EH UT WOS:000184843600023 PM 12931168 ER PT J AU Gearhart, PJ AF Gearhart, PJ TI B cells pay a price SO ONCOGENE LA English DT Editorial Material ID CYTIDINE DEAMINASE AID; SINGLE-STRANDED-DNA; SOMATIC HYPERMUTATION; ANTIBODY DIVERSIFICATION; GENES; URACIL; ENZYME C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 17 TC 2 Z9 2 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 AUG 21 PY 2003 VL 22 IS 35 BP 5379 EP 5380 DI 10.1038/sj.onc.1206874 PG 2 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 711JC UT WOS:000184735000001 PM 12934096 ER PT J AU Berton, TR Matsumoto, T Page, A Conti, CJ Deng, CX Jorcano, JL Johnson, DG AF Berton, TR Matsumoto, T Page, A Conti, CJ Deng, CX Jorcano, JL Johnson, DG TI Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues SO ONCOGENE LA English DT Article DE BRCA1; Cre-lox; epithelium; E2F1 ID DNA-DAMAGE RESPONSE; SUPPRESSOR GENE BRCA1; INTERACT IN-VIVO; BREAST-CANCER; CELL-CYCLE; TRANSCRIPTIONAL ACTIVATION; CENTROSOME AMPLIFICATION; NUCLEAR PHOSPHOPROTEIN; MALIGNANT-TUMORS; OVARIAN-CANCER AB The BRCA1 tumor-suppressor protein has been implicated in the regulation of transcription, DNA repair, proliferation, and apoptosis. BRCA1 is expressed in many proliferative tissues and this is at least in part due to E2F-dependent transcriptional control. In this study, inactivation of a conditional murine Brca1 allele was achieved in a variety of epithelial tissues via expression of the Cre recombinase under the control of a keratin 5 (K5) promoter. The K5 Cre:Brca1 conditional knockout mice exhibited modest epidermal hyperproliferation, increased apoptosis, and were predisposed to developing tumors in the skin, the inner ear canal, and the oral epithelium after 1 year of age. Overexpression of the E2F1 transcription factor in K5 Cre:Brca1 conditional knockout mice dramatically accelerated tumor development. In addition, Brca1 heterozygous female mice that had elevated E2F1 expression developed tumors of the reproductive tract at high incidence. These findings demonstrate that in mice Brca1 functions as a tumor suppressor in other epithelial tissues in addition to the mammary gland. Moreover, inactivation of Brca1 is shown to cooperate with deregulation of the Rb-E2F1 pathway to promote tumorigenesis. C1 Univ Texas, Dept Carcinogenesis, MD Anderson Canc Ctr, Sci Pk Res Div, Smithville, TX 78957 USA. CIEMAT, E-28040 Madrid, Spain. NIDDKD, Biochem & Metab Lab, Bethesda, MD 20892 USA. RP Johnson, DG (reprint author), Univ Texas, Dept Carcinogenesis, MD Anderson Canc Ctr, Sci Pk Res Div, Smithville, TX 78957 USA. RI deng, chuxia/N-6713-2016 FU NCI NIH HHS [T-32 CA9480]; NIEHS NIH HHS [U01 ES11047] NR 74 TC 22 Z9 23 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 AUG 21 PY 2003 VL 22 IS 35 BP 5415 EP 5426 DI 10.1038/sj.onc.1206825 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 711JC UT WOS:000184735000006 PM 12934101 ER PT J AU Li, P Zhang, MC Peach, ML Liu, HP Yang, DJ Roller, PP AF Li, P Zhang, MC Peach, ML Liu, HP Yang, DJ Roller, PP TI Concise and enantioselective synthesis of Fmoc-Pmp(BUt)(2)-OH and design of potent Pmp-containing Grb2-SH2 domain antagonists SO ORGANIC LETTERS LA English DT Article ID HYDROLYTICALLY STABLE ANALOG; ABSOLUTE-CONFIGURATION; ASYMMETRIC-SYNTHESIS; O-PHOSPHOTYROSINE; AMINO-ACIDS; DERIVATIVES; TYROSINE; SPARSOMYCIN; INHIBITORS; RESOLUTION AB L-Phosphonomethylphenylalanine (L-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu-t)(2)-OH was developed in order to incorporate the functionally significant L-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer. C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. RP Li, P (reprint author), NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. EM proll@helix.nih.gov NR 24 TC 15 Z9 15 U1 0 U2 3 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 AUG 21 PY 2003 VL 5 IS 17 BP 3095 EP 3098 DI 10.1021/ol035078+ PG 4 WC Chemistry, Organic SC Chemistry GA 713NW UT WOS:000184865700032 PM 12916990 ER PT J AU Wexler, P AF Wexler, P TI Special issue - Digitial information and tools, part III - Global Web resources - Preface SO TOXICOLOGY LA English DT Editorial Material C1 Natl Lib Med, Toxicol & Environm Hlth Informat Program, NIH, Bethesda, MD 20892 USA. RP Wexler, P (reprint author), Natl Lib Med, Toxicol & Environm Hlth Informat Program, NIH, 2 Democracy Plaza,Suite 510,6707 Democracy Blvd,M, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 21 PY 2003 VL 190 IS 1-2 BP 1 EP 1 DI 10.1016/S0300-483X(03)00191-4 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 724UW UT WOS:000185505900001 ER PT J AU England, L Brenner, R Bhaskar, B Simons-Morton, B Das, A Revenis, M Mehta, N Clemens, J AF England, L Brenner, R Bhaskar, B Simons-Morton, B Das, A Revenis, M Mehta, N Clemens, J TI Breastfeeding practices in a cohort of inner-city women: the role of contraindications SO BMC PUBLIC HEALTH LA English DT Article ID UNITED-STATES; DURATION; INFANTS; MOTHERS; ACCULTURATION; POPULATION; PREDICTORS; INITIATION; INFECTION; DECISION AB Background: Little is known about the role of breastfeeding contraindications in breastfeeding practices. Our objectives were to 1) identify predictors of breastfeeding initiation and duration among a cohort of predominately low-income, inner-city women, and 2) evaluate the contribution of breastfeeding contraindications to breastfeeding practices. Methods: Mother-infant dyads were systematically selected from 3 District of Columbia hospitals between 1995 and 1996. Breastfeeding contraindications and potential predictors of breastfeeding practices were identified through medical record reviews and interviews conducted after delivery ( baseline). Interviews were conducted at 3 - 7 months postpartum and again at 7 - 12 months postpartum to determine breastfeeding initiation rates and duration. Multivariable logistic regression analysis was used to identify baseline factors associated with initiation of breastfeeding. Cox proportional hazards models were generated to identify baseline factors associated with duration of breastfeeding. Results: Of 393 study participants, 201 ( 51%) initiated breastfeeding. A total of 61 women ( 16%) had at lease one documented contraindication to breastfeeding; 94% of these had a history of HIV infection and/or cocaine use. Of the 332 women with no documented contraindications, 58% initiated breastfeeding, vs. 13% of women with a contraindication. In adjusted analysis, factors most strongly associated with breastfeeding initiation were presence of a contraindication ( adjusted odds ratio [AOR], 0.19; 95% confidence interval [CI], 0.08 - 0.47), and mother foreign-born (AOR, 4.90; 95% CI, 2.38 - 10.10). Twenty-five percent of study participants who did not initiate breastfeeding cited concern about passing dangerous things to their infants through breast milk. Factors associated with discontinuation of breastfeeding ( all protective) included mother foreign-born ( hazard ratio [HR], 0.55; 95% CI 0.39 - 0.77) increasing maternal age ( HR for 5-year increments, 0.80; 95% CI, 0.69 - 0.92), and infant birth weight greater than or equal to 2500 grams ( HR, 0.45; 95% CI, 0.26 - 0.80). Conclusions: Breastfeeding initiation rates and duration were suboptimal in this inner-city population. Many women who did not breastfeed had contraindications and/or were concerned about passing dangerous things to their infants through breast milk. It is important to consider the prevalence of contraindications to breastfeeding when evaluating breastfeeding practices in high-risk communities. C1 NICHHD, Div Epidemiol Stat & Prevent Res, US Dept HHS, Bethesda, MD 20895 USA. Res Triangle Inst, Rockville, MD 20852 USA. Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. Georgetown Univ Hosp, Div Neonatol, Washington, DC 20007 USA. Int Vaccine Inst, Seoul, South Korea. RP England, L (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, US Dept HHS, Bethesda, MD 20895 USA. EM lbe9@cdc.gov; brennerr@mail.nih.gov; bbhaskar@rti.org; mortonb@mail.nih.gov; adas@rti.org; mrevenis@cnmc.org; mehtan@gunet.georgetown.edu; jclemens@ivi.int FU NICHD NIH HHS [U18-HD30445, U18-HD30454, U18 HD030445, U18 HD031919, U18-HD31206, U18 HD031206, U18-HD30458, U18-HD31919, U18 HD030447, U18-HD30450, U18-HD30447] NR 35 TC 4 Z9 4 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 20 PY 2003 VL 3 AR 28 DI 10.1186/1471-2458-3-28 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 720JD UT WOS:000185256900001 PM 12930560 ER PT J AU Lopez-Carrillo, L Lopez-Cervantes, M Robles-Diaz, G Ramirez-Espitia, A Mohar-Betancourt, A Meneses-Garcia, A Lopez-Vidal, Y Blair, A AF Lopez-Carrillo, L Lopez-Cervantes, M Robles-Diaz, G Ramirez-Espitia, A Mohar-Betancourt, A Meneses-Garcia, A Lopez-Vidal, Y Blair, A TI Capsaicin consumption, Helicobacter pylori positivity and gastric cancer in Mexico SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE capsaicin; chili pepper; gastric cancer; Helicobacter pylori; histological types; Mexico ID CHILI-PEPPER CONSUMPTION; STOMACH-CANCER; INFECTION; RISK; ASSOCIATION; CARCINOMA AB Gastric cancer (GC) incidence has not declined in Mexico. We assessed whether the intake of capsaicin (CAP), the pungent compound of chili peppers, increases the risk of GC independently of H. pylori positivity (Hp). From 1994 to 1996, a hospital-based case-control study was performed in 3 areas of Mexico; 234 cases of GC and 468 matched controls were enrolled and their diet and other characteristics were inquired. Chili pepper intake was queried by interview and CAP content of chilies was determined in a separate analysis by gas chromatography to estimate CAP intake; IGg Hp serum antibodies were determined by ELISA. The risk of GC was increased (OR = 1.71; 95% CI = 0.76-3.88) among high-level consumers of CAP (90-250 mg of capsaicin per day, approximately 9-25 jalapeno peppers per day) as compared to low-level consumers (0-29.9 mg of capsaicin per day, approximately 0 to less than 3 jalapeno peppers per day; p for trend p = 0.026); this effect was independent of Hp status and other potential GC determinants and was higher among diffuse GC cases (OR = 3.64; 95% CI = 1.09-12.2; p for trend = 0.002) compared to intestinal GC cases (OR = 1.36; 95% CI = 0.31-5.89; p for trend = 0.493). No significant interaction was found between CAP intake and Hp on GC risk. Chili pepper consumption might be an independent determinant of GC in Mexico. (C) 2003 Wiley-Liss. Inc. C1 Inst Nacl Salud Publ, Cuernavaca 62508, Morelos, Mexico. Mexico Natl Inst Med Sci & Nutr, Mexico City, DF, Mexico. Mexico Natl Canc Inst, Mexico City, DF, Mexico. Natl Autonomous Univ Mexico, Mexico City 04510, DF, Mexico. NCI, Rockville, MD USA. RP Lopez-Carrillo, L (reprint author), Inst Nacl Salud Publ, Av Univ 655,Col Santa Maria Ahuacatitlan, Cuernavaca 62508, Morelos, Mexico. OI Lopez-Vidal, Yolanda/0000-0001-7111-8813 NR 27 TC 45 Z9 50 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 20 PY 2003 VL 106 IS 2 BP 277 EP 282 DI 10.1002/ijc.11195 PG 6 WC Oncology SC Oncology GA 700BE UT WOS:000184092100020 PM 12800206 ER PT J AU Engels, EA Rodman, LH Frisch, M Goedert, JJ Biggar, RJ AF Engels, EA Rodman, LH Frisch, M Goedert, JJ Biggar, RJ TI Childhood exposure to simian virus 40-contaminated poliovirus vaccine and risk of AIDS-associated non-Hodgkin's lymphoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE simian virus 40; acquired immunodeficiency syndrome (AIDS); human immunodeficiency virus (HIV); non-Hodgkin's lymphoma; vaccine ID VACUOLATING VIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; UNITED-STATES; SV40 DNA; JC VIRUS; BK VIRUS; SIMIAN-VIRUS-40; MESOTHELIOMA; EPENDYMOMAS AB Persons with acquired immunodeficiency syndrome (AIDS) have increased risk for non-Hodgkin's lymphoma (NHL). Recent studies have reported the detection of DNA sequences from simian virus 40 (SV40), a macaque polyomavirus that contaminated early poliovirus vaccines, in a large proportion of AIDS-associated NHLs. To examine the association between SV40 exposure and NHL risk, we analyzed data from a U.S. registry-based cohort study of persons with AIDS (1980-96). We calculated NHL incidence in persons born in 1958-61 (exposed to SV40-contaminated poliovirus vaccine as children, n = 39,468) and in 1964-67 (born after vaccines were cleared of SV40 and thus unexposed, n = 17,340). Among persons with AIDS, NHL incidence was 11.7 per 1,000 person-years in SV40-exposed individuals (616 NHL cases) and 10.1 per 1,000 person-years in SV40-unexposed individuals (230 cases; unadjusted relative risk 1.15, 95% CI 0.99-1.34, p = 0.06). Because of differences in cohorts' birth years and the evolving demographics of the AIDS epidemic, SV40-exposed subjects were older at AIDS onset than unexposed subjects (mean age 32.0 vs. 27.2 years, p < 0.0001), and the cohorts differed by sex (p < 0.0001) and ethnic group (p < 0.0001). Since NHL incidence was relatively high among whites (p < 0.0001) and homosexual males (p < 0.0001) and increased with age (p = 0.09), comparisons required adjustments for these factors. After adjustment, SV40 exposure was not associated with NHL incidence (adjusted relative risk 0.97, 95% CI 0.79-1.20, p = 0.80). We conclude that childhood exposure to SV40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS-associated NHL. Our findings do not support a role for SV40 in lymphomagenesis among immunosuppressed persons. (C) 2003 Wiley-Liss, Inc. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 37 TC 11 Z9 13 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 AUG 20 PY 2003 VL 106 IS 2 BP 283 EP 287 DI 10.1002/ijc.11211 PG 5 WC Oncology SC Oncology GA 700BE UT WOS:000184092100021 PM 12800207 ER PT J AU Zerhouni, EA AF Zerhouni, EA TI A new vision for the national institutes of health SO JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, 1 Ctr Dr, Bethesda, MD 20892 USA. EM director@NIH.gov NR 0 TC 6 Z9 6 U1 0 U2 0 PU HINDAWI PUBLISHING CORPORATION PI CAYAHOGA FALLS PA PO BOX 3079, CAYAHOGA FALLS, OH 44233 USA SN 1110-7243 J9 J BIOMED BIOTECHNOL JI J. Biomed. Biotechnol. PD AUG 20 PY 2003 IS 3 BP 159 EP 160 AR PII S1110724303306023 PG 2 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 761VR UT WOS:000187936600001 ER PT J AU Domanski, M Norman, J Pitt, B Haigney, M Hanlon, S Peyster, E AF Domanski, M Norman, J Pitt, B Haigney, M Hanlon, S Peyster, E TI Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ANGIOTENSIN-II; MYOCARDIAL-INFARCTION; ALDOSTERONE; SURVIVAL; SPIRONOLACTONE; ENALAPRIL; MORTALITY; FIBROSIS; THERAPY; CAPTOPRIL AB OBJECTIVES We sought to determine whether non-potassium-sparing diuretics (PSDs) in the absence of a PSD may result in progressive heart failure (HF). BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors incompletely suppress ACE activity in HF patients. Furthermore, non-PSDs are activators of aldosterone secretion. We reasoned that non-PSDs, in the absence of a PSD, might result in progressive HF. METHODS In the 6,797 patients in the Studies Of Left Ventricular Dysfunction (SOLVD), we compared the risk of hospitalization for, or death from, HF between those taking a PSD and those who were not, adjusting for known covariates. RESULTS The risk of hospitalization from worsening HF in those taking a PSD relative to those taking only a non-PSD was 0.74 (95% confidence interval [CI] 0.55 to 0.99; p = 0.047). The relative risk for cardiovascular death was 0.74 (95% CI 0.59 to 0.93; p = 0.011), for death from all causes 0.73 (95% CI 0.59 to 0.90; p = 0.004), and for hospitalization for, or death from, HF 0.75 (95% CI 0.58 to 0.97; p = 0.030). Compared with patients not taking any diuretic, the risk of hospitalization or death due to worsening HF in patients taking non-PSDs alone was significantly increased (risk ratio [RR] = 1.31, 95% CI 1.09 to 1.57; p = 0.0004); this was not observed in patients taking PSDs with or without a non-PSD (RR = 0.99, 95% CI 0.76 to 1.30; p = 0.95). CONCLUSIONS The use of PSDs in HF patients is associated with a reduced risk of death from, or hospitalization for, progressive HF or all-cause or cardiovascular death, compared with patients taking only a non-PSD. (C) 2003 by the American College of Cardiology Foundation. C1 Natl Heart Lung & Blood Inst, Clin Trials Grp, Bethesda, MD 20892 USA. Univ Michigan, Ctr Med, Dept Cardiol, Ann Arbor, MI USA. USN, Ctr Med, Bethesda, MD USA. RP Domanski, M (reprint author), Natl Heart Lung & Blood Inst, Clin Trials Grp, 6701 Rocklege Ave, Bethesda, MD 20892 USA. NR 27 TC 172 Z9 187 U1 0 U2 2 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 AUG 20 PY 2003 VL 42 IS 4 BP 705 EP 708 DI 10.1016/S0735-1097(03)00765-4 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 712DB UT WOS:000184780600019 PM 12932605 ER PT J AU Coleman, CN Wallner, PE Abrams, JS AF Coleman, CN Wallner, PE Abrams, JS TI Inflammatory breast issue SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SURGICAL ADJUVANT BREAST; 20-YEAR FOLLOW-UP; RADIATION-THERAPY; RANDOMIZED TRIAL; BRACHYTHERAPY APPLICATOR; CONSERVING THERAPY; CANCER; IRRADIATION; LUMPECTOMY; MASTECTOMY C1 NCI, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Res Program, Div Canc Treatment & Diag, Bldg 10,Rm B3B69,MSC 1002, Bethesda, MD 20892 USA. NR 25 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 20 PY 2003 VL 95 IS 16 BP 1182 EP 1184 DI 10.1093/jnci/djg027 PG 3 WC Oncology SC Oncology GA 713FD UT WOS:000184845700001 PM 12928334 ER PT J AU Key, TJ Appleby, PN Reeves, GK Roddam, A Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Falk, RT Miller, R Schatzkin, A Allen, DS Fentiman, IS Key, TJ Wang, DY Dowsett, M Thomas, HV Hankinson, SE Toniolo, P Koenig, K Shore, RE Zeleniuch-Jacquotte, A Berrino, F Muti, P Micheli, A Krogh, V Sieri, S Pala, V Venturelli, E Secreto, G Barrett-Connor, E Laughlin, GA Kabuto, M Akiba, S Stevens, RG Neriishi, K Land, CE Cauley, JA Kuller, LH Cummings, SR Helzlsouer, KJ Alberg, AJ Bush, TL Comstock, GW Gordon, GB Miller, SR AF Key, TJ Appleby, PN Reeves, GK Roddam, A Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Falk, RT Miller, R Schatzkin, A Allen, DS Fentiman, IS Key, TJ Wang, DY Dowsett, M Thomas, HV Hankinson, SE Toniolo, P Koenig, K Shore, RE Zeleniuch-Jacquotte, A Berrino, F Muti, P Micheli, A Krogh, V Sieri, S Pala, V Venturelli, E Secreto, G Barrett-Connor, E Laughlin, GA Kabuto, M Akiba, S Stevens, RG Neriishi, K Land, CE Cauley, JA Kuller, LH Cummings, SR Helzlsouer, KJ Alberg, AJ Bush, TL Comstock, GW Gordon, GB Miller, SR CA Endogenous Hormones Breast Canc Co TI Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID DEHYDROEPIANDROSTERONE-SULFATE; ENDOGENOUS HORMONES; ENDOMETRIAL CANCER; PROSPECTIVE COHORT; INSULIN; HEIGHT; ESTRADIOL; GLUCOSE; WEIGHT; TESTOSTERONE AB Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. Results: Breast cancer risk increased with increasing BMI (P-trend = .002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m(2) increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol. C1 Univ Oxford, Radcliffe Infirm, Endogenous Hormones & Breast Canc Collaborat Grp, Canc Res UK,Epidemiol Unit, Oxford OX2 6HE, England. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. Univ Missouri, Hlth Sci Ctr, Dept Surg, Columbia, MO USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Ellis Fischel Canc Ctr, Canc Screening Serv, Columbia, MO USA. Canc Res UK, Oxford, England. Royal Marsden Hosp, Dept Acad Biochem, London SW3 6JJ, England. Univ Wales Coll Med, Dept Psychol Med, Cardiff CF4 4XN, S Glam, Wales. Brigham & Womens Hosp, Channing Lab, Dept Med, Nurses Hlth Study Res Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. NYU, Sch Med, Nelson Inst Environm Med, New York, NY USA. Ist Nazl Studio & Cura Tumori, Div Epidemiol, I-20133 Milan, Italy. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Natl Inst Environm Studies, Environm Risk Res Div, Ibaraki, Japan. Kagoshima Univ, Fac Med, Dept Publ Hlth, Kagoshima 890, Japan. Univ Connecticut, Ctr Hlth, Dept Community Med, Farmington, CT USA. Radiat Effects Res Fdn, Dept Clin Studies, Hiroshima, Japan. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. RP Key, TJ (reprint author), Univ Oxford, Radcliffe Infirm, Endogenous Hormones & Breast Canc Collaborat Grp, Canc Res UK,Epidemiol Unit, Gibson Bldg, Oxford OX2 6HE, England. EM Tim.Key@cancer.org.uk RI Cauley, Jane/N-4836-2015; Krogh, Vittorio/K-2628-2016; Sieri, Sabina/K-4667-2016; Venturelli, Elisabetta/B-8790-2017; OI Cauley, Jane/0000-0003-0752-4408; Krogh, Vittorio/0000-0003-0122-8624; Sieri, Sabina/0000-0001-5201-172X; Venturelli, Elisabetta/0000-0002-7427-7032; Micheli, Andrea/0000-0002-4558-4754 NR 38 TC 545 Z9 561 U1 3 U2 42 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 AUG 20 PY 2003 VL 95 IS 16 BP 1218 EP 1226 DI 10.1093/jnci/djg022 PG 9 WC Oncology SC Oncology GA 713FD UT WOS:000184845700011 PM 12928347 ER PT J AU Giovannucci, E Rimm, EB Liu, Y Leitzmann, M Wu, K Stampfer, MJ Willett, WC AF Giovannucci, E Rimm, EB Liu, Y Leitzmann, M Wu, K Stampfer, MJ Willett, WC TI Body mass index and risk of prostate cancer in US health professionals SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FACTOR-BINDING-PROTEIN; SEX-HORMONES; ANDROGEN RECEPTOR; CIGARETTE-SMOKING; SERUM LEVELS; OBESE MEN; INSULIN; WEIGHT; REPRODUCIBILITY; QUESTIONNAIRE AB The relationship between body mass index (BMI) and prostate cancer risk may be complex because obesity is associated with various hormonal factors and because the influence of BMI may differ according to whether the cancers are hereditary or sporadic. We used data from the Health Professionals Follow-Up Study, in which 2896 incident cases of prostate cancer were reported from February 1, 1986, through January 31, 2000, to determine prospectively whether BMI was associated with the risk of hereditary (men <60 years of age or with a positive family history of prostate cancer) and sporadic (men &GE;60 years of age and without such a family history) prostate cancer. The risk of prostate cancer in men with a higher BMI (&GE;30 kg/m(2)) was lower than that in men with a lower BMI (23-24.9 kg/m(2)) but only if they were younger (<60 years old) (relative risk = 0.52, 95% confidence interval = 0.33 to 0.83; P-trend<.001) or had a family history of prostate cancer (relative risk = 0.74, 95% confidence interval = 0.45 to 1.19; P-trend = .01). However, for groups with more sporadic cancers, BMI had a weak, non-statistically significant positive association with prostate cancer. We observed statistically significant interactions between BMI and age (P-interaction<.001, two-sided Wald test) and between BMI and family history of prostate cancer (P-interaction=.006, two-sided Wald test). Patterns for BMI and waist circumference were similar. Because obesity is associated with lower circulating concentrations of testosterone, our results suggest the hypothesis that androgens may play a more direct role for early-onset or hereditary prostate cancers than for sporadic prostate cancers. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Giovannucci, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA055075] NR 28 TC 167 Z9 170 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 20 PY 2003 VL 95 IS 16 BP 1240 EP 1244 DI 10.1093/jnci/djg009 PG 5 WC Oncology SC Oncology GA 713FD UT WOS:000184845700014 PM 12928350 ER PT J AU Engels, EA Frisch, M AF Engels, EA Frisch, M TI Re: Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40 - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 20 PY 2003 VL 95 IS 16 BP 1250 EP 1250 DI 10.1093/jnci/djg031 PG 1 WC Oncology SC Oncology GA 713FD UT WOS:000184845700017 ER PT J AU Hauptmann, M Sigurdson, AJ Chatterjee, N Rutter, JL Hill, DA Doody, MM Struewing, JP AF Hauptmann, M Sigurdson, AJ Chatterjee, N Rutter, JL Hill, DA Doody, MM Struewing, JP TI Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, US Dept HHS, Bethesda, MD 20892 USA. RP Hauptmann, M (reprint author), NCI, Div Canc Epidemiol & Genet, US Dept HHS, 6120 Execut Blvd, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 7 TC 8 Z9 9 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 AUG 20 PY 2003 VL 95 IS 16 BP 1251 EP 1252 DI 10.1093/jnci/djg032 PG 2 WC Oncology SC Oncology GA 713FD UT WOS:000184845700018 PM 12928354 ER PT J AU DeRose, EF Kirby, TW Mueller, GA Bebenek, K Garcia-Diaz, M Blanco, L Kunkel, TA London, RE AF DeRose, EF Kirby, TW Mueller, GA Bebenek, K Garcia-Diaz, M Blanco, L Kunkel, TA London, RE TI Solution structure of the lyase domain of human DNA polymerase lambda SO BIOCHEMISTRY LA English DT Article ID N-TERMINAL DOMAIN; BASE EXCISION-REPAIR; ISOTOPICALLY-ENRICHED PROTEINS; AMBIGUOUS DISTANCE RESTRAINTS; TRIPLE RESONANCE EXPERIMENTS; SIDE-CHAIN RESONANCES; SEQUENTIAL ASSIGNMENT; AUTOMATED ASSIGNMENT; CATALYTIC MECHANISM; CRYSTAL-STRUCTURES AB DNA polymerase lambda (pol lambda) is a recently discovered nuclear enzyme belonging to the pol X family of DNA polymerases that exhibits a 32% sequence identity with the nuclear DNA repair protein, pol beta. Structural modeling suggests that pol lambda contains the palm, fingers, thumb, and 8 kDa lyase domains present in pol P, as well as an additional N-terminal BRCT domain and a serine-proline-rich linker that are presumably involved in protein-protein interactions. The 8 kDa domain of pol P is important for DNA binding and contains the dRP lyase activity, which is the rate-limiting step in the single-nucleotide base excision repair (BER) pathway of damaged DNA. Recently, it was shown that the 8 kDa domain of pol A also contains the dRP lyase activity. To gain further insight into the catalytic mechanism of dRP removal by pol A, we have determined the solution structure of the 8 kDa lyase domain of human DNA pol A via multidimensional NMR methods and the ARIA program. The resulting structures exhibited a high degree of similarity with the 8 kDa lyase domain of pol P. Specifically, the side chains of residues W274, R275, Y279, K307, R308, and K312 are in similar positions to the functionally important side chains of residues H34, K3 5, Y39, K60, K68, and K72. in the 8 kDa lyase domain of pol P. This suggests that, on the basis of the proposed roles of these residues in pol P, the corresponding pol A side chains may be involved in DNA binding and dRP lyase activity. The structural alignment of W274 (pol lambda) with H34 (pol beta) indicates that the former is probably involved in a similar base stacking interaction with template DNA at the position of the gap, in contrast with several previous proposals which aligned D272 with H34. In a few cases for which there is a nonconservative substitution in the sequence alignment, a structural comparison shows a positionally and, hence, probably a functionally equivalent residue, e.g., K60 in pol beta and K307 in pol lambda. Additionally, on the basis of the structural alignment obtained, several previously proposed mechanistic hypotheses can be evaluated. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, E-28049 Madrid, Spain. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Blanco, Luis/I-1848-2015 NR 52 TC 20 Z9 22 U1 1 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 AUG 19 PY 2003 VL 42 IS 32 BP 9564 EP 9574 DI 10.1021/bi034298s PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 711WA UT WOS:000184763000006 PM 12911298 ER PT J AU Ory, S Zhou, M Conrads, TP Veenstra, TD Morrison, DK AF Ory, S Zhou, M Conrads, TP Veenstra, TD Morrison, DK TI Protein phosphatase 2A positively regulates ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites SO CURRENT BIOLOGY LA English DT Article ID MAP KINASE PATHWAY; GENE ENCODES; C-ELEGANS; ACTIVATION; SCAFFOLD; TRANSDUCTION; SUPPRESSOR; PHOSPHORYLATION; LOCALIZATION; ORGANIZATION AB Background: Kinase Suppressor of Ras (KSR) is a conserved component of the Ras pathway that acts as a molecular scaffold to facilitate signal transmission through the MAPK cascade. Although recruitment of KSR1 from the cytosol to the plasma membrane is required for its scaffolding function, the precise mechanism(s) regulating the translocation of KSR1 have not been fully elucidated. Results: Using mass spectrometry to analyze the KSR1 scaffolding complex, we identify the serine/threonine protein phosphatase PP2A as a KSR1-associated protein and show that PP2A is a critical regulator of KSR1 activity. We find that the enzymatic core subunits of PP2A (PR65A and catalytic C) constitutively associate with the N-terminal domain of KSR1, whereas binding of the regulatory PR55B subunit is induced by growth factor treatment. Specific inhibition of PP2A activity prevents the growth factor-induced dephosphorylation event involved in the membrane recruitment of KSR1 and blocks the activation of KSR1-associated MEK and ERK. Moreover, we find that PP2A activity is required for activation of the Raf-1 kinase and that both Raf and KSR1 must be dephosphorylated by PP2A on critical regulatory 14-3-3 binding sites for KSR1 to promote MAPK pathway activation. Conclusions: These findings identify KSR1 as novel substrate of PP2A and demonstrate the inducible dephosphorylation of KSR1 in response to Ras pathway activation. Further, these results elucidate a common regulatory mechanism for KSR1 and Raf-1 whereby their localization and activity are modulated by the PP2A-mediated dephosphorylation of critical 14-3-3 binding sites. C1 NCI, Regulat Cell Growth Lab, Frederick, MD USA. SAIC, Analyt Chem Lab, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Regulat Cell Growth Lab, Frederick, MD USA. RI Ory, Stephane/E-9947-2010 OI Ory, Stephane/0000-0003-4359-1157 FU PHS HHS [N01-C0-12400] NR 38 TC 171 Z9 179 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 19 PY 2003 VL 13 IS 16 BP 1356 EP 1364 DI 10.1016/S0960-9822(03)00535-9 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 714CZ UT WOS:000184895900016 PM 12932319 ER PT J AU DeRijk, RH Schaaf, M Stam, FJ de Jong, IEM Swaab, DF Ravid, R Vreugdenhil, E Cidlowski, JA de Kloet, ER Lucassen, PJ AF DeRijk, RH Schaaf, M Stam, FJ de Jong, IEM Swaab, DF Ravid, R Vreugdenhil, E Cidlowski, JA de Kloet, ER Lucassen, PJ TI Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry SO MOLECULAR BRAIN RESEARCH LA English DT Article DE stress; HPA axis; glucocorticoid receptor; steroid resistance; hippocampus; human ID CORTICOTROPIN-RELEASING HORMONE; PARAVENTRICULAR NUCLEUS; ALZHEIMERS-DISEASE; MESSENGER-RNA; IN-VIVO; EXPRESSION; BRAIN; DEPRESSION; RESISTANCE; TISSUE AB The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR)mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes. Hence, an increased ratio of GRbeta to GRalpha may induce relative corticosteroid-resistance, as e.g. presumed to occur in major depression. To investigate whether GRbeta is involved in the human hippocampus, we studied GRalpha and GRbeta expression levels in postmortem hippocampal tissue of control subjects by quantitative PCR (Taqman RT-PCR) and immunocytochemistry. Taqman RT-PCR demonstrated a very low relative abundance of GRbeta in the human hippocampus (GRalpha:GRbeta ratioapproximate to14 500:1). Immunohistochemical analysis confirmed the occurrence of isolated profiles indeed displaying nuclear staining in the main hippocampal subregions. Subsequent double immunofluorescent analysis revealed that >98% of these GRbeta positive cells were double positive for leucocyte common antigen, that identifies exclusively blood-derived cells of haematopoietic origin, including microglia. We conclude that GRbeta is present in very low amounts in the control human hippocampus, and that of these low numbers of cells, notably, almost all are derived from blood which is inevitably present in postmortem tissue. A functionally relevant role for the GRbeta in control of the human hippocampus is therefore not very likely. Whether this is altered in disease conditions awaits further research. (C) 2003 Elsevier B.V. All rights reserved. C1 Biochem Laboratorium, RijngeestGroep, NL-2342 AJ Oegstgeest, Netherlands. Leiden Univ, Div Med Pharmacol, NL-2300 RA Leiden, Netherlands. Leiden Univ, Ctr Med, Dept Psychiat, Leiden, Netherlands. Netherlands Inst Brain Res, Amsterdam, Netherlands. Netherlands Brain Bank, Amsterdam, Netherlands. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. Univ Amsterdam, Neurobiol Sect, Swammerdam Inst Life Sci, Amsterdam, Netherlands. RP DeRijk, RH (reprint author), Biochem Laboratorium, RijngeestGroep, Endegeesterstraatweg 5, NL-2342 AJ Oegstgeest, Netherlands. NR 46 TC 33 Z9 34 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 19 PY 2003 VL 116 IS 1-2 BP 17 EP 26 DI 10.1016/S0169-328X(03)00209-2 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 723QZ UT WOS:000185444200003 ER PT J AU Das, S Boczan, J Gerwin, C Zald, PB Sheng, ZH AF Das, S Boczan, J Gerwin, C Zald, PB Sheng, ZH TI Regional and developmental regulation of syntaphilin expression in the brain: a candidate molecular element of synaptic functional differentiation SO MOLECULAR BRAIN RESEARCH LA English DT Article DE neurotransmitter release; SNARE; synaptic plasticity; presynaptic; mitochondria ID PROTEIN-PROTEIN INTERACTIONS; PRESYNAPTIC ACTIVE ZONES; NERVE GROWTH-FACTOR; VESICLE ENDOCYTOSIS; MEMBRANE-FUSION; MEDIATED ENDOCYTOSIS; TRANSMITTER RELEASE; SNARE COMPLEX; TIME-COURSE; RAT-BRAIN AB The conserved nature of the basic machinery underlying synaptic function makes it necessary to search for other factors-structural and molecular-that could account for the tremendous diversity found among synapses even within a single neuron. Syntaphilin is a presynaptic membrane protein previously described as a molecular clamp that controls free syntaxin-1A and dynamin-1 availability, and thereby regulates synaptic vesicle exocytosis and endocytosis at the nerve terminal. In this study, we report our finding that syntaphilin expression is developmentally regulated, and show that syntaphilin is expressed most prominently in the mature rat brain, in areas that have been previously characterized to undergo synaptic plastic change. We also find that syntaphilin undergoes divergent subcellular targeting to the mitochondrial outer membrane and the synaptic plasma membrane, giving rise to two neuronal subpopulations of the protein that are modified in their relative enrichment with synaptic maturation and with the formation of cell contacts. Finally, we demonstrate that syntaphilin expression is initiated with induction of neuronal differentiation in PC12 cells. Given its biochemical and functional properties, the spatially and temporally limited nature of syntaphilin expression provides evidence that syntaphilin could be a molecular element of synaptic functional differentiation. Published by Elsevier B.V. C1 NINDS, Synapt Funct Unit, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Unit, NIH, Bldg 36,Room 5A-23,36 Convent Dr, Bethesda, MD 20892 USA. NR 51 TC 14 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 19 PY 2003 VL 116 IS 1-2 BP 38 EP 49 DI 10.1016/S0169-328X(03)00212-2 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 723QZ UT WOS:000185444200005 ER PT J AU Bakowska, JC Morrell, JI AF Bakowska, JC Morrell, JI TI The distribution of mRNA for the short form of the prolactin receptor in the forebrain of the female rat SO MOLECULAR BRAIN RESEARCH LA English DT Article DE prolactin receptor mRNA; brain; ovary; uterine ID GENE-EXPRESSION; LACTATING RATS; LONG FORMS; HYPOTHALAMIC NUCLEI; SIGNAL-TRANSDUCTION; MATERNAL-BEHAVIOR; KNOCKOUT MICE; ESTROUS-CYCLE; PRL-R; BRAIN AB Prolactin exerts its diverse effects on peripheral tissue and on the brain via receptors that have two forms, a short form and a long form. The distribution of the mRNA for both forms of the receptor has been examined in brain and peripheral tissue regions using methods based on regional dissection. Although the cell-specific distribution of the long form of the prolactin receptor has been examined using in situ hybridization in the rat brain, the cell-specific distribution of the short form has not been described. In this study we mapped the distribution of neurons and other cells expressing the short from of the receptor transcript in the forebrain, ovary, and uterus of the female rat by using in situ hybridization with a P-33-labeled cRNA probe specific for the short form of the prolactin receptor mRNA (PRL-SR mRNA). Neurons expressing the PRL-SR mRNA were located predominantly in the preoptic area and hypothalamus as well as in certain limbic structures. Specific nuclei included the anteroventral periventricular nucleus, paraventricular and supraoptic nucleus, medial preoptic area, suprachiasmatic nucleus, and ventromedial and arcuate nuclei of the hypothalamus, as well as the bed nucleus of stria terminalis and the medial amygdala. Scattered neurons expressing PRL-SR mRNA were also found in the cortex, habenula, zona incerta, and thalamus. Cells in the choroid plexus expressed high levels of PRL-SR mRNA, as did the luteal cells of the corpus luteum and the epithelial cells of the uterine glands. These data confirm previous reports and extend our knowledge of the distribution of the short form of the receptor to the cellular level. The neuroanatomic distribution of neurons expressing PRL-SR mRNA suggests that they may influence the mediation and coordination of prolactin-regulated endocrine and behavioral events. (C) 2003 Elsevier B.V. All rights reserved. C1 Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. NINDS, Bethesda, MD 20892 USA. RP Morrell, JI (reprint author), Rutgers State Univ, Ctr Mol & Behav Neurosci, 197 Univ Ave, Newark, NJ 07102 USA. NR 44 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 19 PY 2003 VL 116 IS 1-2 BP 50 EP 58 DI 10.1016/S0169-328X(03)00213-4 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 723QZ UT WOS:000185444200006 ER PT J AU Pardue, S Rapoport, SI Bosetti, F AF Pardue, S Rapoport, SI Bosetti, F TI Co-localization of cytosolic phospholipase A(2) and cyclooxygenase-2 in Rhesus monkey cerebellum SO MOLECULAR BRAIN RESEARCH LA English DT Article DE arachidonic acid; phospholipase A(2); cyclooxygenase; immunohistochemistry; Purkinje cells; cerebellum ID ARACHIDONIC-ACID CASCADE; RAT-BRAIN; GENE-EXPRESSION; INDUCIBLE CYCLOOXYGENASE; SIGNAL-TRANSDUCTION; ALZHEIMER-DISEASE; CHRONIC LITHIUM; PROTEIN-KINASE; PURKINJE-CELLS; MESSENGER-RNAS AB Cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase (COX)-1 and COX-2 play important and integrated roles in the release and subsequent metabolism of arachidonic acid, an important second messenger, in brain and other tissues. Antibodies to each of these enzymes were used to examine their cellular localization and expression in the cerebellum of the adult macaque, using Western blotting and immunohistochemical methods. COX-2 and cPLA(2) immunoreactivities co-localized on the plasma membrane of Purkinje cells, and within punctate intracellular regions. In contrast, COX-1 immunoreactivity was relatively uniform in Purkinje cell cytoplasm, and was more homogeneous in cells of the granular cell layer and occasionally of the molecular layer. COX-1 immumoreactivity was not found on the cell surface. Labeling of Purkinje cell dendrites was not marked for any of the enzymes. cPLA(2) and COX-2 have been shown to be functionally coupled in a number of cell systems, and in brain following lithium chloride administration to rats. The co-localization of cPLA(2) and COX-2 is consistent with evidence of their functional coupling at brain synapses, and of the presence of an unesterified brain arachidonate pool released by cPLA(2) which is the precursor for prostaglandin formation via COX-2. Published by Elsevier B.V. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 6N202, Bethesda, MD 20892 USA. NR 59 TC 8 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 19 PY 2003 VL 116 IS 1-2 BP 106 EP 114 DI 10.1016/S0169-328X(03)00262-6 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 723QZ UT WOS:000185444200012 ER PT J AU Tong, WH Jameson, GNL Huynh, BH Rouault, TA AF Tong, WH Jameson, GNL Huynh, BH Rouault, TA TI Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AZOTOBACTER-VINELANDII; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; MOSSBAUER-SPECTRA; GENETIC-ANALYSIS; FE/S PROTEINS; NIFU PROTEIN; ISCU; BIOSYNTHESIS; FERREDOXIN AB iron-sulfur (Fe-S) clusters serve as cofactors in many proteins that have important redox, catalytic, and regulatory functions. In bacteria, biogenesis of Fe-S clusters is mediated by multiple gene products encoded by the isc and nif operons. In particular, genetic and biochemical studies suggest that IscU, Nfu, and IscA function as scaffold proteins for assembly and delivery of rudimentary Fe-S clusters to target proteins. Here we report the characterization of human Nfu. A combination of biochemical and spectroscopic techniques, including UV-visible absorption and Fe-57 Mossbauer spectroscopies, have been used to investigate the ability of purified human Nfu to assemble Fe-S clusters. The results suggest that Nfu can assemble approximately one labile [4Fe-4S] cluster per two Nfu monomers, and support the proposal that Nfu is an alternative scaffold protein for assembly of clusters that are subsequently used for maturation of targeted Fe-S proteins. Analyses of genomic DNA, transcripts, and translation products indicate that alternative splicing of a common pre-mRNA results in synthesis of two Nfu isoforms with distinct subcellular localizations. Isoform I is localized in the mitochondria, whereas isoform II Is present in the cytosol and the nucleus. These results, together with previous reports of subcellular distributions of isoforms of human IscS and IscU in mitochondria, cytosol, and nucleus suggest that the Fe-S cluster assembly machineries are compartmentalized in higher eukaryotes. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Emory Univ, Dept Phys, Atlanta, GA 30322 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RI Jameson, Guy N. L./J-3258-2015 OI Jameson, Guy N. L./0000-0001-9416-699X FU NIGMS NIH HHS [GM 47295, R01 GM047295] NR 54 TC 113 Z9 116 U1 4 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 19 PY 2003 VL 100 IS 17 BP 9762 EP 9767 DI 10.1073/pnas.1732541100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000026 PM 12886008 ER PT J AU Resnick, MA Inga, A AF Resnick, MA Inga, A TI Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transactivation; evolution; networks; mutation; promoter ID MUTATIONAL ANALYSIS; SUPPRESSOR PROTEIN; CRYSTAL-STRUCTURE; IN-VIVO; TUMORS; PROMOTER; BINDING; CANCER; MICE; TRANSACTIVATION AB There are many sources of genetic diversity, ranging from programmed mutagenesis in antibody genes to random mutagenesis during species evolution or development of cancer. We propose that mutations in DNA sequence-specific transcription factors that target response elements (REs) in many genes can also provide for rapid and broad phenotypic diversity, if the mutations lead to altered binding affinities at individual REs. To test this concept, we examined the in vivo transactivation capacity of wild-type human and murine p53 and 25 partial function mutants. The p53s were expressed in yeast from a rheostatable promoter, and the transactivation capacities toward >15 promoter REs upstream of a reporter gene were measured. Surprisingly, there was wide variation in transactivation by the mutant p53s toward the various REs. This is the first study to address directly the impact of mutations in a sequence-specific transcription factor on transactivation from a wide array of REs. We propose a master gene hypothesis for phenotypic diversity where the master gene is a single transcriptional activator (or repressor) that regulates many genes through different REs. Mutations of the master gene can lead to a variety of simultaneous changes in both the selection of targets and the extent of transcriptional modulation at the individual targets' resulting in a vast number of potential phenotypes that can be created with minimal mutational changes without altering existing protein-protein interactions. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 54 TC 108 Z9 110 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 AUG 19 PY 2003 VL 100 IS 17 BP 9934 EP 9939 DI 10.1073/pnas.1633803100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000057 PM 12909720 ER PT J AU Doolan, DL Southwood, S Freilich, DA Sidney, J Graber, NL Shatney, L Bebris, L Florens, L Dobano, C Witney, AA Appella, E Hoffman, SL Yates, JR Carucci, DJ Sette, A AF Doolan, DL Southwood, S Freilich, DA Sidney, J Graber, NL Shatney, L Bebris, L Florens, L Dobano, C Witney, AA Appella, E Hoffman, SL Yates, JR Carucci, DJ Sette, A TI Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELL EPITOPES; LYMPHOCYTE RESPONSES; PROTEIN ANTIGENS; HLA-A; MALARIA; PEPTIDES; SEQUENCE; VACCINE; CTL; IMMUNIZATION AB The recent explosion in genomic sequencing has made available a wealth of data that can now be analyzed to identify protein antigens, potential targets for vaccine development. Here we present, in the context of Plasmodium falciparum, a strategy that rapidly identifies target antigens from large and complex genomes. Sixteen antigenic proteins recognized by volunteers immunized with radiation-attenuated P. faiciparum sporozoites, but not by mock immunized controls, were identified. Several of these were more antigenic than previously identified and well characterized P. faiciparum-derived protein antigens. The data suggest that immune responses to Plasmodium are dispersed on a relatively large number of parasite antigens. These studies have implications for our understanding of immunodominance and breadth of responses to complex pathogens. C1 Epimmune Inc, San Diego, CA 92121 USA. USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. Henry M Jackson Fdn, Rockville, MD 20852 USA. Scripps Res Inst, La Jolla, CA 92037 USA. Torrey Mesa Res Inst, San Diego, CA 92121 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sette, A (reprint author), Epimmune Inc, San Diego, CA 92121 USA. EM alex@liai.org RI Doolan, Denise/F-1969-2015; Dobano, Carlota/N-4119-2014; OI Dobano, Carlota/0000-0002-6751-4060; Florens, Laurence/0000-0002-9310-6650; Witney, Adam/0000-0003-4561-7170 NR 39 TC 147 Z9 154 U1 0 U2 25 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 AUG 19 PY 2003 VL 100 IS 17 BP 9952 EP 9957 DI 10.1073/pnas.1633254100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000060 PM 12886016 ER PT J AU Wright, G Tan, B Rosenwald, A Hurt, EH Wiestner, A Staudt, LM AF Wright, G Tan, B Rosenwald, A Hurt, EH Wiestner, A Staudt, LM TI A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene expression profile; Bayesian predictor; microarray ID CLASS PREDICTION; CLASSIFICATION; HYPERMUTATION; SIGNATURES; CANCER; XBP-1 AB To classify cancer specimens by their gene expression profiles, we created a statistical method based on Bayes' rule that estimates the probability of membership in one of two cancer subgroups. We used this method to classify diffuse large B cell lymphoma (DLBCL) biopsy samples into two gene expression subgroups based on data obtained from spotted cDNA microarrays. The germinal center B cell-like (GCB) DLBCL subgroup expressed genes characteristic of normal germinal center B cells whereas the activated B cell-like (ABC) DLBCL subgroup expressed a subset of the genes that are characteristic of plasma cells, particularly those encoding endoplasmic reticulum and golgi proteins involved in secretion. We next used this predictor to discover these subgroups within a second set of DLBCL biopsies that had been profiled by using oligonucleotide microarrays [Shipp, M. A., et aL (2002) Nat. Med 8,68-74]. The GCB and ABC DLBCL subgroups identified in this data set had significantly different 5-yr survival rates after multiagent chemotherapy (62% vs. 26%; P = 0.0051), in accord with analyses of other DLBCL cohorts. These results demonstrate the ability of this gene expression-based predictor to classify DLBCLs into biologically and clinically distinct subgroups irrespective of the method used to measure gene expression. C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Canc Res Ctr, NIH, Bldg 10,Room 4N114, Bethesda, MD 20892 USA. NR 15 TC 536 Z9 556 U1 1 U2 14 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 AUG 19 PY 2003 VL 100 IS 17 BP 9991 EP 9996 DI 10.1073/pnas.1732008100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000067 PM 12900505 ER PT J AU Dufresne, A Salanoubat, M Partensky, F Artiguenave, F Axmann, IM Barbe, V Duprat, S Galperin, MY Koonin, EV Le Gall, F Makarova, KS Ostrowski, M Oztas, S Robert, C Rogozin, IB Scanlan, DJ de Marsac, NT Weissenbach, J Wincker, P Wolf, YI Hess, WR AF Dufresne, A Salanoubat, M Partensky, F Artiguenave, F Axmann, IM Barbe, V Duprat, S Galperin, MY Koonin, EV Le Gall, F Makarova, KS Ostrowski, M Oztas, S Robert, C Rogozin, IB Scanlan, DJ de Marsac, NT Weissenbach, J Wincker, P Wolf, YI Hess, WR TI Genome sequence of the cyanobacterium Prochlorococcus marinus SS120, a nearly minimal oxyphototrophic genome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SP STRAIN PCC-7120; DIVINYL CHLOROPHYLL-A; MOLECULAR CHARACTERIZATION; GENE-PRODUCT; PETH GENE; SYNECHOCOCCUS; EVOLUTION; LIGHT; EXPRESSION; PROKARYOTE AB Prochlorococcus marinus, the dominant photosynthetic organism in the ocean, is found in two main ecological forms: high-light-adapted genotypes in the upper part of the water column and low-light-adapted genotypes at the bottom of the illuminated layer. A marinus SS120, the complete genome sequence reported here, is an extremely low-light-adapted form. The genome of A marinus SS120 is composed of a single circular chromosome of 1,751,080 bp with an average G+C content of 36.4%. It contains 1,884 predicted protein-coding genes with an average size of 825 bp, a single rRNA operon, and 40 tRNA genes. Together with the 1.66-Mbp genome of A marinus MED4, the genome of P. marinus SS120 is one of the two smallest genomes of a photosynthetic organism known to date. It lacks many genes that are involved in photosynthesis, DNA repair, solute uptake, intermediary metabolism, motility, phototaxis, and other functions that are conserved among other cyanobacteria. Systems of signal transduction and environmental stress response show a particularly drastic reduction in the number of components, even taking into account the small size of the SS120 genome. In contrast, housekeeping genes, which encode enzymes of amino acid, nucleotide, cofactor, and cell wall biosynthesis, are all present. Because of its remarkable compactness,the genome of A marinusSS120 might approximate the minimal gene complement of a photosynthetic organism. C1 CNRS, Biol Stn, UMR 7127, F-29682 Roscoff, France. Univ Paris 06, F-29682 Roscoff, France. CNRS, Genoscope, F-91057 Evry, France. CNRS, UMR 8030, F-91057 Evry, France. Humboldt Univ, Dept Biol, D-10115 Berlin, Germany. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. Inst Pasteur, Unite Cyanobacteries, Unite Rech Associee 2172, CNRS, F-75724 Paris 15, France. RP Partensky, F (reprint author), CNRS, Biol Stn, UMR 7127, BP 74, F-29682 Roscoff, France. RI Ostrowski, Martin/A-7118-2010; Galperin, Michael/B-5859-2013; Scanlan, David/G-4080-2016; OI Ostrowski, Martin/0000-0002-4357-3023; Galperin, Michael/0000-0002-2265-5572; Scanlan, David/0000-0003-3093-4245; Dufresne, Alexis/0000-0001-8231-9098; Partensky, Frederic/0000-0003-1274-4050; Axmann, Ilka Maria/0000-0002-0856-8667 FU Intramural NIH HHS [Z99 LM999999] NR 54 TC 292 Z9 711 U1 1 U2 37 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 AUG 19 PY 2003 VL 100 IS 17 BP 10020 EP 10025 DI 10.1073/pnas.1733211100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000072 PM 12917486 ER PT J AU Dahl, JL Kraus, CN Boshoff, HIM Doan, B Foley, K Avarbock, D Kaplan, G Mizrahi, V Rubin, H Barry, CE AF Dahl, JL Kraus, CN Boshoff, HIM Doan, B Foley, K Avarbock, D Kaplan, G Mizrahi, V Rubin, H Barry, CE TI The role of Rel(Mtb)-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENCODING ANTIGEN 85A; STRINGENT RESPONSE; ALPHA-CRYSTALLIN; IN-VITRO; ESCHERICHIA-COLI; GENE-EXPRESSION; BOVIS BCG; MACROPHAGES; GROWTH; VIRULENCE AB Long-term survival of nonreplicating Mycobacterium tuberculosis (Mtb) is ensured by the coordinated shutdown of active metabolism through a broad transcriptional program called the stringent response. In Mtb, this response is initiated by the enzymatic action of Rel(Mtb) and deletion of rel(Mtb) produces a strain (H37RvDeltarel(mtb)) severely compromised in the maintenance of long-term viability. Although aerosol inoculation of mice with H37RvDeltarel(Mtb) results in normal initial bacterial growth and containment, the ability of this strain to sustain chronic infection is severely impaired. Significant histopathologic differences were noted in lungs and spleens of mice infected with H37RvDeltarel(Mtb) compared with controls throughout the course of the infection. Microarray analysis revealed that H371RvDeltarel(Mtb) suffers from a generalized alteration of the transcriptional apparatus, as well as specific changes in the expression of virulence factors, cell-wall biosynthetic enzymes, heat shock proteins, and secreted antigens that may alter immune recognition of the recombinant organism. Thus, Rel(Mtb) is critical for the successful establishment of persistent infection in mice by altering the expression of antigenic and enzymatic factors that may contribute to successful latent infection. C1 NIAID, TB Res Sect, Rockville, MD 20852 USA. Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. Publ Hlth Res Inst, Newark, NJ 07103 USA. NHLS, Mol Mycobacteriol Res Unit, ZA-2000 Johannesburg, South Africa. Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. RP Barry, CE (reprint author), Twinbrook 11,Room 239,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [R01 AI054338, R01 AI054338-03] NR 41 TC 201 Z9 206 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 19 PY 2003 VL 100 IS 17 BP 10026 EP 10031 DI 10.1073/pnas.1631248100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000073 PM 12897239 ER PT J AU Vargha-Khadem, F Salmond, CH Watkins, KE Friston, KJ Gadian, DG Mishkin, M AF Vargha-Khadem, F Salmond, CH Watkins, KE Friston, KJ Gadian, DG Mishkin, M TI Developmental amnesia: Effect of age at injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; VOXEL-BASED MORPHOMETRY; HIPPOCAMPAL DAMAGE; EPISODIC MEMORY; SEMANTIC MEMORY; ORGANIZATION; ACQUISITION; INFANTS; FACTS AB Hypoxic-ischemic events sustained within the first year of life can result in developmental amnesia, a disorder characterized by markedly impaired episodic memory and relatively preserved semantic memory, in association with medial temporal pathology that appears to be restricted to the hippocampus. Here we compared children who had hypoxic-ischemic events before 1 year of age (early group, n = 6) with others who showed memory problems after suffering hypoxic-ischemic events between the ages of 6 and 14 years (late group, n = 5). Morphometric analyses of the whole brain revealed that, compared with age-matched controls, both groups had bilateral abnormalities in the hippocampus, putamen, and posterior thalamus, as well as in the right retrosplenial cortex. The two groups also showed similar reductions (approximate to40%) in hippocampal volumes. Neuropsychologically, the only significant differences between the two were on a few tests of immediate memory, where the early group surpassed the late group. The latter measures provided the only clear indication that very early injury can lead to greater functional sparing than injury acquired later in childhood, due perhaps to the greater plasticity of the infant brain. On measures of long-term memory, by contrast, the two groups had highly similar profiles, both showing roughly equivalent preservation of semantic memory combined with marked impairment in episodic memory. It thus appears that, if this selective memory disorder is a special syndrome related to the early occurrence of hypoxia-induced damage, then the effective age at injury for this syndrome extends from birth to puberty. C1 NIMH, Bethesda, MD 20892 USA. McGill Univ, Inst Neurol, Montreal, PQ H3A 1S2, Canada. UCL, Inst Child Hlth, London WC1N 3JH, England. UCL, Inst Neurol, London WC1N 3JH, England. Univ Cambridge, Wolfson Brain Imaging Ctr, Cambridge CB2 3EB, England. RP Mishkin, M (reprint author), NIMH, Bethesda, MD 20892 USA. EM mm@ln.nimh.nih.gov RI Gadian, David/C-4961-2008; Vargha-Khadem, Faraneh/C-2558-2008; Friston, Karl/D-9230-2011; Watkins, Kate/A-6559-2012; OI Friston, Karl/0000-0001-7984-8909; Watkins, Kate/0000-0002-2621-482X NR 35 TC 71 Z9 71 U1 2 U2 13 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 AUG 19 PY 2003 VL 100 IS 17 BP 10055 EP 10060 DI 10.1073/pnas.1233756100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714QY UT WOS:000184926000078 PM 12904585 ER PT J AU Shmelzer, Z Haddad, N Admon, E Pessach, I Leto, TL Eitan-Hazan, Z Hershfinkel, M Levy, R AF Shmelzer, Z Haddad, N Admon, E Pessach, I Leto, TL Eitan-Hazan, Z Hershfinkel, M Levy, R TI Unique targeting of cytosolic phospholipase A(2) to plasma membranes mediated by the NADPH oxidase in phagocytes SO JOURNAL OF CELL BIOLOGY LA English DT Article DE neutrophils; granulocyte-like PCB cells; superoxide production; arachidonic acid; PGE(2) ID ACTIVATED PROTEIN-KINASE; CHRONIC GRANULOMATOUS-DISEASE; ARACHIDONIC-ACID RELEASE; CALCIUM-DEPENDENT TRANSLOCATION; SUPEROXIDE ANION PRODUCTION; RESPIRATORY BURST OXIDASE; HUMAN NEUTROPHILS; C2 DOMAIN; ESSENTIAL REQUIREMENT; OPSONIZED ZYMOSAN AB Cytosolic phospholipase A(2) (cPLA(2))-generated arachidonic acid (AA) has been shown to be an essential requirement for the activation of NADPH oxidase, in addition to its being the major enzyme involved in the formation of eicosanoid at the nuclear membranes. The mechanism by which cPLA(2) regulates NADPH oxidase activity is not known, particularly since the NADPH oxidase complex is localized in the plasma membranes of stimulated cells. The present study is the first to demonstrate that upon stimulation cPLA(2), is transiently recruited to the plasma membranes by a functional NADPH oxidase in neutrophils and in granulocyte-like PLB-985 cells. Coimmunoprecipitation experiments and double labeling immunofluorescence analysis demonstrated the unique colocalization of cPLA(2) and the NADPH oxidase in plasma membranes of stimulated cells, in correlation with the kinetic burst of superoxide production. A specific affinity in vitro binding was detected between GST-p47(phox) or GST-p67(phox) and cPLA(2) in lysates of stimulated cells. The association between these two enzymes provides the molecular basis for AA released by cPLA(2) to activate the assembled NADPH oxidase. The ability of cPLA(2) to regulate two different functions in the same cells (superoxide generation and eicosanoid production) is achieved by a novel dual subcellular localization of cPLA(2) to different targets. C1 Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Biochem, Infect Dis Lab, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. Soroka Med Ctr, Fac Hlth Sci, Dept Physiol, IL-84105 Beer Sheva, Israel. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Levy, R (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Biochem, Infect Dis Lab, IL-84105 Beer Sheva, Israel. RI HERSHFINKEL, Michal/F-1548-2012 NR 74 TC 63 Z9 68 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 18 PY 2003 VL 162 IS 4 BP 683 EP 692 DI 10.1083/jcb.200211056 PG 10 WC Cell Biology SC Cell Biology GA 714JU UT WOS:000184910900014 PM 12913107 ER PT J AU Medvedev, AE Lentschat, A Kuhns, DB Blanco, JCG Salkowski, C Zhang, SL Arditi, MH Gallin, JI Vogel, SN AF Medvedev, AE Lentschat, A Kuhns, DB Blanco, JCG Salkowski, C Zhang, SL Arditi, MH Gallin, JI Vogel, SN TI Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE immunodeficiency; TLR4; IL-1R; inflammation; signal transduction ID RECEPTOR-ASSOCIATED KINASE; SIGNALING PATHWAYS; INNATE IMMUNITY; MICE LACKING; ENDOTOXIN; ACTIVATION; CYTOKINE; CELLS; GENE; TLR4 AB We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1-induced nuclear factor-kappaB and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-lR-associated kinase (IRAK)-1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R. This patient expresses a "compound heterozygous" genotype, with a point mutation (C877T in cDNA) and a two-nucleotide, AC deletion (620-621del in cDNA) encoded by distinct alleles of the IRAK-4 gene (GenBank/EMBL/DDBJ accession nos. AF445802 and AY186092). Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype). When overexpressed in HEK293T cells, neither truncated form augmented endogenous IRAK-1 kinase activity, and both inhibited endogenous IRAK-1 activity modestly. Thus, IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults. C1 Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Sci Applicat Int Corp Frederick Inc, Natl Canc Inst Frederick, Clin Serv Program, Frederick, MD 21702 USA. Cedars Sinai Med Ctr, Div Pediat Infect Dis, Los Angeles, CA 90048 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Vogel, SN (reprint author), Univ Maryland, Dept Microbiol & Immunol, 655 W Baltimore St,Rm 13-009, Baltimore, MD 20101 USA. FU NCI NIH HHS [N01-CO-56000]; NHLBI NIH HHS [HL-66436, R01 HL066436]; NIAID NIH HHS [R56 AI018797, AI-18797, R01 AI018797, R37 AI018797] NR 28 TC 189 Z9 199 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 18 PY 2003 VL 198 IS 4 BP 521 EP 531 DI 10.1084/jem.20030701 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 714HV UT WOS:000184908500001 PM 12925671 ER PT J AU Overwijk, WW Theoret, MR Finkelstein, SE Surman, DR de Jong, LA Vyth-Dreese, FA Dellemijn, TA Antony, PA Spiess, PJ Palmer, DC Heimann, DM Klebanoff, CA Yu, ZY Hwang, LN Feigenbaum, L Kruisbeek, AM Rosenberg, SA Restifo, NP AF Overwijk, WW Theoret, MR Finkelstein, SE Surman, DR de Jong, LA Vyth-Dreese, FA Dellemijn, TA Antony, PA Spiess, PJ Palmer, DC Heimann, DM Klebanoff, CA Yu, ZY Hwang, LN Feigenbaum, L Kruisbeek, AM Rosenberg, SA Restifo, NP TI Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE adoptive cell transfer; immunotherapy; IL-2; recombinant poxvirus; T cell epitope ID THERAPEUTIC ANTICANCER VACCINES; RESPONSES IN-VIVO; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; ANTITUMOR IMMUNITY; REJECTION ANTIGEN; SOLID TUMORS; CANCER; LYMPHOCYTES; IMMUNIZATION AB Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and call be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I-restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 nm(2)), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with all altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cytokine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer. C1 NCI, NIH, Bethesda, MD 20892 USA. Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. Howard Hughes Med Inst, NIH, Bethesda, MD 20815 USA. Sci Applicat Int Corp, NCI, Frederick, MD 21702 USA. RP Restifo, NP (reprint author), NCI, NIH, Bldg 10,Room 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Klebanoff, Christopher/B-8088-2008; Palmer, Douglas/B-9454-2008; Klebanoff, Christopher/D-9581-2011; Liu, Xia/L-9425-2013; OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 51 TC 551 Z9 564 U1 1 U2 31 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 AUG 18 PY 2003 VL 198 IS 4 BP 569 EP 580 DI 10.1084/jem.20030590 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 714HV UT WOS:000184908500005 PM 12925674 ER PT J AU McDonald, JP Frank, EG Plosky, BS Rogozin, IB Masutani, C Hanaoka, F Woodgate, R Gearhart, PJ AF McDonald, JP Frank, EG Plosky, BS Rogozin, IB Masutani, C Hanaoka, F Woodgate, R Gearhart, PJ TI 129-derived strains of mice are deficient in DNA polymerase iota and have normal immunoglobulin hypermutation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE genomic organization; immunoglobulin variable genes; DNA polymerase eta; cytosine deamination; base excision repair ID XERODERMA-PIGMENTOSUM VARIANT; THYMINE-THYMINE DIMER; SOMATIC HYPERMUTATION; POL-IOTA; TRANSLESION SYNTHESIS; LESION BYPASS; IN-VITRO; ETA; FIDELITY; GENES AB Recent studies suggest that DNA polymerase eta (poleta) and DNA polymerase iota (poliota) are involved in somatic hypermutation of immunoglobulin variable genes. To test the role Of poliota in generating mutations in an annual model, we first characterized the biochemical properties of murine poliota. Like its human counter-part, murine poliota is extremely error-prone when catalyzing synthesis on a variety of DNA templates in vitro. Interestingly, when filling in a I base-pair gap, DNA synthesis and subsequent strand displacement was greatest ill the presence of both pols iota and eta. Genomic sequence analysis of Poli led to the serendipitous discovery that 129-derived strains of mice have a nonsense codon mutation in exon 2 that abrogates production of poliota. Analysis of hypermutation in variable genes from 129/SvJ (Poli(-/-)) and C57BL/6J (Pol(+/+)) mice revealed that the overall frequency and spectrum of mutation were normal in poliota-deficient mice. Thus, either poliota does not participate in hypermutation, or its role is nonessential and call be readily assumed by another low-fidelity polymerase. C1 NICHD, Lab Genom Integr, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. Japan Sci & Technol Corp, CREST, Suita, Osaka 5650871, Japan. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Woodgate, R (reprint author), NICHD, Lab Genom Integr, Sect DNA Replicat Repair & Mutagenesis, NIH, Bldg 6,Room 1A13,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Masutani, Chikahide/I-6160-2014 NR 43 TC 142 Z9 153 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 18 PY 2003 VL 198 IS 4 BP 635 EP 643 DI 10.1084/jem.20030767 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 714HV UT WOS:000184908500011 PM 12925679 ER PT J AU Engels, EA Biggar, RJ Marshall, VA Walters, MAKL Gamache, CJ Whitby, D Goedert, JJ AF Engels, EA Biggar, RJ Marshall, VA Walters, MAKL Gamache, CJ Whitby, D Goedert, JJ TI Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDS-associated Kaposi's sarcoma SO AIDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HOMOSEXUAL-MEN; SEXUAL TRANSMISSION; RISK-FACTORS; HUMAN-HERPESVIRUS-8; INFECTION; PROGRESSION; TYPE-1; KS; SEROCONVERSION AB Objective: To identify immunologic and virologic predictors of AIDS-associated Kaposi's sarcoma (KS). Design: Nested case-control analysis of KS risk in a cohort of 132 HIV-infected homosexual men in New York and Washington, DC, USA. Methods: For each KS case, we selected two HIV-infected controls, matched for CD4 cell count and Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8; KSHV) serostatus (enzyme immunoassay for antibody to KSHV protein K8.1). Cell-associated KSHV and Epstein-Barr virus (EBV) viral loads were measured with quantitative real-time PCR assays on samples collected 1 year (median) before KS diagnosis. Results: Thirty-one men developed AIDS-associated KS (incidence 3.1 per 100 person years). Among HIV-infected men, KS incidence was higher among those with K8.1 seropositivity (5.0 versus 1.4 per 100 person years; P = 0.004), low CD4 cell count [hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.24-1.79 per 100 X 10(6) cells/l decline), or high HIV RNA level (HR, 3.96; 95% Cl, 2.19-7.16 per log(10)). In the case-control analysis, nine of 70 evaluated subjects had KSHV viremia, generally low level (median viral load 180 copies per 1 X 10(6) cells). KSHV viremia was associated with increased KS risk (unadjusted odds ratio, 9.1; 95% CI, 1.7-48; odds ratio, 11.7; 95% CI, 1.8-76 after adjustment for K8.1 serostatus, CD4 cell count, and HIV RNA). Among K8.1-seropositive subjects, KS incidence was tenfold higher in those with KSHV viremia (30.3 per 100 person years versus 3.4 per 100 person years in those without viremia). Also, EBV viral loads were higher in cases than in controls (P = 0.07). Conclusions: Among individuals with HIV-KSHV coinfection, KSHV viremia identifies a subgroup with extremely high risk for developing KS. (C) 2003 Lippincott Williams Wilkins. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS, Bethesda, MD 20892 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, DHHS, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-12400] NR 24 TC 91 Z9 97 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 15 PY 2003 VL 17 IS 12 BP 1847 EP 1851 DI 10.1097/01.aids.0000076275.54156.08 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 713BH UT WOS:000184835100015 PM 12891072 ER PT J AU Slavotinek, AM Collins, MT Muenke, M AF Slavotinek, AM Collins, MT Muenke, M TI Non-syndromic hemihyperplasia in a male and his mother SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE hemihypertrophy; familial hemihyperplasia; familial hemihypertrophy ID MEDULLARY SPONGE KIDNEY; BECKWITH-WIEDEMANN-SYNDROME; CONGENITAL HEMIHYPERTROPHY; DIAGNOSTIC-CRITERIA; PROTEUS-SYNDROME; WILMS-TUMOR; ASYMMETRY; MANIFESTATIONS AB We present two family members with non-syndromal hemihyperplasia (HHP), which developed in adolescence. We have reviewed reported familial cases of HHP and conclude that presentation is similar to sporadi cases and that all affected family members have been related through a maternal relative. Published 2003 Wiley-Liss, Inc.dagger C1 UCSF, Dept Pediat, San Francisco, CA USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Slavotinek, AM (reprint author), UCSF, Dept Pediat, Room U585P,531 Parnassus St, San Francisco, CA USA. NR 38 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG 15 PY 2003 VL 121A IS 1 BP 47 EP 51 DI 10.1002/ajmg.a.10177 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 707NK UT WOS:000184516600009 PM 12900901 ER PT J AU Willour, VL Zandi, PP Huo, YQ Diggs, TL Chellis, JL MacKinnon, DF Simpson, SG McMahon, FJ Potash, JB Gershon, ES Reich, T Foroud, T Nurnberger, JI DePaulo, JR McInnis, MG AF Willour, VL Zandi, PP Huo, YQ Diggs, TL Chellis, JL MacKinnon, DF Simpson, SG McMahon, FJ Potash, JB Gershon, ES Reich, T Foroud, T Nurnberger, JI DePaulo, JR McInnis, MG TI Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: Chromosomes 4, 7, 9, 18, 19, 20, and 21 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE 4q; 20p; manic depression; parametric linkage; nonparametric linkage ID AFFECTIVE-DISORDER; LOD SCORES; LINKAGE; ILLNESS; LOCUS; TRANSMISSION; MAPS AB The NIMH genetics initiative on bipolar disorder was established to collect uniformly ascertained bipolar pedigrees for genetic studies. In 1997, the four participating sites published a genome scan on the initial set of 97 bipolar pedigrees. Fifty-six additional bipolar pedigrees have now been ascertained and evaluated. This replication pedigree set contains 354 genotyped subjects, including 139 bipolar I (BPI) subjects, five schizoaffective bipolar type SA/BP subjects, 41 bipolar II (BPII) subjects, and 43 recurrent unipolar (RUP) depression subjects. Our site has recently genotyped the replication study bipolar pedigrees using 107 microsatellite markers from chromosomes 4, 7, 9, 18, 19, 20, and 21. We are now reporting parametric and nonparametric linkage results from this effort. Multipoint nonparametric linkage analysis produced three candidate regions with allele sharing LOD scores greater than or equal to 1.0. The linkage signal on 4q35 peaked between markers D4S3335 and D4S2390 with an allele sharing LOD score of 2.49. This finding exceeds standard criteria for suggestive linkage. Two additional loci approach suggestive linkage levels: the 4q32 finding had its maximum near marker D4S1629 with an allele sharing LOD score of 2.16, and the 20p12 finding peaked at D20S162 with an allele sharing LOD score of 1.82. Multipoint parametric linkage analysis produced similar findings. When we combined the genotype data from the original and the replication pedigree sets, 20p12 yielded a nonparametric LOD score of 2.38, which exceeds standard criteria for suggestive linkage, and a corresponding parametric HLOD score of 2.98. The combined analysis did not provide further support for linkage to 4q32 and 4q35. (C) 2003 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD 21287 USA. Univ Colorado, Sch Med, Denver, CO USA. NIMH, Bethesda, MD 20892 USA. Univ Chicago, Chicago, IL 60637 USA. Washington Univ, St Louis, MO USA. Indiana Univ, Sch Med, Indianapolis, IN USA. RP Willour, VL (reprint author), Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Meyer Bldg,Room 4-132,600 N Wolfe St, Baltimore, MD 21287 USA. RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012; OI McInnis, Melvin/0000-0002-0375-6247; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X FU NIMH NIH HHS [U01 MH 46274, U01 MH 46280, U01 MH 46282] NR 30 TC 30 Z9 33 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD AUG 15 PY 2003 VL 121B IS 1 BP 21 EP 27 DI 10.1002/ajmg.b.20051 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 708CF UT WOS:000184548900004 PM 12898570 ER PT J AU Francomano, CA McKusick, VA Biesecker, LG AF Francomano, CA McKusick, VA Biesecker, LG TI Medical genetic studies in the Amish: Historical perspective - Introduction SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Editorial Material ID OLD ORDER AMISH; BIPOLAR AFFECTIVE-DISORDER; CARTILAGE-HAIR HYPOPLASIA; VAN-CREVELD-SYNDROME; GENOME-WIDE; ATAXIA-TELANGIECTASIA; SPASTIC PARAPLEGIA; TROYER-SYNDROME; MUTATIONS; ACIDURIA C1 NIA, Genet Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Francomano, CA (reprint author), NIA, Genet Lab, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. NR 35 TC 12 Z9 12 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD AUG 15 PY 2003 VL 121C IS 1 BP 1 EP 4 DI 10.1002/ajmg.c.20001 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 707QV UT WOS:000184522100001 PM 12888981 ER PT J AU Agarwala, R Biesecker, LG Schaffer, AA AF Agarwala, R Biesecker, LG Schaffer, AA TI Anabaptist Genealogy Database SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE Amish; Mennonite; Anabaptist; consanguinity; inbreeding; genealogy; Steiner trees ID OLD ORDER AMISH; STEINER TREE PROBLEMS; PREREPRODUCTIVE MORTALITY; HERITABILITY ANALYSIS; DIETARY-CHOLESTEROL; LINKAGE ANALYSIS; EPIDEMIOLOGY; ALGORITHMS; PEDIGREES AB In late 1996 we set out to build a computer-searchable genealogy of the Old Order Amish of Lancaster County, Pennsylvania, for use by geneticists. The goals of the project included: I) using the genealogy to expedite the mapping of genes mutated in three rare recessive disorders under study at the National Institutes of Health (NIH); 2) building a freely available software package, PedHunter, to answer genetically relevant queries on our database and other similar databases; and 3) providing genealogy assistance to researchers outside NIH. All of these scientific goals had to be accomplished while maintaining the confidentiality of the persons in the database and the confidentiality of preliminary research results. We expanded the project to include complementary data sources that contained many individuals who were Anabaptist, but not Amish, and many individuals who never lived in Lancaster County. For this reason, the project was renamed Anabaptist Genealogy Database (AGDB). All of the initial goals of the project have been accomplished, and we recently marked the 5-year anniversary of answering the first of over 100 queries by researchers outside NIH. Thus, it is an opportune time to review the construction of AGDB, summarize its usage to date, and speculate on future projects it might stimulate and facilitate. C1 NCBI, DHHs, NLM, NIH, Bethesda, MD 20894 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Schaffer, AA (reprint author), NCBI, DHHs, NLM, NIH, Bldg 38A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. RI Schaffer, Alejandro/F-2902-2012 NR 42 TC 35 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 0148-7299 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD AUG 15 PY 2003 VL 121C IS 1 BP 32 EP 37 DI 10.1002/ajmg.c.20004 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 707QV UT WOS:000184522100004 PM 12888984 ER PT J AU Platte, P Papanicolaou, GJ Johnston, J Klein, CM Doheny, KF Pugh, EW Roy-Gagnon, MH Stunkard, AJ Francomano, CA Wilson, AF AF Platte, P Papanicolaou, GJ Johnston, J Klein, CM Doheny, KF Pugh, EW Roy-Gagnon, MH Stunkard, AJ Francomano, CA Wilson, AF TI A study of linkage and association of body mass index in the Old Order Amish SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE body mass index; linkage; association ID CONGENITAL LEPTIN DEFICIENCY; AUTOSOMAL GENOMIC SCAN; PREDICT WEIGHT-GAIN; OB GENE REGION; PIMA-INDIANS; FAT DISTRIBUTION; DIABETES-MELLITUS; ENERGY-METABOLISM; WIDE SCAN; US ADULTS AB Obesity is thought to have a genetic component with the estimates of heritability ranging from 0.25-0.40. As part of an ongoing study of obesity in the Old Order Amish, seven two- and three-generation families (157 individuals) were assessed for 21 traits related to obesity, including body mass index (BMI) and BMI-percentile (a standardized distribution of BMI adjusted for age and sex). Genotyping was performed using a panel of 384 short-tandem repeat markers. In this sample, the estimates of heritability ranged from 0.16-0.31 for BMI and from 0.40-0.52 for BMI-percentile. Model-independent linkage analysis identified candidate regions on chromosomes 1, 5, 7, 8, and 11. Given that several markers on 7q were significant for both BMI and BMI-percentile (Pless than or equal to0.001) and that the structural locus for leptin was located on 7q, this region was considered to be the primary candidate region. Subsequent typing of additional flanking markers on 7q corroborated the original findings. Tests of intrafamilial association for alleles at markers in this candidate region were significant at similar levels. Although there is some evidence for linkage and association in the region containing leptin, there appears to be stronger evidence for linkage (P<0.001) and association (P<0.00001) with BMI in a region 10-15 cM further downstream of leptin, flanked by markers D7S1804 and D7S3070 with peak values from D7S495-D7S1798. Evidence from linkage and association studies suggests that this region (D7S1804-D7S3070) maybe responsible, at least in part, for variation in BMI and BMI-percentile in the Old Order Amish. C1 NHGRI, Genometr Sect, IDRB, Triad Technol Ctr,NIH, Baltimore, MD 21224 USA. Univ Trier, Ctr Psychobiol & Psychosomat Res, Trier, Germany. Johns Hopkins Sch Med, Genotyping Lab, CIDR, Inst Med Genet, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Papanicolaou, GJ (reprint author), NHGRI, Genometr Sect, IDRB, Triad Technol Ctr,NIH, 333 Cassell Dr,Suite 2000, Baltimore, MD 21224 USA. EM gjp@nhgri.nih.gov RI Wilson, Alexander/C-2320-2009 FU NCRR NIH HHS [P41 RR 03655]; NHGRI NIH HHS [N01 HG 65403] NR 64 TC 39 Z9 39 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4868 EI 1552-4876 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD AUG 15 PY 2003 VL 121C IS 1 BP 71 EP 80 DI 10.1002/ajmg.c.20005 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 707QV UT WOS:000184522100007 PM 12888987 ER PT J AU Zhang, X Zhao, H Chen, Z Nims, R Weber, SG AF Zhang, X Zhao, H Chen, Z Nims, R Weber, SG TI Effect of polymer concentration on partitioning and molecular recognition in plasticized poly(vinyl chloride) SO ANALYTICAL CHEMISTRY LA English DT Article ID IONIZATION MASS-SPECTROMETRY; SOLID-PHASE MICROEXTRACTION; ARTIFICIAL RECEPTOR; SAMPLE PREPARATION; BULK OPTODES; PREFERENTIAL SOLVATION; LIQUID MEMBRANES; SOLVENT MIXTURES; IMMUNOSORBENTS; BINDING AB Mixtures of poly(vinyl chloride) (PVC) with plasticizers have been used in ion-selective electrodes for many years. The same material has proven useful in solid-phase microextraction (SPME), both with and without artificial receptors. We hypothesized that by changing the polymer concentration in plasticized PVC membranes containing artificial receptor from the standard 33 wt%, the selectivity of the extraction of barbiturates over similar molecules could be improved. Partition coefficients and receptor-substrate formation constants of a target species, phenobarbital, in membranes with various polymer concentrations were determined. Diffusion coefficients of the solute phenobarbital in receptor-free membranes were also determined. Kamlet-Taft solvatochromic properties beta and pi* were measured for the PVC/dioctyl sebacate materials. Cohesive energy densities were calculated for the same materials. Partition coefficients for phenobarbital (from aqueous solution to membrane) decrease as [PVC] increases, while the formation constants for the complex of the solute with its receptor increase. Diffusion coefficients decrease as the polymer concentration increases as well. The increase in polymer concentration brings about a decrease in hydrogen-bonding basicity and an increase in dipolarity and cohesive energy density. The values of the solvatochromic parameters determined at various compositions are highly correlated; thus, it is impossible to calculate how much each factor contributes to the changes associated with partition and complex formation. The solvatochromic "polarizability correction factor" has been determined to be 0 for PVC. In SPME experiments at 30%, 40%, and 50% (w/w) PVC, as polymer concentration increases, selectivity for barbiturate extraction over other cyclic imides becomes better in the presence of barbiturate receptor and worse without receptor. C1 Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. RP Weber, SG (reprint author), Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. OI Weber, Stephen/0000-0002-7970-2632 FU NIGMS NIH HHS [P50 GM067082] NR 48 TC 10 Z9 10 U1 0 U2 3 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 AUG 15 PY 2003 VL 75 IS 16 BP 4257 EP 4264 DI 10.1021/ac0342267 PG 8 WC Chemistry, Analytical SC Chemistry GA 712LA UT WOS:000184798100041 PM 14632144 ER PT J AU Schlucker, S Schaeberle, MD Huffman, SW Levin, IW AF Schlucker, S Schaeberle, MD Huffman, SW Levin, IW TI Raman microspectroscopy: A comparison of point, line, and wide-field imaging methodologies SO ANALYTICAL CHEMISTRY LA English DT Article ID TUNABLE FILTER; MICROSCOPE; SPECTROMETERS; SPECTROSCOPY; ILLUMINATION; EXCITATION; MICROPROBE AB Three different Raman microspectroscopic imaging methodologies using a single experimental configuration are compared; namely, point and line mapping, as representatives of serial imaging approaches, and direct or wide-field Raman imaging employing liquid-crystalline tunable filters are surveyed. Raman imaging data acquired with equivalent low-power 514.5-nm laser excitation and a cooled CCD camera are analyzed with respect to acquisition times, image quality, spatial resolution, intensity profiles along spatial coordinates, and spectral signal-to-noise ratios (SNRs). Point and line mapping techniques provide similar SNRs and reconstructed Raman images at spatial resolutions of -1.1 mum. In contrast, higher spatial resolution is obtained by direct, global imaging (similar to313 nm), allowing subtle morphological features on test samples to be resolved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Schlucker, Sebastian/D-1031-2010 OI Schlucker, Sebastian/0000-0003-4790-4616 NR 23 TC 98 Z9 99 U1 2 U2 30 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 AUG 15 PY 2003 VL 75 IS 16 BP 4312 EP 4318 DI 10.1021/ac034169h PG 7 WC Chemistry, Analytical SC Chemistry GA 712LA UT WOS:000184798100048 PM 14632151 ER PT J AU Ford, BD Liu, Y Mann, MA Krauss, R Phillips, K Gan, L Fischbach, GD AF Ford, BD Liu, Y Mann, MA Krauss, R Phillips, K Gan, L Fischbach, GD TI Neuregulin-1 suppresses muscarinic receptor expression and acetylcholine-activated muscarinic K+ channels in cardiac myocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE acetylcholine; acetylcholine receptor inducing activity; arrhythmia; glial growth factor; heart failure; heregulin; ion channels; neu differentiation factor; receptors ID TISSUE-SPECIFIC REGULATION; HEART-RATE INCREASE; DORSAL AORTIC FLOW; CHICK HEART; DIFFERENTIAL EXPRESSION; VENTRICULAR MYOCYTES; I-KACH; PROTEIN; ERBB2; CELLS AB The neuregulin-1 family of growth factors regulates nicotinic acetylcholine receptor synthesis in skeletal muscle, but its role in cardiac myogenesis remains unclear. Here, we investigate the involvement of neuregulins in the development of cardiac cholinergic responsiveness. Treatment of chick cardiac myocytes with neuregulin-1 inhibited mRNA expression of the M4 muscarinic receptor, but not the M2 receptor. In addition, mRNA levels of GIRK1 were reduced in myocytes by treatment with neuregulin-1. Activation of cholinergic receptors in cultured chick atrial myocytes by carbachol produced an outward potassium current (I-K(ACh)), which was attenuated by 24-48-h pre-treatment with neuregulin-1. These data suggest that neuregulins can regulate cardiac parasympathetic tone and may be involved in the pathogenesis of cardiac arrhythmias and heart failure. (C) 2003 Elsevier Inc. All rights reserved. C1 Morehouse Sch Med, Dept Anat & Neurobiol, Atlanta, GA 30310 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA. RP Ford, BD (reprint author), Morehouse Sch Med, Dept Anat & Neurobiol, 720 Westview Dr SW,MRC 223, Atlanta, GA 30310 USA. FU NINDS NIH HHS [NS18458] NR 36 TC 6 Z9 6 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 15 PY 2003 VL 308 IS 1 BP 23 EP 28 DI 10.1016/S0006-291X(03)01319-6 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 709AG UT WOS:000184602100004 PM 12890474 ER PT J AU Park, SH Yeo, SY Yoo, KW Hong, SK Lee, S Rhee, M Chitnis, AB Kim, CH AF Park, SH Yeo, SY Yoo, KW Hong, SK Lee, S Rhee, M Chitnis, AB Kim, CH TI Zath3, a neural basic helix-loop-helix gene, regulates early neurogenesis in the zebrafish SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE basic helix-loop-helix gene; zath3; neurogenin1; neural plate; neuronal determination; cranial ganglia; neurogenesis; mindbomb; narrowminded ID XENOPUS-EMBRYOS; TRANSGENIC ZEBRAFISH; TRANSCRIPTION FACTOR; ECTOPIC EXPRESSION; LATERAL INHIBITION; ACHAETE-SCUTE; VERTEBRATE; NEURONS; FATE; ECTODERM AB We have isolated a basic helix-loop-helix (bHLH) gene homologous to the Drosophila proneural gene atonal, termed zath3, from zebrafish. zath3 is expressed in neurons of the central nervous system and in subsets of cranial ganglia. Zebrafish mindbomb (mib) mutants have a higher density of zath3 expressing cells and narrowminded (nrd) mutants lack zath3 expression in a domain corresponding to primary sensory neurons showing that the expression of zath3 is regulated by both mib and nrd. Injection of synthetic zath3 RNA into zebrafish embryos expands the neural plate size, promotes ectopic expression of neuronal markers, and partially rescues the deficit of sensory neurons seen in nrd mutants. Interfering with zath3 function using antisense morpholino oligonucleotides (MO) has no significant effect on early neurogenesis. However, a double knock down of zath3 and neurogenin1 (ngn1), another atonal homologue, with morpholinos (MOs) leads to more severe defects in neurogenesis than are seen with ngn1 MO alone: a subtle reduction of motor and inter-neurons, and an almost complete loss all cranial ganglia. This study suggests that zath3 and ngn1 have partially overlapping roles in early neurogenesis. (C) 2003 Published by Elsevier Inc. C1 Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. NICHD, Genet Mol Lab, NIH, Bethesda, MD USA. Pochon CHA Univ, CHA Gen Hosp, Seoul, South Korea. RP Kim, CH (reprint author), Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. NR 31 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 15 PY 2003 VL 308 IS 1 BP 184 EP 190 DI 10.1016/S0006-291X(03)01353-6 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 709AG UT WOS:000184602100029 PM 12890499 ER PT J AU Nemeth, MJ Curtis, DJ Kirby, MR Garrett-Beal, LJ Seidel, NE Cline, AP Bodine, DM AF Nemeth, MJ Curtis, DJ Kirby, MR Garrett-Beal, LJ Seidel, NE Cline, AP Bodine, DM TI Hmgb3: an HMG-box family member expressed in primitive hematopoietic cells that inhibits myeloid and B-cell differentiation SO BLOOD LA English DT Article ID HOMEOBOX GENE; STEM-CELLS; DNA-BINDING; MYELOMONOCYTIC DIFFERENTIATION; MESSENGER-RNA; PROTEIN HMG1; BONE-MARROW; MOUSE; POPULATIONS; PROGENITORS AB Hmgb3 is a member of a family of chromatin-binding proteins that can alter DNA structure to facilitate transcription factor binding. We identified the Hmgb3 cDNA in a subtractive hybridization screen for transcripts that are preferentially expressed in hematopoletic stem cells. We inserted an internal ribosomal entry site-green fluorescence protein cassette into the 3' untranslated region of the X-linked Hmgb3 locus to identify Hmgb3-expressing cells. In adult mice, Hmgb3 mRNA is detected in bone marrow cells, primitive Lin(-), c-kit(+), Sca-1(+), IL-7Ralpha(-) cells, and Ter119(+) erythroid cells. We observed that long-term repopulating ability is entirely contained in the subpopulation of Lin(-), c-kit(HI) cells that express Hmgb3. Most common lymphoid and myeloid progenitors express Hmgb3. Introduction of a retrovirus containing the Hmgb3 cDNA into mouse bone marrow stem cells demonstrated that enforced expression of Hmgb3 inhibited B-cell and myeloid differentiation. We conclude that down-regulation of Hmgb3 protein levels is an important step for myeloid and B-cell differentiation. (C) 2003 by The American Society of Hematology. C1 NHGRI, Genet & Mol Biol Branch, Hematopoiesis Sect, Bethesda, MD 20892 USA. NHGRI, Transgen Mouse Core, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), NHGRI, Genet & Mol Biol Branch, Hematopoiesis Sect, 49 Convent Dr,Rm 3A04, Bethesda, MD 20892 USA. NR 35 TC 48 Z9 50 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 AUG 15 PY 2003 VL 102 IS 4 BP 1298 EP 1306 DI 10.1182/blood-2002-11-3541 PG 9 WC Hematology SC Hematology GA 709XJ UT WOS:000184651600029 PM 12714519 ER PT J AU Poggi, MM Danforth, DN Sciuto, LC Smith, SL Steinberg, SM Liewehr, DJ Menard, C Lippman, ME Lichter, AS Altemus, RM AF Poggi, MM Danforth, DN Sciuto, LC Smith, SL Steinberg, SM Liewehr, DJ Menard, C Lippman, ME Lichter, AS Altemus, RM TI Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy - The National Cancer Institute randomized trial SO CANCER LA English DT Article; Proceedings Paper CT 25th San Antonio Breast Cancer Symposium CY DEC 11-14, 2002 CL SAN ANTONIO, TEXAS DE breast carcinoma; conservation; radiation therapy; mastectomy ID 20-YEAR FOLLOW-UP; CONSERVING SURGERY; STAGE-I; RECURRENCE; RADIATION; RISK AB BACKGROUND. Between 1979-1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results. METHODS. After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival. RESULTS. At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70). CONCLUSIONS. After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups. C1 NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. Univ Michigan, Sch Med, Dept Radiat Oncol, Ann Arbor, MI USA. RP Poggi, MM (reprint author), 5412 30th Pl NW, Washington, DC 20015 USA. NR 20 TC 267 Z9 278 U1 4 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2003 VL 98 IS 4 BP 697 EP 702 DI 10.1002/cncr.11580 PG 6 WC Oncology SC Oncology GA 708JA UT WOS:000184562400005 PM 12910512 ER PT J AU Lacey, JV Swanson, CA Brinton, LA Altekruse, SF Barnes, WA Gravitt, PE Greenberg, MD Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Kurman, RJ Hildesheim, A AF Lacey, JV Swanson, CA Brinton, LA Altekruse, SF Barnes, WA Gravitt, PE Greenberg, MD Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Kurman, RJ Hildesheim, A TI Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix SO CANCER LA English DT Article DE cervical adenocarcinoma; cervical squamous cell carcinoma; human papillomavirus (HPV); obesity; body weight ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; POLYMERASE-CHAIN-REACTION; MULTICENTRIC CASE-CONTROL; 3RD NATIONAL-HEALTH; HUMAN-PAPILLOMAVIRUS; BREAST-CANCER; SEX-HORMONES; POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES AB BACKGROUND. Hormonal factors may play a more prominent role in cervical adenocarcinoma than squamous cell carcinoma. The authors evaluated whether obesity, which can influence hormone levels, was associated with adenocarcinoma and squamous cell carcinoma. METHODS. This case-control study included 124 patients with adenocarcinoma, 139 matched patients with squamous cell carcinoma, and 307 matched community control participants. All participants completed interviews and provided cervicovaginal samples for human papillomavirus (HPV) testing. Polytomous logistic regression-generated odds ratios (ORs) and 95% confidence intervals (95% CIs) for self-reported height and weight, body mass index (BMI; kg/m(2)), and measured waist-to-hip ratio (WHR) for both histologic types were adjusted and stratified for HPV and other confounders. RESULTS. Height, weight, BMI, and WHR were positively associated with adenocarcinoma. BMI greater than or equal to30 kg/m(2) (vs. BMI < 25 kg/m(2); OR, 2.1 and 95% Cl, 1.1-3.8) and WHR in the highest tertile (vs. the lowest tertile; OR, 1.8 and 95% CI, 0.97-3.3) were associated with adenocarcinoma. Neither height nor weight was found to be associated with squamous cell carcinoma, and associations for BMI >= 30 kg/m(2) (OR, 1.6) and WHR in the highest tertile (OR, 1.6) were weaker and were not statistically significant. Analyses using only HPV positive controls showed similar associations. The data were adjusted for and stratified by screening, but higher BMI and WHR were associated with higher disease stage at diagnosis, even among recently and frequently screened patients with adenocarcinoma. Thus, residual confounding by screening could not be excluded as an explanation for the associations. CONCLUSIONS. Obesity and body fat distribution were associated more strongly with adenocarcinoma than with squamous cell carcinoma. Although questions about screening remain, obesity may have a particular influence on the risk of glandular cervical carcinoma. C1 NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Rockville, MD 20852 USA. Georgetown Univ, Dept Obstet & Gynecol, Lombardi Canc Ctr, Washington, DC USA. Roche Mol Syst Inc, Dept Human Genet, Alameda, CA USA. Grad Hosp Philadelphia, Dept Gynecol, Philadelphia, PA 19146 USA. Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. George Washington Univ, Div Gynecol Oncol, Washington, DC USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Hershey, PA 17033 USA. Johns Hopkins Univ, Sch Med, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Lacey, JV (reprint author), NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 40 TC 54 Z9 56 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2003 VL 98 IS 4 BP 814 EP 821 DI 10.1002/cncr.11567 PG 8 WC Oncology SC Oncology GA 708JA UT WOS:000184562400020 PM 12910527 ER PT J AU Takeda, H Sonoshita, M Oshima, H Sugihara, K Chulada, PC Langenbach, R Oshima, M Taketo, MM AF Takeda, H Sonoshita, M Oshima, H Sugihara, K Chulada, PC Langenbach, R Oshima, M Taketo, MM TI Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis SO CANCER RESEARCH LA English DT Article ID PROSTAGLANDIN-E SYNTHASE; FAMILIAL ADENOMATOUS POLYPOSIS; APC(DELTA-716) MOUSE; COLORECTAL ADENOMAS; E-2 BIOSYNTHESIS; KNOCKOUT MICE; COLON-CANCER; COX-2; TUMORIGENESIS; INHIBITOR AB Membrane arachidonic acid is converted by cyclooxygenase (COX) into prostaglandin (PG) G(2) and then to PGH(2) which is subsequently metabolized to PGE(2) by PGE synthase (PGES). Both COX-1 and COX-2 play critical roles in intestinal polyp formation, whereas COX-2 is also expressed in cancers of a variety of organs. Likewise, inducible microsomal PGES (mPGES-1) is expressed in several types of cancer, although its role in benign polyp formation has not been investigated. We demonstrated recently that most COX-2-expressing cells in the polyps are stromal fibroblasts. Here we show colocalization of COX-1, COX-2 and mPGES in the intestinal polyp stromal fibroblasts of Apc(Delta716) mice, a model for familial adenomatous polyposis. Contrary to COX-2 that was induced only in polyps > 1 mm in diameter, COX-1 was found in polyps of any size. In polyps > 1 mm, not only COX-2 but also mPGES was induced in the stromal fibroblasts where COX-1 had already been expressed. Although polyp number and size were markedly reduced in COX-1 (-/-) or COX-2 (-/-) compound mutant Apc mice, both COX-2 and mPGES were induced in the COX-1 (-/-) polyps, whereas COX-1 was expressed in the COX-2 (-/-) polyps. We found also in human familial adenomatous polyposis polyps that COX-2 and mPGES were induced in the COX-1-expressing fibroblasts. On the basis of these results, we propose that COX-1 expression in the stromal cells secures the basal level of PGE2 that can support polyp growth to similar to1 mm, and that simultaneous inductions of COX-2 and mPGES support the polyp expansion beyond similar to1 mm by boosting the stromal PGE(2) production. C1 Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. Tokyo Med & Dent Univ, Dept Digest Surg, Tokyo 1138519, Japan. NIEHS, Lab Expt Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Taketo, MM (reprint author), Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. NR 30 TC 81 Z9 86 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2003 VL 63 IS 16 BP 4872 EP 4877 PG 6 WC Oncology SC Oncology GA 715AM UT WOS:000184948400020 PM 12941808 ER PT J AU Ponce, ML Hibino, S Lebioda, AM Mochizuki, M Nomizu, M Kleinman, HK AF Ponce, ML Hibino, S Lebioda, AM Mochizuki, M Nomizu, M Kleinman, HK TI Identification of a potent peptide antagonist to an active laminin-1 sequence that blocks angiogenesis and tumor growth SO CANCER RESEARCH LA English DT Article ID HUMAN-ENDOTHELIAL CELLS; INTERCELLULAR-ADHESION MOLECULE-1; CAPILLARY-LIKE STRUCTURES; EXTRACELLULAR-MATRIX; BASEMENT-MEMBRANE; GAMMA-1 CHAIN; METASTASIS; ALPHA-1; SITES; THROMBOSPONDIN-1 AB The extracellular matrix plays an important role in many physiological processes. We have identified >20 angiogenic sites in the extracellular matrix protein laminin-1. The most potent sites are A13 (RQVFQVAYII-IKA) and C16 (KAFDITYVRLKF), which are present in homologous NH2-terminal domains of the alpha1 and gamma1 chains, respectively. We reported recently that a scrambled C16 sequence, C16S (DFKLFAVTIKYR), acts as an antagonist to both peptides. Here, we have identified a stronger antiangiogenic peptide, C16Y (C16S with a T to Y substitution), with potent activity in several biological assays including tumor growth. C16Y is more potent in promoting endothelial cell attachment and inhibiting attachment to laminin-1 than either C16 or C16Y. Disruption of tube formation by C16Y is also observed at concentrations at least five times lower than C16S. The minimal active sequence was found to be DFKLFAVY. C16Y is more potent in blocking C16-induced chick chorioallantoic membrane angiogenesis than C16S. Tumor growth studies on the chick chorioallantoic membrane showed that C16Y reduces breast cancer cell growth without affecting cell proliferation. This result suggests that angiogenesis is being inhibited by the peptide. In vivo animal studies demonstrated that C16Y treatment significantly reduced tumor growth and decreased tumor vessel number, as compared with controls, additionally suggesting that angiogenesis was affected. These results indicate that we have identified a more potent antiangiogenesis inhibitor peptide that may be used as a therapeutic to treat cancer. C1 NIDCR, NIH, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. Hokkaido Univ, Grad Sch Environm Earth Sci, Sapporo, Hokkaido 060, Japan. RP Kleinman, HK (reprint author), NIDCR, NIH, Craniofacial Dev Biol & Regenerat Branch, NIH Bldg 30,Room 433,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. NR 32 TC 33 Z9 33 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2003 VL 63 IS 16 BP 5060 EP 5064 PG 5 WC Oncology SC Oncology GA 715AM UT WOS:000184948400047 PM 12941835 ER PT J AU Mathijssen, RHJ Marsh, S Karlsson, MO Xie, RJ Baker, SD Verweij, J Sparreboom, A McLeod, HL AF Mathijssen, RHJ Marsh, S Karlsson, MO Xie, RJ Baker, SD Verweij, J Sparreboom, A McLeod, HL TI Irinotecan pathway genotype analysis to predict pharmacokinetics SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-21, 2002 CL ORLANDO, FLORIDA SP Amer Soc Clin Oncol ID UDP-GLUCURONOSYLTRANSFERASE GENE; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; CLINICAL PHARMACOKINETICS; GILBERTS-SYNDROME; CANCER-PATIENTS; IN-VIVO; CPT-11; METABOLISM; RESISTANCE; PHARMACOGENETICS AB Purpose: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. Experimental Design: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1- (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome P450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. Results: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). Conclusions: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups. C1 Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Uppsala Univ, Dept Pharmaceut Biosci, SE-75124 Uppsala, Sweden. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Expt Therapeut, Baltimore, MD 21231 USA. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, Clin Pharmacol Res Core, 9000 Rockville Pike,Bldg 10,Rm 5A01, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008 FU NIGMS NIH HHS [U01 GM63340] NR 35 TC 164 Z9 181 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2003 VL 9 IS 9 BP 3246 EP 3253 PG 8 WC Oncology SC Oncology GA 718XW UT WOS:000185172600004 PM 12960109 ER PT J AU Villalona-Calero, MA Wientjes, MG Otterson, GA Kanter, S Young, D Murgo, AJ Fischer, B DeHoff, C Chen, D Yeh, TK Song, SH Grever, M Au, JLS AF Villalona-Calero, MA Wientjes, MG Otterson, GA Kanter, S Young, D Murgo, AJ Fischer, B DeHoff, C Chen, D Yeh, TK Song, SH Grever, M Au, JLS TI Phase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small cell lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID FIBROBLAST GROWTH-FACTOR; REFRACTORY PROSTATE-CANCER; AUTOCRINE GROWTH; FACTOR RECEPTOR; PLUS HYDROCORTISONE; POTENT INHIBITOR; LIMITED EFFICACY; ENHANCE ACTIVITY; CARCINOMA-CELLS; BREAST-CANCER AB Purpose: Our preclinical studies have shown that acidic and basic fibroblastic growth factors confer broad spectrum chemoresistance and that low concentrations (10-50 muM) of suramin, a nonspecific fibroblastic growth factor inhibitor, enhance the antitumor activity of paclitaxel in vivo. The present Phase I study evaluated low-dose suramin in combination with paclitaxel/carboplatin in advanced non-small cell lung cancer patients. Experimental Design: Patients received suramin followed by paclitaxel (175-200 mg/m(2)) and carboplatin area under the concentration-time curve of 6 mg/ml/min, every 3 weeks. The initial suramin dose for the first cycle was 240 mg/m(2), and the doses for subsequent cycles were calculated based on the 72-h pretreatment plasma concentrations. The recommended suramin dose would yield plasma concentrations of 10-20 mum at 48 h in greater than or equal to5 of 6 patients. Results: Fifteen patients (11 stage IV, 4 stage IIIB, 9 chemonaive, and 6 previously treated) received 85 courses. The most common toxicities were neutropenia, nausea/vomiting, malaise/fatigue, and peripheral neuropathy. No treatment-related hospitalizations, adrenal dysfunction, or episodes of sepsis occurred. The initial suramin dose resulted in the targeted concentrations of 10-20 mum at 48 h in 5 of the first 6 patients treated but also resulted in peak concentrations > 50 mum in all patients. Dividing the suramin dose to be administered in two doses, 24 h apart, yielded the target concentrations and avoided undesirable peak concentrations. Discernable antitumor activity occurred in 7 of 10 patients with measurable disease, including 2 with prior chemotherapy. The median time to tumor progression is 8.5 months (range, 3-27+ months) for 12 evaluable patients. Conclusions: Low-dose suramin does not increase the toxicity of paclitaxel/carboplatin combination. The suramin dose can be calculated based on clinical parameters. Because of the preliminary antitumor activity observed, efficacy studies in chemonaive and chemorefractory patients are under way. C1 Ohio State Univ, Arthur G James Canc Hosp, Dept Med, Columbus, OH 43210 USA. Ohio State Univ, Arthur G James Canc Hosp, Coll Pharm, Columbus, OH 43210 USA. Richard J Solove Res Inst, Columbus, OH 43210 USA. NCI, Bethesda, MD 20892 USA. RP Villalona-Calero, MA (reprint author), Ohio State Univ, Arthur G James Canc Hosp, Dept Med, B406 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [R21CA91547, R37CA49816, U01CA76576]; NCRR NIH HHS [M01-RR00034] NR 67 TC 25 Z9 25 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2003 VL 9 IS 9 BP 3303 EP 3311 PG 9 WC Oncology SC Oncology GA 718XW UT WOS:000185172600011 PM 12960116 ER PT J AU Chow, HHS Cai, Y Hakim, IA Crowell, JA Shahi, F Brooks, CA Dorr, RT Hara, Y Alberts, DS AF Chow, HHS Cai, Y Hakim, IA Crowell, JA Shahi, F Brooks, CA Dorr, RT Hara, Y Alberts, DS TI Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and Polyphenon E in healthy individuals SO CLINICAL CANCER RESEARCH LA English DT Article ID ULTRAVIOLET-B LIGHT; SKH-1 HAIRLESS MICE; DECAFFEINATED TEA; SKIN; CARCINOGENESIS; ANTIOXIDANT; CAFFEINE; CHEMOPREVENTION; PROTECTION; INHIBITION AB Purpose: Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. Experimental Design: Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. Results: Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema. Conclusions: We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily). C1 Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Mitsui Norin Co Ltd, Shizuoka 42601, Japan. RP Chow, HHS (reprint author), Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. FU NCI NIH HHS [N01-CN-85179] NR 19 TC 355 Z9 373 U1 3 U2 36 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2003 VL 9 IS 9 BP 3312 EP 3319 PG 8 WC Oncology SC Oncology GA 718XW UT WOS:000185172600012 PM 12960117 ER PT J AU Spritzler, J Mildvan, D Russo, A Asthana, D Livnat, D Schock, B Kagan, J Landay, A Haas, DW AF Spritzler, J Mildvan, D Russo, A Asthana, D Livnat, D Schock, B Kagan, J Landay, A Haas, DW CA Adult AIDS Clinical Trials Grp TI Can immune markers predict subsequent discordance between immunologic and virologic responses to Antiretroviral therapy? Adult AIDS clinical trials group SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD38 ANTIGEN EXPRESSION; HIV-INFECTED PATIENTS; 2 NUCLEOSIDE ANALOGS; CD8(+) T-CELLS; PROTEASE INHIBITOR; DISEASE PROGRESSION; PROGNOSTIC VALUE; VIRAL LOAD; HIV-1-INFECTED INDIVIDUALS AB It is unclear why discordant immunologic and virologic responses occur during therapy for human immunodeficiency virus (HIV) infection. This study examined whether markers of immune activation and naive/ memory lymphocyte subsets at study baseline could predict discordance between HIV type 1 (HIV-1) RNA and CD4(+) lymphocyte responses at week 24 of antiretroviral therapy. Ten diverse, prospective antiretroviral studies with 1007 evaluable subjects were included. Subsets of subjects at increased risk for discordance were identified by recursive partitioning. The strongest predictor of more-favorable immunologic than virologic responses was a lower baseline CD4(+) lymphocyte count. Weaker predictors in small subsets of subjects were fewer activated CD4(+) lymphocytes and fewer CD8(+) lymphocytes. Conversely, the strongest predictors of morefavorable virologic than immunologic responses were higher baseline CD4+ lymphocyte count and percentage. Additional predictors in some analyses were higher CD8(+) lymphocyte count or percentage and lower HIV-1 RNA concentrations. Baseline markers of immune activation and naive/ memory lymphocyte subsets had limited ability to predict subsequent discordance. C1 Vanderbilt Univ, Sch Med, Div Infect Dis, Nashville, TN 37212 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Beth Israel Med Ctr, New York, NY 10003 USA. Frontier Sci, Amherst, NY USA. Univ Miami, Miami, FL 33152 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Rush Presbyterian Med Coll, Chicago, IL USA. RP Haas, DW (reprint author), Vanderbilt Univ, Sch Med, Div Infect Dis, 345 24th N,Ste 105, Nashville, TN 37212 USA. FU NIAID NIH HHS [5U01 AI27675, 5U01 AI38855, 5U01 AI46339, 5U01 AI46370, 5U01 AI25919] NR 54 TC 14 Z9 14 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2003 VL 37 IS 4 BP 551 EP 558 DI 10.1086/376986 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 709HC UT WOS:000184618900013 PM 12905140 ER PT J AU Beck, GR Moran, E Knecht, N AF Beck, GR Moran, E Knecht, N TI Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2 SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE osteoblast differentiation; inorganic phosphate; Nrf2; periostin; HMGA1; collagen; osteopontin ID TRANSCRIPTION FACTOR NRF2; MURINE MC3T3-E1 CELLS; ALKALINE-PHOSPHATASE; CHOP GADD153; FASCICLIN-I; EXPRESSION; PROTEIN; INVITRO; MINERALIZATION; IDENTIFICATION AB The process of osteoblast differentiation and matrix mineralization requires a rise in alkaline phosphatase enzymatic activity resulting in the generation of free phosphate. The ability of inorganic phosphate to regulate gene transcription and cellular function represents a potentially novel extracellular signaling mechanism. Using microarray analysis we have identified a discrete set of genes that are either positively or negatively regulated by increased phosphate in MC3T3-E1 cells. The genes downregulated by phosphate encode for osteoblast-related extracellular factors such as collagens, periostin, and decorin. The genes increased by phosphate encode a novel group of transcription factors that may be important in the later stages of osteoblast development in which the environment is high in phosphate. The transcription factor Nrf2 is one such gene. Elevated phosphate levels stimulate an increase in Nrf2 RNA that is not blocked by the translation inhibitor cycloheximide, suggesting that Nrf2 is an immediate response gene. Cloning of the murine nrf2 promoter reveals that elevated phosphate produces an increase in promoter activity that is both time and dose dependent. This analysis reveals multiple genes regulated by the increase in phosphate associated with osteoblast differentiation, adding to our understanding of the intricate communication between osteoblasts and their extracellular environment. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. RP Beck, GR (reprint author), NCI, Ctr Canc Res, Basic Res Lab, Bldg 576,Rm 110, Frederick, MD 21702 USA. FU NCI NIH HHS [CA84573] NR 48 TC 104 Z9 105 U1 1 U2 11 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 AUG 15 PY 2003 VL 288 IS 2 BP 288 EP 300 DI 10.1016/S0014-4827(03)00213-1 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 714ZZ UT WOS:000184946900007 PM 12915120 ER PT J AU Jaszewski, AR Fann, YC Chen, YR Sato, K Corbett, J Mason, RP AF Jaszewski, AR Fann, YC Chen, YR Sato, K Corbett, J Mason, RP TI EPR spectroscopy studies on the structural transition of nitrosyl hemoglobin in the arterial-venous cycle of DEANO-treated rats as it relates to the proposed nitrosyl hemoglobin/nitrosothiol hemoglobin exchange SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE nitrosyl hemoglobin; nitric oxide; heme; in vivo ID NITRIC-OXIDE; PHYSIOLOGICAL CONDITIONS; S-NITROSOHEMOGLOBIN; OXYGEN-BINDING; NO; BLOOD; OXYHEMOGLOBIN; OXYMYOGLOBIN; NITROSATION; OXIDATION AB In vivo studies show a dynamic cycle in which alpha-nitrosylated hemoglobin is mainly in the relaxed state in arterial blood of rats treated with 2-(N,N-diethylamino)-diazenolate-2-oxide, but converts mainly to the tense state during the arterial-venous transit. A detailed analysis shows that different electron paramagnetic resonance spectra recorded for alpha-nitrosyl hemoglobin in arterial and venous blood at 77 K originate only from a different ratio between 5- and 6-coordinate heme without any change in the concentration of nitrosyl hemoglobin. In venous blood, the five- and six-coordination equilibrium of the alpha-nitrosyl heme is shifted in favor of the 5-coordinate state (58% venous vs. 20% arterial). These results are not consistent with the recently proposed exchange of nitrosyl heme with the beta-93 nitrosothiol group of hemoglobin during the arterial-venous cycle. Published by Elsevier Inc. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Jaszewski, AR (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 29 Z9 31 U1 0 U2 3 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 AUG 15 PY 2003 VL 35 IS 4 BP 444 EP 451 DI 10.1016/S0891-5849(03)00324-1 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 707AZ UT WOS:000184488400011 PM 12899946 ER PT J AU Ben-Yosef, T Belyantseva, IA Saunders, TL Hughes, ED Kawamoto, K Van Itallie, CM Beyer, LA Halsey, K Gardner, DJ Wilcox, ER Rasmussen, J Anderson, JM Dolan, DF Forge, A Raphael, Y Camper, SA Friedman, TB AF Ben-Yosef, T Belyantseva, IA Saunders, TL Hughes, ED Kawamoto, K Van Itallie, CM Beyer, LA Halsey, K Gardner, DJ Wilcox, ER Rasmussen, J Anderson, JM Dolan, DF Forge, A Raphael, Y Camper, SA Friedman, TB TI Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration SO HUMAN MOLECULAR GENETICS LA English DT Article ID TIGHT JUNCTION STRANDS; ION-TRANSPORT MECHANISMS; ADHESION MOLECULE JAM; STRIA VASCULARIS; MARGINAL CELLS; INTERCELLULAR-JUNCTIONS; MEMBRANE-PROTEINS; EPITHELIAL-CELLS; INNER-EAR; EXPRESSION AB Tight junctions (TJs) create ion-selective paracellular permeability barriers between extracellular compartments. In the organ of Corti of the inner ear, TJs of the reticular lamina separate K(+)-rich endolymph and Na(+)-rich perilymph. In humans, mutations of the gene encoding claudin 14 TJ protein cause profound deafness but the underlying pathogenesis is unknown. To explore the role of claudin 14 in the inner ear and in other tissues we created a mouse model by a targeted deletion of Cldn14. In the targeted allele a lacZ cassette is expressed under the Cldn14 promoter. In Cldn14-lacZ heterozygous mice beta-galactosidase activity was detected in cochlear inner and outer hair cells and supporting cells, in the collecting ducts of the kidney, and around the lobules of the liver. Cldn14-null mice have a normal endocochlear potential but are deaf due to rapid degeneration of cochlear outer hair cells, followed by slower degeneration of the inner hair cells, during the first 3 weeks of life. Monolayers of MDCK cells expressing claudin 14 show a 6-fold increase in the transepithelial electrical resistance by decreasing paracellular permeability for cations. In wild type mice, claudin 14 was immunolocalized at hair cell and supporting cell TJs. Our data suggest that the TJ complex at the apex of the reticular lamina requires claudin 14 as a cation-restrictive barrier to maintain the proper ionic composition of the fluid surrounding the basolateral surface of outer hair cells. C1 NIDCD, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Univ Michigan, Dept Internal Med, Div Med & Mol Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Kresge Hearing Res Inst, Ann Arbor, MI 48109 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. NIH, Vet Resources Program, Bethesda, MD 20892 USA. Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. UCL, Ctr Auditory Res, London WC1X 8EE, England. UCL, Inst Laryngol & Otol, London WC1X 8EE, England. RP Friedman, TB (reprint author), NIDCD, Genet Mol Lab, NIH, 5 Res Court,Room 2A-19, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov OI Camper, Sally/0000-0001-8556-3379 FU NCI NIH HHS [P30CA46592]; NIAMS NIH HHS [P60AR20557]; NIDCD NIH HHS [1 Z01 DC00039-06]; NIDDK NIH HHS [DK45134] NR 87 TC 185 Z9 193 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2003 VL 12 IS 16 BP 2049 EP 2061 DI 10.1093/hmg/ddg210 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 717AT UT WOS:000185064000011 PM 12913076 ER PT J AU Watts, DH Lambert, J Stiehm, ER Harris, DR Bethel, J Mofenson, L Meyer, WA Mathieson, B Fowler, MG Nemo, G AF Watts, DH Lambert, J Stiehm, ER Harris, DR Bethel, J Mofenson, L Meyer, WA Mathieson, B Fowler, MG Nemo, G CA PACTG 185 Study Team TI Progression of HIV disease among women following delivery SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; pregnancy; disease progression ID IMMUNODEFICIENCY-VIRUS-INFECTION; CONTROLLED-TRIAL; VERTICAL TRANSMISSION; CUBIC MILLIMETER; PERIPHERAL-BLOOD; VIRAL LOAD; ZIDOVUDINE; INFANT; AIDS; PROGESTERONE AB Objective: To assess patterns of HIV disease progression among HIV-1-infected women following delivery. Methods: Four hundred ninety-seven women enrolled in PACTG 185, a phase 3 trial of passive immunoprophylaxis in addition to zidovudine (ZDV) for the prevention of perinatal transmission, were included. Visits occurred twice during pregnancy; at delivery, and at 12, 26, 48, and 78 weeks postpartum. Repeated-measures linear regression and proportional hazards models were applied. Results: Trial treatment (HIV hyperimmune globulin vs. immune globulin) was not related to postpartum disease progression. Longitudinal analysis of HIV-1 RNA demonstrated stable levels during pregnancy, significantly increased HIV-1 RNA by 12 weeks postpartum even on stable therapy, and a gradual increase thereafter. Changes in CD4(+) lymphocyte percentage over 18 months of follow-up were similar for women continuing or stopping ZDV postpartum. Compared with those receiving no therapy, the hazard ratio for AIDS or death among women who received monotherapy postpartum was 0.52 (95% confidence interval [CI]: 0.25-1.04), 0.17 (CI: 0.06-0.49) for women who received combination therapy, and 0.24 (CI: 0.06-1.01) for women who received highly active antiretroviral therapy. Conclusions: RNA levels increased significantly from delivery to 12 weeks postpartum. Changes in HIV-1 RNA and CD4(+) lymphocyte percentage were similar among women continuing or stopping therapy after delivery, and response to antiretroviral therapy was as expected postpartum. C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. WESTAT Corp, Rockville, MD 20850 USA. Quest Diagnost Inc, Baltimore, MD USA. NIH, Off AIDS Res, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NHLBI, Bethesda, MD 20892 USA. RP Watts, DH (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, 6100 Execut Blvd,Room 4B11,MSC 7510, Bethesda, MD 20892 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI-27550, AI-27565]; NICHD NIH HHS [HD-33162] NR 23 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2003 VL 33 IS 5 BP 585 EP 593 DI 10.1097/00126334-200308150-00006 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 711BJ UT WOS:000184718000006 PM 12902802 ER PT J AU Armoni, M Kritz, N Harel, C Bar-Yoseph, F Chen, H Quon, MJ Karnieli, E AF Armoni, M Kritz, N Harel, C Bar-Yoseph, F Chen, H Quon, MJ Karnieli, E TI Peroxisome proliferator-activated receptor-gamma represses GLUT4 promoter activity in primary adipocytes, and rosiglitazone alleviates this effect SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PPAR-GAMMA; INSULIN-RESISTANCE; GLUCOSE-TRANSPORT; DIABETES-MELLITUS; GENE-EXPRESSION; IN-VIVO; RAT; ADIPOGENESIS; LIGAND; KINASE AB The synthetic thiazolidinedione ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) improve insulin sensitivity in type II diabetes and induce GLUT4 mRNA expression in fat and muscle. However, the molecular mechanisms involved are still unclear. We studied the regulatory effects of PPARgamma and its ligands on GLUT4 gene expression in primary rat adipocytes and CHO-K1 cells cotransfected with PPARgamma and the GLUT4 promoter reporter. PPARgamma1 and PPARgamma2 repressed the activity of the GLUT4 promoter in a dose-dependent manner. Whereas this repression was augmented by the natural ligand 15Delta-prostaglandin J(2), it was completely alleviated by rosiglitazone (Rg). Ligand binding-defective mutants PPARgamma1-L468A/E471A and PPARgamma2-L496A/E499A retained the repression effect, which was unaffected by Rg, whereas the PPARgamma2-S112A mutant exhibited a 50% reduced capacity to repress GLUT4 promoter activity. The -66/+163 bp GLUT4 promoter region was sufficient to mediate PPARgamma inhibitory effects. The PPARgamma/retinoid X receptor-alpha heterodimer directly bound to this region, whereas binding was abolished in the presence of Rg. Thus, we show that PPARgamma represses transcriptional activity of the GLUT4 promoter via direct and specific binding of PPARgamma/retinoid X receptor-alpha to the GLUT4 promoter. This effect requires an intact Ser(112) phosphorylation site on PPARgamma and is completely alleviated by Rg, acting via its ligand-binding domain. These data suggest a novel mechanism by which Rg exerts its antidiabetic effects via detaching PPARgamma from the GLUT4 gene promoter, thus leading to increased GLUT4 expression and enhanced insulin sensitivity. C1 Rambam Med Ctr, Inst Endocrinol Diabet & Metab, Unit Mol Endocrinol, IL-31096 Haifa, Israel. Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel. NIH, NCCAM, Bethesda, MD 20892 USA. RP Armoni, M (reprint author), Rambam Med Ctr, Inst Endocrinol Diabet & Metab, Unit Mol Endocrinol, IL-31096 Haifa, Israel. RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915 NR 37 TC 76 Z9 80 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 AUG 15 PY 2003 VL 278 IS 33 BP 30614 EP 30623 DI 10.1074/jbc.M304654200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 710AN UT WOS:000184658800026 PM 12777391 ER PT J AU Heath, MJ Derebail, SS Gorelick, RJ DeStefano, JJ AF Heath, MJ Derebail, SS Gorelick, RJ DeStefano, JJ TI Differing roles of the N- and C-terminal zinc fingers in human immunodeficiency virus nucleocapsid protein-enhanced nucleic acid annealing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MURINE LEUKEMIA-VIRUS; STRAND TRANSFER-REACTIONS; RNA PACKAGING SIGNAL; PRIMER BINDING-SITE; STRONG-STOP DNA; STEM-LOOP SL2; IN-VITRO; REVERSE TRANSCRIPTION; CHAPERONE ACTIVITY; VIRAL-DNA AB The replication process of human immunodeficiency virus requires a number of nucleic acid annealing steps facilitated by the hybridization and helix-destabilizing activities of human immunodeficiency virus nucleocapsid (NC) protein. NC contains two CCHC zinc finger motifs numbered 1 and 2 from the N terminus. The amino acids surrounding the CCHC residues differ between the two zinc fingers. Assays were preformed to investigate the activities of the fingers by determining the effect of mutant and wild-type proteins on annealing of 42-nucleotide RNA and DNA complements. The mutants 1.1 NC and 2.2 NC had duplications of the N- and C-terminal zinc fingers in positions 1 and 2. The mutant 2.1 NC had the native zinc fingers with their positions switched. Annealing assays were completed with unstructured and highly structured oligonucleotide complements. 2.2 NC had a near wild-type level of annealing of unstructured nucleic acids, whereas it was completely unable to stimulate annealing of highly structured nucleic acids. In contrast, 1.1 NC was able to stimulate annealing of both unstructured and structured substrates, but to a lesser degree than the wild-type protein. Results suggest that finger 1 has a greater role in unfolding of strong secondary structures, whereas finger 2 serves an accessory role that leads to a further increase in the rate of annealing. C1 Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP DeStefano, JJ (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, Bldg 231, College Pk, MD 20742 USA. FU NCI NIH HHS [N01-CO-12400]; NIGMS NIH HHS [GM51140, R01 GM051140] NR 76 TC 44 Z9 44 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 AUG 15 PY 2003 VL 278 IS 33 BP 30755 EP 30763 DI 10.1074/jbc.M303819200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 710AN UT WOS:000184658800043 PM 12783894 ER PT J AU Tomita, A Buchholz, DR Obata, K Shi, YB AF Tomita, A Buchholz, DR Obata, K Shi, YB TI Fusion protein of retinoic acid receptor alpha with promyelocytic leukemia protein or promyelocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress transcription in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THYROID-HORMONE RECEPTOR; PLZF-RAR-ALPHA; HISTONE DEACETYLASE COMPLEX; ACUTE MYELOID-LEUKEMIA; N-COR; NUCLEAR RECEPTORS; MOLECULAR PATHOGENESIS; PML; CHROMATIN; SMRT AB Fusion proteins of retinoic acid receptor alpha (RARalpha) with promyelocytic leukemia protein (PML-RARalpha) or with promyelocytic leukemia zinc finger protein (PLZF-RARalpha) are associated with and likely responsible for the development of acute promyelocytic leukemia. These oncoproteins retain the ability to bind DNA and retinoic acid through the RARalpha moiety. This enables them to repress RARalpha target genes in the absence of retinoic acid, but the underlying mechanisms remain to be investigated. Here we use the frog oocyte system to study transcriptional regulation by PML-RARalpha and PLZF-RARalpha in the context of chromatin. We first show that the endogenous corepressor N-CoR forms a complex with TBLR1 (transducin beta-like protein 1-related protein) and that both N-CoR and TBLR1 can interact with unliganded PML-RARalpha and PLZF-RARalpha in vivo. Using chromatin immunoprecipitation, we demonstrate that both oncoproteins recruit TBLR1, as well as N-CoR, to its target promoter, leading to histone deacetylation and transcriptional repression. Furthermore, expression of a dominant negative N-CoR that contains the TBLR1-interacting domain blocks transcription repression by unliganded PML-RARalpha and PLZF-RARalpha. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARalpha and PLZF-RARalpha in transcriptional repression in the context of chromatin. C1 NICHD, Unit Mol Morphogenesis, LGRD, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Unit Mol Morphogenesis, LGRD, NIH, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. RI Obata, Keiko/E-2019-2012 NR 58 TC 34 Z9 36 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 AUG 15 PY 2003 VL 278 IS 33 BP 30788 EP 30795 DI 10.1074/jbc.M303309200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 710AN UT WOS:000184658800047 PM 12794076 ER PT J AU Rosovitz, MJ Schuck, P Varughese, M Chopra, AP Mehra, V Singh, Y McGinnis, LM Leppla, SH AF Rosovitz, MJ Schuck, P Varughese, M Chopra, AP Mehra, V Singh, Y McGinnis, LM Leppla, SH TI Alanine-scanning mutations in domain 4 of anthrax toxin protective antigen reveal residues important for binding to the cellular receptor and to a neutralizing monoclonal antibody SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIZE-DISTRIBUTION ANALYSIS; BACILLUS-ANTHRACIS; LETHAL FACTOR; MAMMALIAN-CELLS; I-DOMAIN; CRYSTAL-STRUCTURE; INTEGRIN; SURFACE; COMPONENT; COLLAGEN AB A panel of variants with alanine substitutions in the small loop of anthrax toxin protective antigen domain 4 was created to determine individual amino acid residues critical for interactions with the cellular receptor and with a neutralizing monoclonal antibody, 14B7. Substituted protective antigen proteins were analyzed by cellular cytotoxicity assays, and their interactions with antibody were measured by plasmon surface resonance and analytical ultracentrifugation. Residue Asp(683) was the most critical for cell binding and toxicity, causing an similar to1000-fold reduction in toxicity, but was not a large factor for interactions with 14B7. Substitutions in residues Tyr(681), Asn(682), and Pro(686) also reduced toxicity significantly, by 10-100-fold. Of these, only Asn(682) and Pro(686) were also critical for interactions with 14B7. However, residues Lys(684), Leu(685), Leu(687), and Tyr(688) were critical for 14B7 binding without greatly affecting toxicity. The K684A and L685A variants exhibited wild type levels of toxicity in cell culture assays; the L687A and Y688A variants were reduced only 1.5- and 5-fold, respectively. C1 NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. Inst Genom & Integrat Biol, Delhi 110007, India. RP Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, NIH, Bldg 30,Rm 303,MSC 4350, Bethesda, MD 20892 USA. RI Ganju, Shahji/F-3409-2012; OI Schuck, Peter/0000-0002-8859-6966 NR 51 TC 96 Z9 99 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 AUG 15 PY 2003 VL 278 IS 33 BP 30936 EP 30944 DI 10.1074/jbc.M301154200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 710AN UT WOS:000184658800067 PM 12771151 ER PT J AU Berezhkovskii, AM Pustovoit, MA Bezrukov, SM AF Berezhkovskii, AM Pustovoit, MA Bezrukov, SM TI Channel-facilitated membrane transport: Average lifetimes in the channel SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ESCHERICHIA-COLI; DIFFUSION AB The transport of many solutes across biological membranes happens with the help of specialized proteins that form water-filled channels traversing the membranes. Recent experimental and theoretical work demonstrates that solute translocation can be facilitated by attractive interactions between the channel and penetrating particle. Here we consider an important aspect of channel-facilitated passive transport, the average lifetimes in the channel for those particles that traverse the channel and those that return, as well as the total average lifetime of the particle in the channel. Exact expressions for the average lifetimes are derived in the framework of a one-dimensional diffusion model. The validity of our one-dimensional analysis is verified by good agreement of the theoretical predictions with the average lifetimes found in three-dimensional Brownian dynamics simulations. (C) 2003 American Institute of Physics. C1 NIH, Math & Stat Comp Lab, CIT, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), LY Karpov Phys Chem Res Inst, Vorontsovo Pole 10,K-64, Moscow 103064, Russia. RI Pustovoit, Mark/B-5249-2008 NR 13 TC 52 Z9 53 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 15 PY 2003 VL 119 IS 7 BP 3943 EP 3951 DI 10.1063/1.1590957 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 706UU UT WOS:000184474100042 ER PT J AU Niranjan, PS Yim, PB Forbes, JG Greer, SC Dudowicz, J Freed, KF Douglas, JF AF Niranjan, PS Yim, PB Forbes, JG Greer, SC Dudowicz, J Freed, KF Douglas, JF TI The polymerization of actin: Thermodynamics near the polymerization line SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ANGLE NEUTRON-SCATTERING; DEUTERIUM-OXIDE; LATTICE MODEL; F-ACTIN; LIVING POLYMERIZATION; PROTEIN SUBUNITS; CULTURED-CELLS; MUSCLE ACTIN; ASSOCIATION; WATER AB Studies of the dependence of actin polymerization on thermodynamic parameters are important for understanding processes in living systems, where actin polymerization and depolymerization are crucial to cell structure and movement. We report measurements of the extent of polymerization, Phi, of rabbit muscle actin as a function of temperature [T=(0-35) degreesC], initial G-actin concentration [[G(0)]=(1-3) mg/ml], and initiating salt concentration [[KCl]=(5-15) mmol/l with bound Ca2+], in H2O and D2O buffers and in the presence of adenosine triphosphate (ATP). A preliminary account of the data and analysis for H2O buffers has appeared previously [P. S. Niranjan, J. G. Forbes, S. C. Greer, J. Dudowicz, K. F. Freed, and J. F. Douglas, J. Chem. Phys. 114, 10573 (2001)]. We describe the details of the studies for H2O buffers, together with new data and analysis for D2O buffers. The measurements show a maximum in Phi(T) for H2O buffers and D2O buffers. For H2O buffers, T-p decreases as either [G(0)] or [KCl] increases. For D2O buffers, T-p decreases as [KCl] increases, but T-p is not monotonic in [G(0)]. The measurements are interpreted in terms of a Flory-Huggins-type lattice model that includes the essential steps: monomer activation, dimerization of activated species, and propagation of trimers to higher order polymers. The competition between monomer activation and chain propagation leads to the observed nonmonotonic variation of Phi(T). The actin polymerization in D2O buffer differs considerably from that in the H2O buffer and underscores the significant deuterium effect on hydrophobic interactions and hydrogen bonding in the polymerization process. (C) 2003 American Institute of Physics. C1 Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. NIAMS, Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH,DHHS, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem Engn, College Pk, MD 20742 USA. Univ Chicago, James Franck Inst, Chicago, IL 60637 USA. Univ Chicago, Dept Chem, Chicago, IL 60637 USA. NIST, Div Polymers, Gaithersburg, MD 20899 USA. RP Greer, SC (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. NR 66 TC 35 Z9 35 U1 1 U2 12 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 15 PY 2003 VL 119 IS 7 BP 4070 EP 4084 DI 10.1063/1.1592499 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 706UU UT WOS:000184474100057 ER PT J AU Shibusawa, Y Ino, Y Kinebuchi, T Shimizu, M Shindo, H Ito, Y AF Shibusawa, Y Ino, Y Kinebuchi, T Shimizu, M Shindo, H Ito, Y TI Purification of single-strand DNA binding protein from an Escherichia coli lysate using counter-current chromatography, partition and precipitation SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE purification; proteins, single-strand DNA binding; single-strand DNA AB Single-strand DNA binding protein (SSB) from Escherichia coli lysate was purified by counter-current chromatography (CCC) using the ammonium sulfate precipitation method in a coiled column. About 5 ml of E. coli lysate was separated by CCC using a polymer phase system composed of 16% (w/w) polyethylene glycol (PEG) 1000 and 17% (w/w) ammonium sulfate aqueous polymer two-phase solvent system. The precipitation of proteins in the lysate took place in the CCC column, and the SSB protein was eluted in the fraction 51-56. Many other impurities were either eluted immediately after the solvent front or precipitated in the column. The identities of the proteins in the fractions and in the precipitate were confirmed by SDS-polyacrylamide gel electrophoresis with Coomassie Brilliant Blue staining. (C) 2003 Elsevier B.V. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, Hachioji, Tokyo 1920392, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. NR 9 TC 13 Z9 17 U1 0 U2 11 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 AUG 15 PY 2003 VL 793 IS 2 BP 275 EP 279 DI 10.1016/S1570-0232(03)00327-1 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 711KK UT WOS:000184739200007 PM 12906901 ER PT J AU Twaddle, NC Churchwell, MI Newbold, RR Delclos, KB Doerge, DR AF Twaddle, NC Churchwell, MI Newbold, RR Delclos, KB Doerge, DR TI Determination using liquid-chromatography-electrospray tandem mass spectroscopy of ethinylestradiol serum pharmacokinetics in adult Sprague-Dawley rats SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE pharmacokinetics; ethinylestradiol ID SPECTROMETRIC DETERMINATION; TISSUE DISTRIBUTION; ETHINYL-ESTRADIOL; RHESUS-MONKEY; IN-VITRO; PHYTOESTROGENS; METABOLISM; BETA; GENISTEIN; EXPOSURE AB The pharmacokinetics of ethinylestradiol (EE2), a potent synthetic estrogen, was investigated in male and female Sprague-Dawley rats as part of a series of endocrine-active compounds, including genistein and nonylphenol. A method based on solid-phase extraction and LC with negative ion electrospray tandem mass spectrometric detection was developed and validated. The limit of detection in untreated rat serum was below 0.01 ng/ml (0.03 nM), the limit of quantification was 0.03 ng/ml (0.10 W), the intra- and inter-day precision was 2-9%, and the intra- and inter-day accuracy was 89-94%. This method was used to determine the serum pharmacokinetics of EE2 in rats following oral gavage administration of 1 mg/kg body weight. EE2 was present in serum primarily in the unconjugated form at concentrations below 0.5 ng/ml. The maximal serum concentration was proportional to dose over the range of 0.04-0.5 mg/kg body weight and pharmacokinetic parameters were determined using model-independent analysis. Significant sex differences were observed for elimination half-times and volumes of distribution, but not for total serum clearance or maximal concentrations. The pharmacokinetic analysis of EE2 will be useful for comparing the toxicological effects of EE2 to those of other environmental estrogens in related rodent endocrine disruptor studies. (C) 2003 Elsevier B.V. All rights reserved. C1 Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Doerge, DR (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NR 18 TC 19 Z9 21 U1 1 U2 6 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 AUG 15 PY 2003 VL 793 IS 2 BP 309 EP 315 DI 10.1016/S1570-0232(03)00331-3 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 711KK UT WOS:000184739200011 PM 12906905 ER PT J AU Yang, JC Sherry, RM Steinberg, SM Topalian, SL Schwartzentruber, DJ Hwu, P Seipp, CA Rogers-Freezer, L Morton, KE White, DE Liewehr, DJ Merino, MJ Rosenberg, SA AF Yang, JC Sherry, RM Steinberg, SM Topalian, SL Schwartzentruber, DJ Hwu, P Seipp, CA Rogers-Freezer, L Morton, KE White, DE Liewehr, DJ Merino, MJ Rosenberg, SA TI Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Biological-Therapy CY NOV 08-10, 2002 CL SAN DIEGO, CALIFORNIA SP Soc Biol Therapy ID CELL CARCINOMA; RECOMBINANT INTERLEUKIN-2; SUBCUTANEOUS INTERLEUKIN-2; HOME-THERAPY; PHASE-II; INTERFERON; MELANOMA; TRIAL AB Purpose : This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. Patients and Methods: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. Results: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04). Conclusion: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated. C1 NCI, Surg Branch, Biostat & Data Management Sect, Dept Pathol, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NIH, Room 2B-37,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-32] NR 23 TC 490 Z9 506 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 15 PY 2003 VL 21 IS 16 BP 3127 EP 3132 DI 10.1200/JCO.2003.02.122 PG 6 WC Oncology SC Oncology GA 712CZ UT WOS:000184780300020 PM 12915604 ER PT J AU Bell, JJ Min, B Gregg, RK Lee, HH Zaghouani, H AF Bell, JJ Min, B Gregg, RK Lee, HH Zaghouani, H TI Break of neonatal Th1 tolerance and exacerbation of experimental allergic encephalomyelitis by interference with B7 costimulation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; T-CELL TOLERANCE; IMMUNE-RESPONSES; DENDRITIC CELLS; NEWBORN MICE; INFLUENZA-VIRUS; IN-VIVO; INDUCTION; ANTIGEN AB Ig-PLP1 is an Ig chimera expressing proteolipid protein-1 (PLP1) peptide corresponding to aa residues 139-151 of PLP. Newborn mice given Ig-PLP1 in saline on the day of birth and challenged 7 wk later with PLP1 peptide in CFA develop an organ-specific neonatal immunity that confers resistance against experimental allergic encephalomyelitis. The T cell responses in these animals comprise Th2 cells in the lymph node and anergic Th1 lymphocytes in the spleen. Intriguingly, the anergic splenic T cells, although nonproliferative and unable to produce IFN-gamma or IL-4, secrete significant amounts of IL-2. In this work, studies were performed to determine whether costimulation through B7 molecules plays any role in the unusual form of splenic Th1 anergy. The results show that engagement of either B7.1 or B7.2 with anti-137 Abs during induction of EAE in adult mice that were neonatally tolerized with Ig-PLP1 restores and exacerbates disease severity. At the cellular level, the anergic splenic T cells regain the ability to proliferate and produce IFN-gamma when stimulated with Ag in the presence of either anti-B7.1 or anti-B7.2 Ab. However, such restoration was abolished when both B7.1 and B7.2 molecules were engaged simultaneously, indicating that costimulation is necessary for reactivation. Surprisingly, both anti-B7.1 and anti-B7.2 Abs triggered splenic dendritic cells to produce IL-12, a key cytokine required for restoration of the anergic T cells. Thus, recovery from neonatally induced T cell anergy requires B7 molecules to serve double functions, namely, costimulation and induction of cytokine production by APCs. C1 Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zaghouani, H (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, M616 Med Sci Bldg, Columbia, MO 65212 USA. FU NIAID NIH HHS [R01 AI48541]; NINDS NIH HHS [R01 NS37406] NR 51 TC 6 Z9 7 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 AUG 15 PY 2003 VL 171 IS 4 BP 1801 EP 1808 PG 8 WC Immunology SC Immunology GA 710EG UT WOS:000184667400026 PM 12902480 ER PT J AU Semnani, RT Liu, AY Sabzevari, H Kubofcik, J Zhou, J Gilden, JK Nutman, TB AF Semnani, RT Liu, AY Sabzevari, H Kubofcik, J Zhou, J Gilden, JK Nutman, TB TI Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; LYMPHATIC FILARIASIS; NITRIC-OXIDE; SUPPRESSOR MACROPHAGES; HELPER-CELLS; HUMAN NAIVE; IN-VIVO; INFECTION; NEMATODE; CYTOKINE AB Parasite Ag-specific T cell unresponsiveness and diminished IFN-gamma production are immunologic hallmarks of patent infection with lymph-dwelling filarial nematodes. Although this diminished responsiveness is directed primarily against the intravascular microfilarial (MF) parasite stage and mediated in part by reduced APC function, the mechanisms involved are not fully understood. In this report, we demonstrate that human dendritic cells (DC) exposed to live MF up-regulate both the cell surface and gene expression of CD54 (ICAM-1). Moreover, live MF result in a 3-fold increase in DC death compared with MF-unexposed DC, primarily due to apoptosis. Notably, microarray and real-time RT-PCR data indicate that live MF concurrently up-regulate mRNA expression of proinflammatory molecules such as IL-8, RANTES, IL-1alpha, TNF-alpha, and IL-beta in DC, the presence of which is also detected at the protein level, while inhibiting the production of IL-12 (p40 and p70) and IL-10. Soluble excretory-secretory products from live MF diminished IL-12 and IL-10 production and induced DC death, although to a lesser degree. Moreover, exposure of DC to live MF resulted in a decrease in the ability of DC to promote CD4(+) T cell production of IFN-gamma and IL-5. Our findings clearly suggest that the interaction between live MF and DC is complex but contributes to the hyporesponsiveness and parasite persistence associated with the MF+ state in the infected human. These data further suggest that MF induce an orchestrated response in APC that leads to a diminished capacity to function appropriately, which in turn has significant consequences for CD4(+) T cells. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol, NIH, Bethesda, MD 20892 USA. RP Semnani, RT (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,4 Ctr Drive,Rm 126, Bethesda, MD 20892 USA. NR 42 TC 63 Z9 69 U1 0 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 AUG 15 PY 2003 VL 171 IS 4 BP 1950 EP 1960 PG 11 WC Immunology SC Immunology GA 710EG UT WOS:000184667400044 PM 12902498 ER PT J AU Tavel, JA Sereti, I Walker, RE Hahn, B Kovacs, JA Jagannatha, S Davey, RT Falloon, J Polis, MA Masur, H Metcalf, JA Stevens, R Rupert, A Baseler, M Lane, HC AF Tavel, JA Sereti, I Walker, RE Hahn, B Kovacs, JA Jagannatha, S Davey, RT Falloon, J Polis, MA Masur, H Metcalf, JA Stevens, R Rupert, A Baseler, M Lane, HC TI A randomized, double-blinded, placebo-controlled trial of intermittent administration of interleukin-2 and prednisone in subjects infected with human immunodeficiency virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CD4(+) CELL COUNTS; SUBCUTANEOUS INTERLEUKIN-2; ANTIRETROVIRAL THERAPY; KAPPA-B; IMPACT AB Intermittent administration of interleukin (IL)-2 produces significant and sustained increases in CD4(+) T lymphocyte count in human immunodeficiency virus (HIV)-infected subjects but can be associated with dose-limiting toxicities. The primary objective of this study was to determine whether concomitant administration of prednisone could decrease these toxicities. HIV-seropositive adults receiving highly active antiretroviral therapy (HAART) were randomized to receive either (1) intermittent subcutaneous IL-2 and placebo, (2) intermittent subcutaneous IL-2 and prednisone, (3) intermittent prednisone, or (4) intermittent placebo. Prednisone decreased levels of proinflammatory cytokines during IL-2 cycles but, despite induction of expression of CD25, blunted increases in IL-2-associated CD4(+) T lymphocyte count. Whereas intermittent administration of IL-2 reduced basal proliferation of CD4(+) T cells, this effect was inhibited by prednisone, suggesting that prednisone potentially interferes with IL-2's long-term effects on survival of T lymphocytes. C1 NIAID, Off Clin Director, NIH, Bethesda, MD 20892 USA. NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, MD USA. RP Tavel, JA (reprint author), NIAID, Off Clin Director, NIH, 9000 Rockville Pike,Rm 11C103, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 15 TC 10 Z9 10 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 AUG 15 PY 2003 VL 188 IS 4 BP 531 EP 536 DI 10.1086/377285 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 708KX UT WOS:000184567000007 PM 12898439 ER PT J AU Winn, RM Gil-Lamaignere, C Roilides, E Simitsopoulou, M Lyman, CA Maloukou, A Walsh, TJ AF Winn, RM Gil-Lamaignere, C Roilides, E Simitsopoulou, M Lyman, CA Maloukou, A Walsh, TJ TI Selective effects of interleukin (IL)-15 on antifungal activity and IL-8 release by polymorphonuclear leukocytes in response to hyphae of Aspergillus species SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Meeting of the International-Immunocompromised-Host-Society CY JUN, 2002 CL BERGEN, NORWAY SP Int Immunocopromised Host Soc ID NATURAL-KILLER-CELLS; RECEPTOR-BETA-CHAIN; HUMAN-NEUTROPHILS; INVASIVE ASPERGILLOSIS; FUNGAL-INFECTIONS; HUMAN MONOCYTES; FUMIGATUS; DAMAGE; EPIDEMIOLOGY; RECRUITMENT AB The effects of interleukin (IL)-15 on human polymorphonuclear leukocyte (PMNL) activity against Aspergillus fumigatus and Aspergillus flavus were investigated. Pretreatment with IL-15 for 2 h increased PMNL oxidative burst, as measured by superoxide anion (O-2(-)) release in response to A. fumigatus (P < .05) but not to A. flavus. However, after 22-h, but not 2-h, treatment with IL-15, there was significant enhancement in PMNL-mediated hyphal damage to A. fumigatus. Furthermore, 22-h exposure to IL-15 mediated an enhanced release of IL-8 from PMNLs challenged with hyphae of A. fumigatus and A. flavus (P < .05). In contrast, IL-15 treatment did not affect the release of tumor necrosis factor-alpha from PMNLs. The selective time- and species-dependent enhancement of O-2(-) production and hyphal damage, as well as its induction of IL-8 release, suggest that IL-15 may play an important role in the immunomodulation of host response to invasive aspergillosis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Rm 13N24O, Bethesda, MD 20892 USA. RI Gil-Lamaignere, Cristina/A-3866-2013 NR 36 TC 24 Z9 27 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 AUG 15 PY 2003 VL 188 IS 4 BP 585 EP 590 DI 10.1086/377099 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 708KX UT WOS:000184567000016 PM 12898448 ER PT J AU Lorenz, JJ Lorenz, MGO Barker, JL AF Lorenz, JJ Lorenz, MGO Barker, JL TI Pixel-based criteria-oriented analysis of time-lapse Ca2+-fluorescence images SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE pixel-by-pixel; criteria of interest; pattern detection; calcium regulation; calcium imaging; fluorescence microscopy; development; hippocampus ID INTRACELLULAR CALCIUM; SYSTEM; CELLS; NEURONS; DISEASE; NEUROGENESIS; HOMEOSTASIS; MICROSCOPE; MEMBRANE; DYNAMICS AB Since its inception, the analysis of time-lapse video-images acquired during Ca2+ imaging experiments using fluorescence microscopy has been progressively optimized for achieving a high temporal resolution. In contrast, the spatial resolution of the acquired images is often compromised during analysis to varying degrees by the need to draw regions of interest (ROI). We developed a strategy to analyze images at the acquired spatial resolution-pixel-by-pixel, grouping all pixels based on criteria of interest (COI) in regard to their associated fluorescence values over time and visualizing the distributions of the pixel-groups detected in a pseudo-colored map. We applied this pixel-based COI-strategy to the analysis of relative intracellular free calcium levels (Ca-i(2+)) in attached cultured embryonic hippocampal cells under baseline and experimental conditions designed to evaluate the contribution of extracellular Ca2+ (Ca-e(2+)) to baseline Ca-i(2+) levels. We discovered distinct groups of Ca-e(2+)-dependent Ca-i(2+) regulation patterns emergent during the earliest phases of hippocampal cell differentiation, which were not limited to inter-cell differences. Thus, pixel-based COI-analysis of time-lapse images can be used to disclose distinct patterns of Ca-e(2+)-dependent Ca-i(2+) levels and their corresponding subcellular distributions in developing hippocampal cells. Such a strategy should be useful in studying the emergence and distribution of Ca-i(2+) signaling at subcellular levels of resolution using fluorescence microscopy. Published by Elsevier B.V. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Adv Technol, NIH, Gaithersburg, MD 20877 USA. RP Lorenz, JJ (reprint author), NCI, Ctr Bioinformat, NIH, 6116 Execut Blvd, Rockville, MD 20892 USA. NR 32 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 15 PY 2003 VL 127 IS 2 BP 157 EP 166 DI 10.1016/S0165-0270(03)00124-9 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 713GZ UT WOS:000184850300005 PM 12906945 ER PT J AU Harry, GJ Bruccoleri, A d'Hellencourt, CL AF Harry, GJ Bruccoleri, A d'Hellencourt, CL TI Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNF alpha-, IL-1 alpha-, and IL-6-neutralizing antibodies SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE astrocyte; microglia; tumor necrosis factor; interleukin-6; trimethyltin ID NECROSIS-FACTOR-ALPHA; ISCHEMIC BRAIN-DAMAGE; TRIMETHYLTIN INTOXICATION; INTERLEUKIN-6 EXPRESSION; CHEMOKINETIC PROPERTIES; CEREBRAL-ISCHEMIA; MOUSE HIPPOCAMPUS; GENE-EXPRESSION; MESSENGER-RNA; MICROGLIA AB The proinflammatory cytokines tumor necrosis factor (TNFalpha), interleukin-1 (IL-1alpha), and interleukin-6 (IL-6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21-day-old male CD-1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule-1 (ICAM-1), glial fibrillary acidic protein (GFAP), antiapoptotic TNFalpha-inducible early response gene (A-20), macrophage inflammatory protein (MIP)-1alpha, TNFalpha, IL-1alpha, IL-6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM-1, A-20, and TNFbeta elevations. Pentoxifylline blocked elevations in A-20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFalpha-neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT-incluced elevations in mRNA levels for ICAM-1 A-20, GFAP, MIP-1alpha, TNFalpha, TNFbeta, and caspase 3 were blocked by anti-TNFalpha. These data demonstrate a significant role for TNFalpha in an acute neuro-injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB-22, a murine acute-phase response gene homologous to the alpha (1)-antichymotrypsin gene. Elevations were similar for,artificial cerebral spinal fluid and anti-IL-1alpha, and significantly increased with anti-TNFalpha, anti-IL-6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFalpha in the pathogenesis of hippocampal injury induced by TMT. Published 2003 Wiley-Liss, Inc. C1 Natl Inst Environm Hlth Sci, Neurotoxicol Grp, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), Natl Inst Environm Hlth Sci, Neurotoxicol Grp, MD C1-04,POB 12233, Res Triangle Pk, NC 27709 USA. NR 53 TC 20 Z9 20 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 15 PY 2003 VL 73 IS 4 BP 526 EP 536 DI 10.1002/jnr.10653 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 707QH UT WOS:000184521000011 ER PT J AU McBain, CJ AF McBain, CJ TI Transient compartmentalization of interneuron dendrites SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID NEURONS C1 NICHHD, Lab Cellular & Synapt Neurophysiol, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, Bethesda, MD 20892 USA. NR 8 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 AUG 15 PY 2003 VL 551 IS 1 BP 1 EP 1 DI 10.1113/jphysiol.2003.047589 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 720EC UT WOS:000185247700001 PM 12813141 ER PT J AU Gainer, H AF Gainer, H TI Transgenic models for molecular and physiological studies in the central nervous system SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID VASOPRESSIN GENE; EXPRESSION; OXYTOCIN; NEURONS C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 1 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 AUG 15 PY 2003 VL 551 IS 1 BP 3 EP 3 DI 10.1113/jphysiol.2003.040840 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 720EC UT WOS:000185247700003 PM 12813155 ER PT J AU Altekruse, SF Tollefson, LK AF Altekruse, SF Tollefson, LK TI Human campylobacteriosis: a challenge for the veterinary profession SO JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Review ID GUILLAIN-BARRE-SYNDROME; JEJUNI-COLI ENTERITIS; RISK-FACTORS; BROILER FLOCKS; THERMOPHILIC CAMPYLOBACTERS; UNITED-STATES; COMPETITIVE-EXCLUSION; CROSS-CONTAMINATION; ESCHERICHIA-COLI; FEED WITHDRAWAL C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. US FDA, Ctr Vet Med, Rockville, MD 20895 USA. RP Altekruse, SF (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd MSC 7234, Rockville, MD 20852 USA. NR 109 TC 27 Z9 28 U1 0 U2 7 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 J9 J AM VET MED ASSOC JI J. Am. Vet. Med. Assoc. PD AUG 15 PY 2003 VL 223 IS 4 BP 445 EP 452 DI 10.2460/javma.2003.223.445 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 710RB UT WOS:000184692300026 PM 12930081 ER PT J AU Green, AJE Sivtseva, TM Danilova, AP Osakovsky, VL Vladimirtsev, VA Zeidler, M Knight, RS Platonov, FA Shatunov, A Alekseev, VP Krivoshapkin, VG Masters, CL Gajdusek, DC Goldfarb, LG AF Green, AJE Sivtseva, TM Danilova, AP Osakovsky, VL Vladimirtsev, VA Zeidler, M Knight, RS Platonov, FA Shatunov, A Alekseev, VP Krivoshapkin, VG Masters, CL Gajdusek, DC Goldfarb, LG TI Viliuisk encephalomyelitis: intrathecal synthesis of oligodonal IgG SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Viliuisk encephalomyelitis; chronic brain inflammation; isoelectric focusing; intrathecal IgG synthesis ID SIMPLEX VIRUS ENCEPHALITIS; CEREBROSPINAL-FLUID; ANTIBODIES; INDEX AB Viliuisk encephalomyelitis (VE) is a neurodegenerative disorder expressed as subacute meningo-encephalitis progressing to a more prolonged pan-encephalitic syndrome with a fatal outcome within I to 10 years. Some-patients survive to a steady state of global dementia and severe spasticity that may last for over 20 years. Multiple micronecrotic foci surrounded by inflammatory infiltrates are observed throughout the cerebral cortex and other gray matter areas. Infectious etiology of VE is strongly suspected, but the causative agent has not been identified. We conducted a search for assays that might be helpful for VE diagnosis and established for the first time that the majority of patients with definite VE show evidence for intrathecal IgG synthesis correlating with the clinical manifestations of the disease. This indicates that the detection of oligoclonal IgG banding in the cerebrospinal fluid is a valuable diagnostic assay for VE. Implications of these findings for a possible etiology of VE are discussed. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIH, CJD, Surveillance Unit, Bethesda, MD 20892 USA. Sakha Repub Inst Hlth, Yakutsk 677000, Russia. Univ Melbourne, Dept Med, Parkville, Vic 3050, Australia. CNRS, Inst Alfred Fessard, Gif Sur Yvette, France. RP Goldfarb, LG (reprint author), NIH, CJD, Surveillance Unit, Bldg 10,Room 4B37,10 Ctr Dr,MSC 1361, Bethesda, MD 20892 USA. RI Shatunov, Aleksey/E-6946-2011 NR 16 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD AUG 15 PY 2003 VL 212 IS 1-2 BP 69 EP 73 DI 10.1016/S0022-510X(03)00107-2 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 692KD UT WOS:000183659500010 PM 12810001 ER PT J AU Lee, N Gorelick, RJ Musier-Forsyth, K AF Lee, N Gorelick, RJ Musier-Forsyth, K TI Zinc finger-dependent HIV-1 nucleocapsid protein-TAR RNA interactions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ACID-CHAPERONE ACTIVITY; PLUS-STRAND TRANSFER; STRONG-STOP DNA; REVERSE TRANSCRIPTION; ORDERED AGGREGATION; SECONDARY STRUCTURE; CRYSTAL-STRUCTURE; IN-VITRO; SEQUENCES; MECHANISM AB In the minus-strand transfer step of HIV-1 reverse transcription, the nucleocapsid protein (NC) promotes annealing of the 3' 'R' (repeat) region of the RNA genome to its complementary sequence located in the newly synthesized minus-strand strong-stop DNA. The R region contains the highly stable transactivation response (TAR) RNA hairpin. To gain insights into the molecular details of TAR RNA-NC interactions, we carried out hydroxyl radical footprinting, as well as gel-shift and fluorescence anisotropy binding assays using wild-type and mutant forms of NC. Our results support the conclusion that NC variants with mutations in their zinc finger domains have dramatically altered TAR RNA binding interactions relative to wild-type NC. These data demonstrate that a specific zinc finger architecture is required for optimal TAR RNA binding, and help to explain the requirement for the zinc finger motifs of NC in its role as a nucleic acid chaperone in minus-strand transfer. C1 Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. SAIC Frederick Inc, AIDS Vaccine Program, NCI, Frederick, MD 21702 USA. RP Musier-Forsyth, K (reprint author), Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA. FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [AI65056]; NIGMS NIH HHS [F32 GM064973, F32 GM64973] NR 52 TC 27 Z9 27 U1 0 U2 0 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 AUG 15 PY 2003 VL 31 IS 16 BP 4847 EP 4855 DI 10.1093/nar/gkg679 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 712DY UT WOS:000184783000022 PM 12907727 ER PT J AU Yu, YK AF Yu, YK TI On a class of integrals of Legendre polynomials with complicated arguments - with applications in electrostatics and biomolecular modeling SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE special functions; integral; electrostatics; molecular modeling AB The exact analytical result for a class of integrals involving (associated) Legendre polynomials of complicated argument is presented. The method employed can in principle be generalized to integrals involving other special functions. This class of integrals also proves useful in the electrostatic problems in which dielectric spheres are involved, which is of importance in modeling the dynamics of biological macromolecules. In fact, with this solution, a more robust foundation is laid for the Generalized Born method in modeling the dynamics of biomolecules. (C) 2003 Elsevier B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Florida Atlantic Univ, Dept Phys, Boca Raton, FL 33431 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 7 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD AUG 15 PY 2003 VL 326 IS 3-4 BP 522 EP 533 DI 10.1016/s0378-4371(03)00335-2 PG 12 WC Physics, Multidisciplinary SC Physics GA 708XZ UT WOS:000184596800019 PM 15759366 ER PT J AU Sullivan, SA Landsman, D AF Sullivan, SA Landsman, D TI Characterization of sequence variability in nucleosome core histone folds SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE sequence conservation ID AMINO-ACID CONSERVATION; SECONDARY STRUCTURE; RESIDUE CONSERVATION; ANGSTROM RESOLUTION; ALIGNMENT; PARTICLE; CHROMATIN; MATRICES; OCTAMER AB The three-helix, similar to65-residue histone fold domain is the most structurally conserved part of the core histones H2A, H2B, H3, and H4. However, it evinces a notable degree of sequence variation within and between histone classes. We used two approaches to characterize sequence variation in these histone folds, toward elucidating their structure/function relationships and evolution. On the one hand we asked how much of the sequence variation seen in structure-based alignments of the folds maintains physicochemical properties at a position, and on the other, whether conservation correlates to structural importance, as measured by the number of residue-to-residue contacts a position makes. Strong physicochemical conservation or correlation of conservation to contacts would support the idea that functional constraints, rather than genetic drift, determines the observed range of variants at a given position. We used an 11-state table of physicochemical properties to classify each position in the core histone fold (CHF) alignments, and a public website (http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/valdar/scorecons_server.pl) to score conservation. We found that, depending on histone class, from 38 to 77% of CHF positions are maximally conserved physicochemically, and that for H2B, H3, and H4 the degree to which a position is conserved correlates positively to the number of contacts made by the residue at that position in the crystal structure of the nucleosome core particle. We also examined the correlation between conservation and the type of contact (e.g., inter- or intrachain, histone-histone, or histone-DNA, etc.). For H2B, H3, and H4 we found a positive correlation between conservation and number of interchain protein contacts. No such correlation or statistical significance was found for DNA or intrachain contacts. This suggests that variations in the CHF sequences could be functionally constrained by requirements to make sufficient interchain histone contacts. We also suggest that inventory of histone residue variants can augment functional studies of histones. An example is presented for histone H3. (C) 2003 Wiley-Liss, Inc. C1 NCBI, Computat Biol Branch, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Landsman, D (reprint author), NCBI, Computat Biol Branch, Natl Lib Med, NIH, Bldg 38A,Room 6N601, Bethesda, MD 20894 USA. RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 36 TC 9 Z9 9 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 15 PY 2003 VL 52 IS 3 BP 454 EP 465 DI 10.1002/prot.10441 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 707KZ UT WOS:000184511000011 PM 12866056 ER PT J AU KewalRamani, VN Coffin, JM AF KewalRamani, VN Coffin, JM TI Weapons of mutational destruction SO SCIENCE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL VIF PROTEIN; REVERSE TRANSCRIPTION; G->A HYPERMUTATION; HIV-1 VIRIONS; TYPE-1 VIF; SOR GENE; DNA; REPLICATION; INFECTION C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP KewalRamani, VN (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NR 29 TC 26 Z9 29 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 AUG 15 PY 2003 VL 301 IS 5635 BP 923 EP 925 DI 10.1126/science.1088965 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711RY UT WOS:000184755900023 PM 12920286 ER PT J AU Xu, JL Prorok, PC AF Xu, JL Prorok, PC TI Modelling and analysing exchangeable binary data with random cluster sizes SO STATISTICS IN MEDICINE LA English DT Article DE beta-binomial; exchangeable binary data; generalized estimating equation; maximum likelihood estimates ID DEVELOPMENTAL TOXICITY; REGRESSION AB Correlated binary data occur very frequently in cluster sample surveys, dependent repeated cancer screening, teratological experiments, ophthalmologic and otolaryngologic studies, and other clinical trials. The standard methods to analyse these data include the use of beta-binomial models and generalized estimating equations with third and fourth moments specified by 'working matrices'. However, in many applications it is reasonable to assume that the data from the same cluster are exchangeable. When all sampled clusters have equal sizes, Bowman and George introduced maximum likelihood estimates (MLEs) of the population parameters such as the marginal means, moments, and correlations of order two and higher. They also extended their approach to sampled clusters with unequal sizes. It seems that their extension has a gap. This paper points out the source of this gap and shows that estimates introduced by Bowman and George are not the MLEs of the parameters which are used to identify the joint distribution of correlated binary data. We show that the MLEs of the population parameters have no closed form in general and should be calculated by numerical methods. We apply our results and a generalized estimating equation procedure to a data set from a double-blind randomized clinical trial comparing two antibiotics, cefaclor and amoxicillin, used for the treatment of acute otitis media. To see the performance of the MLEs with small or moderate sample sizes, several simulation studies are also conducted. Published in 2003 by John Wiley Sons, Ltd. C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Xu, JL (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 17 TC 9 Z9 9 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2003 VL 22 IS 15 BP 2401 EP 2416 DI 10.1002/sim.1527 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 707AJ UT WOS:000184487000002 PM 12872298 ER PT J AU Faraggi, D Reiser, B Schisterman, EF AF Faraggi, D Reiser, B Schisterman, EF TI ROC curve analysis for biomarkers based on pooled assessments SO STATISTICS IN MEDICINE LA English DT Article DE area under the ROC curve; gamma distribution; normal distribution; root mean square error ID RANDOM MEASUREMENT ERROR; DIAGNOSTIC MARKERS; STATISTICAL-INFERENCE; ESTIMATING PREVALENCE; CONFIDENCE-INTERVALS; AREA; DISEASE; P(Y-LESS-THAN-X); TESTS AB Interleukin-6 is a biomarker of inflammation which has been suggested as having potential discriminatory ability for myocardial infarction. Because of its high assaying cost it is very expensive to evaluate this marker. In order to reduce this cost we propose pooling the specimens. In this paper we examine the efficiency of ROC curve analysis, specifically the estimation of the area under the ROC curve, when dealing with pooled data. We study the effect of pooling when there are only a fixed number of individuals available for testing and pooling is carried out to save on the number of assays. Alternatively we examine how many pooled assays of size g are necessary to provide essentially the same information as N individual assays. We measure loss of information by means of the change in root mean square error of the estimate of the area under the ROC curve and study the extent of this loss via a simulation study. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. NICHD, Div Epidemiol Stat & Prevent, NIH, Bethesda, MD USA. RP Faraggi, D (reprint author), Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. RI Reiser, Benjamin/G-6591-2012; OI Reiser, Benjamin/0000-0002-9797-9029; Schisterman, Enrique/0000-0003-3757-641X NR 25 TC 36 Z9 37 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2003 VL 22 IS 15 BP 2515 EP 2527 DI 10.1002/sim.1418 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 707AJ UT WOS:000184487000010 PM 12872306 ER PT J AU Waalkes, MP AF Waalkes, MP TI Edward Bresnick - In memoriam SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Biographical-Item C1 NIEHS, Natl Canc Inst, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Natl Canc Inst, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2003 VL 191 IS 1 BP 1 EP 1 DI 10.1016/S0014-008X(03)00246-1 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 712DE UT WOS:000184781000001 ER PT J AU Kim, AH Kohn, MC Nyska, A Walker, NJ AF Kim, AH Kohn, MC Nyska, A Walker, NJ TI Area under the curve as a dose metric for promotional responses following 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE risk assessment; dosimetry; carcinogenesis; dioxins ID SPRAGUE-DAWLEY RATS; CELL-PROLIFERATION; TUMOR PROMOTION; REAL-TIME; HEPATOCARCINOGENESIS; LIVER; FOCI; EXPRESSION; INDUCTION; MECHANISM AB An underlying basis of risk assessment is that an equivalent risk for a specified dose metric exists that allows for extrapolation of dose-response relationships between species. To better understand the use of area under the curve (AUC) as a dose metric for complex biological responses following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a study was designed using a physiologically based pharmacokinetic model in the female Sprague-Dawley rat that would result in equivalent AUCs of total liver TCDD with differing patterns of exposure. In the first group, rats received a high peak dose of 3500 ng TCDD/kg twice per week in the first week followed by a lower TCDD dose of 81 ng/kg twice per week for the remainder of the study. In the second group, rats received a gavage dose of 350 ng TCDD/kg in corn oil twice per week for the study duration of 15 weeks. Age-matched control rats received corn oil as a vehicle control. Placental glutathione S-transferase (PGST)-positive foci were measured in representative liver lobes by immunohistochemistry, as a representative complex biological response resulting from TCDD exposure. The median volume fraction was 0.045% in control rats and was significantly elevated in TCDD treatment groups. However, the volume fraction of PGST-positive foci was significantly higher in the TCDD group given the high peak dose during the first week of TCDD treatment compared with the group receiving the same average daily dose over the study duration: 0.74 versus 0.20%, respectively. These findings suggest that the peak magnitude of TCDD in liver rather than AUC may play a significant role in the induction of complex biological responses by TCDD. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIEHS, Lab Computat Biol & Risk Anal, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27599 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Walker, NJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, Environm Toxicol Program, POB 12233,MD D4-01,111 TW Alexander Dr,Bldg 101,R, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIEHS NIH HHS [T32-ES07126] NR 33 TC 3 Z9 3 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2003 VL 191 IS 1 BP 12 EP 21 DI 10.1016/S0041-008X(03)00225-4 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 712DE UT WOS:000184781000003 PM 12915100 ER PT J AU Cheng, RYS Zhao, AL Alvord, WG Powell, DA Bare, RM Masuda, A Takahashi, T Anderson, LM Kasprzak, KS AF Cheng, RYS Zhao, AL Alvord, WG Powell, DA Bare, RM Masuda, A Takahashi, T Anderson, LM Kasprzak, KS TI Gene expression dose-response changes in microarrays after exposure of human peripheral lung epithelial cells to nickel(II) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE nickel; lung cancer; microarray; gene expression ID GROWTH-FACTOR-BETA; DIFFERENTIAL EXPRESSION; RIBOSOMAL-PROTEIN; BINDING PROTEIN; CANCER CELLS; DNA; CALMODULIN; IDENTIFICATION; TRANSCRIPTION; ACTIVATION AB Occupational exposure to nickel compounds is associated with lung cancer risk; both genotoxic and epigenetic mechanisms have been proposed. For comprehensive examination of the acute effects of nickel(II) acetate on gene expression in cultured human peripheral lung epithelial HPLID cells, microarray analyses were carried out with cDNA chips (similar to8000 cDNAs). Cells were exposed for 24 h to nontoxic (50, 100, and 200 muM) or toxic (400, 800, and 1600 muM) nickel(II) concentrations. Cluster analysis was applied to the 868 genes with greater than or equal to2-fold change at any concentration. Two main clusters showed marked up- or down-regulation at the highest, toxic concentrations. The data further subdivided into 10 highly cohesive clusters with high probability, and of these only 2 had the same response trend at low nontoxic as at high concentrations, an observation of clear relevance to the process of high- to low-dose extrapolation in risk assessment. There were 113 genes showing greater than or equal to2-fold change at the three lower nontoxic concentrations, those most relevant to in vivo carcinogenesis. In addition to expected responses of metallothionein, ferritin, and heat-shock proteins, the results revealed for the first time changed expression of some potential cancer-related genes in response to low-dose Ni(II): RhoA, dyskerin, interferon regulatory factor 1, RAD21 homologue, and tumor protein, translationally controlled. Overall, most of the genes impacted by nontoxic concentrations of nickel(II) acetate related to gene transcription, protein synthesis and stability, cytoskeleton, signaling, metabolism, cell membrane, and extracellular matrix. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Data Management Serv Inc, Frederick, MD 21702 USA. Aichi Canc Ctr, Res Inst, Div Mol Oncol, Nagoya, Aichi 4648681, Japan. RP Cheng, RYS (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538, Frederick, MD 21702 USA. RI Takahashi, Takashi/I-7262-2014; OI Cheng, Robert/0000-0003-0287-6439 NR 61 TC 26 Z9 31 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2003 VL 191 IS 1 BP 22 EP 39 DI 10.1016/S0041-008X(03)00228-X PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 712DE UT WOS:000184781000004 PM 12915101 ER PT J AU Vende, P Tortorici, MA Taraporewala, ZF Patton, JT AF Vende, P Tortorici, MA Taraporewala, ZF Patton, JT TI Rotavirus NSP2 interferes with the core lattice protein VP2 in initiation of minus-strand synthesis SO VIROLOGY LA English DT Article ID RNA-BINDING ACTIVITY; NONSTRUCTURAL PROTEIN; GENOME REPLICATION; MESSENGER-RNA; IDENTIFICATION; POLYMERASE; PARTICLES; PHOSPHORYLATION; VISUALIZATION; LOCALIZATION AB The rotavirus nonstructural protein NSP2 self-assembles into stable octameric structures that possess nonspecific affinity for single-stranded (ss)RNA and RNA-RNA helix-destabilizing and NTPase activities. Furthermore, NSP2 is a component of replication intermediates with replicase activity and plays a critical role in the packaging and replication of the segmented dsRNA genome of rotavirus. To better understand the function of the protein in genome replication, we examined the effect that purified recombinant NSP2 had on the synthesis of dsRNA by the open core replication system. The results showed that NSP2 inhibited the synthesis of dsRNA from viral mRNA in vitro, in a concentration-dependent manner. The inhibition was overcome by adding increasing amounts of viral mRNA or nonviral ssRNA to the system, indicating that the inhibition was mediated by the nonspecific RNA-binding activity of NSP2. Further analysis revealed that NSP2 interfered with the ability of the open core proteins, GTP, and viral mRNA to form the initiation complex for (-) strand synthesis. Additional experiments indicated that NSP2 did not perturb recognition of viral mRNA by the viral RNA polymerase VP1, but rather interfered with the function of VP2, a protein that is essential for strand initiation and dsRNA synthesis and that forms the T = 1 lattice of the virion core. In contrast to initiation, NSP2 did not inhibit strand elongation. Collectively, the findings provide evidence that the temporal order of interaction of RNA-binding proteins with viral mRNA is a crucial factor impacting the formation of replication intermediates. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr MSC 8026, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 41 TC 6 Z9 7 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 AUG 15 PY 2003 VL 313 IS 1 BP 261 EP 273 DI 10.1016/S0042-6822(03)00302-7 PG 13 WC Virology SC Virology GA 719NJ UT WOS:000185209200024 PM 12951038 ER PT J AU Jagoda, E Contoreggi, C Lee, MJ Kao, CHK Szajek, P Listwak, S Gold, P Chrousos, G Greiner, E Kim, BM Jacobson, AE Rice, KC Eckelman, W AF Jagoda, E Contoreggi, C Lee, MJ Kao, CHK Szajek, P Listwak, S Gold, P Chrousos, G Greiner, E Kim, BM Jacobson, AE Rice, KC Eckelman, W TI Autoradiographic visualization of corticotropin releasing hormone type 1 receptors with a nonpeptide ligand: Synthesis of [Br-76]MJL-1-109-2 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RAT-BRAIN; FUNCTIONAL EXPRESSION; IMAGING AGENTS; CRF1 RECEPTOR; CLONING; PITUITARY; PYRROLOPYRIMIDINES; IDENTIFICATION; ANTAGONISTS; SAUVAGINE AB A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the pathophysiology of stress related diseases. C1 NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. NIDA, Imaging Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. NIDDKD, Med Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, NIH, DHHS, Bethesda, MD 20892 USA. NICHHD, Pediat Endocrinol Sect, PREB, NIH, Bethesda, MD 20892 USA. RP Eckelman, W (reprint author), NIH, Warren G Magnuson Clin Ctr, PET Dept, 10 Ctr Dr, Bethesda, MD 20892 USA. EM eckelman@nih.gov NR 27 TC 27 Z9 27 U1 0 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 AUG 14 PY 2003 VL 46 IS 17 BP 3559 EP 3562 DI 10.1021/jm0304077k PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 711BT UT WOS:000184719100001 PM 12904058 ER PT J AU Amanullah, A Azam, N Balliet, A Hollander, C Hoffman, B Fornace, A Liebermann, D AF Amanullah, A Azam, N Balliet, A Hollander, C Hoffman, B Fornace, A Liebermann, D TI Cell signalling (communication arising) - Cell survival and a Gadd45-factor deficiency SO NATURE LA English DT Editorial Material ID NF-KAPPA-B; TRANSDUCTION; ACTIVATION; DEATH; GENES; LIFE C1 Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA. NCI, Gene Response Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. RP Amanullah, A (reprint author), GlaxoSmithKline, HTB Integrat Biol Initiat, King Of Prussia, PA 19406 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 10 TC 67 Z9 71 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 14 PY 2003 VL 424 IS 6950 BP 741 EP 742 DI 10.1038/424741b PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711HQ UT WOS:000184733900028 PM 12917673 ER PT J AU Thomas, JW Touchman, JW Blakesley, RW Bouffard, GG Beckstrom-Sternberg, SM Margulies, EH Blanchette, M Siepel, AC Thomas, PJ McDowell, JC Maskeri, B Hansen, NF Schwartz, MS Weber, RJ Kent, WJ Karolchik, D Bruen, TC Bevan, R Cutler, DJ Schwartz, S Elnitski, L Idol, JR Prasad, AB Lee-Lin, SQ Maduro, VVB Summers, TJ Portnoy, ME Dietrich, NL Akhter, N Ayele, K Benjamin, B Cariaga, K Brinkley, CP Brooks, SY Granite, S Guan, X Gupta, J Haghighi, P Ho, SL Huang, MC Karlins, E Laric, PL Legaspi, R Lim, MJ Maduro, QL Masiello, CA Mastrian, SD McCloskey, JC Pearson, R Stantripop, S Tiongson, EE Tran, JT Tsurgeon, C Vogt, JL Walker, MA Wetherby, KD Wiggins, LS Young, AC Zhang, LH Osoegawa, K Zhu, B Zhao, B Shu, CL De Jong, PJ Lawrence, CE Smit, AF Chakravarti, A Haussler, D Green, P Miller, W Green, ED AF Thomas, JW Touchman, JW Blakesley, RW Bouffard, GG Beckstrom-Sternberg, SM Margulies, EH Blanchette, M Siepel, AC Thomas, PJ McDowell, JC Maskeri, B Hansen, NF Schwartz, MS Weber, RJ Kent, WJ Karolchik, D Bruen, TC Bevan, R Cutler, DJ Schwartz, S Elnitski, L Idol, JR Prasad, AB Lee-Lin, SQ Maduro, VVB Summers, TJ Portnoy, ME Dietrich, NL Akhter, N Ayele, K Benjamin, B Cariaga, K Brinkley, CP Brooks, SY Granite, S Guan, X Gupta, J Haghighi, P Ho, SL Huang, MC Karlins, E Laric, PL Legaspi, R Lim, MJ Maduro, QL Masiello, CA Mastrian, SD McCloskey, JC Pearson, R Stantripop, S Tiongson, EE Tran, JT Tsurgeon, C Vogt, JL Walker, MA Wetherby, KD Wiggins, LS Young, AC Zhang, LH Osoegawa, K Zhu, B Zhao, B Shu, CL De Jong, PJ Lawrence, CE Smit, AF Chakravarti, A Haussler, D Green, P Miller, W Green, ED TI Comparative analyses of multi-species sequences from targeted genomic regions SO NATURE LA English DT Article ID NONCODING SEQUENCES; MAMMALIAN GENOMES; DNA-SEQUENCES; GENE; SUBSTITUTION; ALIGNMENTS; DIVERGENCE; PREDICTION; EVOLUTION; DELETIONS AB The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding(1-6) and conserved non-coding(4,6,7) regions, including regulatory elements(8-10), and provide insight into the forces that have rendered modern-day genomes(6). As a complement to whole-genome sequencing efforts(3,5, 6), we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non- coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NIH, NIH Intramural Sequencing Ctr, Bethesda, MD 20892 USA. Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21287 USA. Penn State Univ, Dept Comp Sci & Engn, University Pk, PA 16802 USA. Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. New York State Dept Hlth, Wadsworth Ctr Labs & Res, Albany, NY 12201 USA. Inst Syst Biol, Seattle, WA 98103 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov RI Prasad, Arjun/C-6736-2008; Yang, Chen/G-1379-2010; Granite, Stephen/J-9487-2013; OI Granite, Stephen/0000-0002-0956-7500; Siepel, Adam/0000-0002-3557-7219 NR 30 TC 457 Z9 536 U1 1 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 14 PY 2003 VL 424 IS 6950 BP 788 EP 793 DI 10.1038/nature01858 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711HQ UT WOS:000184733900043 PM 12917688 ER PT J AU Dina, OA McCarter, GC de Coupade, C Levine, JD AF Dina, OA McCarter, GC de Coupade, C Levine, JD TI Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain SO NEURON LA English DT Article ID ACTIVATED PROTEIN-KINASE; PERIPHERAL NEUROPATHY; NOCICEPTOR SENSITIZATION; COUPLED RECEPTORS; C-EPSILON; IN-VITRO; TRANSIENT PERMEABILIZATION; CAENORHABDITIS-ELEGANS; THERMAL HYPERALGESIA; ACTIN CYTOSKELETON AB Prostaglandin E-2 (PGE(2)) and epinephrine act directly on nociceptors to produce mechanical hyperalgesia through protein kinase A (PKA) alone or through a combination of PKA, protein kinase C epsilon (PKCepsilon), and extracellular signal-regulated kinase (ERK), respectively. Disruptors of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) markedly attenuated the hyperalgesia in rat paws caused by injection of epinephrine or its downstream mediators. In contrast, the hyperalgesia induced by PGE(2) or its mediators was not affected by any of the cytoskeletal disruptors. These effects were mimicked in vitro, as measured by enhancement of the tetrodotoxin-resistant sodium current. When PGE(2) hyperalgesia was shifted to dependence on PKCepsilon and ERK as well as PKA, as when the tissue is "primed" by prior treatment with carrageenan, it too became dependent on an intact cytoskeleton. Thus, inflammatory mediator-induced mechanical hyperalgesia was differentially dependent on the cytoskeleton such that cytoskeletal dependence correlated with mediation by PKCepsilon and ERK. C1 Univ Calif San Francisco, NIH Pain Ctr, Dept Oral & Maxillofacial Surg, Dept Med,Div Neurosci & Biomed Sci Program, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, NIH Pain Ctr, Dept Oral & Maxillofacial Surg, Dept Med,Div Neurosci & Biomed Sci Program, San Francisco, CA 94143 USA. FU NIDCR NIH HHS [DE08973]; NINDS NIH HHS [NS42546] NR 87 TC 84 Z9 87 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 14 PY 2003 VL 39 IS 4 BP 613 EP 624 DI 10.1016/S0896-6273(03)00473-2 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 712CQ UT WOS:000184779500007 PM 12925276 ER PT J AU Ikeda, T Hikosaka, O AF Ikeda, T Hikosaka, O TI Reward-dependent gain and bias of visual responses in primate superior colliculus SO NEURON LA English DT Article ID SACCADIC EYE-MOVEMENTS; NIGRA PARS RETICULATA; MONKEY CAUDATE-NUCLEUS; OCULOMOTOR FUNCTIONS; SUBSTANTIA-NIGRA; FUNCTIONAL-PROPERTIES; AUDITORY RESPONSES; PREFRONTAL CORTEX; NEURONAL-ACTIVITY; PARIETAL CORTEX AB Eye movements are often influenced by expectation of reward. Using a memory-guided saccade task with an asymmetric reward schedule, we show that visual responses of monkey SC neurons increase when the visual stimulus indicates an upcoming reward. The increase occurred in two distinct manners: (1) reactively, as an increase in the gain of the visual response when the stimulus indicated an upcoming reward; (2) proactively, as an increase in anticipatory activity when reward was expected in the neuron's response field. These effects were observed mostly in saccade-related SC neurons in the deeper layer which would receive inputs from the cortical eye fields and the basal ganglia. These results, together with recent findings, suggest that the gain modulation may be determined by the inputs from both the cortical eye fields and the basal ganglia, whereas the anticipatory bias may be derived mainly from the basal ganglia. C1 Juntendo Univ, Sch Med, Dept Physiol, Bunkyo Ku, Tokyo 1138421, Japan. Univ Tokyo, Dept Neurol, Div Neurosci, Grad Sch Med, Tokyo 113, Japan. Tamagawa Univ, Brain Sci Res Ctr, Tokyo 1940041, Japan. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hikosaka, O (reprint author), Juntendo Univ, Sch Med, Dept Physiol, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan. NR 44 TC 133 Z9 136 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 14 PY 2003 VL 39 IS 4 BP 693 EP 700 DI 10.1016/S0896-6273(03)00464-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 712CQ UT WOS:000184779500013 PM 12925282 ER PT J AU Eyman, M Crispino, M Kaplan, BB Giuditta, A AF Eyman, M Crispino, M Kaplan, BB Giuditta, A TI Squid photoreceptor terminals synthesize calexcitin, a learning related protein SO NEUROSCIENCE LETTERS LA English DT Article DE calexcitin; cp20; photoreceptors; nerve terminals; presynaptic endings; protein synthesis; squid; learning ID SYNAPTOSOMAL FRACTION; ACTIVE POLYSOMES; MEMORY STORAGE; BRAIN; TRANSPORT; ENDINGS; DOMAINS; CALCIUM; AXON; GTP AB Nerve endings of squid photoreceptor neurons generate large synaptosomes upon homogenization of the optic lobe. Using several independent methods, these presynaptic structures have been shown to synthesize a wealth of soluble, cytoskeletal and nuclear encoded mitochondrial proteins, and to account for essentially all the translation activity of the synaptosomal fraction. We are now presenting evidence that calexcitin, a learning related, Ca2+-binding protein of the B photoreceptors of Hermissenda crassicornis (a mollusk), is synthesized and subjected to post-translational modifications in the squid photoreceptor terminals. In view of the essential role of presynaptic protein synthesis in long-term memory formation in Aplysia, our data suggest that a comparable role may be played by calexcitin synthesized in the squid photoreceptor terminals. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Naples Federico II, Dipartimento Fisiol Gen & Ambientale, I-80134 Naples, Italy. NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Giuditta, A (reprint author), Univ Naples Federico II, Dipartimento Fisiol Gen & Ambientale, Via Mezzocannone 8, I-80134 Naples, Italy. NR 20 TC 7 Z9 7 U1 0 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 AUG 14 PY 2003 VL 347 IS 1 BP 21 EP 24 DI 10.1016/S0304-3940(03)00593-7 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 703AF UT WOS:000184257100006 PM 12865132 ER PT J AU Steinberg, MH Barton, F Terrin, M Waclawiw, M Bonds, D AF Steinberg, MH Barton, F Terrin, M Waclawiw, M Bonds, D TI Long-term use of hydroxyurea for sickle cell anemia - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Steinberg, MH (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 13 PY 2003 VL 290 IS 6 BP 754 EP 754 DI 10.1001/jama.290.6.754-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 709VU UT WOS:000184647700020 ER PT J AU Einat, H Yuan, PX Gould, TD Li, JL Du, JH Zhang, L Manji, HK Chen, G AF Einat, H Yuan, PX Gould, TD Li, JL Du, JH Zhang, L Manji, HK Chen, G TI The role of the extracellular signal-regulated kinase signaling pathway in mood modulation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE mood; affect; bipolar disorder; mania; depression; lithium; valproate; ERK; RSK; CREB; RSK; BAD; BDNF ID ELEMENT-BINDING PROTEIN; FORCED SWIM TEST; NEUROTROPHIC FACTOR; NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; CHRONIC LITHIUM; ANIMAL-MODEL; MAP KINASE; MICE; RESPONSES AB The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers. C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH,Dept HHS, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Psychiat, Mol Pathophysiol Lab, Detroit, MI 48201 USA. RP Chen, G (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH,Dept HHS, Bldg 49,Room B1EE16,49 Convent Dr,MSC 4405, Bethesda, MD 20892 USA. RI Einat, Haim/A-7203-2009; Chen, Guang/A-2570-2017 NR 33 TC 361 Z9 372 U1 3 U2 18 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 AUG 13 PY 2003 VL 23 IS 19 BP 7311 EP 7316 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 712UX UT WOS:000184817700009 PM 12917364 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI Application of comparative genomics in the identification and analysis of novel families of membrane-associated receptors in bacteria SO BMC GENOMICS LA English DT Article ID 2-COMPONENT SIGNAL-TRANSDUCTION; ESCHERICHIA-COLI; PSI-BLAST; 7-TRANSMEMBRANE RECEPTORS; 3-DIMENSIONAL STRUCTURE; STAPHYLOCOCCUS-AUREUS; PROTEIN STRUCTURES; SENSORY RHODOPSIN; DATABASE SEARCHES; DOMAIN COMMON AB Background: A great diversity of multi-pass membrane receptors, typically with 7 transmembrane (TM) helices, is observed in the eukaryote crown group. So far, they are relatively rare in the prokaryotes, and are restricted to the well-characterized sensory rhodopsins of various phototropic prokaryotes. Results: Utilizing the currently available wealth of prokaryotic genomic sequences, we set up a computational screen to identify putative 7 (TM) and other multi-pass membrane receptors in prokaryotes. As a result of this procedure we were able to recover two widespread families of 7 TM receptors in bacteria that are distantly related to the eukaryotic 7 TM receptors and prokaryotic rhodopsins. Using sequence profile analysis, we were able to establish that the first members of these receptor families contain one of two distinct N-terminal extracellular globular domains, which are predicted to bind ligands such as carbohydrates. In their intracellular portions they contain fusions to a variety of signaling domains, which suggest that they are likely to transduce signals via cyclic AMP, cyclic diguanylate, histidine phosphorylation, dephosphorylation, and through direct interactions with DNA. The second family of bacterial 7 TM receptors possesses an alpha-helical extracellular domain, and is predicted to transduce a signal via an intracellular HD hydrolase domain. Based on comparative analysis of gene neighborhoods, this receptor is predicted to function as a regulator of the diacylglycerol-kinase-dependent glycerolipid pathway. Additionally, our procedure also recovered other types of putative prokaryotic multi-pass membrane associated receptor domains. Of these, we characterized two widespread, evolutionarily mobile multi-TM domains that are fused to a variety of C-terminal intracellular signaling domains. One of these typified by the Gram-positive LytS protein is predicted to be a potential sensor of murein derivatives, whereas the other one typified by the Escherichia coli UhpB protein is predicted to function as sensor of conformational changes occurring in associated membrane proteins Conclusions: We present evidence for considerable variety in the types of uncharacterized surface receptors in bacteria, and reconstruct the evolutionary processes that model their diversity. The identification of novel receptor families in prokaryotes is likely to aid in the experimental analysis of signal transduction and environmental responses of several bacteria, including pathogens such as Leptospira, Treponema, Corynebacterium, Coxiella, Bacillus anthracis and Cytophaga. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM ananthar@ncbi.nlm.nih.gov; aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 NR 81 TC 42 Z9 42 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 12 PY 2003 VL 4 AR 34 DI 10.1186/1471-2164-4-34 PG 20 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 730JV UT WOS:000185828400002 PM 12914674 ER PT J AU Kaufmann, H Saadia, D Voustianiouk, A Goldstein, DS Holmes, C Yahr, MD Nardin, R Freeman, R AF Kaufmann, H Saadia, D Voustianiouk, A Goldstein, DS Holmes, C Yahr, MD Nardin, R Freeman, R TI Norepinephrine precursor therapy in neurogenic orthostatic hypotension SO CIRCULATION LA English DT Article DE nervous system, autonomic; blood pressure; vasoconstriction; norepinephrine; receptors, adrenergic, alpha ID MULTIPLE SYSTEM ATROPHY; PURE AUTONOMIC FAILURE; L-DOPA; 3,4-DL-THREO-DIHYDROXYPHENYLSERINE; L-THREO-3,4-DIHYDROXYPHENYLSERINE; DIHYDROXYPHENYLSERINE; MULTICENTER; PLACEBO; ACID AB Background-In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine ( NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. Methods and Results-We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH ( 8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine ( from 101 +/- 4 to 141 +/- 5 mm Hg) and standing ( from 60 +/- 4 to 100 +/- 6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions-Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system. C1 CUNY Mt Sinai Sch Med, New York, NY 10029 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Kaufmann, H (reprint author), CUNY Mt Sinai Sch Med, Box 1052, New York, NY 10029 USA. OI Kaufmann, Horacio/0000-0002-1851-9981 FU NCRR NIH HHS [M01-RR00071, M01-RR01032] NR 23 TC 71 Z9 75 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 AUG 12 PY 2003 VL 108 IS 6 BP 724 EP 728 DI 10.1161/01.CIR.0000083721.49847.D7 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 710ZM UT WOS:000184712700018 PM 12885750 ER PT J AU Scarlett, CO Blackshear, PJ AF Scarlett, CO Blackshear, PJ TI Neuroanatomical development in the absence of PKC phosphorylation of the myristoylated alanine-rich C-kinase substrate (MARCKS) protein SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE phosphorylation; protein kinase C (PKC); cortical lamination; forebrain commissures ID PROMINENT CELLULAR SUBSTRATE; ABNORMAL BRAIN-DEVELOPMENT; NEURAL-TUBE DEFECTS; MEMBRANE ASSOCIATION; NERVOUS-SYSTEM; MUTANT MICE; DEFICIENCY; GUIDANCE; NETRIN-1; GAMMA AB The myristoylated alanine-rich C-kinase substrate protein (MARCKS) is a widely expressed target of protein kinase C (PKC) phosphorylation. Disruption of Marcks in mice leads to a number of developmental defects within the central nervous system that are completely prevented by expression of an epitope-tagged wild-type human MARCKS transgene. In the present study, we investigated whether PKC phosphorylation of MARCKS is necessary for normal central nervous system development and postnatal survival. Expression at approximately twice normal levels of a mutant MARCKS protein in which the four PKC phosphorylatable serines were replaced by asparagines did not allow postnatal survival of Marcks(-/-) pups. Nonetheless, the rescued animals exhibited none of the characteristic anatomical defects seen in the brains and retinas of knockout mice, suggesting that PKC phosphorylation of MARCKS is not required for normal central nervous system development. Expression studies showed that transgene expression was limited to the central nervous system, which has implications for the lack of postnatal survival as well as for the pathogenesis of the neuronal ectopia characteristic of MARCKS deficiency. A novel aspect of the MARCKS-deficient phenotype was also noted, absence of the pontine nuclei; this was also largely reversed in Marcks(-/-) animals expressing the mutant transgene. These data raise the possibility of a role for MARCKS in the netrin-regulated process of pontine nuclei formation. C1 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Duke Univ, Dept Med, Res Triangle Pk, NC 27709 USA. Duke Univ, Dept Biochem, Res Triangle Pk, NC 27709 USA. RP NIEHS, Off Clin Res, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 36 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD AUG 12 PY 2003 VL 144 IS 1 BP 25 EP 42 DI 10.1016/S0165-3806(03)00155-x PG 18 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 713LH UT WOS:000184859100003 PM 12888215 ER PT J AU Zhou, FC Sari, Y Powrozek, T Goodlett, CR Li, TK AF Zhou, FC Sari, Y Powrozek, T Goodlett, CR Li, TK TI Moderate alcohol exposure compromises neural tube midline development in prenatal brain SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE fetal alcohol syndrome; alcohol-related neurodevelopmental disorder; neural tube defect; microencephaly; midline defect; S100; nestin ID UTERO ETHANOL EXPOSURE; SEROTONERGIC NEURONS; MICE; MOUSE; GROWTH; EMBRYOPATHY; MIGRATION; ANOMALIES; PLATE; CELLS AB We previously reported that fetal alcohol treatment compromised the development of the midline raphe and the serotonin neurons contained in it. In this study, we report that the timely development of midline neural tissue during neural tube formation is sensitive to alcohol exposure. Pregnant dams were treated from embryonic day 7 (E7, prior to neurulation) or E8.5 (at neurulation) with the following diets: (a) alcohol (ALC), given as either a 20% or 25% ethanol-derived calorie (EDC) liquid diet, or (b) isocaloric liquid diet pair-fed (PF), or (c) standard rat chow (Chow). Fetal brains from each group were examined on E13, E15, or E18. Neural tube development was compromised as a result of alcohol exposure in the following ways: (1) approximately 60% of embryos at E13 and 20% at E15 showed perforation of the floor plate in the diencephalic vesicle, (2) although completely closed at E13, 70-80% of embryos failed to complete the formation of neural tissue at the roof as the alcohol exposure continued to E15, and (3) 60-80% of embryos show delayed 'occlusion' of the ventral canal by newly formed nestin-positive neuroepithelial cells and S100beta-positive glia in the brainstem of E15. The compromised (incomplete) neural tube midline (cNTM) occurred near the ventricles at E13 and E15, but was later completed at E18. In all cases, the cNTM was accompanied by an enlarged ventricle, and dose-dependent brain weight reduction. The midline of the neural tube at the roof and floor plates is known to mediate timely trophic induction for neural differentiation. Prenatal midline deficits also have the potential to affect the development of midline neurons such as raphe, septal nuclei, and the timely crossing of commissural fibers. The results of the liquid diet alcohol exposure paradigm suggest it is more a model for Alcohol-Related Neurodevelopmental Disorder (ARND) featuring neuropsychiatric disorders than for full-blown fetal alcohol syndrome (FAS) with noticeable facial dysmorphogenesis and gross brain retardation. (C) 2003 Elsevier B.V. All rights reserved. C1 Indiana Univ, Sch Med, Dept Cell Biol & Anat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Program Med Neurobiol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, IUPUI, Dept Psychol, Indianapolis, IN 46202 USA. NIAAA, Bethesda, MD 20892 USA. RP Zhou, FC (reprint author), Indiana Univ, Sch Med, Dept Cell Biol & Anat, 635 Barnhill Dr, Indianapolis, IN 46202 USA. RI Goodlett, Charles/C-5979-2015 OI Goodlett, Charles/0000-0002-7821-9999 NR 40 TC 31 Z9 33 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD AUG 12 PY 2003 VL 144 IS 1 BP 43 EP 55 DI 10.1016/S0165-3806(03)00158-5 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 713LH UT WOS:000184859100004 ER PT J AU Pinhasov, A Mandel, S Torchinsky, A Giladi, E Pittel, Z Goldsweig, AM Servoss, SJ Brenneman, DE Gozes, I AF Pinhasov, A Mandel, S Torchinsky, A Giladi, E Pittel, Z Goldsweig, AM Servoss, SJ Brenneman, DE Gozes, I TI Activity-dependent neuroprotective protein: a novel gene essential for brain formation SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE activity-dependent neuroprotective protein; vasoactive intestinal peptide; knockout; embryo; neural tube; gene expression ID VASOACTIVE-INTESTINAL-PEPTIDE; NEUROTROPHIC FACTOR; MOUSE; EXPRESSION; MICE; VIP; GROWTH; RESTRICTION; BLOCKADE; DEFECTS AB We have recently cloned the novel homeobox-containing activity-dependent neuroprotective protein (ADNP). In the current study, mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. To assess the function of ADNP, knockout mice were established. Detailed analysis revealed cranial neural tube closure failure and death on E8.5-9.0 of the ADNP-knockout embryos. The expression of Oct4, a gene associated with germ-line maintenance was markedly augmented in the knockout embryos. In contrast, the expression of Pax6. a gene crucial for cerebral cortex formation, was abolished in the brain primordial tissue of the knockout embryos. Thus. Pax6 and Oct4 constitute a part of the mechanism of action of ADNP on brain formation, inhibiting germ-line division while activating morphogenesis. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment. (C) 2003 Elsevier B.V. All rights reserved. C1 Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Sch Med, Dept Embryol & Teratol, IL-69978 Tel Aviv, Israel. NICHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RI Torchinsky, Arkady/E-6479-2010 NR 30 TC 68 Z9 68 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD AUG 12 PY 2003 VL 144 IS 1 BP 83 EP 90 DI 10.1016/S0165-3806(03)00162-7 PG 8 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 713LH UT WOS:000184859100007 ER PT J AU Sun, XM Thrower, D Qiu, JZ Wu, P Zheng, L Zhou, M Bachant, J Wilson, DM Shen, BH AF Sun, XM Thrower, D Qiu, JZ Wu, P Zheng, L Zhou, M Bachant, J Wilson, DM Shen, BH TI Complementary functions of the Saccharomyces cerevisiae Rad2 family nucleases in Okazaki fragment maturation, mutation avoidance, and chromosome stability SO DNA REPAIR LA English DT Article DE c; Rad2; Rad27 nuclease; exonuclease 1; Okazaki fragment maturation ID NUCLEOTIDE EXCISION-REPAIR; STRUCTURE-SPECIFIC ENDONUCLEASE; STRAND DNA-SYNTHESIS; HUMAN EXONUCLEASE-I; RNA PRIMER REMOVAL; MISMATCH REPAIR; FLAP ENDONUCLEASE-1; REPLICATION FORK; PURIFIED PROTEINS; POLYMERASE DELTA AB Rad2 family nucleases, identified by sequence similarity within their catalytic domains, function in multiple pathways of DNA metabolism. Three members of the Saccharomyces cerevisiae Rad2 family, Rad2, Rad27, and exonuclease 1 (Exo1), exhibit both 5' exonuclease and flap endonuclease activities. Deletion of RAD27 results in defective Okazaki fragment maturation, DNA repair, and subsequent defects in mutation avoidance and chromosomal stability. However, strains lacking Rad27 are viable. The expression profile of EXO1 during the cell cycle is similar to that of RAD27 and other genes encoding proteins that function in DNA replication and repair, suggesting Exo1 may function as a back up nuclease for Rad27 in DNA replication. We show that overexpression of EXO1 suppresses multiple rad27 null mutation-associated phenotypes derived from DNA replication defects, including temperature sensitivity, Okazaki fragment accumulation, the rate of minichromosome loss, and an elevated mutation frequency. While generally similar findings were observed with RAD2, overexpression of RAD2, but not EXO1, suppressed the MMS sensitivity of the rad27null mutant cells. This suggests that Rad2 can uniquely complement Rad27 in base excision repair (BER). Furthermore, Rad2 and Exo1 complemented the mutator phenotypes and cell cycle defects of rad27 mutant strains to differing extents, suggesting distinct in vivo nucleic acid substrates. (C) 2003 Elsevier B.V. All rights reserved. C1 City Hope Natl Med Ctr, Div Mol Biol, Duarte, CA 91010 USA. Beckman Res Inst, Duarte, CA 91010 USA. Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. NIA, Gerontol Res Ctr, IRP, Lab Mol Gerontol,NIH, Baltimore, MD 21224 USA. RP Shen, BH (reprint author), City Hope Natl Med Ctr, Div Mol Biol, 1500 E Duarte Rd, Duarte, CA 91010 USA. FU NCI NIH HHS [CA85344] NR 82 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 12 PY 2003 VL 2 IS 8 BP 925 EP 940 DI 10.1016/S1568-7864(03)00093-4 PG 16 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 711XY UT WOS:000184767400008 PM 12893088 ER PT J AU Bara-Jimenez, W Sherzai, A Dimitrova, T Favit, A Bibbiani, F Gillespie, M Morris, MJ Mouradian, MM Chase, TN AF Bara-Jimenez, W Sherzai, A Dimitrova, T Favit, A Bibbiani, F Gillespie, M Morris, MJ Mouradian, MM Chase, TN TI Adenosine A(2A) receptor antagonist treatment of Parkinson's disease SO NEUROLOGY LA English DT Article ID MPTP-TREATED MONKEYS; A(2A) RECEPTORS; SYNAPTIC TRANSMISSION; MOTOR COMPLICATIONS; L-DOPA; KW-6002; PHOSPHORYLATION; DYSKINESIAS; BLOCKADE; STRIATUM AB Background: Observations in animal models suggest that A(2A) antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A(2A) receptor mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A(2A) antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design ( 40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient's optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone ( p < 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p < 0.05). No medically important drug toxicity occurred. Conclusions: The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 23 TC 231 Z9 236 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 12 PY 2003 VL 61 IS 3 BP 293 EP 296 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 710ZL UT WOS:000184712600004 PM 12913186 ER PT J AU Dame, JB Yowell, CA Omara-Opyene, L Carlton, JM Cooper, RA Li, T AF Dame, JB Yowell, CA Omara-Opyene, L Carlton, JM Cooper, RA Li, T TI Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; malaria; plasmepsin; aspartic proteinase; food vacuole; ortholog; paralog; multigene family ID HUMAN MALARIA PARASITE; FALCIPARUM DIGESTIVE VACUOLE; 2-DIMENSIONAL ELECTROPHORESIS; HEMOGLOBIN DEGRADATION; GENOME SEQUENCE; IN-VITRO; IDENTIFICATION; INHIBITORS; PROTEASES; MODEL AB Plasmepsins are aspartic proteinases of the malaria parasite, and seven groups of plasmepsins have been identified by comparing genomic sequence data available for the genes encoding these enzymes from Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium berghei, and Plasmodium yoelii. The food vacuole plasmepsins typified by plasmepsin 4 from P. falciparum (PfPM4) constitute one of these groups. Genes encoding the ortholog of PfPM4 have been cloned from Plasmodium ovale, Plasmodium malariae, and P. falciparum contains three paralagous food vacuole plasmepsins or plasmepsin-like enzymes that appear to have arisen vivax. In addition, P. by gene duplication, plasmepsins I (PfPM1), 2 (PfPM2) and HAP, and all four were localized to purified food vacuole preparations by two-dimensional gel electrophoresis and mass spectroscopic analysis. The three paralogs of PfPM4 do not have counterparts in the six other Plasmodium spp. examined by genomic DNA blot analysis and by review of available genomic sequence data. The presence of these paralogs among the food vacuole plasmepsins in P. falciparum as compared with the other three species causing malaria in man will impact efforts to rationally design antimalarials targeting the food vacuole plasmepsins. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32611 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Dame, JB (reprint author), Univ Florida, Coll Vet Med, Dept Pathobiol, Box 110880, Gainesville, FL 32611 USA. FU NIAID NIH HHS [R01 AI39211] NR 46 TC 59 Z9 59 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD AUG 11 PY 2003 VL 130 IS 1 BP 1 EP 12 DI 10.1016/S0166-6851(03)00137-3 PG 12 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 719VC UT WOS:000185224900001 PM 14550891 ER PT J AU Engels, EA Gravitt, PE Daniel, RW Quezado, M Shah, KV AF Engels, EA Gravitt, PE Daniel, RW Quezado, M Shah, KV TI Re: Absence of simian virus 40 in human brain tumors from northern india; response to letter from Carbone et al. SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID SV40; QUANTIFICATION; DNA C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NCI, Dept Pathol, Rockville, MD USA. RP Engels, EA (reprint author), Viral Epidemiol Branch, 6120 Execut Blvd,EPS 8010, Rockville, MD 20852 USA. NR 8 TC 2 Z9 2 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 10 PY 2003 VL 106 IS 1 BP 143 EP 145 DI 10.1002/ijc.11192 PG 3 WC Oncology SC Oncology GA 693NP UT WOS:000183723900022 ER PT J AU Li, P Zhang, MC Peach, ML Zhang, XD Liu, HP Nicklaus, M Yang, DJ Roller, PP AF Li, P Zhang, MC Peach, ML Zhang, XD Liu, HP Nicklaus, M Yang, DJ Roller, PP TI Structural basis for a non-phosphorus-containing cyclic peptide binding to Grb2-SH2 domain with high affinity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Grb2; SH2 domains; cyclic peptides; Grb2-SH2 antagonists; phosphotyrosine; tyrosine kinase ID STRUCTURE-BASED DESIGN; SIGNAL-TRANSDUCTION; NONPHOSPHORYLATED INHIBITOR; ABSOLUTE-CONFIGURATION; SH2 DOMAINS; SPARSOMYCIN; SRC AB Blocking the interaction between phosphotyrosine (pTyr) -containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor bound protein 2 (Grb2) is considered to be an effective and non-cytotoxic strategy to develop new antiproliferative agents due to its potential to shut down the Ras activation pathway. Generally, the pTyr-X-Asn minimal binding motif is required for a high-affinity ligand binding to the Grb2-SH2 domain. Using phage-display techniques, we discovered a non-pTyr-containing cyclic peptide G1 with moderate binding affinity from 10(7) different sequences. To understand the structural basis for the high-affinity binding of these novel non-phosphorus-containing inhibitors to the Grb2-SH2 domain, we extensively studied herein the unique functional requirements of the acidic side chain in Tyr-2 position due to the absence of the phosphate group in these nonphosphorylated peptides. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low nanomolar range binding affinity, such as cyclic peptide 20 with an IC50 = 0.026 muM, which is one of the most potent non-phosphorus-containing Grb2-SH2 antagonists reported to date. Whole cell assays indicate that peptide 20 can penetrate the cell membranes and inhibit the association of Grb2 with p185(erbB2) in erbB2-overexpressing MDA-MA-453 cancer cells at low micromolar concentrations. Published by Elsevier Inc. C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. RP Roller, PP (reprint author), NCI, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. OI Nicklaus, Marc/0000-0002-4775-7030 NR 24 TC 15 Z9 16 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 8 PY 2003 VL 307 IS 4 BP 1038 EP 1044 DI 10.1016/S0006-291X(03)01291-9 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 707KP UT WOS:000184510100043 PM 12878216 ER PT J AU DePamphilis, ML AF DePamphilis, ML TI Eukaryotic DNA replication origins: Reconciling disparate data SO CELL LA English DT Editorial Material ID ORC-BINDING; COMPLEX; CELLS AB In this issue of Cell, Anglana and coworkers provide new insight into the nature of mammalian replication origins that helps to reconcile the divergent views that emerged over the past decade. Taken together with other studies, we can see how replication origins have evolved in response to the demands of animal development. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6,Room 416,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 9 TC 21 Z9 22 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 8 PY 2003 VL 114 IS 3 BP 274 EP 275 DI 10.1016/S0092-8674(03)00604-4 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 710KK UT WOS:000184679200003 PM 12914691 ER PT J AU Celeste, A Difilippantonio, S Difilippantonio, MJ Fernandez-Capetillo, O Pilch, DR Sedelnikova, OA Eckhaus, M Ried, T Bonner, WM Nussenzweig, A AF Celeste, A Difilippantonio, S Difilippantonio, MJ Fernandez-Capetillo, O Pilch, DR Sedelnikova, OA Eckhaus, M Ried, T Bonner, WM Nussenzweig, A TI H2AX haploinsufficiency modifies genomic stability and tumor susceptibility SO CELL LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE CHECKPOINT; V(D)J RECOMBINATION; HISTONE H2AX; GENE AMPLIFICATION; SACCHAROMYCES-CEREVISIAE; CHROMOSOMAL-ABERRATIONS; HAPLO-INSUFFICIENCY; VERTEBRATE CELLS; MICE AB Histone H2AX becomes phosphorylated in chromatin domains flanking sites of DNA double-strand breakage associated with gamma-irradiation, meiotic recombination, DNA replication, and antigen receptor rearrangements. Here, we show that loss of a single H2AX allele compromises genomic integrity and enhances the susceptibility to cancer in the absence of p53. In comparison with heterozygotes, tumors arise earlier in the H2AX homozygous null background, and H2AX(-/-) p53(-/-) lymphomas harbor an increased frequency of clonal nonreciprocal translocations and amplifications. These include complex rearrangements that juxtapose the c-myc oncogene to antigen receptor loci. Restoration of the H2AX null allele with wild-type H2AX restores genomic stability and radiation resistance, but this effect is abolished by substitution of the conserved serine phosphorylation sites in H2AX with alanine or glutamic acid residues. Our results establish H2AX as genomic caretaker that requires the function of both gene alleles for optimal protection against tumorigenesis. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RI Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 FU Intramural NIH HHS [Z99 CA999999] NR 63 TC 383 Z9 401 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 8 PY 2003 VL 114 IS 3 BP 371 EP 383 DI 10.1016/S0092-8674(03)00567-1 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 710KK UT WOS:000184679200013 PM 12914701 ER PT J AU Kaminski, RM Gasior, M Carter, RB Witkin, JM AF Kaminski, RM Gasior, M Carter, RB Witkin, JM TI Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE neuroactive steroid; cocaine kindling; sensitization; (mouse) ID ANTIEPILEPTIC DRUGS; NEUROSTEROIDS; ANTICONVULSANT; MECHANISMS; GANAXOLONE; DIAZEPAM; PENTYLENETETRAZOL; RECEPTORS; BRAIN; DISORDERS AB Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABAA modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse. (C) 2003 Elsevier B.V. All rights reserved. C1 NIDA, Addict Res Ctr, Drug Dev Grp, Baltimore, MD 21224 USA. CoCensys Inc, Irvine, CA 92618 USA. RP Kaminski, RM (reprint author), NINDS, Epilepsy Res Sect, NIH, 49 Convent Dr,MSC 4457,Bldg 49 Rm 5A75, Bethesda, MD 20892 USA. NR 42 TC 33 Z9 33 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 AUG 8 PY 2003 VL 474 IS 2-3 BP 217 EP 222 DI 10.1016/S0014-2999(03)02086-7 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 714DA UT WOS:000184896000012 PM 12921865 ER PT J AU Sanzone, S Zeyda, M Saemann, MD Soncini, M Holter, W Fritsch, G Knapp, W Candotti, F Stulnig, TM Parolini, O AF Sanzone, S Zeyda, M Saemann, MD Soncini, M Holter, W Fritsch, G Knapp, W Candotti, F Stulnig, TM Parolini, O TI SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NATURAL-KILLER-CELLS; GENE-PRODUCT SAP; ACTIN CYTOSKELETON; RECEPTOR; LAT; VIRUS; ADAPTER; TCR; VAV; MOLECULE AB Deficiency of SAP ( SLAM ( signaling lymphocyte activation molecule)-associated protein) protein is associated with a severe immunodeficiency, the X-linked lymphoproliferative disease ( XLP) characterized by an inappropriate immune reaction against Epstein-Barr virus infection often resulting in a fatal clinical course. Several studies demonstrated altered NK and T cell function in XLP patients; however, the mechanisms underlying XLP disease are still largely unknown. Here, we show that non-transformed T cell lines obtained from XLP patients were defective in several activation events such as IL-2 production, CD25 expression, and homotypic cell aggregation when cells were stimulated via T cell antigen receptor (TCR).CD3 but not when early TCR-dependent events were bypassed by stimulation with phorbol 12-myristate 13-acetate/ionomycin. Analysis of proximal T cell signaling revealed imbalanced TCR . CD3-induced signaling in SAP-deficient T cells. Although phospholipase Cgamma1 phosphorylation and calcium response were both enhanced in T cells from XLP patients, phosphorylation of VAV and downstream signal transduction events such as mitogen-activated protein kinase phosphorylation and IL-2 production were diminished. Importantly, reconstitution of SAP expression by retroviral-mediated gene transfer completely restored abnormal signaling events in T cell lines derived from XLP patients. In conclusion, SAP mutation or deletion in XLP patients causes profound defects in T cell activation, resulting in immune deficiency. Moreover, these data provide evidence that SAP functions as an essential integrator in early TCR signal transduction. C1 Osped Poliambulanza, Ctr Ric Parco Sci E Menni, I-25124 Brescia, Italy. Lab Interdisciplinare Tecnol Avanzate, Dipartimento Sci & Tecnol Biomed, I-20090 Milan, Italy. Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, A-1090 Vienna, Austria. Univ Vienna, Inst Immunol, A-1090 Vienna, Austria. Childrens Canc Res Inst, A-1090 Vienna, Austria. NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Austrian Acad Sci, Ctr Mol Med, A-1090 Vienna, Austria. RP Parolini, O (reprint author), Osped Poliambulanza, Ctr Ric Parco Sci E Menni, Via Romiglia 4, I-25124 Brescia, Italy. OI Parolini, Ornella/0000-0002-5211-6430; Stulnig, Thomas/0000-0003-3300-6161; Zeyda, Maximilian/0000-0001-5000-1974 NR 52 TC 18 Z9 19 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 AUG 8 PY 2003 VL 278 IS 32 BP 29593 EP 29599 DI 10.1074/jbc.M300565200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707JF UT WOS:000184507000027 PM 12766168 ER PT J AU Prasad, R Bebenek, K Hou, E Shock, DD Beard, WA Woodgate, R Kunkel, TA Wilson, SH AF Prasad, R Bebenek, K Hou, E Shock, DD Beard, WA Woodgate, R Kunkel, TA Wilson, SH TI Localization of the deoxyribose phosphate lyase active site in human DNA polymerase iota by controlled proteolysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; ESCHERICHIA-COLI; XERODERMA-PIGMENTOSUM; MOUSE HOMOLOGS; GENE ENCODES; IN-VITRO; BETA; MUTAGENESIS; ETA; REPLICATION AB Human DNA polymerase iota (pol iota) is a member of the Y-family of low fidelity lesion bypass DNA polymerases. In addition to a probable role in DNA lesion bypass, this enzyme has recently been shown to be required for somatic hypermutation in human B-cells. We found earlier that human pol iota has deoxyribose phosphate (dRP) lyase activity and unusual specificity for activity during DNA synthesis, suggesting involvement in specialized forms of base excision repair (BER). Here, mapping of the domain structure of human pol iota by controlled proteolysis revealed that the enzyme has a 48-kDa NH2-terminal domain and a protease resistant 40-kDa "core domain" spanning residues Met(79) to similar toMet(445). A covalently crosslinked pol iota-DNA complex, representing a trapped intermediate in the dRP lyase reaction, was subjected to controlled proteolysis. Cross-linking was mapped to the 40-kDa core domain, indicating that the dRP lyase active site is in this region. To further evaluate the BER capacity of the enzyme, the dRP lyase and DNA polymerase activities were characterized on DNA substrates representing BER intermediates, and we found that pol iota was able to complement the in vitro single-nucleotide BER deficiency of a DNA polymerase beta null cell extract. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Wilson, SH (reprint author), 111 TW Alexander Dr,POB 12233,MD B2-06, Res Triangle Pk, NC 27709 USA. NR 35 TC 39 Z9 41 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 AUG 8 PY 2003 VL 278 IS 32 BP 29649 EP 29654 DI 10.1074/jbc.M305399200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707JF UT WOS:000184507000034 PM 12777390 ER PT J AU Yu, CR Mahdi, RM Ebong, S Vistica, BP Gery, I Egwuagu, CE AF Yu, CR Mahdi, RM Ebong, S Vistica, BP Gery, I Egwuagu, CE TI Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LYMPHOCYTE-PROLIFERATION; NEGATIVE REGULATION; LINEAGE COMMITMENT; IMMUNE-SYSTEM; INTERLEUKIN-2; DIFFERENTIATION; EXPRESSION; RECEPTOR; PROTEIN; SOCS AB Suppressors of cytokine signaling (SOCS) have been implicated in regulation of T-cell activation and cytokine-mediated differentiation of T-helper cells. In this study we have characterized the pattern of SOCS expression in naive and activated primary T-helper cells, examined whether expression of SOCS genes is regulated by cytokine or T-cell receptor signaling, and analyzed the function of SOCS in differentiated T-cells. We show that SOCS1, SOCS2, SOCS3, CIS ((c) under bar ytokine-(i) under bar nduced (S) under bar H2 protein) genes are constitutively expressed in naive T-helper cells, with SOCS3 being the most abundant. Antigen stimulation of naive T-helper cells down-regulates SOCS3 expression and concomitantly up-regulates SOCS1, SOCS2, and CIS gene transcription, suggesting that SOCS genes are regulated differentially by T-cell activation. Down-regulation of SOCS3 expression is subsequently followed by gradual increase in SOCS3 level and corresponding decline in interleukin 2 (IL-2) secretion. In fact, SOCS3 mRNA levels are inversely correlated with the amount of IL-2 secretion and proliferative responses of differentiating T-helper cells, suggesting mutually antagonistic effects of SOCS3 and IL-2 and feedback regulation of T-cell activation by SOCS3. Furthermore, the degree of SOCS3 inhibition is antigen concentration-dependent and is mediated in part by growth factor independence-1, a T-cell transcription factor that regulates S-phase entry in T-cells. Forced overexpression of SOCS3 inhibits proliferation of T-helper cells, whereas depletion of endogenous SOCS3 by antisense SOCS3 cDNA enhances T-cell receptor- and cytokine-induced proliferation. Taken together, these results suggest a role for SOCS3 in maintaining T-helper cells in a quiescent state. Transient inhibition of SOCS3 by antigen stimulation may therefore be essential in allowing activation of resting T-cells. C1 NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Rm 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. NR 34 TC 72 Z9 79 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 AUG 8 PY 2003 VL 278 IS 32 BP 29752 EP 29759 DI 10.1074/jbc.M300489200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707JF UT WOS:000184507000046 PM 12783879 ER PT J AU Schmidt, C Li, B Bloodworth, L Erlenbach, I Zeng, FY Wess, J AF Schmidt, C Li, B Bloodworth, L Erlenbach, I Zeng, FY Wess, J TI Random mutagenesis of the M-3 muscarinic acetylcholine receptor expressed in yeast - Identification of point mutations that "silence" a constitutively active mutant M-3 receptor and greatly impair receptor/G protein coupling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHEROMONE RESPONSE PATHWAY; ALPHA-FACTOR RECEPTOR; 3RD CYTOPLASMIC LOOP; TRANSMEMBRANE SEGMENTS; 7-TRANSMEMBRANE RECEPTORS; LIGAND-BINDING; C5A RECEPTOR; ACTIVATION; RHODOPSIN; MECHANISMS AB The M-3 muscarinic receptor is a prototypical member of the class I family of G protein-coupled receptors (GPCRs). To facilitate studies on the structural mechanisms governing M-3 receptor activation, we generated an M-3 receptor-expressing yeast strain (Saccharomyces cerevisiae) that requires agonist-dependent M-3 receptor activation for cell growth. By using receptor random mutagenesis followed by a genetic screen in yeast, we initially identified a point mutation at the cytoplasmic end of transmembrane domain (TM) VI (Q490L) that led to robust agonist-independent M-3 receptor signaling in both yeast and mammalian cells. To explore further the molecular mechanisms by which point mutations can render GPCRs constitutively active, we subjected a region of the Q490L mutant M-3 receptor that included TM V-VII to random mutagenesis. We then applied a yeast genetic screen to identify second-site mutations that could suppress the activating effects of the Q490L mutation and restore wild-type receptor-like function to the Q490L mutant receptor. This analysis led to the identification of 12 point mutations that allowed the Q490L mutant receptor to function in a fashion similar to the wild-type receptor. These amino acid substitutions mapped to two distinct regions of the M-3 receptor, the exofacial segments of TM V and VI and the cytoplasmic ends of TM V-VII. Strikingly, in the absence of the activating Q490L mutation, all recovered point mutations severely reduced the efficiency of receptor/G protein coupling, indicating that the targeted residues play important roles in receptor activation and/or receptor/G protein coupling. This strategy should be generally applicable to identify sites in GPCRs that are critically involved in receptor function. C1 NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-05,Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 55 TC 40 Z9 40 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 8 PY 2003 VL 278 IS 32 BP 30248 EP 30260 DI 10.1074/jbc.M304991200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707JF UT WOS:000184507000105 PM 12750375 ER PT J AU Solomon, DA Wang, Y Fox Sr Lambeck, TC Giesting, S Lan, Z Senderowicz, AM Knudsen, ES AF Solomon, DA Wang, Y Fox, SR Lambeck, TC Giesting, S Lan, Z Senderowicz, AM Knudsen, ES TI Cyclin D1 splice variants - Differential effects on localization, RB phosphorylation, and cellular transformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; D-DEPENDENT KINASE; RETINOBLASTOMA-PROTEIN; PRB PHOSPHORYLATION; CDK COMPLEXES; HUMAN CANCER; CELLS; POLYMORPHISM; INHIBITION; EXPRESSION AB Cyclin D1 is a proto-oncogene that functions by inactivation of the retinoblastoma tumor suppressor protein, RB. A common polymorphism in the cyclin D1 gene is associated with the production of an alternate transcript of cyclin D1, termed cyclin D1b. Both the polymorphism and the variant transcript are associated with increased risk for multiple cancers and the severity of a given cancer; however, the underlying activities of cyclin D1b have not been elucidated relative to the canonical cyclin D1a. Because cyclin D1b does not possess the threonine 286 phosphorylation site required for nuclear export and regulated degradation, it has been hypothesized to encode a stable nuclear protein that would constitutively inactivate the RB pathway. Surprisingly, we find that cyclin D1b protein does not inappropriately accumulate in cells and exhibits stability comparable to cyclin D1a. As expected, the cyclin D1b protein was constitutively localized in the nucleus, whereas cyclin D1a was exported to the cytoplasm in S-phase. Despite enhanced nuclear localization, we find that cyclin D1b is a poor catalyst of RB phosphorylation/inactivation. However, cyclin D1b potently induced cellular transformation in contrast to cyclin D1a. In summary, we demonstrate that cyclin D1b specifically disrupts contact inhibition in a manner distinct from cyclin D1a. These data reveal novel roles for D-type cyclins in tumorigenesis. C1 Univ Cincinnati, Dept Cell Biol, Vontz Ctr Mol Studies, Cincinnati, OH 45267 USA. NIDCR, NIH, Bethesda, MD 20892 USA. RP Knudsen, ES (reprint author), Univ Cincinnati, Dept Cell Biol, Vontz Ctr Mol Studies, 3125 Eden Ave, Cincinnati, OH 45267 USA. EM erik.knudsen@uc.edu FU NCI NIH HHS [R01-CA82525]; NIEHS NIH HHS [UO1-ES011038] NR 64 TC 157 Z9 162 U1 1 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 AUG 8 PY 2003 VL 278 IS 32 BP 30339 EP 30347 DI 10.1074/jbc.M303969200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707JF UT WOS:000184507000114 PM 12746453 ER PT J AU Larralde, H Weiss, GH AF Larralde, H Weiss, GH TI Expected number of distinct sites visited by N random walks in the presence of an absorbing boundary SO JOURNAL OF PHYSICS A-MATHEMATICAL AND GENERAL LA English DT Article ID PHOTON MIGRATION; MEDIA; MODEL AB In earlier work we have studied the expected number of distinct sites. (ENDS) visited by N random walkers in time t on a translationally invariant lattice. Optical applications suggest the interest in analysing the same problem for a semi-infinite lattice in three dimensions bounded by a plane of absorbing sites. We here study this problem, showing a multiplicity of time regimes, and at the longest times showing that the ENDS is proportional to Nroott where t is the time. In the absence of a boundary the comparable result is proportional to Nt. Thus, the boundary effect eliminates approximately roott random walks. C1 Univ Nacl Autonoma Mexico, Ctr Ciencias Fis, Cuernavaca 62210, Morelos, Mexico. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Larralde, H (reprint author), Univ Nacl Autonoma Mexico, Ctr Ciencias Fis, Av Univ S-N Col, Cuernavaca 62210, Morelos, Mexico. NR 14 TC 2 Z9 2 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0305-4470 J9 J PHYS A-MATH GEN JI J. Phys. A-Math. Gen. PD AUG 8 PY 2003 VL 36 IS 31 BP 8367 EP 8372 AR PII S0305-4470(03)62694-6 DI 10.1088/0305-4470/36/31/302 PG 6 WC Physics, Multidisciplinary; Physics, Mathematical SC Physics GA 715GF UT WOS:000184962200002 ER PT J AU Grewal, SIS Moazed, D AF Grewal, SIS Moazed, D TI Heterochromatin and epigenetic control of gene expression SO SCIENCE LA English DT Review ID H3 LYSINE-9 METHYLATION; HISTONE METHYLTRANSFERASE ACTIVITY; X-CHROMOSOME INACTIVATION; FISSION YEAST; DNA METHYLATION; RNA INTERFERENCE; DROSOPHILA; CHROMATIN; BINDING; COMPLEX AB Eukaryotic DNA is organized into structurally distinct domains that regulate gene expression and chromosome behavior. Epigenetically heritable domains of heterochromatin control the structure and expression of large chromosome domains and are required for proper chromosome segregation. Recent studies have identified many of the enzymes and structural proteins that work together to assemble heterochromatin. The assembly process appears to occur in a stepwise manner involving sequential rounds of histone modi. cation by silencing complexes that spread along the chromatin fiber by self-oligomerization, as well as by association with specifically modified histone amino-terminal tails. Finally, an unexpected role for noncoding RNAs and RNA interference in the formation of epigenetic chromatin domains has been uncovered. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 65 TC 621 Z9 654 U1 3 U2 56 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 AUG 8 PY 2003 VL 301 IS 5634 BP 798 EP 802 DI 10.1126/science.1086887 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709FT UT WOS:000184615700033 PM 12907790 ER PT J AU Sullivan, NJ Geisbert, TW Geisbert, JB Xu, L Yang, ZY Roederer, M Koup, RA Jahrling, PB Nabel, GJ AF Sullivan, NJ Geisbert, TW Geisbert, JB Xu, L Yang, ZY Roederer, M Koup, RA Jahrling, PB Nabel, GJ TI Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates SO NATURE LA English DT Article ID PASSIVE TRANSFER; INFECTION; GLYCOPROTEINS; CYTOTOXICITY; INJURY; GENE AB Containment of highly lethal Ebola virus outbreaks poses a serious public health challenge. Although an experimental vaccine has successfully protected non-human primates against disease(1), more than six months was required to complete the immunizations, making it impractical to limit an acute epidemic. Here, we report the development of accelerated vaccination against Ebola virus in non-human primates. The antibody response to immunization with an adenoviral (ADV) vector encoding the Ebola glycoprotein (GP) was induced more rapidly than with DNA priming and ADV boosting, but it was of lower magnitude. To determine whether this earlier immune response could nonetheless protect against disease, cynomolgus macaques were challenged with Ebola virus after vaccination with ADV-GP and nucleoprotein (NP) vectors. Protection was highly effective and correlated with the generation of Ebola-specific CD8(+) T-cell and antibody responses. Even when animals were immunized once with ADV-GP/NP and challenged 28 days later, they remained resistant to challenge with either low or high doses of virus. This accelerated vaccine provides an intervention that may help to limit the epidemic spread of Ebola, and is applicable to other viruses. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 17 TC 301 Z9 315 U1 3 U2 78 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 7 PY 2003 VL 424 IS 6949 BP 681 EP 684 DI 10.1038/nature01876 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 708QE UT WOS:000184578800047 PM 12904795 ER PT J AU Manson, JE Hsia, J Johnson, KC Rossouw, JE Assaf, AR Lasser, NL Trevisan, M Black, HR Heckbert, SR Detrano, R Strickland, OL Wong, ND Crouse, JR Stein, E Cushman, M Alving, B Rossouw, JE Pottern, L Ludlam, S McGowan, JA Prentice, R Anderson, G LaCroix, A Patterson, R McTiernan, A Cochrane, B Hunt, J Tinker, L Kooperberg, C McIntosh, M Wang, CY Chen, C Bowen, D Kristal, A Stanford, J Urban, N Weiss, N White, E Shumaker, S Rautaharju, P Prineas, R Naughton, M Stein, E Laskarzewski, P Cummings, S Nevitt, M Dockrell, M Harnack, L Cammarata, F Lindenfelser, S Psaty, B Heckbert, S Wassertheil-Smoller, S Frishman, W Wylie-Rosett, J Barad, D Freeman, R Hays, J Young, R Anderson, J Lithgow, S Bray, P Manson, J Buring, J Gaziano, JM Rexrode, K Chae, C Assaf, AR Carleton, R Wheeler, C Eaton, C Cyr, M Phillips, L Pedersen, M Strickland, O Huber, M Porter, V Beresford, SAA Taylor, VM Woods, NF Henderson, M Kestin, M Hsia, J Gaba, N Ascensao, J Laowattana, S Chlebowski, R Detrano, R Nelson, A Heiner, J Marshall, J Ritenbaugh, C Valanis, B Elmer, P Stevens, V Karanja, N Caan, B Sidney, S Bailey, G Hirata, J Kotchen, JM Barnabei, V Kotchen, TA Gilligan, MAC Neuner, J Howard, BV Adams-Campbell, L Passaro, M Rainford, M Agurs-Collins, T Van Horn, L Greenland, P Khandekar, J Liu, K Rosenberg, C Black, H Powell, L Mason, E Stefanick, ML Hlatky, MA Chen, B Stafford, RS Giudice, LC Lane, D Granek, I Lawson, W San Roman, G Messina, C Jackson, R Harris, R Frid, D Mysiw, WJ Blumenfeld, M Lewis, CE Oberman, A Fouad, MN Shikany, JM West, DS Bassford, T Mattox, J Ko, M Lohman, T Trevisan, M Wactawski-Wende, J Graham, S Chang, J Smit, E Robbins, J Yasmeen, S Lindfors, K Stern, J Hubbell, A Frank, G Wong, N Greep, N MoOnk, B Judd, H Heber, D Elashoff, R Langer, RD Criqui, MH Talavera, GT Garland, CF Hanson, RE Gass, M Wernke, S Watts, N Limacher, M Perri, M Kaunitz, A Williams, RS Brinson, Y Curb, D Petrovitch, H Rodriguez, B Masaki, K Sharma, S Wallace, R Torner, J Johnson, S Snetselaar, L VanVoorhis, B Ockene, I Yood, R Aronson, P Lasser, N Hymowitz, N Lasser, V Safford, M Kostis, J O'Sullivan, MJ Parker, L Estape, R Fernandez, D Margolis, KL Grimm, RH Hunninghake, DB LaValleur, J Hall, KM Brunner, R St Jeor, S Graettinger, W Oujevolk, V Heiss, G Haines, P Ontjes, D Sueta, C Wells, E Kuller, L Caggiula, A Cauley, J Berga, S Milas, NC Johnson, KC Satterfield, S Ke, TW Vile, J Tylavsky, F Brzyski, R Schenken, R Trabal, J Rodriguez-Sifuentes, M Mouton, C Allen, C Laube, D McBride, P Mares-Perlman, J Loevinger, B Burke, G Crouse, R Parsons, L Vitolins, M Hendrix, S Simon, M McNeeley, G Gordon, P Makela, P AF Manson, JE Hsia, J Johnson, KC Rossouw, JE Assaf, AR Lasser, NL Trevisan, M Black, HR Heckbert, SR Detrano, R Strickland, OL Wong, ND Crouse, JR Stein, E Cushman, M Alving, B Rossouw, JE Pottern, L Ludlam, S McGowan, JA Prentice, R Anderson, G LaCroix, A Patterson, R McTiernan, A Cochrane, B Hunt, J Tinker, L Kooperberg, C McIntosh, M Wang, CY Chen, C Bowen, D Kristal, A Stanford, J Urban, N Weiss, N White, E Shumaker, S Rautaharju, P Prineas, R Naughton, M Stein, E Laskarzewski, P Cummings, S Nevitt, M Dockrell, M Harnack, L Cammarata, F Lindenfelser, S Psaty, B Heckbert, S Wassertheil-Smoller, S Frishman, W Wylie-Rosett, J Barad, D Freeman, R Hays, J Young, R Anderson, J Lithgow, S Bray, P Manson, J Buring, J Gaziano, JM Rexrode, K Chae, C Assaf, AR Carleton, R Wheeler, C Eaton, C Cyr, M Phillips, L Pedersen, M Strickland, O Huber, M Porter, V Beresford, SAA Taylor, VM Woods, NF Henderson, M Kestin, M Hsia, J Gaba, N Ascensao, J Laowattana, S Chlebowski, R Detrano, R Nelson, A Heiner, J Marshall, J Ritenbaugh, C Valanis, B Elmer, P Stevens, V Karanja, N Caan, B Sidney, S Bailey, G Hirata, J Kotchen, JM Barnabei, V Kotchen, TA Gilligan, MAC Neuner, J Howard, BV Adams-Campbell, L Passaro, M Rainford, M Agurs-Collins, T Van Horn, L Greenland, P Khandekar, J Liu, K Rosenberg, C Black, H Powell, L Mason, E Stefanick, ML Hlatky, MA Chen, B Stafford, RS Giudice, LC Lane, D Granek, I Lawson, W San Roman, G Messina, C Jackson, R Harris, R Frid, D Mysiw, WJ Blumenfeld, M Lewis, CE Oberman, A Fouad, MN Shikany, JM West, DS Bassford, T Mattox, J Ko, M Lohman, T Trevisan, M Wactawski-Wende, J Graham, S Chang, J Smit, E Robbins, J Yasmeen, S Lindfors, K Stern, J Hubbell, A Frank, G Wong, N Greep, N MoOnk, B Judd, H Heber, D Elashoff, R Langer, RD Criqui, MH Talavera, GT Garland, CF Hanson, RE Gass, M Wernke, S Watts, N Limacher, M Perri, M Kaunitz, A Williams, RS Brinson, Y Curb, D Petrovitch, H Rodriguez, B Masaki, K Sharma, S Wallace, R Torner, J Johnson, S Snetselaar, L VanVoorhis, B Ockene, I Yood, R Aronson, P Lasser, N Hymowitz, N Lasser, V Safford, M Kostis, J O'Sullivan, MJ Parker, L Estape, R Fernandez, D Margolis, KL Grimm, RH Hunninghake, DB LaValleur, J Hall, KM Brunner, R St Jeor, S Graettinger, W Oujevolk, V Heiss, G Haines, P Ontjes, D Sueta, C Wells, E Kuller, L Caggiula, A Cauley, J Berga, S Milas, NC Johnson, KC Satterfield, S Ke, TW Vile, J Tylavsky, F Brzyski, R Schenken, R Trabal, J Rodriguez-Sifuentes, M Mouton, C Allen, C Laube, D McBride, P Mares-Perlman, J Loevinger, B Burke, G Crouse, R Parsons, L Vitolins, M Hendrix, S Simon, M McNeeley, G Gordon, P Makela, P CA Women's Hlth Initiative Investigat TI Estrogen plus progestin and the risk of coronary heart disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HORMONE-REPLACEMENT THERAPY; ESTROGEN/PROGESTIN INTERVENTIONS PEPI; RANDOMIZED CONTROLLED TRIAL; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; CLINICAL-TRIAL; ATHEROSCLEROSIS; PREVENTION; INFLAMMATION; PROGRESSION AB BACKGROUND: Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI). METHODS: The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD). RESULTS: After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD. CONCLUSIONS: Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease. C1 Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. George Washington Univ, Dept Med, Washington, DC USA. Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. NHLBI, Program Off, Bethesda, MD 20892 USA. Brown Univ, Mem Hosp, Sch Med, Pawtucket, RI USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Prevent Cardiol Program, Newark, NJ 07103 USA. Univ Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. Rush Presbyterian St Lukes Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Calif Los Angeles, Div Cardiol, Harbor Res & Educ Inst, Torrance, CA USA. Emory Univ, Woodruff Sch Nursing, Atlanta, GA 30322 USA. Univ Calif Irvine, Heart Dis Prevent Program, Irvine, CA 92717 USA. Wake Forest Univ, Dept Med, Winston Salem, NC 27109 USA. Med Res Labs Int, Highland Hts, KY USA. Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Manson, JE (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02215 USA. RI Kristal, Alan/A-8779-2008; Mysiw, Walter/E-3724-2011; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 34 TC 1183 Z9 1225 U1 5 U2 44 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 AUG 7 PY 2003 VL 349 IS 6 BP 523 EP 534 DI 10.1056/NEJMoa030808 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 708JL UT WOS:000184563500003 PM 12904517 ER PT J AU Tkach, V Tulchinsky, E Lukanidin, E Vinson, C Bock, E Berezin, V AF Tkach, V Tulchinsky, E Lukanidin, E Vinson, C Bock, E Berezin, V TI Role of the Fos family members, c-Fos, Fra-1 and Fra-2, in the regulation of cell motility SO ONCOGENE LA English DT Article DE c-Fos; Fra-1; Fra-2; cell locomotion ID TRANSCRIPTION FACTOR AP-1; DNA-BINDING; TRANSFORMATION; ACTIVATION; JUN; DIFFERENTIATION; MIGRATION; INTERACTS; INVASION; PROTEINS AB The AP-1 transcription factor is composed of members of the Fos, Jun and ATF families, and plays a key role in tumor progression. We investigated whether Fos proteins regulate cell motility, and if so, whether this capacity is related to their transactivation potential. Two cell tines with different expression profiles of AP-1 were employed focusing on the Fos-family members c-Fos, Fra-1 and Fra-2. Transactivation motifs are found in c-Fos, but not in Fra-1 or Fra-2. The adenocarcinoma CSML0 cells display a low motility and do not express Fra-1 or Fra-2, and only very little c-Fos. In contrast, the fibroblastoid L929 cells express both Fra-1 and Fra-2, but no c-Fos, and these cells display a high motility. Transfection with Fra-1 or c-Fos, but not with Fra-2, strongly enhanced the motility of CSML0 cells. The effect of Fra-1 required the presence of the N-terminal domain of this protein. Conversely, transfection with a Fos dominant-negative mutant or with anti-sense fra-1 or fra-2, strongly reduced the motility of L929 cells. Changes in cell motility correlated with the morphological appearance and the degree of contact with the substratum. We conclude that Fos proteins have distinct roles in the regulation of cell motility. C1 Univ Copenhagen, Panum Inst, Prot Lab,Inst Mol Pathol, Sch Med, DK-2200 Copenhagen N, Denmark. Danish Canc Soc, Dept Mol Cell Biol, Inst Canc Biol, DK-2100 Copenhagen, Denmark. NCI, Met Lab, NIH, Bethesda, MD 20892 USA. RP Berezin, V (reprint author), Univ Copenhagen, Panum Inst, Prot Lab,Inst Mol Pathol, Sch Med, Blegdamsvej 3C,Bld 6-2, DK-2200 Copenhagen N, Denmark. NR 29 TC 47 Z9 50 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 AUG 7 PY 2003 VL 22 IS 32 BP 5045 EP 5054 DI 10.1038/sj.onc.1206570 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 708QF UT WOS:000184578900012 PM 12902987 ER PT J AU Clancy, JL Henderson, MJ Russell, AJ Anderson, DW Bova, RJ Campbell, IG Choong, DYH Macdonald, GA Mann, GJ Nolan, T Brady, G Olopade, OI Woollatt, E Davies, MJ Segara, D Hacker, NF Henshall, SM Sutherland, RL Watts, CKW AF Clancy, JL Henderson, MJ Russell, AJ Anderson, DW Bova, RJ Campbell, IG Choong, DYH Macdonald, GA Mann, GJ Nolan, T Brady, G Olopade, OI Woollatt, E Davies, MJ Segara, D Hacker, NF Henshall, SM Sutherland, RL Watts, CKW TI EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer SO ONCOGENE LA English DT Article DE allelic imbalance; amplification; human neoplasms; gene expression; mutation ID COMPARATIVE-GENOMIC-HYBRIDIZATION; POSTERIOR UVEAL MELANOMA; SQUAMOUS-CELL CARCINOMA; DNA-DAMAGE RESPONSE; HUMAN BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; OVARIAN-TUMORS; COPY NUMBER; FREQUENT MULTIPLICATION; CYTOGENETIC ANALYSIS AB EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression. C1 St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Darlinghurst, NSW 2010, Australia. NIDCD, Mol Genet Lab, NIH, Rockville, MD USA. Peter MacCallum Canc Inst, Melbourne, Vic 3000, Australia. Univ Queensland, Populat & Clin Sci Div, Queensland Inst Med Res, Brisbane, Qld, Australia. Univ Queensland, Dept Med, Brisbane, Qld, Australia. Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. Univ Manchester, Sch Biol Sci, Manchester, Lancs, England. Univ Chicago, Med Ctr, Ctr Med Genet, Chicago, IL 60637 USA. Womens & Childrens Hosp, Ctr Med Genet, Adelaide, SA, Australia. Royal Hosp Women, Gynaecol Canc Ctr, Randwick, NSW 2031, Australia. RP Watts, CKW (reprint author), St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, 384 Victoria St, Darlinghurst, NSW 2010, Australia. RI Mann, Graham/G-4758-2014; henderson, Michelle/G-6657-2012; campbell, Ian/F-6006-2011; Macdonald, Graeme/K-4167-2013 OI Mann, Graham/0000-0003-1301-405X; Macdonald, Graeme/0000-0003-0929-110X NR 53 TC 53 Z9 57 U1 1 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 AUG 7 PY 2003 VL 22 IS 32 BP 5070 EP 5081 DI 10.1038/sj.onc.1206775 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 708QF UT WOS:000184578900015 PM 12902990 ER PT J AU Gryder, DS Rogawski, MA AF Gryder, DS Rogawski, MA TI Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE topiramate; kainate receptor; AMPA receptor; amygdala; synaptic current; patch-clamp recording ID CALCIUM-PERMEABLE AMPA; HIPPOCAMPAL-NEURONS; GRANULE CELLS; CYCLOTHIAZIDE; CHANNELS; RECTIFICATION; INTERNEURONS; MODULATION; RESPONSES; FLUX AB Topiramate is a widely used antiepileptic agent whose mechanism of action is poorly understood. The drug has been reported to interact with various ion channel types, including AMPA/kainate receptors. In whole-cell voltage-clamp recordings from principal neurons of the rat basolateral amygdala, topiramate at low concentrations (IC50, similar to0.5 muM) selectively inhibited pharmacologically isolated excitatory synaptic currents mediated by kainate receptors containing the GluR5 subunit. Topiramate also partially depressed predominantly AMPA-receptor-mediated EPSCs, but with lower efficacy. Topiramate did not alter the degree of facilitation in paired-pulse experiments, and it reduced the amplitude of miniature EPSCs without affecting their frequency, demonstrating that the block of synaptic responses occurs postsynaptically. Inhibition of GluR5 kainate receptors could represent a key mechanism underlying the anticonvulsant activity of topiramate. Moreover, these results support the concept that GluR5 kainate receptors represent a novel target for antiepileptic drug development. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, Bldg 49,Room 5A75,49 Convent Dr MSC 4457, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 40 TC 130 Z9 133 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 AUG 6 PY 2003 VL 23 IS 18 BP 7069 EP 7074 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 708UD UT WOS:000184587100011 PM 12904467 ER PT J AU Nardelli-Haefliger, D Wirthner, D Schiller, JT Lowy, DR Hildesheim, A Ponci, F De Grandi, P AF Nardelli-Haefliger, D Wirthner, D Schiller, JT Lowy, DR Hildesheim, A Ponci, F De Grandi, P TI Specific antibody levels at the cervix during the menstrual cycle of women vaccinated with human papillomavirus 16 virus-like particles SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COTTONTAIL RABBIT PAPILLOMAVIRUS; MUCOSAL IMMUNOLOGICAL SYSTEM; FEMALE REPRODUCTIVE-TRACT; GENITAL-TRACT; VAGINAL SECRETIONS; ESTROUS-CYCLE; IMMUNOGLOBULIN-G; UTERINE FLUID; IMMUNIZATION; IMMUNITY AB Background: In early-phase trials, a human papillomavirus 16 (HPV16) virus-like particle (VLP) vaccine has been shown to be well tolerated, immunogenic, and protective against HPV16 in women, most of whom were taking oral contraceptives. Previous studies have not determined whether HPV immunization results in specific antibody levels in the human genital tract or whether these levels might vary during contraceptive or ovulatory cycles. Therefore, we determined the levels of total and specific antibodies in the cervical secretions of women who had been immunized with HPV16 VLPs and examined the influence of the menstrual cycle and oral contraceptive use on these levels. Methods: Two groups of women were immunized, seven who were taking oral contraceptives and 11 who were ovulating. After seroconversion, serum and cervical secretions were collected twice weekly for 5 weeks. Total immunoglobulins (IgG and IgA) and vaccine-specific IgGs were determined by enzyme-linked immunosorbent assay. Nonparametric statistical analyses were used to determine the statistical significance of differences in IgG levels between groups, and correlations between serum- and cervical-specific IgG levels were determined by the Spearman correlation coefficient. Results: All participants developed detectable titers of anti-HPV16 VLP IgGs in their cervical secretions after immunization. The cervical titers of specific IgG and total IgGs and IgAs among participants in the contraceptive group were relatively constant throughout the contraceptive cycle. In contrast, the cervical titers of specific IgG and total IgGs and IgAs among participants in the ovulatory group varied during the menstrual cycle, being highest during the proliferative phase, decreasing approximately ninefold around ovulation, and increasing approximately threefold during the luteal phase. Serum- and cervical-specific IgG levels were correlated (r = .86) in women in the contraceptive group but not in women in the ovulatory group (r = .27). Conclusions: The relatively high titer of anti-HPV16 antibodies at the cervix is promising in terms of vaccine efficacy; however, the decrease in antibody titer around ovulation raises the possibility that the HPV16 VLP vaccine might be less effective during the peri-ovulatory phase. C1 NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. CHU Vaudois, Dept Gynecol, CH-1011 Lausanne, Switzerland. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, Bldg 37,Rm 4106, Bethesda, MD 20892 USA. OI nardelli-haefliger, denise/0000-0003-1812-9905 NR 42 TC 139 Z9 145 U1 0 U2 1 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 AUG 6 PY 2003 VL 95 IS 15 BP 1128 EP 1137 DI 10.1093/jnci/djg018 PG 10 WC Oncology SC Oncology GA 710YL UT WOS:000184710300008 PM 12902442 ER PT J AU Tabak, J Latham, PE AF Tabak, J Latham, PE TI Analysis of spontaneous bursting activity in random neural networks SO NEUROREPORT LA English DT Article DE activity-dependent depression; dissociated spinal culture; positive feedback ID MOUSE SPINAL-CORD; RHYTHMIC ACTIVITY; INTRINSIC DYNAMICS; NEURONAL NETWORKS; SYNAPTIC ACTIVITY; CELL-CULTURE; MECHANISMS; GENERATION; DEPRESSION; SLICE AB Developing networks can generate bursting activity despite the absence of pacemaker cells and inhibitory synapses. Bursts are generated by positive feedback through excitatory connections and terminated by a slow depression of network excitability. Similar activity has been observed in cultures of spinal neurons containing inhibitory synapses. Is burst generation in these cultures operating according to the mechanism proposed for developing networks? To answer this question without perturbing the activity, we analyzed the burst pattern of individual neurons in active cultures. We observed a correlation between burst size and preceding interburst interval and a rapid rise and progressive decrease in firing rate during a burst. These findings are consistent with the mechanism of burst generation proposed for developing networks. C1 NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA. RP Tabak, J (reprint author), NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Rm 3A50,Bldg 49,NIH Campus, Bethesda, MD 20892 USA. RI tabak, joel/K-1549-2013 NR 23 TC 13 Z9 13 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 6 PY 2003 VL 14 IS 11 BP 1445 EP 1449 DI 10.1097/01.wnr.0000082024.91120.20 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 718TA UT WOS:000185161500008 PM 12960761 ER PT J AU Kimmel, PL Barisoni, L Kopp, JB AF Kimmel, PL Barisoni, L Kopp, JB TI Pathogenesis and treatment of HIV-associated renal diseases: Lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ACTIVE ANTIRETROVIRAL THERAPY; SOLID-ORGAN TRANSPLANTATION; CONVERTING ENZYME GENE; TUBULAR EPITHELIAL-CELLS; CHEMOKINE RECEPTOR CCR5; HEPATITIS-C VIRUS; INFECTED PATIENTS; NEPHROTIC SYNDROME AB HIV infection is associated with several renal syndromes, including acute renal failure. Chronic renal failure directly linked to HIV infection includes thrombotic microangiopathic renal diseases, immune-mediated glomerulonephritides, and HIV-associated nephropathy. A renal biopsy may be necessary for diagnosis. The development of HIV-associated nephropathy has been definitively linked to renal cellular infection, but the disease affects only a minority of patients, typically men of African descent. Therefore, factors determining disease expression in infected patients must now be emphasized. The pathogenic mechanisms involved in HIV-associated renal disease remain obscure. Genetic factors, as well as renal cellular responses, mediated by HIV proteins (including an immune-activated microenvironment) capable of presenting antigen in susceptible hosts probably explain most cases. HIV-associated nephropathy has a characteristic pathologic phenotype, including glomerular, tubular, and interstitial changes, and ultrastructural findings. Infection of the glomerular epithelial cell, or podocyte, and consequent structural and biochemical changes may be pivotal in pathogenesis. The HIV-1 transgenic mouse is an important model for understanding disease pathogenesis, particularly the role of HIV proteins in mediating renal tissue injury. Rigorously controlled randomized trials have not evaluated treatment, but corticosteroids and angiotensin-converting enzyme inhibitors have been used. Highly active antiretroviral therapy seems to have decreased the incidence of end-stage renal disease related to HIV infection and, in case reports, to have improved renal functional and pathologic outcomes of HIV-associated nephropathy. Outcomes in patients undergoing hemodialysis and peritoneal dialysis have improved, and current research focuses on renal transplantation for treatment of HIV-infected patients. C1 George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK NIH HHS [R01-DK-40811] NR 143 TC 93 Z9 97 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 5 PY 2003 VL 139 IS 3 BP 214 EP 226 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 707RH UT WOS:000184523300007 PM 12899589 ER PT J AU Gao, XG Wen, XL Esser, L Quinn, B Yu, L Yu, CA Xia, D AF Gao, XG Wen, XL Esser, L Quinn, B Yu, L Yu, CA Xia, D TI Structural basis for the quinone reduction in the bc(1) complex: A comparative analysis of crystal structures of mitochondrial cytochrome bc(1) with bound substrate and inhibitors at the Qi site SO BIOCHEMISTRY LA English DT Article ID ELECTRON-TRANSPORT CHAIN; RAT-LIVER MITOCHONDRIA; PROTONMOTIVE Q-CYCLE; ANTIMYCIN-A ANALOGS; C REDUCTASE; B GENE; SACCHAROMYCES-CEREVISIAE; RESPIRATORY-CHAIN; THERMODYNAMIC PROPERTIES; RHODOBACTER-SPHAEROIDES AB Cytochrome bc(1) is an integral membrane protein complex essential to cellular respiration and photosynthesis. The Q cycle reaction mechanism of bc(1) postulates a separated quinone reduction (Q(i)) and quinol oxidation (Q(i)) site. In a complete catalytic cycle, a quinone molecule at the Q(i) site receives two electrons from the b(H) heme and two protons from the negative side of the membrane; this process is specifically inhibited by antimycin A and NQNO. The structures of bovine mitochondrial bc(1) in the presence or absence of bound substrate ubiquinone and with either the bound antimycin A(1) or NQNO were determined and refined. A ubiquinone with its first two isoprenoid repeats and an antimycin A(1) were identified in the Q(i) pocket of the substrate and inhibitor bound structures, respectively; the NQNO, on the other hand, was identified in both Q(i) and Q(o) pockets in the inhibitor complex. The two inhibitors occupied different portions of the Q(i) pocket and competed with substrate for binding. In the Q(i) pocket, the NQNO behaves similarly to stigmatellin, inducing an iron-sulfur protein conformational arrest. Extensive binding interactions and conformational adjustments of residues lining the Q(i) pocket provide a structural basis for the high affinity binding of antimycin A and for phenotypes of inhibitor resistance. A two-water-mediated ubiquinone protonation mechanism is proposed involving three Q(i) site residues His(201), Lys(227), and Asp(228). C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI ID, IMCACAT/D-5867-2014 FU NIGMS NIH HHS [GM 30721] NR 52 TC 133 Z9 140 U1 3 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 5 PY 2003 VL 42 IS 30 BP 9067 EP 9080 DI 10.1021/bi0341814 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707FE UT WOS:000184499000017 PM 12885240 ER PT J AU Sondej, M Vazquez-Ibar, JL Farshidi, A Peterkofsky, A Kaback, HR AF Sondej, M Vazquez-Ibar, JL Farshidi, A Peterkofsky, A Kaback, HR TI Characterization of a lactose permease mutant that binds IIA(Glc) in the absence of ligand SO BIOCHEMISTRY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; LAC CARRIER PROTEIN; CYSTEINE-SCANNING MUTAGENESIS; ESCHERICHIA-COLI; MEMBRANE-TRANSPORT; SUBSTRATE-BINDING; ENZYME IIA(GLC); PHOSPHOENOLPYRUVATE; MECHANISM; TRANSLOCATION AB Enzyme IIA(Glc) of the Escherichia coli phosphoenolpyruvate: glucose phosphotransferase system plays a direct role in regulating inducible transport systems. Dephosphorylated IIA(Glc) binds directly to lactose permease in a reaction that requires binding of a galactosidic substrate. A double-Cys mutation (Ile129 --> Cys/Lys131 --> Cys) was introduced into helix IV of the permease near the IIA(Glc) binding site in cytoplasmic loop IV/V and in the vicinity of the galactoside binding site at the interface of helices IV, V, and VIII. The mutant no longer requires galactoside for IIA(Glc) binding as demonstrated by both a [I-125]IIA(Glc) binding assay and a newly developed fluorescence anisotropy assay. Further characterization of the mutant shows that it binds substrate with high affinity, but is almost completely defective in all modes of translocation across the cytoplasmic membrane. The data are consistent with the interpretation that the double mutant is locked in an inward-facing conformation. C1 Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Physiol & Immunol, MacDonald Res Labs 5 748, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Microbiol, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Mol Genet, Inst Mol Biol, Los Angeles, CA 90095 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kaback, HR (reprint author), Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Physiol & Immunol, MacDonald Res Labs 5 748, Box 951662, Los Angeles, CA 90095 USA. FU NIDDK NIH HHS [DK51131:08] NR 37 TC 4 Z9 4 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 AUG 5 PY 2003 VL 42 IS 30 BP 9153 EP 9159 DI 10.1021/bi034406a PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707FE UT WOS:000184499000026 PM 12885249 ER PT J AU Kopka, K Wagner, S Riemann, B Law, MP Puke, C Luthra, SK Pike, VW Wichter, T Schmitz, W Schober, O Schafers, M AF Kopka, K Wagner, S Riemann, B Law, MP Puke, C Luthra, SK Pike, VW Wichter, T Schmitz, W Schober, O Schafers, M TI Design of new beta(1)-selective adrenoceptor ligands as potential radioligands for in vivo Imaging SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; PROTEIN-COUPLED RECEPTORS; IDIOPATHIC DILATED CARDIOMYOPATHY; CARDIAC SYMPATHETIC INNERVATION; BETA-ADRENERGIC AGONISTS; HUMAN-HEART; ASYMMETRIC-SYNTHESIS; BLOCKING-AGENTS; DOWN-REGULATION; SMOOTH-MUSCLE AB In general, the failing human heart is characterized by a selective reduction in beta(1)-drenoceptors (beta(1)-ARs) without change in beta(2)-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N''-[2-[3-aryloxy-2-hydroxy-propylamino]ethyl]-urea derivatives and chain-elongated analogues, related to the established beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [I-125]iodocyanopindolol ([I-125]ICyp), and ventricular membrane preparations of wildtype mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity beta(1)-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r-t). Future steps will include radiolabelling and pharmacokinetic evaluation of the beta(1)-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Hosp Munster, Dept Nucl Med, D-48149 Munster, Germany. Univ Hosp Munster, Inst Pharmacol & Toxicol, D-48149 Munster, Germany. Hammersmith Hosp, Imaging Res Solut Ltd, London W12 0NN, England. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Univ Hosp Munster, Dept Cardiol & Angiol, D-48149 Munster, Germany. RP Kopka, K (reprint author), Univ Hosp Munster, Dept Nucl Med, Albert Schweitzer Str 33, D-48149 Munster, Germany. RI Schober, Otmar/A-8670-2008 NR 67 TC 20 Z9 21 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 5 PY 2003 VL 11 IS 16 BP 3513 EP 3527 DI 10.1016/S0968-0896(03)00297-9 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 708HC UT WOS:000184560300014 PM 12878144 ER PT J AU Wang, TJ Nam, BH D'Agostino, RB Wolf, PA Lloyd-Jones, DM MacRae, CA Wilson, PW Polak, JF O'Donnell, CJ AF Wang, TJ Nam, BH D'Agostino, RB Wolf, PA Lloyd-Jones, DM MacRae, CA Wilson, PW Polak, JF O'Donnell, CJ TI Carotid intima-media thickness is associated with premature parental coronary heart disease - The Framingham Heart Study SO CIRCULATION LA English DT Article DE atherosclerosis; carotid arteries; genetics; epidemiology; risk factors ID CARDIOVASCULAR RISK-FACTORS; FAMILY-HISTORY; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; DIABETES-MELLITUS; WALL THICKNESS; ATHEROSCLEROSIS; ADULTS; CLASSIFICATION; ABNORMALITIES AB Background-A family history of coronary heart disease (CHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. We hypothesized that an important mediator of the familial predisposition to CHD is subclinical atherosclerosis, which is detectable by noninvasive imaging. Methods and Results-We studied 1662 subjects (mean age 57, 51% women) in the Framingham Offspring Study who underwent carotid ultrasonography and had both biological parents in the original (parental) cohort. Parental CHD events were validated prospectively by a physician endpoint committee. The associations of carotid intima-media thickness (IMT) with premature parental CHD (occurring before age 60) and any parental CHD (no age restriction) were examined in age- and multivariable-adjusted analyses. Age-adjusted mean internal carotid IMT was higher in subjects who had at least one parent with premature CHD than in those without a validated parental history of premature CHD (men 1.13 versus 1.04 mm, P<0.01; women 0.92 versus 0.85 mm, P=0.03). In both sexes, these differences remained significant after adjustment for cardiovascular risk factors. In analyses without a restriction on parental age of CHD onset, the association between carotid IMT and parental CHD was not statistically significant. There was also no significant association of common carotid IMT with premature or any parental CHD. Conclusions-These findings suggest that subclinical atherosclerosis, assessed in the carotid arteries, is more prevalent in individuals with a family history of CHD. Early-onset parental CHD, in particular, identifies offspring with a strong familial predisposition to atherosclerosis. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte,Suite No 2, Framingham, MA 01702 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [N01-HC-25195] NR 37 TC 64 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 AUG 5 PY 2003 VL 108 IS 5 BP 572 EP 576 DI 10.1161/01.CIR.0000081764.35431.DE PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 708CH UT WOS:000184549200014 PM 12874190 ER PT J AU Cohen-Fix, O AF Cohen-Fix, O TI Meiosis: Polo, FEAR and the art of dividing reductionally SO CURRENT BIOLOGY LA English DT Editorial Material ID SINGLE-DIVISION MEIOSIS; CHROMOSOME SEGREGATION; SACCHAROMYCES-CEREVISIAE; COHESIN REC8; KINASE CDC5; SEPARATION; SLK19P AB Recent studies on the regulation of meiosis have uncovered new roles for old acquaintances: the pololike kinase Cdc5 has been found to dictate proper kinetochore orientation during meiosis I, while the FEAR pathway is essential for some, but not all, aspects of meiosis I exit. C1 NIDDK, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDK, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 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 AUG 5 PY 2003 VL 13 IS 15 BP R603 EP R605 DI 10.1016/S0960-9822(03)00526-8 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 709PJ UT WOS:000184633300016 PM 12906813 ER PT J AU Cookson, MR AF Cookson, MR TI Crystallizing ideas about Parkinson's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ALPHA-SYNUCLEIN; DJ-1; PATHOGENESIS; MUTATIONS; PROTEIN; STRESS C1 Natl Inst Aging, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), Natl Inst Aging, Lab Neurogenet, NIH, Bldg 10,Rm 6C103,MSC 1589,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 24 TC 6 Z9 7 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2003 VL 100 IS 16 BP 9111 EP 9113 DI 10.1073/pnas.1633722100 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709HP UT WOS:000184620000004 PM 12886009 ER PT J AU Vocadlo, DJ Hang, HC Kim, EJ Hanover, JA Bertozzi, CR AF Vocadlo, DJ Hang, HC Kim, EJ Hanover, JA Bertozzi, CR TI A chemical approach for identifying O-GlcNAc-modified proteins in cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LINKED N-ACETYLGLUCOSAMINE; NUCLEAR-PORE; TETRATRICOPEPTIDE REPEATS; INSULIN-RESISTANCE; SIALIC-ACID; UDP-GLCNAC; IN-VIVO; GLYCOSYLATION; TRANSFERASE; GLYCOPROTEINS AB The glycosylation of serine and threonine residues with a single GlcNAc moiety is a dynamic posttranslational modification of many nuclear and cytoplasmic proteins. We describe a chemical strategy directed toward identifying O-GlcNAc-modified proteins from living cells or proteins modified in vitro. We demonstrate, in vitro, that each enzyme in the hexosamine salvage pathway, and the enzymes that affect this dynamic modification (UDP-Glc-NAc:polypeptidtyltransferase and O-GlcNAcase), tolerate analogues of their natural substrates in which the N-acyl side chain has been modified to bear a bio-orthogonal azide moiety. Accordingly, treatment of cells with N-azidoacetylglucosamine results in the metabolic incorporation of the azido sugar into nuclear and cytoplasmic proteins. These O-azidoacetylglucosamine-modified proteins can be covalently derivatized with various biochemical probes at the site of protein glycosylation by using the Staudinger ligation. The approach was validated by metabolic labeling of nuclear pore protein p62, which is known to be posttranslationally modified with O-GlcNAc. This strategy will prove useful for both the identification of O-GlcNAc-modified proteins and the elucidation of the specific residues that bear this saccharide. C1 Lawrence Berkeley Natl Lab, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USA. Lawrence Berkeley Natl Lab, Dept Mol & Cell Biol, Mat Sci Div, Berkeley, CA 94720 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Bertozzi, CR (reprint author), Lawrence Berkeley Natl Lab, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USA. RI Vocadlo, David/E-5508-2014 OI Vocadlo, David/0000-0001-6897-5558 FU NIGMS NIH HHS [GM066047, R01 GM066047] NR 43 TC 294 Z9 302 U1 13 U2 69 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 AUG 5 PY 2003 VL 100 IS 16 BP 9116 EP 9121 DI 10.1073/pnas.1632821100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709HP UT WOS:000184620000006 PM 12874386 ER PT J AU Miranda, KM Paolocci, N Katori, T Thomas, DD Ford, E Bartberger, MD Espey, MG Kass, DA Feelisch, M Fukuto, JM Wink, DA AF Miranda, KM Paolocci, N Katori, T Thomas, DD Ford, E Bartberger, MD Espey, MG Kass, DA Feelisch, M Fukuto, JM Wink, DA TI A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Angeli's salt; superoxide dismutase; heme protein; cGMP; calcitonin gene-related peptide ID GENE-RELATED PEPTIDE; SUPEROXIDE-DISMUTASE; AQUEOUS-SOLUTION; IN-VIVO; BIOLOGICAL-SYSTEMS; NITROSYL HYDRIDE; ANGELIS SALT; CELL-DEATH; L-ARGININE; ANION AB The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual redox reactions in biological systems. However, several recent studies have demonstrated distinct pharmacological effects for donors of these two species. Here, infusion of the HNO donor Angeli's salt into normal dogs resulted in elevated plasma levels of calcitonin gene-related peptide, whereas neither the NO donor diethylamine/NONOate nor the nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely, plasma cGMP was increased by infusion of diethylamine/NONOate or nitroglycerin but was unaffected by Angeli's salt. These results suggest the existence of two mutually exclusive response pathways that involve stimulated release of discrete signaling agents from HNO and NO. In light of both the observed dichotomy of HNO and NO and the recent determination that, in contrast to the O-2/O-2(-) couple, HNO is a weak reductant the relative reactivity of HNO with common biomolecules was determined. This analysis suggests that under biological conditions, the lifetime of HNO with respect to oxidation to NO, dimerization, or reaction with O-2 is much longer than previously assumed. Rather, HNO is predicted to principally undergo addition reactions with thiols and ferric proteins. Calcitonin gene-related peptide release is suggested to occur via altered calcium channel function through binding of HNO to a ferric or thiol site. The orthogonality of HNO and NO may be due to differential reactivity toward metals and thiols and in the cardiovascular system, may ultimately be driven by respective alteration of cAMP and cGMP levels. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. Louisiana State Univ, Ctr Hlth Sci, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. RP Miranda, KM (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Rm B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009; Feelisch, Martin/C-3042-2008; OI Feelisch, Martin/0000-0003-2320-1158; Paolocci, Nazareno/0000-0001-7011-997X NR 56 TC 166 Z9 170 U1 4 U2 18 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 AUG 5 PY 2003 VL 100 IS 16 BP 9196 EP 9201 DI 10.1073/pnas.1430507100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709HP UT WOS:000184620000020 PM 12865500 ER PT J AU Belyakov, IM Earl, P Dzutsev, A Kuznetsov, VA Lemon, M Wyatt, LS Snyder, JT Ahlers, JD Franchini, G Moss, B Berzofsky, JA AF Belyakov, IM Earl, P Dzutsev, A Kuznetsov, VA Lemon, M Wyatt, LS Snyder, JT Ahlers, JD Franchini, G Moss, B Berzofsky, JA TI Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; CELL-DEFICIENT MICE; NEUTRALIZING MONOCLONAL-ANTIBODIES; HUMAN-IMMUNODEFICIENCY-VIRUS; INFLUENZA-VIRUS; B-CELLS; VIRAL REPLICATION; MUCOSAL; IMMUNITY; STRAIN AB The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4(+) nor CD8(+) T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Labs, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Belyakov, IM (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 51 TC 207 Z9 210 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2003 VL 100 IS 16 BP 9458 EP 9463 DI 10.1073/pnas.1233578100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709HP UT WOS:000184620000065 PM 12869693 ER PT J AU Packer, MA Stasiv, Y Benraiss, A Chmielnicki, E Grinberg, A Westphal, H Goldman, SA Enikolopov, G AF Packer, MA Stasiv, Y Benraiss, A Chmielnicki, E Grinberg, A Westphal, H Goldman, SA Enikolopov, G TI Nitric oxide negatively regulates mammalian adult neurogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NEURAL STEM-CELLS; FOCAL CEREBRAL-ISCHEMIA; RAT BRAIN; NEUROTROPHIC FACTOR; GROWTH-FACTOR; NEURONAL DIFFERENTIATION; DROSOPHILA DEVELOPMENT; SUBVENTRICULAR ZONE; PRECURSOR CELLS; S-NITROSYLATION AB Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Cornell Univ, Coll Med, Dept Neurol & Neurosci, New York, NY 10021 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Enikolopov, G (reprint author), Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. RI Enikolopov, Grigori/B-7771-2009; Packer, Michael/B-3594-2013 OI Enikolopov, Grigori/0000-0001-8178-8917; NR 48 TC 206 Z9 219 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2003 VL 100 IS 16 BP 9566 EP 9571 DI 10.1073/pnas.1633579100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 709HP UT WOS:000184620000083 PM 12886012 ER PT J AU Peddi, S Roth, BL Glennon, RA Westkaemper, RB AF Peddi, S Roth, BL Glennon, RA Westkaemper, RB TI Ring substituted analogues of 5-aminomethyl-10,11-dihydro-dibenzo[a,d]cycloheptene (AMDH): Potential modes of binding to the 5-HT2A receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SEROTONIN RECEPTOR; LIGAND 9-(AMINOMETHYL)-9,10-DIHYDROANTHRACENE; RHODOPSIN; AFFINITY; HELICES AB The synthesis and 5-HT2A receptor affinities of 2-substituted-5-aminomethyl-10,11-dihydrodibenzo[a,d]cycloheptene (AMDH) derivatives are described. Comparison of the effects of substitution on affinities allowed assignment of potential binding modes in comparison with DOB-like agonists/antagonists and 3-substituted 1-(aminomethyl)-9,10-dihydroanthracene structures. (C) 2003 Elsevier Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA. Case Western Reserve Univ, Sch Med, NIMH Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. RP Westkaemper, RB (reprint author), Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA. RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [KO2MH01366, MH57969]; PHS HHS [N0280005] NR 18 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 4 PY 2003 VL 13 IS 15 BP 2565 EP 2568 DI 10.1016/S0960-894X(03)00504-3 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 701VY UT WOS:000184190700030 PM 12852967 ER PT J AU Lee, K Gao, Y Yao, ZJ Phan, J Wu, L Liang, J Waugh, DS Zhang, ZY Burke, TR AF Lee, K Gao, Y Yao, ZJ Phan, J Wu, L Liang, J Waugh, DS Zhang, ZY Burke, TR TI Tripeptide inhibitors of Yersinia protein-tyrosine phosphatase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID SIGNAL-TRANSDUCTION INHIBITORS; MIMETICS; PHOSPHOTYROSINE; DESIGN; MECHANISM; PEPTIDES; SITE; 1B AB The protein-tyrosine phosphatase (PTP) 'YopH' is a virulence factor of Yersinia pestis, the causative agent of plague. Potential use of Yersinia as a bioterrorism agent renders YopH inhibitors of therapeutic importance. Previously, we had examined the inhibitory potencies of a variety of phosphotyrosyl (pTyr) mimetics against the human PTP1B enzyme by displaying them in the EGFR-derived hexapeptide sequence, 'Ac-Asp-Ala-Asp-Glu-Xxx-Leu-amide', where Xxx=pTyr mimetic. The poor inhibitory potencies of certain of these pTyr mimetics were attributed to restricted orientation within the PTP1B catalytic pocket incurred by extensive peripheral interaction of the hexapeptide platform. Utilizing the smaller tripeptide platform. 'Fmoc-Glu-Xxx-Leu-amide' we demonstrate herein that several of the low affinity hexapeptide-expressed pTyr mimetics exhibit high PTP1B affinity within the context of the tripeptide platform. Of particular note, the mono-anionic 4(carboxydifluoroinethyl)Phe residue exhibits affinity equivalent to the di-anionic F(2)Pmp residue, which had previously been among the most potent PTP-binding motifs. Against YopH, it was found that all tripeptides having Gin residues with an unprotected side chain carboxyl were inactive. Alternatively, in their Glu-OBn ester forms, several of the tripeptides exhibited good YopH affinity with the mono-anionic peptide, Fmoc-Glu(OBn)-Xxx-Leu-amide, where Xxx = 4-(carboxymethyloxy)Phe providing an IC50 value of 2.8 muM. One concern with such inhibitors is that they may potentially function by non-specific mechanisms. Studies with representative inhibitors. while failing to provide evidence of a non-specific promiscuous mode of inhibition, did indicate that non-classical inhibition may be involved. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, CCR, NIH, Frederick, MD 21702 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 FU NIAID NIH HHS [AI48506] NR 27 TC 24 Z9 25 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 4 PY 2003 VL 13 IS 15 BP 2577 EP 2581 DI 10.1016/S0960-894X(03)00481-5 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 701VY UT WOS:000184190700033 PM 12852970 ER PT J AU Haddad, W Cooper, CJ Zhang, Z Brown, JB Zhu, YC Issekutz, A Fuss, I Lee, H Kansas, GS Barrett, TA AF Haddad, W Cooper, CJ Zhang, Z Brown, JB Zhu, YC Issekutz, A Fuss, I Lee, H Kansas, GS Barrett, TA TI P-selectin and P-selectin glycoprotein ligand 1 are major determinants for Th1 cell recruitment to nonlymphoid effector sites in the intestinal lamina propria SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE memory T cells; lamina propria; small intestine; interleukin-12; leukocyte migration ID T-CELLS; IN-VIVO; LYMPHOCYTE MIGRATION; BETA-7 INTEGRINS; CD4(+); EXPRESSION; ADHESION; COLITIS; IL-12; INTERLEUKIN-12 AB The recruitment of activated T cell subsets to sites of effector immune responses is mediated by homing receptors induced upon activation in secondary lymphoid tissue. Using an adoptive transfer model, the intestinal recruitment of CD4(+) T cells activated with intraperitoneal antigen in complete Freund's adjuvant was examined. The data demonstrate that activated CD4(+) T cells recruited to intestinal Peyer's patches (PP) and lamina propria (LP) up-regulate functional P-selectin glycoprotein ligand 1 (PSGL-1). Blockade of IL-12 inhibited functional PSGL-1 expression and reduced PP and LP CD4(+) T cell recruitment by >40%. P-Selectin blockade reduced LP recruitment of activated cells by 56% without affecting PP recruitment. Studies of mice examined 3 d after adoptive transfer of differentiated T cell subsets revealed that Th1 but not Th2 cells were recruited to small intestine PP and LP. Mucosal addressin cell adhesion molecule blockade reduced Th1 recruitment to PP by 90% and to LP by >72%, whereas P-selectin blockade reduced Th1 recruitment to PP by 18% and Th1 recruitment to LP by 84%. These data suggest that IL-12-induced functional PSGL-1 expression is a major determinant for the recruitment of Th1 effector cells to noninflamed as well as inflamed intestine. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Microbiol Immunol, Chicago, IL 60611 USA. Dalhousie Univ, Dept Pediat Pathol & Microbiol Immunol, Halifax, NS B3J 3G9, Canada. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Barrett, TA (reprint author), Northwestern Univ, Sch Med, Dept Med, 745 N Fairbanks,Searle 10-455, Chicago, IL 60611 USA. FU NIAID NIH HHS [AI50837, R01 AI050837]; NIDDK NIH HHS [DK54778, P30 DK052574, P30 DK52574, R01 DK054778, R01 DK054778-03]; NIGMS NIH HHS [K08 GM000709, K08 GM00709-01] NR 33 TC 56 Z9 59 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 4 PY 2003 VL 198 IS 3 BP 369 EP 377 DI 10.1084/jem.20020691 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 712TQ UT WOS:000184813700001 PM 12885868 ER PT J AU Riteau, B Barber, DF Long, EO AF Riteau, B Barber, DF Long, EO TI Vav1 phosphorylation is induced by beta 2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE natural killer cell; lipid raft; LFA-1; Vav1; 2B4 ID EXCHANGE FACTOR; INTERCELLULAR-ADHESION; T-CELLS; ACTIVATION; CYTOTOXICITY; RECEPTORS; PATHWAY; KINASE; SYK; NEUTROPHILS AB The guanine nucleotide exchange factor Vav1 regulates actin polymerization and contributes to cytotoxicity by natural killer (NK) cells. An open question is how Vav1 becomes activated and what receptor can signal upstream of actin cytoskeleton rearrangement upon NK cell contact with target cells. Using transfected insect cells that express ligands of human NK cell receptors, we show that engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK. Binding of activation receptor 2134 to its ligand CD48 was not sufficient for Vav1 phosphorylation. However, coengagement of 2134 with LFA-1 resulted in an enhancement of Vav1 phosphorylation that was sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 was recruited to a detergent-resistant membrane (DRM) fraction only when 2B4 and LFA-1 were coengaged, but not after LFA-1 engagement. Therefore, binding of LFA-1 to ICAM-1 on target cells may initiate an early signaling cascade in NK cells through activation of Vav1, leading to cytoskeleton reorganization and amplification of signals from other activation receptors. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH Twinbrook 2, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barber, Domingo/G-1257-2010; Long, Eric/G-5475-2011 OI Barber, Domingo/0000-0001-8824-5405; Long, Eric/0000-0002-7793-3728 NR 31 TC 87 Z9 90 U1 0 U2 0 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 AUG 4 PY 2003 VL 198 IS 3 BP 469 EP 474 DI 10.1084/jem.20021995 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 712TQ UT WOS:000184813700010 PM 12885870 ER PT J AU Wang, XZ Yao, ZJ Liu, HP Zhang, MC Yang, DJ George, C Burke, TR AF Wang, XZ Yao, ZJ Liu, HP Zhang, MC Yang, DJ George, C Burke, TR TI Synthesis of a phosphotyrosyl analogue having X-1, X-2 and phi angles constrained to values observed for an SH2 domain-bound phosphotyrosyl residue SO TETRAHEDRON LA English DT Article DE phosphotyrosyl analogue; protein-tyrosine-kinase; SH2 domains ID SIGNAL-TRANSDUCTION INHIBITORS; TYROSINE KINASE INHIBITORS; SRC HOMOLOGY-2 DOMAIN; 1,2,3-TRISUBSTITUTED CYCLOPROPANES; MANNICH REACTION; BINDING LIGANDS; DESIGN; PEPTIDE; GRB2; ANTAGONISTS AB Src homology 2 (SH2) domains provide connectivity in protein-tyrosine kinase (PTK)-dependent signaling through their high affinity association with phosphotyrosyl (pTyr)-containing peptide sequences. Because recognition of pTyr residues is central to SH2 domain-binding affinity, design of pTyr-mimicking residues has been one component of SH2 domain signaling antagonist development. Reported herein is the synthesis of (+/-)-(rel-1R,2R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-8-O-phosphoryl-1,5-methano-3-benzazocine-2carboxylic acid methyl ester (3c) as a monomeric pTyr-mimicking analogue that constrains three torsion angles (chi(1) = 168degrees; chi(2)= -85degrees; phi(1) = -113degrees) to values approximating those observed for a pTyr residue bound to the Grb2 SH2 domain (chi(1) = 182degrees; chi(2)= -89degrees; phi(1) = -132degrees). Compound 3c differs from our previously reported analogue, (+/-)-(rel-1R,2R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-1-methyl-1,5-methano-3-benzazocin-8-ol. in lacking a methyl substituent at the bridgehead 1-position. Molecular modeling studies had indicated that this methyl group could potentially hinder SH2 domain binding. Synthesis of the desmethyl derivative was achieved by formation of the methanobenzazocine ring system using an intramolecular electrophilic cyclization that proceeds through an activated acyliminium intermediate. Importantly, the correct relative (2R) stereochemistry at the 'alpha-carboxyl'-bearing carbon is obtained through base-catalyzed equilibration of a (2S/2R) diastereomeric mixture that results from intramolecular ring closure. Comparison of Grb2 SH2 domain-binding affinity of 3c (IC50=1167 muM) with conformationally flexible phosphorylated (+/-)-N-acetyl-tyrosine methyl ester (15; IC50=1469 muM) revealed no apparent enhancement in affinity. This apparent ineffectiveness of 'local conformational constraint' on SH2 domain-binding affinity of the monomeric pTyr mimetic is consistent with previous reports obtained by conformationally constraining pTyr-mimicking residues that were contained within peptide platforms. Although not providing high binding affinity in its current form, the novel 1,5-methano-3-benzazocine ring system may afford a novel platform for further elaboration and development of small molecule SH2 domain signaling antagonists. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. Univ Michigan, Sch Med, Dept Hematol Oncol, Ann Arbor, MI 48109 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, POB B,Bldg 376,Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 40 TC 12 Z9 12 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD AUG 4 PY 2003 VL 59 IS 32 BP 6087 EP 6093 DI 10.1016/S0040-4020(03)00978-5 PG 7 WC Chemistry, Organic SC Chemistry GA 708WT UT WOS:000184593700012 ER PT J AU Mozumdar, BC Hornsby, DN Gogate, AS Intriere, LA Hanson, R McGreal, K Kelly, P Ros, P AF Mozumdar, BC Hornsby, DN Gogate, AS Intriere, LA Hanson, R McGreal, K Kelly, P Ros, P TI Radiology scheduling: References of users of radiologic services and impact on referral base and extension SO ACADEMIC RADIOLOGY LA English DT Article DE scheduling; electronic order entry; telephone AB Rationale and Objectives. To study end-user attitudes and preferences with respect to radiology scheduling systems and to assess implications for retention and extension of the referral base. A study of the institution's historical data indicated reduced satisfaction with the process of patient scheduling in recent years. Methods. Sixty physicians who referred patients to a single, large academic radiology department received the survey. The survey was designed to identify (A) the preferred vehicle for patient scheduling (on-line versus telephone scheduling) and (13) whether ease of scheduling was a factor in physicians referring patients to other providers. Referring physicians were asked to forward the survey to any appropriate office staff member in case the latter scheduled appointments for patients. Users were asked to provide comments and suggestions for improvement. The statistical method used was the analysis of proportions. Results. Thirty-three responses were received, corresponding to a return rate of 55%. Twenty-six of the 33 respondents (78.8%, P < .01) stated they were willing to try an online scheduling system; 16 of which tried the system. Twelve of the 16 (75%, P < .05) preferred the on-line application to the telephone system, stating logistical simplification as the primary reason for preference. Three (18.75%) did not consider online scheduling to be more convenient than traditional telephone scheduling. One respondent did not indicate any preference. Eleven of 33 users (33.33%, P < .001) stated that they would change radiology service providers if expectations of scheduling ease are not met. Conclusion. On-line scheduling applications are becoming the preferred scheduling vehicle. Augmenting their capabilities and availability can simplify the scheduling process, improve referring physician satisfaction, and provide a competitive advantage. Referrers are willing to change providers if scheduling expectations are not met. C1 Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Mozumdar, BC (reprint author), NIH, Imaging Sci Program, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C657,10 Ctr Dr, Bethesda, MD 20892 USA. NR 5 TC 5 Z9 5 U1 0 U2 2 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2003 VL 10 IS 8 BP 908 EP 913 DI 10.1016/S1076-6332(03)00002-3 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 714AT UT WOS:000184890700015 PM 12945929 ER PT J AU Ferrucci, L Turchi, A Fumagalli, S Di Bari, M Silvestrini, G Zacchei, S Nesti, A Magherini, L Tarantini, F Pini, R Antonini, E Masotti, G Marchionni, N AF Ferrucci, L Turchi, A Fumagalli, S Di Bari, M Silvestrini, G Zacchei, S Nesti, A Magherini, L Tarantini, F Pini, R Antonini, E Masotti, G Marchionni, N TI Sex-related differences in the length of disability prior to death in older persons SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE chronic disease; disability; functional status; health surveys; life expectancy; older persons ID ACTIVE LIFE EXPECTANCY; CARDIOVASCULAR HEALTH; GENDER-DIFFERENCES; POPULATION; MORTALITY; DYNAMICS; PEOPLE; AGE AB Background and aims: It is acknowledged that, in spite of their generally worse health, women live longer than men. However, whether women also enjoy longer disability-free lives is still unclear. Using data from a representative, Italian cohort followed for 6 years, this study aimed at estimating differences between men and women in the age of disability onset and in total survival. Methods: In 1989, 651 persons aged greater than or equal to65 years were interviewed and their medical status was assessed by a geriatrician. In 1995, the time of onset of disability was reconstructed by re-interviewing 392 survivors and collecting proxy information for 201 subjects who had died. No information was available for 58 subjects who refused to be re-interviewed or were lost to follow-up. Data on changes in functional status were also collected by proxy interview for 34 additional persons who had died during the follow-up period, although they had not been originally interviewed at baseline. Results: Of the 235 deaths, 113 were men and 122 were women. On average, the age at death was 3.5 years higher among women than among men. However, the age at onset of disability was similar in the two sexes. In survival analysis in which age was the time variable, women were as likely as men to develop disability, but significantly less likely to die over the follow-up period. Conclusions: Compared with men, women experience longer disability before death. This may be due to sex-related differences in the lifetime prevalence of lethal vs. disabling diseases. ((C))2003, Editrice Kurtis. C1 Univ Florence, Unit Gerontol & Geriatr Med, Dept Crit Care Med & Surg, I-50141 Florence, Italy. Azienda Osped Careggi, Florence, Italy. NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD USA. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. RP Marchionni, N (reprint author), Univ Florence, Unit Gerontol & Geriatr Med, Dept Crit Care Med & Surg, Via Oblate 4, I-50141 Florence, Italy. RI Tarantini, Francesca/I-6332-2012; DI BARI, MAURO/J-1524-2012; OI Pini, Riccardo/0000-0002-7940-7908 NR 22 TC 19 Z9 19 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD AUG PY 2003 VL 15 IS 4 BP 310 EP 314 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 741QA UT WOS:000186467700007 PM 14661822 ER PT J AU Mellins, CA Kang, E Leu, CS Havens, JF Chesney, MA AF Mellins, CA Kang, E Leu, CS Havens, JF Chesney, MA TI Longitudinal study of mental health and psychosocial predictors of medical treatment adherence in mothers living with HIV disease SO AIDS PATIENT CARE AND STDS LA English DT Article; Proceedings Paper CT 14th International AIDS Conference CY JUL 07-12, 2002 CL BARCELONA, SPAIN ID ACTIVE ANTIRETROVIRAL THERAPY; QUALITY-OF-LIFE; UNITED-STATES; DRUG-USERS; DEPRESSIVE SYMPTOMS; REPORTED ADHERENCE; SEROPOSITIVE WOMEN; CLINICAL-TRIALS; INFECTED WOMEN; CARE AB Cross-sectional studies to date that examine psychosocial correlates of antiretroviral adherence have insufficiently addressed the challenges of long-term adherence. This longitudinal study examined mental health, substance abuse, and psychosocial predictors of long-term adherence to antiretroviral medications and medical appointments among HIV-seropositive mothers recruited from an infectious disease clinic of a large urban medical center. Individual interviews were conducted at baseline and two follow-up points, 8 to 18 months after enrollment. Based on a model of health behavior, we examined psychiatric and psychosocial predictors of adherence to antiretroviral medications and medical appointments over time. Presence of a psychiatric disorder, negative stressful life events, more household members, and parenting stress were significantly associated with both missed pills and missed medical appointments at follow-up. Baseline substance abuse was associated with missed pills at follow-up and lack of disclosure to family members at baseline was associated with missed medical appointments at follow-up. These findings suggest that interventions that integrate mental health, substance abuse and medical care may be important to improving the medical adherence and health of HIV-seropositive women, particularly in multistressed populations with substantial caregiving and other life demands. C1 New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. Columbia Univ, Dept Psychiat, New York, NY USA. Natl Ctr Complementary & Alternat Med, NIH, Bethesda, MD USA. RP Mellins, CA (reprint author), New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, Box 15,1051 Riverside Dr, New York, NY 10032 USA. FU NIMH NIH HHS [P30 MH59037, P50-MH43520, P50 MH42459] NR 46 TC 73 Z9 73 U1 3 U2 9 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD AUG PY 2003 VL 17 IS 8 BP 407 EP 416 DI 10.1089/108729103322277420 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 715DR UT WOS:000184955700004 PM 13678542 ER PT J AU Carr, LG Spence, JP Eriksson, CJP Lumeng, L Li, TK AF Carr, LG Spence, JP Eriksson, CJP Lumeng, L Li, TK TI AA and ANA rats exhibit the R100Q mutation in the GABA(A) receptor alpha(6) subunit SO ALCOHOL LA English DT Article DE GABA(A) receptor alpha(6) subunit; polymorphism; rat lines; alcohol preference ID ALCOHOL-PREFERRING RATS; DRINKING BEHAVIOR; ETHANOL; CONSUMPTION; PREFERENCE; RESPONSES; STRAINS; LINES; SNP AB The R100Q mutation in the gamma-aminobutyric acid type A (GABA(A)) receptor alpha(6) subunit was previously identified in Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats as a candidate gene influencing alcohol preference and sensitivity. The purpose of the current study was to determine to what extent this mutation and alcohol preference observed in the sP and sNP lines was present in other independently selected rat lines, including inbred alcobol-preferring (iP) and inbred alcohol-nonpreferring (W), high-alcohol-drinking I (HAD1) and low-alcohol-drinking I (LAD1), high-alcohol-drinking 2 (HAD2) and low-alcohol-drinking 2 (LAD2), and Alko Alcohol (AA) and Alko Non-Alcohol (ANA). Sequence analysis was first performed to screen for the R100Q mutation in several samples. Later, a genotyping assay was conducted to assess the frequency of the R100Q mutation in larger sample sizes. The R100Q mutation was identified only in the AA/ANA population, with a significantly (P < .0001) higher frequency in the alcohol-nonpreferring ANA line. The absence of the R100Q mutation in the other rat lines that were selectively bred for alcohol consumption and alcohol preference may be due to genetic diversity among the Wistar stocks used to develop the various lines. (C) 2003 Elsevier Inc. All rights reserved. C1 Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Pharmacol, Indianapolis, IN 46202 USA. Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki 00101, Finland. NIAAA, NIH, Bethesda, MD 20892 USA. RP Carr, LG (reprint author), Indiana Univ, Sch Med, Dept Med, 975 W Walnut St,IB 407, Indianapolis, IN 46202 USA. FU NIAAA NIH HHS [AA10707, AA07611] NR 23 TC 20 Z9 21 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD AUG-OCT PY 2003 VL 31 IS 1-2 BP 93 EP 97 DI 10.1016/j.alcohol.2003.07.003 PG 5 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 747UQ UT WOS:000186823600012 PM 14615016 ER PT J AU Le Fauve, CE Lowman, C Litten, RZ Mattson, ME AF Le Fauve, CE Lowman, C Litten, RZ Mattson, ME TI Introduction: National Institute on Alcohol Abuse and Alcoholism Workshop on Treatment Research Priorities and Health Disparities SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material C1 NIAAA, Div Clin & Prevent Res, Treatment Res Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Le Fauve, CE (reprint author), NIAAA, Div Clin & Prevent Res, Treatment Res Branch, NIH,Dept Hlth & Human Serv, Willco Bldg,Suite 505,6000 Execut Blvd, Bethesda, MD 20892 USA. NR 21 TC 8 Z9 8 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2003 VL 27 IS 8 BP 1318 EP 1320 DI 10.1097/01.ALC.0000080383.74960.09 PG 3 WC Substance Abuse SC Substance Abuse GA 714AX UT WOS:000184891100017 PM 12966328 ER PT J AU Lowman, C Le Fauve, CE AF Lowman, C Le Fauve, CE TI Health disparities and the relationship between race, ethnicity,and substance abuse treatment outcomes SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT Workshop on Treatment Research Priorities and Health Disparities CY SEP 23-24, 2002 CL BERHESDA, MARYLAND SP Natl Inst Alcohol Abuse & Alcoholism C1 NIAAA, Treatment Res Branch, Div Clin & Prevent Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lowman, C (reprint author), NIAAA, Treatment Res Branch, Div Clin & Prevent Res, NIH,Dept Hlth & Human Serv, Willco Bldg,Suite 505,6000 Execut Blvd, Bethesda, MD 20892 USA. NR 8 TC 14 Z9 14 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2003 VL 27 IS 8 BP 1324 EP 1326 DI 10.1097/01.ALC.0000080346.62012.DC PG 3 WC Substance Abuse SC Substance Abuse GA 714AX UT WOS:000184891100019 PM 12966330 ER PT J AU Herd, JA Hoogwerf, BJ Barton, F Terrin, ML Czajkowski, SM Lindquist, R Dupuis, G AF Herd, JA Hoogwerf, BJ Barton, F Terrin, ML Czajkowski, SM Lindquist, R Dupuis, G TI Heart rate and blood pressure responses to mental stress and clinical cardiovascular events in men and women after coronary artery bypass grafting: The Post Coronary Artery Bypass Graft (Post-CABG) biobehavioral study SO AMERICAN HEART JOURNAL LA English DT Article ID INDUCED MYOCARDIAL-ISCHEMIA; LEFT-VENTRICULAR FUNCTION; BETA-ADRENERGIC-BLOCKADE; MIDDLE-AGED MEN; PSYCHOPHYSIOLOGICAL INVESTIGATIONS; POSTINFARCTION PATIENTS; EJECTION FRACTION; A BEHAVIOR; REACTIVITY; DISEASE AB Background The Post-Coronary Artery Bypass Graft (CABG) biobehavioral study measured the heart rate (HR) and blood pressure (BP) responses to mental stress testing (MST) after surgery and prospectively observed the clinical events in patients who had undergone recent CABG surgery. To the extent that CABG surgery restores myocardial blood flow and prevents myocardial ischemia, patients who have recently recovered from CABG surgery may have nearly normal HR and BP responses to MST. Methods A study population of 521 patients (351 men, 170 women) from the cohort of 759 patients in the Post-CABG biobehavioral Study was monitored during a mirror tracing test (MTT) and a speech test task (STT) at the 6-month post-CABG surgery follow-up. Medical status for as long as 3 years after CABG surgery was ascertained from questionnaires and medical records. Results The HR and BP responses during MTT and STT were similar to those reported in other studies of healthy individuals and patients without myocardial ischemia during MST. In contrast to results from other studies of patients with coronary artery disease, the quartile of Post-CABG biobehavioral study patients with the greatest responses in HR, systolic BP (SBP) and diastolic BP (DBP) during MST had half the rate of clinical events (10% in 3 years) as the quartile (20%) with the lowest changes in HR and BP (HR, P =.01; SBP, P =.07; DBP, P =.01). Conclusions Vigorous HR and BP responses to MST may be markers for a lower risk of incidence of clinical cardiovascular events among patients who have undergone recent CABG surgery. C1 Maryland Med Res Inst, Baltimore, MD 21210 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Cleveland Clin Fdn, Dept Med, Cleveland, OH 44195 USA. NHLBI, Div Behav Med, Bethesda, MD 20892 USA. Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Univ Quebec, Montreal, PQ H3C 3P8, Canada. RP Terrin, ML (reprint author), Maryland Med Res Inst, 600 Wyndhurst Ave, Baltimore, MD 21210 USA. FU NHLBI NIH HHS [N01-HC-7501-7506] NR 35 TC 6 Z9 6 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2003 VL 146 IS 2 BP 273 EP 279 DI 10.1016/S0002-8703(03)00182-0 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 710XP UT WOS:000184708400018 PM 12891195 ER PT J AU Caballero, B Himes, JH Lohman, T Davis, SM Stevens, J Evans, M Going, S Pablo, J AF Caballero, B Himes, JH Lohman, T Davis, SM Stevens, J Evans, M Going, S Pablo, J CA Pathways Study Res Grp TI Body composition and overweight prevalence in 1704 schoolchildren from 7 American Indian communities SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE body composition; obesity; American Indians; obesity prevention; children ID PRESCHOOL-CHILDREN; EXPERT COMMITTEE; UNITED-STATES; MASS INDEX; OBESITY; ADOLESCENTS; HEALTH; WEIGHT; RECOMMENDATIONS; ADIPOSITY AB Background: Nationwide data on obesity prevalence in American Indian communities are limited. Objective: We describe the body composition and anthropometric characteristics of schoolchildren from 7 American Indian communities enrolled in the Pathways study, a randomized field trial evaluating a program for the primary prevention of obesity. Design: A total of 1704 children in 41 schools were enrolled in the study. Basic anthropometric measurements included weight, height, and triceps and subscapular skinfold thicknesses. Percentage body fat was estimated from bioelectrical impedance and anthropometric variables with the use of an equation developed and validated for this population. Results: The children's mean (+/- SD) age was 7.6 +/- 0.6 y, and their mean weight and height were 32.1 +/- 8.9 kg and 129.8 +/- 6.3 cm, respectively. Mean body mass index (BMI; in kg/m(2)) was 18.8 +/- 3.9, and mean percentage body fat was 32.6 +/- 6.8%. With the use of current Centers for Disease Control and Prevention reference values, 30.5% of girls and 26.8% of boys were above the 95th percentiles for BMI-for-age, and 21% of girls and 19.6% of boys were between the 85th and 95th percentiles. Although there was a wide range in BMI across study sites and for both sexes, the percentage of children with a BMI above the 95th percentile was consistently higher than the national averages in all communities studied and in both girls and boys. Conclusions: Overweight can be documented in a substantial number of American Indian children by the time they reach elementary school. Despite differences in the prevalence of overweight observed among communities, rates are uniformly high relative to national all-race averages. C1 Johns Hopkins Univ, Ctr Human Nutr, Baltimore, MD 21205 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Arizona, Dept Physiol, Tucson, AZ USA. Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA. Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. NHLBI, Bethesda, MD 20892 USA. Tohono Oodham Nation, Sells, AZ USA. RP Caballero, B (reprint author), Johns Hopkins Univ, Ctr Human Nutr, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [U01-HL-50885, U01 HL050867, U01 HL050869, U01-HL-50905, U01-HL-50907] NR 34 TC 49 Z9 49 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2003 VL 78 IS 2 BP 308 EP 312 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 704XE UT WOS:000184366300019 PM 12885714 ER PT J AU Leitzmann, MF Tsai, CJ Stampfer, MJ Rimm, EB Colditz, GA Willett, WC Giovannucci, EL AF Leitzmann, MF Tsai, CJ Stampfer, MJ Rimm, EB Colditz, GA Willett, WC Giovannucci, EL TI Alcohol consumption in relation to risk of cholecystectomy in women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE alcohol; cholelithiasis; cholecystectomy; cohort; women ID HIGH-DENSITY-LIPOPROTEIN; CLINICAL GALLBLADDER-DISEASE; BILE CHOLESTEROL SATURATION; GALLSTONE-DISEASE; UNITED-STATES; SYMPTOMATIC GALLSTONES; DANISH POPULATION; PHYSICAL-ACTIVITY; NUCLEATION TIME; PREVALENCE AB Background: Alcohol consumption has been linked to a lower risk of gallstone disease. However, the magnitude of the association is uncertain, and little is known about the relation of alcohol consumption patterns and individual types of alcoholic beverages to gallstone disease risk. Objective: We prospectively examined the association between alcohol intake and cholecystectomy, a surrogate for symptomatic gallstone disease, in a large cohort of women. Design: Women from the Nurses' Health Study who had no history of gallstone disease in 1980 (n = 80 898) were followed for 20 y. Alcohol consumption, which was measured every 2-4 y by food-frequency questionnaires, was used to predict subsequent cholecystectomy through multivariate analysis. Results: We ascertained 7831 cases of cholecystectomy. Relative to subjects who had no alcohol intake, subjects who had alcohol intakes of 0.1-4.9, 5.0-14.9, 15.0-29.9, 30.0-49.9, and greater than or equal to 50.0 g/d had multivariate relative risks of cholecystectomy of 0.95, 0.86, 0.80, 0.67, and 0.62 (95% CI: 0.49, 0.79), respectively. Relative to subjects who never consumed alcohol, subjects who consumed alcohol 1-2, 3-4, 5-6, and 7 d/wk had multivariate relative risks of cholecystectomy of 0.94, 0.88, 0.87, and 0.73 (0.63, 0.84), respectively. All alcoholic beverage types were inversely associated with cholecystectomy risk, independent of consumption patterns (for quantity of alcohol consumed, P = 0.04, 0.001, and 0.003 for wine, beer, and liquor, respectively; for frequency of alcohol consumption, P = 0.01, 0.07, and <0.0001 for wine, beer, and liquor, respectively). Conclusions: The intake of all alcoholic beverage types is inversely associated with the risk of cholecystectomy. Recommendations regarding the benefit of consuming moderate quantities of alcohol should be weighed against the potential health hazards. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Ctr Canc Prevent, Boston, MA 02115 USA. Harvard Univ, Dana Farber Canc Inst, Program Epidemiol, Boston, MA USA. RP Leitzmann, MF (reprint author), NCI, 6120 Execut Blvd,EPS 3028, Rockville, MD 20852 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 87969, 5T32 CA09001-26]; NIAAA NIH HHS [AA11181]; NIDDK NIH HHS [DK 46200] NR 53 TC 27 Z9 27 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2003 VL 78 IS 2 BP 339 EP 347 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 704XE UT WOS:000184366300024 PM 12885719 ER PT J AU Umar, A Viner, JL Anderson, WF Hawk, ET AF Umar, A Viner, JL Anderson, WF Hawk, ET TI Development of COX inhibitors in cancer prevention and therapy SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE cyclooxygenases; COX-1; COX-2; cancer prevention; cancer therapy; molecular target; clinical trials; nonsteroidal antiinflammatory drugs (NSAIDs); celecoxib; sulindac; aspirin ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; FAMILIAL ADENOMATOUS POLYPOSIS; HUMAN COLON-CANCER; PROSTAGLANDIN-H-SYNTHASE; HUMAN GASTRIC-CARCINOMA; ABERRANT CRYPT FOCI; FEMALE A/J MICE; TRANSITIONAL-CELL CARCINOMA; HUMAN COLORECTAL-CANCER AB dOn the strength of in vitro, in vivo, observational, and clinical data, nonsteroidal antiinflammatory drugs (NSAIDs)-also referred to as COX inhibitors-have emerged as lead compounds for cancer prevention, and possible adjuncts to cancer therapy. Thus far, the routine use of NSAIDs for these indications is limited, largely owing to toxicity concerns, the paucity of efficacy data for any specific target organ, and uncertainties with regard to the most appropriate regimen (i.e., the best agent, formulation, dose, route of administration, and duration). Strategies to address these concerns primarily aim to improve the therapeutic index (i.e., benefit:risk ratio) of COX inhibitors by 1) minimizing systemic exposures whenever feasible, 2) achieving greater mechanistic specificity, 3) coadministering agents that provide prophylaxis against common toxicities, and 4) coadministering other effective anticancer agents. Clinical trials testing most of these strategies have been completed or are under way. The National Cancer Institute has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs as preventive and therapeutic anticancer agents. Discovering how to apply NSAIDs in persons with-or at risk for-cancer, although challenging, has the potential for considerable clinical and public health benefits. C1 NCI, Div Canc Prevent, EPN, Bethesda, MD 20892 USA. NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Hawk, ET (reprint author), NCI, Div Canc Prevent, EPN, Suite 2141,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 193 TC 20 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2003 VL 26 IS 4 SU 2 BP S48 EP S57 DI 10.1097/01.COC.0000074157.28792.02 PG 10 WC Oncology SC Oncology GA 712EF UT WOS:000184783700003 PM 12902856 ER PT J AU Prieto, VG Argenyi, ZB Barnhill, RL Duray, PH Elenitsas, R From, L Guitart, J Horenstein, MG Ming, ME Piepkorn, MW Rabkin, MS Reed, JA Selim, MA Trotter, MJ Johnson, MM Shea, CR AF Prieto, VG Argenyi, ZB Barnhill, RL Duray, PH Elenitsas, R From, L Guitart, J Horenstein, MG Ming, ME Piepkorn, MW Rabkin, MS Reed, JA Selim, MA Trotter, MJ Johnson, MM Shea, CR TI Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 91st Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 23-MAR 01, 2002 CL CHICAGO, ILLINOIS SP US & Canadian Acad Pathol DE frozen sections; accuracy; concordance; melanocytic; en face ID LENTIGO-MALIGNA-MELANOMA; MOHS MICROGRAPHIC SURGERY; EMBEDDED TANGENTIAL SECTIONS; PRIMARY CUTANEOUS MELANOMA; RUSH PERMANENT SECTIONS; TUMOR THICKNESS; QUALITY-CONTROL; MANAGEMENT; LIMITATIONS; EXPERIENCE AB To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly. Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per derimtopathologist and per case. One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (68%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (kappa range per dermatopathologist, -0.1282 to 0.6615). If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions. C1 Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. NIH, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Toronto, Toronto, ON, Canada. Northwestern Univ, Chicago, IL 60611 USA. Univ S Alabama, Mobile, AL 36688 USA. Rabkin Dermatopathol, Pittsburgh, PA USA. Baylor Coll Med, Houston, TX 77030 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Calgary, Calgary, AB, Canada. Univ Chicago, Chicago, IL 60637 USA. RP Prieto, VG (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Box 85,1515 Holcombe Blvd, Houston, TX 77030 USA. NR 31 TC 43 Z9 44 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2003 VL 120 IS 2 BP 203 EP 208 DI 10.1309/J1Q0V35EUTMVR193 PG 6 WC Pathology SC Pathology GA 705XP UT WOS:000184422600007 PM 12931550 ER PT J AU Matise, TC Sachidanandam, R Clark, AG Kruglyak, L Wijsman, E Kakol, J Buyske, S Chui, B Cohen, P de Toma, C Ehm, M Glanowski, S He, CS Heil, J Markianos, K McMullen, I Pericak-Vance, MA Silbergleit, A Stein, L Wagner, M Wilson, AF Winick, JD Winn-Deen, ES Yamashiro, CT Cann, HM Lai, E Holden, AL AF Matise, TC Sachidanandam, R Clark, AG Kruglyak, L Wijsman, E Kakol, J Buyske, S Chui, B Cohen, P de Toma, C Ehm, M Glanowski, S He, CS Heil, J Markianos, K McMullen, I Pericak-Vance, MA Silbergleit, A Stein, L Wagner, M Wilson, AF Winick, JD Winn-Deen, ES Yamashiro, CT Cann, HM Lai, E Holden, AL TI A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HUMAN GENOME; SEQUENCE VARIATION; GENOTYPING ERRORS; GENETIC MAPS; MARKERS; CONSTRUCTION; DISEQUILIBRIUM; RECOMBINATION; PROGRAM; IDENTIFICATION AB Recent advances in technologies for high-throughout single-nucleotide polymorphism ( SNP) - based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with 1770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set. C1 Rutgers State Univ, Dept Genet, Piscataway, NJ 08840 USA. Rutgers State Univ, Dept Stat, Piscataway, NJ 08840 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. Celera Genom, Rockville, MD USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Amersham Biosci, Chandler, AZ USA. Fdn Jean Dausset CEPH, Paris, France. GlaxoSmithKline Inc, Res Triangle Pk, NC USA. Duke Univ, Med Ctr, Durham, NC USA. NHGRI, NIH, Baltimore, MD USA. Roche Mol Syst, Pleasanton, CA USA. First Genet Trust, Deerfield, IL USA. RP Matise, TC (reprint author), Rutgers State Univ, Dept Genet, 604 Allison Rd, Piscataway, NJ 08840 USA. EM matise@biology.rutgers.edu RI Buyske, Steven/B-8130-2009; Wilson, Alexander/C-2320-2009; OI Buyske, Steven/0000-0001-8539-5416; sachidanandam, ravi/0000-0001-9844-4459 NR 46 TC 84 Z9 85 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2003 VL 73 IS 2 BP 271 EP 284 DI 10.1086/377137 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 702KW UT WOS:000184223900005 PM 12844283 ER PT J AU Gillanders, E Juo, SHH Holland, EA Jones, M Nancarrow, D Freas-Lutz, D Sood, R Park, N Faruque, M Markey, C Kefford, RF Palmer, J Bergman, W Bishop, DT Tucker, MA Bressac-de Paillerets, B Hansson, J Stark, M Gruis, N Bishop, JN Goldstein, AM Bailey-Wilson, JE Mann, GJ Hayward, N Trent, J AF Gillanders, E Juo, SHH Holland, EA Jones, M Nancarrow, D Freas-Lutz, D Sood, R Park, N Faruque, M Markey, C Kefford, RF Palmer, J Bergman, W Bishop, DT Tucker, MA Bressac-de Paillerets, B Hansson, J Stark, M Gruis, N Bishop, JN Goldstein, AM Bailey-Wilson, JE Mann, GJ Hayward, N Trent, J CA Lund Melanoma Study Grp Melanoma Genetics Consortium TI Localization of a novel melanoma susceptibility locus to 1p22 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DYSPLASTIC NEVUS SYNDROME; FAMILIAL MELANOMA; LINKAGE ANALYSIS; GERMLINE MUTATIONS; CUTANEOUS MELANOMA; PANCREATIC-CANCER; CDKN2A MUTATIONS; DUTCH FAMILIES; PRONE FAMILIES; RISK AB Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta = 0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores 13 in this subset, with the highest parametric LOD score, 4.95 (theta = 0) ( nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22. C1 Translat Genom Res Inst, Phoenix, AZ 85004 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Epidemiol, New York, NY USA. Columbia Univ, Columbia Genome Ctr, New York, NY USA. Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. Queensland Canc Fund Res Unit, Brisbane, Qld, Australia. Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. Canc Res UK Clin Ctr, Genet Epidemiol Div, Leeds, W Yorkshire, England. Inst Gustave Roussy, Villejuif, France. Karolinska Hosp, Dept Oncol Pathol, S-10401 Stockholm, Sweden. Univ Hosp, Lund Canc Ctr, Dept Oncol, Lund, Sweden. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Trent, J (reprint author), Translat Genom Res Inst, 400 N 5th St,Suite 1600, Phoenix, AZ 85004 USA. RI Stark, Mitchell/E-3542-2010; Juo, Suh-Hang/A-1765-2010; Juo, Suh-Hang/C-9545-2009; Mann, Graham/G-4758-2014; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; OI Stark, Mitchell/0000-0002-4510-2161; Mann, Graham/0000-0003-1301-405X; hayward, nicholas/0000-0003-4760-1033; Gruis, Nelleke/0000-0002-5210-9150; Bailey-Wilson, Joan/0000-0002-9153-2920; Bishop, Tim/0000-0002-8752-8785 FU NCI NIH HHS [CA88363, R01 CA088363] NR 42 TC 75 Z9 77 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2003 VL 73 IS 2 BP 301 EP 313 DI 10.1086/377140 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 702KW UT WOS:000184223900007 PM 12844286 ER PT J AU Harwell, TS Nelson, RG Little, RR McDowall, JM Helgerson, SD Gohdes, D AF Harwell, TS Nelson, RG Little, RR McDowall, JM Helgerson, SD Gohdes, D TI Testing for microalbuminuria in 2002: Barriers to implementing current guidelines SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE albuminuria/diagnosis; creatinine/urine; laboratories; mass screening; Montana; reference values; specimen handling; diabetes mellitus (DM); cardiovascular disease (CVD) ID RISK; ALBUMINURIA AB Background Testing for microalbuminuria is recommended to detect early kidney damage in patients with diabetes or other diseases. However, few studies have examined laboratory practices for microalbuminuria testing in the general community. Methods: In 2002, all laboratories in Montana and reference laboratories used by Montana laboratories for microalbuminuria measurement were surveyed by mail to ascertain if they provided testing for microalbuminuria, specific tests performed, and units and cutoff values used to report microalbuminuria results. Results: One hundred three of 126 laboratories (82%) responded to the survey. Overall, 79% of laboratories offered quantitative testing for microalbuminuria, either on site or through a reference laboratory. Twenty-five laboratories (24%) surveyed provided quantitative testing for microalbuminuria on site. Only 14 of 23 laboratories offering albumin-creatinine ratios on site reported results in units and cutoff values consistent with current recommendations. Fewer laboratories provided 24-hour (6 of 17 laboratories) or other timed (2 of 7 laboratories) testing, and many of these laboratories did not report results using recommended units and cutoff values. Overall, only 11 of 25 laboratories (44%) with on-site testing reported microalbuminuria values from 1 or more types of specimens exclusively using recommended units and cutoff values. Conclusion: Quantitative testing for microalbuminuria is not offered universally, and results often are reported in units and cutoff values that differ from current clinical recommendations. C1 Montana Dept Publ Hlth & Human Serv, Helena, MT 59620 USA. NIDDKD, Phoenix, AZ USA. Univ Missouri, Sch Med, Columbia, MO USA. RP Harwell, TS (reprint author), Montana Dept Publ Hlth & Human Serv, Cogswell Bldg,C-317,POB 202951, Helena, MT 59620 USA. RI Nelson, Robert/B-1470-2012; OI Little, Randie/0000-0001-6450-8012 FU ODCDC CDC HHS [U32/CCU815663-04] NR 10 TC 13 Z9 13 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2003 VL 42 IS 2 BP 245 EP 248 DI 10.1016/S0272-6386(03)00648-6 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 708FV UT WOS:000184557300004 PM 12900804 ER PT J AU Hostetter, TH AF Hostetter, TH TI Detecting early chronic kidney disease: Are clinical laboratories a problem? SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID DEPENDENT DIABETIC-PATIENTS; PREVENT RENAL-FAILURE; COST-EFFECTIVENESS; ECONOMIC-EVALUATION; NEPHROPATHY; MICROALBUMINURIA; INHIBITORS; TRIAL C1 NIDDK, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. RP Hostetter, TH (reprint author), NIDDK, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. NR 20 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2003 VL 42 IS 2 BP 392 EP 394 DI 10.1016/S0272-6386(03)00689-9 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 708FV UT WOS:000184557300026 PM 12900826 ER PT J AU Gollust, SE Thompson, RE Gooding, HC Biesecker, BB AF Gollust, SE Thompson, RE Gooding, HC Biesecker, BB TI Living with achondroplasia in an average-sized world: An assessment of quality of life SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE short stature; quality of life; achondroplasia; self-esteem; illness perception; social functioning ID NONLETHAL CHONDRODYSPLASIAS; PSYCHOSOCIAL-ASPECTS; DWARFING CONDITIONS; BONE DYSPLASIAS; CHRONIC ILLNESS; SHORT STATURE; HEALTH-STATUS; SELF-ESTEEM; ADULTS; CHILDREN AB Mutations in the gene encoding fibroblast growth factor receptor 3 cause achondroplasia, the most common form of inherited skeletal dysplasia. Although there are more than 10,000 individuals with achondroplasia living in the United States, there has been little study of their quality of life (QOL). For this study, surveys were collected from 189 individuals affected with achondroplasia (ACH) and 136 unaffected first-degree relatives (FDRs) of affected individuals. Individuals affected with achondroplasia had lower annual income, less education, and were less likely to be married than FDRs. They also differed significantly in their perceptions of achondroplasia, with FDRs believing that achondroplasia is a more serious condition. Total QOL indices and indices in each of four QOL subdomains were significantly lower in affected individuals than in relatives. When controlling for demographic characteristics and affected status, having lower self-esteem scores and perceiving achondroplasia as more serious were the independent factors most highly associated with lower QOL. A qualitative analysis of open responses to questions about the advantages and disadvantages of achondroplasia revealed that individuals were as likely to cite disadvantages relating to social barriers as they were to cite those relating to health and functioning. We interpret the low QOL scores to reflect the social challenges that individuals with achondroplasia regularly experience in the average-sized world. Genetics professionals should considersources of lower QOL for affected individuals in their counseling sessions to acknowledge the relative importance of non-medical contributions. Published 2003 Wiley-Liss, Inc. C1 NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Biostat Ctr, Baltimore, MD USA. RP Biesecker, BB (reprint author), NHGRI, NIH, Med Genet Branch, 10 Ctr Dr,Bldg 10,Room 10C101, Bethesda, MD 20892 USA. NR 53 TC 27 Z9 29 U1 1 U2 12 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG 1 PY 2003 VL 120A IS 4 BP 447 EP 458 DI 10.1002/ajmg.a.20127 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 707NG UT WOS:000184516300001 PM 12884421 ER PT J AU Penninx, BWJH Guralnik, JM Onder, G Ferrucci, L Wallace, RB Pahor, M AF Penninx, BWJH Guralnik, JM Onder, G Ferrucci, L Wallace, RB Pahor, M TI Anemia and decline in physical performance among older persons SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; IRON-DEFICIENCY; HEALTH; PREVALENCE; POPULATION; MORTALITY; PREDICTOR; DISEASE; PEOPLE AB PURPOSE: Anemia is prevalent in old age and is potentially modifiable, but its effects on physical function have not been determined. We examined whether anemia in older persons increases the risk of subsequent decline in physical function, as measured by objective performance-based tests. METHODS: Participants in this 4-year prospective cohort study included 1146 participants, aged 71 years or older, living in Iowa and Washington counties, Iowa. Anemia was defined according to World Health Organization (WHO) criteria as a hemoglobin concentration below 12 g/dL in women and below 13 g/dL in men. An assessment of standing balance, a timed 2.4-m walk, and a timed test of five chair rises were used to assess physical performance; these were combined into a 0 (poor) to 12 (excellent) summary scale. RESULTS: After adjustment for baseline performance score, health status, and demographic characteristics, anemia was associated with greater mean decline in physical performance over 4 years; the adjusted mean decline was 2.3 (95% confidence interval [CI]: 1.7 to 2.8) in subjects with anemia and 1.4 (95% CI: 1.2 to 1.5) in those without anemia (P = 0.003). The association between anemia and greater physical decline was also present in participants who were free of diseases associated with anemia (cancer, infectious disease, and renal failure), and after adjustment for serum cholesterol, iron, and albumin levels. Persons with borderline anemia, a hemoglobin concentration within 1 g/dL above the WHO criteria, also showed greater mean physical decline (1.8;,95% CI: 1.5 to 2.2) than did those with higher hemoglobin concentrations (P = 0.02). CONCLUSION: This study suggests that anemia in old age is an independent risk factor for decline in physical performance. C1 Wake Forest Univ Hlth Sci, Sticht Ctr Aging, Winston Salem, NC 27157 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. I Fraticini Natl Res Inst, Dept Geriatr, Florence, Italy. Univ Iowa, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. RP Penninx, BWJH (reprint author), Wake Forest Univ Hlth Sci, Sticht Ctr Aging, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. EM bpenninx@wfubmc.edu FU NIA NIH HHS [5P60 AG 10484-07, N01-AG-1-2112, N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106] NR 31 TC 147 Z9 152 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2003 VL 115 IS 2 BP 104 EP 110 DI 10.1016/S0002-9343(03)00263-8 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 707RJ UT WOS:000184523400004 PM 12893395 ER PT J AU Brown, ML Klabunde, CN Mysliwiec, P AF Brown, ML Klabunde, CN Mysliwiec, P TI Current capacity for endoscopic colorectal cancer screening in the United States: Data from the National Cancer Institute Survey of Colorectal Cancer Screening Practices SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID CLINICAL GUIDELINES; RECOMMENDATIONS; SURVEILLANCE; COLONOSCOPY; DIAGNOSIS; RATIONALE; PATTERNS; UPDATE AB PURPOSE: There is a national goal in the United States to increase the level of colorectal cancer screening, but there is currently little information on resources for the delivery of endoscopic screening and follow-up diagnostic and surveillance procedures. The purpose of this study was to provide nationally representative data on endoscopic resources at the provider level. METHODS: A nationally representative survey of primary care physicians, general surgeons, and gastroenterologists that was conducted during 1999 to 2000 provided data from survey responses by 1235 primary care physicians, 349 gastroenterologists, and 316 general surgeons. RESULTS: We estimated that 65% of all sigmoidoscopy procedures were performed by primary care physicians, 25% by gastroenterologists, and 10% by general surgeons. Only 30% of all primary care physicians performed any procedures, and average volume among those who did was relatively low (seven per month). Gastroenterologists performed two thirds of all colonoscopy procedures, with most of the remainder performed by general surgeons. CONCLUSION: There is potential to increase the capacity to perform screening sigmoidoscopy procedures through primary care delivery. However, without careful consideration of organizational factors, this could result in increased cost and quality control problems. Increasing the capacity for screening colonoscopy is feasible, but will require attention to other problems, such as avoiding overfrequent (e.g., annual or biennial) procedures in low-risk patients. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Brown, ML (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room EPN 4005, Bethesda, MD 20892 USA. NR 20 TC 88 Z9 88 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2003 VL 115 IS 2 BP 129 EP 133 DI 10.1016/S0002-9343(03)00297-3 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 707RJ UT WOS:000184523400008 PM 12893399 ER PT J AU Wadhawan, R Vohr, BR Fanaroff, AA Perritt, RL Duara, S Stoll, BJ Goldberg, R Laptook, A Poole, K Wright, LL Oh, W AF Wadhawan, R Vohr, BR Fanaroff, AA Perritt, RL Duara, S Stoll, BJ Goldberg, R Laptook, A Poole, K Wright, LL Oh, W TI Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cesarean delivery; labor; extremely low birth weight ID INTRAVENTRICULAR HEMORRHAGE; NATIONAL-INSTITUTE; CHILD-HEALTH; RESEARCH NETWORK; PRETERM INFANTS; CEREBRAL-PALSY; RISK-FACTORS AB OBJECTIVE: The purpose of this study was to examine the influence of labor on extremely-low-birth-weight infants who were born by cesarean delivery with reference to neonatal and neurodevelopmental outcomes. We hypothesized that infants who are born by cesarean delivery without labor will have better outcomes than those infants who are born by cesarean delivery with labor. STUDY DESIGN: This was a retrospective cohort study of extremely-low-birth-weight infants (birth weight, 401-1000 g) who were born by cesarean delivery and cared for in the National Institute for Child Health and Human Development Neonatal Network, during calendar years 1995 to 1997. A total of 1606 extremely-low-birth-weight infants were born by cesarean delivery and survived to discharge. Of these, 1273 infants (80.8%) were examined in the network follow-up clinics at 18 to 22 months of corrected age and had a complete data set (667 infants were born without labor, 606 infants were born with labor). Outcome variables that were examined include intraventricular hemorrhage grade 3 to 4, periventricular leukomalacia, and neurodevelopmental impairment. RESULTS: Mothers in the cesarean delivery without labor group were older (P<.001), more likely to be married (P <.05), less likely to be supported by Medicaid (P<.01), more likely to have preeclampsia/ hypertension (P<.001), more likely to receive prenatal steroids (P<.005), and less likely to have received antibiotics (P<.001). Infants who were born by cesarean delivery without labor had higher gestational age (P<.001), lower birth weight (P<.01), and were less likely to be outborn (P<.001). By univariate analysis, infants who were born by cesarean delivery with labor had a higher incidence of grade 3 to 4 intraventricular hemorrhage (23.3% vs 12.1%, P<.001), periventricular leukomalacia (8.5% vs 4.7%, P<02), and neurodevelopmental impairment (41.7% vs 34.6%, P<.02). Logistic regression analysis that controlled for all maternal and neonatal demographic and clinical variables that were statistically associated with labor or no labor revealed that the significant differences in grade 3 to 4 intraventricular hemorrhage, periventricular leukornalacia, and neurodevelopmental impairment were no longer evident. CONCLUSION: In extremely-low-birth-weight infants who were born by cesarean delivery and after control for other risk factors, labor does not appear to play a significant role in adverse neonatal outcomes and neurodevelopmental impairment at 18 to 22 months of corrected age. C1 NICHHD, Neonatal Res Network, Bethesda, MD 20892 USA. RP Wadhawan, R (reprint author), 101 Dudley St, Providence, RI 02905 USA. FU NCRR NIH HHS [M01 RR 08084, M01 RR00997, M01 RR 00070, M01 RR 06022, M01 RR 00750]; NICHD NIH HHS [U10 HD40461, U10 HD27871, U10 HD27856, U10 HD21364, U10 HD27881, U01 HD36790, U10 HD27853, U10 HD27851, U10 HD21415, U10 HD34216, U10 HD27904, U10 HD21373, U10 HD27880, U10 HD40689, U10 HD21385, U10 HD21397] NR 24 TC 24 Z9 25 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2003 VL 189 IS 2 BP 501 EP 506 DI 10.1067/S0002-9378(03)00360-0 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 719RV UT WOS:000185219100047 PM 14520225 ER PT J AU Minkoff, H Hershow, R Watts, DH Frederick, M Cheng, I Tuomala, R Pitt, J Zorrilla, CD Hammill, H Adeniyi-Jones, SY Thompson, B AF Minkoff, H Hershow, R Watts, DH Frederick, M Cheng, I Tuomala, R Pitt, J Zorrilla, CD Hammill, H Adeniyi-Jones, SY Thompson, B TI The relationship of pregnancy to human immunodeficiency virus disease progression SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE human immunodeficiency virus; pregnancy; women; human immunodeficiency virus-1 RNA; CD4 cell count ID HIV-INFECTION; AIDS; WOMEN; INFANTS; PROGRAM; COHORT AB OBJECTIVE: This study was undertaken to determine the effect of pregnancy on progression of human immunodeficiency virus (HIV) disease. STUDY DESIGN: We compared the immunologic, clinical, and virologic courses of 953 women who had no additional pregnancy after their index pregnancy, with the courses of 329 women who had a second pregnancy subsequent to their index pregnancy. Baseline variables included use of antiretroviral therapy, and CD4 and HIV RNA values. A linear spline growth curve model was used to describe trajectories of variables. The Cox proportional hazards model was used to assess selected covariates on the time to development of clinical class C events or death. RESULTS: Women with repeat pregnancies were less likely to be on antiretroviral therapy at baseline and had a higher CD4% count immediately after their first delivery. The average trajectory of CD4 values in the one-pregnancy group was almost identical to the average trajectory in the repeat pregnancy group. RNA levels in the single-pregnancy group started higher but ended lower than in the second-pregnancy group, although slope differences were modest. There were no significant differences in time to class C events, although women in the repeat-pregnancy group tended to survive longer. CONCLUSION: Repeat pregnancies do not have significant effects on the course of HIV disease. C1 Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. Suny Downstate Med Ctr, New York, NY USA. Univ Illinois, Dept Internal Med, Chicago, IL USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Clin Trials & Surveys Corp, Baltimore, MD USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Columbia Univ, Dept Pediat, Boston, MA USA. Univ Puerto Rico, Dept Obstet & Gynecol, San Juan, PR 00936 USA. Baylor Coll Med, Dept Family & Community Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. NIAID, Houston, TX USA. RP Minkoff, H (reprint author), Maimonides Hosp, Dept Obstet & Gynecol, 967 48th St, Brooklyn, NY 11219 USA. FU NCRR NIH HHS [RR00188, RR00645]; NIAID NIH HHS [1 U01 AI 50274-01, N01 AI 85339, U01 AI 34841, U01 AI 34858]; NICHD NIH HHS [U01 HD 36117, U01 HD 41983]; NIDA NIH HHS [9U01 DA 15054, U01 DA 15053] NR 24 TC 29 Z9 30 U1 1 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2003 VL 189 IS 2 BP 552 EP 559 DI 10.1067/S0002-9378(03)00467-8 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 719RV UT WOS:000185219100055 PM 14520233 ER PT J AU Silveira, C Ferreira, R Muccioli, C Nussenblatt, R Belfort, R AF Silveira, C Ferreira, R Muccioli, C Nussenblatt, R Belfort, R TI Toxoplamosis transmitted to a newborn from the mother infected 20 years earlier SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID TOXOPLASMA-GONDII AB PURPOSE: To present a case of congenital toxoplasmosis in a newborn whose mother had a 20,year history of a chorioretinal macular scar and positive serology for toxoplasmosis. DESIGN/METHODS: Case report. SETTING/RESULTS: A 38-year-old woman who had been treated for ocular toxoplasmosis 20 years earlier delivered a newborn who presented with a focal necrotizing retinochoroiditis characteristic of toxoplasmosis, as well as positive immunoglobulin (Ig) G and M serology for toxoplasmosis. The workup was negative for other entities. CONCLUSION: This case suggests that women with old retinal scars due to toxoplasmosis and long,standing IgG antibodies to toxoplasmosis are also at risk of transmitting this disease to the fetus. C1 Univ Fed Sao Paulo, Vis Inst, BR-0402362 Sao Paulo, Brazil. Clin Silveira, Erechim, RS, Brazil. Clin Silveira, Porto Alegre, RS, Brazil. NEI, NIH, Bethesda, MD 20892 USA. RP Belfort, R (reprint author), Univ Fed Sao Paulo, Vis Inst, Rua Botucatu 824, BR-0402362 Sao Paulo, Brazil. RI Belfort Jr, Rubens/E-2252-2012; Muccioli, Cristina/C-3419-2013 OI Belfort Jr, Rubens/0000-0002-8422-3898; NR 7 TC 38 Z9 43 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 2003 VL 136 IS 2 BP 370 EP 371 DI 10.1016/S0002-9394(03)00191-0 PG 2 WC Ophthalmology SC Ophthalmology GA 702YT UT WOS:000184253200029 PM 12888070 ER PT J AU Souto, JT Aliberti, JC Campanelli, AP Livonesi, MC Maffei, CML Ferreira, BR Travassos, LR Martinez, R Rossi, MA Silva, JS AF Souto, JT Aliberti, JC Campanelli, AP Livonesi, MC Maffei, CML Ferreira, BR Travassos, LR Martinez, R Rossi, MA Silva, JS TI Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis-infected mice is modulated by interferon-gamma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NF-KAPPA-B; CRYPTOCOCCUS-NEOFORMANS INFECTION; IFN-GAMMA; BLASTOMYCES-DERMATITIDIS; LISTERIA-MONOCYTOGENES; NUDE-MICE; IN-VIVO; MACROPHAGES; EXPRESSION; CELLS AB Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions. Here, we evaluated the expression of chemokines and chemokine receptors and their regulation by IFN-gamma in the course of Paracoccidioides brasiliensis (Pb) infection in mice. We found an association between KC and MEP-1alpha (CCL3) production and neutrophil infiltration in the lungs of Pb-infected mice during the early acute phase of infection. High levels of RANTES/CCL5, MCP-1/CCL2, EP-10/CXCL10, and Mig/CXCL9 simultaneously with mononuclear cell infiltration in the lungs was found. in the absence of IFN-gamma (GKO mice) we observed increased production of KC and MIP-1alpha and chronic neutrophilia. Moreover, we found a change in the chemokine receptor profiles expressed by wild-type (WT) versus GKO animals. Increased expression of CXCR3 and CCR5, and low levels of CCR3 and CCR4 were observed in the lungs of Pb-infected WT mice, whereas the opposite effect was observed in the lungs of GKO mice. Con sistent with these results, infected cells from WT mice preferentially migrated in response to IP-10 (CXCR3 ligand), while those from GKO mice migrated in re sponse to eotaxin/CCL11 (CCR3 ligand). These results suggest that IFN-gamma modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb-infected mice. C1 Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Cell Biol, BR-14049900 Ribeirao Preto, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Internal Med, BR-14049900 Ribeirao Preto, Brazil. Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo, Brazil. Univ Fed Rio Grande Norte, Dept Microbiol & Parasitol, BR-59072970 Natal, RN, Brazil. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Silva, JS (reprint author), Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, Brazil. RI Silva, Joao/A-4484-2008; Ferreira, Beatriz/C-2003-2012; Aliberti, Julio/G-4565-2012; Travassos, Luiz/J-3631-2012; Campanelli, Ana Paula/B-9144-2012; Aliberti, Julio/I-7354-2013 OI Ferreira, Beatriz/0000-0002-6781-2236; Aliberti, Julio/0000-0003-3420-8478 NR 47 TC 41 Z9 44 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2003 VL 163 IS 2 BP 583 EP 590 DI 10.1016/S0002-9440(10)63686-3 PG 8 WC Pathology SC Pathology GA 704XF UT WOS:000184366400020 PM 12875978 ER PT J AU Laurence, LE AF Laurence, LE TI Comments on the establishment of the National Institute of Medical Rehabilitation Research SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Editorial Material C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Laurence, LE (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD AUG PY 2003 VL 82 IS 8 BP 580 EP 581 DI 10.1097/01.phm.0000084293.70478.76 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 702RW UT WOS:000184238100002 PM 12872013 ER PT J AU He, ML Zemkova, H Koshimizu, T Tomic, M Stojilkovic, SS AF He, ML Zemkova, H Koshimizu, T Tomic, M Stojilkovic, SS TI Intracellular calcium measurements as a method in studies on activity of purinergic P2X receptor channels SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE ATP-gated receptor channels; inward currents; intracellular calcium signals; desensitization-inactivation; voltage-gated calcium influx; localized and global calcium signals ID ATP-GATED CHANNELS; C-TERMINAL DOMAIN; EXTRACELLULAR PH; P-2X RECEPTOR; RECOMBINANT HUMAN; SENSORY NEURONS; CELLS; DESENSITIZATION; PURINOCEPTOR; ZINC AB Extracellular nucleotide-activated purinergic receptors (P2XRs) are a family of cation-permeable channels that conduct small cations, including Ca2+, leading to the depolarization of cells and subsequent stimulation of voltage-gated Ca2+ influx in excitable cells. Here, we studied the spatiotemporal characteristics of intracellular Ca2+ signaling and its dependence on current signaling in excitable mouse immortalized gonadotropin-releasing hormone-secreting cells (GT1) and nonexcitable human embryonic kidney cells (HEK-293) cells expressing wild-type and chimeric P2XRs. In both cell types, P2XR generated depolarizing currents during the sustained ATP stimulation, which desensitized in order (from rapidly desensitizing to nondesensitizing): P2X(3)R > P2X(2b) + X4R > P2X(2b)R > P2X(2a) + X4R > P2X(4)R > P2X(2a)R > P2X(7)R. HEK-293 cells were not suitable for studies on P2XR-mediated Ca2+ influx because of the coactivation of endogenously expressed Ca2+-mobilizing purinergic P2Y receptors. However, when expressed in GT1 cells, all wild-type and chimeric P2XRs responded to agonist binding with global Ca2+ signals, which desensitized in the same order as current signals but in a significantly slower manner. The global distribution of Ca2+ signals was present independently of the rate of current desensitization. The temporal characteristics of Ca2+ signals were not affected by voltage-gated Ca2+ influx and removal of extracellular sodium. Ca2+ signals reflected well the receptor-specific EC50 values for ATP and the extracellular Zn2+ and pH sensitivities of P2XRs. These results indicate that intracellular Ca2+ measurements are useful for characterizing the pharmacological properties and messenger functions of P2XRs, as well as the kinetics of channel activity, when the host cells do not express other members of purinergic receptors. C1 NICHHD, ERRB, NIH, Bethesda, MD 20892 USA. RP He, ML (reprint author), NICHHD, ERRB, NIH, Bldg 49,Rm 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Zemkova, Hana/C-1844-2012; Tomic, Melanija/C-3371-2016 NR 47 TC 37 Z9 37 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 2003 VL 285 IS 2 BP C467 EP C479 DI 10.1152/ajpcell.00042.2003 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 697JT UT WOS:000183939900026 PM 12711592 ER PT J AU Bregonzio, C Armando, I Ando, H Jezova, M Baiardi, G Saavedra, JM AF Bregonzio, C Armando, I Ando, H Jezova, M Baiardi, G Saavedra, JM TI Anti-inflammatory effects of angiotensin II AT(1) receptor antagonism prevent stress-induced gastric injury SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE gastric blood flow; prostaglandins; tumor necrosis factor ID SPONTANEOUSLY HYPERTENSIVE RATS; NECROSIS-FACTOR-ALPHA; INTERACTIONS IN-VIVO; SMOOTH-MUSCLE CELLS; MUCOSAL INJURY; MESSENGER-RNA; UP-REGULATION; PROTEIN-KINASE; NITRIC-OXIDE; BLOOD-FLOW AB Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT(1) receptor antagonist candesartan before cold-restraint stress. AT(1) receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT(1) blockade increased gastric blood flow by 40-50%, prevented gastric ulcer formation by 70-80% after cold-restraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-alpha and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE(2). AT(1) receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects ( with reduction in TNF-alpha and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE2 release. Angiotensin II has a crucial role, through stimulation of AT(1) receptors, in the production and progression of stress-induced gastric injury, and AT(1) receptor antagonists could be of therapeutic benefit. C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Bregonzio, C (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,Bldg 10,Rm 2D-57, Bethesda, MD 20892 USA. NR 55 TC 85 Z9 89 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2003 VL 285 IS 2 BP G414 EP G423 DI 10.1152/ajpgi.00058.2003 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 698TY UT WOS:000184015900020 PM 12686508 ER PT J AU Lawler, C Suk, WA Pitt, BR St Croix, CM Watkins, SC AF Lawler, C Suk, WA Pitt, BR St Croix, CM Watkins, SC TI Multimodal optical imaging SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Review DE fluorescent probes; green fluorescent protein; fluorescence resonance energy transfer; electron paramagnetic resonance; electron microscopy ID SINGLE LIVING CELLS; FLUORESCENCE MICROSCOPY; ELECTRON-MICROSCOPY; CHEMICAL-ANALYSIS; PEBBLE SENSORS; LIVE CELLS; RAT-HEART; LUNG; PROTEIN; NANOSENSORS AB The recent resurgence of interest in the use of intravital microscopy in lung research is a manifestation of extraordinary progress in visual imaging and optical microscopy. This review evaluates the tools and instrumentation available for a number of imaging modalities, with particular attention to recent technological advances, and addresses recent progress in use of optical imaging techniques in basic pulmonary research.(1) Limitations of existing methods and anticipated future developments are also identified. Although there have also been major advances made in the use of magnetic resonance imaging, positron emission tomography, and X-ray and computed tomography to image intact lungs and while these technologies have been instrumental in advancing the diagnosis and treatment of patients, the purpose of this review is to outline developing optical methods that can be evaluated for use in basic research in pulmonary biology. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, Pittsburgh, PA 15260 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. RP St Croix, CM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, 3344 Forbes Ave, Pittsburgh, PA 15260 USA. NR 51 TC 3 Z9 3 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD AUG PY 2003 VL 285 IS 2 BP L269 EP L280 DI 10.1152/ajplung.00424.2002 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 698HE UT WOS:000183992300001 PM 12851207 ER PT J AU Dmitrieva, NI Bulavin, DV Burg, MB AF Dmitrieva, NI Bulavin, DV Burg, MB TI High NaCl causes Mre11 to leave the nucleus, disrupting DNA damage signaling and repair SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE renal cells; cell cycle arrest; H2AX; chk1 ID DOUBLE-STRAND BREAKS; MEDULLARY EPITHELIAL-CELLS; MURINE KIDNEY-CELLS; REQUIRES P38 KINASE; HYPERTONIC STRESS; HISTONE H2AX; IONIZING-RADIATION; G-2/M CHECKPOINT; G2/M CHECKPOINT; CHK1 AB High NaCl causes DNA double-strand breaks and cell cycle arrest, but the mechanism of its genotoxicity has been unclear. In this study, we describe a novel mechanism that contributes to this genotoxicity. The Mre11 exonuclease complex is a central component of DNA damage response. This complex assembles at sites of DNA damage, where it processes DNA ends for subsequent activation of repair and initiates cell cycle checkpoints. However, this does not occur with DNA damage caused by high NaCl. Rather, following high NaCl, Mre11 exits from the nucleus, DNA double-strand breaks accumulate in the S and G(2) phases of the cell cycle, and DNA repair is inhibited. Furthermore, the exclusion of Mre11 from the nucleus by high NaCl persists following UV or ionizing radiation, also preventing DNA repair in response to those stresses, as evidenced by absence of H2AX phosphorylation at places of DNA damage and by impaired repair of damaged reporter plasmids. Activation of chk1 by phosphorylation on Ser345 generally is required for DNA damage-induced cell cycle arrest. However, chk1 does not become phosphorylated during high NaCl-induced cell cycle arrest. Also, high NaCl prevents ionizing and UV radiation-induced phosphorylation of chk1, but cell cycle arrest still occurs, indicating the existence of alternative mechanisms for the S and G(2)/M delays. DNA breaks that occur normally during processes such as DNA replication and transcription, as well as damages to DNA induced by genotoxic stresses, ordinarily are rapidly repaired. We propose that inhibition of this repair by high NaCl results in accumulation of DNA damage, accounting for the genotoxicity of high NaCl, and that cell cycle delay induced by high NaCl slows accumulation of DNA damage until the DNA damage-response network can be reactivated. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. NCI, Gene Response Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 38 TC 43 Z9 43 U1 2 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG PY 2003 VL 285 IS 2 BP F266 EP F274 DI 10.1152/ajprenal.00060.2003 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 697KM UT WOS:000183941900010 PM 12684226 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Buried in mud, digging for gold SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2003 VL 93 IS 8 BP 1245 EP 1245 DI 10.2105/AJPH.93.8.1245 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 708CG UT WOS:000184549100018 PM 12893603 ER PT J AU Engels, F AF Engels, F TI The condition of the working class in England SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. RP Engels, F (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. NR 0 TC 1 Z9 1 U1 1 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2003 VL 93 IS 8 BP 1246 EP 1249 DI 10.2105/AJPH.93.8.1246 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 708CG UT WOS:000184549100019 PM 12893604 ER PT J AU Brown, TM Fee, E AF Brown, TM Fee, E TI Friedrich Engels: Businessman and revolutionary SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. NR 3 TC 3 Z9 3 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2003 VL 93 IS 8 BP 1248 EP 1249 DI 10.2105/AJPH.93.8.1248 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 708CG UT WOS:000184549100020 PM 12893605 ER PT J AU Cooper, PJ Chico, ME Bland, M Griffin, GE Nutman, TB AF Cooper, PJ Chico, ME Bland, M Griffin, GE Nutman, TB TI Allergic symptoms, atopy, and geohelminth infections in a rural area of Ecuador SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE allergy; atopy; geohelminths; schoolchildren ID SKIN-TEST REACTIVITY; SCHOOL-AGE-CHILDREN; HELMINTHIC INFECTION; ASCARIS-LUMBRICOIDES; SERUM IGE; ASTHMA; PARASITES; PREVALENCE; URBAN; RISK AB Geohelminth infections may affect the expression of allergic disease. To investigate the relationship between geolhelminth infections, atopy, and symptoms of allergic disease, we studied 4,433 schoolchildren from 71 schools in a rural tropical area in Ecuador. Information was collected on allergic symptoms, allergen skin test reactivity, and presence of geohelminth infections. Allergic symptoms were of low prevalence (2.1% had recent wheeze), but prevalence of skin test reactivity was relatively high (118.2%). The presence of geohelminth infections was protective against allergen skin test reactivity (odds ratio 0.62, 95% confidence interval 0.50-0.76, p < 0.001) and symptoms of exercise-induced wheeze (odds ratio 0.59, 95% confidence interval 0.40-0.87, p = 0.008) but not against other wheeze symptoms or symptoms of allergic rhinitis or atopic eczema. Infection intensity with Ascaris lumbricoides or Trichuris trichiura was associated with a reduction in the prevalence of allergen skin test reactivity but not with allergic symptoms. There was no evidence of interactions between geolhelminth infection and allergen skin test reactivity on the risks of allergic symptoms. The results suggest that geohelminth infections do not explain the low prevalence of allergic symptoms in the study population. C1 Univ London St Georges Hosp, Sch Med, Dept Infect Dis, London SW17 0RE, England. Univ London St Georges Hosp, Sch Med, Dept Publ Hlth Sci, London SW17 0RE, England. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cooper, PJ (reprint author), SALUDESA, Casilla 17-14-30, Carcelen, Quito, Ecuador. NR 26 TC 85 Z9 90 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2003 VL 168 IS 3 BP 313 EP 317 DI 10.1164/rccm.200211-1320OC PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 706RB UT WOS:000184466400014 PM 12714349 ER PT J AU Sarlis, NJ Gourgiotis, L Koch, CA Skarulis, MC Brucker-Davis, F Doppman, JL Oldfield, EH Patronas, NJ AF Sarlis, NJ Gourgiotis, L Koch, CA Skarulis, MC Brucker-Davis, F Doppman, JL Oldfield, EH Patronas, NJ TI MR imaging features of thyrotropin-secreting pituitary adenomas at initial presentation SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article; Proceedings Paper CT 2nd Meeting of the Neuroendocrinology Section of the German-Society-of-Endocrinology CY OCT, 1999 CL GOTTINGEN, GERMANY SP German Soc Endocrinol, Neuroendocrinol Sect ID THERAPY; TUMORS AB OBJECTIVE. We report the MR imaging characteristics of thyrotropin-producing pituitary adenomas at their initial presentation and also report the role of MR imaging in predicting surgical outcome in these rare tumors. MATERIALS AND METHODS. We reviewed the records and MR images of 21 patients with thyrotropin-producing pituitary adenomas from 1984 to 1999. The imaging features of these tumors were examined, including enhancing characteristics and tumor volumes. A staging system of tumor invasion was designed by grading cavernous and sphenoid sinus invasion and suprasellar extension. A cumulative invasion score was then used as a predictor of short-term surgical outcome. RESULTS. Twenty patients had macroadenomas, and one patient had a microadenoma. In 17 of 21 patients, the thyrotropin-producing pituitary adenoma was clearly visualized as a hypoenhancing mass compressing the normal pituitary gland. Conversely, in four patients, the pituitary gland was not discernible because of complete distortion by the adenoma. Thyrotropin-producing pituitary adenomas were large and showed a tendency to invade surrounding structures. Tumor volume ranged from 0.42 to 94.2 cm(3) (mean +/- SD, 16.0 +/- 17.8 cm(3)). The mean score of tumor invasion was 4.77 +/- 2.06 of a maximal possible value of 9.0. A high staging score was found to be predictive of an unfavorable response to surgery. CONCLUSION. Thyrotropin-producing pituitary adenomas are usually large tumors at initial presentation with hypoenhancing features compared with normal pituitary tissue; they tend to be invasive. Greater amounts of invasion correlate with incomplete surgical removal of the tumor and continued hormonal secretion. C1 NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Univ Nice, Ctr Hosp, Dept Endocrine Med & Diabet, F-06002 Nice 01, France. NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Sarlis, NJ (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Unit 435, 1515 Holcombe Blvd, Houston, TX 77030 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 16 TC 14 Z9 17 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2003 VL 181 IS 2 BP 577 EP 582 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 704CV UT WOS:000184320900047 PM 12876051 ER PT J AU Gorbach, A Simonton, D Hale, DA Swanson, SJ Kirk, AD AF Gorbach, A Simonton, D Hale, DA Swanson, SJ Kirk, AD TI Objective, real-time, intraoperative assessment of renal perfusion using infrared imaging SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE imaging techniques; infrared; kidney; reperfusion ID DELAYED GRAFT FUNCTION; ISCHEMIA-REPERFUSION INJURY; BLOOD-FLOW; TRANSPLANTED KIDNEYS; MONOCLONAL-ANTIBODY; IMMUNE-SYSTEM; ALLOGRAFT; ADHESION; IMMUNOSUPPRESSION; REDUCTION AB Allograft ischemia induces delayed graft function and is correlated with increasing rates of rejection. There is not currently a way to objectively measure the effects of ischemia in real-time, nor to relate therapies combating reperfusion injury with their intended effects. An infrared (IR) method utilizing a focal plane array detector camera was developed for real-time intraoperative IR imaging of renal allografts, and evaluated in a pilot trial to quantify perfusion in recipients of live (n=8) and cadaveric donor (n=5) allografts. Digital images were taken for 3-8 min postreperfusion. Image data were compared to ischemic time and allograft function to assess potential clinical relevance. Cold ischemic time ranged from 0.5 to 29h and was bimodally distributed between living and cadaveric donors. Renal rewarming time (RT) as determined by IR imaging correlated with cold ischemic time (p < 0.001, R-2=0.81), and predicted the subsequent return of renal function with FIT negatively correlated to the regression slopes of creatinine (p = 0.02, R-2 = 0.38) and BUN (p = 0.07, R-2 = 0.26). Intraoperative IR imaging noninvasively provides clinically relevant real-time whole kidney assessment of reperfusion. This technology may aide in the objective assessment of therapies designed to limit reperfusion injury, and allow for quantitative assessment of allograft ischemic damage. C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Bethesda, MD USA. RP Kirk, AD (reprint author), NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 30 TC 23 Z9 23 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2003 VL 3 IS 8 BP 988 EP 993 DI 10.1034/j.1600-6143.2003.00158.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 705MQ UT WOS:000184399200014 PM 12859534 ER PT J AU Adegoke, OJ Blair, A Shu, XO Sanderson, M Jin, F Dosemeci, M Addy, CL Zheng, W AF Adegoke, OJ Blair, A Shu, XO Sanderson, M Jin, F Dosemeci, M Addy, CL Zheng, W TI Occupational history and exposure and the risk of adult leukemia in Shanghai SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE leukemia; occupational exposures; risk factor; case-control study ID MORTALITY PATTERNS; LYMPHOID NEOPLASMS; PETROLEUM WORKERS; CHEMICAL-INDUSTRY; UNITED-KINGDOM; BENZENE; CANCER; CHINA; MALIGNANCIES; WOMEN AB PURPOSE: Evaluation of the association of selected occupational exposures with leukemia risk. METHODS: Population-based case-control study of 486 leukemia subjects and 502 healthy controls residing in Shanghai from 1987 to 1989. Adjusted odds ratios (OR) were calculated for the association between occupational factors and leukemia risk. RESULTS: Significant increase in leukemia risk was observed in chemical manufacturing industry workers (OR = 3.1, 95% CI = 1.0-9.8). Increased risks for leukemia were observed from self-reported exposures to benzene (OR = 1.7, 95% CI = 1.1-2.6), radioactive materials (OR = 3.7, 95% CI = 1.310.2), synthetic fiber dust (OR = 2.0, 95% CI = 1.2-3.5), and toluene (OR = 1.6, 95% CI = 1.0-2.5). Dose-response relations of leukemia risk was observed with the duration of exposure to benzene (OR = 3.3, 95% CI = 1.6-6.9 for greater than or equal to15 years exposure; p for trend <0.01), radioactive materials (OR = 5.2, 95% CI = 1.1-24.7 for greater than or equal to15 years exposure; p for trend = 0.02), paints (OR 2.3, 95% CI = 1.2-4.7 for greater than or equal to15 years exposure; p for trend = 0.09), and toluene (OR = 2.9, 95 % CI 1.3-6.7 for greater than or equal to15 years exposure; p for trend = 0.02). CONCLUSIONS: Adult leukemia risk may be associated with working in the chemical industry, and exposure to benzene, synthetic fiber dust, radioactive materials, and toluene in the study population. Ann Epidemiol 2003;13:485-494. (C) 2003 Elsevier Inc. All rights reserved. C1 Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. Univ S Carolina, Norman J Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Adegoke, OJ (reprint author), Meharry Med Coll, Sch Med, Dept Surg, 1005 Dr DB Todd Jr Blvd, Nashville, TN 37208 USA. FU NCI NIH HHS [1U54-CA9140801] NR 43 TC 22 Z9 22 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2003 VL 13 IS 7 BP 485 EP 494 DI 10.1016/S1047-2797(03)00037-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 716QH UT WOS:000185039500001 PM 12932623 ER PT J AU Hardy, J AF Hardy, J TI Alzheimer's disease: Genetic evidence points to a single pathogenesis SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID GAMMA-SECRETASE ACTIVITY; AMYLOID BETA-PROTEIN; AGE-OF-ONSET; SPASTIC PARAPARESIS; MISSENSE MUTATIONS; TRANSGENIC MICE; PRESENILIN-1; PLAQUES; ALLELE; FAMILIES C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RI Hardy, John/C-2451-2009 NR 23 TC 16 Z9 17 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2003 VL 54 IS 2 BP 143 EP 144 DI 10.1002/ana.10624 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 704RA UT WOS:000184352700002 PM 12891664 ER PT J AU Hague, S Rogaeva, E Hernandez, D Gulick, C Singleton, A Hanson, M Johnson, J Weiser, R Gallardo, M Ravina, B Gwinn-Hardy, K Crawley, A St George-Hyslop, PH Lang, AE Heutink, P Bonifati, V Hardy, J Singleton, A AF Hague, S Rogaeva, E Hernandez, D Gulick, C Singleton, A Hanson, M Johnson, J Weiser, R Gallardo, M Ravina, B Gwinn-Hardy, K Crawley, A St George-Hyslop, PH Lang, AE Heutink, P Bonifati, V Hardy, J Singleton, A TI Early-onset Parkinson's disease caused by a compound heterozygous DJ-1 mutation SO ANNALS OF NEUROLOGY LA English DT Article AB Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons I through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD. C1 NIA, Neurogenet Lab, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Hosp Univ Caracas, Caracas, Venezuela. Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. Erasmus Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. Univ Roma La Sapienza, Dept Neurol Sci, Rome, Italy. RP Singleton, A (reprint author), NIA, Neurogenet Lab, Mol Genet Sect, NIH, Bldg 10,Room 6C103,MSC1589,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Gwinn, Katrina/C-2508-2009; Johnson, Janel/A-7136-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 8 TC 154 Z9 164 U1 2 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2003 VL 54 IS 2 BP 271 EP 274 DI 10.1002/ana.10663 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 704RA UT WOS:000184352700023 PM 12891685 ER PT J AU O'Keefe, BR Smee, DF Turpin, JA Saucedo, CJ Gustafson, KR Mori, T Blakeslee, D Buckheit, R Boyd, MR AF O'Keefe, BR Smee, DF Turpin, JA Saucedo, CJ Gustafson, KR Mori, T Blakeslee, D Buckheit, R Boyd, MR TI Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID VIRUS-INACTIVATING PROTEIN; HIGH-MANNOSE OLIGOSACCHARIDES; INFLUENZA-A VIRUSES; NEURAMINIDASE INHIBITORS; ENVELOPE GLYCOPROTEINS; ANTIGENIC STRUCTURE; BINDING; GP120; RESISTANCE AB The novel antiviral protein cyanovirin-N (CV-N) was initially discovered based on its potent activity against the human immunodeficiency virus (HIV). Subsequent studies identified the HIV envelope glycoproteins gp120 and gp41 as molecular targets of CV-N. More recently, mechanistic studies have shown that certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) found on the HIV envelope glycoproteins comprise the specific sites to which CV-N binds. Such selective, carbohydrate-dependent interactions may account, at least in part, for the unusual and unexpected spectrum of antiviral activity of CV-N described herein. We screened CV-N against a broad range of respiratory and enteric viruses, as well as flaviviruses and herpesviruses. CV-N was inactive against rhinoviruses, human parainfluenza virus, respiratory syncytial virus, and enteric viruses but was moderately active against some herpesvirus and hepatitis virus (bovine viral diarrhea virus) strains (50% effective concentration [EC50] = similar to1 mug/ml) while inactive against others. Remarkably, however, CV-N and related homologs showed highly potent antiviral activity against almost all strains of influenza A and B virus, including clinical isolates and a neuraminidase inhibitor-resistant strain (EC50 = 0.004 to 0.04 mug/ml). When influenza virus particles were pretreated with CV-N, viral titers were lowered significantly (>1,000-fold). Further studies identified influenza virus hemagglutinin as a target for CV-N, showed that antiviral activity and hemagglutinin binding were correlated, and indicated that CV-N's interactions with hemagglutinin involved oligosaccharides. These results further reveal new potential avenues for antiviral therapeutics and prophylaxis targeting specific oligosaccharide-comprised sites on certain enveloped viruses, including HIV, influenza virus, and possibly others. C1 Univ S Alabama, Coll Med, Canc Res Inst, Mobile, AL 36688 USA. NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. So Res Inst, Retrovirus Res Lab, Frederick, MD 21702 USA. Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA. Omniviral Therapeut LLC, Germantown, MD 20874 USA. RP Boyd, MR (reprint author), Univ S Alabama, Coll Med, Canc Res Inst, CSAB 170, Mobile, AL 36688 USA. FU NCI NIH HHS [N01CO12400]; PHS HHS [N01-C0-12400] NR 31 TC 88 Z9 102 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2003 VL 47 IS 8 BP 2518 EP 2525 DI 10.1128/AAC.47.8.2518-2525.2003 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 706JD UT WOS:000184449800021 PM 12878514 ER PT J AU Moreau, JM Dyer, KD Bonville, CA Nitto, T Vasquez, NL Easton, AJ Domachowske, JB Rosenberg, HF AF Moreau, JM Dyer, KD Bonville, CA Nitto, T Vasquez, NL Easton, AJ Domachowske, JB Rosenberg, HF TI Diminished expression of an antiviral ribonuclease in response to pneumovirus infection in vivo SO ANTIVIRAL RESEARCH LA English DT Article DE pneumovirus; ribonuclease; inflammation ID RESPIRATORY SYNCYTIAL VIRUS; EOSINOPHIL-DERIVED NEUROTOXIN; IMMUNE EVASION; A SUPERFAMILY; DIFFERENTIAL EXPRESSION; PULMONARY INFLAMMATION; CATIONIC PROTEIN; RAPID EVOLUTION; PNEUMONIA VIRUS; HOST-DEFENSE AB The mouse eosinophil-associated ribonucleases (mEars) are species specific, divergent orthologs of the human antiviral RNase A ribonucleases, eosinophil-derived neurotoxin (RNase 2) and eosinophil cationic protein (RNase 3). We show here that mEar 2 is also an antiviral ribonuclease, as micromolar concentrations promote a similar tosixfold reduction in the infectivity of pneumonia virus of mice (PVM) for target respiratory epithelial cells in vitro. Although initially identified as a component of eosinophilic leukocytes, mEar 2 mRNA and protein were also detected in lung tissue accompanied by enzymatically active mEar 2 in bronchoalveolar lavage fluid (BALF). At t = 3 days post-inoculation with PVM (strain J3666), we observed the characteristic inflammatory response accompanied by diminished expression of total mEar mRNA and protein in lung tissue and a corresponding fivefold drop in ribonuclease activity in BALF No change in mEar expression was observed in response to infection with PVM strain 15, a replication-competent strain of PVM that does not elicit a cellular inflammatory response. However, mEar expression is not directly dependent on inflammation per se, as diminished expression of mEar mRNA and BAL ribonuclease activity were also observed in PVM-infected, inflammation-deficient, MIP-1alpha -/- mice. We propose that this mechanism may represent a novel virus-mediated evasion strategy, with a mechanism that is linked in some fashion to virus-specific pathogenicity. Published by Elsevier B.V. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. SUNY Syracuse, Dept Pediat, Syracuse, NY USA. Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. RP Rosenberg, HF (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N104,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 55 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2003 VL 59 IS 3 BP 181 EP 191 DI 10.1016/S0166-3542(03)00111-6 PG 11 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 717PG UT WOS:000185098100005 PM 12927308 ER PT J AU Alvarez-Salas, LM Benitez-Hess, ML DiPaolo, JA AF Alvarez-Salas, LM Benitez-Hess, ML DiPaolo, JA TI Advances in the development of ribozymes and antisense oligodeoxynucleotides as antiviral for agents for human papillomaviruses SO ANTIVIRAL THERAPY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO SELECTION; C-RAF KINASE; HAIRPIN RIBOZYME; HAMMERHEAD RIBOZYME; SELF-CLEAVAGE; TYPE-16 E6; SECONDARY STRUCTURE; CERVICAL-CANCER; OLIGONUCLEOTIDE COMPLEMENTARY AB Urogenital human papillomavirus (HPV) infections are the most common viral sexually transmitted disease in women. On a worldwide basis cervical cancer is the second most prevalent cancer of women. Although HPV infection is not sufficient to induce cancer, the causal relation between high-risk HPV infection and cervical cancer is well established. Over 99% of cervical cancers are positive for high-risk HPV. Therefore, there is a need for newer approaches to treat HPV infection. Two novel approaches for inactivating gene expression involve ribozymes and oligonucleotides. Methods for identification of target genes involved in neoplastic transformation and tumour growth have been established, and these will lead to therapeutic approaches without any damage to normal cellular RNA molecules, which is often associated with conventional therapeutics. Ribozymes and oligonucleotides represent rational antiviral approaches for inhibiting the growth of cervical lesions and carcinomas by interfering with E6/E7 RNA production. The E6 and E7 genes of high-risk HPVs cooperate to immortalize primary epithelial cells and because they are found in cervical cancer are considered the hallmark of cervical cancer. The use and modification of ribozymes and antisense oligodeoxynucleotides can inhibit the growth of HPV-16 and HPV-18 immortalized cells, and tumour cells by eliminating E6/E7 transcript. Hammerhead and hairpin ribozymes have been widely studied because of their potential use for gene therapy and their place as therapeutic tools for cervical cancer is being evaluated. Although antiviral ribozymes and antisense molecules have been effective as in vitro or in vivo inhibitors of high-risk HPV-positive cells, none is currently in clinical trial. There are, however, a number of other antisense therapies in Phase I-III clinical trial for several oncogenes. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. CINVESTAV, Dept Genet & Mol Biol, Lab Gene Therapy, Mexico City, DF, Mexico. RP DiPaolo, JA (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dipaoloj@dc37a.nci.nih.gov NR 140 TC 26 Z9 27 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2003 VL 8 IS 4 BP 265 EP 278 PG 14 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YQ UT WOS:000231266500002 PM 14518695 ER PT J AU Bartlett, JA Tebas, P Bassett, R Huang, WZ Kuritzkes, D Reisler, R Loyack, N Robison, K AF Bartlett, JA Tebas, P Bassett, R Huang, WZ Kuritzkes, D Reisler, R Loyack, N Robison, K CA ACTG A5064 Team TI Early intensification with abacavir in subjects at high risk for incomplete viral suppression SO ANTIVIRAL THERAPY LA English DT Article ID HIV-INFECTION; THERAPY C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. Washington Univ, St Louis, MO USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. RP Bartlett, JA (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. EM jab5@duke.edu RI Tebas, Pablo/A-7061-2008 FU NCRR NIH HHS [5M01RR00044, K24 RR16482]; NIAID NIH HHS [U01-AI39156, K24 AI-01744-01, U01 AI 38858] NR 9 TC 2 Z9 2 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2003 VL 8 IS 4 BP 361 EP 363 PG 3 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YQ UT WOS:000231266500014 PM 14518706 ER PT J AU Weinberger, DR McClure, RK AF Weinberger, DR McClure, RK TI Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry - Reply SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID BRAIN VOLUME CHANGES; SCHIZOPHRENIA; MORPHOLOGY C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, 10 Ctr Dr,Bldg 10,Room 3C-101,MSC 1255, Bethesda, MD 20892 USA. NR 11 TC 3 Z9 3 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2003 VL 60 IS 8 BP 848 EP 849 DI 10.1001/archpsyc.60.8.848 PG 2 WC Psychiatry SC Psychiatry GA 709HJ UT WOS:000184619500011 ER PT J AU Schiffman, M Castle, PE AF Schiffman, M Castle, PE TI Human papillomavirus - Epidemiology and public health SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT Conference of the College-of-American-Pathologists-Strategic-Series CY SEP 21-22, 2000 CL ROSEMONT, PENNSYLVANIA SP Amer Pathol Strateg Sci Series ID SQUAMOUS INTRAEPITHELIAL LESIONS; MULTICENTRIC CASE-CONTROL; GRADE CERVICAL NEOPLASIA; COSTA-RICA; HIGH-RISK; SEXUAL-BEHAVIOR; HPV TYPES; INFECTION; CANCER; WOMEN AB Approximately 15 types of human papillomavirus (HPV) infection cause virtually all cases of cervical cancer. Human papillomavirus 16 is the major type, accounting for approximately 50% of cases. The major steps of cervical carcinogenesis include HPV infection, viral persistence and progression to precancer (as opposed to viral clearance), and invasion. Human papillomavirus is the most common sexually transmitted infection. However, most HPV infections become undetectable by even sensitive HPV DNA testing within I to 2 years. The prevalence of infection peaks at young ages and declines thereafter, perhaps as the result of HPV type-specific acquired immunity. Most HPV infections are neither microscopically evident nor visible, making HPV DNA detection the diagnostic reference standard. Poorly defined immunologic factors are the major determinants of viral outcome. Smoking, multiparity, and long-term oral contraceptive use increase the risk of persistence and progression. Other sexually transmitted infections (eg, Chlamydia trachomatis), chronic inflammation, and nutritional factors might also play a role. Overt, long-term viral persistence in the absence of precancer is uncommon. New prevention strategies can be derived from the evolving knowledge of HPV carcinogenesis. Human papillomavirus vaccination is the ultimate prevention strategy, and large-scale trials are already underway. In the meantime, HPV DNA diagnostics are more sensitive although less specific than cytology, permitting a consideration of lengthened screening intervals. In terms of public health education, clinicians and patients will need to shift discussions of the mildly abnormal Papanicolaou test to consideration of HPV infection as a common sexually transmitted infection that rarely-causes cervical cancer. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Room 7066,6120 Execut Blvd, Rockville, MD 20852 USA. NR 35 TC 158 Z9 177 U1 0 U2 7 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2003 VL 127 IS 8 BP 930 EP 934 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 710AQ UT WOS:000184659000005 PM 12873163 ER PT J AU Schiffman, M Solomon, D AF Schiffman, M Solomon, D TI Findings to date from the ASCUS-LSIL triage study (ALTS) SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT Conference of the College-of-American-Pathologists-Strategic-Series CY SEP 21-22, 2000 CL ROSEMONT, PENNSYLVANIA SP Amer Pathol Strateg Sci Series ID ATYPICAL SQUAMOUS CELLS; UNDETERMINED SIGNIFICANCE; CERVICAL CYTOLOGY; BETHESDA-SYSTEM; RANDOMIZED TRIAL; WOMEN; REPRODUCIBILITY; PARTICIPANTS; MANAGEMENT; STRATEGIES AB Controversy exists in the United States regarding the proper evaluation and management of low-grade squamous intraepithelial lesion (LSIL) and equivocal (atypical squamous cells of undetermined significance [ASCUS, now ASC-US]) cervical cytologic interpretations. To address this issue, the National Cancer Institute initiated the ASCUS-LSIL Triage Study (ALTS). ALTS is a multicenter, randomized clinical trial designed to evaluate 3 alternative methods of management, namely, immediate colposcopy, cytologic follow-up, and triage by human papillomavirus (HPV) DNA testing. This article summarizes the major findings of ALTS that have been published to date. Patients with ASCUS (n = 3488) or LSIL (n = 1572) were randomly assigned to research arms between November 1996 and December 1998, and were monitored for 2 years. The disease outcome was histologic cervical intraepithelial neoplasia (CIN) 3/cancer. The prevalence of oncogenic HPV was too high to permit effective triage of LSIL using HPV DNA testing by Hybrid Capture 2. However, for the women referred with a cytologic interpretation of ASCUS, HPV triage proved useful, with sensitivity equivalent to immediate colposcopy and a halving of colposcopic referrals. Among older women with ASCUS, HPV testing remained sensitive for detecting CIN 3 and cancer, but the referral percentage was dramatically lower compared to younger women. ALTS yielded insight into the performance of cytology and histopathology; experienced pathologists differed significantly in their interpretation's of cervical abnormalities, especially histologic CIN I and cytologic ASCUS. Nonetheless, it was possible to distinguish a relatively uncommon type of ASCUS, equivocal for high-grade squamous intraepithelial lesion, that has a high positive predictive value for identifying women with underlying high-grade CIN. Many additional analyses are underway. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, Breast & Gynecol Canc Res Grp,Div Canc Prevent, NIH, Rockville, MD 20852 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Room 7066,6120 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [CN-55105, CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159] NR 22 TC 150 Z9 157 U1 0 U2 1 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2003 VL 127 IS 8 BP 946 EP 949 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 710AQ UT WOS:000184659000008 PM 12873166 ER PT J AU Wright, VL AF Wright, VL TI A phenomenological exploration of spirituality among African American women recovering from substance abuse SO ARCHIVES OF PSYCHIATRIC NURSING LA English DT Article ID CHEMICAL DEPENDENCY; RELIGION; COMMUNITY; SUPPORT; ALCOHOL AB Spirituality among African American women recovering from substance abuse is a recovery phenomena: little is known about the individual's experience in this process. The ameliorating effect of spirituality covering a broad range of positive outcomes has been consistent across populations, regardless of gender, race, study design, and religious affiliation. Giorgi's phenomenological method was used to explore and described the meaning of spirituality of 15 African American women recovering from substance abuse. The findings are described and discussed relative to the state of the science on spirituality. Implications for substance abuse and recovery practitioners are presented. (C) 2003 Elsevier Inc. All rights reserved. C1 NINDS, NIH, Stroke Neurosci Unit, Bethesda, MD 20891 USA. RP Wright, VL (reprint author), NINDS, NIH, Stroke Neurosci Unit, 10 Ctr Dr,Rm3N258,MSC 1294, Bethesda, MD 20891 USA. NR 55 TC 4 Z9 4 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0883-9417 J9 ARCH PSYCHIAT NURS JI Arch. Psychiatr. Nurs. PD AUG PY 2003 VL 17 IS 4 BP 173 EP 185 DI 10.1016/S0883-9417(03)00088-8 PG 13 WC Nursing; Psychiatry SC Nursing; Psychiatry GA 720AF UT WOS:000185237600005 PM 14508773 ER PT J AU Norton, JA Kivlen, M Li, M Schneider, D Chuter, T Jensen, RT AF Norton, JA Kivlen, M Li, M Schneider, D Chuter, T Jensen, RT TI Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors SO ARCHIVES OF SURGERY LA English DT Article; Proceedings Paper CT 74th Annual Meeting of the Pacific-Coast-Surgical-Association CY FEB 16-18, 2003 CL MONTEREY, CALIFORNIA SP Pacific Coast Surg Assoc ID ZOLLINGER-ELLISON-SYNDROME; LONG-TERM; DISEASE; METASTASES; GASTRINOMA; PANCREAS; OUTCOMES; SURGERY; CANCER; CURE AB Background: There is considerable controversy about the treatment of patients with malignant advanced neuroendocrine tumors of the pancreas and duodenum. Aggressive surgery remains a potentially efficacious antitumor therapy but is rarely performed because of its possible morbidity and mortality. Hypothesis: Aggressive resection of advanced neuroendocrine tumors can be performed with acceptable morbidity and mortality rates and may lead to extended survival. Design: The medical records of patients with advanced neuroendocrine tumors who underwent surgery between 1997 and 2002 by a single surgeon at the University of California, San Francisco, were reviewed in an institutional review board-approved protocol. Main Outcome Measures: Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates were recorded. Disease-free survival was defined as no tumor identified on radiological imaging studies and no detectable abnormal hormone levels. Proportions were compared statistically using the Fisher exact test. Kaplan-Meier curves were used to estimate survival rates. Results: Twenty patients were identified (11 men and 9 women). Of these, 10 (50%) had gastrinoma, 1 had insulinoma, and the remainder had nonfunctional tumors; 2 had multiple endocrine neoplasia type 1, and 1 had von Hippel-Linclau disease. The mean age was 55 years (range, 34-72 years). In 10 patients (50%), tumors were thought to be unresectable according to radiological imaging studies because of multiple bilobar liver metastases (n = 6), superior mesenteric vein invasion (n = 3), and extensive nodal metastases (n = 1). Tumors were completely removed in 15 patients (75%). Surgical procedures included 8 proximal pancreatectomies (pancreatoduodenectomy or whipple procedure), 3 total pancreatectomies, 9 distal pancreatectomies, and 3, tumor enucleations from the pancreatic head. Superior mesenteric vein reconstruction was done in 3 patients. Liver resections were done in 6 patients, and an extended periaortic node dissection was performed in 1, The spleen was removed in 11 patients, and the left kidney was removed as a result of tumor metastases in 2. Eighteen patients had primary pancreatic tumors, and 2 had duodenal tumors; 2 patients with multiple endocrine neoplasia type 1 had both pancreatic and duodenal tumors. The mean tumor size was 8 cm (range, 0.5-23 cm). Of the patients, 14 (70%) had lymph node metastases and 8 (40%) had liver metastases. The mean postoperative hospital stay was 11.5 days (range, 6-26 days). Six patients (30%) had postoperative complications. There was a significantly greater incidence of pancreatic fistulas with enucleations compared with resections (P = .04). There were no operative deaths. The mean follow-up period was 19 months (range, 1-96 months); 18 patients (90%) are alive, 2 died of progressive tumor, and 12 (60%) are disease-free. The actuarial overall survival rate is 80% at 5 years, and disease-free survival rates indicate that all tumors will recur by the 7-year follow-up visit. Conclusions: Aggressive surgery including pancreatectomy, splenectomy, superior mesenteric vein reconstruction, and liver resection can be done with acceptable morbidity and low mortality rates for patients with advanced neuroendocrine tumors. Although survival rates following surgery are excellent, most patients will develop a recurrent tumor. These findings suggest that conventional contraindications to surgical resection, such as superior mesenteric vein invasion and nodal or distant metastases, should be reconsidered in patients with advanced neuroendocrine tumors. C1 Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. NIDDKD, Digest Dis Branch, Bethesda, MD 20892 USA. RP Norton, JA (reprint author), Univ Calif San Francisco, Dept Surg, 533 Parnassus Ave,U-371,Box 0790, San Francisco, CA 94143 USA. NR 26 TC 120 Z9 127 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD AUG PY 2003 VL 138 IS 8 BP 859 EP 865 DI 10.1001/archsurg.138.8.859 PG 7 WC Surgery SC Surgery GA 709HB UT WOS:000184618800011 PM 12912744 ER PT J AU Holvoet, P Harris, TB Tracy, RP Verhamme, P Newman, AB Rubin, SM Simonsick, EM Colbert, LH Kritchevsky, SB AF Holvoet, P Harris, TB Tracy, RP Verhamme, P Newman, AB Rubin, SM Simonsick, EM Colbert, LH Kritchevsky, SB TI Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderly - Findings from the health, aging, and body composition study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; coronary heart disease; cardiovascular risk; lipoproteins; oxidized lipids ID C-REACTIVE PROTEIN; LOW-DENSITY LIPOPROTEINS; ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; PARTICLE-SIZE; CHOLESTEROL; MARKER; INFLAMMATION; PREDICTOR; MEN AB Objective - Although circulating oxidized LDL (oxLDL) is elevated in persons with coronary heart disease (CHD), whether oxLDL is elevated in persons with high CHD risk before any events is unknown. Therefore, we studied the association between high, predicted CHD risk and oxLDL in the Health ABC cohort. Methods and Results - This cohort included 385 persons with CHD and 1183 persons at high risk; the latter were all persons with CHD risk equivalents: noncoronary forms of clinical atherosclerotic disease, diabetes, and a 10-year risk for CHD > 20% by Framingham scoring. The remaining 1535 participants were at low risk. Levels of oxLDL were 1.18 =/- 0.61 mg/dL for low-risk persons, 1.50 +/- 0.81 mg/dL for high-risk persons without diagnosed CHD, and 1.32 +/- 0.83 mg/dL for persons with CHD ( P < 0.001). The odds ratio for high CHD risk in the highest quintile of oxLDL, compared with the lowest quintile and after adjusting for age, sex, race, LDL cholesterol, smoking status, and C-reactive protein, was 2.79 ( P < 0.001). Conclusion - The odds ratio for elevated oxLDL among persons with high CHD risk before any CHD events was higher than that among persons with established CHD. A likely explanation is that once CHD is diagnosed, individuals are frequently treated with a statin, which is associated with lowering of LDL cholesterol and oxLDL levels. C1 Katholieke Univ Leuven, CEHA, B-3000 Louvain, Belgium. NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Holvoet, P (reprint author), Katholieke Univ Leuven, CEHA, Campus Gasthuisberg O&N,Herestr 49, B-3000 Louvain, Belgium. RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIA NIH HHS [N01-AG-6-2103, N01-AG-6-2106, N01-AG-6-210] NR 28 TC 107 Z9 111 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2003 VL 23 IS 8 BP 1444 EP 1448 DI 10.1161/01.ATV.0000080379.05071.22 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 710JQ UT WOS:000184677400023 PM 12791672 ER PT J AU Mayes, MD Lacey, JV Beebe-Dimmer, J Gillespie, BW Cooper, B Laing, TJ Schottenfeld, D AF Mayes, MD Lacey, JV Beebe-Dimmer, J Gillespie, BW Cooper, B Laing, TJ Schottenfeld, D TI Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CAPTURE-RECAPTURE METHODS; LIFE-TABLE ANALYSIS; LUPUS-ERYTHEMATOSUS; DEMOGRAPHIC FACTORS; SCLERODERMA; EPIDEMIOLOGY; MORTALITY; FEATURES; CLASSIFICATION; ASCERTAINMENT AB Objective. To estimate the prevalence, incidence, survival, and disease characteristics of systemic sclerosis (SSc) in the Detroit tricounty area. Methods. A census of SSc cases for the period 1989-1991 was conducted in the Detroit area, using multiple sources for case identification. Diagnoses were verified by medical record review. Capture-recapture analysis was used to estimate the total SSc population. Cases of localized scleroderma (morphea and linear disease) were excluded. Results. Based on 706 verified cases of SSc, prevalence was initially estimated to be 242.0 cases per million adults (95% confidence interval [95% CI] 213-274), with an annual incidence of 19.3 new cases per million adults per year (95% CI 12.4-30.2). Capture-recapture analysis, based on the degree of overlap of verified cases among multiple sources, resulted in a revised prevalence estimate of 276 cases per million adults (95% CI 245-310). Sex- and race-specific prevalence estimates were significantly higher for women than for men, and for blacks than for whites. The average age at diagnosis was significantly younger for blacks than for whites. Compared with white patients, black patients were almost twice as likely to have diffuse disease (prevalence proportion ratio 1.86, 95% CI 1.48-2.35). Median survival was similar to11 years. Factors negatively affecting survival included male sex (hazard ratio 1.81, 95% CI 1.29-2.55) and older age at diagnosis (hazard ratio 1.04, 95% CI 1.03-1.05). Conclusion. This. study establishes baseline estimates of SSc occurrence and characteristics in a large US cohort consisting primarily of black adults and white adults. These data should, facilitate research regarding the role of geographic, ethnic, racial, and environmental factors for this disease in comparison populations. C1 Univ Texas, Hlth Sci Ctr, Div Rheumatol, Houston, TX 77030 USA. NCI, Rockville, MD USA. Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Med, Ann Arbor, MI 48109 USA. RP Mayes, MD (reprint author), Univ Texas, Hlth Sci Ctr, Div Rheumatol, 6431 Fannin St,MSB 5-270, Houston, TX 77030 USA. FU NIAMS NIH HHS [N01 AR 02251, N01 AR 52217] NR 40 TC 362 Z9 377 U1 2 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2003 VL 48 IS 8 BP 2246 EP 2255 DI 10.1002/art.11073 PG 10 WC Rheumatology SC Rheumatology GA 708TG UT WOS:000184585000021 PM 12905479 ER PT J AU McGaha, TL Le, MH Kodera, T Stoica, C Zhu, JF Paul, WE Bona, CA AF McGaha, TL Le, MH Kodera, T Stoica, C Zhu, JF Paul, WE Bona, CA TI Molecular mechanisms of interleukin-4 - Induced up-regulation of type I collagen gene expression in murine fibroblasts SO ARTHRITIS AND RHEUMATISM LA English DT Article ID COL1A2 PROMOTER ACTIVITY; GROWTH-FACTOR-BETA; SKIN TSK MICE; SYSTEMIC-SCLEROSIS; POTENTIAL ROLE; IL-4; SCLERODERMA; FIBROSIS; RECEPTOR; HOMEOSTASIS AB Objective. There is evidence that interleukin-4 (IL-4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL-4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma-like syndrome characterized by diffuse cutaneous hyperplasia. Methods. Expression of the IL-4 receptor was determined by flow cytometry and Western blotting. The IL-4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT-6) in IL-4 induction of alpha2(1) collagen promoter activity and message levels via luciferase reporter assay and real-time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP-1) and Sp-1 upon stimulation with IL-4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay. Results. Flow cytometry and Western blotting showed that IL-4 receptor a expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL-4 stimulation, janus-activated kinase 1 (JAK-1) and JAK-2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL-4, displaying increased synthesis of alpha1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the -300 to +54 murine a2(1) collagen promoter. Overexpression of STAT-6 enhanced this effect, whereas expression of a dominant-negative STAT-6 abrogated the ability of IL-4 to induce alpha1(I) collagen mRNA in TSK/+. fibroblasts. Moreover, IL-4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis. Conclusion. Our observations indicate that IL-4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL-4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter. C1 CUNY Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Bona, CA (reprint author), CUNY Mt Sinai Sch Med, Dept Microbiol, Box 1124,1 Gustave L Levy Pl, New York, NY 10029 USA. RI Zhu, Jinfang/B-7574-2012; OI McGaha, Tracy/0000-0003-4721-9301 FU NIAID NIH HHS [P01 AI 24671-14] NR 35 TC 37 Z9 38 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2003 VL 48 IS 8 BP 2275 EP 2284 DI 10.1002/art.11089 PG 10 WC Rheumatology SC Rheumatology GA 708TG UT WOS:000184585000024 PM 12905482 ER PT J AU Okada, S Weatherhead, E Targoff, IN Wesley, R Miller, FW AF Okada, S Weatherhead, E Targoff, IN Wesley, R Miller, FW CA Int Myositis Collab Study Grp TI Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease SO ARTHRITIS AND RHEUMATISM LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHY; MYOSITIS-SPECIFIC AUTOANTIBODIES; UVB-RADIATION; IMMUNE-SYSTEM; DERMATOMYOSITIS; MICE; IMMUNOSUPPRESSION; POLYMYOSITIS; IRRADIATION; AUTOANTIGEN AB Objective. To determine if geoclimatic factors may influence the nature and frequency of dermatomyositis (DM), polymyositis, and associated autoantibodies around the world. Methods. We assessed, in the first global evaluation of these conditions, the relationship between 13 geoclimatic variables that may modulate disease and the relative proportion of DM and its associated autoantibody anti-Mi-2, directed against an SNF2-superfamily helicase associated with the nucleosome remodeling and histone acetylation and deacetylation complex, in a global myositis population. Altogether, 919 consecutive patients from populations at 15 locations were studied. Results. Univariate and multivariate analyses demonstrated that of the variables evaluated, surface ultraviolet (UV) radiation intensity (irradiance) most strongly contributed to the relative proportion of DM and was strongly related to the proportion of anti-Mi-2 autoantibodies (weighted r = 0.939, P < 4 x 10(-7) and weighted r = 0.69, P = 0.02, respectively). Published ethnogeographic immunogenetic allele frequencies imply that the striking differences in the proportion of DM- and DM-specific autoantibodies observed around the world are not the result of inherent global variations in known genetic risk factors. Conclusion. These data suggest that UV radiation exposure may modulate the clinical and immunologic expression of an autoimmune disease in different populations around the world. C1 NIEHS, Off Clin Res, NIH, DHHS, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Univ Colorado, Cooperat Inst Res Environm Sci, Boulder, CO 80309 USA. Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FW (reprint author), NIEHS, Off Clin Res, NIH, DHHS, 9 Mem Dr,NIH Bldg 9,Room 1W107,MSC 0958, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov RI Song, Yeong Wook/J-2765-2012; Weatherhead, Elizabeth/I-7091-2015; OI Weatherhead, Elizabeth/0000-0002-9252-4228; Miller, Frederick/0000-0003-2831-9593 NR 45 TC 74 Z9 76 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2003 VL 48 IS 8 BP 2285 EP 2293 DI 10.1002/art.11090 PG 9 WC Rheumatology SC Rheumatology GA 708TG UT WOS:000184585000025 PM 12905483 ER PT J AU Kumagai, H Oki, T Tamitsu, K Feng, SZ Ono, M Nakajima, H Bao, YC Kawakami, Y Nagayoshi, K Copeland, NG Gilbert, DJ Jenkins, NA Kawakami, T Kitamura, T AF Kumagai, H Oki, T Tamitsu, K Feng, SZ Ono, M Nakajima, H Bao, YC Kawakami, Y Nagayoshi, K Copeland, NG Gilbert, DJ Jenkins, NA Kawakami, T Kitamura, T TI Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID MOLECULAR-CLONING; GENE SUPERFAMILY; CYTOKINE RECEPTOR; IG RECEPTOR; NK CELLS; ACTIVATION; MEMBER; ANTIGEN; DNA; HUMAN-CHROMOSOME-17 AB We have identified and characterized two mouse cDNAs in a mouse antigen-stimulated bone marrow-derived mast cell cDNA library. both of which encode type I transmembrane proteins. The genes were closely mapped in the distal region of mouse chromosome I I and expressed not only in mast cells but also widely in leukocytes. The extracellular domains of their encoded proteins contain a single variable immunoglobulin (Ig) motif sharing about 90% identity with amino acids, showing that they comprise a pair of molecules and belong to the Ig superfamily. We named these molecules leukocyte mono-Ig-like receptor1 and 2 (LMIR1 and 2). The intracellular domain of LMIR1 contains several immunoreceptor tyrosine-based inhibition motifs (ITIMs). When cross-linked, the intracellular domain was tyrosine phosphorylated and capable of recruiting tyrosine phosphatases, SHP-1 and SHP-2 and inositol polyphosphate 5-phosphatase, SHIP. LMIR2, on the other hand, contains a short cytoplasmic tail and a characteristic transmembrane domain carrying two positively charged amino acids associated with three kinds of immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules, DAP10, DAP12, and FcRgamma. These findings suggest that a new pair of ITIM/ITAM -bearing receptors, LMIR1 and 2, regulate mast cell-mediated inflammatory responses through yet to be defined ligand(s). (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Tokyo, Inst Med Sci, Div Cell Therapy, Adv Clin Res Ctr,Minato Ku, Tokyo 1088639, Japan. Univ Tokyo, Inst Med Sci, Div Hematopoiet Factors, Adv Clin Res Ctr,Minato Ku, Tokyo 1088639, Japan. Chugai Pharmaceut Co Ltd, Toshima Ku, Tokyo 1718545, Japan. Ehime Univ, Sch Med, Dept Pathol 2, Shigenobu, Ehime 7910295, Japan. La Jolla Inst Allergy Immunol, Div Allergy, San Diego, CA 92121 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Kitamura, T (reprint author), Univ Tokyo, Inst Med Sci, Div Cell Therapy, Adv Clin Res Ctr,Minato Ku, 6-1 Shirokanedai 4 Chome, Tokyo 1088639, Japan. RI Kawakami, Toshiaki/O-1616-2015 NR 44 TC 47 Z9 52 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 1 PY 2003 VL 307 IS 3 BP 719 EP 729 DI 10.1016/S0006-291X(03)01245-2 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 707KK UT WOS:000184509700046 PM 12893283 ER PT J AU Calvert, RJ Tepper, S Diwan, BA Anderson, LM Kritchevsky, D AF Calvert, RJ Tepper, S Diwan, BA Anderson, LM Kritchevsky, D TI Treatment with lovastatin, cholestyramine or niacin alters K-ras membrane association in mouse lung in a strain-dependent manner: results in females SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cholesterol; cholestyramine; K-ras; lovastatin; lung; mouse; niacin; sex difference ID CORONARY ATHEROSCLEROSIS PREVENTION; ESTROGEN-RECEPTOR-ALPHA; LONG-TERM TREATMENT; CANCER RISK; SERUM-CHOLESTEROL; GENE-EXPRESSION; SEX-DIFFERENCES; TUMOR FORMATION; NICOTINIC-ACID; GUINEA-PIG AB Hypocholesterolemic drugs may themselves increase (cholestyramine, CS) or decrease (lovastatin, Lov) peripheral tissue de novo cholesterol biosynthesis. This will alter the abundance of prenyl groups and potentially increase (CS) or decrease (Lov) K-ras membrane localization, with possible pro- or anti-carcinogenic effects (K-ras is a proto-oncogene frequently mutated in lung cancer). Female A/J, Swiss, and C57BL/6 mice were fed 2 or 4% CS, 1% niacin, or injected with Lov three (Lov-3x) or five (Lov-5x) times per week. After three weeks, serum cholesterol and triglycerides were determined enzymatically. Total, membrane, and cytoplasmic K-ras proteins were determined in lung homogenates by immunoprecipitation followed by Western blotting with a K-ras specific antibody. CS feeding increased membrane K-ras as hypothesized in A/J and C57BL/6 mice, but had no effect in Swiss mice. Lov failed in all three strains to reduce membrane K-ras. and resulted in an increase in total K-ras in A/J and C57BL/6 mice, while again lacking effect in Swiss mice. Niacin had no effect on K-ras protein in any mouse strain. These results differ from our published results for male mice of the same strains, particularly for A/J mice. Increased amounts of K-ras protein in the membrane fraction of A/J females (but not males) treated with either Lov or CS imply that if K-ras were to become mutated, CS could result in increased lung tumorigenesis and Lov would be less likely to be protective in females. In the light of these data, both sexes should be included in future animal and human chemoprevention trials. (C) 2003 Elsevier Science Inc. All rights reserved. C1 US FDA, Ctr Food Safety & Appl Nutr, Div Res & Appl Technol, Off Nutr Prod Labeling & Dietary Supplements, College Pk, MD 20740 USA. NCI, Frederick Canc Res & Dev Ctr, Basic Res Program, Frederick, MD 21702 USA. Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. NCI, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. RP Calvert, RJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Res & Appl Technol, Off Nutr Prod Labeling & Dietary Supplements, College Pk, MD 20740 USA. FU NHLBI NIH HHS [HL00735]; ODCDC CDC HHS [N01-CD-12400] NR 49 TC 3 Z9 3 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 2003 VL 66 IS 3 BP 393 EP 403 DI 10.1016/S0006-2952(03)00211-9 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 713NL UT WOS:000184864500005 PM 12907238 ER PT J AU Wenthold, RJ Sans, N Standley, S Prybylowski, K Petralia, RS AF Wenthold, RJ Sans, N Standley, S Prybylowski, K Petralia, RS TI Early events in the trafficking of N-methyl-D-aspartate (NMDA) receptors SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Meeting on Ion Channels and Assembly CY APR 13-16, 2003 CL HARROGATE, ENGLAND DE endoplasmic reticulum; N-methyl-D-aspartate receptor (NMDA receptor); PDZ protein; post-synaptic density; synapse; trafficking ID ER RETENTION SIGNAL; NR1 SPLICE VARIANTS; MOLECULAR DETERMINANTS; AMPA RECEPTORS; HIPPOCAMPAL SYNAPSES; SURFACE EXPRESSION; DOMAIN INTERACTION; SUBUNITS; NEURONS; LOCALIZATION AB The N-methyl-D-aspartate (NMDA) receptor plays a central role at excitatory synapses where it has been implicated in multiple functions associated with synaptic plasticity. While this receptor has been intensely studied with respect to its physiology and pharmacology, its cell-biological properties, such as subunit assembly, post-translational processing and trafficking in neurons, are only beginning to be addressed. Critical to many of the functions of the NMDA receptor are the multiple proteins with which it interacts. While these interactions have been most thoroughly studied with respect to the receptor at the synapse, the same proteins may also interact with the receptor much earlier in its biosynthetic pathway and play important roles in receptor trafficking from the endoplasmic reticulum to the synapse. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Wenthold, RJ (reprint author), NIDCD, Neurochem Lab, NIH, Bldg 50,Room 4140, Bethesda, MD 20892 USA. NR 40 TC 18 Z9 18 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2003 VL 31 BP 885 EP 888 DI 10.1042/BST0310885 PN 4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 713CD UT WOS:000184837100034 PM 12887327 ER PT J AU Petit, F Arnoult, D Viollet, L Estaquier, M AF Petit, F Arnoult, D Viollet, L Estaquier, M TI Intrinsic and extrinsic pathways signaling during HIV-1 mediated cell death SO BIOCHIMIE LA English DT Review DE apoptosis; mitochondria; bcl-2; cytokines; fas; HIV; pathogenesis ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; APOPTOSIS-INDUCING FACTOR; CYTOCHROME-C RELEASE; TUMOR-NECROSIS-FACTOR; BLOOD MONONUCLEAR-CELLS; BCL-2 FAMILY-MEMBERS; ACTIVATION-INDUCED CELL; AFRICAN-GREEN MONKEYS; FAS CD95 EXPRESSION AB Infection with human immunodeficiency virus (HIV) is characterized by the gradual depletion of CD4+ T lymphocytes. The incorporation of the concept of apoptosis as a rationale to explain progressive T cell depletion has led to growing research in this field during the last 10 years. In parallel, the biochemical pathways implicated in programmed cell death have been extensively studied. Thus, the influence of mitochondrial control in the two major apoptotic pathways-the extrinsic and intrinsic pathways-is now well admitted. In this review, we summarized our current knowledge of the different pathways involved in the death of T cells in the course of HIV infection. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 Inst Pasteur, Unite Physiopathol Infect Lentivirales, F-75724 Paris 15, France. NINDS, NIH, Biochem Sect, Bethesda, MD 20892 USA. RP Estaquier, M (reprint author), Inst Pasteur, Unite Physiopathol Infect Lentivirales, 28 Rue Dr Roux, F-75724 Paris 15, France. OI Estaquier, Jerome/0000-0002-9432-8044 NR 262 TC 21 Z9 24 U1 2 U2 3 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD AUG PY 2003 VL 85 IS 8 BP 795 EP 811 DI 10.1016/j.biochi.2003.09.007 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 743FB UT WOS:000186560800012 PM 14585547 ER EF