FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Henkin, L Bergman, RN Bowden, DW Ellsworth, DL Haffner, SM Langefeld, CD Mitchell, BD Norris, JM Rewers, M Saad, MF Stamm, E Wagenknecht, LE Rich, SS AF Henkin, L Bergman, RN Bowden, DW Ellsworth, DL Haffner, SM Langefeld, CD Mitchell, BD Norris, JM Rewers, M Saad, MF Stamm, E Wagenknecht, LE Rich, SS TI Genetic epidemiology of insulin resistance and visceral adiposity: The IRAS family study design and methods SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE atherosclerosis; genetic epidemiology; insulin resistance; visceral adiposity ID DEPENDENT DIABETES-MELLITUS; CARDIOVASCULAR RISK-FACTORS; CORONARY HEART-DISEASE; ABDOMINAL FAT DISTRIBUTION; QUANTITATIVE-TRAIT LOCI; BODY-FAT; PIMA-INDIANS; FOLLOW-UP; VARIANCE-COMPONENTS; PEDIGREE ANALYSIS AB PURPOSE: Insulin resistance and visceral adiposity are associated with increased risk of type 2 diabetes. In this report, we describe the methods of the IRAS Family Study, which was designed to identify the genetic and environmental risk factors for insulin resistance and visceral adiposity. METHODS: Families from two ethnic groups (African American and Hispanic) have been recruited from three clinical sites. Blood samples for DNA as well as other standard measures were collected. A CT scan (visceral adiposity) and a frequently sampled glucose tolerance test (insulin resistance) were performed. Preliminary estimates of heritability for indirect measures related to insulin resistance and visceral adiposity were obtained using a variance component,, approach in the first 93 families (approximately 1000 individuals). RESULTS: Estimates of heritability ranged from low (0.08) for fasting insulin and HOMA, to moderate (0.28) for fasting glucose, to high (0.54) for BMI. After adjustment for age, gender and ethnicity, all heritability estimates were significantly greater than zero (p < 0.05). CONCLUSIONS: These results are consistent with the expectation that intermediate measures of insulin resistance and visceral adiposity are heritable, and that the IRAS Family Study has statistical power to detect these intermediate phenotypes of type 2 diabetes and atherosclerosis. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, MRI Ctr, Winston Salem, NC 27157 USA. Univ So Calif, Los Angeles, CA 90089 USA. NHLBI, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Maryland, College Pk, MD 20742 USA. Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. RP Henkin, L (reprint author), Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, MRI Ctr, 3rd Floor, Winston Salem, NC 27157 USA. OI Mitchell, Braxton/0000-0003-4920-4744 FU NHLBI NIH HHS [HL60894-02, HL60931-02, HL60977-02, HL61019-02, HL61210-02]; NIDDK NIH HHS [R01 DK029867] NR 66 TC 94 Z9 95 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD APR PY 2003 VL 13 IS 4 BP 211 EP 217 AR PII S1047-2797(02)00412-X DI 10.1016/S1047-2797(02)00412-X PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 665AR UT WOS:000182097900001 PM 12684185 ER PT J AU Devereux, RB Roman, MJ Liu, JE Lee, ET Wang, WY Fabsitz, RR Welty, TK Howard, BV AF Devereux, RB Roman, MJ Liu, JE Lee, ET Wang, WY Fabsitz, RR Welty, TK Howard, BV TI An appraisal of Echocardiography as an epidemiological tool: The strong heart study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE echocardiography; epidemiology; obesity; prognosis ID LEFT-VENTRICULAR MASS; CARDIOVASCULAR RISK-FACTORS; AMERICAN-INDIANS; SYSTOLIC FUNCTION; DISEASE; HYPERTROPHY; RELIABILITY; POPULATION; GEOMETRY; VOLUME AB PURPOSE: Despite the prognostic importance of left ventricular (LV) mass (LVM) by M-mode echocardiography, concern exists about bias introduced by missing data. The American Society of Echocardiography has made recommendations for linear measurements of LV wall thickness and internal dimension used to calculate LVM, but it is unknown whether their substitution for suboptimal M-modes improves measurement yield and reduces bias. METHODS: LVM measurement yield and associations of missing data with risk factors were assessed in 3487 American Indian participants in Strong Heart Study (SHS) Phase II and compared to data from other large-scale studies. RESULTS: In SHS, LVM was measurable in 3188 (91%) participants compared to 4947/6148 (80%) Framingham participants studied by classic M-mode technique, with less decrease in measurement yield with age in SHS. In univariate SHS analyses, missing LVM was significantly associated with male gender, older age, greater height, body mass index, fat-free mass, waist/hip ratio, fibrinogen and, marginally, diabetes but not smoking, blood pressure, or lipids. In logistic regression analysis, missing LVM was independently associated with male gender, older age, greater body mass index and lower forced expiratory volume (FEV1) (with a low multiple R-2 [.04]), but not other risk factors. Doppler stroke volume, a measure of hemodynamic volume toad, was measurable in 96% of SHS participants; missing values were weakly associated with older age, higher creatinine and lower FEV1. During 48 +/- 11 months of follow-up, inability to measures LV mass or stroke volume was not associated with higher rates of cardiovascular events or death (p = 0.25 to 0.96). CONCLUSIONS: Improvements in echocardiographic methods have increased the yield of LVM in middle,aged and older adults and allow even more consistent assessment of cardiac volume load. Despite small persistent biases, due to associations of missing LVM and Doppler stroke volume data with male gender, greater obesity, lower FEV1 and (for LVM only) older age, individuals with missing measurement are not at higher risk of cardiovascular events. (C) 2003 Elsevier Science Inc. Alt rights reserved. C1 Cornell Univ, Med Ctr, New York Hosp, New York, NY 10021 USA. Univ Oklahoma, Hlth Sci Ctr, Sch Publ Hlth, Oklahoma City, OK USA. NHLBI, Bethesda, MD 20892 USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. MedStar Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. FU NCRR NIH HHS [M10RR0047-34]; NHLBI NIH HHS [U01-HL41642, U01-HL41652, U01-HL41654] NR 31 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD APR PY 2003 VL 13 IS 4 BP 238 EP 244 AR PII S1047-2797(02)00264-8 DI 10.1016/S1047-2797(02)00264-8 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 665AR UT WOS:000182097900005 PM 12684189 ER PT J AU Parker, AS Cerhan, JR Janney, CA Lynch, CF Cantor, KP AF Parker, AS Cerhan, JR Janney, CA Lynch, CF Cantor, KP TI Smoking cessation and renal cell carcinoma SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE smoking cessation; case-control; renal cell carcinoma; smoothing spline regression; generalized additive models; GAM ID TOBACCO USE; RISK-FACTORS; CANCER; CATEGORIZATION; IOWA AB PURPOSE: The magnitude and timing of the reported decrease in risk of renal cell carcinoma (RCC) attributed to smoking cessation is not well characterized. Furthermore, conclusions from previous investigations have been hampered by unstable risk estimates, broad exposure categories and/or insufficient adjustment for the inverse correlation of cessation years with lifetime smoking exposure. METHODS: To address these issues, we report data from a population-based case-control study conducted in Iowa from 1986 to 1989. RCC cases (n = 387) were identified through the Iowa Cancer Registry, while controls (n = 2,333) were randomly selected from the general population, frequency-matched on age and sex. Subjects provided detailed information on a mailed questionnaire regarding their smoking history as well as other anthropometric, lifestyle, dietary and medical history risk factors. RESULTS: Smoothing spline regression analysis provided evidence of a consistent inverse linear trend between years of cessation and risk of RCC. In categorical analysis, compared with current smokers, those quitting greater than or equal to30 years ago experienced a 50% reduction in risk of RCC (OR = 0.5; 95% CI 0.3 to 0.8) after adjustment for age, sex, BMI, hypertension and pack-years of smoking. Risk among long-term quitters was similar to risk among never smokers (OR = 0.6; 95% CI 0.4 to 0.8). In contrast, cessation of <10 years, 10 to 19 years and 20 to 29 years all resulted in a less pronounced reduction in RCC risk (similar to20% to 30%). CONCLUSIONS: Our findings suggest that while cessation of smoking is indeed associated with a linear decrease in RCC risk even after adjustment for potential confounders, this benefit may not be sizeable until more than 20 years following cessation. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. Univ Iowa, Sch Publ Hlth, Dept Epidemiol, Iowa City, IA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Parker, AS (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. FU NCI NIH HHS [N01-CP-85614, N01-CP-5106] NR 20 TC 25 Z9 26 U1 0 U2 2 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 APR PY 2003 VL 13 IS 4 BP 245 EP 251 AR PII S1047-2797(02)00271-5 DI 10.1016/S1047-2797(02)00271-5 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 665AR UT WOS:000182097900006 PM 12684190 ER PT J AU Wang, WY Lee, ET Fabsitz, R AF Wang, WY Lee, ET Fabsitz, R TI Estimating means of a set of measures from small samples by using multivariate composite estimating concept - The Strong Heart Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE multivariate composite estimator; mean squared error; small sample site AB In this study, we describe a method employing the multivariate composite estimating (MCE) concept to estimate the means of a set of measurements based on small samples from different groups in a population as well as the grand means of the measurements for the population. The advantages if these estimators over simple averages used in the literature are that they have lower mean squared errors, and they improve on simple averages by taking account of variations and correlations among the set of measurements as well as differences among group. An application to the Strong Heart Study baseline exam data is provided. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Oklahoma City, OK 73190 USA. NHLBI, Bethesda, MD 20892 USA. RP Wang, WY (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, POB 26901, Oklahoma City, OK 73190 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 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 APR PY 2003 VL 13 IS 4 BP 280 EP 285 AR PII S1047-2797(02)00416-7 DI 10.1016/S1047-2797(02)00416-7 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 665AR UT WOS:000182097900011 PM 12684195 ER PT J AU Stellman, SD Chen, Y Muscat, JE Djordjevic, MV Richie, JP Lazarus, P Thompson, S Altorki, N Berwick, M Citron, ML Harlap, S Kaur, TB Neugut, AI Olson, S Travaline, JM Witorsch, P Zhang, ZF AF Stellman, SD Chen, Y Muscat, JE Djordjevic, MV Richie, JP Lazarus, P Thompson, S Altorki, N Berwick, M Citron, ML Harlap, S Kaur, TB Neugut, AI Olson, S Travaline, JM Witorsch, P Zhang, ZF TI Lung cancer risk in white and black Americans SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE lung cancer; cigarettes; smoking; risk; racial differences; dosage; menthol ID LOS-ANGELES-COUNTY; S-TRANSFERASE M1; AFRICAN-AMERICANS; UNITED-STATES; GENETIC-POLYMORPHISM; CIGARETTE-SMOKING; NONMENTHOL CIGARETTES; FAMILY HISTORY; ORAL-CANCER; CAUCASIANS AB PURPOSE: To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black bales than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS: A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS. We confirmed prior reports that smoking prevalence is higher hut overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack-years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS. Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. Amer Hlth Fdn, Div Epidemiol, Valhalla, NY 10595 USA. NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. Amer Hlth Fdn, Div Nutrit Carcinogenesis, Valhalla, NY 10595 USA. H Lee Moffitt Canc Ctr, Div Canc Control, Tampa, FL 33612 USA. H Lee Moffitt Canc Ctr, Div Mol Oncol, Tampa, FL 33612 USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. Presbyterian Hosp, Div Thorac Surg, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. ProHlth Inc, Lake Success, NY 11042 USA. NYU, Kaplan Canc Ctr, New York, NY 10016 USA. NYU, Dept Obstet & Gynecol, New York, NY 10016 USA. Temple Univ Hosp & Med Sch, Dept Obstet & Gynecol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Div Pulm, Philadelphia, PA 19140 USA. Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Pharmacol, Washington, DC 20007 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. RP Stellman, SD (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 630 W 168th St,PH-18, New York, NY 10032 USA. OI Berwick, Marianne/0000-0001-5062-2180 FU NCI NIH HHS [CA-17613, CA-68384, CA-91401] NR 48 TC 67 Z9 68 U1 2 U2 7 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 APR PY 2003 VL 13 IS 4 BP 294 EP 302 AR PII S1047-2797(02)00420-9 DI 10.1016/S1047-2797(02)00420-9 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 665AR UT WOS:000182097900013 PM 12684197 ER PT J AU Sawaki, L Yaseen, Z Kopylev, L Cohen, LG AF Sawaki, L Yaseen, Z Kopylev, L Cohen, LG TI Age-dependent changes in the ability to encode a novel elementary motor memory SO ANNALS OF NEUROLOGY LA English DT Article ID INDUCED MOVEMENT THERAPY; PLASTICITY; CORTEX; MECHANISMS AB In healthy individuals, motor training elicits cortical plasticity that encodes the kinematic details of the practiced movements and is thought to underlie recovery of function after stroke. The influence of age on this form of plasticity is incompletely understood. We studied 55 healthy subjects and identified a substantial decrease in training-dependent plasticity as a function of age in the absence of differences in training kinematics. These results suggest that the ability of the healthy aging motor cortex to reorganize in response to training decreases with age. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N 226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 20 TC 91 Z9 94 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 APR PY 2003 VL 53 IS 4 BP 521 EP 524 DI 10.1002/ana.10529 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 660PQ UT WOS:000181841900013 PM 12666120 ER PT J AU Wright, MA Schuler, B Szabo, E Grem, JL AF Wright, MA Schuler, B Szabo, E Grem, JL TI Sustained partial response of an intra-abdominal desmoid tumor treated with gemcitabine, 5-fluorouracil and leucovorin SO ANNALS OF ONCOLOGY LA English DT Letter ID CHEMOTHERAPY; INDOMETHACIN C1 Natl Naval Med Res Inst, NCI Navy Med Oncol, Bethesda, MD 20814 USA. RP Grem, JL (reprint author), Natl Naval Med Res Inst, NCI Navy Med Oncol, Bethesda, MD 20814 USA. EM gremj@mail.nih.gov NR 7 TC 2 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2003 VL 14 IS 4 BP 659 EP 660 DI 10.1093/annonc/mdg155 PG 2 WC Oncology SC Oncology GA 694QX UT WOS:000183786400028 PM 12649120 ER PT J AU Bray, M AF Bray, M TI Pathogenesis and potential antiviral therapy of complications of smallpox vaccination SO ANTIVIRAL RESEARCH LA English DT Review DE vaccinia virus; progressive vaccinia; generalized vaccinia; eczema vaccinatum; vaccinia keratitis; vaccination complications; smallpox; orthopoxvirus; cidofovir; ribavirin; interferon; antiviral therapy ID VIRUS ORTHOPOXVIRUS INFECTIONS; IMMUNE-RESPONSE MODIFIERS; ATOPIC-DERMATITIS; LYMPHOCYTE-RESPONSES; POXVIRUS INFECTIONS; INTERFERON-GAMMA; GENITAL HERPES; MOUSE MODEL; VACCINIA; CIDOFOVIR AB Vaccination against smallpox may result in a variety of complications, ranging in severity from benign to lethal. Universal vaccination was halted in the US in 1972, so almost half the present population has never been vaccinated. Because side effects occur most often in first-time vaccinees, current plans for rapid large-scale vaccination in the event of bioterrorist attack raise concerns about the occurrence of a large number of adverse events. Most complications result from the excessive replication of vaccinia virus, making them potential targets for antiviral therapy. Effective treatment is especially needed for persons with atopic dermatitis or eczema, who are unusually susceptible to the initiation and spread of vaccinia infection because of defects of innate immunity in the skin, and for individuals with defective cell-mediated immunity, who are unable to eliminate vaccinia infection once it has begun. In the past, many complications were treated with vaccinia immune globulin (VIG) and/or the antiviral drug methisazone, but neither was tested in placebo-controlled trials. New antiviral drugs are now available, but have not yet been evaluated for treating vaccinia infections in humans. Both laboratory research and clinical studies are needed to help prevent serious complications in any major vaccination campaign. Published by Elsevier Science B.V. C1 NIAID, Off Director, Off Clin Res, Biodef Clin Res Branch, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Off Director, Off Clin Res, Biodef Clin Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 105 TC 73 Z9 77 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 APR PY 2003 VL 58 IS 2 BP 101 EP 114 DI 10.1016/S0166-3542(03)00008-1 PG 14 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 683VZ UT WOS:000183172800001 PM 12742570 ER PT J AU Ait-Khaled, M Rakik, A Griffin, P Stone, C Richards, N Thomas, D Falloon, J Tisdale, M AF Ait-Khaled, M Rakik, A Griffin, P Stone, C Richards, N Thomas, D Falloon, J Tisdale, M CA CNA2007 Int Study Team TI HIV-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study SO ANTIVIRAL THERAPY LA English DT Article ID INHIBITOR AMPRENAVIR; COMBINATION THERAPY; CROSS-RESISTANCE; IN-VITRO; EFAVIRENZ; ABACAVIR; RT; SUSCEPTIBILITY; ZIDOVUDINE; LAMIVUDINE AB Objective: To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen. Methods: Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs other ART. The median follow-up was 48 weeks (range week 16-72). Results: Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had >= 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): 6 to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V108I (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the 6190 mutations (OR=8.9, P < 0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and I54V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates. Conclusion: Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir. C1 GlaxoSmithKline Inc, HIV Clin Dev & Med Affairs Europe, Greenford, Middx, England. GlaxoSmithKline Inc, Int Clin Virol, Stevenage, Herts, England. GlaxoSmithKline Inc, Stat, Greenford, Middx, England. GlaxoSmithKline Inc, N Amer Med Affairs, Res Triangle Pk, NC USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Ait-Khaled, M (reprint author), GlaxoSmithKline Inc, HIV Clin Dev & Med Affairs Europe, Greenford, Middx, England. EM mak75231@gsk.com NR 21 TC 19 Z9 20 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 APR PY 2003 VL 8 IS 2 BP 111 EP 120 PG 10 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YH UT WOS:000231265600005 PM 12741623 ER PT J AU Bhargava, R Levin, IW AF Bhargava, R Levin, IW TI Time-resolved Fourier transform infrared spectroscopic imaging SO APPLIED SPECTROSCOPY LA English DT Article DE time-resolved spectroscopy; Fourier transform infrared imaging; microspectroscopy; polymer-dispersed liquid crystals; molecular dynamics ID NEMATIC LIQUID-CRYSTAL; FIELD-INDUCED REORIENTATION; SCAN FT-IR; ELECTRIC-FIELD; FLEXIBLE POLYMERS; RAPID-SCAN; DYNAMICS; 5CB; SPECTROMETER; SYSTEMS AB Fourier transform infrared (FT-IR) imaging allows simultaneous spectral characterization of large spatial areas due to its multichannel detection advantage. The acquisition of large amounts of data in the multichannel configuration results, however, in a poor temporal resolution of sequentially acquired data sets, which limits the examination of dynamic processes to processes that have characteristic time scales of the order of minutes. Here, we introduce the concept and instrumental details of a time-resolved infrared spectroscopic imaging modality that permits the examination of repetitive dynamic processes whose half-lives are of the order of milliseconds. As an illustration of this implementation of step-scan FTIR imaging, we examine the molecular responses to external electric-field perturbations of a microscopically heterogeneous polymer-liquid crystal composite. Analysis of the spectroscopic data using conventional univariate and generalized two-dimensional (2D) correlation methods emphasizes an additional capability for accessing of simultaneous spatial and temporal chemical measurements of molecular dynamic processes. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. OI Bhargava, Rohit/0000-0001-7360-994X NR 61 TC 31 Z9 31 U1 0 U2 10 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 201B BROADWAY ST, FREDERICK, MD 21701 USA SN 0003-7028 J9 APPL SPECTROSC JI Appl. Spectrosc. PD APR PY 2003 VL 57 IS 4 BP 357 EP 366 DI 10.1366/00037020360625880 PG 10 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 704UF UT WOS:000184358300001 PM 14658631 ER PT J AU Cao, HP Dzineku, F Blackshear, PJ AF Cao, HP Dzineku, F Blackshear, PJ TI Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE tristetraprolin; tumor necrosis factor-alpha; protein expression and purification; protein phosphorylation; mRNA ARE-binding protein; mitogen-activated protein kinase ID MESSENGER-RNA TURNOVER; ZINC-FINGER PROTEINS; AU-RICH ELEMENTS; P38 MAP KINASE; ESCHERICHIA-COLI; MAIZE ENDOSPERM; TRANSCRIPTION FACTOR; FUSION PROTEIN; PHOSPHORYLATION; SEQUENCE AB Tristetraprolin (TTP) is an mRNA-binding protein, but studies of this interaction have been difficult due to problems with the purification of recombinant TTP. In the present study, we expressed human and mouse TTP as glutathione S-transferase and maltose-binding protein (MBP) fusion proteins in Escherichia coli, and purified them by affinity resins and Mono Q chromatography. TTP cleaved from the fusion protein was identified by immunoblotting, MALDI-MS, and protein sequencing, and was further purified to homogeneity by continuous-elution SDS-gel electrophoresis. Purified recombinant TTP bound to the AU-rich element of tumor necrosis factor-alpha (TNFalpha) mRNA and this binding was dependent on Zn2+. Results from sizing columns suggested that the active species might be in the form of an oligomer of MBP-TTP. Recombinant TTP was phosphorylated by three members of the mitogen-activated protein (MAP) kinase family, p42, p38, and JNK, with half-maximal phosphorylation occurring at approximately 0.5. 0.25, and 0.25 muM protein, respectively. Phosphorylation by these kinases did not appear to affect the ability of TTP to bind to TNFalpha mRNA under the assay conditions. This study describes a procedure for purifying nonfusion protein TTP to homogeneity, demonstrates that TTP's RNA-binding activity is zinc dependent, and that TTP can be phosphorylated by JNK as well as by the other members of the greater MAP kinase family. (C) 2003 Published by Elsevier Science (USA). C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Cao, HP (reprint author), NIEHS, Lab Signal Transduct, Mail Drop F3-04, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [Z01 ES090080-08] NR 52 TC 54 Z9 55 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD APR 1 PY 2003 VL 412 IS 1 BP 106 EP 120 DI 10.1016/S0003-9861(03)00012-2 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 660ZK UT WOS:000181865800014 PM 12646273 ER PT J AU Maciag, A Bialkowska, A Espiritu, I Powell, D Alvord, WG Kasprzak, KS Anderson, LM Witschi, HR AF Maciag, A Bialkowska, A Espiritu, I Powell, D Alvord, WG Kasprzak, KS Anderson, LM Witschi, HR TI Gestation stage-specific oxidative deoxyribonucleic acid damage from sidestream smoke in pregnant rats and their fetuses SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article DE DNA damage; 8-oxo-dG; environmental tobacco smoke; fetus; rat model ID ENVIRONMENTAL TOBACCO-SMOKE; COVALENT DNA MODIFICATIONS; CHILDHOOD-CANCER; CIGARETTE-SMOKE; PATAS MONKEYS; PARENTAL USE; LUNG-CANCER; TRANSPLACENTAL EXPOSURE; PRENATAL EXPOSURE; MATERNAL EXPOSURE AB Transplacental exposure to environmental tobacco smoke (ETS) is a possible cancer risk factor in offspring. The authors exposed pregnant Sprague-Dawley rats to a relevant dose of ETS (1 mg/m(3)) from gestation day 4 to days 16 or 21. They then assayed tissues for levels of 8-oxo-2'-deoxyguanosine (8-oxo-dG), a marker of oxidative deoxyribonucleic acid damage. ETS exposure ending on gestation day 16 resulted in statistically significant increases in 8-oxo-dG in maternal liver and kidney and in fetal kidney. On gestation day 21, there were significant 8-oxo-dG increases in fetal liver and brain. These gestational stage- and tissue-specific increases of 1.2- to 1.4-fold are similar to the putative relative increases in risk of human cancers related to ETS. C1 NCI, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. Univ Calif Davis, Ctr Hlth & Environm, Davis, CA 95616 USA. Data Management Serv Inc, Frederick, MD USA. RP Anderson, LM (reprint author), NCI, Lab Comparat Carcinogenesis, Bldg 538, Frederick, MD 21702 USA. FU NIEHS NIH HHS [ES05707, ES07908, ES07499] NR 55 TC 6 Z9 7 U1 0 U2 1 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0003-9896 J9 ARCH ENVIRON HEALTH JI Arch. Environ. Health PD APR PY 2003 VL 58 IS 4 BP 238 EP 244 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 746JW UT WOS:000186744100008 PM 14655905 ER PT J AU Chan, CC Datiles, M Kaiser-Kupfer, MI Kupfer, C AF Chan, CC Datiles, M Kaiser-Kupfer, MI Kupfer, C TI Congenital iridocorneal malformation in Rieger syndrome SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material C1 NEI, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. OI Datiles, Manuel III B./0000-0003-4660-1664 NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD APR PY 2003 VL 121 IS 4 BP 582 EP 583 DI 10.1001/archopht.121.4.582 PG 2 WC Ophthalmology SC Ophthalmology GA 664QM UT WOS:000182071800024 PM 12695262 ER PT J AU Nansel, TR Overpeck, MD Haynie, DL Ruan, WJ Scheidt, PC AF Nansel, TR Overpeck, MD Haynie, DL Ruan, WJ Scheidt, PC TI Relationships between bullying and violence among US youth SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PROBLEM BEHAVIORS; ADOLESCENTS; SCHOOL; ASSOCIATION; STUDENTS; HANDGUNS; RISK AB Objective: To determine the extent to which bullying and being bullied, both in and away from school, is associated with involvement in violent behavior. Design, Setting, and Participants: A US representative cross-sectional sample of 15 686 students in grades 6 through 10 in public and private schools completed the World Health Organization's Health Behaviour in School-aged Children survey in 1998. Main Outcome Measures: Self-report of weapon carrying, weapon carrying in school, physical fighting, and being injured in a physical fight. Results: Involvement in each of the violence-related behaviors ranged from 13% to 23% of boys and 4% to 11% of girls. Bullying others and being bullied were consistently related to each violence-related behavior for both boys and girls. Greater odds of involvement occurred with bullying others than being bullied, and greater odds of involvement occurred with bullying that took place away from school than that occurring in school. For example, the adjusted odds ratio for weapon carrying associated with being bullied in school weekly was 1.5, for bullying others in school 2.6, for being bullied away from school 4.1, and for bullying others away from school 5.9. Conclusion: Bullying should not be considered a normative aspect of youth development, but rather a marker for more serious violent behaviors, including weapon carrying, frequent fighting, and fighting-related injury. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Maternal & Child Hlth Bur, Hlth Resources & Serv Adm, Bethesda, MD USA. RP Nansel, TR (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 7B13,MSC 7510, Bethesda, MD 20892 USA. OI Nansel, Tonja/0000-0002-8298-7595; Haynie, Denise/0000-0002-8270-6079 NR 26 TC 162 Z9 166 U1 8 U2 25 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD APR PY 2003 VL 157 IS 4 BP 348 EP 353 DI 10.1001/archpedi.157.4.348 PG 6 WC Pediatrics SC Pediatrics GA 664ZX UT WOS:000182096100009 PM 12695230 ER PT J AU Jung, YJ Kim, HH Kong, HS Kim, YM AF Jung, YJ Kim, HH Kong, HS Kim, YM TI Synthesis and properties of 5-aminosalicyl-taurine as a colon-specific prodrug of 5-aminosalicylic acid SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Article DE 5-aminosalicyltaurine; colon-specific prodrug of 5-aminosalicylic acid; inflammatory bowel disease; colon-targeting ID INFLAMMATORY BOWEL-DISEASE; PEPTIDE DRUGS; LUNG INJURY; TAURINE; METABOLISM AB 5-Aminosalicylic acid (5-ASA) is an active ingredient of therapeutic agents used for Crohn's disease and ulcerative colitis. Because it is absorbed rapidly and extensively in the upper intestine, delivery of the agent specifically to the colon is necessary. We selected taurine as a colon-specific promoiety and designed 5-aminosalicyltaurine (5-ASA-Tau) as a new colon-specific prodrug of 5-aminosalicylic acid (5-ASA). It was expected that introduction of taurine would restrict the absorption of the prodrug and show additive effect to the anti-inflammatory action of 5-ASA after hydrolysis. 5-ASA-Tau was prepared in good yield by a simple synthetic route. The apparent partition coefficient of 5-ASA-Tau in 1-octanol/pH 6.8 phosphate buffer or CHCl3/pH 6.8 phosphate buffer was 0.10 or 0.18, respectively, at 37degreesC. To determine the chemical and biochemical stability in the upper intestinal environment, 5-ASA-Tau was incubated in pH 1.2 and 6.8 buffer solutions, and with the homogenates of tissue and contents of stomach or small intestine of rats at 37degreesC. 5-ASA was not detected from any of the incubation medium with no change in the concentration of 5-ASA-Tau. On incubation of 5-ASA-Tau with the cecal and colonic contents of rats, the fraction of the dose released as 5-ASA was 45% and 20%, respectively, in 8 h. Considering low partition coefficient and stability in the upper intestine, 5-ASA-Tau might be nonabsorbable and stable in the upper intestine. After oral administration, it would be delivered to the colon in intact form and release 5-ASA and taurine. These results suggested 5-ASA-Tau as a promising colon-specific prodrug of 5-ASA. C1 Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. NCI, Dept Cell & Canc Biol, Med Branch, Rockville, MD 20850 USA. RP Kim, YM (reprint author), Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. NR 17 TC 11 Z9 12 U1 1 U2 2 PU PHARMACEUTICAL SOCIETY KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD APR PY 2003 VL 26 IS 4 BP 264 EP 269 DI 10.1007/BF02976953 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 673DB UT WOS:000182563700003 PM 12735682 ER PT J AU Nyska, A Ghanayem, BI AF Nyska, A Ghanayem, BI TI Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 Rats and B6C3F1 mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE methacrylonitrile; carcinogenicity; F344/N rat; B6C3F1 mouse; olfactory epithelium; atrophy ID 2-CYANOETHYLENE OXIDE; CYTOCHROME-P-450 2E1; ACRYLONITRILE; METABOLISM; DISPOSITION; TESTS; IDENTIFICATION; GLUTATHIONE; MECHANISM; CHEMICALS AB Methacrylonitrile is an unsaturated aliphatic nitrile. It is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics, and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. Methacrylonitrile was nominated for study by the National Cancer Institute (USA) because of the potential for human exposure, structural similarity to the known carcinogen acrylonitrile, and a lack of toxicity and carcinogenicity data. Doses selected for the 2-year study were based on the results of the 13-week gavage studies. Groups of 50 male and 50 female animals were exposed by gavage to 0, 3, 10, or 30 mg/kg in F344 rats, and 0, 1.5, 3 or 6 mg/kg in B6C3F1 mice, 5 days per week for 2 years. Urinary excretion of N-acetyl-S-(2-cyanopropyl)-L-cysteine (NACPC) and N-acetyl-S-(2-hydroxypropyl)-L-cysteine (NAHPC) were measured as markers of exposure at various time points after methacrylonitrile administration, and demonstrated that exposure of animals to methacrylonitrile occurred as intended. Urinary excretion of NACPC and NAHPC increased in rats and mice in a dose-dependent manner. In contrast to observations in rats, the ratios of NACPC/creatinine were generally higher in female than in male mice. Further, the ratios of NAHPC/creatinine in rats were significantly greater at all time points and all doses than the corresponding ratios of NACPC/creatinine in male and female mice. In both rats and mice, survival was not affected by treatment. In rats, mean body weights of the 30 mg/kg groups were less than those of the vehicle controls after weeks 21 and 37 for males and females, respectively. No treatment-related effect on body weight was seen in mice. There were no neoplasms (in either species) or non-neoplastic lesions (mice only) that were attributed to methacrylonitrile administration. In rats, the incidences of olfactory epithelial atrophy and metaplasia of the nose were significantly greater in 30 mg/kg males and females than those in the vehicle controls. Increased incidences of cytoplasmic vacuolation occurred in the liver of males and females. Testing methacrylonitrile in a battery of short-term in vitro and in vivo tests showed no evidence of genotoxicity. In conclusion, under the conditions of these 2-year gavage studies, there was no evidence of a carcinogenic activity of methacrylonitrile in male or female F344/N rats or B6C3F1 mice. Methacrylonitrile-related non-neoplastic lesions were seen in the nose and liver of rats. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, NIH, MD B3-06,POB 12233, Res Triangle Pk, NC 27709 USA. NR 46 TC 6 Z9 8 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD APR PY 2003 VL 77 IS 4 BP 233 EP 242 DI 10.1007/s00204-002-0434-7 PG 10 WC Toxicology SC Toxicology GA 682GH UT WOS:000183083000007 PM 12698239 ER PT J AU Jawaheer, D Seldin, MF Amos, CI Chen, WV Shigeta, R Etzel, C Damle, A Xiao, XL Chen, D Lum, RF Kern, M Criswell, LA Albani, S Nelson, JL Clegg, DO Pope, R Schroeder, HW Bridges, SL Pisetsky, DS Ward, R Kastner, DL Wilder, RL Pincus, T Callahan, LF Flemming, D Wener, MH Gregersen, PK AF Jawaheer, D Seldin, MF Amos, CI Chen, WV Shigeta, R Etzel, C Damle, A Xiao, XL Chen, D Lum, RF Kern, M Criswell, LA Albani, S Nelson, JL Clegg, DO Pope, R Schroeder, HW Bridges, SL Pisetsky, DS Ward, R Kastner, DL Wilder, RL Pincus, T Callahan, LF Flemming, D Wener, MH Gregersen, PK CA No Amer Rheumatoid Arthrit Consort TI Screening the rheumatoid arthritis genome for susceptibility genes - A replication study and combined analysis of 512 multicase families SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; AUTOIMMUNE-DISEASES; LINKAGE ANALYSIS; CHROMOSOME 18Q21; CROHNS-DISEASE; COMPLEX TRAITS; WIDE SEARCH; ASSOCIATION; LOCUS; RAT AB Objective. A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings. Methods. We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL. Results. Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398),17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome I showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates. Conclusion. These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q. C1 Univ Calif Davis, Davis, CA 95616 USA. Univ Texas, Houston, TX USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Utah, Salt Lake City, UT USA. Northwestern Univ, Sch Med, Chicago, IL USA. Univ Alabama, Birmingham, AL USA. Vet Adm Hosp, Durham, NC USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Oxford, Oxford, England. NIAMSD, NIH, Bethesda, MD 20892 USA. MedImmune Inc, Gaithersburg, MD USA. Vanderbilt Univ, Nashville, TN USA. Univ N Carolina, Chapel Hill, NC USA. Natl Naval Med Res Inst, Bethesda, MD USA. Univ Washington, Sch Med, Seattle, WA USA. RP Gregersen, PK (reprint author), N Shore LIJ Res Inst, Ctr Genome & Human Genet, 350 Community Dr, Manhasset, NY 11030 USA. EM peterg@nshs.edu FU NCRR NIH HHS [1-P41-RR-03655, 5-M01-RR-00079, M01 RR000079]; NIAMS NIH HHS [R01 AR044422, N01-AR-7-2232, R01-AR44222] NR 42 TC 162 Z9 172 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 APR PY 2003 VL 48 IS 4 BP 906 EP 916 DI 10.1002/art.10989 PG 11 WC Rheumatology SC Rheumatology GA 665HZ UT WOS:000182115300006 PM 12687532 ER PT J AU Matsumoto, I Lee, DM Goldbach-Mansky, R Sumida, T Hitchon, CA Schur, PH Anderson, RJ Coblyn, JS Weinblatt, ME Brenner, M Duclos, B Pasquali, JL El-Gabalawy, H Mathis, D Benoist, C AF Matsumoto, I Lee, DM Goldbach-Mansky, R Sumida, T Hitchon, CA Schur, PH Anderson, RJ Coblyn, JS Weinblatt, ME Brenner, M Duclos, B Pasquali, JL El-Gabalawy, H Mathis, D Benoist, C TI Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders SO ARTHRITIS AND RHEUMATISM LA English DT Article ID T-CELL; AUTOANTIBODIES; CLASSIFICATION; DISEASE; CRITERIA; ENZYME; GPI; RECOGNITION; SYSTEM; SERA AB Objective. Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects. Methods. Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting. Results. Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus. Conclusion. No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Univ Tsukuba, Ibaraki, Japan. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Tsukuba, Ibaraki, Japan. Univ Manitoba, Winnipeg, MB, Canada. Hop Hautepierre, Hop Univ Strasbourg, Strasbourg, France. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Manitoba, Winnipeg, MB, Canada. RP Benoist, C (reprint author), Joslin Diabet Ctr, 1 Joslin Pl,Room 475, Boston, MA 02215 USA. FU NIAMS NIH HHS [K08-AR-0221401] NR 26 TC 86 Z9 96 U1 2 U2 4 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 APR PY 2003 VL 48 IS 4 BP 944 EP 954 DI 10.1002/art.10898 PG 11 WC Rheumatology SC Rheumatology GA 665HZ UT WOS:000182115300010 PM 12687536 ER PT J AU Chen, CT Fishbein, KW Torzilli, PA Hilger, A Spencer, RGS Horton, WE AF Chen, CT Fishbein, KW Torzilli, PA Hilger, A Spencer, RGS Horton, WE TI Matrix fixed-charge density as determined by magnetic resonance microscopy of bioreactor-derived hyaline cartilage correlates with biochemical and biomechanical properties SO ARTHRITIS AND RHEUMATISM LA English DT Article ID HOLLOW-FIBER BIOREACTOR; ARTICULAR-CARTILAGE; FLUID-FLOW; MRI; CHONDROCYTES; TISSUE; SPECTROSCOPY AB Objective. To use noninvasive magnetic resonance imaging (MRI), biochemical analyses, and mechanical testing of engineered neocartilage grown in a hollow-fiber bioreactor (HFBR) to establish tissue properties, and to test the hypothesis that MRI can be used to monitor biochemical and biomechanical properties of neocartilage. Methods. Chondrocytes from. day 16 embryonic chick sterna were inoculated into an HFBR and maintained for up to 4 weeks with and without exposure to chondroitinase ABC. The fixed-charge density (FCD) of the cartilage was determined using the MRI gadolinium exclusion method. The sulfated glycosaminoglycan (S-GAG), hydroxyproline, and DNA contents were determined using biochemical procedures, while dynamic and equilibrium moduli were determined from mechanical indentation tests. Results. S-GAG content, tissue cross-sectional area, and equilibrium modulus of the neocartilage increased with development time. There was a gradient of S-GAG content across the length of control neocartilage at the 4-week time point, with higher values being found toward the inflow region. Exposure to chondroitinase ABC resulted in a decrease in tissue area, negative FCD, proteoglycan content, and equilibrium and dynamic moduli. The treated bioreactors displayed a length wise variation in S-GAG content, with higher values toward the outflow end. Linear correlations were established among FCD, proteoglycan content, and biomechanical properties. Conclusion. HFBR-derived neocartilage showed regional variation in S-GAG content under control conditions, and in the decrease of S-GAG in response to enzyme treatment. In addition, the results support the hypothesis that tissue parameters derived from MRI can be used to noninvasively monitor focal neocartilage formation and biochemical and biomechanical properties. C1 NE Ohio Univ, Coll Med, Rootstown, OH 44272 USA. Hosp Special Surg, Lab Soft Tissue Res, New York, NY USA. NIA, NIH, Baltimore, MD USA. RP Spencer, RGS (reprint author), NE Ohio Univ, Coll Med, 4209 State Route 44, Rootstown, OH 44272 USA. OI Fishbein, Kenneth/0000-0002-6353-4603 FU NIAMS NIH HHS [AR-046459, AR-45748, R01 AR045748] NR 27 TC 47 Z9 49 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2003 VL 48 IS 4 BP 1047 EP 1056 DI 10.1002/art.10991 PG 10 WC Rheumatology SC Rheumatology GA 665HZ UT WOS:000182115300022 PM 12687548 ER PT J AU Darveau, RP McFall-Ngai, M Ruby, E Miller, S Mangan, DF AF Darveau, RP McFall-Ngai, M Ruby, E Miller, S Mangan, DF TI Host tissues may actively respond to beneficial microbes SO ASM NEWS LA English DT Article ID BACTERIA C1 Univ Washington, Sch Dent, Seattle, WA 98195 USA. Univ Hawaii, Honolulu, HI 96822 USA. Natl Inst Dent & Craniofacial Res, Infect Dis & Immun Branch, Bethesda, MD USA. RP Darveau, RP (reprint author), Univ Washington, Sch Dent, Seattle, WA 98195 USA. NR 12 TC 5 Z9 5 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD APR PY 2003 VL 69 IS 4 BP 186 EP 191 PG 6 WC Microbiology SC Microbiology GA 757HQ UT WOS:000187557300016 ER PT J AU Tsao, JCI Fanurik, D Zeltzer, LK AF Tsao, JCI Fanurik, D Zeltzer, LK TI Long-term effects of a brief distraction intervention on children's laboratory pain reactivity SO BEHAVIOR MODIFICATION LA English DT Article DE experimental pain; cold pressor task; laboratory pain; coping; distraction; children ID COLD PRESSOR PAIN; SICKLE-CELL DISEASE; COPING STRATEGIES; ATTENTION; DISTRESS; UTILITY AB This 2-year follow-up study examined the effects of a brief behavioral intervention on task-based coping and pain reactivity to the cold pressor task (CPT). In the original study by Fanurik et al. (1993), 64 children (aged 8 to 10) whose coping style was categorized as "attender" or "distracter," based on primary coping strategy during baseline CPT trial;, received a 5-minute intervention (attention-focusing, distraction training, or control, randomly assigned). In the present study, 51 (32 female) of the original sample were readministered the CPT, and their coping style and pain responsivity were reassessed. Both distracters and attenders given distraction training preferred use of distraction at follow-up. The distraction training group also demonstrated greater tolerance at follow-up compared to controls, although pain ratings did not differ by intervention group. Our findings suggest that a brief distraction intervention has long-term effects on task-based coping and experimental pain reactivity. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Coll Hlth Profess, Gainesville, FL 32610 USA. Univ Arkansas Med Sci, Arkansas Childrens Hosp, Little Rock, AR 72205 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Tsao, JCI (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, Coll Hlth Profess, Box 100165,HSC, Gainesville, FL 32610 USA. OI Zeltzer, Lonnie/0000-0001-9306-9450 NR 16 TC 13 Z9 13 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD APR PY 2003 VL 27 IS 2 BP 217 EP 232 DI 10.1177/0145445503251583 PG 16 WC Psychology, Clinical SC Psychology GA 655PX UT WOS:000181562600003 PM 12705106 ER PT J AU Breitenstein, C Floel, A Drager, B Knecht, S AF Breitenstein, C Floel, A Drager, B Knecht, S TI Lateralisation may be a side issue for understanding language development SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID APHASIA; SPEECH AB We add evidence in support of Corballis's gestural theory of language. Using transcranial magnetic stimulation, we found that productive and receptive linguistic tasks excite the motor cortices for both hands. This indicates that the language and the hand motor systems are still tightly linked in modem man. The bilaterality of the effect, however, implies that lateralisation is a secondary issue. C1 Univ Munster, Dept Neurol, D-48129 Munster, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Breitenstein, C (reprint author), Univ Munster, Dept Neurol, D-48129 Munster, Germany. EM caterina.breitenstein@uni-muenster.de; floela@ninds.nih.gov; dragerb@uni-muenster.de; knecht@uni-muenster.de RI Floel, Agnes/A-9426-2017 NR 14 TC 0 Z9 0 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD APR PY 2003 VL 26 IS 2 BP 214 EP + PG 12 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 843XR UT WOS:000223121100038 ER PT J AU Bradley, MA Sabatinelli, D Lang, PJ Fitzsimmons, JR King, W Desai, P AF Bradley, MA Sabatinelli, D Lang, PJ Fitzsimmons, JR King, W Desai, P TI Activation of the visual cortex in motivated attention SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID FACIAL EXPRESSIONS; HUMAN BRAIN; AVERSIVE STIMULI; FUNCTIONAL MRI; PHOBIC FEAR; EMOTION; STARTLE; FMRI; MODULATION; AROUSAL AB Functional activation (measured with fMRI) in occipital cortex was more extensive when participants view pictures strongly related to primary motive states (i.e., victims of violent death, viewer-directed threat, and erotica). This functional activity was greater than that observed for less intense emotional (i.e., happy families or angry faces) or neutral images (i.e., household objects, neutral faces). Both the extent and strength of functional activity were related to the judged affective arousal of the different picture contents, and the same pattern of functional activation was present whether pictures were presented in color or in grayscale. It is suggested that more extensive visual system activation reflects "motivated attention," in which appetitive or defensive motivational engagement directs attention and facilitates perceptual processing of survival-relevant stimuli. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32610 USA. RP Bradley, MA (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, Box 100165 HSC, Gainesville, FL 32610 USA. RI Frank, David/E-8213-2012; OI sabatinelli, dean/0000-0001-7409-8504 FU NIDCR NIH HHS [DE 13956]; NIMH NIH HHS [MH37757, P50-MH52384] NR 68 TC 278 Z9 285 U1 5 U2 30 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2003 VL 117 IS 2 BP 369 EP 380 DI 10.1037/0735-7044.117.2.369 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 661FM UT WOS:000181880600019 PM 12708533 ER PT J AU Tudor, G Gutierrez, P Aguilera-Gutierrez, A Sausville, EA AF Tudor, G Gutierrez, P Aguilera-Gutierrez, A Sausville, EA TI Cytotoxicity and apoptosis of benzoquinones: redox cycling, cytochrome c release, and BAD protein expression SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE antitumor quinones; NQO1; redox cycling; hydroxyl radicals; apoptosis; cytochrome c release; BAD protein ID OXIDOREDUCTASE DT-DIAPHORASE; TUMOR-CELL-LINES; COLON-CARCINOMA CELLS; INDUCED DNA DAMAGE; MITOMYCIN-C; BIOREDUCTIVE ACTIVATION; CYTO-TOXICITY; SEQUENCE SELECTIVITY; QUINONE REDUCTASE; ANTICANCER AGENTS AB The metabolic activation of a variety of quinone-based anticancer agents occurs, in part, as a result of the bioreductive activation by the flavoprotein NAD(P)H:quinone-acceptor oxidoreductase (NQO1) (EC 1.6.99.2). Using the COMPARE algorithm (http://dtp.nci.nih.gov), a significant statistical correlation has been found in the NCI in vitro anticancer drug screen between high endogenous expression of the pro-apoptotic protein BAD, NQO1 enzymatic activity, and the cytotoxicity of certain antitumor quinones. Two statistically correlated groups of quinones can be discerned: positive-correlated compounds, which are more active in cell lines expressing high baseline levels of BAD protein and NQO1 activity (e.g. the MCF-7 breast carcinoma), and negative-correlated compounds, which are more active in cell lines with undetectable levels of BAD and NQO1 activity (e.g. the HL-60 myeloid leukemia). In the present study, the relationship between quinone structure, redox cycling, and cytotoxicity in the MCF-7 and HL-60 cell lines was investigated. A good biological correlation exists between cytotoxicity and NQO1 activity, BAD protein levels and apoptosis, but not always between cytotoxicity and intracellular reactive oxygen species levels. The overall markedly increased cytotoxicity of the aziridinylbenzoquinone compounds used in this study is accompanied by apoptosis, which occurs mostly through a cytochrome c-independent pathway. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NCI, Dev Therapeut Program, DCTD, Rockville, MD 20852 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. Univ Maryland, Ctr Canc, Baltimore, MD 21201 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, DCTD, EPN 8018,6130 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [NM01 CO 12400] NR 48 TC 59 Z9 59 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD APR 1 PY 2003 VL 65 IS 7 BP 1061 EP 1075 DI 10.1016/S0006-2952(03)00013-3 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 668FU UT WOS:000182280300005 PM 12663042 ER PT J AU Kakuta, Y Li, L Pedersen, LC Pedersen, LG Negishi, M AF Kakuta, Y Li, L Pedersen, LC Pedersen, LG Negishi, M TI Heparan sulphate N-sulphotransferase activity: reaction mechanism and substrate recognition SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 678th Meeting of the Biochemical-Society CY DEC 16-18, 2002 CL LONDON, ENGLAND SP Biochem Soc, Dextra Lab Ltd, Sigma-Aldrich DE acceptor substrate binding; catalytic mechanism; glycosaminylglycan; heparan sulphate N-sulphotransferase; molecular modelling; X-ray crystal structure ID CRYSTAL-STRUCTURE; ESTROGEN SULFOTRANSFERASE; COMPLEX; SULFATE AB Human heparan sulphate N-deacetylase/N-sulphotransferase 1 sulphates the NH3+ group of the glucosamine moiety of the heparan chain in heparan sulphate/heparin biosynthesis. An open cleft that runs perpendicular to the sulphate donor 3'-phosphoadenosine 5'-phosphosulphate may constitute the acceptor substrate-binding site of the sulphotransferase domain (hNST1) [Kakuta, Sueyoshi, Negishi and Pedersen (1999) J. Biol. Chem. 274, 10673-10676]. When a hexasaccharide model chain is docked into the active site, only a trisaccharide (-IdoA-GlcN-IdoA-) portion interacts directly with the cleft residues: Trp-713, His-716 and His-720 from alpha helix 6, and Phe-640, Glu-641, Glu-642, Gin-644 and Asn-647 from random coil (residues 640-647). Mutation of these residues either abolishes or greatly reduces hNST1 activity. Glu-642 may play the critical role of catalytic base in the sulphuryl group transfer reaction, as indicated by its hydrogen-bonding distance to the NH3+ group of the glucosamine moiety in the model and by mutational data. C1 NIEHS, Pharm Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharm Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 NR 17 TC 12 Z9 12 U1 0 U2 6 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 APR PY 2003 VL 31 BP 331 EP 334 DI 10.1042/BST0310331 PN 2 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 669EK UT WOS:000182338800006 PM 12653630 ER PT J AU Foster, JS Palmer, RJ Kolenbrander, PE AF Foster, JS Palmer, RJ Kolenbrander, PE TI Human oral cavity as a model for the study of genome-genome interactions SO BIOLOGICAL BULLETIN LA English DT Article; Proceedings Paper CT Workshop on Outcomes of Genome-Genome Interactions CY MAY 01-03, 2002 CL MARINE BIOL LAB, WOODS HOLE, MASSACHUSETTS HO MARINE BIOL LAB ID ACTINOMYCES-NAESLUNDII; BACTERIAL DIVERSITY; BIOFILMS; COAGGREGATION; SPECIFICITY AB The enormous diversity of culturable bacteria within the oral microbial community coupled with experimental accessibility renders the human oral cavity a valuable model to investigate genome-genome interactions. The complex interactions of oral bacteria result in the formation of biofilms on the surfaces of the oral cavity. One mechanism thought to be important in biofilm formation is the coaggregation of bacterial partners. In this paper, we examine the role of coaggregation in oral biofilms and develop protocols to elucidate the spatial organization of bacterial species retained within oral biofilms. To explore these issues, we have employed two experimental systems: the saliva-coated flowcell and the retrievable enamel chip. From flowcell studies, we have determined that coaggregation can greatly influence the ability of an oral bacterial species to grow and be retained within the developing biofilm. To examine the spatial architecture of oral biofilms, fluorescent in situ hybridization protocols were developed that successfully target specific members of the oral microbial community. Together, these approaches provide insight into the development of oral biofilms and expand our understanding of genome-genome interactions. C1 NIDCR, Ofal Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Kolenbrander, PE (reprint author), NIDCR, Ofal Infect & Immun Branch, NIH, Bldg 30,Room 310,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. NR 17 TC 18 Z9 21 U1 1 U2 1 PU MARINE BIOLOGICAL LABORATORY PI WOODS HOLE PA 7 MBL ST, WOODS HOLE, MA 02543 USA SN 0006-3185 J9 BIOL BULL-US JI Biol. Bull. PD APR PY 2003 VL 204 IS 2 BP 200 EP 204 DI 10.2307/1543559 PG 5 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA 671HZ UT WOS:000182460500014 PM 12700154 ER PT J AU Narayanan, J Hayakawa, Y Fan, JF Kirk, KL AF Narayanan, J Hayakawa, Y Fan, JF Kirk, KL TI Convenient syntheses of biogenic aldehydes, 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde SO BIOORGANIC CHEMISTRY LA English DT Article DE dopal; dopegal; Davis reagent; amine metabolites; neurotoxicity AB The title compounds were prepared from a common precursor, a bis-THP-protected dihydroxyphenylacetic acid methyl ester. Key steps are the introduction of the alpha-hydroxyl group by Davis oxaziridine reagent and formation of the aldehydes by DIBALH ester reduction. Published by Elsevier Science (USA). C1 NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD USA. NR 6 TC 6 Z9 8 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0045-2068 J9 BIOORG CHEM JI Bioorganic Chem. PD APR PY 2003 VL 31 IS 2 BP 191 EP 197 DI 10.1016/S0045-2068(03)00019-1 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 678GQ UT WOS:000182858500009 PM 12729575 ER PT J AU Tokumasu, F Jin, AJ Feigenson, GW Dvorak, JA AF Tokumasu, F Jin, AJ Feigenson, GW Dvorak, JA TI Nanoscopic lipid domain dynamics revealed by atomic force microscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID DETERGENT-RESISTANT MEMBRANES; LIGHT-SCATTERING; BILAYER; RAFTS; SURFACE; CHOLESTEROL; CELLS; MONOLAYERS; VESICLES; PHOSPHATIDYLCHOLINE AB Intrinsic heterogeneities, represented as domain formations in biological membranes, are important to both the structure and function of the membranes. We observed domain formations in mixed lipid bilayers of dipalmitoylphosphatidylcholine (DPPC), dilauroylphosphatidylcholine (DLPC), and cholesterol (chol) in a fluid environment using an atomic force microscope (AFM). At room temperature, we demonstrated that both microscopic and nanoscopic domains coexist and the DPPC-rich domain is similar to1.4 nm higher than the surrounding DLPC-rich membrane areas as a consequence of intrinsic phase differences. DPPC-rich microscopic domains became larger as DPPC concentration increased. In cholesterol-free mixtures, nanoscopic DPPC-rich domain sizes ranged from 26 to 46 nm depending on phospholipid concentration. Domain size varied between 33 and 48 nm in the presence of cholesterol (0 less than or equal to [chol] less than or equal to 40). The nanoscopic domains were markedly fragmented near [chol] = 0.135 and appeared to fuse more readily into microscopic domains at higher and lower [chol]. By phase balance analyses we demonstrated phase behavior differences between a free-vesicle GUV system studied by confocal light microscopy and a supported membrane system studied by AFM. We propose a new three-dimensional phase diagram elucidating the effects of a solid substrate support on lipid phase behavior relevant to complex membrane phase phenomena in biological systems. C1 NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. RP Dvorak, JA (reprint author), NIAID, Lab Malaria & Vector Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Jin, Albert/0000-0003-3826-1081; Tokumasu, Fuyuki/0000-0003-2790-1071 NR 48 TC 105 Z9 108 U1 3 U2 32 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2003 VL 84 IS 4 BP 2609 EP 2618 DI 10.1016/S0006-3495(03)75066-8 PG 10 WC Biophysics SC Biophysics GA 682ZZ UT WOS:000183123100047 PM 12668469 ER PT J AU Zborowski, M Ostera, GR Moore, LR Milliron, S Chalmers, JJ Schechter, AN AF Zborowski, M Ostera, GR Moore, LR Milliron, S Chalmers, JJ Schechter, AN TI Red blood cell magnetophoresis SO BIOPHYSICAL JOURNAL LA English DT Article ID MAGNETIC-SUSCEPTIBILITY; TRACKING VELOCIMETRY; OXYGEN-AFFINITY; HEMOGLOBIN; TRANSPORT; AGE AB The existence of unpaired electrons in the four heme groups of deoxy and methemoglobin (metHb) gives these species paramagnetic properties as contrasted to the diamagnetic character of oxyhemoglobin. Based on the measured magnetic moments of hemoglobin and its compounds, and on the relatively high hemoglobin concentration of human erythrocytes, we hypothesized that differential migration of these cells was possible if exposed to a high magnetic field. With the development of a new technology, cell tracking velocimetry, we were able to measure the migration velocity of deoxygenated and metHb-containing erythrocytes, exposed to a mean magnetic field of 1.40 T and a mean gradient of 0.131 T/mm, in a process we call cell magnetophoresis. Our results show a similar magnetophoretic mobility of 3.86 x 10(-6) mm(3) s/kg for erythrocytes with 100% deoxygenated hemoglobin and 3.66 x 10(-6) mm(3) s/kg for erythrocytes containing 100% metHb. Oxygenated erythrocytes had a magnetophoretic mobility of from -0.2 x 10(-6) mm(3) s/kg to +0.30 x 10(-6) mm(3) s/kg, indicating a significant diamagnetic component relative to the suspension medium, in agreement with previous studies on the hemoglobin magnetic susceptibility. Magnetophoresis may open up an approach to characterize and separate cells for biochemical analysis based on intrinsic and extrinsic magnetic properties of biological macromolecules. C1 Cleveland Clin Fdn, Dept Biomed Engn ND20, Lerner Res Inst, Cleveland, OH 44915 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Chem Engn, Columbus, OH 43210 USA. RP Zborowski, M (reprint author), Cleveland Clin Fdn, Dept Biomed Engn ND20, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44915 USA. RI Chalmers, Jeffrey/D-2305-2009; OI Schechter, Alan N/0000-0002-5235-9408 FU NCI NIH HHS [R01 CA062349, R01 CA62349, R33 CA81662] NR 37 TC 118 Z9 123 U1 1 U2 23 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2003 VL 84 IS 4 BP 2638 EP 2645 DI 10.1016/S0006-3495(03)75069-3 PG 8 WC Biophysics SC Biophysics GA 682ZZ UT WOS:000183123100050 PM 12668472 ER PT J AU Miller, JH Draper, LR Kempner, ES AF Miller, JH Draper, LR Kempner, ES TI Direct radiation damage is confined to a single polypeptide in rabbit immunoglobulin G SO BIOPHYSICAL JOURNAL LA English DT Article ID SARCOPLASMIC-RETICULUM; PUMP PROTEIN; TARGET SIZE; INACTIVATION; ENERGY AB Frozen rabbit immunoglobulin G was exposed to high-energy electrons. The surviving polypeptide subunits were determined and analyzed by radiation target analysis. Each subunit was independently damaged by radiation whether or not they were bound by disulfide bridges to other subunits, demonstrating that in IgG radiation-deposited energy did not travel across disulfide bonds. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. RP Kempner, ES (reprint author), NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. NR 16 TC 5 Z9 5 U1 0 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2003 VL 84 IS 4 BP 2781 EP 2785 DI 10.1016/S0006-3495(03)75082-6 PG 5 WC Biophysics SC Biophysics GA 682ZZ UT WOS:000183123100063 PM 12668485 ER PT J AU Liu, YV Clark, DJ Tchernajenko, V Dahmus, ME Studitsky, VM AF Liu, YV Clark, DJ Tchernajenko, V Dahmus, ME Studitsky, VM TI Role of C-terminal domain phosphorylation in RNA polymerase II transcription through the nucleosome SO BIOPOLYMERS LA English DT Article DE chromatin; nucleosome; transcription; RNA polymerase II; transcript elongation ID ELONGATION COMPLEX; DNA INTERACTIONS; CALF THYMUS; TEMPLATES; INITIATION; CHROMATIN; INVITRO; PROCESSIVITY; ACETYLATION; PROMOTER AB End-initiated transcription of a 256 base-pair (bp) template containing a single uniquely positioned nucleosome by yeast and calf thymus nuclear RNA polymerases II (pol II) was analyzed in vitro. The nucleosome-specific pausing pattern is similar to the pattern observed in the case of transcription of the same nucleosome by yeast RNA polymerase III. However, the pausing pattern is clearly different from the patterns observed previously during transcription by promoter-initiated and assembled pol II. This suggests that end-initiated and promoter-initiated RNA polymerases differ in the way they progress through the nucleosome. The rates of transcription through the nucleosome by pol II are significantly lower than the rates observed in the case of SP6 polymerase and RNA polymerase III. Using calf thymus pol II, we have investigated the possibility that phosphorylation of the C-terminal domain (CTD) facilitates transcription through the nucleosome. The rates of transcription through the nucleosome by phosphorylated (110) and nonphosphorylated (IIA) forms of calf thymus pol II are very similar. This suggests that CTD phosphorylation is not sufficient to facilitate transcription through the nucleosome by end-initiated pol II. (C) 2003 Wiley Periodicals, Inc. C1 Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. NIDDK, LCDB, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Div Biol Sci, Sect Mol & Cellular Biol, Davis, CA 95616 USA. RP Studitsky, VM (reprint author), Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, 540 E Canfield Ave, Detroit, MI 48201 USA. RI Studitsky, Vasily/A-9382-2014 FU NIGMS NIH HHS [GM33300, GM58650] NR 45 TC 9 Z9 9 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD APR PY 2003 VL 68 IS 4 BP 528 EP 538 DI 10.1002/bip.10302 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 669RG UT WOS:000182363800006 PM 12666177 ER PT J AU Alexander, PG Tuan, RS AF Alexander, PG Tuan, RS TI Carbon monoxide-induced axial skeletal dysmorphogenesis in the chick embryo SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE carbon monoxide; axial skeleton; scoliosis; dysmorphogenesis; chick embryo; Paraxis; apoptosis ID PARAXIAL MESODERM; SOMITE DEVELOPMENT; MOUSE EMBRYOS; CELL-DEATH; EXPRESSION; SEGMENTATION; APOPTOSIS; REGULATOR; EXPOSURE; HYPOXIA AB BACKGROUND: Congenital axial skeletal defects affect two to three individuals per 1,000 live births. Without strong evidence for heritability, the cause is assumed to be multi-factorial. Carbon monoxide (CO), an increasingly prevalent environmental toxicant, is a potential environmental component in the etiology of these defects. The chick embryo is a useful model for the characterization and assessment of the mechanism(s) of action of basic developmental mechanisms. METHODS: We have determined a critical period and dose for CO teratogenicity and established a model of CO-induced axial skeletal dysmorphogenesis in the chick embryo. The resulting phenotypes reveal a spectrum of axial skeletal defects ranging from minor defects of the vertebral canal and inter-vertebral discs, to thoraco-lumbar scoliosis, to a tailless phenotype reminiscent of caudal dysgenesis syndrome. These axial skeletal defects have been related to earlier developmental defects in somitogenesis, including errors in segmentation and epithelialization and the expression of the somitic epithelialization factor, Paraxis. We have examined patterns of cell death and apoptosis in CO exposed chick embryos to assess the target tissue(s) involved in the teratogenicity of CO. RESULTS: With respect to the embryonic axis, the neural tube was found to be the most sensitive to CO-induced apoptosis, followed by the somitic mesoderm and Hensen's node. CONCLUSIONS: We hypothesize that the somitic defects and the resulting axial skeletal dysmorphogenesis are caused by disrupted neural tube or ectoderm functions related to somite formation and maintenance. We also hypothesize that CO-induced dysmorphogenesis at this critical period of somitogenesis is caused by the overabundance of CO acting endogenously as a cellular signal, while coincidentally exerting its influence as a toxicant of oxygen delivery or utilization. Published 2003 Wiley-Liss, Inc. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Grad Program Dev Biol & Teratol, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Rm 1503,MSC8022, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR 45181]; NIDCR NIH HHS [DE 12864]; NIEHS NIH HHS [ES 07005, ES 07282] NR 44 TC 14 Z9 15 U1 3 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD APR PY 2003 VL 67 IS 4 BP 219 EP 230 DI 10.1002/bdra.10041 PG 12 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 720XE UT WOS:000185286800002 PM 12854657 ER PT J AU Tyl, RW Price, CJ Marr, MC Myers, CB van Birgelen, APJM Jahnke, GD AF Tyl, RW Price, CJ Marr, MC Myers, CB van Birgelen, APJM Jahnke, GD TI Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article ID FATTY-ACID OXIDATION; FINAL REPORT; FOOD-INTAKE; MERCAPTOACETATE; 2-MERCAPTOACETATE; HAIRDRESSERS; INHIBITORS; INGESTION; SINGLE; DIETS AB BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair-care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed-mated Sprague-Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6-19 (rats) or 6-29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6-19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment-related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment-related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6-29 resulted in maternal dose-related toxicity at the dosing site in all groups; no maternal systemic toxicity embryo/fetal toxicity, or treatment-related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ! 65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. (C) 2003 Wiley-Liss, Inc. C1 RTI Int, Ctr Life Sci & Toxicol, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Natl Toxicol Program, Dev & Reprod Toxicol Grp, Res Triangle Pk, NC USA. RP Tyl, RW (reprint author), RTI Int, Ctr Life Sci & Toxicol, Hermann Lab Bldg,POB 12194,3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES-65405] NR 73 TC 3 Z9 3 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 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD APR PY 2003 VL 68 IS 2 BP 144 EP 161 DI 10.1002/bdrb.10001 PG 18 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 734LD UT WOS:000186056600007 PM 12866706 ER PT J AU Yoon, BH Park, CW Chaiworapongsa, T AF Yoon, BH Park, CW Chaiworapongsa, T TI Intrauterine infection and the development of cerebral palsy SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article; Proceedings Paper CT 1st International Preterm Labour Congress CY JUN, 2002 CL MONTREUX, SWITZERLAND ID TUMOR-NECROSIS-FACTOR; BIRTH-WEIGHT INFANTS; WHITE-MATTER LESIONS; CYSTIC PERIVENTRICULAR LEUKOMALACIA; UMBILICAL-CORD PLASMA; INTRAVENTRICULAR HEMORRHAGE; RISK-FACTORS; FACTOR-ALPHA; MATERNAL INFECTION; MULTIPLE-SCLEROSIS AB Cerebral palsy is a serious motor disorder that appears in early life. The expectation that improved obstetrical and neonatal care would decrease the rate of this condition has not been realised. Recent evidence indicates that white matter brain lesions, often termed periventricular leukomalacia (PVL), are the most important identifiable risk factors for the development of cerebral palsy. The hypothesis under examination is that inflammatory cytokines released during the course of intrauterine infection play a central role in the genesis of preterm parturition, fetal PVL, and cerebral palsy. We examined the relationship between umbilical cord plasma concentrations of cytokines at birth and the occurrence of PVL in preterm gestation and demonstrated that umbilical cord plasma concentrations of interleukin (IL)-6 was a significant independent predictor of PVL-associated lesions. We also demonstrated that preterm neonates born to mothers with elevated amniotic fluid concentrations of pro-inflammatory cytokines were at increased risk for the subsequent development of PVL and cerebral palsy. Histological chorioamnionitis and congenital neonatal infection-related morbidity were more common in neonates with PVL than those without PVL in this study. We have also been able to induce PVL-like brain white matter lesions in the fetal rabbit after experimental ascending intrauterine infection. In support of this hypothesis, we were able to demonstrate overexpression of tumour necrosis factor-alpha and IL-6 in histological sections of neonatal brains with PVL. Moreover, the presence of funisitis, a histological counterpart of the fetal inflammatory response syndrome, and elevated concentrations of amniotic fluid IL-6 and IL-8 were strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years in our recent study. Therefore, clinical and experimental data provide strong support for the hypothesis. There are significant implications of our findings. First, cytokine determinations in amniotic fluid provide information about the risk of PVL and cerebral palsy before birth. Second, the process responsible for some cases of PVL and cerebral palsy begins during intrauterine life, implying that effective strategies for the prevention of cerebral palsy associated with PVL must begin in utero. C1 NICHHD, Perinatal Res Branch, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Med, Dept Obstet & Gynaecol, Seoul, South Korea. RP Yoon, BH (reprint author), Seoul Natl Univ Hosp, Dept Obstet & Gynecol, Chongno Gu, 28 Yongon Dong, Seoul 110744, South Korea. RI Yoon, Bo Hyun/H-6344-2011; Park, Chan-Wook/J-5498-2012 NR 40 TC 163 Z9 170 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD APR PY 2003 VL 110 SU 20 BP 124 EP 127 DI 10.1016/S1470-0328(03)00063-6 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 670XT UT WOS:000182435900027 PM 12763129 ER PT J AU Trabattoni, D Saresella, M Biasin, M Boasso, A Piacentini, L Ferrante, P Dong, HD Maserati, R Shearer, GM Chen, LP Clerici, M AF Trabattoni, D Saresella, M Biasin, M Boasso, A Piacentini, L Ferrante, P Dong, HD Maserati, R Shearer, GM Chen, LP Clerici, M TI B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; PROGRAMMED CELL-DEATH; CD8(+) T-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; LYMPHOCYTE-ACTIVATION; TYPE-2 CYTOKINES; IL-10 PRODUCTION; HUMAN MONOCYTES; IFN-GAMMA AB The ligation of programmed death-ligand 1 (B7-H1) to T cells results in the preferential production of interleukin 10 (IL-10). We investigated if B7-H1 would be upregulated in HIV infection, a disease characterized by increased IL-10 production, by measuring, B7-H1, B7-1 (CD80), and B7-2 (CD86) expression and mRNA in 36 HIV-infected patients and in 22 healthy controls (HCs). Results showed that (1) B7-H1 expression and mRNA are augmented in cells of HIV patients; (2) increased IL-10 production in these patients is largely induced by B7-H1-expressing CD14(+) cells; (3) an inverse correlation is detected between B7-H1 expression and CD4 counts, whereas the up-regulation of B7-H1 is directly associated with HIV plasma viremia; (4) antiviral therapy results in the parallel down modulation of IL-10 production and B7-H1 expression/synthesis; and (5) B7-H1/CD80 and B7-H1/CD86 mRNA ratios are increased in peripheral blood mononuclear cells (PBMCs) of HIV patients compared with HCs. B7-H1 synthesis and expression are up-regulated in HIV infection, and the degree of dysregulation correlates with the severity of disease. Aberrant antigen presentation by antigen-presenting cells (APCs) that exhibit increased B7-H1 expression and IL-10 production in HIV infection could be responsible for T-lymphocyte unresponsiveness and loss of protective immunity. B7-H1 is a surrogate marker potentially involved in AIDS disease progression. C1 Univ Milan, Cattedra Immunol,Chair Immunol, Dipartimento Sci Preclin, LITA Vialba, I-20157 Milan, Italy. Univ Milan, Cattedra Immunol,Chair Virol, Dipartimento Sci Preclin, LITA Vialba, I-20157 Milan, Italy. Ist Ric & Cura Carattere Sci, Dept Biol, Don C Gnocchi Fdn, Milan, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Mayo Clin, Dept Immunol, Rochester, MN USA. IRCCS San Matteo, Infect Dis Clin, Pavia, Italy. RP Clerici, M (reprint author), Univ Milan, Cattedra Immunol,Chair Immunol, Dipartimento Sci Preclin, LITA Vialba, Via GB Grassi 74, I-20157 Milan, Italy. RI Trabattoni, Daria/G-7424-2012; Saresella, Marina/G-7810-2012; biasin, mara/G-7426-2012; Piacentini, Luca/K-8908-2016; OI Piacentini, Luca/0000-0003-1022-4481; Clerici, Mario/0000-0001-5920-6191; Ferrante, Pasquale/0000-0001-7040-7293; Boasso, Adriano/0000-0001-9673-6319 NR 59 TC 120 Z9 136 U1 1 U2 9 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 APR 1 PY 2003 VL 101 IS 7 BP 2514 EP 2520 DI 10.1182/blood-2002-10-3065 PG 7 WC Hematology SC Hematology GA 660FR UT WOS:000181823600018 PM 12468426 ER PT J AU Anaissie, EJ Stratton, SL Dignani, MC Lee, CK Summerbell, RC Rex, JH Monson, TP Walsh, TJ AF Anaissie, EJ Stratton, SL Dignani, MC Lee, CK Summerbell, RC Rex, JH Monson, TP Walsh, TJ TI Pathogenic molds (including Aspergillus species) in hospital water distribution systems: a 3-year prospective study and clinical implications for patients with hematologic malignancies SO BLOOD LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Hematology CY DEC 01-05, 2000 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Hematol ID BONE-MARROW TRANSPLANTATION; FILAMENTOUS FUNGI; DRINKING-WATER; INFECTIONS; EPIDEMIOLOGY AB The incidence of mold infections in patients with hematologic malignancies continues to increase despite the widespread use of air filtration systems, suggesting the presence of other hospital sources for these molds. Water sources are known to harbor pathogenic molds. We examined samples from water, water surfaces, air, and other environment sources from a bone marrow transplantation unit with optimal air precautions. Molds (Aspergillus species, others) were recovered in 70% of 398 water samples, in 22% of 1311 swabs from plumbing structures and environmental surfaces, and in 83% of 274 indoor air samples. Microscopic examination of the water plumbing lines revealed hyphal forms compatible with molds. Four findings suggest that indoor airborne molds were aerosolized from the water: (1) higher mean airborne concentrations of molds in bathrooms (16.1 colony-forming units [CFU]/m(3)) than in patient rooms (7 CFU/m(3)) and hallways (8.6 CFU/m(3); P = .00005); (2) a strong type and rank correlation between molds isolated from hospital water and those recovered from indoor hospital; (3) lack of seasonal correlation between the airborne mold concentration in outdoor and indoor air; and (4) molecular relatedness between a clinical strain and a water-related strain (previously reported). Hospital water distribution systems may serve as a potential indoor reservoir of Aspergillus and other molds leading to aerosolization of fungal spores and potential exposure for patients. C1 Univ Arkansas Med Sci, Myeloma & Transplantat Res Ctr, Arkansas Canc Res Ctr, Myeloma Inst Res & Treatment, Little Rock, AR 72205 USA. Cent Bur Schimmelcultures, NL-3740 AG Baarn, Netherlands. Univ Texas, Sch Med, Ctr Infect Dis, Houston, TX 77030 USA. John L McClellan Mem Vet Adm Med Ctr, Little Rock, AR USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. NCI, Immunocompromised Host Sect, NIH, Bethesda, MD 20892 USA. RP Anaissie, EJ (reprint author), Univ Arkansas Med Sci, Myeloma & Transplantat Res Ctr, Arkansas Canc Res Ctr, Myeloma Inst Res & Treatment, 4301 W Markham,Mail Slot 776, Little Rock, AR 72205 USA. OI Dignani, Maria Cecilia/0000-0002-7446-6183 NR 29 TC 104 Z9 109 U1 0 U2 5 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 APR 1 PY 2003 VL 101 IS 7 BP 2542 EP 2546 DI 10.1182/blood-2002-02-0530 PG 5 WC Hematology SC Hematology GA 660FR UT WOS:000181823600022 PM 12468437 ER PT J AU Muul, LM Tuschong, LM Soenen, SL Jagadeesh, GJ Ramsey, WJ Long, ZF Carter, CS Garabedian, EK Alleyne, M Brown, M Bernstein, W Schurman, SH Fleisher, TA Leitman, SF Dunbar, CE Blaese, RM Candotti, F AF Muul, LM Tuschong, LM Soenen, SL Jagadeesh, GJ Ramsey, WJ Long, ZF Carter, CS Garabedian, EK Alleyne, M Brown, M Bernstein, W Schurman, SH Fleisher, TA Leitman, SF Dunbar, CE Blaese, RM Candotti, F TI Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; T-CELL REPERTOIRE; BONE-MARROW; NORMAL INDIVIDUALS; RETROVIRAL VECTOR; INFECTED PATIENTS; IN-VIVO; DEFICIENCY; LYMPHOCYTES; TRANSPLANTATION AB The first human gene therapy experiment begun in September 1990 used a retroviral vector containing the human adenosine deaminase (ADA) cDNA to transduce mature peripheral blood lymphocytes from patients with ADA deficiency, an inherited disorder of immunity. Two patients who had been treated with intramuscular injections of pegylated bovine ADA (PEG-ADA) for 2 to 4 years were enrolled in this trial and each received a total of approximately 10(11) cells in 11 or 12 infusions over a period of about 2 years. No adverse events were observed. During and after treatment, the patients continued to receive PEG-ADA, although at a reduced dose. Ten years after the last cell infusion, approximately 20% of the first patient's lymphocytes still carry and express the retroviral gene, indicating that the effects of gene transfer can be remarkably long lasting. On the contrary, the persistence of gene-marked cells is very low (< 0.1%), and no expression of the transgene is detectable in lymphocytes from the second patient who developed persisting antibodies to components of the gene transfer system. Data collected from these original patients have provided novel information about the longevity of T lymphocytes in humans and persistence of gene expression in vivo from vectors driven by the Moloney murine leukemia virus long-terminal repeat (LTR) promoter. This long-term follow-up has also provided unique evidence supporting the safety of retroviral-mediated gene transfer and illustrates clear examples of both the potential and the pitfalls of gene therapy in humans. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Genet Therapy, Gaithersburg, MD USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Fund Inherited Dis Res, Newtown, PA USA. RP Muul, LM (reprint author), NIAMS, NIH, Bldg 10,Rm 9N252, Bethesda, MD 20892 USA. OI Schurman, Shepherd/0000-0002-9133-7906 NR 31 TC 109 Z9 116 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2003 VL 101 IS 7 BP 2563 EP 2569 DI 10.1182/blood-2002-09-2800 PG 7 WC Hematology SC Hematology GA 660FR UT WOS:000181823600026 PM 12456496 ER PT J AU Fiuza, C Bustin, M Talwar, S Tropea, M Gerstenberger, E Shelhamer, JH Suffredini, AF AF Fiuza, C Bustin, M Talwar, S Tropea, M Gerstenberger, E Shelhamer, JH Suffredini, AF TI Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; GLYCATION END-PRODUCTS; NF-KAPPA-B; GROUP CHROMOSOMAL-PROTEINS; NITRIC-OXIDE SYNTHASE; FACTOR-ALPHA; PLASMINOGEN ACTIVATION; NEURITE OUTGROWTH; FLOW-CYTOMETRY; TNF-ALPHA AB Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule I (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-a (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signalrelated kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-κB and Sp1. These effects are partially mediated by TNFα autocrine stimulation, as anti-TNFα antibodies significantly decrease chemokine and adhesion molecule responses (P&LE;.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, Mol Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Suffredini, AF (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 7D-43,10 Ctr Dr, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 NR 63 TC 429 Z9 495 U1 2 U2 21 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 APR 1 PY 2003 VL 101 IS 7 BP 2652 EP 2660 DI 10.1182/blood-2002-05-1300 PG 9 WC Hematology SC Hematology GA 660FR UT WOS:000181823600038 PM 12456506 ER PT J AU Brenchley, JM Karandikar, NJ Betts, MR Ambrozak, DR Hill, BJ Crotty, LE Casazza, JP Kuruppu, J Migueles, SA Connors, M Roederer, M Douek, DC Koup, RA AF Brenchley, JM Karandikar, NJ Betts, MR Ambrozak, DR Hill, BJ Crotty, LE Casazza, JP Kuruppu, J Migueles, SA Connors, M Roederer, M Douek, DC Koup, RA TI Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8(+) T cells SO BLOOD LA English DT Article ID PRIMARY HIV-INFECTION; EPSTEIN-BARR-VIRUS; RHEUMATOID-ARTHRITIS; HEALTHY-INDIVIDUALS; IMMUNE-SYSTEM; HUMAN CYTOMEGALOVIRUS; SHORTENED TELOMERES; 2 SUBSETS; IN-VITRO; LYMPHOCYTES AB Virus-specific CD8(+) T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8(+) T cells to secrete cytokines and proliferate in response to HIM antigen stimulation. We find that a large proportion of HIV-specific CD8(+) T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8(+) T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8(+) T cells, CD4(+) T cells, and INK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57(+) HIV-specific CD8(+) T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8(+) T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA. RP Koup, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011; OI Crotty Alexander, Laura/0000-0002-5091-2660 FU NIAID NIH HHS [AI49990, R01 AI47603] NR 69 TC 465 Z9 475 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2003 VL 101 IS 7 BP 2711 EP 2720 DI 10.1182/blood-2002-07-2103 PG 10 WC Hematology SC Hematology GA 660FR UT WOS:000181823600046 PM 12433688 ER PT J AU Yipp, BG Robbins, SM Resek, ME Baruch, DI Looareesuwan, S Ho, M AF Yipp, BG Robbins, SM Resek, ME Baruch, DI Looareesuwan, S Ho, M TI Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow SO BLOOD LA English DT Article ID PROTEIN-TYROSINE KINASES; INFECTED ERYTHROCYTES; CELL-ADHESION; MEMBRANE GLYCOPROTEIN; E-SELECTIN; C-SRC; ALKALINE-PHOSPHATASE; CD36; BINDING; CAVEOLAE AB The pathogenicity of Plasmodium falciparum is due to the unique ability of infected erythrocytes (IRBCs) to adhere to vascular endothelium. We investigated whether adhesion of IRBCs to CD36, the major cytoadherence, receptor on human dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36-binding domain from P falciparum erythrocyte membrane protein 1 (PfEMP1), as well is an anti-CD36 monoclonal antibody (mAb) that inhibits IRBC binding, activated the mitogen-activated protein (MAP) kinase pathway that was dependent on Src-family kinase activity. Treatment of HDMECs with a Src-family kinase selective inhibitor (13131) inhibited adhesion of IRBCs in a flow-chamber assay by 72% (P <.001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/severe combined immunodeficient (SCID) mouse model in vivo. The effect of PP1 could be, mimicked L by levamisole, a specific alkaline-phosphatase inhibitor. Firm adhesion to PP1-treated endothelium was restored by exogenous alkaline phosphatase. In contrast, inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 MAP kinase pathways had no immediate effect on IRBC adhesion. These results suggest a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases, and an ectoalkaline phosphatase. Targeting endothelial ectoalkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria. C1 Univ Calgary, Hlth Sci Ctr, Dept Microbiol & Infect Dis, Immunol Res Grp, Calgary, AB T2N 4N1, Canada. Univ Calgary, Dept Oncol, Calgary, AB T2N 1N4, Canada. Univ Calgary, Dept Mol Biol & Biochem, Calgary, AB T2N 1N4, Canada. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Mahidol Univ, Fac Trop Med, Bangkok, Thailand. RP Ho, M (reprint author), Univ Calgary, Hlth Sci Ctr, Dept Microbiol & Infect Dis, Immunol Res Grp, Calgary, AB T2N 4N1, Canada. NR 50 TC 52 Z9 54 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2003 VL 101 IS 7 BP 2850 EP 2857 DI 10.1182/blood-2002-09-2841 PG 8 WC Hematology SC Hematology GA 660FR UT WOS:000181823600065 PM 12517811 ER PT J AU Arieh, SVB Laham, N Schechter, C Yewdell, JW Coligan, JE Ehrlich, R AF Arieh, SVB Laham, N Schechter, C Yewdell, JW Coligan, JE Ehrlich, R TI A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules SO BLOOD LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; HEREDITARY HEMOCHROMATOSIS PROTEIN; HUMAN CYTOMEGALOVIRUS-INFECTION; CELL-SURFACE EXPRESSION; GENE-PRODUCTS US2; HEAVY-CHAINS; ENDOPLASMIC-RETICULUM; TRANSFERRIN RECEPTOR; PEPTIDE TRANSLOCATION; MEMBRANE-PROTEIN AB HFE is a nonclassical class I molecule that associates with beta2-microglobulin (beta2m) and with the transferrin receptor. HFE accumulates in transferrin-containing endosomes, and its overexpression in human cell lines correlates with decreased transferrin receptor (TFR)-mediated iron uptake and decreased intracellular iron pools. A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis. We previously suggested that viruses could also interfere with iron metabolism through the production of proteins that inactivate HFE, similarly to classical class proteins. In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation. Here we demonstrate that the stable expression of HCMV US2 in HEK 293 cells constitutively expressing HFE leads to loss of HFE expression both intracellularly and on the cell surface, and the significant reduction of classical class I expression. Both HFE and classical class I molecules are targeted to degradation via a similar pathway. This HCMV US2-mediated degradation of HFE leads to increased intracellular iron pools as indicated by reduced synthesis of TfR and increased ferritin synthesis. Whether this interference with regulation of iron metabolism potentiates viral replication and/or promotes damage of HCMV-infected tissues remains to be determined. Nevertheless, the deleterious effect of US2 on the expression of HFE and classical class I major histo-compatibility complexes (MHC) provides HCMV with an efficient tool for altering cellular metabolic functions, as well as supporting the escape of virus-infected cells from cytotoxic T lymphocyte (CTL)-mediated immune responses. C1 Tel Aviv Univ, Dept Cell Res & Immunol, George S Wise Fac Life Sci, IL-69978 Tel Aviv, Israel. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Schechter, C (reprint author), Tel Aviv Univ, Dept Cell Res & Immunol, George S Wise Fac Life Sci, IL-69978 Tel Aviv, Israel. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 52 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2003 VL 101 IS 7 BP 2858 EP 2864 DI 10.1182/blood-2002-07-2158 PG 7 WC Hematology SC Hematology GA 660FR UT WOS:000181823600066 ER PT J AU Lotze, M Braun, C Birbaumer, N Anders, S Cohen, LG AF Lotze, M Braun, C Birbaumer, N Anders, S Cohen, LG TI Motor learning elicited by voluntary drive SO BRAIN LA English DT Article DE motor performance; active and passive training; TMS; fMRI; motor learning ID TRANSCRANIAL MAGNETIC STIMULATION; INTRACORTICAL INHIBITION; PASSIVE MOVEMENTS; MUSCLE RESPONSES; HUMAN-BRAIN; CORTEX; PLASTICITY; REPRESENTATION; FACILITATION; FMRI AB Motor training consisting of voluntary movements leads to performance improvements and results in characteristic reorganizational changes in the motor cortex. It has been proposed that repetition of passively elicited movements could also lead to improvements in motor performance. In this study, we compared behavioural gains, changes in functional MRI (fMRI) activation in the contralateral primary motor cortex (cM1) and in motor cortex excitability measured with transcranial magnetic stimulation (TMS) after a 30 min training period of either voluntarily (active) or passively (passive) induced wrist movements, when alertness and kinematic aspects of training were controlled. During active training, subjects were instructed to perform voluntary wrist flexion-extension movements of a specified duration (target window 174-186 ms) in an articulated splint. Passive training consisted of wrist flexion- extension movements elicited by a torque motor, of the same amplitude and duration range as in the active task. fMRI activation and TMS parameters of motor cortex excitability were measured before and after each training type. Motor performance, measured as the number of movements that hit the target window duration, was significantly better after active than after passive training. Both active and passive movements performed during fMRI measurements activated cM1. Active training led to more prominent increases in (i) fMRI activation of cM1; (ii) recruitment curves (TMS); and (iii) intracortical facilitation (TMS) than passive training. Therefore, a short period of active motor training is more effective than passive motor training in eliciting performance improvements and cortical reorganization. This result is consistent with the concept of a pivotal role for voluntary drive in motor learning and neurorehabilitation. C1 Univ Tubingen, Inst Med Psychol & Verhaltensneurobiol, D-72074 Tubingen, Germany. Univ Trent, Ctr Cognit Neurosci, Trent, Italy. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Lotze, M (reprint author), Univ Tubingen, Inst Med Psychol & Verhaltensneurobiol, Gartenstr 29, D-72074 Tubingen, Germany. RI Braun, Christoph/E-4561-2010 OI Braun, Christoph/0000-0002-7836-4010 NR 34 TC 269 Z9 279 U1 2 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2003 VL 126 BP 866 EP 872 DI 10.1093/brain/awg079 PN 4 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 655HT UT WOS:000181545800010 PM 12615644 ER PT J AU Sabri, F Chiodi, F Piret, JP Wei, CH Major, E Westermark, B Masucci, MG Levitsky, V AF Sabri, F Chiodi, F Piret, JP Wei, CH Major, E Westermark, B Masucci, MG Levitsky, V TI Soluble factors released by virus specific activated cytotoxic T-lymphocytes induce apoptotic death of astroglioma cell lines SO BRAIN PATHOLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; TUMOR-NECROSIS-FACTOR; INTERFERON-GAMMA; FAS LIGAND; HUMAN ASTROCYTES; IFN-GAMMA; MALIGNANT GLIOMA; KILLER-CELLS; FACTOR-ALPHA; TNF-ALPHA AB Astrocytomas and astrogliomas represent the most common types of primary tumors in human central nervous system and are associated with high mortality due to the absence of efficient therapy. Here we demonstrate that, upon antigen-specific activation, cytotoxic T-lymphocytes (CTLs) secrete products that inhibit proliferation and induce apoptosis in a significant proportion of astroglioma cell lines. This effect is tumor specific in that normal cultured astrocytes do not develop apoptotic changes upon exposure to supernatant of activated CTLs. Experiments with purified lymphokines and lymphokine specific blocking antibodies indicate that synergistic activities of tumor necrosis factor (TNF)-alpha and interferon (INF)-gamma are required for the apoptosis inducing effect on some astroglioma cell lines. However, this effect appears to be dependent on additional factors produced by activated CTLs. Our results suggest that local application of factors released by activated CTLs or induction of CTL migration and activation in the tumor site may have a therapeutic effect in patients with astrogilomas. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Univ Uppsala, Dept Pathol, Uppsala, Sweden. NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Levitsky, V (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. RI Masucci, Maria/B-8588-2009 NR 45 TC 3 Z9 4 U1 0 U2 1 PU INT SOC NEUROPATHOLOGY PI LOS ANGELES PA UCLA MEDICAL CENTER, SECTION NEUROPATHOLGY, C H S 18-126, LOS ANGELES, CA 90095-1732 USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD APR PY 2003 VL 13 IS 2 BP 165 EP 175 PG 11 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 744DZ UT WOS:000186613800005 PM 12744470 ER PT J AU Watson, REB Zokaie, S Kapasi, A Moskovitz, J Griffiths, CEM AF Watson, REB Zokaie, S Kapasi, A Moskovitz, J Griffiths, CEM TI Methionine sulphoxide reductase a is reduced in photoaged human skin SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract CT Annual meeting of the British-Society-for-Investigative-Dermatology CY APR 07-09, 2003 CL UNIV SOUTHAMPTON, SOUTHAMPTON, ENGLAND SP British Soc Investigative Dermatol HO UNIV SOUTHAMPTON C1 Univ Manchester, Hope Hosp, Dermatol Ctr, Dermatopharmacol Unit, Manchester, Lancs, England. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD APR PY 2003 VL 148 IS 4 MA P8 BP 859 EP 859 PG 1 WC Dermatology SC Dermatology GA 680XH UT WOS:000183005000091 ER PT J AU Yoon, M Lee, H Jeong, S Kim, JJ Nicol, CJ Nam, KW Kim, M Cho, BG Oh, GT AF Yoon, M Lee, H Jeong, S Kim, JJ Nicol, CJ Nam, KW Kim, M Cho, BG Oh, GT TI Peroxisome proliferator-activated regulation of lipid metabolism by receptor alpha is involved in the ginseng SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE ginseng; ginsenosides; lipid metabolism; PPAR alpha; Wy14,643 ID B-16 MELANOMA-CELLS; PANAX-GINSENG; GLUCOCORTICOID RECEPTOR; LIPOPROTEIN METABOLISM; GENE-EXPRESSION; FATTY LIVER; CHOLESTEROL; MODULATION; ACIDS; RATS AB 1 Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of the key genes involved in lipid metabolism following activation of this receptor by various ligands. Ginseng, a highly valuable medicine in oriental societies, is also reported to modulate lipid metabolism, although the mechanism of its action remains unknown. In order to test our hypothesis that ginseng exerts its effects by altering PPARalpha-mediated pathways, the effects of Korean red ginseng on PPARalpha function and serum lipid profiles were investigated using in vivo and in vitro approaches. 2 In vivo administration of ginseng extract (GE) and ginsenosides (GS) not only inhibited mRNA levels of acyl-CoA oxidase, a rate-limiting enzyme for PPARalpha-mediated peroxisomal fatty acid beta-oxidation, induced by the potent PPARalpha ligand Wy14,643 in a dose- and time-dependent manner, but also inhibited the induction of PPARalpha target genes expected following treatment with Wyl4,643. 3 Consistent with the in vivo data, both GE and GS caused dose-dependent decreases in the endogenous expression of a luciferase reporter gene containing the PPAR responsive element (PPRE), while GS significantly decreased the magnitude of reporter gene activation in the presence of Wyl4,643. 4 Serological studies demonstrated that, compared with vehicle-treated mice, treatment with GS significantly increased serum concentrations of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol. Compared to groups treated with Wy14,643 alone, which significantly decreased serum triglyceride and HDL cholesterol levels versus controls, coadministration of either GE or GS with Wy14,643 modestly increased serum triglycerides and HDL cholesterol. 5 These results indicate that the effects of ginseng on serum lipid profiles may be mediated by changes in the expression of PPARalpha target genes, providing the first evidence that in vivo and in vitro treatments of ginseng modulate PPARalpha action. In addition, these data suggest that ginseng can act as an inhibitor of PPARalpha function, which may have therapeutic implications. C1 Mokwon Univ, Dept Life Sci, Taejon 302729, South Korea. Korea Res Inst Biosci & Biotechnol, Res Genet Ctr, Taejon 305600, South Korea. NIH, Lab Metab, Div Basic Sci, Bethesda, MD 20892 USA. Korea Ginseng & Tobacco Res Inst, Div Ginseng Prod Dev, Qual Verificat Lab, Taejon 305345, South Korea. RP Yoon, M (reprint author), Mokwon Univ, Dept Life Sci, 800 Seo Gu,Doan Gong, Taejon 302729, South Korea. NR 39 TC 41 Z9 44 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 IS 7 BP 1295 EP 1302 DI 10.1038/sj.bjp.0705169 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 669WE UT WOS:000182372800018 PM 12711630 ER PT J AU Wihlborg, AK Malmsjo, M Eyjolfsson, A Gustafsson, R Jacobson, K Erlinge, D AF Wihlborg, AK Malmsjo, M Eyjolfsson, A Gustafsson, R Jacobson, K Erlinge, D TI Extracellular nucleotides induce vasodilatation in human arteries via prostaglandins, nitric oxide and endothelium-derived hyperpolarising factor SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE coronary circulation; endothelium; endothelium-derived hyperpolarising factor; human; nitric oxide; nucleotide; P2 receptor; vasodilatation ID VASCULAR SMOOTH-MUSCLE; RAT HEPATIC-ARTERY; DEPENDENT RELAXATION RESISTANT; CONGESTIVE-HEART-FAILURE; UTP-GAMMA-S; P2 RECEPTORS; GUINEA-PIG; CORONARY-ARTERIES; MESENTERIC-ARTERY; PHOSPHOLIPASE-C AB 1 The present study was aimed at examining P2 receptor-mediated vasodilatation in human vessels. The isometric tension was recorded in isolated segments of the human left internal mammary artery branches precontracted with 1 muM noradrenaline. 2 Endothelial denudation abolished the dilator responses. 3 The selective P2Y(1), agonist, 2-MeSADP, induced a potent vasodilatation (pEC(50) = 6.9 +/- 0. 1). The P2Y(1), antagonist of 10 muM, MRS 2216, shifted the 2-MeSADP concentration-response curve 1.1 log units to the right. The combined P2Y(1) and P2X agonist, 2-MeSATP, stimulated a dilatation with a potency similar to that of 2-MeSADP. Furthermore, MRS 2216 had a similar antagonistic effect on both 2-MeSATP and 2-MeSADP indicating that P2X receptors do not mediate vasodilatation. 4 Both the P2Y(2/4) agonist, UTPgammaS and the P2Y(6) agonist, UDPbetaS, stimulated potent dilatations (pEC(50) = 7.8 +/- 0.4 for UTPgammaS and 8.4 +/- 0.2 for UDPbetaS). 5 The 2-MeSADP-induced nitric oxide (NO)-mediated dilatation was studied in the presence of 10 muM indomethacin, 50 nm charybdotoxin and 1 muM apamin. The involvement of the endothelium-derived hyperpolarising factor (EDHF) was investigated in the presence of 0.1 MM L-NOARG and indomethacin. The involvement of prostaglandins was investigated in the presence of L-NOARG, charybdotoxin and apamin. Both NO, EDHF and prostaglandins mediated 2-MeSADP dilatation with similar efficacy (E-max = 25 +/- 5% for NO, 25 +/- 6% for EDHF and 27 +/- 5% for prostaglandins). 6 In conclusion, extracellular nucleotides induce endothelium-derived vasodilatation in human vessels by stimulating P2Y(1), P2Y(2/4) and P2Y(6) receptors, while P2X receptors are not involved. Endothelial P2Y receptors mediate dilatation by release of EDHF, NO and prostaglandins. C1 Lund Univ, Dept Cardiol, Biomed Ctr C12, S-22100 Lund, Sweden. NIH, Mol Recognit Sect, Bethesda, MD 20892 USA. RP Erlinge, D (reprint author), Univ Lund Hosp, Dept Cardiol, S-22185 Lund, Sweden. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 48 TC 54 Z9 54 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 IS 8 BP 1451 EP 1458 DI 10.1038/sj.bjp.0705186 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 680HH UT WOS:000182969900009 PM 12721100 ER PT J AU Gavins, FNE Gao, JL Murphy, PM Flower, RJ Perretti, M AF Gavins, FNE Gao, JL Murphy, PM Flower, RJ Perretti, M TI An annexin 1 peptide reduces myocardial ischaemia reperfusion in the mouse SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract CT Meeting of the British-Pharmacological-Society-Clinical-Pharmacology-Section CY JAN 07-10, 2003 CL LONDON, ENGLAND SP British Pharmacol Soc Clin Pharmacol Sect ID RECEPTOR C1 William Harvey Res Inst, London EC1M 6BQ, England. NIAID, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 SU S MA 18P BP U9 EP U9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 667GT UT WOS:000182223500019 ER PT J AU Stanford, SJ San, H Nabel, EG Hislop, AA Haworth, SG Mitchell, JA AF Stanford, SJ San, H Nabel, EG Hislop, AA Haworth, SG Mitchell, JA TI Heme oxygenase-1 deficient mice do not appear to have pulmonary hypertension SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract CT Meeting of the British-Pharmacological-Society-Clinical-Pharmacology-Section CY JAN 07-10, 2003 CL LONDON, ENGLAND SP British Pharmacol Soc Clin Pharmacol Sect C1 Univ London Imperial Coll Sci Technol & Med, Royal Brompton, Crit Care Unit, London SW3 6NP, England. NHLBI, Vasc Biol Branch, Bethesda, MD USA. Inst Child Hlth, London WC1N 1EH, England. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 SU S MA 50P BP U25 EP U25 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 667GT UT WOS:000182223500051 ER PT J AU Wray, J Zeldin, D Warner, TD Bishop-Bailey, D AF Wray, J Zeldin, D Warner, TD Bishop-Bailey, D TI Cytochrome P450 2J2 over-expression activates peroxisome proliferator-activated receptor-alpha SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract CT Meeting of the British-Pharmacological-Society-Clinical-Pharmacology-Section CY JAN 07-10, 2003 CL LONDON, ENGLAND SP British Pharmacol Soc Clin Pharmacol Sect C1 BArts & London, William Harvey Res Inst, London EC1M 6BQ, England. NIEHS, Res Triangle Pk, NC 27709 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 SU S MA 169P BP U85 EP U85 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 667GT UT WOS:000182223500170 ER PT J AU Yona, S Hannon, R Gao, JL Murphy, PM Buckingham, JC Flower, RJ Perretti, M AF Yona, S Hannon, R Gao, JL Murphy, PM Buckingham, JC Flower, RJ Perretti, M TI Alterations in the annexin 1 pathway are associated with modified neutrophil activation SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract CT Meeting of the British-Pharmacological-Society-Clinical-Pharmacology-Section CY JAN 07-10, 2003 CL London, ENGLAND SP British Pharmacol Soc, Clin Pharmacol Sect ID RECEPTOR C1 WHRI, London, England. NIAID, NIH, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Neuroendocrinol, London, England. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2003 VL 138 SU S MA 13P BP U7 EP U7 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 667GT UT WOS:000182223500014 ER PT J AU de Smet, MD Shen, DF Pepose, J Chan, CC AF de Smet, MD Shen, DF Pepose, J Chan, CC TI Microdissection combined with the polymerase chain reaction to identify potentiating viral co-infection in patients with HIV/AIDS with ocular infection SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Article DE cytomegalovirus; herpesvirus; Epstein-Barr virus; human herpesvirus 8; polymerase chain reaction; microdissection; AIDS; HIV ID EPSTEIN-BARR-VIRUS; PRIMARY INTRAOCULAR LYMPHOMA; CASTLEMANS-DISEASE; KAPOSIS-SARCOMA; GENE-EXPRESSION; HERPES-SIMPLEX; AIDS; HUMAN-HERPESVIRUS-8; DNA; CYTOMEGALOVIRUS AB Background: In the presence of several coexisting infections, superimposed tissue necrosis or tissue metaplasia, it may be difficult to recognize standard histologic morphology on hematoxylin-eosin slides. Tissue microdissection combined with the polymerase chain reaction (PCR-MD) offers the advantages of high specificity and relative speed. The objective of this study was to describe the use of PCR-MD in identifying potentiating viral co-infection in patients with HIV/AIDS with retinitis and choroiditis. Methods: Eyes from two patients with HIV/AIDS with several ocular infections were studied by a variety of techniques, including standard histologic examination, immunochemistry, electron microscopy and in situ hybridization. PCR-MD was used to identify coexisting viral infections. Results: Histologic examination showed cytomegalovirus retinitis in both cases. Use of PCR-MD allowed the identification of Epstein-Barr virus within a zone of fulminant varicella-zoster virus retinitis in one patient. PCR-MD confirmed the presence of human herpesvirus 8 in the second patient, who had ocular lymphoma. Interpretation: PCR-MD can be used to demonstrate coexisting viral infection in ocular specimens from patients with unusually fulminant courses. Co-infections may contribute to the observed clinical course and should be considered in patients with rapid progression or unusual presentation. C1 Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. NEI, Immunol Lab, Clin Immunopathol Sect, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP de Smet, MD (reprint author), G2-217,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. OI de Smet, Marc/0000-0002-9217-5603 NR 27 TC 2 Z9 2 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD APR PY 2003 VL 38 IS 3 BP 207 EP 213 PG 7 WC Ophthalmology SC Ophthalmology GA 672DF UT WOS:000182505300004 PM 12733688 ER PT J AU Hoffman, RM Hunt, WC Gilliland, FD Stephenson, RA Potosky, AL AF Hoffman, RM Hunt, WC Gilliland, FD Stephenson, RA Potosky, AL TI Patient satisfaction with treatment decisions for clinically localized prostate carcinoma. Results from the prostate cancer outcomes study. SO CANCER LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 02-05, 2001 CL SAN DIEGO, CALIFORNIA SP Soc Gen Internal Med DE prostatic neoplasms; patient satisfaction; treatment outcomes; prostatectomy; hormonal antineoplastic agents; radiotherapy ID QUALITY-OF-LIFE; EXTERNAL-BEAM RADIATION; RADICAL PROSTATECTOMY; SEXUAL FUNCTION; THERAPY; SEQUELAE; MEN AB BACKGROUND. Men with early-stage prostate carcinoma can choose aggressive treatment or conservative management. The authors used data from a population-based cohort of men with clinically locatized prostate carcinoma to describe satisfaction with treatment decisions 24 months after diagnosis and to examine the association of demographic, socioeconomic, and clinical characteristics with treatment satisfaction. METHODS. The authors evaluated 2365 men with clinically localized prostate carcinoma, diagnosed between October 1994 and October 1995, in one of six Surveillance, Epidemiology, and End Results turner registries and who were available for 24 month follow-up. Medical record review and patient-completed surveys provided demographic, socioeconomic, and clinical data and measured treatment satisfaction. Logistic regression analyses were used to identify factors associated with satisfaction. RESULTS. Overall, 59.2% of subjects were delighted or very pleased with their treatment selection. The perception of being cancer free (66.4%), maintaining urinary (64.2%) and bowel (60.5%) control and normal erectile function (65.9%), having good general health (71.3%), and preserving social relationships (68.1%) were significantly associated with being satisfied (P < 0.05). Men receiving no active treatment were less satisfied (50.5%, P < 0.001) than actively treated men, and Hispanic men were less satisfied than non-Hispanic white men after undergoing radical prostatectomy (50.1% vs. 58.0%, P = 0.05) or androgen deprivation (29.7% vs. 71.8%, P < 0.02). CONCLUSIONS. The majority of men were satisfied with their treatment selection for clinically localized prostate carcinoma. Receiving an active treatment, believing oneself to be free of cancer, avoiding treatment complications, and having good overall health and social support were positively associated with satisfaction. Cancer 2003;97:1653-62. Published 2003 by the American Cancer Society.* C1 New Mexico VA Hlth Care Syst 111GIM, Med Serv, Albuquerque, NM 87108 USA. Univ New Mexico, Hlth Sci Ctr, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Univ Utah, Sch Med, Div Urol, Salt Lake City, UT USA. Univ Utah, Sch Med, Utah Canc Registry, Salt Lake City, UT USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Hoffman, RM (reprint author), New Mexico VA Hlth Care Syst 111GIM, Med Serv, 1501 San Pedro Dr SE,111GIM, Albuquerque, NM 87108 USA. EM rhoffman@unm.edu FU NCI NIH HHS [N01PC67010, N01CN67009, N01PC67000, N01PC67005, N01PC67006, N01PC67007] NR 26 TC 91 Z9 94 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 1 PY 2003 VL 97 IS 7 BP 1653 EP 1662 DI 10.1002/cncr.11233 PG 10 WC Oncology SC Oncology GA 660CQ UT WOS:000181816600009 PM 12655522 ER PT J AU Irwin, ML Crumley, D McTiernan, A Bernstein, L Baumgartner, R Gilliland, FD Kriska, A Ballard-Barbash, R AF Irwin, ML Crumley, D McTiernan, A Bernstein, L Baumgartner, R Gilliland, FD Kriska, A Ballard-Barbash, R TI Physical activity levels before and after a diagnosis of breast carcinoma - The health, eating, activity, and lifestyle (HEAL) study SO CANCER LA English DT Article DE exercise; prognosis; treatment; stage; body weight; obesity ID RECEIVING ADJUVANT CHEMOTHERAPY; GROWTH-FACTOR-I; POSTMENOPAUSAL WOMEN; CANCER-PATIENTS; WEIGHT-GAIN; SEX-HORMONES; INSULIN; EXERCISE; MANAGEMENT; FATIGUE AB BACKGROUND. increased body weight at the time patients are diagnosed with breast carcinoma has been associated with an increased risk of recurrence and reduced survival. Weight gain also is common after diagnosis. Increasing physical activity (PA) after diagnosis may minimize these adverse outcomes. In this population-based study, the authors investigated whether PA levels after diagnosis declined from prediagnosis levels and whether any changes in PA varied by disease stage, adjuvant treatment, patient age, or body mass index (BMI) in 812 patients with incident breast carcinoma (from in situ to Stage IIIa). METHODS. Types of sports and household activities and their frequency and duration for the year prior to diagnosis and for the month prior to the interview (i.e., 4-12 months postdiagnosis) were assessed during a baseline interview. RESULTS. Patients decreased their total PA by an estimated 2.0 hours per week from prediagnosis to postdiagnosis, an 11% decrease (P < 0.05). Greater decreases in sports PA were observed among women who were treated with radiation and chemotherapy (50% decrease) compared with women who underwent surgery only (24% decrease) or who were treated with radiation only (23%; (P < 0.05). Greater decreases in sports PA were observed among obese patients (41% decrease) compared with patients of normal weight (24% decrease; P < 0.05). CONCLUSIONS. PA levels were reduced significantly after patients were diagnosed with breast carcinoma. Greater decreases in PA observed among heavier patients implied a potential for greater weight gain among women who already were overweight. Randomized, controlled trials are needed to evaluate how PA may improve the prognosis for patients with breast carcinoma.(C) American Cancer Society C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Univ New Mexico, Div Epidemiol & Prevent Med, Albuquerque, NM 87131 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NCI, Appl Res Program, Div Canc Control & Populat Si, Bethesda, MD 20892 USA. RP Irwin, ML (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, POB 208034, New Haven, CT 06520 USA. EM melinda.irwin@yale.edu OI Kriska, Andrea/0000-0002-3522-0869 FU NCI NIH HHS [N01-CN-05228, N01 CN005228, N01 PC035138-22, N01 PC067010, N01-CN-75036-20, T32 CA009661, T32 CA09661]; NCRR NIH HHS [M01 RR000037, M01-RR-00037] NR 29 TC 266 Z9 271 U1 1 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 1 PY 2003 VL 97 IS 7 BP 1746 EP 1757 DI 10.1002/cncr.11227 PG 12 WC Oncology SC Oncology GA 660CQ UT WOS:000181816600019 PM 12655532 ER PT J AU Vallera, DA Elson, M Brechbiel, MW Dusenbery, KE Burns, LJ Skubitz, KM Jaszcz, WB Ramsay, NK Panoskaltsis-Mortari, A Kuroki, DW Wagner, JE Kersey, JH AF Vallera, DA Elson, M Brechbiel, MW Dusenbery, KE Burns, LJ Skubitz, KM Jaszcz, WB Ramsay, NK Panoskaltsis-Mortari, A Kuroki, DW Wagner, JE Kersey, JH TI Preclinical studies targeting normal and leukemic hematopoietic cells with yttrium-90-labeled antiCD45 antibody in vitro and in vivo in nude mice SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE radiopharmaceutical; radioimmunoconjugate; 90Y; leukemia; bone marrow transplantation; nude mice; tumor; anti-CD45 ID NON-HODGKINS-LYMPHOMA; ALLOGENEIC MARROW TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; MONOCLONAL-ANTIBODY; PHASE-I; IDEC-Y2B8 RADIOIMMUNOTHERAPY; IBRITUMOMAB TIUXETAN; DOSIMETRY; BINDING; TUMORS AB A study was undertaken to investigate the suitability of using a high affinity (Kd=1.1 nM) anti-CD45 monoclonal antibody for delivering the high energy beta-particle emitting isotope Y-90 to lymphohematopoietic target cells in vivo. The antibody, AHN-12, recognized the tyrosine phosphatase CD45 expressed on the surface of normal and malignant hematopoietic cells and studies showed that it reacted with both CD45-expressing normal peripheral blood cells and leukemia cells from patients. The antibody was readily labeled with Y-90 using the highly stable chelate 1B4M-DTPA and the radioimmunoconjugate was designated Y-90-anti-CD45. The agent selectively bound to CD45(+) B cell line Daudi, but not CD45(-) control cells and significantly (p=0.007) more bound to Daudi tumors growing in athymic nude mice than did a control non-reactive antibody. Moreover, biodistribution data correlated well to an anti-Daudi effect observed against established tumors in nude mice. The effect was dose dependent and irreversible with the best results in mice receiving a single dose of 137 muCi Y-90-anti-CD45. These mice displayed a significantly (p<0.0095) better anti-tumor effect than a control Y-90-labeled antibody and survived over 135 days with no evidence of tumor. Histology studies showed no significant injury to kidney, liver, or small intestine even at 254 μCi, the highest dose tested. Because radiolabeled anti-CD45 antibody can be used to deliver radiation selectively to lymphohematopoietic tissue, these data indicate that this agent may be used to improve treatment of hematopoietic malignancies, particularly leukemia and lymphoma, when combined with hematopoietic stem cell transplantation in a future clinical trial. C1 Univ Minnesota, Ctr Canc, Dept Therapeut Radiol Radiat Oncol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Vallera, DA (reprint author), Univ Minnesota, Ctr Canc, Dept Therapeut Radiol Radiat Oncol, Mayo Mail Code 367,Harvard St & E River Rd, Minneapolis, MN 55455 USA. NR 46 TC 9 Z9 11 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD APR PY 2003 VL 18 IS 2 BP 133 EP 145 DI 10.1089/108497803765036300 PG 13 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 676AV UT WOS:000182730500001 PM 12804039 ER PT J AU Newcomer, LM Newcomb, PA Potter, JD Yasui, Y Trentham-Dietz, A Storer, BE Longnecker, MP Baron, JA Daling, JR AF Newcomer, LM Newcomb, PA Potter, JD Yasui, Y Trentham-Dietz, A Storer, BE Longnecker, MP Baron, JA Daling, JR TI Postmenopausal hormone therapy and risk of breast cancer by histologic type (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; carcinoma; hormone replacement therapy; infiltrating duct; lobular carcinoma ID REPLACEMENT THERAPY; MENOPAUSAL ESTROGEN; WOMEN; CARCINOMA; RELIABILITY; INFORMATION; DENSITY; HEALTH; AGE AB Objective: Postmenopausal hormone use and risk of breast cancer by histopathology was examined in a large multi-centered population-based case-control study. Methods: Women younger than 75 years newly diagnosed with invasive breast cancer between 1988 and 1991 were identified from statewide tumour registries in Wisconsin, Massachusetts, New Hampshire, and Maine. Only postmenopausal women were included in this analysis. Breast cancer cases (lobular (n = 219), ductal, NOS (n = 2172), and specific ductal subtypes (n = 242)) were compared with randomly selected population controls (n = 3179) using adjusted multi-variable polytomous logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for each histology. Results: Lobular carcinoma was associated with recent (within 2 years) estrogen therapy (OR: 1.8, 95% CI: 1.0-3.4) and recent use of combined estrogen-plus-progestin therapy (OR: 3.6, 95% CI: 1.8-7.6). Risk of ductal carcinoma was not associated with recent use of either estrogen alone (OR: 0.9, 95% CI: 0.7-1.2) or combined therapy (OR: 0.9, 95% CI: 0.6-1.3). No associations were found with ductal subtypes. Conclusions: The association between postmenopausal hormone use and risk of breast cancer may depend on histopathology. Of particular interest is the association between combined hormone therapy and increased risk of lobular carcinoma. This lesion is increasingly common but, nonetheless, comprises fewer than 10% of invasive breast cancers. C1 Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98109 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Newcomer, LM (reprint author), Fred Hutchinson Canc Res Ctr, Dept Epidemiol, 1100 Fairview Ave N,MP-474,POB 19024, Seattle, WA 98109 USA. RI Yasui, Yutaka/E-2564-2015; OI Yasui, Yutaka/0000-0002-7717-8638; Potter, John/0000-0001-5439-1500; Longnecker, Matthew/0000-0001-6073-5322 FU NCI NIH HHS [CA47147, CA47305] NR 35 TC 57 Z9 60 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2003 VL 14 IS 3 BP 225 EP 233 DI 10.1023/A:1023634907723 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 673LY UT WOS:000182583500003 PM 12814201 ER PT J AU Inskip, PD Devesa, SS Fraumeni, JF AF Inskip, PD Devesa, SS Fraumeni, JF TI Trends in the incidence of ocular melanoma in the United States, 1974-1998 SO CANCER CAUSES & CONTROL LA English DT Article DE epidemiology; eye neoplasms; melanoma; nonionizing radiation ID UVEAL MELANOMA; MALIGNANT-MELANOMA; EPIDEMIOLOGIC ASPECTS; HOST FACTORS; RISK; RADIATION; EYE; SUNLIGHT; EXPOSURE; AUSTRALIA AB Background: A recent report noted a fourfold risk of ocular melanoma associated with employment in occupations involving use of cellular telephones. Methods: To aid interpretation of this finding, and clarify how subsite-specific temporal variation in incidence of ocular melanoma compares with that for cutaneous melanoma, we examined time trends in the incidence of melanoma among whites in the United States, based on data collected through the surveillance, Epidemiology, and End Results (SEER) program for 1974-1998. Results: The incidence of ocular melanoma decreased over time in both sexes, with no indication of a recent increase during the 1990s. The annual percent change was -0.7% for males (95% confidence interval: -2.3, 0.9) and -1.2% for females (95% confidence interval: -2.5, 0.0). Time trends appeared to differ by subsite of ocular melanoma; rates were. at for the choroid, decreased for the ciliary body, and increased for the conjunctiva (among males only) beginning in the 1980s. In contrast, all subsites of cutaneous melanoma, including the face and adjacent areas, showed marked increases in incidence over the observation period. Conclusions: The dramatic increase in use of cellular telephones has not been accompanied by an increase in the incidence of ocular melanoma. Further study is required to explain the different time trends for subsites of ocular melanoma, and for ocular versus facial and other cutaneous melanomas. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Execut Plaza S,Room 7052,6120 Execut Blvd, Bethesda, MD 20892 USA. EM inskippe@mail.nih.gov NR 37 TC 47 Z9 47 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2003 VL 14 IS 3 BP 251 EP 257 DI 10.1023/A:1023684502638 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 673LY UT WOS:000182583500005 PM 12814204 ER PT J AU Liotta, LA Espina, V Mehta, AI Calvert, V Rosenblatt, K Geho, D Munson, PJ Young, L Wulfkuhle, J Petricoin, EF AF Liotta, LA Espina, V Mehta, AI Calvert, V Rosenblatt, K Geho, D Munson, PJ Young, L Wulfkuhle, J Petricoin, EF TI Protein microarrays: Meeting analytical challenges for clinical applications SO CANCER CELL LA English DT Review ID CATALYZED REPORTER DEPOSITION; LASER CAPTURE MICRODISSECTION; GENE-EXPRESSION ANALYSIS; SIGNAL AMPLIFICATION; ANTIBODY ARRAYS; CANCER; TECHNOLOGY; PROTEOMICS; MICROENVIRONMENT; IMMUNOASSAYS C1 NCI, FDA NCI Clin Proteom Program, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, FDA NCI Clin Proteom Program, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, FDA NCI Clin Proteom Program, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. OI Espina, Virginia/0000-0001-5080-5972 NR 53 TC 289 Z9 307 U1 4 U2 23 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD APR PY 2003 VL 3 IS 4 BP 317 EP 325 DI 10.1016/S1535-6108(03)00086-2 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 671TQ UT WOS:000182480500005 PM 12726858 ER PT J AU Sherman-Baust, CA Weeraratna, AT Rangel, LBA Pizer, ES Cho, KR Schwartz, DR Shock, T Morin, PJ AF Sherman-Baust, CA Weeraratna, AT Rangel, LBA Pizer, ES Cho, KR Schwartz, DR Shock, T Morin, PJ TI Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells SO CANCER CELL LA English DT Article ID GENE-EXPRESSION; DRUG-RESISTANCE; TUMOR-CELLS; SERIAL ANALYSIS; TRIPLE-HELIX; DNA ADDUCTS; STAGE-III; CAM-DR; CARCINOMA; APOPTOSIS AB The mechanisms of drug resistance in cancer are poorly understood. Serial analysis of gene expression (SAGE) profiling of cisplatin-resistant and sensitive cells revealed many differentially expressed genes. Remarkably, many ECM genes were elevated in cisplatin-resistant cells. COL6A3 was one of the most highly upregulated genes, and cultivation of cisplatin-sensitive cells in the presence of collagen VI protein promoted resistance in vitro. Staining of ovarian tumors with collagen VI antibodies confirmed collagen VI expression in vivo and suggested reorganization of the extracellular matrix in the vicinity of the tumor. Furthermore, the presence of collagen VI correlated with tumor grade, an ovarian cancer prognostic factor. These results suggest that tumor cells may directly remodel their microenvironment to increase their survival in the presence of chemotherapeutic drugs. C1 NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. Univ Michigan, Dept Pathol, Sch Med, Ann Arbor, MI 48109 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 47 TC 143 Z9 147 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD APR PY 2003 VL 3 IS 4 BP 377 EP 386 DI 10.1016/S1535-6108(03)00058-8 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 671TQ UT WOS:000182480500010 PM 12726863 ER PT J AU Rauscher, GH Sandler, DP Poole, C Pankow, J Shore, D Bloomfield, CD Olshan, AF AF Rauscher, GH Sandler, DP Poole, C Pankow, J Shore, D Bloomfield, CD Olshan, AF TI Is family history of breast cancer a marker of susceptibility to exposures in the incidence of de novo adult acute leukemia? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROXY RESPONDENTS; CIGARETTE-SMOKING; ATOMIC-BOMB; RISK; BENZENE AB The risk factors for adult acute leukemia incidence have been difficult to establish. Family history of cancer might interact with environmental exposures to produce associations that are otherwise difficult to detect. In addition to family history of leukemia or other hematopoietic cancers, family history of breast cancer could be a marker of susceptibility, because leukemia and breast cancer are known to cluster in families that have specific germ-line mutations. In a population-based case control study of 779 incident adult acute leukemia patients and 625 controls, we estimated the relative risk for exposed individuals with a family history compared with unexposed individuals without a family history (RR11), along with a measure of interdependence, the interaction contrast ratio. Combined with a family history of breast cancer, ever-smoking [RR11 = 2.4, 95% confidence interval (Cl): 1.2-4.8], general solvent exposure (RR11 = 1.9, 95% CI: 1.1-3.4), aromatic hydrocarbon exposure (RR11, = 3.8, 95% CI: 1.1-14), and diagnostic ionizing radiation exposure (RR11 = 2.1, 95% CI: 1.2-3.8) were all associated with increased incidence. Furthermore, there was no increased incidence associated with any of these exposures in the absence of a family history of breast cancer and no increased incidence for family history of breast cancer in the absence of exposures. The pattern of relative risks strongly suggested synergy across exposures. Family history of breast cancer might be a marker of susceptibility to a range of leukemia risk factors, whose effects are generally weak or nonexistent when considered alone. C1 Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60612 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Ohio State Univ, Canc & Leukemia Grp B, Columbus, OH 43210 USA. RP Rauscher, GH (reprint author), Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, 816 SPHPI,MC 923,1603 W Taylor, Chicago, IL 60612 USA. OI Rauscher, Garth/0000-0003-0374-944X; Sandler, Dale/0000-0002-6776-0018; Pankow, James/0000-0001-7076-483X FU NCI NIH HHS [CA31946, CA09330-20, CA57699-06] NR 38 TC 9 Z9 10 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2003 VL 12 IS 4 BP 289 EP 294 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 667WR UT WOS:000182258000001 PM 12692102 ER PT J AU Wideroff, L Freedman, AN Olson, L Klabunde, CN Davis, W Srinath, KP Croyle, RT Ballard-Barbash, R AF Wideroff, L Freedman, AN Olson, L Klabunde, CN Davis, W Srinath, KP Croyle, RT Ballard-Barbash, R TI Physician use of genetic testing for cancer susceptibility: Results of a national survey SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-OVARIAN CANCER; FAMILIAL ADENOMATOUS POLYPOSIS; FOLLOW-UP CARE; INHERITED PREDISPOSITION; COLORECTAL-CANCER; RISK; BRCA1; INDIVIDUALS; MUTATION; WOMEN AB Genetic testing for inherited germ-line mutations associated with cancer susceptibility is an emerging technology in medical practice. Limited information is currently available about physician use of cancer susceptibility tests (CSTs). In 1999-2000, a nationally representative survey was conducted to estimate prevalence of CST use by United States physicians and assess demographic, training, practice setting, and practice patterns associated with use. A stratified random sample of clinicians in eight specialties was selected from a file of all licensed physicians. In total, 1251 physicians, including 820 in primary care and 431 in tertiary care, responded to a 15-min questionnaire by mail, telephone, fax, or Internet (response rate = 71.0%). In the previous 12 months, 31.2% [95% confidence interval (CI), 28.5-33.9] overall, including 30.6% (95% CI, 27.5-33.7) in primary care and 33.4% (95% CL 27.9-38.9) in tertiary rare, had ordered CSTs or referred patients elsewhere for risk assessment or testing. More physicians referred patients elsewhere [26.7% (95% Cl, 24.2-29.2)] than directly ordered tests [7.9% (95% CL 6.3-9.5)]. Factors associated with ordering or referring included practice location in the Northeast [odds ratio (OR), 2.30; 95% Cl, 1.46-3.63%], feeling qualified to recommend CSTs (OR, 1.96; 95% CI = 1.41-2.72), receiving CST advertising materials (OR, 1.97; 95% Cl, 1.40-2.78%), and most notably, having patients who asked whether they can or should get tested (OR, 5.52; 95% CI, 3.97-7.67%). Lower CST use was associated with not knowing if there were local testing and counseling facilities (OR, 0.39; 95% Cl, 0.23-0.66%). These findings underscore the importance of establishing effective clinical approaches to test use and promoting physician education to facilitate communication with patients about cancer genetics. C1 NCI, ARP, EPN 4005, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. ABT Associates Inc, Chicago, IL 60610 USA. RP Wideroff, L (reprint author), NCI, ARP, EPN 4005, Div Canc Control & Populat Sci, MSC 7344,6130 Execut Blvd, Bethesda, MD 20892 USA. RI Hernandez, Jessica/G-6527-2011 NR 54 TC 86 Z9 86 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2003 VL 12 IS 4 BP 295 EP 303 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 667WR UT WOS:000182258000002 PM 12692103 ER PT J AU Sherman, ME Wang, SS Tarone, R Rich, L Schiffman, M AF Sherman, ME Wang, SS Tarone, R Rich, L Schiffman, M TI Histopathologic extent of cervical intraepithelial neoplasia 3 lesions in the atypical squamous cells of undetermined significance low-grade squamous tntraepithelial lesion triage study: Implications for subject safety and lead-time bias SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASCUS-LSIL TRIAGE; TERM FOLLOW-UP; PAPANICOLAOU TEST; NATURAL-HISTORY; CARCINOMA; DYSPLASIA; WOMEN; ABNORMALITIES; STRATEGIES; MANAGEMENT AB Cervical intraepithelial neoplasia 3 (CIN3) is the precursor of most squamous carcinomas and serves as a surrogate end point. However, small CIN3 lesions are rarely associated with concurrent invasion. We hypothesized that aggressive follow-up for cytology of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) leads predominantly to detection of smaller CIN3 lesions than those usually associated with cancer. We assessed this hypothesis in a masked histopathologic review of 330 CIN3 lesions in the ASCUS LSILTriage Study, focusing on ASCUS referrals. ASCUS referrals underwent randomized management [colposcopy for repeat cytology of high-grade squamous intraepithelial lesion (HSIL), colposcopy for oncogenic human papillomavirus (HPV) detection or repeat HSIL, or immediate colposcopy]; then all were followed with repeat cytology for 2 years, followed by colposcopy and aggressive treatment. We assessed all CIN3 lesions qualitatively and measured 39 of them. CIN3 lesions were overwhelmingly small. Compared with enrollment, lesions found at follow-up or exit involved fewer tissue fragments (P < 0.01) and showed less diffuse gland involvement (P = 0.03). CIN3 lesions found postenrollment after HPV testing involved the fewest tissue fragments [versus immediate colposcopy (P = 0.04) or repeat cytology of HSIL (P = 0.02)], and none showed diffuse gland involvement. The median distal-proximal length was 6.5 mm (median replacement of total epithelium = 5%) in the 39 measured cases. We conclude that CIN3 lesions underlying ASCUS or LSIL generally lack features associated with invasion, particularly if managed using HPV testing, suggesting that aggressive management leads to early detection of CIN3 but probably prevents relatively few cancers in screened populations. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Sherman, ME (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7080, Rockville, MD 20892 USA. FU NCI NIH HHS [CN55154, CN55105, CN55153, CN55155, CN55156, CN55157, CN55158, CN55159] NR 28 TC 59 Z9 59 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2003 VL 12 IS 4 BP 372 EP 379 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 667WR UT WOS:000182258000012 PM 12692113 ER PT J AU Lamar, CA Dorgan, JF Longcope, C Stanczyk, FZ Falk, RT Stephenson, HE AF Lamar, CA Dorgan, JF Longcope, C Stanczyk, FZ Falk, RT Stephenson, HE TI Serum sex hormones and breast cancer risk factors in postmenopausal women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LIFE-STYLE FACTORS; PROLACTIN LEVELS; UNITED-STATES; ESTROGEN; MENOPAUSAL; REPRODUCIBILITY AB Postmenopausal women with elevated serum estrogens and androgens are at an increased risk of breast cancer. We evaluated associations of serum estrogen and androgen levels with age, anthropometry, and reproductive history to assess whether these characteristics could potentially modify breast cancer risk through hormonal mechanisms. A cross-sectional study was conducted among 133 postmenopausal women who donated blood to the serum bank (Columbia, MO) and served as controls in a previous prospective nested case control study of serum hormones and breast cancer risk. Standard regression methods were used to calculate adjusted means and test for trends in relationships of serum hormone concentrations with breast cancer risk factors. All analyses were performed on the log(e) scale, and all models included assay batch, date, and time of blood collection. Serum levels of estradiol, non-sex hormone binding globulin bound estradiol, estrone, estrone sulfate, and testosterone increased significantly with increasing body mass index (BMI), whereas sex hormone binding globulin levels decreased. After adjusting for BMI, milliparous women tended to have higher testosterone levels compared with parous women (P = 0.05), but there was no evidence of a trend of decreasing testosterone with increasing parity. Dehydroepiandrosterone, its sulfate, and androstenediol decreased significantly with increasing age. Although BMI and parity could potentially modify breast cancer risk through hormonal mechanisms, age-related increases in breast cancer incidence do not appear to be mediated through changes in serum levels of the hormones evaluated. C1 NIAMSD, Extramural Program, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. Univ Missouri, Ctr Hlth Sci, Dept Surg, Columbia, MO 65212 USA. RP Lamar, CA (reprint author), NIAMSD, Extramural Program, NIH, 1 Democracy Plaza,6701 Democracy Blvd,suite 800, Bethesda, MD 20892 USA. NR 21 TC 39 Z9 39 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2003 VL 12 IS 4 BP 380 EP 383 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 667WR UT WOS:000182258000013 PM 12692114 ER PT J AU Lan, Q Rothman, N Chow, WH Lissowska, J Doll, MA Xiao, GH Zatonski, W Hein, DW AF Lan, Q Rothman, N Chow, WH Lissowska, J Doll, MA Xiao, GH Zatonski, W Hein, DW TI No apparent association between NAT1 and NAT2 genotypes and risk of stomach cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID MOLECULAR-GENETICS; ADENOCARCINOMA; POLYMORPHISMS; WARSAW; POLAND; CARCINOGENESIS C1 NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. RP Lan, Q (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, MSC 7240,6120 Execut Blvd,EPS 8109, Bethesda, MD 20892 USA. RI Hein, David/A-9707-2008; OI Lissowska, Jolanta/0000-0003-2695-5799 FU NCI NIH HHS [R01 CA034627, R01 CA034627-17] NR 14 TC 11 Z9 11 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2003 VL 12 IS 4 BP 384 EP 386 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 667WR UT WOS:000182258000014 PM 12692115 ER PT J AU Dionne, SO Smith, MH Marincola, FM Lake, DF AF Dionne, SO Smith, MH Marincola, FM Lake, DF TI Functional characterization of CTL against gp100 altered peptide ligands SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE gp100; melanoma; CTL; HLA altered peptide ligands ID TUMOR-INFILTRATING LYMPHOCYTES; CLASS-I MOLECULES; METASTATIC MELANOMA; IMMUNE-RESPONSE; MHC MOLECULE; ANTIGEN; BINDING; IDENTIFICATION; IMMUNOGENICITY; MOTIFS AB In this study, four modified gp100 peptides were designed by combining amino acids from the melanoma peptide antigen gp100((209-217)) with preferred primary and auxiliary HLA-A *0201 anchor residues previously identified from combinatorial peptide library screening with recombinant HLA-A*0201. These modified peptides demonstrated stronger binding affinity for the HLA-A*0201 molecule compared to wild-type gp100 peptide. Nine CTL lines generated from patients immunized with the g209-2 M peptide and one CTL line from a non-immunized patient were tested for the ability to respond to these modified gp100 peptides. Stimulation of CTL by two of four modified peptides induced higher levels of IFN-gamma secretion than the wild-type gp100 peptide, demonstrating that higher peptide binding affinity for HLA molecules does not necessarily equate to functional activity of CTL. Two major and one minor CTL recognition pattern were observed, irrespective of previous peptide immunization, suggesting that multiple, rationally designed modified tumor peptides for the same epitope stimulate a broad CTL response by activating multiple CTL capable of cross-reacting with the natural antigenic peptide. C1 Univ Arizona, Arizona Canc Ctr, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. Univ Arizona, Dept Biochem, Tucson, AZ 85724 USA. NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD USA. RP Lake, DF (reprint author), Univ Arizona, Arizona Canc Ctr, Dept Microbiol & Immunol, 1515 N Campbell Ave,Levy Bldg 4906, Tucson, AZ 85724 USA. FU NCI NIH HHS [CA94852]; NIAID NIH HHS [AI43480] NR 27 TC 14 Z9 14 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD APR PY 2003 VL 52 IS 4 BP 199 EP 206 DI 10.1007/s00262-002-0358-3 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA 675QH UT WOS:000182705700001 PM 12669244 ER PT J AU Recio, JA Merlino, G AF Recio, JA Merlino, G TI Hepatocyte growth factor/scatter factor induces feedback up-regulation of CD44v6 in melanoma cells through Egr-1 SO CANCER RESEARCH LA English DT Article ID FACTOR SCATTER FACTOR; HEPARAN-SULFATE PROTEOGLYCAN; RECEPTOR TYROSINE KINASE; C-MET; FIBROBLAST-GROWTH; IN-VIVO; SIGNAL-TRANSDUCTION; CARCINOMA-CELLS; BINDING DOMAINS; FACTOR ISOFORMS AB The hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met and variants of the CD44 family of surface adhesion molecules, including CD44v6, have been implicated in cancer progression and metastasis. CD44 isoforms bearing heparin sulfate chains can bind to HGF/SF and facilitate its presentation to c-Met. Here, we demonstrate that HGF/SF-Met binding up-regulates the expression of CD44v6 in murine melanoma cells, serving to compensate for loss by internalization. c-Met-mediated CD44v6 up-regulation was achieved through transcriptional activation of the immediate early gene egr-1. Enhanced egr-1 expression was apparent at the level of RNA 40 min after exposure to HGF/SF, and Egr-1 protein was detectable between 1 and 2 h post-treatment. CD44v6 RNA levels were correspondingly elevated 2 h after HGF/SF exposure. HGF/SF induced egr-1 activation via the Ras>Erk1/2 pathway but not through either phosphatidylinositol 3'-kinase or protein kinase C. Binding of NK2, a naturally occurring splice variant of HGF/SF, to c-Met failed to induce either Egr-1 or CD44v6, accounting at least in part for its antagonistic behavior. We also identified an Egr-1-binding site in the mouse CD44 gene promoter that accounts for its responsiveness to HGF/SF in melanoma cells. The compensatory up-regulation of both c-Met and CD44v6 in response to HGF/SF has important implications with respect to strategies used by cancer cells to sustain stimulation of growth- and metastasis-promoting pathways associated with tumor progression. C1 NCI, Mol Genet Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Merlino, G (reprint author), NCI, Mol Genet Sect, Mol Biol Lab, NIH, Bldg 37,Room 5002,37 Convent Dr,MSC 4263, Bethesda, MD 20892 USA. NR 85 TC 52 Z9 55 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2003 VL 63 IS 7 BP 1576 EP 1582 PG 7 WC Oncology SC Oncology GA 661NP UT WOS:000181896900022 PM 12670907 ER PT J AU Waki, T Tamura, G Sato, M Terashima, M Nishizuka, S Motoyama, T AF Waki, T Tamura, G Sato, M Terashima, M Nishizuka, S Motoyama, T TI Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia SO CANCER SCIENCE LA English DT Article ID CPG-ISLAND METHYLATION; DNA METHYLATION; MICROSATELLITE INSTABILITY; COLORECTAL-CANCER; CELL-LINES; E-CADHERIN; HYPERMETHYLATION; EXPRESSION; PHENOTYPE; HMLH1 AB Silencing of tumor suppressor and tumor-related genes by hypermethylation at promoter CpG islands is frequently found in human tumors, including gastric cancer. Promoter methylation is not restricted to cancer cells, and is also present in non-neoplastic cells as an age-related tissue-specific phenomenon. To clarify the physiological consequence of DAP-kinase and RUNX3 age-related methylation in gastric epithelia, we investigated the promoter methylation status of these genes in both neoplastic and nonneoplastic gastric epithelia obtained at autopsy and surgery, as well as in 10 gastric cancer cell lines. Methylation of DAP-kinase and RUNX3 was detected in 10% (1/10) and 70% (7/10) of the cell lines, respectively, and was almost concordant with their expression status. Among autopsy samples, methylation of these genes was not seen in non-neoplastic gastric epithelia from persons who were aged 22 years and below (0%; 0/4). DAP-kinase was methylated in 87% (13/15) of non-neoplastic gastric epithelia of persons who were aged 45 years or older, while RUNX3 methylation in non-neoplastic gastric epithelia was restricted to individuals who were aged 77 years or older. Among samples obtained from patients with stomach cancer, methylation was observed in both the neoplastic and the corresponding nonneoplastic gastric epithelia; 43% (40/93) and 73% (68/93) for DAP-kinase, and 45% (42/93) and 8% (7/93) for RUNX3, respectively. Frequencies of DAP-kinase and RUNX3 methylation differed significantly in non-neoplastic gastric epithelia (P<0.01), although those in gastric cancers were almost the same. RUNX3 methylation is mostly cancer-specific, except for very old individuals, and therefore may be a possible molecular diagnostic marker and malignancy predictor. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 9909585, Japan. Fukushima Med Univ, Dept Surg, Fukushima 9601295, Japan. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), Yamagata Univ, Sch Med, Dept Pathol, 2-2-2 Iida Nishi, Yamagata 9909585, Japan. NR 25 TC 85 Z9 99 U1 0 U2 1 PU JAPANESE CANCER ASSOC PI TOKYO PA C/O JAPANESE FOUNDATION CANCER RESEARCH,1-37-1, KAMI-IKEBUKURO, TOSHIMA-KU, TOKYO, 170-0012, JAPAN SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD APR PY 2003 VL 94 IS 4 BP 360 EP 364 DI 10.1111/j.1349-7006.2003.tb01447.x PG 5 WC Oncology SC Oncology GA 690FW UT WOS:000183537600009 PM 12824905 ER PT J AU Landi, MT Bertazzi, PA Baccarelli, A Consonni, D Masten, S Lucier, G Mocarelli, P Needham, L Caporaso, N Grassman, J AF Landi, MT Bertazzi, PA Baccarelli, A Consonni, D Masten, S Lucier, G Mocarelli, P Needham, L Caporaso, N Grassman, J TI TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident SO CARCINOGENESIS LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; SIGNAL-TRANSDUCTION PATHWAYS; MESSENGER-RNA EXPRESSION; SPRAGUE-DAWLEY RATS; LUNG-CANCER; CELL-CYCLE; RETINOBLASTOMA PROTEIN; TRANSCRIPTION FACTOR; CYTOCHROME-P450 1B1; HUMAN-LYMPHOCYTES AB Approximately 20 years after the Seveso, Italy, accident we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on cancer using mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are mediated by the aryl hydrocarbon receptor (AhR). We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking. To our knowledge, this is the most comprehensive investigation to date designed to evaluate the key genes in the pathway, including AhR, aryl hydrocarbon receptor nuclear translocator, CYP1A1 and CYP1B1 transcripts and CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity in a population heavily exposed to dioxin. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or p.p.t.) and were negatively associated with AhR mRNA in unstimulated peripheral blood mononuclear cells (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. In addition, there was a strong positive correlation between AhR and CYP1A1 expression (P = 0.001) and between AhR and CYP1B1 expression (P = 0.006). CYP1A1 expression was also strongly correlated with EROD activity (P = 0.001). The analysis of the expression of dioxin-inducible genes involved in carcinogenesis may help in determining dose-response relationships for human exposure to dioxin in vivo and in assessing the variability of human response, which may indicate the presence of subjects more susceptible to disease as a result of such exposures. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Univ Milan Bicocca, Hosp Desio, Dept Lab Med, Milan, Italy. Ctr Dis Control & Prevent, Ctr Environm Hlth, Atlanta, GA USA. CUNY Brooklyn Coll, Brooklyn, NY 11210 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Needham, Larry/E-4930-2011; masten, scott/R-1403-2016; bertazzi, pietro alberto/D-5039-2017; OI masten, scott/0000-0002-7847-181X; bertazzi, pietro alberto/0000-0003-3475-2449; Baccarelli, Andrea/0000-0002-3436-0640 NR 50 TC 35 Z9 37 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2003 VL 24 IS 4 BP 673 EP 680 DI 10.1093/carcin/bgg002 PG 8 WC Oncology SC Oncology GA 676HK UT WOS:000182745100007 PM 12727795 ER PT J AU Iida, M Anna, CH Hartis, J Bruno, M Wetmore, B Dubin, JR Sieber, S Bennett, L Cunningham, ML Paules, RS Tomer, KB Houle, CD Merrick, AB Sills, RC Devereux, TR AF Iida, M Anna, CH Hartis, J Bruno, M Wetmore, B Dubin, JR Sieber, S Bennett, L Cunningham, ML Paules, RS Tomer, KB Houle, CD Merrick, AB Sills, RC Devereux, TR TI Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643 SO CARCINOGENESIS LA English DT Review ID PEROXISOME PROLIFERATOR WY-14,643; NF-KAPPA-B; HUMAN HEPATOCELLULAR-CARCINOMA; UNSCHEDULED DNA-SYNTHESIS; POLYMERASE CHAIN-REACTION; ACTIVATED RECEPTOR-ALPHA; B6C3F1 MICE; RAT-LIVER; CDNA MICROARRAYS; BETA-CATENIN AB We hypothesized that the mouse liver tumor response to non-genotoxic carcinogens would involve some common early gene and protein expression changes that could ultimately be used to predict chemical hepatocarcinogenesis. In order to identify a panel of genes to test, we analyzed global differences in gene and protein expression in livers from B6C3F1 mice following dietary treatment with two rodent carcinogens, the benzodiazepine anti-anxiety drug oxazepam (2500 p.p.m.) and the hypolipidemic agent Wyeth (Wy)-14,643 (500 p.p.m.) compared with livers from untreated mice. Male mice were exposed for 2 weeks and 1, 3 or 6 months to oxazepam or Wy-14,643 in an age-matched study design. By histopathological evaluation, no liver preneoplastic foci or tumors were detected at 6 months in treated or control groups. By cDNA microarray analysis [NIEHS Mouse Chip (8700 genes); n = 3 individual livers/group, four hybridizations/sample], expression of 36 genes or 220 genes were changed relative to control livers following 6 months of oxazepam or Wy-14,643 treatment, respectively. To obtain a more comprehensive picture of gene/protein expression changes, we also conducted a proteomics study by 2D-gel electrophoresis followed by matrix assisted laser desorption/ionization-mass spectrometry on cytoplasmic, nuclear, and microsomal subcellular fractions of the same liver samples utilized for the cDNA microarray analysis. Real-time PCR, western blot analysis and immunohistochemistry were utilized for validation and to expand the results to other time points. Cyp2b20, growth arrest- and damage-inducible gene beta (Gadd45beta), tumor necrosis factor alpha-induced protein 2 and insulin-like growth factor binding protein 1 (Igfbp5) genes and proteins were upregulated by oxazepam, and Cyp2b20, Cyclin D1, proliferating cell nuclear antigen, Igfbp5, Gadd45beta and cell death-inducing DNA fragmentation factor alpha subunit-like effector A exhibited higher expression after Wy-14,643 treatment. Most of these genes/proteins were also deregulated at 2 weeks. There appeared to be more distinct than common changes in the expression of carcinogenesis-related genes/proteins between the two compounds, suggesting that the major carcinogenic pathways are different for these compounds and may be distinct for different chemical classes. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Ctr Toxicogenom, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Expt Pathol Labs Inc, Res Triangle Pk, NC 27709 USA. RP Devereux, TR (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 101 TC 35 Z9 36 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2003 VL 24 IS 4 BP 757 EP 770 DI 10.1093/carcin/bgg011 PG 14 WC Oncology SC Oncology GA 676HK UT WOS:000182745100017 PM 12727805 ER PT J AU Baler, R AF Baler, R TI The circadian E-Box SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article; Proceedings Paper CT 17th National Meeting of the Argentine-Society-for-Neurochemistry CY OCT 23-25, 2002 CL CORDOBA, ARGENTINA SP Argentine Soc Neurochem C1 NIH, Bethesda, MD 20892 USA. RP Baler, R (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD APR PY 2003 VL 23 IS 2 BP 224 EP 224 PG 1 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 659AV UT WOS:000181755000012 ER PT J AU Dreher, JC Grafman, J AF Dreher, JC Grafman, J TI Dissociating the roles of the rostral anterior cingulate and the lateral prefrontal cortices in performing two tasks simultaneously or successively SO CEREBRAL CORTEX LA English DT Article ID EVENT-RELATED FMRI; POSITRON EMISSION TOMOGRAPHY; POSTERIOR PARIETAL CORTEX; BASE-LINE CONDITIONS; COGNITIVE CONTROL; WORKING-MEMORY; EXECUTIVE PROCESSES; NEURAL BASIS; SELECTIVE ATTENTION; VISUAL-ATTENTION AB A fundamental question about the nature of cognitive control is whether performing two tasks successively or simultaneously activates distinct brain regions. To investigate this question, we designed a functional magnetic resonance imaging (fMRI) study that compared task-switching and dual-task performance. The results showed that performing two tasks successively or simultaneously activated a common prefronto-parietal neural network relative to performing each task separately. More importantly, we found that the anterior cingulate and the lateral prefrontal cortices were differently activated in dual-task and task-switching situations. When performing two tasks simultaneously, as compared to performing them in succession, activation was found in the rostral anterior cingulate cortex. In contrast, switching between two tasks, relative to performing them simultaneously, activated the left lateral prefrontal cortex and the bilateral intra-parietal sulcus region. We interpret these results as indicating that the rostral anterior cingulate cortex serves to resolve conflicts between stimulus-response associations when performing two tasks simultaneously, while the lateral prefrontal cortex dynamically selects the neural pathways needed to perform a given task during task switching. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457 NR 75 TC 105 Z9 106 U1 4 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2003 VL 13 IS 4 BP 329 EP 339 DI 10.1093/cercor/13.4.329 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 660KK UT WOS:000181832200001 PM 12631562 ER PT J AU van Turennout, M Bielamowicz, L Martin, A AF van Turennout, M Bielamowicz, L Martin, A TI Modulation of neural activity during object naming: Effects of time and practice SO CEREBRAL CORTEX LA English DT Article ID INFERIOR PREFRONTAL CORTEX; EVENT-RELATED FMRI; FUNCTIONAL MRI; RECOGNITION MEMORY; TEMPORAL CORTEX; WORD GENERATION; HUMAN BRAIN; REPETITION; MECHANISMS; SPECIFICITY AB Repeated exposure to objects improves our ability to identify and name them, even after a long delay. Previous brain imaging studies have demonstrated that this experience-related. facilitation of object naming is associated with neural changes in distinct brain regions. We used event-related functional magnetic resonance imaging (fMRI) to examine the modulation of neural activity in the object naming system as a function of experience and time. Pictures of common objects were presented repeatedly for naming at different time intervals (1 h, 6 h and 3 days) before scanning, or at 30 s intervals during scanning. The results revealed that as objects became more familiar with experience, activity in occipitotemporal and left inferior frontal regions decreased while activity in the left insula and basal ganglia increased. In posterior regions, reductions in activity as a result of multiple repetitions did not interact with time, whereas in left inferior frontal cortex larger decreases were observed when repetitions were spaced out over time. This differential modulation of activity in distinct brain regions provides support for the idea that long-lasting object priming is mediated by two neural mechanisms. The first mechanism may involve changes in object-specific representations in occipitotemporal cortices, the second may be a form of procedural learning involving a reorganization in brain circuitry that leads to more efficient name retrieval. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP van Turennout, M (reprint author), FC Donders Ctr Cognit Neuroimaging, POB 9101, NL-6500 HB Nijmegen, Netherlands. RI martin, alex/B-6176-2009 NR 48 TC 89 Z9 91 U1 2 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2003 VL 13 IS 4 BP 381 EP 391 DI 10.1093/cercor/13.4.381 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 660KK UT WOS:000181832200006 PM 12631567 ER PT J AU Singleton, A AF Singleton, A TI Familiality in simple and complex disease SO CLINICAL AUTONOMIC RESEARCH LA English DT Review DE genetics; complex disease; familiality AB Establishing the existence of a genetic contribution to disease is the first step in identifying the underlying gene defect(s). This can present a considerable challenge, particularly in diseases where the genetic contribution is complex in nature. Clinically well-characterized cohorts and large inter-institutional collaborations will be required to identify genes involved in complex disease. C1 NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Singleton, A (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bldg 10,Room 6C103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009 NR 5 TC 1 Z9 1 U1 0 U2 1 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD APR PY 2003 VL 13 IS 2 BP 88 EP 90 DI 10.1007/s10286-003-0091-9 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 683WK UT WOS:000183173900003 PM 12720091 ER PT J AU Sausville, EA AF Sausville, EA TI Is another Bcr-Abl inhibitor needed for chronic myelogenous leukemia? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; IMATINIB MESYLATE; IN-VITRO; RESISTANCE; STI-571; STI571; CELLS; AMPLIFICATION; PATIENT C1 NCI, Dev Therapeut Program, Rockville, MD 20852 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, 6130 Execut Blvd,Room 8018, Rockville, MD 20852 USA. NR 18 TC 1 Z9 1 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 APR PY 2003 VL 9 IS 4 BP 1233 EP 1234 PG 2 WC Oncology SC Oncology GA 664NP UT WOS:000182067400003 PM 12684388 ER PT J AU Brewer, HB AF Brewer, HB TI New features of the National Cholesterol Education Program Adult Treatment Panel III lipid-lowering guidelines SO CLINICAL CARDIOLOGY LA English DT Article; Proceedings Paper CT Symposium on Reaching Goal - Conquering the Treatment Gaps in Dyslipidemia Management CY MAR, 2002 CL ATLANTA, GEORGIA DE statins; low-density lipoprotein cholesterol; hypercholesterolemia; Adult Treatment Panel III ID CORONARY HEART-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; MYOCARDIAL-INFARCTION; PRIMARY PREVENTION; MEN; PRAVASTATIN; MORTALITY; EVENTS; RISK AB The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for lipid-lowering therapy to reduce coronary heart disease (CHD) risk contain a number of features that distinguish them from the previous ATP guidelines. These new features include modifications in lipid/lipoprotein levels considered optimal, abnormal, or reflective of risk; increased focus on primary prevention through use of Framingham risk scoring to define risk in persons with multiple lipid/nonlipid risk factors; and increased focus on the association of the metabolic syndrome with CHD risk. The introduction of the category of CHD risk equivalents-including persons with atherosclerotic disease, diabetes, or 10-year CHD risk > 20% based on Framingham scoring-results in an increase over previous guidelines in the proportion of patients categorized as being at high risk and therefore eligible for more intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Use of the new secondary therapeutic target of non-high-density lipoprotein cholesterol should improve management of lipid risk factors in patients who have elevated triglyceride levels after LDL-C goals have been met. These new features of the NCEP ATP III guidelines should improve identification and treatment of patients with dyslipidemias associated with CHD risk. 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 15 TC 14 Z9 16 U1 0 U2 0 PU CLINICAL CARDIOLOGY PUBL CO PI MAHWAH PA PO BOX 832, MAHWAH, NJ 07430-0832 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD APR PY 2003 VL 26 IS 4 SU 3 BP 19 EP 24 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 663DW UT WOS:000181991800004 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Mass spectrometry-based diagnostics: The upcoming revolution in disease detection SO CLINICAL CHEMISTRY LA English DT Editorial Material ID BIOMARKER DISCOVERY; PROTEOMIC PATTERNS; PROSTATE-CANCER; PROTEIN; SERUM C1 NCI, US FDA, Clin Proteom Program, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, US FDA, Clin Proteom Program, Lab Pathol,Ctr Canc Res, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), NCI, US FDA, Clin Proteom Program, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NR 20 TC 71 Z9 73 U1 0 U2 5 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD APR PY 2003 VL 49 IS 4 BP 533 EP 534 DI 10.1373/49.4.533 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 660DK UT WOS:000181818400001 PM 12651801 ER PT J AU Artz, AS Ershler, WB Longo, DL AF Artz, AS Ershler, WB Longo, DL TI Pneumococcal vaccination and revaccination of older adults SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID COMMUNITY-ACQUIRED PNEUMONIA; INFLUENZAE TYPE-B; CAPSULAR POLYSACCHARIDE VACCINE; RESISTANT STREPTOCOCCUS-PNEUMONIAE; IMPAIRED ANTIBODY-RESPONSES; LINKED-IMMUNOSORBENT-ASSAY; CELL-WALL POLYSACCHARIDE; VIRUS-INFECTED SUBJECTS; CONJUGATE VACCINE; ELDERLY PATIENTS AB As individuals advance in age, the risk of infection, bacteremia, and mortality caused by Streptococcus pneumoniae rises. Retrospective data demonstrate that the licensed penumococcal polysaccharide vaccine (PPV) is effective in older persons in reducing serotype-specific invasive disease. PPV demonstrates good immunogenicity in older adults, generally comparable to that in younger subjects, although certain cohorts respond less well. The response to PPV is T cell independent, however, and does not elicit immunologic memory. The duration of the anti-capsular polysaccharide antibody response appears to wane as early as 3 years after vaccination. In older persons, revaccination induces an antibody response, although it may not be as strong as that from the initial vaccine. While revaccination of older adults has been recommended, clinical efficacy has not yet been proven. Measures of antibody function may be at least as important in determining protection as are quantitative antibody levels. Additional studies of immunogenicity, particularly regarding revaccination, will facilitate the design of an optimal pneumocoeeal vaccination policy. Research into conjugate- and protein-based pneumococcal vaccines, which elicit T-cell-dependent responses and induce immunologic memory, is needed in older persons. In the meantime, administering to PPV to recommended groups should be a public health priority. C1 Univ Chicago Hosp, Chicago, IL 60657 USA. Inst Adv Studies Aging & Geriatr Med, Washington, DC USA. NIA, Baltimore, MD 21224 USA. RP Artz, AS (reprint author), Univ Chicago Hosp, 5841 S Maryland Ave,MC 2115, Chicago, IL 60657 USA. NR 151 TC 94 Z9 98 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD APR PY 2003 VL 16 IS 2 BP 308 EP + DI 10.1128/CMR.16.2.308-318.2003 PG 12 WC Microbiology SC Microbiology GA 668QX UT WOS:000182305600009 PM 12692100 ER PT J AU Rolan, P Atkinson, AJ Lesko, LJ AF Rolan, P Atkinson, AJ Lesko, LJ CA Sci Organizing Comm Conf Report Co TI Use of biomarkers from drug discovery through clinical practice: Report of the Ninth European Federation of Pharmaceutical Sciences Conference on Optimizing Drug Development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID SURROGATE END-POINTS; MORTALITY AB The Ninth European Federation for Pharmaceutical Sciences (EUFEPS) Conference on Optimizing Drug Development was held in Basel, Switzerland, December 10-12, 2001. The overall objective of the conference was to find new ways of advancing the integration of biomarkers into drug development and clinical practice to make drug development more efficient and the clinical use of drugs more effective. The aim of this conference report is to summarize the key ideas and recommendations that were identified at the meeting, both by formal presentation and from the breakout sessions, which all participants were encouraged to join. Rather than providing a synopsis of each individual presentation, the report is organized along the key themes that emerged during the meeting. C1 Medeval Ltd, Manchester M15 6SH, Lancs, England. NIH, Ctr Clin, Bethesda, MD 20892 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Rolan, P (reprint author), Medeval Ltd, Manchester Sci Pk, Manchester M15 6SH, Lancs, England. NR 22 TC 57 Z9 59 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD APR PY 2003 VL 73 IS 4 BP 284 EP 291 DI 10.1016/S0009-9236(02)00025-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 666LM UT WOS:000182178800003 PM 12709718 ER PT J AU McDonald, MD Grosell, M Wood, CM Walsh, PJ AF McDonald, MD Grosell, M Wood, CM Walsh, PJ TI Branchial and renal handling of urea in the gulf toadfish, Opsanus beta: the effect of exogenous urea loading SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY LA English DT Article DE gills; gulf toadfish; kidney; Opsanus beta; transport kinetics; urea; urea infusion; urea transport protein (tUT) ID MEDULLARY COLLECTING DUCTS; WATER RAINBOW-TROUT; URINARY-BLADDER; BUFO-VIRIDIS; BASOLATERAL MEMBRANE; ALKALINE ENVIRONMENT; SALT ACCLIMATION; TRANSPORT; EXCRETION; SKIN AB The objective of this study was to determine whether the pulsatile facilitated diffusion transport mechanism (tUT) found in the gills of the gulf toadfish (Opsanus beta) and the active secretion transporter thought to be present in its kidney could be saturated when faced with elevated plasma urea concentrations. Toadfish were infused with four consecutive exogenous urea loads at a rate of 0, 150, 300 and 600 p,mol kg(-1) h(-1). Initial plasma and urine urea concentrations were 8.1+/-0.9 and 12.4+/-1.5 mmol l(-1), respectively, and steadily increased with increasing infused loads of urea to a maximum of 36.8+/-2.8 mmol l(-1) in the plasma and 39.8+/-6.5 mmol l(-1) in the urine. There was only a very weak relationship (r=0.17) between pulse size (measured as branchial excretion during pulsatile excretion of urea) and plasma urea concentration (slope=9.79 mumol-N kg(-1) per mmol-N l(-1); P<0.05) suggesting that the branchial excretion mechanism was already saturated at normal plasma urea concentrations. Urine flow rate (0.15+/-0.03 ml kg(-1) h(-1)) and glomerular filtration rate (0.025+/-0.004 ml kg(-1) h(-1)) remained constant throughout the experiment despite the increased volume load. Renal urea secretion rate maintained a strong linear relationship (r=0.84) to plasma urea levels (slope = 0.391 μmol-N kg(-1) h(-1) per mmol-N l(-1); P<0.001) with no observable transport maximum, suggesting that the renal secretory transport mechanism was not saturated even at plasma urea levels well above normal, in contrast to the branchial excretion mechanism. (C) 2003 Elsevier Science Inc. All rights reserved. C1 McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP McDonald, MD (reprint author), McMaster Univ, Dept Biol, 1280 Main St W, Hamilton, ON L8S 4K1, Canada. NR 50 TC 32 Z9 32 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1095-6433 J9 COMP BIOCHEM PHYS A JI Comp. Biochem. Physiol. A-Mol. Integr. Physiol. PD APR PY 2003 VL 134 IS 4 BP 763 EP 776 DI 10.1016/S1095-6433(03)00010-2 PG 14 WC Biochemistry & Molecular Biology; Physiology; Zoology SC Biochemistry & Molecular Biology; Physiology; Zoology GA 666MA UT WOS:000182180000009 PM 12814785 ER PT J AU Thompson, ED Mayer, GD Balesaria, S Glover, CN Walsh, PJ Hogstrand, C AF Thompson, ED Mayer, GD Balesaria, S Glover, CN Walsh, PJ Hogstrand, C TI Physiology and endocrinology of zinc accumulation during the female squirrelfish reproductive cycle SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY LA English DT Article DE squirrelfish; fish; reproduction; liver; ovary; zinc; metallothionein (MT); sex steroids; 17 beta-estradiol (E-2); vitellogenin (VTG) ID METALLOTHIONEIN; PROTEIN; CELLS; VITELLOGENIN; EXPRESSION; BINDING; LIVER; GENE AB Females of the squirrelfish family (Holocentridae) accumulate higher levels of hepatic zinc than any other studied animal. This accumulation is accompanied by high expression of the zinc-binding protein, metallothionein (MT), and is strongly correlated to the onset of sexual maturity. In an attempt to further characterize the timeframe of this accumulation, and to possibly discern any potential mediators, we examined the physiology and endocrinology of the yearly reproductive cycle of mature female squirrelfish. There are two separate reproductive events during the year in December-January and again in March-April, as evidenced by peaks in ovarian growth, VTG production, steroid levels, zinc accumulation and redistribution. Increased hepatic zinc seems to be preceded by a necessary increase in MT, but this was not clearly correlated to plasma 17beta-estradiol, testosterone, or progesterone levels. The plasma zinc protein vitellogenin (VTG) is one, but probably not the predominant, vehicle for the transport of hepatic zinc to the ovary. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Univ Kentucky, TH Morgan Sch Biol Sci, Lexington, KY 40506 USA. Kings Coll London, Sch Life & Hlth Sci, London SE1 9NN, England. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS, Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Univ Kentucky, TH Morgan Sch Biol Sci, 101 Morgan Bldg, Lexington, KY 40506 USA. EM edthom0@uky.edu RI Mayer, Gregory/K-4496-2012; Hogstrand, Christer/C-9041-2013; Mayer, Gregory/A-8459-2017; OI Mayer, Gregory/0000-0002-2652-9856; Mayer, Gregory/0000-0002-2652-9856; Glover, Chris/0000-0001-9170-5759 FU NIEHS NIH HHS [P30 ES 05705] NR 28 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1095-6433 EI 1531-4332 J9 COMP BIOCHEM PHYS A JI Comp. Biochem. Physiol. A-Mol. Integr. Physiol. PD APR PY 2003 VL 134 IS 4 BP 819 EP 828 DI 10.1016/S1095-6433(03)00015-1 PG 10 WC Biochemistry & Molecular Biology; Physiology; Zoology SC Biochemistry & Molecular Biology; Physiology; Zoology GA 666MA UT WOS:000182180000014 PM 12814790 ER PT J AU Crawley, JN AF Crawley, JN TI Behavioral phenotyping of rodents SO COMPARATIVE MEDICINE LA English DT Article ID INBRED MOUSE STRAINS; TRANSGENIC MICE; KNOCKOUT MICE; MUTANT MICE; TESTS; PROFILES; DISEASE; MEMORY; GENE; RECOMMENDATIONS AB Established methods for analyzing behavioral traits in mutant lines of mice allow researchers to understand the outcomes of genetic manipulations in the nervous system. A rigorous six-tiered behavioral phenotyping strategy is described. Recommendations are offered for the design of mouse behavioral testing suites in animal housing facilities. C1 NIMH, Intramural Res Program, Sect Behav Genomics, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Intramural Res Program, Sect Behav Genomics, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 62 TC 50 Z9 51 U1 1 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD APR PY 2003 VL 53 IS 2 BP 140 EP 146 PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 678RH UT WOS:000182879900007 PM 12784847 ER PT J AU Shipp, AC Patterson, AP AF Shipp, AC Patterson, AP TI The National Institutes of Health system for enhancing the science, safety, and ethics of recombinant DNA research SO COMPARATIVE MEDICINE LA English DT Article ID MOLECULES AB Oversight of recombinant DNA research by the National Institutes of Health (NIH) is predicated on ethical and scientific responsibilities that are akin, in many ways, to those that pertain to the oversight of animal research. The NIH system of oversight, which originated more than 25 years ago, is managed by the NIH Office of Biotechnology Activities (OBA), which uses various tools to fulfill its oversight responsibilities. These tools include the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) and the Recombinant DNA Advisory Committee. The OBA also undertakes special initiatives to promote the analysis and dissemination of information key to our understanding of recombinant DNA, and in particular, human gene transfer research. These initiatives include a new query-capable database, an analytical board of scientific and medical experts, and conferences and symposia on timely scientific, safety, and policy issues. Veterinary scientists can play an important role in the oversight of recombinant DNA research and in enhancing our understanding of the many safety and scientific dimensions of the field. These roles include developing appropriate animal models, reporting key safety data, enhancing institutional biosafety review, and promoting compliance with the NIH Guidelines. C1 NIH, Off Biotechnol Activ, Bethesda, MD 20892 USA. RP Shipp, AC (reprint author), NIH, Off Biotechnol Activ, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD APR PY 2003 VL 53 IS 2 BP 159 EP 164 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 678RH UT WOS:000182879900009 PM 12784849 ER PT J AU Berger, VW Rezvani, A Makarewicz, VA AF Berger, VW Rezvani, A Makarewicz, VA TI Direct effect on validity of response run-in selection in clinical trials SO CONTROLLED CLINICAL TRIALS LA English DT Article DE clinical relevance; inference discrepancy; inference population; target population ID TO-TREAT ANALYSIS; DOUBLE-BLIND; PLACEBO; FLUOXETINE; EFFICIENCY; PERIOD AB A run-in is a period prior to randomization during which potential participants who have met all entry criteria for a randomized clinical trial are assigned the same regimen, either the control (possibly placebo) or the experimental treatment. Typically, the intention is to exclude from the subsequent study (i.e., randomization) some segment of this cohort, based on their experiences during the run-in period. Selecting patients based on the run-in thereby forces differential representation of certain subpopulations relative to others. Previous studies have addressed the potential for a run-in to jeopardize validity through unintended mechanisms. While these concerns are valid, they leave open the possibility that modifications to the design of the run-in might be able to preserve validity, even if patient selection is based on the results of the run-in. As such, we address the potential for selecting patients based on response during a run-in period to jeopardize validity directly, through its intended effect of overrepresenting (relative to the screened population) some segments in the randomized portion of the trial and underrepresenting others. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NCI, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Washington Coll State Maryland, Chestertown, MD USA. Johns Hopkins Univ, Baltimore, MD USA. RP Berger, VW (reprint author), NCI, EPN 3131,6130 Execut Blvd,MSC-7354, Bethesda, MD 20892 USA. NR 39 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD APR PY 2003 VL 24 IS 2 BP 156 EP 166 DI 10.1016/S0197-2456(02)00316-1 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 661PP UT WOS:000181899200005 PM 12689737 ER PT J AU Bautista, OM Kusek, JW Nyberg, LM McConnell, JD Bain, RP Miller, G Crawford, ED Kaplan, SA Sihelnik, SA Brawer, MK Lepor, H AF Bautista, OM Kusek, JW Nyberg, LM McConnell, JD Bain, RP Miller, G Crawford, ED Kaplan, SA Sihelnik, SA Brawer, MK Lepor, H CA MTOPS Res Grp TI Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE clinical trials; benign prostatic hyperplasia; medical therapy; BPH progression ID TRANS-URETHRAL PROSTATECTOMY; LONGITUDINAL DATA; HYPERPLASIA; FINASTERIDE; TERAZOSIN; EFFICACY; MEN; REGRESSION; MODELS; SAFETY AB Alpha-blockers and 5-alpha-reductase inhibitors are medical therapies that are being used as alternatives to surgical interventions to relieve symptoms of benign prostatic hyperplasia (BPH). Taken as monotherapy, alpha-blockers and 5-alpha-reductase inhibitors have each been shown to provide relief from BPH symptoms. Treatment with finasteride over 4 years has been shown to reduce both BPH symptoms and the likelihood of acute urinary retention and the need for surgery. Direct comparison of the alpha-blocker terazosin with finasteride has been done, but only for a period of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) trial is a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to evaluate the long-term efficacy of the alpha-blocker doxazosin and the 5-alpha-reductase inhibitor finasteride, whether taken as a monotherapy or in combination, in preventing or delaying the progression of BPH. We describe in this paper the design of the MTOPS trial, the concept of BPH progression, the definition and methods of determining the primary outcome events and the proposed statistical analysis methods. A unique feature of MTOPS is the inclusion of prostate biopsies on a subgroup of randomized participants. Volunteers among randomized participants are to undergo a biopsy of the prostate at predetermined time points during the trial. Studies that will be conducted using the tissue specimens collected in MTOPS can potentially provide information at the molecular level on the natural history of BPH among medically treated and untreated men with moderate to severe symptoms of BPH. (C) 2003 Elsevier Science Inc. All rights reserved. C1 George Washington Univ, Biostat Ctr, Rockville, MD 20852 USA. NIDDKD, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Merck Res Labs, Blue Bell, PA USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. New York Presbyterian Hosp, New York, NY USA. Ctr Urol Care Berks Cty, W Reading, PA USA. NW Prostate Inst, Seattle, WA USA. NYU, Sch Med, New York, NY USA. RP Bautista, OM (reprint author), George Washington Univ, Biostat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. NR 57 TC 47 Z9 51 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD APR PY 2003 VL 24 IS 2 BP 224 EP 243 AR PII S0197-2456(02)00263-5 DI 10.1016/S0197-2456(02)00263-5 PG 20 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 661PP UT WOS:000181899200011 PM 12689743 ER PT J AU Chariot, A Meuwis, MA Bonif, M Leonardi, A Merville, MP Gielen, J Piette, J Siebenlist, U Bours, V AF Chariot, A Meuwis, MA Bonif, M Leonardi, A Merville, MP Gielen, J Piette, J Siebenlist, U Bours, V TI NF-kappa B activating scaffold proteins as signaling molecules and putative therapeutic targets SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE NF-kappa B; scaffold proteins; IKK; NEMO/IKK gamma; genetic diseases; cancer; inflammation ID RECEPTOR-ASSOCIATED FACTOR-2; X-LINKED DISORDER; IL-1 RECEPTOR; INTERLEUKIN-1 RECEPTOR; INCONTINENTIA PIGMENTI; ECTODERMAL DYSPLASIA; GENE-EXPRESSION; BINDING-PROTEIN; TNF RECEPTOR; TRANSDUCTION PATHWAY AB Activation of transcription factors such as NF-kappaB occurs through signaling pathways involving sequential phosphorylation of a variety of substrates by distinct kinases. Proper assemby and activation of these kinases require interaction with non-enzymatic and essential partners named scaffold proteins. Here, we describe how the NF-kappaB activating scaffold proteins involved in the signaling pathways triggered by the proinflammatory cytokines TNFalpha, IL-1beta and by the CD40 ligand play such roles. We also illustrate the human genetic diseases that are linked to mutations affecting genes coding for these proteins. We suggest that these scaffold proteins may be specifically targeted by novel therapeutical agents for the treatment of inflammation or cancers. C1 CHU Sart Tilman, Lab Med Chem & Human Genet, B-4000 Liege, Belgium. CHU Sart Tilman, Ctr Cellular & Mol Therapy, Lab Virol & Immunol, B-4000 Liege, Belgium. Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol, Naples, Italy. CNR, Ist Endocrinol & Oncol Sperimentale, I-00185 Rome, Italy. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chariot, A (reprint author), CHU Sart Tilman, Med Chem Lab, CTCM, 3 B23, B-4000 Liege, Belgium. NR 84 TC 13 Z9 14 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD APR PY 2003 VL 10 IS 7 BP 593 EP 602 DI 10.2174/0929867033457926 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 653GR UT WOS:000181427300003 PM 12678791 ER PT J AU Finkel, T AF Finkel, T TI Oxidant signals and oxidative stress SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID TRANSCRIPTION FACTOR FOXO3A; PROTEIN-KINASE ACTIVATION; N-TERMINAL KINASE; HYDROGEN-PEROXIDE; C-MYC; INDUCED APOPTOSIS; REDOX REGULATION; S-NITROSYLATION; ACTIVE-SITE; IN-VIVO AB Although oxidants clearly possess the capacity to behave in a random and destructive fashion, growing evidence suggests that in many instances the production of reactive oxygen species is tightly regulated and their downstream targets exquisitely specific. This past year, several notable advances have been made in defining the specific redox-dependent targets of intracellular oxidants, as well as the myriad pathways that appear to employ oxidants as effector molecules. These new studies have significantly altered our understanding of how reactive oxygen species participate in diverse processes from tumourigenesis to ageing. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiovasc Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 54 TC 861 Z9 903 U1 9 U2 65 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD APR PY 2003 VL 15 IS 2 BP 247 EP 254 DI 10.1016/S095500674(03)00002-4 PG 8 WC Cell Biology SC Cell Biology GA 666NL UT WOS:000182183300017 PM 12648682 ER PT J AU Gong, M Rong, YS AF Gong, M Rong, YS TI Targeting multi-cellular organisms SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; NUCLEAR TRANSFER; MOUSE EMBRYOS; GENE KNOCKOUT; STEM-CELLS; MUTATIONS; REPAIR; LINES AB For many years, biologists' efforts in achieving gene targeting by homologous recombination in multicellular organisms have been hampered by the difficulty in culturing pluripotent stem cells. Recent advances have eliminated this requirement for several animal species. For large mammals, cloning by nuclear transfer has led to the first knockout sheep and pigs. For Drosophila, whole organism gene targeting was accomplished by a method for the generation of linear DNA in vivo. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rong, YS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bldg 37,Rm 6056D, Bethesda, MD 20892 USA. RI rong, yikang/G-6179-2011 NR 29 TC 16 Z9 19 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2003 VL 13 IS 2 BP 215 EP 220 DI 10.1016/S0959-437X(03)00018-2 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 666ND UT WOS:000182182600016 PM 12672500 ER PT J AU Love, PE Chan, AC AF Love, PE Chan, AC TI Regulation of thymocyte development: only the meek survive SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID T-CELL DEVELOPMENT; IMMATURE CD4(+)CD8(+) THYMOCYTES; NF-KAPPA-B; NEGATIVE SELECTION; C-CBL; POSITIVE SELECTION; IN-VIVO; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; THYMIC SELECTION AB T cell antigen receptor-induced signals are required for normal T cell development and function. Recent studies have investigated the mechanism(s) by which signals of different strengths are converted into distinct cellular fates during thymocyte development. These studies indicate the importance of the strength and duration of signals activated through PLC and PKC pathways in shaping the mature TCR repertoire. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. EM pel@helix.nih.gov; acc@gene.com NR 49 TC 19 Z9 19 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2003 VL 15 IS 2 BP 199 EP 203 DI 10.1016/S0952-7915(03)00002-5 PG 5 WC Immunology SC Immunology GA 657XL UT WOS:000181691600011 PM 12633670 ER PT J AU Masse, E Majdalani, N Gottesman, S AF Masse, E Majdalani, N Gottesman, S TI Regulatory roles for small RNAs in bacteria SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID BINDING PROTEIN CSRA; OMPA MESSENGER-RNA; SM-LIKE PROTEIN; ESCHERICHIA-COLI; HOST FACTOR; COMPARATIVE GENOMICS; RIBOSOME BINDING; IRON-METABOLISM; GENE-EXPRESSION; NONCODING RNAS AB Small RNAs can act to regulate both the synthesis of proteins, by affecting mRNA transcription, translation and stability, and the activity of specific proteins by binding to them. As a result of recent genome-wide screens, around 50 small RNAs have now been identified in Escherichia coli. These include many that require the RNA-binding protein Hfq for their activity; most of these RNAs act by pairing with their target mRNAs. Small RNAs can both positively and negatively regulate translation, can simultaneously regulate multiple mRNA targets, and can change the pattern of polarity within an operon. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. NR 56 TC 97 Z9 105 U1 1 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD APR PY 2003 VL 6 IS 2 BP 120 EP 124 DI 10.1016/S1369-5274(03)00027-4 PG 5 WC Microbiology SC Microbiology GA 679KZ UT WOS:000182922400006 PM 12732300 ER PT J AU Callicott, JH AF Callicott, JH TI An expanded role for functional neuroimaging in schizophrenia SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID WORKING-MEMORY; PREFRONTAL CORTEX; VENTRICULAR SIZE; FMRI; DYSFUNCTION; ACTIVATION; MECHANISM; DEFICITS; MRI AB Functional magnetic resonance imaging is a surprisingly versatile tool in the quest for disentangling the complexities of mental illnesses such as schizophrenia. Yet, the identification of pathognomonic physiological features of the illness or even a consensus regarding the interpretation of reported findings remain unfulfilled goals, in spite of the increasing sophistication of this technology. Nonetheless, by providing quantification of brain function during various cognitive challenges, functional MRI has been used to leap ahead of these quandaries to identify relationships between genetic variation and brain function. By examining recent findings and efforts to link these findings to genes, this article will review these exciting developments in schizophrenia research. C1 NIMH, Clin Brain Disorders Branch, Unit Funct MRI, Bethesda, MD 20892 USA. RP Callicott, JH (reprint author), NIMH, Clin Brain Disorders Branch, Unit Funct MRI, Bldg 10,Room 4D-20,MSC 1389, Bethesda, MD 20892 USA. RI Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 29 TC 22 Z9 24 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2003 VL 13 IS 2 BP 256 EP 260 DI 10.1016/S0959-4388(03)00041-2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 682LG UT WOS:000183092700018 PM 12744982 ER PT J AU Chen, WJ Wahl, SM AF Chen, WJ Wahl, SM TI TGF-beta: the missing link in CD4(+)CD25(+) regulatory T cell-mediated immunosuppression SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE suppressor cells; autoimmune diseases; tolerance; Smad; TGF-beta receptor type II ID GROWTH-FACTOR-BETA; IMMUNOLOGICAL SELF-TOLERANCE; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; IN-VITRO; ACTIVATION; MICE; EXPRESSION; PHENOTYPE; RECEPTOR; IL-4 AB A unique population of CD4(+) T lymphocytes that constitutively express CD25 has been recognized as anergic/suppressor cells. While the immunosuppressive activity of these CD4(+)CD25(+) cells has been validated and implicated in tolerance, autoimmunity, transplantation, cancer and infectious diseases, the mechanism(s) by which they function still remains controversial. Although the involvement of TGF-beta was initially discounted, emerging evidence now links this cytokine with CD4(+)CD25(+) T cell-mediated suppression of antigen-activated T cells. In this perspective, we summarize recently published studies, as well as our own data, which shed light on how cell membrane-bound TGF-beta can deliver a regulatory signal to target cells via a contact-dependent process. Moreover, suppressor T cell function is a complex process, tightly regulated by multiple factors, including IL-2, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and glucocorticoid induced TNF receptor (GITR). Collectively, multiple previously unconnected puzzle pieces are beginning to be linked into a more coherent, albeit incomplete picture of CD4(+)CD25(+) T cell-mediated suppression. Published by Elsevier Science Ltd. C1 NIDCR, Cellular Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), NIDCR, Cellular Immunol Sect, Oral Infect & Immun Branch, NIH, Room 332,Bldg 10, Bethesda, MD 20892 USA. NR 35 TC 154 Z9 170 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD APR PY 2003 VL 14 IS 2 BP 85 EP 89 DI 10.1016/S1359-6101(03)00003-0 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 665DJ UT WOS:000182104100001 PM 12651220 ER PT J AU Perfetto, SP Ambrozak, DR Koup, RA Roederer, M AF Perfetto, SP Ambrozak, DR Koup, RA Roederer, M TI Measuring containment of viable infectious cell sorting in high-velocity cell sorters SO CYTOMETRY PART A LA English DT Article DE flow cytometry; high-speed sorting; biosafety; biohazard ID MYCOBACTERIUM-TUBERCULOSIS; B-VIRUS; FLOW; TRANSMISSION; GUIDELINES; SAMPLES; SALIVA AB Background: With the advent of high-speed sorters, aerosols are a considerable safety concern when sorting viable infectious materials. We describe a four-part safety procedure for validating the containment. Methods: This procedure includes aerosol containment, physical barriers, environmental controls, and personal protection. The Aerosol Management System (AMS) produces a negative pressure within the sort chamber, where aerosols are forced through a HEPA filter. Physical barriers include the manufacturer's standard plastic shield and panels. The flow cytometer was contained within a BSL-3 laboratory for maximum environmental control, and the operator was protected by a respiratory system. Containment was measured by using highly fluorescent Glo-Germ particles under the same conditions as the cell sort. Results: Escaping aerosols were vacuumed for 10 min onto a glass slide and examined. With the AMS active and the cytometer producing the maximum aerosols possible, Glo-Germ particles remained within the sort chamber. Measurements taken directly outside the door averaged fewer than one particle per slide, and those taken at 2 ft away and on top of the sorter were completely negative. Conclusions: With this monitoring system in place, aerosols can be efficiently measured, thus reducing the risk to the operator while sorting viable infectious cells. Published 2003 Wiley-Liss, Inc.(dagger) C1 NIH, Vaccine Res Ctr, NAID, Bethesda, MD 20892 USA. RP Perfetto, SP (reprint author), NIH, Vaccine Res Ctr, NAID, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. NR 18 TC 14 Z9 15 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD APR PY 2003 VL 52A IS 2 BP 122 EP 130 DI 10.1002/cyto.a.10033 PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 671ER UT WOS:000182452800008 PM 12655656 ER PT J AU Toro, JR Sanchez, S Turiansky, G Blauvelt, A AF Toro, JR Sanchez, S Turiansky, G Blauvelt, A TI Topical cidofovir for the treatment of dermatologic conditions: verruca, condyloma, intraepithelial neoplasia, herpes simplex and its potential use in smallpox SO DERMATOLOGIC CLINICS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-PAPILLOMAVIRUS INFECTION; RECALCITRANT MOLLUSCUM CONTAGIOSUM; CYTOMEGALOVIRUS DNA-POLYMERASE; SARCOMA-ASSOCIATED HERPESVIRUS; ANAL CYTOLOGIC ABNORMALITIES; NEGATIVE HOMOSEXUAL MEN; KAPOSIS-SARCOMA; CONTROLLED TRIAL; PHOSPHONYLMETHOXYALKYL DERIVATIVES AB Cidofovir is new medication that demonstrates pharmacologic activity against many DNA viruses. Recent studies have shown that topical cidofovir is effective in the treatment of recalcitrant cutaneous viral infections caused by herpesviruses, poxviruses, and papillomaviruses. This article reviews the pharmacology of cidofovir and its uses in selected dermatologic conditions. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Univ Puerto Rico, Dept Dermatol, San Juan, PR 00936 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 7012, Bethesda, MD 20892 USA. NR 58 TC 15 Z9 16 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0733-8635 J9 DERMATOL CLIN JI Dermatol. Clin. PD APR PY 2003 VL 21 IS 2 BP 301 EP + DI 10.1016/S0733-8635(02)00116-X PG 10 WC Dermatology SC Dermatology GA 674DK UT WOS:000182621600011 PM 12757253 ER PT J AU Hong, A Lee-Kong, S Iida, T Sugimura, I Lilly, MA AF Hong, A Lee-Kong, S Iida, T Sugimura, I Lilly, MA TI The p27(cip/kip) ortholog dacapo maintains the Drosophila oocyte in prophase of meiosis I SO DEVELOPMENT LA English DT Article DE oogenesis; meiosis; dacapo; p27; Drosophila; cyclin E; oocyte differentiation ID DEPENDENT KINASE INHIBITOR; UBIQUITIN-PROTEASOME PATHWAY; CYCLIN-E; RECOMBINATION NODULES; SYNAPTONEMAL COMPLEX; MELANOGASTER FEMALES; CELL-PROLIFERATION; TRANSCRIPTION FACTOR; AXIS DETERMINATION; BICAUDAL-D AB Animal oocytes undergo a highly conserved developmental arrest in prophase of meiosis I. Often this marks a period of rapid growth for the oocyte and is necessary to coordinate meiotic progression with the developmental events of oogenesis. In Drosophila, the oocyte develops within a 16-cell germline cyst. Throughout much of oogenesis, the oocyte remains in prophase of meiosis I. By contrast, its 15 mitotic sisters enter the endocycle and become polyploid in preparation for their role as nurse cells. How germline cysts establish and maintain these two independent cell cycles is unknown. We demonstrate a role for the p21(CIP)/p27(Kip1)/p57(Kip2)-like cyclin-dependent kinase inhibitor (cki) dacapo in the maintenance of the meiotic cycle in Drosophila oocytes. Our data indicate that it is through the differential regulation of the cki Dacapo that two modes of cell-cycle regulation are independently maintained within the common cytoplasm of ovarian cysts. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lilly, MA (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Lilly, Mary/0000-0003-1564-619X NR 48 TC 48 Z9 49 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2003 VL 130 IS 7 BP 1235 EP 1242 DI 10.1242/dev.00352 PG 8 WC Developmental Biology SC Developmental Biology GA 663GX UT WOS:000181998800003 PM 12588841 ER PT J AU Liu, CQ Nakamura, E Knezevic, V Hunter, S Thompson, K Mackem, S AF Liu, CQ Nakamura, E Knezevic, V Hunter, S Thompson, K Mackem, S TI A role for the mesenchymal T-box gene Brachyury in AER formation during limb development SO DEVELOPMENT LA English DT Article DE brachyury; limb development; AER formation; FGF; WNT ID APICAL ECTODERMAL RIDGE; HOLT-ORAM-SYNDROME; CHICK LIMB; VERTEBRATE LIMB; DORSOVENTRAL POLARITY; TRANSCRIPTION FACTOR; MESODERM FORMATION; SONIC HEDGEHOG; FEEDBACK LOOP; BUD AB During limb development, several signaling centers organize limb pattern. One of these, the apical ectodermal ridge (AER), is critical for proximodistal limb outgrowth mediated by FGFs. Signals from the underlying mesoderm, including WNTs and FGFs, regulate early steps of AER induction. Ectodermal factors, particularly En1, play a critical role in regulating morphogenesis of a mature, compact AER along the distal limb apex, from a broad ventral ectodermal precursor domain. Contribution of mesodermal factors to the morphogenesis of a mature AER is less clear. We previously noted that the chick T gene (Brachyury), the prototypical T-box transcription factor, is expressed in the limb bud as well as axial mesoderm and primitive streak. Here we show that T is expressed in lateral plate mesoderm at the onset of limb bud formation and subsequently in the subridge mesoderm beneath the AER. Retroviral misexpression of T in chick results in anterior extension of the AER and subsequent limb phenotypes consistent with augmented AER extent and function. Analysis of markers for functional AER in mouse T-/- null mutant limb buds reveals disrupted AER morphogenesis. Our data also suggest that FGF and WNT signals may operate both upstream and downstream of T. Taken together, the results show that T plays a role in the regulation of AER formation, particularly maturation, and suggest that T may also be a component of the epithelialmesenchymal regulatory loop involved in maintenance of a mature functioning AER. C1 NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mackem, S (reprint author), NCI, Pathol Lab, Canc Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Liu, Chunqiao/O-3391-2013 OI Liu, Chunqiao/0000-0002-0299-7401 NR 75 TC 25 Z9 25 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2003 VL 130 IS 7 BP 1327 EP 1337 DI 10.1242/dev.00354 PG 11 WC Developmental Biology SC Developmental Biology GA 663GX UT WOS:000181998800011 PM 12588849 ER PT J AU Geling, A Itoh, M Tallafuss, A Chapouton, P Tannhauser, B Kuwada, JY Chitnis, AB Bally-Cuif, L AF Geling, A Itoh, M Tallafuss, A Chapouton, P Tannhauser, B Kuwada, JY Chitnis, AB Bally-Cuif, L TI bHLH transcription factor Her5 links patterning to regional inhibition of neurogenesis at the midbrain-hindbrain boundary SO DEVELOPMENT LA English DT Article DE zebrafish; midbrain-hindbrain boundary; MHB; neurogenesis; Her5; bHLH; E(spl); hairy; proliferation; cyclin-dependent kinase inhibitor; p27 ID CENTRAL-NERVOUS-SYSTEM; LOOP-HELIX FACTOR; MAMMALIAN NEURONAL DIFFERENTIATION; CELL-CYCLE; NEURAL DIFFERENTIATION; EXPRESSION PATTERN; ZEBRAFISH HOMOLOG; ISTHMIC ORGANIZER; EMBRYONIC ZEBRAFISH; LATERAL INHIBITION AB The midbrain-hindbrain (MH) domain of the vertebrate embryonic neural plate displays a stereotypical profile of neuronal differentiation, organized around a neuron-free zone ('intervening zone', IZ) at the midbrain-hindbrain boundary (MHB). The mechanisms establishing this early pattern of neurogenesis are unknown. We demonstrate that the MHB is globally refractory to neurogenesis, and that forced neurogenesis in this area interferes with the continued expression of genes defining MHB identity. We further show that expression of the zebrafish bHLH Hairy/E(spl)-related factor Her5 prefigures and then precisely delineates the IZ throughout embryonic development. Using morpholino knock-down and conditional gain-of-function assays, we demonstrate that Her5 is essential to prevent neuronal differentiation and promote cell proliferation in a medial compartment of the IZ. We identify one probable target of this activity, the zebrafish Cdk inhibitor p27(Xic1). Finally, although the her5 expression domain is determined by anteroposterior patterning cues, we show Her5 does not retroactively influence MH patterning. Together, our results highlight the existence of a mechanism that actively inhibits neurogenesis at the MHB, a process that shapes MH neurogenesis into a pattern of separate neuronal clusters and might ultimately be necessary to maintain MHB integrity. Her5 appears as a partially redundant component of this inhibitory process that helps translate early axial patterning information into a distinct spatiotemporal pattern of neurogenesis and cell proliferation within the MH domain. C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Inst Dev Genet, Natl Res Ctr Environm & Hlth, GSF, D-85764 Neuherberg, Germany. Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. Tech Univ Munich, Inst Virol, Zebrafish Neurogenet Jr Res Grp, Munich, Germany. RP Chitnis, AB (reprint author), NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. OI Tallafuss, Alexandra/0000-0002-4636-9394 NR 88 TC 60 Z9 60 U1 1 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2003 VL 130 IS 8 BP 1591 EP 1604 DI 10.1242/dev.00375 PG 14 WC Developmental Biology SC Developmental Biology GA 673QW UT WOS:000182592500010 PM 12620984 ER PT J AU Shakes, DC Sadler, PL Schumacher, JM Abdoirasulnia, M Golden, A AF Shakes, DC Sadler, PL Schumacher, JM Abdoirasulnia, M Golden, A TI Developmental defects observed in hypomorphic anaphase-promoting complex mutants are linked to cell cycle abnormalities SO DEVELOPMENT LA English DT Article DE mat-1/cdc-27; asymmetric cell divisions; meiosis; cell cycle; APC/C; Caenorhabditis elegans ID SISTER-CHROMATID SEPARATION; NEMATODE CAENORHABDITIS-ELEGANS; ANTERIOR-POSTERIOR AXIS; C-ELEGANS; FISSION YEAST; MEIOSIS-I; CHROMOSOME SEGREGATION; GENETIC INTERFERENCE; ANTEROPOSTERIOR AXIS; MEIOTIC MATURATION AB In C elegans, mutants in the anaphase-promoting complex or cyclosome (APC/C) exhibit defects in germline proliferation, the formation of the vulva and male tail, and the metaphase to anaphase transition of meiosis I. Oocytes lacking APC/C activity can be fertilized but arrest in metaphase of meiosis I and are blocked from further development. To examine the cell cycle and developmental consequences of reducing but not fully depleting APC/C activity, we analyzed defects in embryos and larvae of mat1/cdc-27 mutants grown at semi-permissive temperatures. Hypomorphic embryos developed to the multicellular stage but were slow to complete meiosis I and displayed aberrant meiotic chromosome separation. More severely affected embryos skipped meiosis 11 altogether and exhibited striking defects in meiotic exit. These latter embryos failed to produce normal eggshells or establish normal asymmetries prior to the first mitotic division. In developing larvae, extended M-phase delays in late-dividing cell lineages were associated with defects in the morphogenesis of the male tail. This study reveals the importance of dosage-specific mutants in analyzing molecular functions of a ubiquitously functioning protein within different cell types and tissues, and striking correlations between specific abnormalities in cell cycle progression and particular developmental defects. C1 Coll William & Mary, Dept Biol, Williamsburg, VA 23187 USA. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. Univ Texas, Grad Sch Biomed Sci, Genes & Dev Program, Houston, TX 77030 USA. RP Shakes, DC (reprint author), Coll William & Mary, Dept Biol, Williamsburg, VA 23187 USA. RI Schumacher, Jill/B-2932-2012 FU NIGMS NIH HHS [GM060359-01, R01 GM062181-01, R01 GM062181-02, R01 GM062181-03, R15 GM060359] NR 76 TC 49 Z9 55 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2003 VL 130 IS 8 BP 1605 EP 1620 DI 10.1242/dev.00385 PG 16 WC Developmental Biology SC Developmental Biology GA 673QW UT WOS:000182592500011 PM 12620985 ER PT J AU Fernandez-Capetillo, O Mahadevaiah, SK Celeste, A Romanienko, PJ Camerini-Otero, RD Bonner, WM Manova, K Burgoyne, P Nussenzweig, A AF Fernandez-Capetillo, O Mahadevaiah, SK Celeste, A Romanienko, PJ Camerini-Otero, RD Bonner, WM Manova, K Burgoyne, P Nussenzweig, A TI H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis SO DEVELOPMENTAL CELL LA English DT Article ID MALE MEIOTIC NUCLEI; XY-BODY; HISTONE H2AX; PACHYTENE SPERMATOCYTES; PSEUDOAUTOSOMAL REGION; GENOMIC INSTABILITY; SPERMATOGENESIS; GENE; MICE; PROTEIN AB During meiotic prophase in male mammals, the X and Y chromosomes condense to form a macrochromatin body, termed the sex, or XY, body, within which X- and Y-linked genes are transcriptionally repressed. The molecular basis and biological function of both sex body formation and meiotic sex chromosome inactivation (MSCI) are unknown. A phosphorylated form of H2AX, a histone H2A variant implicated in DNA repair, accumulates in the sex body in a manner independent of meiotic recombination-associated doublestrand breaks. Here we show that the X and Y chromosomes of histone H2AX-deficient spermatocytes fail to condense to form a sex body, do not initiate MSCI, and exhibit severe defects in meiotic pairing. Moreover, other sex body proteins, including macroH2A1.2 and XMR, do not preferentially localize with the sex chromosomes in the absence of H2AX. Thus, H2AX is required for the chromatin remodeling and associated silencing in male meiosis. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Med Res, Div Dev Genet, London NW7 1AA, England. NIDDKD, Genet & Biochem Branch, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 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 NR 65 TC 317 Z9 334 U1 4 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD APR PY 2003 VL 4 IS 4 BP 497 EP 508 DI 10.1016/S1534-5807(03)00093-5 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 675KE UT WOS:000182692800008 PM 12689589 ER PT J AU Wu, YY Liu, Y Levine, EM Rao, MS AF Wu, YY Liu, Y Levine, EM Rao, MS TI Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Hes1; Hes5; Notch1; GRP; development; differentiation; promotion; astrocyte; oligodendrocyte ID CENTRAL-NERVOUS-SYSTEM; NEUROEPITHELIAL STEM-CELLS; HELIX TRANSCRIPTION FACTORS; SPLIT COMPLEX GENES; CHICK SPINAL-CORD; PROGENITOR CELLS; NEURONAL DIFFERENTIATION; SIGNALING PATHWAY; BHLH PROTEINS; NOTCH AB To determine the role of Hes genes in the differentiation process of neuroepithelial (NEP) cells to glial restricted precursor cells (GRPs) and subsequently GRPs to oligodendrocytes and astrocytes, we have examined the effects of Hes1 and Hes5 on glial differentiation. We find that both Hes1 and Hes5 are expressed by GRPs and that Hes1 can drive GRIPs to an astrocyte cell fate at the expense of oligodendrocyte differentiation. Overexpression of Hes1 in GRIPs results in the up-regulation of the astrocyte markers glial fibrillary acidic protein and CD44 and the down-regulation of oligodendrocyte markers myelin proteolipid protein/DM20, GalC, and CNPase. Transcription factors involved in oligodendrocyte differentiation, such as Nkx2.2, Olig1, and Mash1, are also down-regulated in Hes1-overexpressing cells. The effect of Hes1 on gliogenesis is stage-specific as Hes1 does not direct NEP cells to an astrocytic fate. In contrast to Hes1, Hes5 does not promote astrocyte differentiation. Instead, it inhibits both astrocyte and oligodendrocyte differentiation. Overexpression of Notch1 has an effect on gliogenesis similar to that of Hes1 and the mRNA levels of Hes1 are up-regulated in cells overexpressing Notch1, suggesting that Notch1 could be an upstream activator of Hes1. (C) 2003 Wiley-Liss, Inc. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. Univ Utah, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. RP Rao, MS (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Levine, Edward/N-3878-2015 OI Levine, Edward/0000-0003-1725-2805 NR 63 TC 77 Z9 81 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2003 VL 226 IS 4 BP 675 EP 689 DI 10.1002/dvdy.10278 PG 15 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 663GW UT WOS:000181998700011 PM 12666205 ER PT J AU Stumvoll, M Tataranni, PA Stefan, N Vozarova, B Bogardus, C AF Stumvoll, M Tataranni, PA Stefan, N Vozarova, B Bogardus, C TI Glucose allostasis SO DIABETES LA English DT Article ID INSULIN SECRETORY DYSFUNCTION; DIABETES-MELLITUS; RESISTANCE; SENSITIVITY; TOLERANCE; RISK AB In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic beta-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n = 413) and Caucasians (n = 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physio-logic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Stumvoll, M (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 19 TC 65 Z9 66 U1 1 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2003 VL 52 IS 4 BP 903 EP 909 DI 10.2337/diabetes.52.4.903 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 662AM UT WOS:000181923200001 PM 12663459 ER PT J AU Zatechka, DS Kador, PF Garcia-Castineiras, S Lou, MF AF Zatechka, DS Kador, PF Garcia-Castineiras, S Lou, MF TI Diabetes can alter the signal transduction pathways in the lens of rats SO DIABETES LA English DT Article; Proceedings Paper CT 14th International Congress of Eye Research CY OCT, 2000 CL SANTA FE, NEW MEXICO ID ACTIVATED PROTEIN-KINASE; FIBROBLAST GROWTH-FACTOR; ALDOSE REDUCTASE INHIBITOR; PHOSPHATIDYLINOSITOL-3 KINASE; EPITHELIAL-CELLS; FACTOR RECEPTORS; INSULIN; DIFFERENTIATION; RETINOPATHY; 3-KINASE AB Diabetes is known to affect cataract formation by means of osmotic stress induced by activated aldose reductase in the sorbitol pathway. In addition, alterations in the bioavailability of numerous extralenticular growth factors has been reported and shown to result in various consequences. We have found that the basic fibroblast growth factor (bFGF) accumulates in the vitreous, humor of 3- and 8 week diabetic. rats. Consequently, the associating signal transduction cascades were severely disrupted, including upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK. Conversely, under diabetic condition, we observed a dramatic inhibition of phospliatidylinositol-3 kinase activity in lenses obtained from the same animal. Rats treated wit h the aldose reductase inhibitor A-L01576 for the duration of the diabetic condition showed that the diabetes-induced lenticular signaling alterations were normalized, comparable to controls. However, treatment of AL01576 vitro was ineffective at normalizing the altered constituents in extracted diabetic vitreous after the onset of diabetes. The effect of AL01576 in the high galactose-induced cataract model in vitro wits also examined. Administration of AL01576 to lens organ culture normalized the aberrant signaling effects and morphological characteristics associated with in vitro sugar cataract formation. In conclusion, our findings demonstrate diabetes-associated alterations in the lens signal transduction parameters and the effectiveness of AL01576 at normalizing such alterations. The causes for these alterations can be attributed to elevated vitreal bFGF in conjunction with osmotic stress and associated attenuation in redox status of the lens. C1 Univ Nebraska, Dept Vet & Biomed Sci & Ophthalmol, Lincoln, NE USA. Univ Puerto Rico, Dept Biochem, San Juan, PR USA. NEI, Bethesda, MD 20892 USA. RP Lou, MF (reprint author), 134 VBS, Lincoln, NE 68583 USA. NR 53 TC 24 Z9 26 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2003 VL 52 IS 4 BP 1014 EP 1022 DI 10.2337/diabetes.52.4.1014 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 662AM UT WOS:000181923200016 PM 12663474 ER PT J AU Umbricht, A Hoover, DR Tucker, MJ Leslie, JM Chaisson, RE Preston, KL AF Umbricht, A Hoover, DR Tucker, MJ Leslie, JM Chaisson, RE Preston, KL TI Opioid detoxification with buprenorphine, clonidine, or methadone in hospitalized heroin-dependent patients with HIV infection SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE opioid dependence; pain management; HIV; heroin; withdrawal ID AMBULATORY AIDS PATIENTS; OPIATE-WITHDRAWAL; PAIN; MORPHINE; PHARMACOLOGY; TOLERANCE; SYMPTOMS; TRIAL; ABUSE; SCALE AB With the growing role of intravenous drug use in the transmission of HIV infection, HIV-infected patients frequently present with comorbid opioid dependence. Yet, few empirical evaluations of the efficacy and consequences of opioid detoxification medications in medically ill HIV-infected patients have been reported. In a randomized, double-blind clinical trial, we evaluated the impact of three medications on the signs and symptoms of withdrawal and on the pain severity in heroin-dependent HIV-infected patients (N = 55) hospitalized for medical reasons on an inpatient AIDS service. Patients received a 3-day pharmacologic taper with intramuscular buprenorphine (n = 21), oral clonidine (n = 16), or oral methadone (n = 18), followed by a clonidine transdermal patch on the fourth day. Observed and self-reported measures of opioid withdrawal and pain were taken 1-3 times daily for up to 4 days. Opiate administration used as medically indicated for pain was-also recorded. Observer- and subject-rated opiate withdrawal scores decreased significantly following the first dose of medication and overall during treatment. Among all 55 subjects, self-reported and observer-reported pain decreased after treatment (on average observer-rated opioid withdrawal scale (OOWS) scores declined 5.6 units and short opioid withdrawal scale (SOWS) declined 4.8 units, P < 0.001, for both) with no indication of increased pain during medication taper. There were no significant differences of pain decline and other measures of withdrawal between the three treatment groups. During the intervention period, supplemental opiates were administered as medically indicated for pain to 45% of the patients; only 34% of men versus 62% of women received morphine (P < 0.05). These findings suggest buprenorphine, clonidine, and methadone regimens each decrease opioid withdrawal in medically ill HIV-infected patients. Published by Elsevier Science Ireland Ltd. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Rutgers State Univ, Dept Stat, Inst Hlth Hlth Care Policy & Aging Res, Piscataway, NJ 08854 USA. Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 32 TC 38 Z9 39 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2003 VL 69 IS 3 BP 263 EP 272 AR PII S0376-8716(02)00325-3 DI 10.1016/S0376-8716(02)00325-3 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 665BU UT WOS:000182100400005 PM 12633912 ER PT J AU Pope, HG Gruber, AJ Hudson, JI Cohane, G Huestis, MA Yurgelun-Todd, D AF Pope, HG Gruber, AJ Hudson, JI Cohane, G Huestis, MA Yurgelun-Todd, D TI Early-onset cannabis use and cognitive deficits: what is the nature of the association? SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE cannabis; cognitive; neuropsychological ID CHRONIC MARIJUANA USE; HYPERACTIVITY DISORDER; ABSTINENCE SYMPTOMS; EXECUTIVE FUNCTIONS; CONDUCT DISORDER; ATTENTION; DYSFUNCTION; INITIATION; EXPOSURE; ADULTS AB . Background: Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life. Methods: We analyzed neuropsychological test results from 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure, all of whom had undergone a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. We compared early-onset cannabis users with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin. Results: The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late-onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, when we adjusted for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant. Conclusions: Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1) innate differences between groups in cognitive ability, antedating first cannabis use; (2) an actual neurotoxic effect of cannabis on the developing brain; or (3) poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Biol Psychiat Lab, Dept Psychiat,Mclean Hosp, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Cognit Neuroimaging Lab, Dept Psychiat,McLean Hosp, Belmont, MA 02478 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP Pope, HG (reprint author), Harvard Univ, Sch Med, Biol Psychiat Lab, Dept Psychiat,Mclean Hosp, 115 Mill St, Belmont, MA 02478 USA. FU NIDA NIH HHS [5R37 DA-10346, DA12483-1] NR 49 TC 252 Z9 257 U1 3 U2 27 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2003 VL 69 IS 3 BP 303 EP 310 AR PII S0376-8716(02)00334-4 DI 10.1016/S0376-8716(02)00334-4 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 665BU UT WOS:000182100400009 PM 12633916 ER PT J AU Jacobson, KA Kim, HS Ravi, G Kim, SKY Lee, K Chen, AS Chen, WZ Kim, SG Barak, D Liang, BT Gao, ZG AF Jacobson, KA Kim, HS Ravi, G Kim, SKY Lee, K Chen, AS Chen, WZ Kim, SG Barak, D Liang, BT Gao, ZG TI Engineering of A(3) adenosine and P2Y nucleotide receptors and their ligands SO DRUG DEVELOPMENT RESEARCH LA English DT Article; Proceedings Paper CT 7th International Symposium on Adenosine and Adenine Nucleotides CY MAY 26-31, 2002 CL GOLD COAST, AUSTRALIA DE G-protein-coupled receptors; nucleosides; nucleotides; structure-activity relationships; purines; ARs ID SITE-DIRECTED MUTAGENESIS; BIOLOGICAL-ACTIVITY; A-3 RECEPTOR; IB-MECA; AGONISTS; NUCLEOSIDES; ANALOGS; A(1); IDENTIFICATION; ANTAGONISTS AB Modification of the ribose moiety of nucleotides and nucleosides has provided new insights into structural and conformational requirements for ligands at P2Y nucleotide receptors and at adenosine receptors (ARs). Methanocarba derivatives (containing a rigid bicyclic ring system in place of ribose) of adenosine, ATP, ADP, UTP, UDP, and other receptor agonist analogs were synthesized. Biological evaluation led to the conclusion that in general the Northern (N)-conformation was favored over the Southern (S)-conformation of the pseudoribose moiety at A(1) and A(3) ARs and at P2Y(1), P2Y(2), P2Y(4), or P2Y(11) receptors, but not P2Y(6) receptors. At the hA(3) AR a new full agonist, MRS1898, the (N)-methanocarba equivalent of CI-IB-MECA (2-chloro-N-6-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine), had a K-i value of 1.9 nM in binding to the hA(3) AR expressed in CHO cells. Functional assays confirmed the selectivity of MRS1898, although Cl-l B-MECA was even more functionally selective for human A(3) vs. hA(1) and hA(2A) ARs. Thirty muM MRS1898 did not induce apoptosis in HL-60 cells, suggesting that some of the proapoptotic effects of CI-IB-MECA may be non receptor-mediated. Manipulation of the sequence of A(3) ARs through site-directed mutagenesis has led to pharmacologically unique constructs: constitutively active receptors and "neoceptors." Such engineered receptors may later prove to have potential for cardioprotection through gene transfer. Effects of single amino acid replacement were interpreted using a rhodopsin-based model of ligand-A(3) receptor interactions, leading to the proposal that a movement of the conserved W243 in TM6 may be involved in AR activation. (C) 2003 Wiley-Liss, Inc. C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. Univ Connecticut, Ctr Hlth, Dept Cardiol, Farmington, CT USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 36 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD APR PY 2003 VL 58 IS 4 BP 330 EP 339 DI 10.1002/ddr.10168 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 686XQ UT WOS:000183346600006 ER PT J AU Stevens, JC Dean, DC Preusch, PC Correia, MA AF Stevens, JC Dean, DC Preusch, PC Correia, MA TI The changing environment of graduate and postdoctoral training in drug metabolism: Viewpoints from academia, industry, and government SO DRUG METABOLISM AND DISPOSITION LA English DT Article AB This article is an invited report of a symposium sponsored by the Drug Metabolism Division of the American Society for Pharmacology and Experimental Therapeutics held at Experimental Biology 2002 in New Orleans. The impetus for the symposium was a perceived shortage in the supply of graduate students qualified for drug metabolism research positions in industry, academia, and government. For industry, recent hiring stems largely from the expansion of drug metabolism departments in an effort to keep pace with the demands of drug discovery and new technologies. In turn, regulatory scientists are need to review and verify the results of the increased number and volume of studies required for drug development and approval. Thus the initial source of training, academia, has been forced to recognize these external hiring pressures while trying to attract and retain the faculty, postdoctoral scientists, and students necessary for active teaching and research programs. The trend of the expansion of the interdisciplinary nature of traditional drug metabolism to include emerging technologies such as pharmacogenetics, transporters, and proteomics and the implications for future needs in training and funding were acknowledged. There was also consensus on the value of partnerships between academia and industry for increasing student interest and providing training in disciplines directly applicable to industrial drug metabolism research. Factors affecting the sources of these trainees, such as federal funding, the number of trainees per institution, and recent issues with immigration restrictions that have limited the flow of scientists were also discussed. C1 Pharmacia Corp, Global Drug Metab, Kalamazoo, MI 49007 USA. Merck Res Labs, Dept Drug Metab, Rahway, NJ USA. Natl Inst Gen Med Sci, Div Pharmacol Physiol & Biol Chem, Bethesda, MD USA. Univ Calif San Francisco, Dept Cellular & Molec Pharmacol, San Francisco, CA USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA USA. Univ Calif San Francisco, Ctr Liver, San Francisco, CA USA. RP Stevens, JC (reprint author), Pharmacia Corp, Global Drug Metab, 301 Henrietta St,7265-600-306, Kalamazoo, MI 49007 USA. NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD APR PY 2003 VL 31 IS 4 BP 360 EP 366 DI 10.1124/dmd.31.4.360 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 660UQ UT WOS:000181852500022 PM 12642460 ER PT J AU Sparreboom, A Danesi, R Ando, Y Chan, J Figg, WD AF Sparreboom, A Danesi, R Ando, Y Chan, J Figg, WD TI Pharmacogenomics of ABC transporters and its role in cancer chemotherapy SO DRUG RESISTANCE UPDATES LA English DT Review DE pharmacogenetics; polymorphisms; ABC transporters; chemotherapy ID ATP-BINDING-CASSETTE; RESISTANCE-ASSOCIATED PROTEIN; DUBIN-JOHNSON-SYNDROME; HUMAN MDR1 GENE; SINGLE NUCLEOTIDE POLYMORPHISMS; P-GLYCOPROTEIN EXPRESSION; HEALTHY JAPANESE SUBJECTS; MESSENGER-RNA EXPRESSION; ORGANIC ANION TRANSPORT; MULTIDRUG-RESISTANCE AB ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer. Published by Elsevier Science Ltd. C1 NCI, Clin Pharmacol Res Core, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Pisa, Div Pharmacol & Chemotherapy, Dept Oncol, I-56126 Pisa, Italy. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Canc Res Ctr, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 135 TC 148 Z9 160 U1 0 U2 13 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD APR PY 2003 VL 6 IS 2 BP 71 EP 84 DI 10.1016/S1368-7646(03)00005-0 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 677MJ UT WOS:000182811900002 PM 12729805 ER PT J AU Little, RE Zadorozhnaja, TD Hulchiy, OP Mendel, NA Shkyryak-Nyzhnyk, ZA Chyslovska, N Gladen, BC AF Little, RE Zadorozhnaja, TD Hulchiy, OP Mendel, NA Shkyryak-Nyzhnyk, ZA Chyslovska, N Gladen, BC TI Placental weight and its ratio to birthweight in a Ukrainian city SO EARLY HUMAN DEVELOPMENT LA English DT Article DE birthweight; placental weight; ponderal index ID CORONARY HEART-DISEASE; 2 URBAN AREAS; BIRTH-WEIGHT; FETAL WEIGHT; WOMEN; PREGNANCY; COHORT; SIZE; RISK; HYPERTENSION AB Background: Placental weight and its ratio to birthweight have recently been reported to predict later chronic disease. These fetal growth indicators have been measured in the west for over a century with consistent results when methods of preparation were comparable. We investigated whether recent difficult conditions in the former eastern bloc have altered placental weight or its relationship to other fetal size measures from what has historically been reported. Methods: Placentas were obtained from 1621 singleton births of at least 28 weeks gestation in a Ukrainian city during 19931994, using a systematic protocol. Maternal characteristics were obtained from questionnaires. Pregnancy complications and birth size measures (infant weight, length, crown-rump length, and head circumference) were abstracted from medical records. We examined relationships of placental weight and ratio to these variables. Results: Placental weight ranged from 100 to 1000 g, with a mean of 470 g. Mean placental ratio was 13.9%. Placental weights increased and ratios decreased with gestational age. Larger ratios were related to larger maternal BMI. Absolute measures of infant size and placental weight were mutually positively correlated. Placental ratio, infant length, and ponderal index (PI) were nearly uncorrelated. Conclusions: Absolute and relative weights of Ukrainian placentas were similar to historical reports, as were their relationships to other infant size indicators. Placental weight ratio (PWR), ponderal index, and infant length measured different birth size dimensions. Placental availability, consistency of placental measurements, and placental ratio's reflection of an independent facet of fetal growth make the placenta a useful research tool. Published by Elsevier. Science Ireland Ltd. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Inst Pediat Obstet & Gynecol, Kiev, Ukraine. Natl Med Univ, Kiev, Ukraine. Kyiv Med Acad Post Diploma Educ, Kiev, Ukraine. RP Gladen, BC (reprint author), NIEHS, Biostat Branch, Mail Drop A3-O3,POB 12233, Res Triangle Pk, NC 27709 USA. OI Mendel, Mykola/0000-0001-9507-7817 NR 31 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-3782 J9 EARLY HUM DEV JI Early Hum. Dev. PD APR PY 2003 VL 71 IS 2 BP 117 EP 127 DI 10.1016/S0378-3782(02)00118-4 PG 11 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 668HU UT WOS:000182284900003 PM 12663149 ER PT J AU Lutz, M Burke, LJ LeFevre, P Myers, FA Thorne, AW Crane-Robinson, C Bonifer, C Filippova, GN Lobanenkov, V Renkawitz, R AF Lutz, M Burke, LJ LeFevre, P Myers, FA Thorne, AW Crane-Robinson, C Bonifer, C Filippova, GN Lobanenkov, V Renkawitz, R TI Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor SO EMBO JOURNAL LA English DT Article DE chromatin; CTCF; enhancer blocking; histone acetylation; thyroid hormone ID IMPRINTING CONTROL REGION; C-MYC GENE; TRANSCRIPTIONAL ACTIVITY; HISTONE DEACETYLASES; CHROMATIN-STRUCTURE; INSULATOR FUNCTION; ERYTHROID-CELLS; LYSOZYME LOCUS; BINDING SITES; PROTEIN CTCF AB The highly conserved, ubiquitously expressed, zinc finger protein CTCF is involved in enhancer blocking, a mechanism crucial for shielding genes from illegitimate enhancer effects. Interestingly, CTCF-binding sites are often flanked by thyroid hormone response elements (TREs), as at the chicken lysozyme upstream silencer. Here we identify a similar composite site positioned upstream of the human c-myc gene. For both elements, we demonstrate that thyroid hormone abrogates enhancer blocking. Relief of enhancer blocking occurs even though CTCF remains bound to the lysozyme chromatin. Furthermore, chromatin immuno-precipitation analysis of the lysozyme upstream region revealed that histone H4 is acetylated at the CTCF-binding site. Loss of enhancer blocking by the addition of T3 led to increased histone acetylation, not only at the CTCF site, but also at the enhancer and the promoter. Thus, when TREs are adjacent to CTCF-binding sites, thyroid hormone can regulate enhancer blocking, thereby providing a new property for what was previously thought to be constitutive enhancer shielding by CTCF. C1 Univ Giessen, Inst Genet, D-35392 Giessen, Germany. Univ Leeds, St Jamess Univ Hosp, Mol Med Unit, Leeds LS9 7TF, W Yorkshire, England. Univ Portsmouth, Fac Sci, Inst Biomed & Biomol Sci, Biophys Lab, Portsmouth PO1 2DT, Hants, England. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Renkawitz, R (reprint author), Univ Giessen, Inst Genet, Heinrich Buff Ring 58-62, D-35392 Giessen, Germany. RI Bonifer, Constanze/B-3000-2009 NR 52 TC 63 Z9 66 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD APR 1 PY 2003 VL 22 IS 7 BP 1579 EP 1587 DI 10.1093/emboj/cdg147 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666CT UT WOS:000182159500013 PM 12660164 ER PT J AU Birger, Y West, KL Postnikov, YV Lim, JH Furusawa, T Wagner, JP Laufer, CS Kraemer, KH Bustin, M AF Birger, Y West, KL Postnikov, YV Lim, JH Furusawa, T Wagner, JP Laufer, CS Kraemer, KH Bustin, M TI Chromosomal protein HMGN1 enhances the rate of DNA repair in chromatin SO EMBO JOURNAL LA English DT Article DE chromatin; chromosomal proteins; HMGN; knockout mouse; UV repair ID NUCLEOTIDE EXCISION-REPAIR; HIGH-MOBILITY; XERODERMA-PIGMENTOSUM; MITOTIC PHOSPHORYLATION; PYRIMIDINE DIMERS; HISTONE H1; GENE; TRANSCRIPTION; DAMAGE; ACTIVATION AB We report that HMGN1, a nucleosome binding protein that destabilizes the higher-order chromatin structure, modulates the repair rate of ultraviolet light (UV)-induced DNA lesions in chromatin. Hmgn1(-/-) mouse embryonic fibroblasts (MEFs) are hypersensitive to UV, and the removal rate of photoproducts from the chromatin of Hmgn1(-/-) MEFs is decreased as compared with the chromatin of Hmgn1(+/+) MEFs; yet, host cell reactivation assays and DNA array analysis indicate that the nucleotide excision repair (NER) pathway in the Hmgn1(-/-) MEFs remains intact. The UV hypersensitivity of Hmgn1(-/-) MEFs could be rescued by transfection with plasmids expressing wild-type HMGN1 protein, but not with plasmids expressing HMGN1 mutants that do not bind to nucleosomes or do not unfold chromatin. Transcriptionally active genes, the main target of the NER pathways in mice, contain HMGN1 protein, and loss of HMGN1 protein reduces the accessibility of transcribed genes to nucleases. By reducing the compaction of the higher-order chromatin structure, HMGN1 facilitates access to UV-damaged DNA sites and enhances the rate of DNA repair in chromatin. C1 NCI, Prot Sect, LM, NIH, Bethesda, MD 20892 USA. NCI, DNA Repair Sect, Basic Res Labs, CCR,NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, LM, NIH, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004517-31] NR 52 TC 99 Z9 99 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD APR 1 PY 2003 VL 22 IS 7 BP 1665 EP 1675 DI 10.1093/emboj/cdg142 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666CT UT WOS:000182159500021 PM 12660172 ER PT J AU Di Pasquale, G Chiorini, JA AF Di Pasquale, G Chiorini, JA TI PKA/PrKX activity is a modulator of AAV/adenovirus interaction SO EMBO JOURNAL LA English DT Article DE AAV; adenovirus; PKA; viral interference ID HERPES-SIMPLEX VIRUS; HUMAN-PAPILLOMAVIRUS TYPE-16; DEPENDENT PROTEIN-KINASE; CAMP-RESPONSE ELEMENT; ADENOASSOCIATED VIRUS; CYCLIC-AMP; TRANSCRIPTIONAL ACTIVATION; DNA AMPLIFICATION; REP78 PROTEIN; BINDING-SITE AB Interference between viruses occurs when infection by one virus results in the inhibition of replication of another virus. Adeno-associated virus (AAV2) is a human parvovirus with the unique characteristics of a dependence upon a helper virus for a productive infection and the ability to interfere with the replication of the helper virus. Previously, we demonstrated that AAV2 Rep78 and Rep52 interact and inhibit cAMP-dependent protein kinase A (PKA) and its novel homolog PrKX. We hypothesized that modulation of PKA activity by AAV2 may be responsible for inhibition of helper virus replication. In this study we demonstrate that adenovirus replication is sensitive to PKA activity and that AAV2 Rep78/ Rep52 proteins contain an inhibitory domain similar to that of the heat-stable PKA inhibitor. This domain, while not directly necessary for AAV2 replication and packaging, is necessary to preserve AAV2 replication fitness during an Ad co-infection. Furthermore, a mutant AAV2 virus lacking this region fails to inhibit adenovirus replication. Thus, inhibition of PKA activity by AAV2 constitutes a novel form of viral interference. C1 NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), NIDCR, Gene Therapy & Therapeut Branch, NIH, 10-1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. NR 51 TC 30 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD APR 1 PY 2003 VL 22 IS 7 BP 1716 EP 1724 DI 10.1093/emboj/cdg153 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666CT UT WOS:000182159500026 PM 12660177 ER PT J AU Shimizu, C Fuda, H Yanai, H Strott, CA AF Shimizu, C Fuda, H Yanai, H Strott, CA TI Conservation of the hydroxysteroid sulfotransferase SULT2B1 gene structure in the mouse: Pre- and postnatal expression, kinetic analysis of isoforms, and comparison with prototypical SULT2A1 SO ENDOCRINOLOGY LA English DT Article ID HUMAN CYTOSOLIC SULFOTRANSFERASES; CHOLESTEROL SULFATE; RAT-BRAIN; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; TISSUE DISTRIBUTION; MOLECULAR-CLONING; CRYSTAL-STRUCTURE; FROG BRAIN; NEUROSTEROIDS; KERATINOCYTES AB A novel mouse hydroxysteroid sulfotransferase cDNA has been cloned, and organization of its gene structure has been determined. The new mouse sulfotransferase, SULT2B1a, and its closely related isoform, SULT2B1b, are derived from a single SULT2B1 gene as a result of an alternative exon I and differential splicing. Thus, the only structural distinction between the two SULT2B1 isoforms is at their amino-terminal ends. Importantly, in contrast to the prototypical mouse hydroxysteroid sulfotransferase SULT2A1, the SULT2B1 isoforms have a predilection for cholesterol. Real-time RT-PCR reveals that the SULT2B1a isoform is most abundantly expressed in the brain and spinal cord, whereas SULT2B1b and SULT2A1 are weakly, if at all, expressed in the central nervous system. On the other hand, the SULT2B1b isoform is the most prominent hydroxysteroid sulfotransferase expressed in skin, whereas SULT2A1 is strikingly expressed in the liver. The substrate specificities and differential expression patterns of the three SULT2 isozymes strongly suggest that they have distinct biologic roles to play. Of further interest, the mouse SULT2B1 and SULT2A1 genes are differentially expressed during embryonic development, with the former being expressed at all stages from E8.5-E19, whereas the latter is not expressed until E19. It is speculated that, during embryonic development, SULT2B1b is required for production of cholesterol sulfate essential for normal skin development, whereas SULT2B1a produces pregnenolone sulfate, an essential neurosteroid during development of the central nervous system. C1 NICHHD, Sect Steroid Regulat Endocrinol & Reprod, Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHHD, Sect Steroid Regulat Endocrinol & Reprod, Res Branch, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. NR 36 TC 39 Z9 40 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2003 VL 144 IS 4 BP 1186 EP 1193 DI 10.1210/en.2002-221011 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 666QX UT WOS:000182188900008 PM 12639899 ER PT J AU Nikodemova, M Kasckow, J Liu, HG Manganiello, V Aguilera, G AF Nikodemova, M Kasckow, J Liu, HG Manganiello, V Aguilera, G TI Cyclic adenosine 3 ',5 '-monophosphate regulation of corticotropin-releasing hormone promoter activity in AtT-20 cells and in a transformed hypothalamic cell line SO ENDOCRINOLOGY LA English DT Article ID MONOPHOSPHATE-RESPONSIVE ELEMENT; GENE-EXPRESSION; FACTOR CRF; INTERMEDIATE ROLE; MESSENGER-RNA; RAT-BRAIN; IN-VIVO; IDENTIFICATION; STIMULATION; VASOPRESSIN AB The regulation of CRH promoter activity by cAMP was studied in two cell lines, the pituitary corticotroph cell line AtT-20 and the immortalized hypothalamic cell line 4B, which expresses CRH and vasopressin. In 4B cells transfected with a CRH promoter-luciferase construct, the adenylyl cyclase stimulator, forskolin, increased luciferase activity in parallel with increases in intracellular cAMP. In 4B cells, however, the phosphodiesterase inhibitor, isobutylmethylxanthine, potentiated forskolin-stimulated cAMP without affecting further increases in luciferase activity. In AtT-20 cells, forskolin plus isobutylmethylxanthine elevated cAMP only slightly, but increased luciferase activity to levels similar to those observed in 4B cells. AtT-20 cells were also unresponsive to 8-bromo-cAMP, due in part to higher phosphodiesterase (PDE) activities. Although both cells contained PDE1, -3, and -4, inhibition of either PDE4 or PDE1 potentiated luciferase activity stimulated by submaximal forskolin concentrations in 4B cells, while only simultaneous inhibition of PDE3 and PDE4 was effective in AtT-20 cells. The data show that minor elevations in intracellular cAMP are sufficient for full stimulation of CRH promoter activity regardless of the cell line. Furthermore, poor CRH promoter activation in AtT-20 cells appears to result from deficient cAMP production and rapid cAMP degradation by PDE. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45267 USA. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N 262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 30 Z9 30 U1 1 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2003 VL 144 IS 4 BP 1292 EP 1300 DI 10.1210/en.2002-220990 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 666QX UT WOS:000182188900021 PM 12639912 ER PT J AU Nilsson, O Falk, J Ritzen, EM Baron, J Savendahl, L AF Nilsson, O Falk, J Ritzen, EM Baron, J Savendahl, L TI Raloxifene acts as an estrogen agonist on the rabbit growth plate SO ENDOCRINOLOGY LA English DT Article ID LONGITUDINAL BONE-GROWTH; RECEPTOR-ALPHA; BREAST-CANCER; LONG BONES; CHONDROCYTES; RATS; BETA; SENESCENCE; MECHANISMS; WOMEN AB Estrogen treatment has been used to induce growth plate fusion, thereby reducing the final height in girls expected to achieve extreme tall stature. The treatment is effective, in terms of limiting final height, but concerns have been raised that it might also increase the risk for malignancies later in life. Raloxifene, a selective estrogen receptor modulator, has been shown to act as an estrogen agonist on bone density but as an estrogen antagonist on breast and uterine tissue. The effect of raloxifene treatment on growth plate fusion and final height is unknown. The aim of this study was to determine whether raloxifene would act as an estrogen agonist or antagonist on growth plate cartilage. Ovariectomized immature rabbits were treated for 4 wk with vehicle (controls), estradiol cypionate (E2), or raloxifene. Tibial growth velocity was decreased in both E2- (P < 0.001) and raloxifene-treated animals (P < 0.001), compared with controls. E2 and raloxifene treatment also decreased chondrocyte proliferation and the height of the proximal tibial growth plate. In addition, E2 and raloxifene hastened fusion of the distal tibial growth plate (P < 0.05) and decreased the number of proliferative and hypertrophic chondrocytes per column in the proximal tibial growth plate. As expected, the uterus was enlarged by estrogen, but not raloxifene, treatment. We conclude that raloxifene acts as an estrogen agonist on the growth plate, accelerating growth plate senescence and thus hastening epiphyseal fusion. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Women & Child Hlth, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden. RP Nilsson, O (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. OI Savendahl, Lars/0000-0003-1067-4976; Nilsson, Ola/0000-0002-9986-8138 NR 25 TC 18 Z9 18 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2003 VL 144 IS 4 BP 1481 EP 1485 DI 10.1210/en.2002-221108 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 666QX UT WOS:000182188900041 PM 12639932 ER PT J AU Dixit, VD Sridaran, R Edmonsond, MA Taub, D Thompson, WE AF Dixit, VD Sridaran, R Edmonsond, MA Taub, D Thompson, WE TI Gonadotropin-releasing hormone attenuates pregnancy-associated thymic involution and modulates the expression of antiproliferative gene product prohibitin SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR MESSENGER-RNA; CELL NUCLEAR ANTIGEN; MITOCHONDRIAL PROTEINS; LYMPHOID ORGANS; BREAST-CANCER; GNRH RECEPTOR; B-LYMPHOCYTES; MEMBRANE; SELF; PROGESTERONE AB Thymic involution during pregnancy is believed to be a critical adaptive mechanism for regulation and control of the maternal immune system. These regulatory feedback mechanisms are important for the survival of the semiallogeneic fetus. In the present study, we examined the effects of GnRH on pregnancy-induced thymic involution by characterizing the expression patterns of prohibitin (PHB), an antiproliferative gene product, GnRH, and GnRH receptor (GnRH-R) proteins in the rat thymus and in mature splenic lymphocytes. GnRH agonist infusions in pregnant rats markedly attenuated pregnancy-induced thymic involution resulting in significant increases in thymic weight and thymocyte numbers. In addition, histological examination of the thymus revealed increase in cortical cellularity. Western blot analyses revealed a significant increase of total PHB protein content in thymi during pregnancy. Furthermore, distinct changes in PHB isoform expression were observed in the pregnant involuting thymi with greater expression of the basic PHB isoform. Basic isoform expression decreased in pregnant rats and was comparable with nonpregnant rat thymi upon GnRH agonist treatment. PHB is mainly expressed in mature cells of the thymic medulla, where it strongly colocalized with GnRH. We have observed GnRH-R immunoreactivity mainly in thymic medulla. Furthermore, as assessed by immunofluorescence double labeling with proliferating cell nuclear antigen, PHB was preferentially expressed in nonproliferating thymocytes. In this study, we demonstrated that GnRH, GnRH-R, and PHB show characteristic polarized expression in thymocytes. In addition, GnRH and PHB were coexpressed in mature splenic T cells. Our results suggest that PHB and GnRH are involved in thymic growth and may be important for maturation of T lymphocytes. C1 Morehouse Sch Med, Dept Obstet & Gynecol, Cooperat Reprod Sci Res Ctr, Atlanta, GA 30310 USA. NIA, Dept Physiol, Cooperat Reprod Sci Res Ctr, Lab Immunol,NIH, Baltimore, MD 21224 USA. RP Thompson, WE (reprint author), Morehouse Sch Med, Dept Obstet & Gynecol, Cooperat Reprod Sci Res Ctr, 720 Westview Dr SW, Atlanta, GA 30310 USA. FU NCPDCID CDC HHS [NCI-P50-CA83591]; NICHD NIH HHS [HD-41749]; NIGMS NIH HHS [GM-08248] NR 50 TC 34 Z9 38 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2003 VL 144 IS 4 BP 1496 EP 1505 DI 10.1210/en.2002-220955 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 666QX UT WOS:000182188900043 PM 12639934 ER PT J AU Gladen, BC Doucet, J Hansen, LG AF Gladen, BC Doucet, J Hansen, LG TI Assessing human polychlorinated biphenyl contamination for epidemiologic studies: Lessons from patterns of congener concentrations in Canadians in 1992 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE congeners; environmental monitoring; epidemiologic methods; organochlorine insecticides; polychlorinated biphenyls ID PREPUBERTAL FEMALE RATS; HUMAN-MILK; PCB CONGENERS; ORGANOCHLORINE PESTICIDES; ENZYME-INDUCTION; PLASMA-LEVELS; BLOOD-LEVELS; BREAST-MILK; 2 LOTS; EXPOSURE AB Humans are always exposed to mixtures of polychlorinated. biphenyls (PCBs), so assessment of their health effects is complicated. Because the original sources are relatively standard mixtures that change in predictable ways while traversing the environment, there is substantial uniformity in the congener mixtures people carry. To the extent that concentrations are highly correlated, measuring multiple congeners within correlated groups would be unnecessary and estimation of separate biologic effects would. be impossible. We examined correlation patterns in previously collected data on 38 congeners (and 14 other organochlorines) from 497 human milk samples from Canada from 1992. Congener's 138,153, 156, 157, 170, 183, 187, 194, 199, and 203 were highly intercorrelated; 180 had slightly lower correlations with this group. Congeners 74, 105, and 118 were highly intercorrelated and moderately to highly correlated with the first group. Congener 99 had moderate correlations with,both these groups, and congener 66 had lesser correlations with the primary group. In contrast, congeners 28, 44, 49, 60, 90/101, 128, 137, and 193 showed little correlation with any other congeners. The remaining 14 congeners were uninformative; they were quantified in fewer than 30% of samples, and varying lipid concentrations meant that those quantified were not necessarily at higher concentrations than those not quantified. In study of human health effects of PCBs, the congener pattern present in the population under study should be examined when deciding which congeners to measure; instead of solely redundant or uninformative congeners, attention should be given to other congeners that may be more useful in addressing the question of interest. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Toxicol Res Div, Ottawa, ON, Canada. Univ Illinois, Dept Vet Biosci, Urbana, IL 61801 USA. RP Gladen, BC (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. NR 45 TC 33 Z9 34 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2003 VL 111 IS 4 BP 437 EP 443 DI 10.1289/ehp.5858 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 665WM UT WOS:000182144300028 PM 12676596 ER PT J AU Pritchard, JB French, JE Davis, BJ Haseman, JK AF Pritchard, JB French, JE Davis, BJ Haseman, JK TI The role of transgenic mouse models in carcinogen identification SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE carcinogens; hazard identification; mouse model; mutagenesis screening; transgenic models ID HA-RAS GENE; INDUCED SKIN TUMORS; P53-DEFICIENT MICE; AVAILABLE DATA; TG.AC MICE; RODENT CARCINOGENICITY; INDUCED TUMORIGENESIS; CHEMICAL CARCINOGENS; RAPID INDUCTION; KNOCKOUT MOUSE AB In this article, we examine existing data on the use of transgenic mouse models for identification of human carcinogens. We focus on the three most extensively studied of these mice, Trp53+/-, Tg/AC, and RasH2, and compare their performance with the traditional 2-year rodent bioassay. Data on 99 chemicals were evaluated. Using the International Agency for Research on Cancer/Report on Carcinogens determinations for the carcinogenicity of these chemicals to humans as the standard for comparison, we evaluated a variety of potential testing strategies ranging from individual transgenic models to combinations of these three models with each other and with traditional rodent assays. The individual transgenic models made the "correct" determinations (positive for carcinogens; negative for noncarcinogens) for 74-81% of the chemicals, with an increase to as much as 83% using combined strategies (e.g., Trp53+/- for genotoxic chemicals and RasH2 for all chemicals). For comparison, identical analysis of chemicals in this data set that were tested in the 2-year, two-species rodent bioassay yielded correct determinations for 69% of the chemicals. However, although the transgenic models had a high percentage of correct determinations, they did miss a number of known or probable human carcinogens, whereas the bioassay missed none of these chemicals. Therefore, we also evaluated mixed strategies using transgenic models and the rat bioassay. These strategies yielded approximately 85% correct determinations, missed no carcinogens, and cut the number of positive determinations for human noncarcinogens in half. Overall, the transgenic models performed well, but important issues of validation and standardization need further attention to permit their regulatory acceptance and use in human risk assessment. C1 NIEHS, Lab Pharmcol & Chem, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Lab Expt Carcinogenesis & Mutagenesis, Environm Toxicol Program, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Lab Womens Hlth, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Biostat Branch, Environm Biol & Med Program, Res Triangle Pk, NC USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmcol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. NR 135 TC 84 Z9 87 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2003 VL 111 IS 4 BP 444 EP 454 DI 10.1289/ehp.5778 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 665WM UT WOS:000182144300029 PM 12676597 ER PT J AU Branum, AM Collman, GW Correa, A Keim, SA Kessel, W Kimmel, CA Klebanoff, MA Longnecker, MP Mendola, P Rigas, M Selevan, SG Scheidt, PC Schoendorf, K Smith-Khuri, E Yeargin-Allsopp, M AF Branum, AM Collman, GW Correa, A Keim, SA Kessel, W Kimmel, CA Klebanoff, MA Longnecker, MP Mendola, P Rigas, M Selevan, SG Scheidt, PC Schoendorf, K Smith-Khuri, E Yeargin-Allsopp, M CA Natl Children's Study Interagency TI The National Children's Study of Environmental Effects on Child Health and Development SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE child; cohort studies; environment; human milk; pregnancy ID INFANT-DEATH-SYNDROME; BREAST-MILK; POLYCHLORINATED-BIPHENYLS; THYROID-HORMONES; CEREBRAL-PALSY; EXPOSURE; PREVALENCE; MOTHERS; TRENDS; RISK AB Increasing recognition that children may be more susceptible than adults to environmental exposures and that they experience potentially life-long consequences of such exposures has led to widespread support for a large new cohort study in the United States. In this article, we propose a framework for a new cohort study of children, with follow-up beginning before birth and continuing to age 21 years. We also describe the administrative structure that has been built to develop the proposal further. The structure includes a partnership between federal and nonfederal scientists and relies on a collaborative, interdisciplinary research effort of unprecedented scale in medical research. We discuss briefly how the proposed cohort could be used to examine, among many other things, the effect of chemical contaminants in breast milk on children's health and development. C1 NICHD, Natl Childrens Study Program Off, Rockville, MD 20892 USA. Ctr Dis Control & Prevent, Infant & Child Hlth Studies Branch, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NIEHS, Chem Exposures & Mol Biol Branch, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. CDC, Natl Ctr Birth Defects & Dev Disabil, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. US Dept HHS, Off Secretary, Washington, DC 20201 USA. US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. NICHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Natl Hlth & Environm Effects Res Lab, Chapel Hill, NC USA. US EPA, Natl Exposure Res Lab, Las Vegas, NV 89193 USA. RP Scheidt, PC (reprint author), NICHD, Natl Childrens Study Program Off, 6100 Execut Blvd,MSC 7510, Rockville, MD 20892 USA. RI Keim, Sarah/F-8929-2013; OI Keim, Sarah/0000-0003-3490-3649; Longnecker, Matthew/0000-0001-6073-5322; Mendola, Pauline/0000-0001-5330-2844 NR 67 TC 52 Z9 53 U1 1 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2003 VL 111 IS 4 BP 642 EP 646 DI 10.1289/ehp.5781 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 665WM UT WOS:000182144300058 PM 12676629 ER PT J AU Melnick, RL Kamel, F Huff, J AF Melnick, RL Kamel, F Huff, J TI Declaring chemicals "not carcinogenic to humans" requires validation, not speculation SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID PEROXISOME PROLIFERATORS C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Melnick, RL (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 5 Z9 5 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2003 VL 111 IS 4 BP A203 EP A204 DI 10.1289/ehp.111-a203 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 665WM UT WOS:000182144300004 PM 12676636 ER PT J AU Lee, CR Pieper, JA Frye, RF Hinderliter, AL Blaisdell, JA Goldstein, JA AF Lee, CR Pieper, JA Frye, RF Hinderliter, AL Blaisdell, JA Goldstein, JA TI Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes SO EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE CYP2C9; polymorphisms; flurbiprofen ID CYTOCHROME P4502C9; HEALTHY-VOLUNTEERS; DOSE REQUIREMENT; GLUCOSE RESPONSE; ALLELIC VARIANT; AMINO-ACID; IN-VITRO; CYP2C9; POLYMORPHISMS; TOLBUTAMIDE AB Objective: This study was conducted to examine differences in flurbiprofen metabolism among individuals with the CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Methods: Fifteen individuals with the CYP2C9*1/*1 (n = 5) *1/*2(n = 5), and *1/*3(n = 5) genotypes received a single 50-mg oral dose of flurbiprofen. Plasma and urine samples were collected over 24 h, and flurbiprofen and 4'-hydroxyflurbiprofen pharmacokinetic data were compared across genotypes. Results: CYP2C9 genotype was a significant predictor of flurbiprofen metabolism and accounted for 59% of the variability in flurbiprofen AUC(0-infinity), and approximately 50% of the variability in flurbiprofen oral clearance, formation clearance to 4'-hydroxyflurbiprofen, and the 0 to 24-h urinary metabolic ratio of flurbiprofen to 4'-hydroxyflurbiprofen. Flurbiprofen AUC(0-infinity) was significantly higher and all measures of flurbiprofen clearance were significantly lower in the C YP2C9*1/*3 individuals than in those with *1/*1. Significant differences in these parameters were not detected between *1/*2 subjects and *1/*1 subjects. Conclusions: CYP2C9 genotype is a significant predictor of flurbiprofen disposition in humans by altering CYP2C9-mediated metabolism and reducing systemic clearance. The effects are most pronounced in individuals carrying the *3 allele. C1 Univ N Carolina, Div Pharmacotherapy, Chapel Hill, NC 27599 USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. Univ N Carolina, Div Cardiol, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Lee, CR (reprint author), Univ N Carolina, Div Pharmacotherapy, Chapel Hill, NC 27599 USA. RI Goldstein, Joyce/A-6681-2012; OI Lee, Craig/0000-0003-3595-5301; Frye, Reginald/0000-0002-1841-1401 FU NCRR NIH HHS [RR00046] NR 21 TC 50 Z9 52 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6970 J9 EUR J CLIN PHARMACOL JI Eur. J. Clin. Pharmacol. PD APR PY 2003 VL 58 IS 12 BP 791 EP 794 DI 10.1007/s00228-003-0574-6 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 682RF UT WOS:000183105300002 PM 12698304 ER PT J AU Kamnasaran, D O'Brien, PC Zackai, EH Muenke, M Ferguson-Smith, MA Cox, DW AF Kamnasaran, D O'Brien, PC Zackai, EH Muenke, M Ferguson-Smith, MA Cox, DW TI Rearrangement in the PITX2 and MIPOL1 genes in a patient with a t(4;14) chromosome SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE midline-defects; central nervous system; corpus callosum; flow sorted chromosomes ID HOMEOBOX TRANSCRIPTION FACTOR; FLOW-SORTED CHROMOSOMES; RIEGER-SYNDROME GENE; LEFT-RIGHT ASYMMETRY; 14Q13 BREAKPOINT; EXPRESSION; IDENTIFICATION; ISOFORMS; LOCALIZATION; ANOMALIES AB We report the molecular characterization of a patient with mild craniofacial and acallosal central nervous system midline defects and a t(4;14)(q25)(q13) chromosome. With the use of flow sorted chromosomes, the translocation breakpoint junction was defined within a 100 kb region with markers mapping to chromosomes 4q25 and 14q13. Analysis of genomic sequences demonstrated that the breakpoint junction at 14q13 was within the third intron of the 5' untranslated region of the MIPOL1 gene (GI: 22048098). On chromosome 4q25, two breakpoint junctions were found. One was about 47 kb distal to the 5' end of a putative gene (GI: 8923996) with unknown function but with partial similarity to kinases, and a second breakpoint was within the 3' end of the PITX2 gene (GI: 21361182) that resulted in the deletion of exons 6 and 7 of this gene. We also searched for microdeletions in a panel of candidate genes mapping within 2 Mb of the translocation breakpoint junction on chromosomes 4 and 14, however, no evidence for deletions or rearrangements was found. The finding of two breaks on chromosome 4q25 suggests a complex microrearrangement, such as an inversion, in addition to a translocation in this patient. C1 Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada. Ctr Vet Sci, Dept Clin Vet Med, Cambridge, Cambs, England. Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Cox, DW (reprint author), Univ Alberta, Dept Med Genet, 8-39 Med Sci Bldg, Edmonton, AB T6G 2H7, Canada. NR 34 TC 10 Z9 10 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD APR PY 2003 VL 11 IS 4 BP 315 EP 324 DI 10.1038/sj.ejhg.5200963 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 672DL UT WOS:000182505800005 PM 12700605 ER PT J AU Shibagaki, N Udey, MC AF Shibagaki, N Udey, MC TI Dendritic cells transduced with TAT protein transduction domain-containing tyrosinase-related protein 2 vaccinate against murine melanoma SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE dendritic cell; protein transduction; melanoma; cytotoxic lymphocyte; vaccination ID LIGAND-TREATED MICE; IN-VIVO; ANTITUMOR IMMUNITY; FLT3 LIGAND; GENETIC IMMUNIZATION; TUMOR-IMMUNITY; T-CELLS; ANTIGEN; IDENTIFICATION; DELIVERY AB Incorporation of an 11 amino acid region of the HIV TAT protein transduction domain (TAT PTD) into proteins facilitates rapid, efficient entry into cells. We previously showed that rTAT-PTD-OVA-transduced dendritic cells (DC) stimulated antigen (Ag)-specific CTL and Th cells, and vaccinated against OVA-expressing tumors. Here we studied B16 melanoma in C57BL/6 mice, using murine tyrosinase-related protein 2 (Trp2) as a candidate tumor Ag. We produced a 472-amino acid N-terminal fragment of Trp2 protein (rTrp2Delta) with or without PTD. Although PTD-deficient rTrp2Delta was ineffective, mice given rTAT-PTD-Trp2Delta-transduced DC were efficiently primed for Trp2(180-188) peptide-specific and B16-reactive CTL. In 58% of such mice, growth of melanomas was prevented. Trp2180-188 peptide-pulsed DC protected 35% of recipients, and irradiated GM-CSF-producing B16 cells protected 75%. rTAT-PTD-Trp2Delta-transduced DC induced a more vigorous memory response to B16 rechallenge than the other regimens, and protected 30% of recipients from progressive tumor development in treatment studies. In this setting, Trp2 peptide-treated DC protected 20% and irradiated GM-CSF-producing cells protected 0%. Both tumor prevention and tumor treatment were CD8(+) T cell dependent. Vaccination with rTAT-PTD-Trp2Delta-transduced DC induced a robust CTL response and durable anti-melanoma immunity. This approach should be clinically applicable, and offers theoretical and practical advantages to those that are in current use. C1 NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. NR 41 TC 47 Z9 51 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2003 VL 33 IS 4 BP 850 EP 860 DI 10.1002/eji.200323709 PG 11 WC Immunology SC Immunology GA 666PW UT WOS:000182186500004 PM 12672050 ER PT J AU Borszcz, PD Peterson, M Standeven, L Kirwan, S Sandusky, M Shaw, A Long, EO Burshtyn, DN AF Borszcz, PD Peterson, M Standeven, L Kirwan, S Sandusky, M Shaw, A Long, EO Burshtyn, DN TI KIR enrichment at the effector-target cell interface is more sensitive than signaling to the strength of ligand binding SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE signal transduction; NK cell; enhanced green fluorescent protein ID NATURAL-KILLER-CELLS; INHIBITORY RECEPTOR; IMMUNOLOGICAL SYNAPSE; NK CELLS; HLA-C; ERYTHROPOIETIN RECEPTOR; FUNCTIONAL TRANSFER; CRYSTAL-STRUCTURE; IMMUNE SYNAPSES; T-CELLS AB Target cell lysis by natural killer cells is inhibited by killer cell immunoglobulin-like receptors (KIR) that bind major histocompatibility complex class I molecules. Many lymphocyte receptors, including KIR, become enriched at the interface with ligand-bearing cells. The contribution of the enrichment to inhibitory signaling has not been determined. We now describe a KIR variant with enhanced green fluorescent protein (EGFP) at the N terminus that can mediate inhibitory signaling, but its enrichment is markedly reduced. This receptor is only slightly weaker at inhibiting lysis than the same KIR tagged with EGFP in the cytoplasmic tail, even though the latter enriched as extensively as wild-type KIR. A slight defect was also detected in the ability of the receptor to reduce adhesion to target cells and for binding of a soluble counterpart to cell surface HLA-C. Our findings suggest that the strength of the interaction required to readily detect receptor enrichment exceeds that required for signaling. C1 Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB T6G 2S2, Canada. NIAID, Immunogenet Lab, NIH, Rockville, MD USA. Univ Alberta, Fac Med & Dent, Dept Oncol, Edmonton, AB, Canada. Univ Alberta, Fac Med & Dent, Cross Canc Inst, Edmonton, AB, Canada. RP Burshtyn, DN (reprint author), Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB T6G 2S2, Canada. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 40 TC 20 Z9 20 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2003 VL 33 IS 4 BP 1084 EP 1093 DI 10.1002/eji.200323582 PG 10 WC Immunology SC Immunology GA 666PW UT WOS:000182186500029 PM 12672075 ER PT J AU Gulyaeva, N Zaslavsky, A Lechner, P Chlenov, M McConnell, O Chait, A Kipnis, V Zaslavsky, B AF Gulyaeva, N Zaslavsky, A Lechner, P Chlenov, M McConnell, O Chait, A Kipnis, V Zaslavsky, B TI Relative hydrophobicity and lipophilicity of drugs measured by aqueous two-phase partitioning, octanol-buffer partitioning and HPLC. A simple model for predicting blood-brain distribution SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article; Proceedings Paper CT 17th International Symposium on Medicinal Chemistry CY SEP 01-05, 2002 CL BARCELONA, SPAIN DE hydrophobicity; lipophilicity; log P; aqueous two-phase partitioning; octanol-buffer partitioning; HPLC; blood-brain barrier ID POLAR MOLECULAR-SURFACE; LIQUID-CHROMATOGRAPHY; BARRIER PERMEATION; ORGANIC-COMPOUNDS; 2-PHASE SYSTEMS; SOLUTES; PENETRATION; DESCRIPTORS; TRANSPORT AB Relative hydrophobicity and lipophilicity of 63 compounds with known permeability through the blood-brain barrier (BBB) was examined by partitioning in aqueous dextran-poly(ethylene glycol) two-phase system and octanol-buffer system, and by gradient RP-HPLC at pH 7.4. Combination of the relative hydrophobicity estimates, N(CH2) obtained by aqueous two-phase partitioning and the lipophilicity (log D-exp or log D-HPLC) values obtained by the shake-flask technique or HPLC technique allows one to differentiate between compounds capable of crossing the BBB and those that cannot. A simple model for predicting blood-brain distribution is proposed. Published by Editions scientifiques et medicales Elsevier SAS. C1 Analiza Inc, Cleveland, OH 44128 USA. Wyeth Ayerst Res, Discovery Analyt Chem, Princeton, NJ USA. NCI, Bethesda, MD 20892 USA. RP Zaslavsky, B (reprint author), Analiza Inc, 26101 Miles Rd, Cleveland, OH 44128 USA. OI Zaslavsky, Boris/0000-0003-0771-6696 NR 26 TC 54 Z9 54 U1 0 U2 12 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR PY 2003 VL 38 IS 4 BP 391 EP 396 DI 10.1016/S0223-5234(03)00044-8 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 685YE UT WOS:000183291500010 PM 12750026 ER PT J AU Bymaster, FP Carter, PA Yamada, M Gomeza, J Wess, J Hamilton, SE Nathanson, NM McKinzie, DL Felder, CC AF Bymaster, FP Carter, PA Yamada, M Gomeza, J Wess, J Hamilton, SE Nathanson, NM McKinzie, DL Felder, CC TI Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine; knockout mice; muscarinic receptors; muscarinic M-1 receptors; muscarinic M-2 receptors ID ACETYLCHOLINE-RECEPTOR; KNOCKOUT MICE; ALZHEIMERS-DISEASE; HUMAN IRIS; IN-VIVO; MEMORY; ACTIVATION; NEURONS; LACKING; RATS AB Muscarinic agonist-induced parasympathomimetic effects, in vivo phosphoinositide hydrolysis and seizures were evaluated in wild-type and muscarinic M-1 -M-5 receptor knockout mice. The muscarinic agonist oxotremorine induced marked hypothermia in all the knockout mice, but the hypothermia was reduced in M-2 and to a lesser extent in M-3 knockout mice. Oxotremorine-induced tremor was abolished only in the M-2 knockout mice. Muscarinic agonist-induced salivation was reduced to the greatest extent in M-3 knockout mice, to a lesser degree in M-1 and M-4 knockout mice, and was not altered in M-2 and M-5 knockout mice. Pupil diameter under basal conditions was increased only in the M-3 knockout mice. Pilocarpine-induced increases in in vivo phosphoinositide hydrolysis were completely absent in hippocampus and cortex of M-1 knockout mice, but in vivo phosphoinositide hydrolysis was unaltered in the M-2 -M-5 knockout mice. A high dose of pilocarpine (300 mg/kg) caused seizures and lethality in wild-type and M-2 -M-5 knockout mice, but produced neither effect in the M-1 knockout mice. These data demonstrate a major role for M-2 and M-3 muscarinic receptor subtypes in mediating parasympathomimetic effects. Muscarinic M-1 receptors activate phosphoinositide hydrolysis in cortex and hippocampus of mice, consistent with the role of M-1 receptors in cognition. Muscarinic M-1 receptors appear to be the only muscarinic receptor subtype mediating seizures. C1 Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Res Div, Indianapolis, IN 46285 USA. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. RP Bymaster, FP (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Res Div, Indianapolis, IN 46285 USA. OI Nathanson, Neil/0000-0002-9216-121X NR 48 TC 71 Z9 75 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2003 VL 17 IS 7 BP 1403 EP 1410 DI 10.1046/j.1460-9568.2003.02588.x PG 8 WC Neurosciences SC Neurosciences & Neurology GA 671GZ UT WOS:000182458100008 PM 12713643 ER PT J AU Podgornik, R Hansen, PL AF Podgornik, R Hansen, PL TI Membrane pinning on a disordered substrate SO EUROPHYSICS LETTERS LA English DT Article AB We investigate interactions between an elastic membrane and a substrate characterized by quenched positional disorder in the height function. We show that the positional disorder transforms the standard secondary DLVO minimum into two separate states: the hovering state characterized by a planar membrane at a finite separation from the interface and a pinned state where the membrane follows closely the asperities of the substrate and is, as a consequence, quite corrugated. The transition between the two states is continuous and depends on the parameters of the underlying DLVO potential as well as the parameters describing the quenched height-height correlation function of the substrate. C1 NICHD, LPSB, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Dept Phys, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. Univ So Denmark, MEMPHYS, Ctr Biomembrane Phys, Dept Chem, DK-5230 Odense M, Denmark. RP Podgornik, R (reprint author), NICHD, LPSB, NIH, Bld 12A Rm 2041, Bethesda, MD 20892 USA. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 10 TC 1 Z9 1 U1 0 U2 0 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0295-5075 J9 EUROPHYS LETT JI Europhys. Lett. PD APR PY 2003 VL 62 IS 1 BP 124 EP 130 DI 10.1209/epl/i2003-00107-2 PG 7 WC Physics, Multidisciplinary SC Physics GA 661GB UT WOS:000181881900019 ER PT J AU Stewart, LMV Song, K Hsing, AY Danielpour, D AF Stewart, LMV Song, K Hsing, AY Danielpour, D TI Regulation of Trespin expression by modulators of cell growth, differentiation, and apoptosis in prostatic epithelial cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Trespin; ov-serpin; TGF-beta; dexamethasone; IGF-I; prostate; differentiation; apoptosis ID ACTIVATOR INHIBITOR TYPE-2; SMOOTH-MUSCLE CELLS; FACTOR-BETA; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; DOWN-REGULATION; SERPIN PROTEINASE-INHIBITOR-9; KERATINOCYTE DIFFERENTIATION; MEDIATED APOPTOSIS; MESANGIAL CELLS AB We recently identified a novel rat ov-serpin, Trespin, which inhibits the trypsin-like serine proteinase plasmin and is expressed in several tissues, including prostate. In this report Trespin expression was studied in prostatic cell lines, NRP-152, NRP-154, and DP-153, derived from the Lobund-Wistar rat. Northern blots revealed Trespin mRNA is expressed in,NRP-152 and DP-153 basal epithelial cell lines but not in the luminal line, NRP-154. Similarly, Trespin levels drop >30-fold following transdifferentiation of NRP-152 cells toward a luminal variant, further suggesting Trespin expression is specific for basal prostatic epithelial cells. Trespin expression in NRP-152 cells is up-regulated by dexamethasone (Dex) and insulin-like growth factor-I (IGF-I), each of which stimulate growth and prevent differentiation and apoptosis. However, Dex (alone) facilitates loss of Trespin by TGF-beta, yet enhances the ability of LR3-IGF-I to reverse such loss, similar to the pattern of apoptosis induced by TGF-beta. Likewise, several apoptosis inducers markedly decrease Trespin mRNA levels. HEK293 cells stably overexpressing Trespin display increased cell proliferation and partial resistance to growth inhibition and phosphorylation of c-Jun induced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Together these data strongly suggest that Trespin has critical functions tied to the regulation of growth, differentiation, and apoptosis of prostatic epithelial cells. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Case Western Reserve Univ Hosp, Ireland Canc Ctr, Res Labs, Dept Pharmacol, Cleveland, OH 44106 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Danielpour, D (reprint author), Ireland Canc Ctr, Res Labs, Samuel Gerber Bldg,Suite 200,Lab 3,11001 Cedar Rd, Cleveland, OH 44106 USA. FU NCI NIH HHS [1R01-CA3069-03] NR 49 TC 10 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD APR 1 PY 2003 VL 284 IS 2 BP 303 EP 315 DI 10.1016/S0014(02)00037-X PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 663HK UT WOS:000182000000013 PM 12651162 ER PT J AU Rouan, F Lo, CW Fertala, A Wahl, M Jost, M Rodeck, U Uitto, J Richard, G AF Rouan, F Lo, CW Fertala, A Wahl, M Jost, M Rodeck, U Uitto, J Richard, G TI Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE connexin; erythrokeratodermia variabilis; gap junctions; intracellular calcium; mutation ID GAP JUNCTION PROTEIN; HELA-CELLS; ERYTHROKERATODERMIA VARIABILIS; MUTATIONS; DEAFNESS; EXPRESSION; TERMINUS; CHANNELS; PERMEABILITY; TRAFFICKING AB Recently, we identified several missense mutations of the connexin gene GJB3 encoding connexin 31 (Cx31) in erythrokeratodermia variabilis (EKV), an autosomal dominant skin disorder. These mutations include G12D, which replaces a conserved glycine residue in the amino-terminus of Cx31 and is associated with a severe EKV phenotype. In contrast, the biologic relevance of the GJB3 sequence variant R32W located in the first transmembrane domain of Cx31 is disputed. To examine the effects of these sequence variants on Cx31 biogenesis and gap junction activity we expressed wild type and mutant Cx31-Flag constructs in HeLa cells. Using immunostaining, all expression variants were detected in the cytoplasm and in a punctate pattern at the cell surface, indicating that G12D and R32W did not interfere with either protein synthesis or transport to the cell membrane. Similarly, oligomerization into hemichannels appeared not impaired when expressing either Cx31 mutant as assessed by size exclusion chromatography, immunoblotting and immunostaining. However, dye transfer experiments and monitoring of intracellular calcium levels in response to serum stimulation revealed that G12D-Cx31 did not form functional gap junction channels, probably due to incorrect assembly or altered properties of Cx31 channels. In contrast, intercellular coupling between cells expressing R32W-Cx31 was comparable to that of wtCx31, suggesting that R32W is a functionally inconsequential polymorphism of Cx31. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. RP Rouan, F (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Bluemle Life Sci Bldg,Suite 450,233 S 10th St, Philadelphia, PA 19107 USA. FU NCI NIH HHS [CA81001]; NIAMS NIH HHS [P01-AR38923, KO8-AR02141] NR 27 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 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD APR PY 2003 VL 12 IS 2 BP 191 EP 197 DI 10.1034/j.1600-0625.2003.120210.x PG 7 WC Dermatology SC Dermatology GA 668RL UT WOS:000182306900010 PM 12702148 ER PT J AU Ikeyama, S Kokkonen, G Martindale, JL Wang, XT Gorospe, M Holbrook, NJ AF Ikeyama, S Kokkonen, G Martindale, JL Wang, XT Gorospe, M Holbrook, NJ TI Effects of aging and calorie restriction of Fischer 344 rats on hepatocellular response to proliferative signals SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE hepatocytes; aging; oxidative stress; proliferation; epidermal growth factor ID ACTIVATED PROTEIN-KINASE; LIFE-SPAN EXTENSION; AGE-RELATED DECLINE; GROWTH-FACTOR RECEPTOR; DIETARY RESTRICTION; LIVER-REGENERATION; DNA-SYNTHESIS; CELL-PROLIFERATION; REGULATED KINASES; OXIDATIVE STRESS AB It is well established that the proliferative potential of the liver declines with aging. Epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats, and this reduction correlates with diminished activation of the extracellular signal-regulated kinase (ERK) pathway and lower phosphorylation of the EGF receptor on residue Y1173. Calorie restriction (CR) can increase rodent life span and retard many age-associated declines in physiologic function, but its influence on cell proliferation is unknown. Here, we investigated the effects of long-term CR on proliferation of hepatocytes derived from young and aged rats following in vitro stimulation with either low-dose hydrogen peroxide or EGF. CR reduced the proliferative response of hepatocytes derived from young hosts, but long-term CR was associated with enhanced proliferation in aged cells relative to that of ad libitum (AL)-fed animals. ERK activation mirrored the effects of CR on proliferation, in that young CR cells exhibited lower ERK activation than young AL cells, but old Ck cells showed higher ERK activation than old AL cells. Finally, a decline in EGF receptor phosphorylation on Y1173, which normally occurs with aging, was absent in cells of old hosts maintained on long-term CR, supporting the view that alterations in this early signaling event underlie the age-related decline in proliferative potential in rat hepatocytes. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Intramural Res Program,NIH,Cell Stress & Aging Se, Baltimore, MD 21224 USA. Yale Univ, Sch Med, Sect Geriatr, New Haven, CT 06520 USA. RP Ikeyama, S (reprint author), NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Intramural Res Program,NIH,Cell Stress & Aging Se, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 49 TC 16 Z9 16 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD APR PY 2003 VL 38 IS 4 BP 431 EP 439 AR PII S0531-5565(02)00239-5 DI 10.1016/S0531-5565(02)00239-5 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 673AK UT WOS:000182556200011 PM 12670630 ER PT J AU Tuo, JS Jaruga, P Rodriguez, H Bohr, VA Dizdaroglu, M AF Tuo, JS Jaruga, P Rodriguez, H Bohr, VA Dizdaroglu, M TI Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress SO FASEB JOURNAL LA English DT Article DE GS; fibroblast cell line; gamma irradiation ID TRANSCRIPTION-COUPLED REPAIR; B GENE-PRODUCT; EXCISION-REPAIR; DNA-DAMAGE; XERODERMA-PIGMENTOSUM; MAMMALIAN-CELLS; PREFERENTIAL REPAIR; IONIZING-RADIATION; ESCHERICHIA-COLI; ACTIVE GENES AB Cockayne syndrome (CS) is a genetic human disease with clinical symptoms that include neurodegeneration and premature aging. The disease is caused by the disruption of CSA, CSB, or some types of xeroderma pigmentosum genes. It is known that the CSB protein coded by the CS group B gene plays a role in the repair of 8-hydroxyguanine (8-OH-Gua) in transcription-coupled and non-strand discriminating modes. Recently we reported a defect of CSB mutant cells in the repair of another oxidatively modified lesion 8-hydroxyadenine (8-OHAde). We show here that primary fibroblasts from CS patients lack the ability to efficiently repair these particular types of oxidatively induced DNA damages. Primary fibroblasts of 11 CS patients and 6 control individuals were exposed to 2 Gy of ionizing radiation to induce oxidative DNA damage and allowed to repair the damage. DNA from cells was analyzed using liquid chromatography/isotope dilution mass spectrometry to measure the biologically important lesions 8-OH-Gua and 8-OHAde. After irradiation, no significant change in background levels of 8-OH-Gua and 8-OH Ade was observed in control human cells, indicating their complete cellular repair. In contrast, cells from CS patients accumulated significant amounts of these lesions, providing evidence for a lack of DNA repair. This was supported by the observation that incision of 8-OH-Gua- or 8-OHAde-containing oligodeoxynucleotides by whole cell extracts of fibroblasts from CS patients was deficient compared to control individuals. This study suggests that the cells from CS patients accumulate oxidatively induced specific DNA base lesions, especially after oxidative stress. A deficiency in cellular repair of oxidative DNA damage might contribute to developmental defects in CS patients. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Dizdaroglu, M (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM miral@nist.gov RI Jaruga, Pawel/M-4378-2015 NR 47 TC 96 Z9 96 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2003 VL 17 IS 6 BP 668 EP 674 DI 10.1096/fj.02-0851com PG 7 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 673KL UT WOS:000182580100012 PM 12665480 ER PT J AU Wan, RQ Camandola, S Mattson, MP AF Wan, RQ Camandola, S Mattson, MP TI Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats SO FASEB JOURNAL LA English DT Article DE caloric restriction; cardiovascular disease; glucose metabolism; stress response ID CALORIC RESTRICTION; INSULIN-RESISTANCE; BLOOD-PRESSURE; FOOD-RESTRICTION; LIFE-SPAN; VOLUNTARY EXERCISE; DIABETES-MELLITUS; FISCHER-344 RATS; BRAIN-DAMAGE; BODY-WEIGHT AB Hypertension and insulin resistance syndrome are risk factors for cardiovascular disease, and it is therefore important to identify interventions that can reduce blood pressure and improve glucose metabolism. We performed experiments aimed at determining whether intermittent fasting (IF) can improve cardiovascular health and also tested the hypothesis that beneficial effects of IF can be mimicked by dietary supplementation with 2-deoxy-D-glucose (2DG) a non-metabolizable glucose analog. Four-month-old male rats were implanted with telemetry probes to allow continuous monitoring of heart rate, blood pressure, physical activity, and body temperature. Rats were then maintained for 6 months on one of three different dietary regimens: ad libitum feeding, IF, or 2DG supplementation. Rats on the IF regimen consumed 30% less food over time and had reduced body weights compared with rats fed ad libitum, whereas rats on the 2DG regimen did not reduce their food intake and maintained their body weight. Heart rate and blood pressure were significantly decreased within 1 month in rats on IF and 2DG diets and were maintained at reduced levels thereafter. Body temperature was significantly decreased in group IF, but not in group 2DG. Levels of serum glucose and insulin were significantly decreased in rats maintained on IF and 2DG-supplemented diets, suggesting that IF and 2DG diets affect insulin sensitivity in a similar manner. Finally, rats in groups IF and 2DG exhibited increased levels of plasma adrenocorticotropin and corticosterone, indicating that these diets induced a stress response. We conclude that reductions in blood pressure, heart rate, and insulin levels, similar to or greater than those obtained with regular physical exercise programs, can be achieved by IF and by dietary supplementation with 2DG by a mechanism involving stress responses. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 45 TC 65 Z9 66 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2003 VL 17 IS 6 BP 1133 EP + DI 10.1096/fj.02-0996fje PG 19 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 673KL UT WOS:000182580100026 PM 12709404 ER PT J AU Tadokoro, T Kobayashi, N Zmudzka, BZ Ito, S Wakamatsu, K Yamaguchi, Y Korossy, KS Miller, SA Beer, JZ Hearing, VJ AF Tadokoro, T Kobayashi, N Zmudzka, BZ Ito, S Wakamatsu, K Yamaguchi, Y Korossy, KS Miller, SA Beer, JZ Hearing, VJ TI UV-induced DNA damage and melanin content in human skin differing in racial/ethnic origin SO FASEB JOURNAL LA English DT Article DE melanocytes; skin color; photocarcinogenesis; cyclobutane pyrimidine dimers ID CYCLOBUTANE PYRIMIDINE DIMERS; CULTURED HUMAN MELANOCYTES; ULTRAVIOLET-B; 6-4 PHOTOPRODUCTS; MALIGNANT-MELANOMA; P53 GENE; CANCER; RADIATION; INDUCTION; EXPOSURE AB DNA damage induced by UV radiation is a critical event in skin photocarcinogenesis. However, the role of racial/ethnic origin in determining individual UV sensitivity remains unclear. In this study, we examined the relationships between melanin content and DNA damage induced by UV exposure in situ in normal human skin of different racial/ethnic groups, phototypes, and UV sensitivities. The minimal erythema dose (MED) was established for each subject exposed to UVA/UVB radiation, and skin was biopsied before as well as 7 min, 1 day, and 1 wk after UV exposure. There was great variation among individuals in the amount of DNA damage incurred and rates of its removal. The results show that after exposure to 1 MED of UV, the skin of subjects from all groups suffered significant DNA damage, and that increasing content of constitutive melanin inversely correlated with the amount of DNA damage. It is clear from these results that measured erythemal UV sensitivity of the skin (MED) is a more useful predictor of DNA photodamage than is racial/ethnic origin or skin phototype and that rates of DNA damage removal following UV radiation may be the critical determinant of the UV sensitivity (including predisposition to cancer) of the skin. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20852 USA. Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi 4701192, Japan. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1B25, Bethesda, MD 20892 USA. EM hearingv@nih.gov RI Yamaguchi, Yuji/B-9312-2008 NR 48 TC 148 Z9 155 U1 2 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2003 VL 17 IS 6 BP 1177 EP + DI 10.1096/fj.02-0865fje PG 22 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 673KL UT WOS:000182580100042 PM 12692083 ER PT J AU Liu, J Matyakhina, L Han, ZQ Sandrini, F Bei, T Stratakis, CA Papasopoulos, V AF Liu, J Matyakhina, L Han, ZQ Sandrini, F Bei, T Stratakis, CA Papasopoulos, V TI Molecular cloning, chromosomal localization of human peripheral-type benzodiazepine receptor- and protein kinase A regulatory subunit type 1A (PRKAR1A)-associated protein PAP7 and studies in PRKAR1A mutant cells and tissues SO FASEB JOURNAL LA English DT Article DE PBR; adrenal cortex; gonads; chromosome 1; steroidogenesis ID DIAZEPAM-BINDING INHIBITOR; LEYDIG TUMOR-CELLS; NODULAR ADRENOCORTICAL DISEASE; CARNEY COMPLEX; ENDOCRINE OVERACTIVITY; STEROID-BIOSYNTHESIS; SPOTTY PIGMENTATION; ADRENAL-CORTEX; STEROIDOGENESIS; CHOLESTEROL AB A mouse protein that interacts with the peripheral-type benzodiazepine receptor (PBR) and cAMP-dependent protein kinase A (PKA) regulatory subunit RIalpha. (PRKAR1A), named PBR and PKA-associated protein 7 (PAP7), was identified and shown to be involved in hormone-induced steroid biosynthesis. We report the identification of the human PAP7 gene, its expression pattern, genomic structure, and chromosomal mapping to 1q32-1q41. Human PAP7 is a 60-kDa protein highly homologous to the rodent protein. PAP7 is widely present in human tissues and highly expressed in seminal vesicles, pituitary, thyroid, pancreas, renal cortex, enteric epithelium, muscles, myocardium and in steroidogenic tissues, including the gonads and adrenal cortex. These tissues are also targets of Carney complex (CNC), a multiple neoplasia syndrome caused by germline inactivating PRKAR1A mutations (PRKAR1A-mut) and associated with primary pigmented nodular adrenocortical disease (PPNAD) and increased steroid synthesis. PAP7 and PRKAR1A expression were studied in PPNAD and in lymphoblasts from patients bearing PRKAR1A-mut. Like PRKAR1A, PAP7 was decreased in CNC lymphocytes and PPNAD nodules, but not in the surrounding cortex. These studies showed that, like in the mouse, human PAP7 is highly expressed in steroidogenic tissues, where it follows the pattern of PRKAR1A expression, suggesting that it participates in PRKAR1A-mediated tumorigenesis and hypercortisolism. C1 Georgetown Univ, Sch Med,Med Ctr, Dept Cell Biol, Div Hormone Res, Washington, DC 20057 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20057 USA. Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. NICHHD, Sect Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Papasopoulos, V (reprint author), Georgetown Univ, Sch Med,Med Ctr, Dept Cell Biol, Div Hormone Res, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM papadopv@georgetown.edu NR 41 TC 22 Z9 23 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2003 VL 17 IS 6 BP 1189 EP + DI 10.1096/fj.02-1066fje PG 27 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 673KL UT WOS:000182580100047 PM 12692076 ER PT J AU Burkman, RT Tang, MTC Malone, KE Marchbanks, PA McDonald, JA Folger, SG AF Burkman, RT Tang, MTC Malone, KE Marchbanks, PA McDonald, JA Folger, SG TI Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women's Contraceptive and Reproductive Experiences Study SO FERTILITY AND STERILITY LA English DT Article DE breast cancer; infertility; infertility drugs; human menopausal gonadotropins (hMG) ID FERTILITY DRUGS; COHORT; PROGESTERONE; CYCLES; LINK AB Objective: To determine the association between infertility drug use and invasive breast cancer in a population-based case-control study. Design: Multicenter case-control study. Setting: Women aged 35 to 64 years in metropolitan Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle. Patient(s): The 4,575 case patients had histologically confirmed primary invasive breast cancer. The 4,682 control subjects were women without breast cancer identified in the same geographic locations using randomized-digit dialing. Intervention(s): A standardized questionnaire focusing on reproductive health and family history as well as use of oral contraceptives and other hormones and infertility drugs was administered to all subjects. Data on the type of breast cancer were also obtained. Main Outcome Measure(s): Odds ratios examining the association between use of various infertility drugs and invasive breast cancer. Result(s): Overall, a history of infertility drug use was not associated with the risk of developing breast cancer. Compared with women who never used any fertility medication, however, women using human menopausal gonadotropin (hMG) for greater than or equal to6 months or for at least six cycles had a relative risk of breast cancer ranging between 2.7 to 3.8. Conclusion(s): Long-term use of certain infertility drugs could adversely affect risk of breast cancer. Additional confirmatory studies are needed. (C) 2003 by American Society for Reproductive Medicine. C1 NCI, Surveillance Epidemiol & End Results Registries, Atlanta, GA USA. NCI, Surveillance Epidemiol & End Results Registries, Detroit, MI USA. NCI, Surveillance Epidemiol & End Results Registries, Los Angeles, CA USA. NCI, Surveillance Epidemiol & End Results Registries, Seattle, WA USA. Univ Penn, Philadelphia, PA 19104 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NICHHD, Bethesda, MD 20892 USA. RP Burkman, RT (reprint author), Baystate Med Ctr, Dept Obstet & Gynecol, 759 Chestnut St, Springfield, MA 01199 USA. FU NCI NIH HHS [N01 CN-0532, N01 CN-65064, N01 PC-57010, N01 PC-67006]; NICHD NIH HHS [N01 HD 2-3166, N01 HD 3-3168, N01 HD 3-3174, N01 HD 3-3175, N01 HD 3-3176, Y01 HD-7022] NR 24 TC 45 Z9 49 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2003 VL 79 IS 4 BP 844 EP 851 DI 10.1016/S0015-0282(02)04950-6 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 664DA UT WOS:000182045400002 PM 12749419 ER PT J AU Ramirez, DC Chen, YR Mason, RP AF Ramirez, DC Chen, YR Mason, RP TI Immunochemical detection of hemoglobin-derived radicals formed by reaction with hydrogen peroxide: Involvement of a protein-tyrosyl radical SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE hemoglobin; hydrogen peroxide; immuno-spin trapping; red blood cells; free radicals ID RED-BLOOD-CELLS; ELECTRON-SPIN-RESONANCE; CYTOCHROME-C; HUMAN MYOGLOBIN; CROSS-LINKING; METHEMOGLOBIN; METMYOGLOBIN; HEME; H2O2; GENERATION AB To investigate the involvement of a hemoglobin radical in the human oxyhemoglobin (oxyHb) or metHb/ H2O2 system, we have used a new approach called "immuno-spin trapping," which combines the specificity and sensitivity of both spin trapping and antigen: antibody interactions. Previously, a novel rabbit polyclonal anti-DMPO nitrone adduct antiserum, which specifically recognizes protein radical-derived nitrone adducts, was developed and validated in our laboratory. In the present study, the formation of nitrone adducts on hemoglobin was shown to depend on the oxidation state of the iron heme, the concentrations of H2O2 and DMPO, and time as determined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The presence of reduced glutathione or L-ascorbate significantly decreased the level of nitrone adducts on metHb in a dose-dependent manner. To confirm the ELISA results, Western blotting analysis showed that only the complete system (oxy- or metHb/DMPO/H2O2) generates epitopes recognized by the antiserum. The specific modification of tyrosine residues on metHb by iodination nearly abolished antibody binding, while the thiylation of cysteine residues caused a small but reproducible decrease in the amount of nitrone adducts. These findings strongly suggest that tyrosine residues are the site of formation of the immunochemically detectable hemoglobin radical-derived nitrone adducts. In addition, we were able to demonstrate the presence of hemoglobin radical-derived nitrone adducts inside red blood cells exposed to H2O2 and DMPO. In conclusion, our new approach showed several advantages over EPR spin trapping with the anti-DMPO nitrone adduct antiserum by demonstrating the formation of tyrosyl radical-derived nitrone adduct(s) in human oxyHb/metHb at much lower concentrations than was possible with EPR and detecting radicals inside RBC exposed to H2O2. Published by Elsevier Science Inc. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27713 USA. RP Ramirez, DC (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr,Room F048-MD F0-02, Res Triangle Pk, NC 27713 USA. EM ramirez1@niehs.nih.gov RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 NR 49 TC 57 Z9 57 U1 1 U2 10 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 APR 1 PY 2003 VL 34 IS 7 BP 830 EP 839 DI 10.1016/S0891-5849(02)01437-5 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 658RX UT WOS:000181735200006 PM 12654471 ER PT J AU Ferrari, N Glod, J Lee, J Kobiler, D Fine, HA AF Ferrari, N Glod, J Lee, J Kobiler, D Fine, HA TI Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors SO GENE THERAPY LA English DT Article DE bone marrow; endothelial progenitor; cancer therapy; anti-angiogenesis ID HEMATOPOIETIC-CELLS; TUMOR ANGIOGENESIS; CD34(+) CELLS; STEM-CELLS; GROWTH; NEOVASCULARIZATION; PRECURSORS; BLOOD; MODEL; TRANSDUCTION AB Human and mouse proliferation-competent, bone marrow or peripheral circulation derived endothelial progenitor-like cells (EPCs) were isolated, expanded and genetically engineered ex vivo to express the beta galactosidase (beta-gal), green fluorescence protein or thymidine kinase (TK) genes using retrovirus-mediated gene transfer. Genetically labeled EPCs were transplanted into sublethally irradiated tumor-bearing mice and were found to migrate to and incorporate into the angiogenic vasculature of growing tumors while maintaining transgene expression. Ganciclovir treatment resulted in significant tumor necrosis in animals previously administered TK-expressing EPCs with no systemic toxicity. These results demonstrate the feasibility of using genetically modified EPCs as angiogenesis-selective gene-targeting vectors and the potential of this approach to mediate non-toxic and systemic antitumor responses. C1 NINDS, Neurooncol Branc, NCI, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), CelMed Biosci Inc, 2310 Alfred Nobel Blvd, St Laurent, PQ H4S 2A4, Canada. OI Ferrari, Nicoletta/0000-0002-6027-1035 NR 36 TC 65 Z9 72 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD APR PY 2003 VL 10 IS 8 BP 647 EP 656 DI 10.1038/sj.gt.3301883 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 667KP UT WOS:000182231000006 PM 12692593 ER PT J AU Hall, FS Li, XF Goeb, M Roff, S Hoggatt, H Sora, I Uhl, GR AF Hall, FS Li, XF Goeb, M Roff, S Hoggatt, H Sora, I Uhl, GR TI Congenic C57BL/6 mu opiate receptor (MOR) knockout mice: baseline and opiate effects SO GENES BRAIN AND BEHAVIOR LA English DT Article DE analgesia; conditioned place preference; congenic; locomotion; transgenic knockout mice ID INBRED MOUSE STRAINS; MORPHINE-INDUCED ANALGESIA; CENTRAL-NERVOUS-SYSTEM; G-PROTEIN ACTIVATION; OPIOID-RECEPTOR; DEFICIENT MICE; GENE; RESPONSES; LACKING; ANTINOCICEPTION AB Homozygous mu-opioid receptor (MOR) knockout (KO) mice developed on a chimeric C57B6/129SV background lack morphine-induced antinociception, locomotion and reward. Therefore it appears that MOR largely mediates these morphine actions. However, one factor that could affect the extent of knockout deficits in morphine-induced behavior is the genetic background against which the gene deletion is expressed. To examine the effect of genetic background chimeric C57B6/129SV MOR knockout mice from the 15th generation of those developed in our laboratory were backcrossed for 10 successive generations with C57BL/6 mice, a strain which is more sensitive to many of the properties of morphine, to produce congenic MOR (con-MOR) KO mice. Heterozygote conMOR KO mice display attenuated morphine locomotion and reduced morphine analgesia compared to wild-type mice. Homozygote conMOR KO mice display baseline hyperalgesia, no morphine place preference, no morphine analgesia and no morphine locomotion. These results are not qualitatively different from those observed in the MOR KO strain with a chimeric C57B6/129SV background, and suggest that although the strain has separate influences on these functions, it does not substantially interact with deletion of the p opiate receptor gene. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 49 TC 30 Z9 31 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD APR PY 2003 VL 2 IS 2 BP 114 EP 121 DI 10.1034/j.1601-183X.2003.00016.x PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 665YA UT WOS:000182147800006 PM 12884968 ER PT J AU Cherkasova, VA Hinnebusch, AG AF Cherkasova, VA Hinnebusch, AG TI Translational control by TOR and TAP42 through dephosphorylation of eIF2 alpha kinase GCN2 SO GENES & DEVELOPMENT LA English DT Article DE TOR; TAP42; translational control; eIF2 alpha kinase; GCN2 ID UNFOLDED PROTEIN RESPONSE; UNCHARGED TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; SIGNALING PATHWAY; EIF-2-ALPHA KINASE; GENE-EXPRESSION; CELL-GROWTH; YEAST; INITIATION; ACTIVATION AB Yeast protein kinase GCN2 stimulates the translation of transcriptional activator GCN4 by phosphorylating eIF2alpha in response to amino acid starvation. Kinase activation requires binding of uncharged tRNA to a histidyl tRNA synthetase-related domain in GCN2. Phosphorylation of serine 577 (Ser 577) in GCN2 by another kinase in vivo inhibits GCN2 function in rich medium by reducing tRNA binding activity. We show that rapamycin stimulates eIF2alpha phosphorylation by GCN2, with attendant induction of GCN4 translation, while reducing Ser 577 phosphorylation in nonstarved cells. The alanine 577 (Ala 577) mutation in GCN2 (S577A) dampened the effects of rapamycin on eIF2alpha phosphorylation and GCN4 translation, suggesting that GCN2 activation by rapamycin involves Ser 577 dephosphorylation. Rapamycin regulates the phosphorylation of Ser 577 and eIF2alpha by inhibiting the TOR pathway. Rapamycin-induced dephosphorylation of Ser 577, eIF2alpha phosphorylation, and induction of GCN4 all involve TAP42, a regulator of type 2A-related protein phosphatases. Our results add a new dimension to the regulation of protein synthesis by TOR proteins and demonstrate cross-talk between two major pathways for nutrient control of gene expression in yeast. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. NR 46 TC 172 Z9 181 U1 1 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 1 PY 2003 VL 17 IS 7 BP 859 EP 872 DI 10.1101/gad.1069003 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 664CT UT WOS:000182044700007 PM 12654728 ER PT J AU Hur, GM Lewis, J Yang, QF Lin, Y Nakano, H Nedospasov, S Liu, ZG AF Hur, GM Lewis, J Yang, QF Lin, Y Nakano, H Nedospasov, S Liu, ZG TI The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation SO GENES & DEVELOPMENT LA English DT Article DE RIP; NF-kappa B; DNA damage; genotoxic stress; signaling ID RECEPTOR-1 SIGNALING COMPLEX; TNF RECEPTOR-1; IONIZING-RADIATION; IKK ACTIVATION; CELL-DEATH; RECRUITMENT; APOPTOSIS; PROTEIN; PHOSPHORYLATION; PATHWAYS AB The transcription factor NF-kappaB is activated when cells are exposed to genotoxic stress. It has been suggested that DNA damage will trigger a cytoplasmic signaling that leads to the activation of IKK and NF-kappaB, but the signaling components upstream of IKK have not yet been identified. Here we report that the receptor interacting protein, RIP, is the IKK upstream component, essential for the activation of NF-kappaB by DNA damage. Also, our findings suggest that this NF-kappaB activation by DNA damage is not mediated by autocrine or TNF-R1 signaling pathway. In wild-type fibroblasts, DNA damage induced by agents such as adriamycin, campthothecin, and ionizing radiation induces NF-kappaB activation. We found, however, that DNA damage failed to activate NF-kappaB in RIP-/- fibroblasts. The induction Of IkappaBalpha degradation by DNA damage was normal in TNF-R1-/-, TRAF2-/-, TRAF5-/- and FADD-/- fibroblasts or when de novo protein synthesis was blocked. More importantly, the reconstitution of RIP expression in RIP-/- cells restores DNA damage-induced NF-kappaB activation. We also found that RIP forms a complex with IKK in response to DNA damage. Therefore, our study provides a possible mechanism for the initiation of the cytoplasmic signaling to activate NF-kappaB in response to DNA damage. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Japan Sci & Technol Corp, Juntendo Univ, Sch Med, Dept Immunol,PREST, Tokyo, Japan. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 FU NCI NIH HHS [N01CO12400] NR 31 TC 99 Z9 103 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 1 PY 2003 VL 17 IS 7 BP 873 EP 882 DI 10.1101/gad.1062403 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 664CT UT WOS:000182044700008 PM 12654725 ER PT J AU Jugessur, A Lie, RT Wilcox, AJ Murray, JC Taylor, JA Saugstad, OD Vindenes, HA Abyholm, F AF Jugessur, A Lie, RT Wilcox, AJ Murray, JC Taylor, JA Saugstad, OD Vindenes, HA Abyholm, F TI Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: A case-parent triad analysis SO GENETIC EPIDEMIOLOGY LA English DT Article DE birth defects; genetic-epidemiological study; linkage disequilibrium; case-parent triad design; log-linear model; gene-gene interaction ID GROWTH-FACTOR-ALPHA; RECURRENCE-PATTERN ANALYSIS; NONSYNDROMIC ORAL CLEFTS; CANDIDATE GENES; NO EVIDENCE; PALATE FUSION; LIP; POPULATION; LINKAGE; MICE AB We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL +/- P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL +/- P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32i among children homozygous for both the MSXI-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL +/- P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSXI-CA A4 allele, raising the possibility of interaction between these two genes. (C) 2003 Wiley-Liss, Inc. C1 Haukeland Univ Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. Univ Bergen, Sect Med Stat, N-5020 Bergen, Norway. Univ Bergen, Med Birth Registry Norway, N-5020 Bergen, Norway. NIEHS, Epidemiol Branch, Durham, NC USA. Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. Natl Hosp Norway, Dept Pediat Res, Oslo, Norway. Haukeland Univ Hosp, Dept Plast Surg, N-5021 Bergen, Norway. Natl Hosp Norway, Dept Plast Surg, Oslo, Norway. RP Jugessur, A (reprint author), Haukeland Univ Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. OI Wilcox, Allen/0000-0002-3376-1311 FU NIDCR NIH HHS [DE08559, DE11948] NR 45 TC 53 Z9 60 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2003 VL 24 IS 3 BP 230 EP 239 DI 10.1002/gepi.10223 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 664TR UT WOS:000182077700008 PM 12652527 ER PT J AU Brudno, M Do, CB Cooper, GM Kim, MF Davydov, E Green, ED Sidow, A Batzoglou, S AF Brudno, M Do, CB Cooper, GM Kim, MF Davydov, E Green, ED Sidow, A Batzoglou, S CA NISC Comparative Sequencing Progra TI LAGAN and Multi-LAGAN: Efficient tools for large-scale multiple alignment of genomic DNA SO GENOME RESEARCH LA English DT Article ID SEQUENCE ALIGNMENT; SEARCH; CONSERVATION; SIMILARITIES; IMPROVEMENT; PROTEINS; PROGRAM; SERVER; BLAST AB To compare entire genomes from different species, biologists increasingly need alignment methods that are efficient enough to handle long sequences, and accurate enough to correctly align the conserved biological features between distant species. We present LAGAN, a system for rapid global alignment of two homologous genomic sequences, and Multi-LAGAN, a system for multiple global alignment of genomic sequences. We tested our systems on a data set consisting of greater than 12 Mb of high-quality sequence from 12 vertebrate species. All the sequence was derived from the genomic region orthologous to an similar to1.5-Mb region on human chromosome 7q31.3. We found that both LAGAN and Multi-LAGAN compare favorably with other leading alignment methods in correctly aligning protein-coding exons, especially between distant homologs such as human and chicken, or human and fugu. Multi-LAGAN produced the most accurate alignments, while requiring just 75 minutes on a personal computer to obtain the multiple alignment of all 12 sequences. Multi-LAGAN is a practical method for generating multiple alignments of long genomic sequences at any evolutionary distance. Our systems are publicly available at http:/ / lagan.stanford.edu. C1 Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. Stanford Univ, Dept Genet, Stanford, CA 94305 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Batzoglou, S (reprint author), Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. RI Cooper, Gregory/D-6914-2011 OI Cooper, Gregory/0000-0001-5509-9923 NR 37 TC 640 Z9 669 U1 2 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD APR PY 2003 VL 13 IS 4 BP 721 EP 731 DI 10.1101/gr.926603 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 664DK UT WOS:000182046300018 PM 12654723 ER PT J AU Mir, AA Myakishev, MV Polesskaya, OO Moitra, J Petersen, D Miller, L Orosz, A Vinson, C AF Mir, AA Myakishev, MV Polesskaya, OO Moitra, J Petersen, D Miller, L Orosz, A Vinson, C TI A search for candidate genes for lipodystrophy, obesity and diabetes via gene expression analysis of A-ZIP/F-1 mice SO GENOMICS LA English DT Article DE genome scan; candidate genes; lipodystrophy; leptin; insulin; diabetes; obesity; microarray; S100A8; SLPI1 ID GENOME-WIDE SEARCH; CONGENITAL GENERALIZED LIPODYSTROPHY; MAJOR SUSCEPTIBILITY LOCUS; QUANTITATIVE-TRAIT LOCI; BODY-MASS INDEX; ADIPOSE-TISSUE; TRANSGENIC MICE; PIMA-INDIANS; INDEPENDENT REPLICATION; INSULIN-RESISTANCE AB Genome scans for diabetes have identified many regions of the human genome that correlate with the disease state. To identify candidate genes for type 2 diabetes, we examined the trans-enic A-ZIP/F-1 mouse. This mouse model has no white fat, resulting in abnormal levels of glucose, insulin, and leptin, making the A-ZIP/F-1 mice a good model for lipodystrophy and insulin resistance. We used cDNA-based microarrays to find differentially expressed genes in four tissues of these mice. We examined these results in the context of human linkage scans for lipodystrophy, obesity, and type 2 diabetes. We combined 199 known human orthologs of the misregulated mouse genes with 33 published human genome scans on a genome map. integrating expression data with human linkage results permitted us to suggest and prioritize candidate genes for lipodystrophy and related disorders. These genes include a cluster of 3 S100A genes on chromosome 1 and SLPI1 on chromosome 20. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIH, Lab Metab, Baltimore, MD 21224 USA. NIDA, IRP, Mol Neurobiol Branch, NIH, Baltimore, MD 21224 USA. NCI, Div Clin Sci, Med Branch, NIH, Baltimore, MD 21224 USA. RP Vinson, C (reprint author), NIH, Lab Metab, Baltimore, MD 21224 USA. NR 55 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR PY 2003 VL 81 IS 4 BP 378 EP 390 DI 10.1016/S0888-7543(03)00024-7 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 667KQ UT WOS:000182231100005 PM 12676562 ER PT J AU Quadagno, J Stahl, SM AF Quadagno, J Stahl, SM TI Challenges in nursing home care: A research agenda SO GERONTOLOGIST LA English DT Editorial Material ID QUALITY C1 Florida State Univ, Pepper Inst Aging & Publ Policy, Tallahassee, FL 32306 USA. NIA, Behav & Social Res Program, NIH, Bethesda, MD 20892 USA. RP Quadagno, J (reprint author), Florida State Univ, Pepper Inst Aging & Publ Policy, Tallahassee, FL 32306 USA. NR 22 TC 7 Z9 7 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD APR PY 2003 VL 43 SI 2 BP 4 EP 6 PG 3 WC Gerontology SC Geriatrics & Gerontology GA 670XJ UT WOS:000182435100001 PM 12711719 ER PT J AU Emmen, JMA Korach, KS AF Emmen, JMA Korach, KS TI Estrogen receptor knockout mice: phenotypes in the female reproductive tract SO GYNECOLOGICAL ENDOCRINOLOGY LA English DT Review DE estrogen; estrogen receptor; mouse; reproductive tract ID BETA MESSENGER-RNA; ALPHA ER-ALPHA; GROWTH-FACTOR; TARGETED DISRUPTION; OVARIAN STIMULATION; GENE POLYMORPHISMS; CHROMOSOMAL LOCALIZATION; DIFFERENTIAL EXPRESSION; PROGESTERONE-RECEPTOR; TISSUE DISTRIBUTION AB There is a broad spectrum of organ systems that respond to estrogen hormones, including the female and male reproductive tracts, mammary gland, the skeleton, cardiovascular system and central nervous system. The physiological effects Of estrogens are mediated by the estrogen receptor, a member of the nuclear receptor superfamily of transcription factors. Two estrogen receptors have been, identified: the originally described estrogen receptor a (ERalpha) and the more recently discovered estrogen receptor beta(ERbeta). Three different estrogen receptor knockout (ERKO) mouse models were generated, carrying a null mutation in the ERalpha gene (alphaERKO), the ERbeta gene (betaERKO) or both genes (alphabetaERKO). The generation of the different ERKO mice provides ideal models for studying the physiological consequences of the complete lack of estrogen receptor activity and the distinct roles of both estrogen receptors in various tissues. This review summarizes the phenotypes principally seen in the female reproductive system of the different ERKO mice. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233,MD B3-02, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 59 TC 15 Z9 15 U1 0 U2 2 PU PARTHENON PUBLISHING GROUP PI LANCASTER PA RICHMOND HOUSE, WHITE CROSS, SOUTH ROAD, LANCASTER LA1 4XQ, ENGLAND SN 0951-3590 J9 GYNECOL ENDOCRINOL JI Gynecol. Endocrinol. PD APR PY 2003 VL 17 IS 2 BP 169 EP 176 PG 8 WC Endocrinology & Metabolism; Obstetrics & Gynecology SC Endocrinology & Metabolism; Obstetrics & Gynecology GA 668YB UT WOS:000182323200012 PM 12737678 ER PT J AU Harris, KM AF Harris, KM TI How do patients choose physicians? Evidence from a national survey of enrollees in employment-related health plans SO HEALTH SERVICES RESEARCH LA English DT Article DE consumer choice of physician; patient choice of physician; quality information; doctor-switching; physician-switching; and racial differences ID CONSUMER INFORMATION; CARE; QUALITY; MARKET; TRUST; PRICE AB Objective. This study examines the process by which patients search for and choose physicians. Data Source. A survey to a random sample of individuals between the ages of 21 and 64 with employer-related health benefits, drawn from a nationally representative panel of households. Study Design. Logit models are used to measure the effect of patient characteristics on the probability of (1) using alternative sources of information to support the choice of a current physician, (2) seriously considering another physician before choosing a current physician, and (3) stating a willingness to switch physicians when information suggests that other health plan doctors receive higher quality ratings: Principal Findings. Although a minority of respondents actively searches for a physician, there appears to be substantial variation in the degree of consumer activism across patient subgroups. Poor health status, higher levels of service use in the past year, and stronger ties to individual physicians are associated with less consumer activism. At the same time, greater levels of consumer activism were found among racial and ethnic minorities, among those who report using information to choose their physicians, and among those who switched physicians as a result of dissatisfaction some time in the past five years. Source of quality information (medical experts versus patient advocates) did not influence stated willingness to switch physicians. Conclusions. Despite predictions of the increasing importance of consumer choice in shaping the health care delivery system, the results dargely confirm the image depicted in the previous literature of patients as passive health care consumers of physician services, and highlight the importance of investments in the development of decision support tools in consumer-driven health care systems. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RAND Corp, Arlington, VA USA. RP Harris, KM (reprint author), NIAAA, NIH, 6000 Execut Blvd,Suite 505, Bethesda, MD 20892 USA. NR 31 TC 57 Z9 57 U1 1 U2 8 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD APR PY 2003 VL 38 IS 2 BP 711 EP 732 DI 10.1111/1475-6773.00141 PG 22 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 677EF UT WOS:000182793400014 PM 12785569 ER PT J AU Thorgeirsson, SS AF Thorgeirsson, SS TI Hunting for tumor suppressor genes in liver cancer SO HEPATOLOGY LA English DT Editorial Material ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN HEPATOCELLULAR-CARCINOMA; PEUTZ-JEGHERS-SYNDROME; CELL-LINES; BREAST-CANCER; LKB1; RETINOBLASTOMA; ABNORMALITIES; EXPRESSION; REVEALS C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 4146A1,37 Convent Dr,MSC4262, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 23 TC 12 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2003 VL 37 IS 4 BP 739 EP 741 DI 10.1053/jhep.2003.50174 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 663KK UT WOS:000182004600003 PM 12668963 ER PT J AU Jensen, MR Factor, VM Fantozzi, A Helin, K Huh, CG Thorgeirsson, SS AF Jensen, MR Factor, VM Fantozzi, A Helin, K Huh, CG Thorgeirsson, SS TI Reduced hepatic tumor incidence in cyclin G1-deficient mice SO HEPATOLOGY LA English DT Article ID DNA-DAMAGE; RETROVIRAL VECTOR; CHROMOSOMAL LOCALIZATION; G1 CONSTRUCT; G2/M ARREST; NUDE-MICE; GENE; EXPRESSION; GROWTH; P53 AB Cyclin G1 is a transcriptional target of the tumor suppressor p53, and its expression is increased after DNA damage. Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A. To understand the biologic role of cyclin G1, we have generated cyclin G1-deficient mice. In agreement with previous results, we showed that these mice develop normally, and that proliferation and induction of cellular senescence in cyclin G1-deficient mouse embryo fibroblasts are indistinguishable from wild-type fibroblasts. However, we found that the p53 levels in the cyclin G1-deficient mice are 2-fold higher that in wild-type mice. Moreover, we showed that treatment of mice with the alkylating agent 1,4-bis [N,N'-di(ethylene)-phosphamide]piperazine (Dipin), followed by partial hepatectomy, decreased G1-S transition in cyclin G1-null hepatocytes as compared with wild type. Finally, we found a significant decrease in tumor incidence, mass, and malignancy in both male and female cyclin G1-null mice after treatment with the potent hepatocarcinogen N-diethylnitrosamine. Taken with recent published data, our results suggest that cyclin G1, together with Mdm2, constitute a part of a negative feedback system that attenuates the activity of p53. In conclusion, our data suggest that the decreased tumor susceptibility after loss of cyclin G1 function is caused by the increased tumor suppressor action of p53. C1 NCI, Expt Carcinogenesis Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. European Inst Oncol, Dept Expt Oncol, Milan, Italy. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Canc Res Ctr, NIH, 37 Convent Dr,MSC 4262,Bldg 37,Room 4146, Bethesda, MD 20892 USA. RI Jensen, Michael/E-9677-2011; OI Helin, Kristian/0000-0003-1975-6097 NR 43 TC 45 Z9 52 U1 0 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2003 VL 37 IS 4 BP 862 EP 870 DI 10.1053/jhep.2003.50137 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 663KK UT WOS:000182004600019 PM 12668979 ER PT J AU Soza, A Hoofnagle, JH AF Soza, A Hoofnagle, JH TI Threshold for neutropenia in the adjustment of interferon treatment in HCV infection - Reply SO HEPATOLOGY LA English DT Letter ID HEPATITIS-C; THERAPY C1 NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Soza, A (reprint author), NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2003 VL 37 IS 4 BP 950 EP 950 DI 10.1053/jhep.2003.50153 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 663KK UT WOS:000182004600037 ER PT J AU Kubo, E Singh, DP Fatma, N Shinohara, T Zelenka, P Reddy, VN Chylack, LT AF Kubo, E Singh, DP Fatma, N Shinohara, T Zelenka, P Reddy, VN Chylack, LT TI Cellular distribution of lens epithelium-derived growth factor (LEDGF) in the rat eye: loss of LEDGF from nuclei of differentiating cells SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE LEDGF; immunohistochemistry; differentiation; in situ hybridization; lentoid body; LEC explants ID DEPENDENT KINASE INHIBITOR; OXIDATIVE-STRESS; FIBER DIFFERENTIATION; APAF-1 APOPTOSOME; FACTOR FGF; SURVIVAL; EXPRESSION; P57(KIP2); GENE; KERATINOCYTES AB Lens epithelium-derived growth factor (LEDGF) enhances the survival and growth of cells. To understand LEDGF's spatial localization and its putative function(s) during proliferation and differentiation, we localized LEDGF during terminal differentiation in whole rat lenses, lens epithelial cell (LEC) explants stimulated with FGF-2, and insulin, iris, human LECs with lentoids. In addition, intracellular localization of LEDGF was performed in other ocular tissues: ciliary body, retina, and cornea. We found the immunopositivity of nuclear LEDGF decreased in LECs of the equatorial region. In contrast, immunopositivity of LEDGF was detected in the cytoplasm of LECs and superficial fiber cells. After treating LEC explants with FGF-2 and insulin, which are known to be differentiating factors for LECs, the nuclei of these cells showed no LEDGF immunopositivity, but explants did express p57(kip2), a differentiation marker protein. Also, immunopositive LEDGF was not detected in the nuclei of differentiated cells, lentoid body, and corneal epithelial cells. This demonstrated that the loss of LEDGF from the nucleus may be associated with the process of terminal differentiation that might be in some way common with the biochemical mechanisms of apoptosis. The spatial and temporal distribution of LEDGF in the present study also provides a vision for further investigation as to how this protein is involved in cell fate determination. C1 Univ Nebraska, Med Ctr, Dept Ophthalmol, Omaha, NE 68198 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Ophthalm Res, Boston, MA 02115 USA. Fukui Med Univ, Dept Ophthalmol, Fukui, Japan. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Ophthalmol & Visual Sci, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. RP Singh, DP (reprint author), Univ Nebraska, Med Ctr, Dept Ophthalmol, Wittson Hall,Room 2009, Omaha, NE 68198 USA. OI Shinohara, Toshimichi/0000-0002-7197-9039 FU NEI NIH HHS [EY07003, EY10824, EY12015, EY13394] NR 53 TC 24 Z9 24 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD APR PY 2003 VL 119 IS 4 BP 289 EP 299 DI 10.1007/s00418-003-0518-3 PG 11 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 684ZF UT WOS:000183235800003 PM 12692670 ER PT J AU Trovato, M Grosso, M Vitarelli, E Ruggeri, RM Alesci, S Trimarchi, F Barresi, G Benvenga, S AF Trovato, M Grosso, M Vitarelli, E Ruggeri, RM Alesci, S Trimarchi, F Barresi, G Benvenga, S TI Distinctive expression of STAT3 in papillary thyroid carcinomas and a subset of follicular adenomas SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE hepatocyte growth factor; c-met; interleukin 6; interleukin 6 receptor; STAT3 ID HEPATOCYTE GROWTH-FACTOR; C-MET; TYROSINE KINASE; SCATTER FACTOR; FACTOR-RECEPTOR; RT-PCR; REARRANGEMENTS; HGF; INTERLEUKIN-6; ACTIVATION AB Hepatocyte growth factor (HGF), HGF receptor (c-met) and the interleukin 6 (IL-6) are expressed in thyroid nodules. In extra-thyroidal tissues, the HGF/c-met and IL-6/IL-6 receptor (IL-6R) systems activate STAT3, a member of the signal transducers and activators of transcription (STATs) family. To evaluate whether either system utilizes STAT3 in thyroid nodules, we examined the immunohistochemical expression of HGF, c-met, IL-6, IL-6R, STAT3 in 6 normal thyroids and in 68 thyroid nodules. STAT3 expression was observed in 12/12 (100%) papillary thyroid carcinomas (PTC) but in none of the follicular tumors. Among benign thyroid nodules, only 2/10 (20%) follicular adenomas (FA) were STAT3(+). All these 14 STAT3(+) cases expressed both HGF and c-met, but only 5 PTC co-expressed IL-6 and IL-6R and the 2 FA were IL-6(+) but IL-6R(-). The remaining 8 FA were all HGF(-)/c-met(-), but IL-6(+); of these 8, only 2 were also IL-6R(+). In conclusion, in thyroid nodules STAT3 is expressed only in PTC and a number of FA. Since these cases are consistently HGF(+)/c-met(+) and only one-third of them co-express IL-6/IL-6R, STAT3 expression correlates with the HGF/c-met expression, not with the IL-6/IL-6R expression. The 100% rate of expression of the HGF/c-met/STAT3 signaling in PTC could be relevant for the establishment of the papillary phenotype. Because of the communeness of a HGF/c-met/STAT3 pattern between all PTC and a subset of FA, we speculate that a fraction of FA may progress to PTC. C1 Univ Messina Policlin, Cattedra Endocrinol, Clin Expt Dept Med & Pharmacol, Endocrinol Sect, I-98125 Messina, Italy. Univ Messina Policlin, Dept Pathol, I-98125 Messina, Italy. NICHHD, Pediat & Reprod & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Benvenga, S (reprint author), Univ Messina Policlin, Cattedra Endocrinol, Clin Expt Dept Med & Pharmacol, Endocrinol Sect, Padiglione H 4 Piano, I-98125 Messina, Italy. NR 42 TC 18 Z9 19 U1 0 U2 0 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD APR PY 2003 VL 18 IS 2 BP 393 EP 399 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 655WP UT WOS:000181575900008 PM 12647789 ER PT J AU Mocellin, S Wang, E Panelli, M Rossi, CR Marincola, FM AF Mocellin, S Wang, E Panelli, M Rossi, CR Marincola, FM TI Use of laser scanning cytometry to study tumor microenvironment SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE laser scanning cytometry; tumor biology ID COMPARATIVE GENOMIC HYBRIDIZATION; PARAFFIN-EMBEDDED TISSUE; DNA-PLOIDY ANALYSIS; CELL-CYCLE; IMMUNOPHENOTYPIC ANALYSIS; METASTATIC MELANOMA; FLOW-CYTOMETRY; CHROMOSOMAL INSTABILITY; MULTIPARAMETER ANALYSIS; IMMUNE RESPONSIVENESS AB The study of phenomena occurring in the tumor microenvironment is a challenging task because of technical difficulties, particularly when dealing with hypocellular specimens. Laser scanning cytometry (LSC) is a new laboratory technology that has been recently introduced to overcome the limitations of other traditional technologies. By combining the properties and the advantages of flow cytometry (FC) and immunohistochemistry (IHC), LSC allows the investigator to obtain objective information on DNA content, protein expression and cellular localization is combination with morphological features. It has been already shown that LSC results are reliable compared to more traditional technologies, and its implementation in the clinical routine is under way. Its use in oncology, which is rapidly expanding, spans from apoptosis analysis to DNA content quantitation and tumor cell phenotyping. Here we describe the technology underlying this novel fluorescence-based device, review its use in oncology by dissecting the phenomena occur-ring in the tumor microenvironment and propose its application for the immunological follow-up of malignant lesions undergoing immunotherapeutic manipulation. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Padua, Dept Oncol & Surg Sci, Surg Branch, I-35100 Padua, Italy. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C-711,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. RI Rossi, Carlo Riccardo/A-7685-2010 OI Rossi, Carlo Riccardo/0000-0001-7875-5655 NR 58 TC 2 Z9 2 U1 0 U2 0 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD APR PY 2003 VL 18 IS 2 BP 609 EP 615 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 655WP UT WOS:000181575900030 PM 12647811 ER PT J AU Lizee, G Aerts, JL Gonzalez, MI Chinnasamy, N Morgan, RA Topalian, SL AF Lizee, G Aerts, JL Gonzalez, MI Chinnasamy, N Morgan, RA Topalian, SL TI Real-time quantitative reverse transcriptase-polymerase chain reaction as a method for determining lentiviral vector titers and measuring transgene expression SO HUMAN GENE THERAPY LA English DT Article ID RNA-PROCESSING ENZYME; VIVO GENE DELIVERY; IN-VIVO; RETROVIRAL VECTORS; RT-PCR; CELLS; IDENTIFICATION; TRANSDUCTION; THERAPY; ELEMENT AB The use of lentiviral vectors for basic research and potential future clinical applications requires methodologies that can accurately determine lentiviral titers and monitor viral transgene expression within target cells, beyond the context of reporter genes typically used for this purpose. Here we describe a quantitative RT-PCR (qRT-PCR) method that achieves both goals using primer sequences that are specific for the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), an enhancer contained in many retroviral vectors and that is incorporated in the 3' UTR of nascent transgene transcripts. Quantitation of titers of three recombinant lentiviruses, genetically identical except for the transgene, demonstrated consistent differences in titer that were likely due to transgene-associated toxicity in producer cells and target cells. Viruses encoding the tumor-associated antigens tyrosinase and neo-poly(A) polymerase yielded reproducibly lower titers than a virus encoding enhanced green fluorescent protein (GFP) at the viral RNA, integrated DNA, and transgene mRNA levels, as measured by WPRE qPCR. Furthermore, the magnitude of differences in expression of the three transgenes in transduced target cells could not have been predicted by measuring vector DNA integration events. Since transgene expression in target cells is the most common goal of lentiviral transduction, and since methods to quantify transgene expression on the protein level are not always readily available, qRT-PCR based on a nucleotide sequence included in the transcript provides a useful tool for titering novel recombinant lentiviruses. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. St Lukes Hosp, Milwaukee, WI 53215 USA. RP Topalian, SL (reprint author), NCI, Surg Branch, NIH, 10-2B47, Bethesda, MD 20892 USA. RI Aerts, Joeri/J-6957-2014 OI Aerts, Joeri/0000-0002-9902-3696 NR 38 TC 73 Z9 81 U1 2 U2 6 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2003 VL 14 IS 6 BP 497 EP 507 DI 10.1089/104303403764539387 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 673VT UT WOS:000182601500001 PM 12718761 ER PT J AU Vozarova, B Fernandez-Real, JM Knowler, WC Gallart, L Hanson, RL Gruber, JD Ricart, W Vendrell, J Richart, C Tataranni, PA Wolford, JK AF Vozarova, B Fernandez-Real, JM Knowler, WC Gallart, L Hanson, RL Gruber, JD Ricart, W Vendrell, J Richart, C Tataranni, PA Wolford, JK TI The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians SO HUMAN GENETICS LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; PIMA-INDIANS; INSULIN SENSITIVITY; CIRCULATING INTERLEUKIN-6; GENE; INFLAMMATION; RESISTANCE; TRANSCRIPTION; PREVALENCE; MARKERS AB Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position -174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians-a population with high rates of insulin resistance and T2DM-and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (-174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P = 0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P = 0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P = 0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Hosp Univ Josep Trueta, Diabet Endocrinol & Nutr Unit, Girona, Spain. Univ Rovira & Virgili, Hosp Univ Joan XXIII, Endocrinol & Res Unit, Tarragona, Spain. RP Wolford, JK (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Ricart, Wifredo/0000-0002-3452-9098; de Courten, Barbora/0000-0001-8760-2511; Fernandez-Real, Jose Manuel/0000-0002-7442-9323 NR 28 TC 124 Z9 129 U1 0 U2 8 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2003 VL 112 IS 4 BP 409 EP 413 DI 10.1007/s00439-003-0912-x PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 671KP UT WOS:000182464200012 PM 12589429 ER PT J AU Pan, CJ Chen, LY Mansfield, BC Salani, B Varesio, L Chou, JY AF Pan, CJ Chen, LY Mansfield, BC Salani, B Varesio, L Chou, JY TI The signature motif in human glucose-6-phosphate transporter is essential for microsomal transport of glucose-6-phosphate SO HUMAN GENETICS LA English DT Article ID DISEASE TYPE 1B AB Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Sequence alignments identify a signature motif shared by G6PT and a family of transporters of phosphorylated metabolites. Two null signature motif mutations have been identified in the G6PT gene of GSD-Ib patients. In this study, we characterize the activity of seven additional mutants within the motif. Five mutants lack microsomal G6P uptake activity and one retains residual activity, suggesting that in G6PT the signature motif is a functional element required for microsomal glucose-6-phosphate transport. C1 NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Ist Giannina Gaslini, Mol Biol Lab, I-16148 Genoa, Italy. RP Chou, JY (reprint author), NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. RI varesio, luigi/J-8261-2016 OI varesio, luigi/0000-0001-5659-2218 NR 8 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2003 VL 112 IS 4 BP 430 EP 433 DI 10.1007/s00439-002-0903-3 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 671KP UT WOS:000182464200016 PM 12560945 ER PT J AU Taylor, JP Tanaka, F Robitschek, J Sandoval, CM Taye, A Markovic-Plese, S Fischbeck, KH AF Taylor, JP Tanaka, F Robitschek, J Sandoval, CM Taye, A Markovic-Plese, S Fischbeck, KH TI Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPANDED POLYGLUTAMINE; ANDROGEN RECEPTOR; INTRANUCLEAR INCLUSIONS; NUCLEAR-LOCALIZATION; MUSCULAR-ATROPHY; TRANSGENIC MICE; AGGREGATION; DISEASE; SYSTEM AB Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Taylor, JP (reprint author), NINDS, Neurogenet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3B-14, Bethesda, MD 20892 USA. FU NINDS NIH HHS [K22-NS44125-01] NR 28 TC 279 Z9 288 U1 0 U2 6 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 APR 1 PY 2003 VL 12 IS 7 BP 749 EP 757 DI 10.1093/hmg/ddg074 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 662ZZ UT WOS:000181981400006 PM 12651870 ER PT J AU Deng, CX Wang, RH AF Deng, CX Wang, RH TI Roles of BRCA1 in DNA damage repair: a link between development and cancer SO HUMAN MOLECULAR GENETICS LA English DT Review ID EARLY EMBRYONIC LETHALITY; DOUBLE-STRAND BREAKS; TRANSCRIPTION-COUPLED REPAIR; SUPPRESSOR GENE BRCA1; TARGETED DISRUPTION; MISMATCH REPAIR; MICE LACKING; GENOMIC INSTABILITY; IONIZING-RADIATION; CHROMOSOME SYNAPSIS AB DNA damage causes devastating problems for developing organisms. Recent studies reveal that BRCA1 plays essential roles in homologous recombinational repair, non-homologous end joining, and nucleotide excision repair. BRCA1 mediates these functions by interaction with components of the DNA repair machinery and by regulating expression of genes that are involved in these DNA damage repair pathways. Consequently, the absence of BRCA1 results in accumulation of chromosome damage, cell cycle abnormalities and apoptosis, leading to developmental abnormalities and adult tumorigenesis. In this review, we discuss recent advances regarding our understanding of the functions of BRCA1 in DNA damage repair and cellular responses that link development and cancer. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 128 TC 87 Z9 87 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 1 PY 2003 VL 12 SI 1 BP R113 EP R123 DI 10.1093/hmg/ddg082 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 672HN UT WOS:000182515300013 PM 12668603 ER PT J AU Roessler, E Muenke, M AF Roessler, E Muenke, M TI How a Hedgehog might see holoprosencephaly SO HUMAN MOLECULAR GENETICS LA English DT Review ID STEROL-SENSING DOMAIN; CENTRAL-NERVOUS-SYSTEM; BASAL-CELL CARCINOMAS; HUMAN SONIC HEDGEHOG; VENTRAL NEURAL-TUBE; PROTEIN-KINASE-A; LEFT-RIGHT AXIS; CUBITUS-INTERRUPTUS; SIGNALING PATHWAY; LIMB DEVELOPMENT AB Detailed knowledge of the Hedgehog signaling pathway is fundamental to an understanding of vertebrate development as well as several birth defects in humans. Here we review various aspects of Hedgehog synthesis, secretion, distribution and function in the context of the most common anomaly of the developing forebrain in humans, holoprosencephaly. Genetic studies in numerous model organisms are beginning to elucidate the factors that are likely candidates for the causes of early embryonic defects in humans, including holoprosencephaly. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 10,10C103, Bethesda, MD 20892 USA. NR 150 TC 40 Z9 41 U1 1 U2 10 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 APR 1 PY 2003 VL 12 SI 1 BP R15 EP R25 DI 10.1093/hmg/ddg058 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 672HN UT WOS:000182515300003 PM 12668593 ER PT J AU Slavotinek, A Biesecker, LG AF Slavotinek, A Biesecker, LG TI Genetic modifiers in human development and malformation syndromes, including chaperone proteins SO HUMAN MOLECULAR GENETICS LA English DT Article ID BARDET-BIEDL-SYNDROME; HIRSCHSPRUNG-DISEASE; CYSTIC-FIBROSIS; DIGENIC INHERITANCE; AGGREGATE FORMATION; ALAGILLE-SYNDROME; TRIALLELIC INHERITANCE; MOLECULAR CHAPERONES; HUNTINGTONS-DISEASE; JAGGED1 MUTATIONS AB Rapid developments in the elucidation of simple Mendelian traits in humans, the complexity of genotype-phenotype relationships, and the growing appreciation of complex genetic traits have conspired to focus interest on the role of modifier genes in humans. This paper reviews categories of genetic modifiers and their effects and then discusses non-Mendelian inheritance patterns involving modifier genes. Although genetic models from many disease classes of human and model systems will be considered, we focus this review on the implications for the understanding of pleiotropic malformation syndromes. Genetic modifiers have so far been molecularly defined in relatively few malformation syndromes, but the rapid acknowledgement of their critical role in human development is an exciting advance in contemporary attempts to understand the relationship of phenotype and genotype. C1 Univ Calif San Francisco, Dept Pediat, Div Genet, San Francisco, CA 94143 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Slavotinek, A (reprint author), Univ Calif San Francisco, Dept Pediat, Div Genet, Room U585P,533 Parnassus St, San Francisco, CA 94143 USA. NR 74 TC 24 Z9 24 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 1 PY 2003 VL 12 SI 1 BP R45 EP R50 DI 10.1093/hmg/ddg099 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 672HN UT WOS:000182515300006 PM 12668596 ER PT J AU Scriver, CR Hurtubise, M Konecki, D Phommarinh, M Prevost, L Erlandsen, H Stevens, R Waters, PJ Ryan, S McDonald, D Sarkissian, C AF Scriver, CR Hurtubise, M Konecki, D Phommarinh, M Prevost, L Erlandsen, H Stevens, R Waters, PJ Ryan, S McDonald, D Sarkissian, C TI PAHdb 2003: What a locus-specific knowledgebase can do SO HUMAN MUTATION LA English DT Article DE phenylalanine hydroxylase; phenylketonuria; PKU; database; genotype-phenotype; hyperphenylalaninemia; HPA ID HUMAN PHENYLALANINE-HYDROXYLASE; KINETIC VARIANT FORM; STRUCTURAL BASIS; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; PHENYLKETONURIA MUTATIONS; RECURRENT MUTATION; QUEBEC POPULATIONS; MISSENSE MUTATION; NORTHERN-IRELAND AB PAHdb, a legacy of and resource in genetics, is a relational locus-specific database (http:// www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n = 439, putative disease-causing) and benign alleles (n = 41, putative untranslated polymorphisms) at the human phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or by in vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are point mutations causing missense in translation of which few have a primary effect on PAH enzyme kinetics. Most apparently have a secondary effect on its function through misfolding, aggregation, and intracellular degradation of the protein. Some point mutations create new splice sites. A subset of primary PAH mutations that are tetrahydrobiopterin-responsive is highlighted on a Curators' Page. A clinical module describes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylketonuria [PKU]), their inheritance, and their treatment. PAHdb contains data on the mouse gene (Pah) and on four orthologous mutant mouse models and their use (for example, in research on oral treatment of PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]). (C) 2003 Wiley-Liss, Inc. C1 McGill Univ, Hlth Sci Ctr, Dept Human Genet, Montreal, PQ, Canada. McGill Univ, Hlth Sci Ctr, Dept Biol, Montreal, PQ, Canada. McGill Univ, Hlth Sci Ctr, Dept Pediat, Montreal, PQ, Canada. NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA USA. Childrens & Womens Hlth Ctr British Columbia, Biochem Genet Lab, Vancouver, BC, Canada. Wichita State Univ, Dept Biol Sci, Wichita, KS 67208 USA. RP Scriver, CR (reprint author), McGill Univ, Ctr Hosp, Montreal Childrens Hosp, Inst Res, A-717,2300 Tupper St, Montreal, PQ H3H 1P3, Canada. EM charles.scriver@mcgill.ca RI Stevens, Raymond/K-7272-2015 OI Stevens, Raymond/0000-0002-4522-8725 NR 78 TC 102 Z9 110 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD APR PY 2003 VL 21 IS 4 BP 333 EP 344 DI 10.1002/humu.10200 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 662CB UT WOS:000181927400002 PM 12655543 ER PT J AU Hsu, YT Hou, Q Cymbalyuk, E Youle, R AF Hsu, YT Hou, Q Cymbalyuk, E Youle, R TI Generation and characterization of species-specific anti-Bcl-X-L monoclonal antibodies SO HYBRIDOMA AND HYBRIDOMICS LA English DT Article ID CELL-DEATH; APOPTOSIS; BAX; BCL-X(L); MITOCHONDRIA; INHIBITION; CYTOSOL AB Bcl-X-L is a pro-survival member of the Bcl-2 family that plays an important role in apoptosis regulation. As a first step to carry out the molecular characterization of this protein, we have generated five monoclonal antibodies (MAbs) directed against synthetic peptides corresponding to the flexible loop region of human and murine Bcl-X-L. These antibodies display species specificity and are suitable for Western blotting, immunofluorescence labeling, and immunoprecipitation. These results suggest that these antibodies can serve as important tools for the detection and purification of endogenous and ectopically expressed human and murine Bcl-X-L. C1 Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hsu, YT (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 173 Ashley Ave,Basic Sci Bldg,Room 526, Charleston, SC 29425 USA. FU NINDS NIH HHS [R01 NS40932] NR 11 TC 3 Z9 3 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0272-457X J9 HYBRIDOMA HYBRIDOM JI Hybrid. Hybridomics PD APR PY 2003 VL 22 IS 2 BP 91 EP 95 DI 10.1089/153685903321948012 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 689FY UT WOS:000183482000004 PM 12831534 ER PT J AU Freitag, MH Larson, MG Levy, D Benjamin, EJ Wang, TJ Leip, EP Wilson, PWF Vasan, RS AF Freitag, MH Larson, MG Levy, D Benjamin, EJ Wang, TJ Leip, EP Wilson, PWF Vasan, RS TI Plasma brain natriuretic peptide levels and blood pressure tracking in the Framingham Heart Study SO HYPERTENSION LA English DT Article DE natriuretic peptides; blood pressure; hypertension, essential; epidemiology; hemodynamics ID ESSENTIAL-HYPERTENSION; GENE-EXPRESSION; ATRIAL; DISEASE; ACTIVATION; STIFFNESS; RECEPTOR; IMPACT AB Increased brain natriuretic peptide (BNP) expression in the ventricles antedates elevated blood pressure (BP) in experimental studies. We hypothesized that higher plasma BNP levels in nonhypertensive individuals may be associated with a greater likelihood of future BP increase and/or hypertension. We evaluated the relations of plasma BNP to longitudinal BP tracking and incidence of hypertension in 1801 nonhypertensive Framingham Heart Study participants (mean age, 56 years; 57% women) by using gender-specific multivariable logistic regression. Progression of BP stage was defined as an increment of one or more BP categories, as classified by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Hypertension was defined as a systolic BP greater than or equal to140 or diastolic BP greater than or equal to90 mm Hg or use of antihypertensive medications. On follow-up 4 years from baseline, progression of BP category was observed in 36.2% of men and 33.1% of women; hypertension developed in 16.4% of men and 15.5% of women. In multivariable models adjusting for known risk factors, elevated plasma BNP level was associated with increased risk of BP progression in men (odds ratio of 1.15 for trend across categories, P=0.046) but not in women (P=0.82). There were no significant trends of increasing incidence of hypertension across BNP categories in men or women. In our community-based sample, higher plasma BNP levels were associated with increased risk of BP progression in men but not women. Additional investigations are warranted to confirm these findings and elucidate the basis for these gender-related differences. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. MetroW Med Ctr, Framingham, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. RI Freitag, Michael/G-4887-2011; OI Freitag, Michael/0000-0002-7572-2011; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL04334, N01-HC-25195] NR 37 TC 41 Z9 49 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2003 VL 41 IS 4 BP 978 EP 983 DI 10.1161/01.HYP.0000061116.20490.8D PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 663PH UT WOS:000182013600018 PM 12623868 ER PT J AU Shechter, G Devernay, F Coste-Maniere, E Quyyumi, A McVeigh, ER AF Shechter, G Devernay, F Coste-Maniere, E Quyyumi, A McVeigh, ER TI Three-dimensional motion tracking of coronary arteries in biplane cineangiograms SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE angiocardiography; geometric modeling; stereo vision; tracking ID ANGIOGRAPHIC IMAGES; CARDIAC MOTION; RECONSTRUCTION; SURGERY; MODEL; REGISTRATION; EXPERIENCE; SEQUENCES; ROBOTICS; SNAKES AB A three-dimensional (3-D) method for tracking the coronary arteries through a temporal sequence of biplane X-ray angiography images is presented. A 3-D centerline model of the coronary vasculature is reconstructed from a biplane image pair at one time frame, and its motion is tracked using a coarse-to-fine hierarchy of motion models. Three-dimensional constraints on the length of the arteries and on the spatial regularity of the motion field are used to overcome limitations of classical two-dimensional vessel tracking methods, such as tracking vessels through projective occlusions. This algorithm was clinically validated in five patients by tracking the motion of the left coronary tree over one cardiac cycle. The root mean square reprojection errors were found to be submillimeter in 93% (54/58) of the image pairs. The performance of the tracking algorithm was quantified in three dimensions using a deforming vascular phantom. RMS 3-D distance errors were computed between centerline models tracked in the X-ray images and gold-standard centerline models of the phantom generated from a gated 3-D magnetic resonance image acquisition. The mean error was 0.69(+/-0.06) mm over eight temporal phases and four different biplane orientations. C1 Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA. INRIA, Chir Grp, F-06902 Sophia Antipolis, France. NHLBI, Lab Cardiac Energet, NIH, DHHS, Bethesda, MD 20892 USA. Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. RP Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA. EM guy@jhu.edu RI Devernay, Frederic/B-4629-2009 OI Devernay, Frederic/0000-0002-7061-4898 FU Intramural NIH HHS [Z01 HL004608-08] NR 39 TC 67 Z9 70 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD APR PY 2003 VL 22 IS 4 BP 493 EP 503 DI 10.1109/TMI.2003.809090 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 682EP UT WOS:000183078600003 PM 12774895 ER PT J AU Seminario, MC Wange, RL AF Seminario, MC Wange, RL TI Lipid phosphatases in the regulation of T cell activation: living up to their PTEN-tial SO IMMUNOLOGICAL REVIEWS LA English DT Review ID PROTEIN-KINASE-B; NF-KAPPA-B; TUMOR-SUPPRESSOR PTEN; GLYCOGEN-SYNTHASE KINASE-3; PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY; LHERMITTE-DUCLOS-DISEASE; NUCLEAR RECEPTOR NUR77; PHOSPHOLIPASE C-GAMMA; TEC FAMILY KINASES; P70 S6 KINASE AB The initiating events associated with T activation in response to stimulation of the T cell antigen receptor (TCR) and costimulatory receptors, such as CD28, are intimately associated with the enzymatically catalyzed addition of phosphate not only to key tyrosine, threonine and serine residues in proteins but also to the D3 position of the myo-inositol ring of phosphatidylinositol (PtdIns). This latter event is catalyzed by the lipid kinase phosphoinositide 3-kinase (PI3K). The consequent production of PtdIns(3,4)P-2 and PtdIns(3,4,5)P-3 serves both to recruit signaling proteins to the plasma membrane and to induce activating conformational changes in proteins that contain specialized domains for the binding of these phospholipids. The TCR signaling proteins that are subject to regulation by PI3K include Akt, phospholipase Cgamma1 (PLCgamma1), protein kinase C zeta (PKC-zeta), Itk, Tec and Vav, all of which play critical roles in T cell activation. As is the case for phosphorylation of protein substrates, the phosphorylation of PtdIns is under dynamic regulation, with the D3 phosphate being subject to hydrolysis by the 3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), thereby placing PTEN in direct opposition to PI3K. In this review we consider recent data concerning how PTEN may act in regulating the process of T cell activation. C1 NIA, Cellular & Mol Biol Lab, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Wange, RL (reprint author), NIA, Cellular & Mol Biol Lab, IRP, NIH,DHHS, GRC Bldg,MSC-12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 198 TC 38 Z9 43 U1 1 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD APR PY 2003 VL 192 IS 1 BP 80 EP 97 DI 10.1034/j.1600-065X.2003.00013.x PG 18 WC Immunology SC Immunology GA 663MG UT WOS:000182008900008 PM 12670397 ER PT J AU Ojaimi, C Brooks, C Casjens, S Rosa, P Elias, A Barbour, A Jasinskas, A Benach, J Katona, L Radolf, J Caimano, M Skare, J Swingle, K Akins, D Schwartz, I AF Ojaimi, C Brooks, C Casjens, S Rosa, P Elias, A Barbour, A Jasinskas, A Benach, J Katona, L Radolf, J Caimano, M Skare, J Swingle, K Akins, D Schwartz, I TI Profiling of temperature-induced changes in Borrelia burgdorferi gene expression by using whole genome arrays SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; 32-KILOBASE CIRCULAR PLASMIDS; OUTER-SURFACE-PROTEIN; ESCHERICHIA-COLI; MAMMALIAN HOST; IN-VITRO; DIFFERENTIAL EXPRESSION; EXTRACHROMOSOMAL DNAS; IXODES-SCAPULARIS; MOLECULAR-CLONING AB Borrelia burgdorferi is the etiologic agent of Lyme disease, the most prevalent arthropod-borne disease in the United States. The genome of the type strain, B31, consists of a 910,725-by linear chromosome and 21 linear and circular plasmids comprising 610,694 bp. During its life cycle, the spirochete exists in distinctly different environments, cycling between a tick vector and a mammalian host. Temperature is one environmental factor known to affect B. burgdorferi gene expression. To identify temperature-responsive genes, genome arrays containing 1,662 putative B. burgdorferi open reading frames (ORFs) were prepared on nylon membranes and employed to assess gene expression in B. burgdorferi B31 grown at 23 and 35 degreesC. Differences in expression of more than 3.5 orders of magnitude could be readily discerned and quantitated. At least minimal expression from 91% of the arrayed ORFs could be detected. A total of 215 ORFs were differentially expressed at the two temperatures; 133 were expressed at significantly greater levels at 35 degreesC, and 82 were more significantly expressed at 23 degreesC. Of these 215 ORFs, 134 are characterized as genes of unknown function. One hundred thirty-six (63%) of the differentially expressed genes are plasmid encoded. Of particular interest is plasmid lp54 which contains 76 annotated putative genes; 31 of these exhibit temperature-regulated expression. These findings underscore the important role plasmid-encoded genes may play in adjustment of B. burgdorferi to growth under diverse environmental conditions. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. SUNY Stony Brook, Ctr Infect Dis, Stony Brook, NY 11794 USA. Univ Utah, Ctr Med, Dept Pathol, Salt Lake City, UT USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. Univ Connecticut, Ctr Hlth, Ctr Microbial Pathogenesis, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Med & Genet, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Dev Biol, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Pathol, Farmington, CT USA. Texas A&M Univ, Dept Med & Microbiol Immunobiol, Hlth Sci Ctr, College Stn, TX USA. RP Akins, D (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. OI Barbour, Alan/0000-0002-0719-5248 FU NCRR NIH HHS [P20 RR015564, RR 15564]; NIAID NIH HHS [R01 AI045801-04, AI 07364, AI 27044, AI 29735, AI 37248, AI 42345, AI 45801, R01 AI027044, R01 AI029735, R01 AI037248, R01 AI042345, R01 AI045801, R01 AI045801-05A1, R37 AI027044, R56 AI027044, R56 AI029735, T32 AI007364] NR 66 TC 183 Z9 184 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2003 VL 71 IS 4 BP 1689 EP 1705 DI 10.1128/IAI.71.4.1689-1705.2003 PG 17 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 662BQ UT WOS:000181926200011 PM 12654782 ER PT J AU Chung, S Mondon, P Chang, YC Kwon-Chung, KJ AF Chung, S Mondon, P Chang, YC Kwon-Chung, KJ TI Cryptococcus neoformans with a mutation in the tetratricopeptide repeat-containing gene, CCN1, causes subcutaneous lesions but fails to cause systemic infection SO INFECTION AND IMMUNITY LA English DT Article ID CAPSULE-ASSOCIATED GENE; SACCHAROMYCES-CEREVISIAE; CROOKED NECK; CELL-CYCLE; DNA-REPLICATION; SNAP HELIX; VIRULENCE; PROTEIN; URA5; TRANSFORMATION AB We studied a Cryptococcus neoformans strain that caused feline chronic nasal granuloma without disseminated disease. This strain, B-4551, grows at temperatures up to 35 degreesC and fails to cause systemic infection in mice. Many cells of B-4551 formed short hyphal elements in feline nasal tissue and occasionally at 35 degreesC in vitro. A complementation and sequence analysis revealed that the temperature-sensitive (TS) phenotype of B-4551 was due to deletion of a lysine residue in the cryptococcal CCN1 gene. B-4551 complemented with the wild type CCN1 gene grew at 37 C and caused fatal systemic infection in mice. The CCN1 gene encodes a protein containing 16 copies of a tetra tricopeptide repeat. CCN1 is homologous to the Saccharomyces cerevisiae CLF1 gene, which is required for pre-mRNA splicing, cell cycle progression, and DNA replication, and to the Drosophila melanogaster crn gene, which is involved in neurogenesis. CLF1 complemented the Ts phenotype of B-4551. CCN1, however, failed to rescue the clf1 mutant in S. cerevisiae. These results indicate that the Ccn1p may not be as functionally diverse as Clf1p in yeast. C1 NIAID, MMS, LCI, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, MMS, LCI, NIH, Bldg 10,11C304, Bethesda, MD 20892 USA. NR 31 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2003 VL 71 IS 4 BP 1988 EP 1994 DI 10.1128/IAI.71.4.1988-1994.2003 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 662BQ UT WOS:000181926200046 PM 12654817 ER PT J AU Virtaneva, K Graham, MR Porcella, SF Hoe, NP Su, H Graviss, EA Gardner, TJ Allison, JE Lemon, WJ Bailey, JR Parnell, MJ Musser, JM AF Virtaneva, K Graham, MR Porcella, SF Hoe, NP Su, H Graviss, EA Gardner, TJ Allison, JE Lemon, WJ Bailey, JR Parnell, MJ Musser, JM TI Group a Streptococcus gene expression in humans and cynomolgus macaques with acute pharyngitis SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCUS; COMPLETE NUCLEOTIDE-SEQUENCE; REVERSE-TRANSCRIPTASE-PCR; HUMAN SEROLOGIC RESPONSE; HYALURONIC-ACID CAPSULE; PYROGENIC EXOTOXIN-B; IN-VIVO; STAPHYLOCOCCUS-AUREUS; REGULATORY SYSTEM; VIRULENCE FACTOR AB The molecular mechanisms used by group A Streptococcus (GAS) to survive on the host mucosal surface and cause acute pharyngitis are poorly understood. To provide new information about GAS host-pathogen interactions, we used real-time reverse transcription-PCR (RT-PCR) to analyze transcripts of 17 GAS genes in throat swab specimens taken from 18 pediatric patients with pharyngitis. The expression of known and putative virulence genes and regulatory genes (including genes in seven two-component regulatory systems) was studied. Several known and previously uncharacterized GAS virulence gene regulators were highly expressed compared to the constitutively expressed control gene pros. To examine in vivo gene transcription in a controlled setting, three cynomolgus macaques were infected with strain MGAS5005, an organism that is genetically representative of most serotype M1 strains recovered from pharyngitis and invasive disease episodes in North America and Western Europe. These three animals developed clinical signs and symptoms of GAS pharyngitis and seroconverted to several GAS extracellular proteins. Real-time RT-PCR analysis of throat swab material collected at intervals throughout a 12-day infection protocol indicated that expression profiles of a subset of GAS genes accurately reflected the profiles observed in the human pediatric patients. The results of our study demonstrate that analysis of in vivo GAS gene expression is feasible in throat swab specimens obtained from infected human and nonhuman primates. In addition, we conclude that the cynomolgus macaque is a useful nonhuman primate model for the study of molecular events contributing to acute pharyngitis caused by GAS. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Pediat Med Grp, Houston, TX 77098 USA. Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Columbus, OH 43210 USA. RP Musser, JM (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. FU NIAID NIH HHS [N01AO02738, N01 AO 02738] NR 60 TC 49 Z9 52 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2003 VL 71 IS 4 BP 2199 EP 2207 DI 10.1128/IAI.71.4.2199-2207.2003 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 662BQ UT WOS:000181926200071 PM 12654842 ER PT J AU Gomez, G Sitkovsky, MV AF Gomez, G Sitkovsky, MV TI Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE immunosuppressive loop; metabolic switch; hypoxia ID NECROSIS-FACTOR-ALPHA; EXTRACELLULAR ADENOSINE; ENDOTOXEMIC MICE; PHOSPHOLIPASE-C; A(2A) RECEPTORS; HUMAN MONOCYTES; A(3) RECEPTORS; TNF-ALPHA; CELLS; ACTIVATION AB G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals. Published by Elsevier Science Ltd. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, 10 11N311,10 Ctr Dr MSC 1892, Bethesda, MD 20892 USA. NR 43 TC 17 Z9 17 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD APR PY 2003 VL 35 IS 4 BP 410 EP 414 AR PII S1357-2725(02)00177-2 DI 10.1016/S1357-2725(02)00177-2 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 652MP UT WOS:000181383200003 PM 12565702 ER PT J AU Dionne, R AF Dionne, R TI Relative efficacy of selective COX-2 inhibitors compared with over-the-counter ibuprofen SO INTERNATIONAL JOURNAL OF CLINICAL PRACTICE LA English DT Article; Proceedings Paper CT International Ibuprofen Conference CY APR 15-16, 2002 CL ROYAL COLL PHYSICIANS, LONDON, ENGLAND HO ROYAL COLL PHYSICIANS ID DENTAL PAIN; PLACEBO; CYCLOOXYGENASE-2; SUPPRESSION; ANALGESIA; CELECOXIB; MODEL AB Non-steroidal anti-inflammatory drugs (NSAIDs) suppress the activity of both isoforms of cyclo-oxygenase (COX). Inhibition of COX-1, the constitutive isoform, is primarily responsible for the adverse gastrointestinal effects of the NSAIDs whereas inhibition of COX-2, the inducible isoform, accounts for their therapeutic effects. COX-2 inhibitors such as celecoxib and rofecoxib appear to be as effective as non-selective NSAIDs in the treatment of chronic inflammatory disease but their analgesic efficacy and their safety at the higher doses required for analgesia are less certain. There is consistent evidence that COX-1 plays a major role in the early pain response following injury and that analgesia is increased when both COX-1 and COX-2 are inhibited simultaneously. Early postoperative nociception may cause hyperalgesia at a later time by a process of central plasticity. In an experimental model of pain, ibuprofen promptly suppresses prostaglandin E-2 concentrations whereas celecoxib has no discernible effect until 90-120 minutes postoperatively, when COX-2 activity is induced. Both drugs significantly reduce pain compared with placebo but celecoxib appears to have a slower onset of action. The analgesic effect of ibuprofen is well characterised for acute pain and short-term treatment is well tolerated. C1 NIDCR, NIH, Bethesda, MD USA. RP Dionne, R (reprint author), NIDCR, NIH, Bethesda, MD USA. NR 11 TC 3 Z9 3 U1 0 U2 0 PU MEDICOM INTERNATIONAL PI SURREY PA CHURSTON HOUSE, PORTSMOUTH RD, ESHER, SURREY KT10 9AD, ENGLAND SN 1368-5031 J9 INT J CLIN PRACT JI Int. J. Clin. Pract. PD APR PY 2003 SU 135 BP 18 EP 22 PG 5 WC Medicine, General & Internal; Pharmacology & Pharmacy SC General & Internal Medicine; Pharmacology & Pharmacy GA 672HQ UT WOS:000182515500005 PM 12723742 ER PT J AU Leitzmann, MF Giovannucci, EL AF Leitzmann, MF Giovannucci, EL TI Commentary: Can dietary fatty acids affect colon cancer risk? SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID COLORECTAL-CANCER C1 NCI, Nutr Epidemiol Branch, Rockville, MD 20852 USA. RP Leitzmann, MF (reprint author), NCI, Nutr Epidemiol Branch, 6120 Execut Blvd,EPS 3028, Rockville, MD 20852 USA. NR 13 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2003 VL 32 IS 2 BP 209 EP 210 DI 10.1093/ije/dyg068 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 674GT UT WOS:000182629600010 PM 12714538 ER PT J AU Inskip, PD Tarone, RE Hatch, EE Wilcosky, TC Fine, HA Black, PM Loeffler, JS Shapiro, WR Selker, RG Linet, MS AF Inskip, PD Tarone, RE Hatch, EE Wilcosky, TC Fine, HA Black, PM Loeffler, JS Shapiro, WR Selker, RG Linet, MS TI Sociodemographic indicators and risk of brain tumours SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE brain cancer; brain tumours; social class; glioma; meningioma; acoustic neuroma; epidemiology ID CENTRAL-NERVOUS-SYSTEM; DESCRIPTIVE EPIDEMIOLOGY; SOCIOECONOMIC-STATUS; CRANIAL MENINGES; HEALTH-INSURANCE; MEDICAL-CARE; CANCER; TUMORS; MORTALITY; GLIOMAS AB Background To better understand patterns of occurrence or diagnosis of brain tumours in different segments of the population, we evaluated associations between sociodemographic variables and the relative incidence of brain tumours as part of a multi-faceted case-control study. Methods The study was conducted at hospitals in three US cities between 1994 and 1998. In all, 489 glioma cases (354 high-grade, 135 low-grade), 197 meningioma cases, 96 acoustic neuroma cases, and 799 controls admitted to the same hospitals for any of a variety of non-neoplastic diseases or conditions were enrolled and interviewed. Logistic regression was used to estimate odds ratios (OR), calculate 95% CI, and test for trends. Results The OR showed significant positive associations with household income for low-grade glioma, meningioma, and acoustic neuroma, but not for high-grade glioma. Positive associations were observed with level of education for low-grade glioma and acoustic neuroma, but not for high-grade glioma or meningioma. Jewish religion was associated with a significantly elevated risk for meningioma (OR = 4.3; 95% CI: 2.0-9.0). Being single at the time of tumour diagnosis or enrolment was associated with significantly reduced risks for meningioma (OR = 0.4; 95% CI: 0.3-0.6) and low- or high-grade glioma (OR = 0.6; 95% CI: 0.5-0.8), but not for acoustic neuroma. Conclusions Associations with sociodemographic variables varied considerably among the different subtypes of brain tumour, including between low-grade and high-grade glioma. The general pattern was for associations with indicators of affluence and education to be stronger for tumours that tend to grow more slowly and have less catastrophic effects, although the evidence was mixed for meningioma. We cannot isolate the specific factors underlying the observed associations, but intrapopulation differences in the completeness or timing of diagnosis may have played a role. There is less opportunity for such influences to operate for the rapidly progressing, high-grade gliomas than for more slowly growing tumours. C1 NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Res Triangle Inst, Epidemiol & Med Studies Program, Res Triangle Pk, NC 27709 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. St Josephs Hosp & Med, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. Western Penn Hosp, Div Neurosurg, Pittsburgh, PA 15224 USA. RP Inskip, PD (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 7052, Bethesda, MD 20892 USA. OI Hatch, Elizabeth/0000-0001-7901-3928 NR 63 TC 46 Z9 49 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2003 VL 32 IS 2 BP 225 EP 233 DI 10.1093/ije/dyg051 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 674GT UT WOS:000182629600013 PM 12714541 ER PT J AU Mai, V Flood, A Peters, U Lacey, JV Schairer, C Schatzkin, A AF Mai, V Flood, A Peters, U Lacey, JV Schairer, C Schatzkin, A TI Dietary fibre and risk of colorectal cancer in the Breast Cancer Detection Demonstration Project (BCDDP) follow-up cohort SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cancer; cohort; colon; dietary fibre; nutrition; rectum ID CORONARY HEART-DISEASE; FIBER; RECURRENCE; EPIDEMIOLOGY; PREVENTION; ADENOMAS; FRUIT; MEN AB Background The hypothesis that increased intake of dietary fibre lowers the risk of colorectal cancer (CRC) has recently been weakened by results from cohort and intervention studies that did not detect such an association. We investigated the association between dietary fibre intake and risk of CRC in a cohort of women that prospectively answered a food frequency questionnaire (FFQ). Methods We studied 45 491 women in the Breast Cancer Detection Demonstration Project (BCDDP) follow-up cohort. A 62-item FFQ was administered from 1987 and 1989 to assess dietary intake. Participants received follow-up questionnaires (in 1992-1995 and 1995-1998) on which they reported incident cancers. Cases were also identified through searches of the National Death Index and state cancer registries. Cox proportional hazard regression was used to generate risk ratios and 95% CI for quintiles of total fibre intake and fibre subtypes. Results During a mean follow-up time of 8.5 years we identified 487 colorectal cancer cases. The 10th and 90th percentiles of dietary fibre intake were 5.4 g and 18.2 g respectively. For total fibre we observed no association with colorectal cancer (fifth versus first quintile, RR = 0.94, 95% CI: 0.71-1.23). Analyses by subgroup of fibre and by anatomical subsite did not reveal any stronger inverse associations. Conclusions Within a cohort of older women characterized by a relatively low fibre intake, there was little evidence that dietary fibre intake lowers the risk of colorectal cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Mai, V (reprint author), Univ Maryland, Sch Med, Div Epidemiol & Prevent Med, 10 S Pine St,MSTF-934, Baltimore, MD 21201 USA. NR 18 TC 43 Z9 43 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2003 VL 32 IS 2 BP 234 EP 239 DI 10.1093/ije/dyg052 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 674GT UT WOS:000182629600014 PM 12714542 ER PT J AU Winget, MD Baron, JA Spitz, MR Brenner, DE Warzel, D Kincaid, H Thornquist, M Feng, ZD AF Winget, MD Baron, JA Spitz, MR Brenner, DE Warzel, D Kincaid, H Thornquist, M Feng, ZD TI Development of common data elements: the experience of and recommendations from the early detection research network SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE early detection research network; common data element; cancer AB There have been an increasing number of large research consortia in recent years funded by the National Cancer Institute (NCI) to facilitate multi-disciplinary, multi-institutional cancer research. Some of these consortia have central data collection plans similar to a multi-center clinical trial whereas others plan to store data Locally and pool or share the data at a later date. Regardless of the goal of the consortium, there is a need to standardize the way certain data are collected and stored, transferred, or reported across the institutions involved. This communication is a report of the process and current status of the development of common data elements (CDEs) by the Early Detection Research Network (EDRN). The development of the CDEs involved several stages with each stage requiring input from multidisciplinary experts in oncology, epidemiology, biostatistics, pathology, informatics, and study coordination. An effort was made to be consistent with other consortia developing similar CDEs and to follow data standards when available. Initial focus was on identifying the minimum data that would be necessary to collect on all EDRN study participants and EDRN specimens. There are currently CDEs in the development or pilot phase for eight different organ sites and 13 different types of specimen procurements and plans to develop CDEs for 12 or more additional types of specimens. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98109 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. RP Winget, MD (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, 1100 Fairview Ave N,MP-859, Seattle, WA 98109 USA. FU NCI NIH HHS [CA86368] NR 8 TC 21 Z9 22 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1386-5056 J9 INT J MED INFORM JI Int. J. Med. Inform. PD APR PY 2003 VL 70 IS 1 BP 41 EP 48 DI 10.1016/S1386-5056(03)00005-4 PG 8 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 679DQ UT WOS:000182905900005 PM 12706181 ER PT J AU North, KE Williams, JT Welty, TK Best, LG Lee, ET Fabsitz, RR Howard, BV MacCluer, JW AF North, KE Williams, JT Welty, TK Best, LG Lee, ET Fabsitz, RR Howard, BV MacCluer, JW TI Evidence for joint action of genes on diabetes status and CVD risk factors in American Indians: the Strong Heart Family Study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE pleiotropy; diabetes status; CVD risk factors; American Indians; Strong Heart Family Study ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; INSULIN-RESISTANCE SYNDROME; IMPAIRED GLUCOSE-TOLERANCE; TRAIT LINKAGE ANALYSIS; AGED 45-74 YEARS; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; FIBRINOGEN CONCENTRATION; METABOLIC SYNDROME; MEXICAN-AMERICANS AB OBJECTIVES: Previous research among American Indians of the strong heart family study (SHFS) has demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes. Moreover, we recently demonstrated that genetic effects on CVD risk factors differed in diabetic and nondiabetic individuals. In this paper, we investigated whether a significant genetic influence on diabetes status could be identified, and whether there is evidence for joint action of genes on diabetes status and related CVD risk factors. METHODS AND RESULTS: Approximately 950 men and women, age 18 or older, in 32 extended families, were examined between 1997 and 1999. We estimated the effects of genes and environmental covariates on diabetes status using a threshold model and a maximum likelihood variance component approach. Diabetes status exhibited a residual heritability of 22% (h(2) = 0.22). We also estimated the genetic and environmental correlations between diabetes susceptibility and eight risk factors for CVD. All eight CVD risk factors displayed significant genetic correlations with diabetes status (BMI (rho(G) = 0.55), fibrinogen (rho(G) = 0.40), HDL-C (rho(G) = 0.37), In triglycerides (rho(G) = 0.65), FAT (rho(G) = 0.38), PAI-1 (rho(G) = 0.67), SBP (rho(G) = 0.57), and WHR (rho(G) = 0.58)). Three of eight traits (HDL-C (rho(E) = -0.32), In triglycericles (rho(E) = 0.33), and fibrinogen (rho(E) = 0.20)) displayed significant environmental correlations with diabetes status. CONCLUSIONS: These findings suggest that in the context of a high prevalence of diabetes, still unidentified diabetes genes may play an important role in influencing variation in CVD risk factors. C1 Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, Chapel Hill, NC 27514 USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78284 USA. Tribal Chairmens Hlth Board, Aberdeen Area, Rapid City, SD USA. Missuori Breaks Ind Res Inc, Timber Lake, SD USA. Univ Oklahoma, Hlth Sci Ctr, Sch Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. RP North, KE (reprint author), Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [U01 HL41654, U01 HL41642, U01 HL65521, U01 HL65520, U01 HL41652] NR 77 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 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD APR PY 2003 VL 27 IS 4 BP 491 EP 497 DI 10.1038/sj.ijo.0802261 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 664ZR UT WOS:000182095600011 PM 12698956 ER PT J AU Huff, J AF Huff, J TI Absence of carcinogenic activity in Fischer rats and B6C3F1 mice following 103-week inhalation exposures to toluene SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article DE benzene; carcinogenesis bioassay; dime thylbenzene; long-term studies; methylbenzene; National Toxicology Program; toluene; xylene ID NATIONAL TOXICOLOGY PROGRAM; INDUCED HEPATOCYTE PROLIFERATION; TERM CHEMICAL CARCINOGENESIS; BUTYL ETHER MTBE; CELL-PROLIFERATION; RAMAZZINI-FOUNDATION; LIVER CARCINOGENESIS; BOLOGNA INSTITUTE; RISK ASSESSMENT; DIET NTP-2000 AB Toluene, methylbenzene, is used to back-blend gasoline, as a chemical intermediate, and as a solvent; more than 7 million tonnes arc produced each year in the United States. Following 14-15-week toxicity studies to estimate appropriate exposure concentrations for the carcinogenesis bioassays, toxicology and carcinogenesis studies of toluene (>99% pure) were conducted by whole-body inhalation exposures of F344/N rats and B6C3F1 mice of each sex for 15 months or two years. Toluene levels were 0 (chamber controls), 600, and 1,200 ppm for rats and 0, 120, 600, and 1200 ppm for mice. Exposures were 6.5 hr/day 5 days/wk. Genetic toxicology studies using Salmonella typhimurium, mouse L5178Ylymphoma cells, and Chinese hamster ovary cells were negative. No chemically related neoplasm was found in male rats, and one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with the toluene exposure. For mice, no biologically important increase was observed for any nonneoplastic or neoplastic lesion. Studies by others had reported carcinogenicity of toluene, especially for total malignant tumors. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 71 TC 4 Z9 5 U1 0 U2 1 PU ABEL PUBLICATION SERVICES PI BURLINGTON PA 1611 AQUINAS COURT, BURLINGTON, NC 27215 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD APR-JUN PY 2003 VL 9 IS 2 BP 138 EP 146 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 817ET UT WOS:000221161500007 PM 12848242 ER PT J AU Becker, ML Buder, EH Ward, JP AF Becker, ML Buder, EH Ward, JP TI Spectrographic description of vocalizations in captive Otolemur garnettii SO INTERNATIONAL JOURNAL OF PRIMATOLOGY LA English DT Article DE Garnett's greater bush baby; galago; vocal communication; spectrograms; prosimian ID LOUD CALLS; PRIMATE VOCALIZATIONS; BARBARY MACAQUES; COMMUNICATION; REPERTOIRE; BUSHBABIES; PHYLOGENY; MONKEYS; SENEGAL; VIEW AB To advance knowledge of the vocal communication associated with close proximity social interactions in Garnett's greater bush baby (Otolemur garnettii), we measured acoustic and temporal properties of vocalizations from videotaped recordings of captives in two main social contexts: mother-infant interactions and adult male-female pair introductions and reintroductions. We used a real-time sonagraph or software program to display, edit, and analyze vocal waveforms, and to provide wideband and narrowband spectrograms. Vocalization characteristics measured include fundamental frequency ( via inspection of harmonics) and spectral features such as formant frequency, intensity, and duration. The vocal repertoire contained 4 major types of vocalizations: 1) barks and complex multiple bark sequences, 2) low frequency flutter/hums and growls, 3) high frequency clicks and spits, and 4) noisy shrieks. We describe several vocalizations for the first time and provide a clear classification of some of them on the basis of call durations (long/short growls). Complex bark sequences, previously described as distant communication calls, were invariant and were not often emitted by individuals when in close proximity. When classified spectrographically, the remaining 3 call types, which occurred when individuals were in close proximity, were less stereotypical, and gradations within call types were apparent. Our results show that although nocturnal and non-gregarious, complex communicatory signals of bush babies constitute a vocal repertoire formerly thought to be characteristic only of diurnal, gregarious primates. C1 Univ Memphis, Sch Audiol & Speech Language Pathol, Memphis, TN 38152 USA. Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. RP Becker, ML (reprint author), NIAAA, NIH, Clin Studies Lab, Primate Unit, NIHAC POB 529, Poolesville, MD 20837 USA. EM mbecker@mail.nih.gov RI Zimmermann, Elke/D-2281-2015 NR 46 TC 9 Z9 10 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0164-0291 EI 1573-8604 J9 INT J PRIMATOL JI Int. J. Primatol. PD APR PY 2003 VL 24 IS 2 BP 415 EP 446 DI 10.1023/A:1023013619714 PG 32 WC Zoology SC Zoology GA 661YJ UT WOS:000181917400015 ER PT J AU Nonnenmacher, B Pintos, J Bozzetti, MC Mielzinska-Lohnas, I Lorincz, AT Ikuta, N Schwartsmann, G Villa, LL Schiller, JT Franco, E AF Nonnenmacher, B Pintos, J Bozzetti, MC Mielzinska-Lohnas, I Lorincz, AT Ikuta, N Schwartsmann, G Villa, LL Schiller, JT Franco, E TI Epidemiologic correlates of antibody response to human papillomavirus among women at low risk of cervical cancer SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE human papillomavirus; ELISA serology; cervical cancer ID VIRUS-LIKE PARTICLES; INTRAEPITHELIAL NEOPLASIA; HPV DNA; TYPE-16; SEROREACTIVITY; INFECTION; SEROPOSITIVITY; DETERMINANTS; CAPSIDS; MARKER AB A population at low risk for developing cervical cancer in Southern Brazil was studied to identify the main determinants of serological response to human papillomavirus (HPV). Enzyme-linked immunosorbent assay tests were performed in 976 women to detect serum IgG antibodies against HPV 16 L1 virus-like particles (VLPs) and HPVs 16,18,6 and 11 L1 VLPs as a mixture of antigens. Women with four or more sexual partners were more likely to be seropositive than women with one partner (HPV 16 serology odds ratio [OR] =3.06, 95% confidence interval [CI]: 2.0-4.8; HPV 6/11/16/18 serology OR=4.64, 95% CI: 3.0-7.2). HPV DNA and both serological responses were associated. Those positives to HPV 16 serology were Wice as likely to have a cytological diagnosis of squamous intraepithelial lesions (SILs) than seronegatives (OR=2.07; 95% CI: 1.0-4.5, and OR = 1.73; 95% CI: 0.8-3.8). Seropositivity to HPV 16 and HPV 6/11/16/ 18 antigens seem to be better markers of past sexual activity than current HPV infection, and humoral response to HPV 16 or HPV 6/11/16/18 may not be a strong indicator of cervical lesions in populations at low risk for cervical lesions. C1 Digene Co, Gaithsburg, MD USA. Ludwig Inst Canc Res, Sao Paulo, Brazil. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. McGill Univ, Dept Oncol, Montreal, PQ, Canada. UFRGS, Posgrad Clin Med, Porto Alegre, RS, Brazil. RP Nonnenmacher, B (reprint author), Rua Comendador Rheingantz 431-401, BR-90450020 Porto Alegre, RS, Brazil. RI Schwartsmann, Gilberto/G-4256-2016; OI Schwartsmann, Gilberto/0000-0002-7850-1644; Bozzetti, Mary /0000-0002-6405-3983; Franco, Eduardo/0000-0002-4409-8084 NR 27 TC 18 Z9 19 U1 0 U2 1 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD APR PY 2003 VL 14 IS 4 BP 258 EP 265 DI 10.1258/095646203321264872 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 667RF UT WOS:000182246000007 PM 12716496 ER PT J AU Branton, PA Lininger, R Tavassoli, FA AF Branton, PA Lininger, R Tavassoli, FA TI Papillary endothelial hyperplasia of the breast: The great impostor for angiosarcoma - A clinicopathologic review of 17 cases SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Review DE papillary endothelial hyperplasia; breast or mammary vascular tumors ID BENIGN LESION; MISTAKEN AB Seventeen cases of papillary endothelial hyperplasia (PEH, Masson's vegetant intravascular hemangioendothelioma) involving breast or mammary subcutaneous tissues are described. The mean patient age was 59; 14 (82%) were female and 12 (71%) presented with a mass. Nine women had mammographic evaluation, 3 of whom had microcalcifications. Five neoplasms were discovered by routine mammography. Sixteen cases were 2.7 cm or less in greatest dimension, and 8 (47%) were associated with a thrombus and/or cavernous hemangioma. Follow-up in 10 cases (up to nearly 8 years) showed no recurrences. Fifty-nine percent of the cases were received at AFIP for consultation with a working diagnosis of angiosarcoma. Features that help distinguish PEH from angiosarcoma include circumscription of the lesion, location in a vessel or association with thrombus, and papillary architecture without significant cytologic atypia or areas of solid growth. The recognition of the morphologic features of this lesion and its inclusion in the differential diagnosis of vascular mammary tumors will reduce the likelihood of its misdiagnosis as an angiosarcoma and avoid unnecessary and aggressive therapy. C1 Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. RP Tavassoli, FA (reprint author), NINDS, Mol Pathologenesis Unit, NIH, Bldg 10,Room 5D37,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 13 TC 13 Z9 16 U1 0 U2 1 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD APR PY 2003 VL 11 IS 2 BP 83 EP 87 DI 10.1177/106689690301100203 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 678AA UT WOS:000182841400003 PM 12754624 ER PT J AU Qtaishat, NM Redmond, TM Pepperberg, DR AF Qtaishat, NM Redmond, TM Pepperberg, DR TI Acute radiolabeling of retinoids in eye tissues of normal and Rpe65-deficient mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; LEBER CONGENITAL AMAUROSIS; OUTER SEGMENT RENEWAL; BINDING PROTEIN; VISUAL CYCLE; MOUSE MODEL; MEMBRANE-RECEPTOR; RHODOPSIN REGENERATION; CHILDHOOD BLINDNESS; MICROSOMAL PROTEIN AB PURPOSE. Mice with a targeted disruption of the gene encoding RPE65, a protein ordinarily highly expressed in the retinal pigment epithelium (RPE), accumulate abnormally high levels of all-trans retinyl ester in the RPE and exhibit very little 11-cis retinal in the retina. The present study was undertaken to determine whether the Rpe65-deficient mouse exhibits an abnormal flux of retinoid between the systemic circulation and the eye tissues. METHODS. Dark-adapted Rpe65-deficient mice (Rpe65(-/-)) and wild-type control mice (Rpe65(+/+)) of approximate ages 1 and 3 months received an intraperitoneal injection of all-trans (3 H)retinol. The mice were maintained in darkness for a defined period (approximate to 1.5, 4.5, 24, or 48 hours) and then anesthetized, exsanguinated, and killed. Retinoids contained in the retina, RPE, serum, and liver were extracted and analyzed for (H-3) radioactivity and molar level. RESULTS. The specific activity (SA, in counts per minute per nanomole) of serum all-trans (H-3)retinol in all mice exhibited a peak at postinjection times of 1.5 or 4.5 hours, and by 48 hours declined to approximately 7% or less of the peak. In Rpe65(+/+) mice, the average SA of RPE (H-3)retinyl ester similarly exhibited, an early peak (.4.5 hours) and by 48 hours declined to approximately 6% to 10% of the peak. By contrast, the average SA of RPE (H-3)retinyl ester in Rpe65(-/-) mice exhibited a-peak at 24 or 48 hours. Radioactivity and molar data for serum all-trans retinol and RPE retinyl ester obtained at 4.5 hours were analyzed to infer the molar influx of all-trans retinol from the circulation into the RPE. Levels of all-trans retinol influx derived from this analysis (mean +/- SD: 0.014 +/- 0.004 nmol in 1-month RPe65(+/+) mice; 0.021 +/- 0.009 nmol in 1-month RPe65(-/-) mice; 0.016 +/- 0.013 nmol in 3-month Rpe65(+/+) mice; 0.026 +/- 0.018 nmol in 3-month Rpe65(-/-) mice) did not differ significantly from one another (P > 0.169). However, the inferred fractional influx (molar amount of entering all-trans retinol divided by the molar amount of RPE retinyl ester) in Rpe65(+/+) animals (0.34 +/- 0.04 and 0.10 +/- 0.03, respectively, for 1- and 3-month mice) substantially exceeded that for Rpe65(-/-) animals (0.055 +/- 0.023 and 0.015 +/- 0.006, respectively, for 1- and 3-month mice). Significant levels of (H-3)retinaldehydes were detected in the retinas of Rpe65(+/+) mice, but not in those of RPe65(-/-) mice, after the longer postinjection periods. CONCLUSIONS. The results indicate preservation of a substantial inward flux of all-trans retinol from the circulation into the RPE of Rpe65(-/-) mice, despite the presence of abnormally high molar levels of RPE retinyl ester. They further imply the occurrence of a robust outward movement of all-trans retinol from the RPE into the circulation in Rpe65(+/+) mice, and substantial impairment of this efflux process in Rpe65(-/-) mice. These findings raise the hypothesis that in normal RPE, 11-cis retinal and/or 11-cis retinol stimulate the efflux of all-trans retinol at the RPE basolateral membrane. In 3-month Rpe65(+/+) mice, the observed relationship between the SAs of retinaldehydes in the retina and of RPE retinyl ester is consistent with a last-in/first-out processing of all-trans retinol to 11-cis retinal within normally functioning RPE. C1 Univ Illinois, Dept Ophthalmol & Visual Sci, Coll Med, Lions Illinois Eye Res Inst, Chicago, IL 60612 USA. NEI, Bethesda, MD 20892 USA. RP Pepperberg, DR (reprint author), Univ Illinois, Dept Ophthalmol & Visual Sci, Coll Med, Lions Illinois Eye Res Inst, 1855 W Taylor St, Chicago, IL 60612 USA. OI Redmond, T. Michael/0000-0002-1813-5291 FU NEI NIH HHS [EY01792, EY05494] NR 47 TC 25 Z9 25 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2003 VL 44 IS 4 BP 1435 EP 1446 DI 10.1167/iovs.02-0679 PG 12 WC Ophthalmology SC Ophthalmology GA 660TG UT WOS:000181848900010 PM 12657577 ER PT J AU Gwiazda, J Hyman, L Hussein, M Everett, D Norton, TT Kurtz, D Leske, MC Manny, R Marsh-Tootle, W Scheiman, M AF Gwiazda, J Hyman, L Hussein, M Everett, D Norton, TT Kurtz, D Leske, MC Manny, R Marsh-Tootle, W Scheiman, M CA COMET Grp TI A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EMMETROPIZATION; SCHOOLCHILDREN; ABERRATIONS; DESIGN; COMET; LOCUS; EYES; MAPS AB PURPOSE. The purpose of the Correction of Myopia Evaluation Trial (COMET) was to evaluate the effect of progressive addition lenses (PALS) compared with single vision lenses (SVLs) on the progression of juvenile-onset myopia. METHODS. COMET enrolled 469 children (ages 6-11 years) with myopia between - 1.25 and - 4.50 D spherical equivalent. The children were recruited at four colleges of optometry in the United States and were ethnically diverse. They were randomly assigned to receive either PALS with a +2.00 addition (n = 235) or SVLs (n = 234), the conventional spectacle treatment for myopia, and were followed for 3 years. The primary outcome measure was progression of myopia, as determined by autorefraction after cycloplegia with 2 drops of 1% tropicamide at each annual visit. The secondary outcome measure was change in axial length of the eyes, as assessed by A-scan ultrasonography. Child-based analyses (i.e., the mean of the two eyes) were used. Results were adjusted for important covariates, by using multiple linear regression. RESULTS. Of the 469 children (mean age at baseline, 9.3+/- 1.3 years), 462 (98.5%) completed the 3-year visit. Mean (+/-SE) 3-year increases in myopia (spherical equivalent) were - 1.28 +/- 0.06 D in the PAL group and - 1.48 +/- 0.06 D in the SVL group. The 3-year difference in progression of 0.20 +/- 0.08 D between the two groups was statistically significant (P = 0.004). The treatment effect was observed primarily in the first year. The number of prescription changes differed significantly by treatment group only in the first-year. At 6 months, 17% of the PAL group versus 30% of the SVL group needed a prescription change (P = 0.0007), and, at 1 year, 43% of the PAL group versus 59% of the SVL group required a prescription change (P = 0.002). Interaction analyses identified a significantly larger treatment effect of PALS in children with lower versus higher baseline accommodative response at near (P = 0.03) and with lower versus higher baseline myopia (P = 0.04). Mean (+/- SE) increases in the axial length of eyes of children in the PAL and SVL groups, respectively, were: 0.64 +/- 0.02 mm and 0.75 +/- 0.02 mm, with a statistically significant 3-year mean difference of 0.11 +/- 0.03 mm (P = 0.0002). Mean changes in axial length correlated with those in refractive error (r = 0.86 for PAL and 0.89 for SVL). CONCLUSIONS. Use of PALS compared with SVLs slowed the progression of myopia in COMET children by a small, statistically significant amount only during the first year. The size of the treatment effect remained similar and significant for the next 2 years. The results provide some support for the COMET rationale-that is, a role for defocus in progression of myopia. The small magnitude of the effect does not warrant a change in clinical practice. C1 New England Coll Optometry, Boston, MA 02115 USA. SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. NEI, Bethesda, MD 20892 USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. Univ Houston, Coll Optometry, Houston, TX USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. RP Gwiazda, J (reprint author), New England Coll Optometry, 424 Beacon St, Boston, MA 02115 USA. FU NEI NIH HHS [EY11754, EY11740, EY11752, EY11755, EY11756, EY11805] NR 26 TC 252 Z9 267 U1 7 U2 37 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2003 VL 44 IS 4 BP 1492 EP 1500 DI 10.1167/iovs.02-0816 PG 9 WC Ophthalmology SC Ophthalmology GA 660TG UT WOS:000181848900017 PM 12657584 ER PT J AU Narfstrom, K Katz, ML Bragadottir, R Seeliger, M Boulanger, A Redmond, TM Caro, L Lai, CM Rakoczy, PE AF Narfstrom, K Katz, ML Bragadottir, R Seeliger, M Boulanger, A Redmond, TM Caro, L Lai, CM Rakoczy, PE TI Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LEBER CONGENITAL AMAUROSIS; PIGMENT-EPITHELIUM; ADENOASSOCIATED VIRUS; MICROSOMAL PROTEIN; NIGHT BLINDNESS; BRIARD DOGS; DYSTROPHY; MODEL; EXPRESSION; VISION AB PURPOSE. To assess the efficacy of AAV-mediated gene therapy to restore vision in a large number of RPE65(-/-) dogs and to determine whether systemic and local side effects are caused by the treatment. METHODS. Normal RPE65 dog cDNA was subcloned into an rAAV vector under control of a cytomegalovirus promoter, and an AAV.GFP control vector was also produced with the titers 2 x 10(12) particles/mL and 2 x 10(10) transducing U/mL, respectively. RPE65(-/-) dogs, aged 4 to 30 months were treated with subretinal injections of the AAV.RPE65 and control vectors, respectively, in each eye, and three 24- to 30-month-old normal control dogs with the latter. Baseline and postoperative systemic and ophthalmic examinations, blood screenings, vision testing, and electroretinography (ERG) were performed. Two RPE65-/- dogs were killed at 3 and 6 months after treatment for morphologic examination of the retinas. RESULTS. RPE65-/- dogs were practically blind from birth with nonrecorclable or low-amplitude ERGS. Construct injections or sham surgeries were performed in 28 eyes; 11 were injected subretinally with the AAV.RPE65 construct. ERGS at 3 months after surgery showed that in the latter eyes, dark-adapted b-wave amplitudes recovered to an average of 28% of normal, and light adapted b-wave amplitudes to 32% of normal. ERG amplitudes were not reduced during a 6- to 9-month follow-up. No systemic side effects were observed, but uveitis developed in nine AAV.RPE65.-treated eyes. No uveitis was observed in the eyes treated with the control vector. Immunocytochemistry showed expression of RPE65 in the retinal pigment epithelium (RPE) of AAV.RPE65-treated eyes. Fluorescence microscopy showed expression of green fluorescent protein (GFP) in the RPE and, to a lesser extent, in the neural retinas of AAV.GFP-treated eyes. Ultrastructurally, a reversal of RPE lipid droplet accumulation was observed at the AAV.RPE65 transgene injection site, but not at the site of injection of the control vector. CONCLUSIONS. In 10 of 11 treated RPE65(-/-) eyes, gene transfer resulted in development of vision, both subjectively apparent by loss of nystagmus, and objectively recorded by ERG. Structurally, there was reversal of lipid droplet accumulation in the RPE. Uveitis developed in 75% of the transgene-treated eyes, a complication possibly due to an immunopathogenic response to the RPE65 molecule. C1 Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Vis Sci Grp, Columbia, MO 65211 USA. Univ Missouri, Sch Med, Mason Eye Inst, Dept Ophthalmol, Columbia, MO 65211 USA. Ullevaal Univ Hosp, Dept Ophthalmol, Oslo, Norway. Univ Eye Hosp, Dept Pathophysiol Vis & Neuroophthalmol, Tubingen, Germany. NEI, NIH, Bethesda, MD 20892 USA. Univ Western Australia, Ctr Ophthalmol & Visual Sci, Nedlands, WA 6009, Australia. RP Narfstrom, K (reprint author), Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Vis Sci Grp, A379 Clydesdale Hall, Columbia, MO 65211 USA. OI Redmond, T. Michael/0000-0002-1813-5291 NR 22 TC 162 Z9 168 U1 0 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2003 VL 44 IS 4 BP 1663 EP 1672 DI 10.1167/iovs.02-0595 PG 10 WC Ophthalmology SC Ophthalmology GA 660TG UT WOS:000181848900040 PM 12657607 ER PT J AU Choi, JS Kim, JA Joo, CK AF Choi, JS Kim, JA Joo, CK TI Activation of MAPK and CREB by GM1 induces survival of RGCs in the retina with axotomized nerve SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GANGLION-CELLS; NEUROTROPHIC FACTOR; GROWTH-FACTOR; NEUROPROTECTIVE AGENTS; DOPAMINERGIC-NEURONS; TRANSCRIPTION FACTOR; NITRIC-OXIDE; RAT RETINA; ADULT-RATS; IN-VITRO AB PURPOSE. Neuronal cells undergo apoptosis when the supply of neurotrophic factor is limited by injury, trauma, or neurodegenerative disease. Ganglioside has both neuritogenic and neurotropic functions. Exogenously administered monosialoganglioside (GM1) has been shown to have a stimulatory effect on neurite outgrowth and to prevent degeneration of neuronal cells in the central nervous system. Even though GM1 has been shown to mimic, or have synergy with, neurotrophic factors, the neuroprotective mechanism of GM1 has not been well understood. In this study, optic nerve transection, or axotomy, was used as an in vivo model system for injury, to examine the protective mechanism of GM1 in injured retinal ganglion cells. METHODS. GM1 was injected into the vitreous body before axotomy, and the protective effect of GM1 observed with regard to activation of mitogen-activated protein kinase (MAPK) and phosphorylation of cAMP-responsive element-binding (CREB) protein. Activation of MAPK and CREB were examined by Western blot analysis and immunohistochemistry, and the surviving retinal ganglion cells were counted after retrograde fluorescence labeling. RESULTS. GM1 inhibited the degeneration of axotomized retinal ganglion cells. In addition, GM1 enhanced the activation of MAPK and CREB with the treatment of GM1 in the retina with axotomized nerve. Treatment of MAPK inhibitor PD98059 with GM1 reduced the protective action of GM1 and prevented GM1-induced phosphorylation of CREB. CONCLUSIONS. GM1 protected the axotomized retinal ganglion cells (RGCs) from cell death after axotomy through the activation of MAPK and CREB. C1 Catholic Univ Korea, Coll Med, Dept Ophthalmol & Visual Sci, Seoul 137701, South Korea. NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Joo, CK (reprint author), Catholic Univ Korea, Coll Med, Dept Ophthalmol & Visual Sci, 505 Banpo Dong, Seoul 137701, South Korea. NR 50 TC 48 Z9 55 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2003 VL 44 IS 4 BP 1747 EP 1752 DI 10.1167/iovs.01-0886 PG 6 WC Ophthalmology SC Ophthalmology GA 660TG UT WOS:000181848900050 PM 12657617 ER PT J AU Grimm, TA Beer, BE Hirsch, VM Clouse, KA AF Grimm, TA Beer, BE Hirsch, VM Clouse, KA TI Simian immunodeficiency viruses from multiple lineages infect human macrophages: Implications for cross-species transmission SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE simian immunodeficiency virus; HIV; human macrophages; cross-species transmission; infection; primate model ID AFRICAN-GREEN MONKEYS; BLOOD MONONUCLEAR-CELLS; RED-CAPPED MANGABEY; PRIMATE LENTIVIRUSES; NATURAL INFECTION; MANDRILLUS SPHINX; SOOTY MANGABEYS; CYCLE ARREST; SIV; HIV-1 AB Zoonotic transfer of simian immunodeficiency virus (SIV) from chimpanzees and sooty mangabeys to humans has been documented on at least seven occasions. Several recently identified SIV isolates have also been shown to replicate efficiently in human peripheral blood mononuclear cells (PBMCs) in vitro, indicative of the potential for additional cross-species transmission via T cell infection. Although SIV predominantly uses the macrophage-tropic HIV chemokine coreceptor CCR5, little is known about the ability of SIV to infect human macrophages. In this study, 16 SIV isolates belonging to five different primate lentivirus lineages were tested for their ability to infect human monocyte-derived macrophages (MDMs). Twelve of the viruses were capable of infecting MDMs, and 11 of these were also able to replicate in human PBMCs. The replication capacity of the isolates differed within and between the various families and was dependent on particular donor macrophages. Our results suggest that most simian lentiviruses characterized to date not only have the ability to infect primary human T lymphocytes but also replicate efficiently in macrophages, thereby increasing the potential for cross-species transmission into the human population. Comparative studies using these isolates may facilitate the identification of characteristics that contribute to virus infectivity and pathogenicity. C1 US FDA, Cell Biol Lab, Div Monoclonal Antibodies, Off Therapeut Res & Review,Ctr Biol Evaluat & Rev, Rockville, MD 20852 USA. NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. RP Clouse, KA (reprint author), US FDA, Cell Biol Lab, Div Monoclonal Antibodies, Off Therapeut Res & Review,Ctr Biol Evaluat & Rev, HFM-558,1401 Rockville Pike, Rockville, MD 20852 USA. NR 49 TC 22 Z9 22 U1 0 U2 1 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 APR 1 PY 2003 VL 32 IS 4 BP 362 EP 369 DI 10.1097/00126334-200304010-00003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 661FB UT WOS:000181879600003 PM 12640192 ER PT J AU Havlik, RJ Simonsick, EM Sutton-Tyrrell, K Newman, A Danielson, ME Brock, DB Pahor, M Lakatta, E Spurgeon, H Vaitkevicius, P AF Havlik, RJ Simonsick, EM Sutton-Tyrrell, K Newman, A Danielson, ME Brock, DB Pahor, M Lakatta, E Spurgeon, H Vaitkevicius, P TI Association of physical activity and vascular stiffness in 70-to 79-year-olds: The health ABC study SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE exercise; pulse-wave velocity; aging ID CORONARY HEART-DISEASE; ARTERIAL STIFFNESS; OLDER ADULTS; AGE; WOMEN; TIME AB Although it is well established that stiff blood vessels contribute to systolic hypertension and increased cardiovascular disease with aging, risk factors for vascular stiffness are still being defined. The Health, Aging, and Body Composition study is a longitudinal investigation of the determinants of physical-functional decline in a well-functioning biracial cohort of 3,075 men and women, age 70-79, in Pittsburgh, PA, and Memphis, TN. Aortic pulse-wave velocity (APWV), an index of vascular stiffness, was measured in 2,488 participants. Self-reported physical activity and exercise habits and fitness/walking endurance were also assessed. Moderate or greater physical activity, exercise, and fitness variables were independently associated with less vascular stiffness, even after inclusion of heart rate, visceral fat, and other correlates of APWV. Physical activity's association with APWV was particularly strong when levels of physical activity were quite low, suggesting that a minimal amount of physical activity might be sufficient to reduce arterial stiffness in older adults. C1 NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38105 USA. RP Havlik, RJ (reprint author), NIA, Bethesda, MD 20892 USA. RI Santana, Fabio/C-8745-2012; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 NR 18 TC 10 Z9 10 U1 0 U2 2 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 156 EP 166 PG 11 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900003 ER PT J AU Guralnik, JM Leveille, S Volpato, S Marx, MS Cohen-Mansfield, J AF Guralnik, JM Leveille, S Volpato, S Marx, MS Cohen-Mansfield, J TI Targeting high-risk older adults into exercise programs for disability prevention SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE functional limitations; physical performance; clinical trials; aging ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; ELDERLY PEOPLE; PERFORMANCE; PREDICTOR; COMMUNITY; DISEASE; WOMEN AB Epidemiological studies have demonstrated that, using objective performance measures of physical functioning, disability risk can be predicted in nondisabled older adults. This makes it possible to recruit a nondisabled but at-risk population for clinical trials of disability prevention. Successful disability prevention in this population, for example through an exercise program, would have a major public health impact. To enhance the development of exercise interventions in this group it would be valuable to have additional information not available from existing epidemiologic studies. This report examines the evidence that functional limitations preceding disability can be identified in a community-dwelling population and that it is feasible to recruit these people into studies. It introduces a series of articles examining the characteristics of this population: motivators and barriers to exercise, exercise habits and preferences, the impact of positive and negative affect, and the impact of pain and functional limitations on attitudes toward exercise. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Res Inst Aging, Hebrew Home Greater Washington, Rockville, MD 20852 USA. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 NR 19 TC 12 Z9 12 U1 1 U2 2 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 219 EP 228 PG 10 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900007 ER PT J AU Marx, MS Cohen-Mansfield, J Guralnik, JM AF Marx, MS Cohen-Mansfield, J Guralnik, JM TI Recruiting community-dwelling elderly at risk for physical disability into exercise research SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE recruitment strategies; participant retention; geriatric; physically frail ID LOWER-EXTREMITY FUNCTION; OLDER ADULTS; SUBSEQUENT DISABILITY; HEALTH PROMOTION; STRATEGIES AB The article describes the process of identifying 100 community-dwelling elderly adults at risk for physical disability, yet not functionally disabled, for participation in a research project to develop appropriate exercise programs for at-risk elderly. Over a period of 14 months, initial contact was made with 941 older adults, 11% of whom (10 1 people) were eligible for and willing to complete all stages of the study protocol. The most successful recruitment strategies were a mass mailing followed by a telephone call and advertising in a newspaper with a large circulation (rather than a local paper). Aspects of the recruitment and retention of study participants are discussed. C1 Res Inst Aging, Hebrew Home Greater Washington, Rockville, MD 20852 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Marx, MS (reprint author), Res Inst Aging, Hebrew Home Greater Washington, 6121 Montrose Rd, Rockville, MD 20852 USA. NR 24 TC 11 Z9 12 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 229 EP 241 PG 13 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900008 ER PT J AU Cohen-Mansfield, J Marx, MS Guralnik, JM AF Cohen-Mansfield, J Marx, MS Guralnik, JM TI Motivators and barriers to exercise in an older community-dwelling population SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE physical activity; facilitators to exercise; perceived incentives ID PHYSICAL-ACTIVITY; PERCEIVED BARRIERS; ADULTS; WOMEN; SCALE; DETERMINANTS; AUSTRALIANS; VALIDATION; BENEFITS; AGE AB This study aimed to ascertain perceived barriers and motivators to exercise in people age 74-85 and to clarify the meaning of these barriers and motivators by examining participant characteristics that relate to them. 324 community-dwelling participants age 74-85 completed a health questionnaire that included items on barriers and motivators to exercise, as well as questions on demographic variables, health, and exercise. Selected participants then completed a physical-performance battery to measure functional performance. Barriers and motivators were related internally, as well as to many other factors including pain and depressed affect on the Geriatric Depression Scale. The findings suggest a need for individualized and comprehensive approaches to the presentation of exercise programs. Health interventions are needed that will address both physical pain and depressed affect and explain the importance of exercise even in the presence of health problems. An understanding of the context of reported barriers and motivators is necessary for correct interpretation and program development. C1 Res Inst Aging, Hebrew Home Greater Washington, Rockville, MD 20852 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Cohen-Mansfield, J (reprint author), Res Inst Aging, Hebrew Home Greater Washington, 6121 Montrose Rd, Rockville, MD 20852 USA. NR 30 TC 96 Z9 96 U1 3 U2 23 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 242 EP 253 PG 12 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900009 ER PT J AU Chang, ML Leveille, S Cohen-Mansfield, J Guralnik, JM AF Chang, ML Leveille, S Cohen-Mansfield, J Guralnik, JM TI The association of physical-performance level with attitude toward exercise in older adults SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE vigorous exercisers; physical performance; elderly; disability; fitness ID WOMEN; PREDICTORS; LIFE; FITNESS; QUALITY; MEN AB The Hebrew Home Study of Impairment and Exercise is a cross-sectional community-based study of nondisabled adults age 75-85 years that assessed attitude toward exercise by asking level of agreement with four statements evaluating participants' perceptions of the health benefits and personal rewards of exercise. A physical-performance battery evaluated lower extremity function on a scale of 0 to 12. Attitude toward exercise was compared across 4 groups: non-vigorous exercisers with scores of 4-6 (n = 21), 7-9 (n = 90), or 10-12 (n = 113) and vigorous exercisers (n = 71). Vigorous exercisers had a significantly better attitude toward exercise than the reference group did, with odds ratios of 1.8-5.5 in all attitude statements. The lowest and moderate-performance groups had less positive attitudes toward exercise than the reference group did, with odds ratios of 0.27-0.62 for all statements. There was a highly significant gradient with better attitude toward exercise and higher functional-status level. Future work in improving older adults' compliance with exercise should take into account the less positive attitude of those with functional limitations toward the benefits of exercise. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Hebrew Home Greater Washington Res Inst, Rockville, MD 20852 USA. RP Chang, ML (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. NR 31 TC 4 Z9 4 U1 1 U2 1 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 254 EP 264 PG 11 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900010 ER PT J AU Ostir, GV Cohen-Mansfield, J Leveille, S Volpato, S Guralnik, JM AF Ostir, GV Cohen-Mansfield, J Leveille, S Volpato, S Guralnik, JM TI The association of positive and negative affect and exercise self-efficacy in older adults SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE emotion; functional ability; aging; elderly ID SUBSEQUENT DISABILITY; PHYSICAL-ACTIVITY; HEALTH; AGE; MEN; AMERICANS; PREDICTOR; SAMPLE; WOMEN; LIFE AB This study investigated whether positive or negative affect has an independent association with exercise self-efficacy. Participants (N = 324) age 75-85 were classified as high or at-risk performers, and three exercise-self-efficacy items (scored 1-10) were assessed. For at-risk performers, positive affect was significantly associated with confidence in the ability to perform strength and flexibility (b = 0.83, SE = 0.23, p = .001) and aerobic exercise (b = 0.59, SE = 0.28, p = .04) and with the perception that exercise would not worsen preexisting symptoms (b = 0.73, SE = 0.24, p = .001). Among high performers, nonsignificant associations were found for positive and negative affect and exercise-self-efficacy. For at-risk performers, higher positive affect was associated with an increased odds ratio of 2.72 for scoring 10 on the muscle strength and flexibility item, 4.08 on the aerobic item, and 2.94 on the item assessing preexisting symptoms. The results suggest that improving at-risk older adults' positive affect might increase their participation in exercise. C1 Univ Texas, Med Branch, Div Geriatr, Galveston, TX 77555 USA. Hebrew Home Greater Washington Res Inst Aging, Rockville, MD 20852 USA. Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Ostir, GV (reprint author), Univ Texas, Med Branch, Div Geriatr, Galveston, TX 77555 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 NR 29 TC 9 Z9 10 U1 3 U2 10 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 265 EP 274 PG 10 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900011 ER PT J AU Leveille, SG Cohen-Mansfield, J Guralnik, JM AF Leveille, SG Cohen-Mansfield, J Guralnik, JM TI The impact of chronic musculoskeletal pain on exercise attitudes, self-efficacy, and physical activity SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE epidemiology; aging; health behavior; arthritis ID OLDER ADULTS; DISABILITY; PROGRESSION; COMMUNITY AB The authors examined the relationship between musculoskeletal pain, self-efficacy, attitudes and beliefs about exercise, and physical activity in 75- to 85-year-old adults. Participants rated their pain during the preceding month in their back, hips, knees, and feet on a scale of 0 to 10. Pain was categorized by number of sites of moderate to severe pain. Among the 325 participants, 42.8% reported at least moderate pain in at least I site. Having more pain sites was associated with younger age, lower income, depressed mood, and poorer self-rated health. Participants with more pain sites scored lower on exercise attitudes, beliefs, and self-efficacy, but the self-efficacy scale was most strongly associated with physical activity. Participants with 2-4 pain sites and low self-efficacy were >4 times as likely to be sedentary as those with no pain and high self-efficacy. These findings suggest that improving self-efficacy for exercise might be an important component of programs to increase physical activity in adults with chronic musculoskeletal pain. C1 Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Res Inst Aging, Hebrew Home Greater Washington, Rockville, MD 20852 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Leveille, SG (reprint author), Hebrew Rehabil Ctr Aged, 1200 Ctr St, Boston, MA 02131 USA. NR 21 TC 5 Z9 6 U1 2 U2 5 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD APR PY 2003 VL 11 IS 2 BP 275 EP 283 PG 9 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 665VA UT WOS:000182140900012 ER PT J AU Trivedi, L Valerio, C Slater, JE AF Trivedi, L Valerio, C Slater, JE TI Endotoxin content of standardized allergen vaccines SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE endotoxin; lipopolysaccharide; allergen; allergen vaccine; allergen immunotherapy; Limulus amebocyte lysate; endotoxin-neutralizing protein; standardization; protease ID LIMULUS AMEBOCYTE LYSATE; SYSTEMIC REACTIONS; ASTHMA; IMMUNOTHERAPY; MITE; EXPOSURE; LAL AB Background: Endotoxin is a ubiquitous and potent proinflammatory agent. Previous limited studies suggest that it is present in allergen vaccines and that this could affect the safety and efficacy of allergen immunotherapy. The endotoxin content of standardized allergen vaccines is unknown. Objective: The purpose of this study was to quantify the amount of endotoxin contained in standardized allergen vaccines. Methods: The endotoxin content of 14 allergen vaccines was measured by using the Limulus amebocyte lysate (LAL) gel-clot assay. To account for (1,3)-beta-D-glucan and protease interference, vaccines were selectively depleted of endotoxin and then retested with the gel-clot assay. Proteases were also heat-inactivated in selected vaccines. Fifty-eight lots of vaccines were tested, including at least two manufacturers per vaccine. Results: The endotoxin content of the 58 vaccines ranged from undetectable to 34,000 EU/mL. Cat pelt (12,735 EU/mL; range, 5177 to 33,805) had significantly more endotoxin activity than cat hair (2883 EU/mL; range, 1 to 16,962), and Dermatophagoides farinae extracts (4619 EU/mL; range, 849 to 8485) had more than Dermatophagoides pteronyssinus (11 EU/mL; range, 1 to 34). Grass (160 EU/mL; range, 3 to 1561) and ragweed pollen (341 EU/mL; range, 8 to 1697) vaccines contained less endotoxin. (1,3)-beta-D-glucan interference was significant (>10%) only in three ragweed vaccines and two grass vaccines. Heat inactivation had no effect. There were considerable differences in endotoxin content of the same vaccines made by different manufacturers. Conclusions: The endotoxin content of standardized allergen vaccines is extremely variable. Interference by proteases and (1,3)-beta-D-glucans is minimal. The effects of the high levels of endotoxin in some vaccines on the immunomodulatory changes associated with allergen immunotherapy require further study. C1 NIAID, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Slater, JE (reprint author), US FDA, Ctr Drug Evaluat & Res, Lab Immunobiochem HFM422, 1401 Rockville Pike, Rockville, MD 20852 USA. NR 34 TC 3 Z9 4 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2003 VL 111 IS 4 BP 777 EP 783 DI 10.1067/mai.2003.1338 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 667WW UT WOS:000182258500017 ER PT J AU Kulka, M AF Kulka, M TI Long term effects of Thl and Th2 cytokines on stem cell Factor-dependent human mast cell division, survival and antigen-drivan activation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 60th Anniversary Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 07-12, 2003 CL DENVER, COLORADO SP Amer Acad Allergy Asthma & Immunol C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2003 VL 111 IS 4 MA L9 BP 910 EP 910 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 667WW UT WOS:000182258500055 ER PT J AU Zheng, G Al-Saleh, MF AF Zheng, G Al-Saleh, MF TI Improving the best linear unbiased estimator for the scale parameter of symmetric distributions by using the absolute value of ranked set samples SO JOURNAL OF APPLIED STATISTICS LA English DT Article ID ALLOCATION AB Ranked set sampling is a cost efficient sampling technique when actually measuring sampling units is difficult but ranking them is relatively easy. For a family of symmetric location-scale distributions with known location parameter, we consider a best linear unbiased estimator for the scale parameter. Instead of using original ranked set samples, we propose to use the absolute deviations of the ranked set samples from the location parameter. We demonstrate that this new estimator has smaller variance than the best linear unbiased estimator using original ranked set samples. Optimal allocation in the absolute value of ranked set samples is also discussed for the estimation of the scale parameter when the location parameter is known. Finally, we perform some sensitivity analyses for this new estimator when the location parameter is unknown but estimated using ranked set samples and when the ranking of sampling units is imperfect. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Yarmouk Univ, Dept Stat, Irbid, Jordan. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Rockledge 2,6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 27 TC 8 Z9 8 U1 0 U2 1 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0266-4763 J9 J APPL STAT JI J. Appl. Stat. PD APR PY 2003 VL 30 IS 3 BP 253 EP 265 DI 10.1080/0266476022000030039 PG 13 WC Statistics & Probability SC Mathematics GA 639HZ UT WOS:000180623600001 ER PT J AU Kolker, DE Fukuyama, H Huang, DS Takahashi, JS Horton, TH Turek, FW AF Kolker, DE Fukuyama, H Huang, DS Takahashi, JS Horton, TH Turek, FW TI Aging alters circadian and light-induced expression of clock genes in golden hamsters SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Article DE aging; circadian rhythm; gene expression; light induced; Clock; Bmal1; Per1; Per2; hamster ID MULTIPLE SIGNALING PATHWAYS; MESSENGER-RNA EXPRESSION; SUPRACHIASMATIC NUCLEUS; AGED RATS; RHYTHMS; PERIOD; MPER1; CELLS; FIBROBLASTS; MECHANISM AB Aging alters numerous aspects of circadian biology, including the amplitude of rhythms generated by the suprachiasmatic nuclei (SCN) of the hypothalamus, the site of the central circadian pacemaker in mammals, and the response of the pacemaker to environmental stimuli such as light. Although previous studies have described molecular correlates of these behavioral changes, to date only 1 study in rats has attempted to determine if there are age-related changes in the expression of genes that comprise the circadian clock itself. We used in situ hybridization to examine the effects of age on the circadian pattern of expression of a subset of the genes that comprise the molecular machinery of the circadian clock in golden hamsters. Here we report that age alters the 24-h expression profile of Clock and its binding partner Bmal1 in the hamster SCN. There is no effect of age on the 24-h profile of either Per1 or Per2 when hamsters are housed in constant darkness. We also found that light pulses, which induce smaller phase shifts in old animals than in young, lead to decreased induction of Per1, but not of Per2, in the SCN of old hamsters. C1 Northwestern Univ, Dept Neurobiol & Physiol, Evanston, IL 60208 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Turek, FW (reprint author), NICHD, Endocrinol & Reprod Res Branch, NIH, 49 Convent Dr,Bldg 49,Room 6A-36,MSC 4510, Bethesda, MD 20892 USA. RI Jelinek, Milan/C-8515-2011; Takahashi, Joseph/E-8482-2012 OI Takahashi, Joseph/0000-0003-0384-8878 FU NHLBI NIH HHS [R01-HL 59598]; NIA NIH HHS [P01-AG11412] NR 44 TC 78 Z9 84 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0748-7304 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD APR PY 2003 VL 18 IS 2 BP 159 EP 169 DI 10.1177/0748730403251802 PG 11 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 661KJ UT WOS:000181889500007 PM 12693870 ER PT J AU Shi, S Gronthos, S AF Shi, S Gronthos, S TI Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE bone marrow; dental pulp; mesenchymal stem cells; perivascular; STRO-1; CD146 ID ADULT HUMAN BONE; STROMAL CELLS; MONOCLONAL-ANTIBODY; IN-VITRO; MICROVASCULAR PERICYTES; OSTEOGENIC PRECURSORS; SMOOTH-MUSCLE; CULTURES; DIFFERENTIATION; STRO-1 AB Mesenchymal stem cell populations have previously been identified in adult bone marrow and dental pulp that are capable of regenerating the bone marrow and dental pulp microenvironments, respectively. Here we show that these stem cell populations reside in the microvasculature of their tissue of origin. Human bone marrow stromal stem cells (BMSSCs) and dental pulp stem cells (DPSCs) were isolated by immunoselection using the antibody, STRO-1, which recognizes an antigen on perivascular cells in bone marrow and dental pulp tissue. Freshly isolated STRO-1 positive BMSSCs and DPSCs were tested for expression of vascular antigens known to be expressed by endothelial cells (von Willebrand factor, CD146), smooth muscle cells, and pericytes (alpha-smooth muscle actin, CD146), and a pericyte-associated antigen (3G5), by immunohistochemistry, fluorescence-activated cell sorting (FACS), and/or immunomagnetic bead selection. Both BMSSCs and DPSCs lacked expression of von Willebrand factor but were found to be positive for alpha-smooth muscle actin and CD146. Furthermore, the majority of DPSCs expressed the pericyte marker, 3G5, while only a minor population of BMSSCs were found to be positive for 3G5. The finding that BMSSCs and DPSCs both display phenotypes consistent with different perivascular cell populations, regardless of their diverse ontogeny and developmental potentials, may have further implications in understanding the factors that regulate the formation of mineralized matrices and other associated connective tissues. C1 Inst Med & Vet Sci, Mesenchymal Stem Cell Grp, Matthew Roberts Fdn Lab, Div Hematol, Adelaide, SA 5000, Australia. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Gronthos, S (reprint author), Inst Med & Vet Sci, Mesenchymal Stem Cell Grp, Matthew Roberts Fdn Lab, Div Hematol, Frome Rd, Adelaide, SA 5000, Australia. EM stan.gronthos@imvs.sa.gov.au NR 56 TC 720 Z9 760 U1 6 U2 50 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 APR PY 2003 VL 18 IS 4 BP 696 EP 704 DI 10.1359/jbmr.2003.18.4.696 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 658WM UT WOS:000181744000012 PM 12674330 ER PT J AU Gronthos, S Chen, SQ Wang, CY Robey, PG Shi, ST AF Gronthos, S Chen, SQ Wang, CY Robey, PG Shi, ST TI Telomerase accelerates osteogenesis of bone marrow stromal stem cells by upregulation of CBFA1, osterix, and osteocalcin SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE telomerase; bone marrow stromal stem cells; CBFA1; osterix; osteocalcin ID LIFE-SPAN; OSTEOBLAST DIFFERENTIATION; IN-VIVO; RETINOBLASTOMA PROTEIN; EXPRESSION; CYCLE; TRANSCRIPTION; E2F; ASSOCIATION; FIBROBLASTS AB Telomerase activity can prevent telomere shortening and replicative senescence in human somatic cells. We and others have previously demonstrated that forced expression of telomerase in human bone marrow stromal stem cells (BMSSCs) was able to extend their life-span and enhance their bone-forming capability, without inducing malignant transformation. In this study, we determined that telomerase was able to accelerate calcium accumulation of human BMSSCs under osteogenic inductive conditions. Similarly, xenogeneic transplantation of telomerase-expressing BMSSCs (BMSSC-Ts) yielded ectopic bone formation at 2 weeks post-transplantation, 2-4 weeks earlier than typically seen with BMSSCs transfected with empty vector (BMSSC-Cs). Low-density DNA array analysis revealed that telomerase activity increases the expression of G1 regulating genes including cyclin D3, cyclin E1, E2F-4, and DP2, associated with hyperphosphorylation of retinoblastoma (pRb), leading to the extended proliferative capacity of BMSSC-Ts. Importantly, BMSSC-T transplants showed a higher number of human osteogenic cells at 8 weeks post transplantation compared with the BMSSC-C transplants, coupled with a significantly increased osteogenic capacity. One possible mechanism leading to accelerated osteogenesis by BMSSC-Ts may be attributed, at least in part, to the upregulation of the important osteogenic genes such as CBFA1, osterix, and osteocalcin in vitro. Taken together, these findings show that telomerase can accelerate cell cycle progression from G1-to-S phase and enhance osteogenic differentiation of BMSSCs, because of the upregulation of CBFA1, osterix, and osteocalcin. C1 NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. Univ Michigan, Dept Biol & Mat Sci, Lab Mol Signaling & Apoptosis, Ann Arbor, MI 48109 USA. Univ Michigan, Mol & Cellular Biol Program, Ann Arbor, MI 48109 USA. RP Shi, ST (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, Bldg 30,Room 228,30 Convent Dr, Bethesda, MD 20892 USA. EM sshi@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 42 TC 83 Z9 88 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 APR PY 2003 VL 18 IS 4 BP 716 EP 722 DI 10.1359/jbmr.2003.18.4.716 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 658WM UT WOS:000181744000014 PM 12674332 ER PT J AU Rudolf, R Kogel, T Kuznetsov, SA Salm, T Schlicker, O Hellwig, A Hammer, JA Gerdes, HH AF Rudolf, R Kogel, T Kuznetsov, SA Salm, T Schlicker, O Hellwig, A Hammer, JA Gerdes, HH TI Myosin Va facilitates the distribution of secretory granules in the F-actin rich cortex of PC12 cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE secretory granules; myosin va; hCgB-GFP; cell cortex; F-actin; organelle transport ID GREEN FLUORESCENT PROTEIN; CHROMAFFIN CELLS; MOTOR PROTEINS; REAL-TIME; TRANSPORT; ORGANELLE; VISUALIZATION; LIGHT; MELANOCYTES; MICROSCOPY AB Neuroendocrine secretory granules, the storage organelles for neuropeptides and hormones, are formed at the trans-Golgi network, stored inside the cell and exocytosed upon stimulation. Previously, we have reported that newly formed secretory granules of PC12 cells are transported in a microtubule-dependent manner from the trans-Golgi network to the F-actin-rich cell cortex, where they undergo short directed movements and exhibit a homogeneous distribution. Here we provide morphological and biochemical evidence that myosin Va is associated with secretory granules. Expression of a dominant-negative tail domain of myosin Va in PC12 cells led to an extensive clustering of secretory granules close to the cell periphery, a loss of their cortical restriction and a strong reduction in their motility in the actin cortex. Based on this data we propose a model that implies a dual transport system for secretory granules: after microtubule-dependent delivery to the cell periphery, secretory granules exhibit a myosin Va-dependent transport leading to their restriction and even dispersal in the F-actin-rich cortex of PC12 cells. C1 Univ Heidelberg, Interdisciplinary Ctr Neurosci, Dept Neurobiol, D-69120 Heidelberg, Germany. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gerdes, HH (reprint author), Univ Heidelberg, Interdisciplinary Ctr Neurosci, Dept Neurobiol, Neuenheimer Feld 364, D-69120 Heidelberg, Germany. RI Rudolf, Ruediger/A-6476-2009; OI Rudolf, Ruediger/0000-0002-0833-1053; Kogel, Tanja/0000-0002-6876-2998 NR 43 TC 84 Z9 86 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD APR 1 PY 2003 VL 116 IS 7 BP 1339 EP 1348 DI 10.1242/jcs.00317 PG 10 WC Cell Biology SC Cell Biology GA 664KE UT WOS:000182059600016 PM 12615975 ER PT J AU Morley, SC Sun, GP Bierer, BE AF Morley, SC Sun, GP Bierer, BE TI Inhibition of actin polymerization enhances commitment to and execution of apoptosis induced by withdrawal of trophic support SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE apoptosis; Cytochalasin D; actin; cytokine-withdrawal ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; RECEPTOR ZETA-CHAIN; T-CELL ACTIVATION; CYTOCHALASIN-D; FLOW-CYTOMETRY; LYMPHOCYTES; CYTOSKELETON; CLEAVAGE; MECHANISM; FAMILY AB We have previously shown, using jasplakinolide, that stabilization of the actin cytoskeleton enhanced apoptosis induced upon cytokine withdrawal (Posey and Bierer [1999] J. Biol. Chem. 274:4259-4265). It remained possible, however, that a disruption in the regulation of actin dynamics, and not simply F-actin stabilization, was required to affect the transduction of an apoptotic signal. We have now tested the effects of cytochalasin D, awe I I-characterized agent that promoted actin depolymerization. Actin depolymerization did not affect CD95 (Fas)-induced death of Jurkat T cells in the time course studied but did enhance the commitment to cytokine withdrawal-induced apoptosis of factor-dependent cell lines. The induction of cell death was not the result of direct cytoskeletal collapse, since treatment of the cells with cytochalasin D in the presence of IL-2 did not promote death. As with jasplakinolide, the enhancement of commitment to apoptosis could be delayed by overexpression of the anti-apoptotic protein Bcl-x(L), but, unlike jasplakinolide, cytochalasin D modestly affected the "execution" stage of apoptosis as well. Taken together, these results suggest that changes in actin dynamics, i.e., the rate of actin polymerization and depolymerization, modulate the transduction of the apoptotic signal committing lymphocytes, withdrawn from required growth factors, to the death pathway. Published 2003 Wiley-Liss, Inc.(dagger). C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. Div Med Sci, Comm Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Bierer, BE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Dana 810,44 Binney St, Boston, MA 02115 USA. NR 52 TC 41 Z9 43 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 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD APR 1 PY 2003 VL 88 IS 5 BP 1066 EP 1076 DI 10.1002/jcb.10449 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 656HC UT WOS:000181601700019 ER PT J AU Esposito, DL Li, YH Vanni, C Mammarella, S Veschi, S Della Loggia, F Mariani-Costantini, R Battista, P Quon, MJ Cama, A AF Esposito, DL Li, YH Vanni, C Mammarella, S Veschi, S Della Loggia, F Mariani-Costantini, R Battista, P Quon, MJ Cama, A TI Clinical case seminar - A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RAT ADIPOSE-CELLS; AMINO-ACID POLYMORPHISM; IRS-1 GENE; GLUCOSE-TOLERANCE; PHOSPHATIDYLINOSITOL 3'-KINASE; CODON-972 POLYMORPHISM; VARIANT SEQUENCES; FULL ACTIVATION; MELLITUS; TRANSLOCATION AB Naturally occurring mutations in insulin receptor substrate-1 (IRS-1) have previously been implicated in impaired insulin action. We now report a novel mutation in IRS-1 with substitution of Arg for Thr(608) that was identified in a patient with type 2 diabetes mellitus. We detected the T608R mutation in 1 of 136 chromosomes from diabetic patients and in 0 of 120 chromosomes from nondiabetic controls, suggesting that this is a rare IRS-1 variant. Conservation of Thr(608) in human, monkey, rat, mouse, and chicken IRS-1 sequences is consistent with a crucial function for this residue. Moreover, Thr(608) is located near the YMXM motif containing Tyr(612) that is important for binding and activation of phosphoinositol 3-kinase (PI 3-kinase). To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. C1 NIH, Diabet Unit, Clin Invest Lab, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Univ G DAnnunzio, Sect Mol Pathol, Dept Oncol & Neurosci, I-66013 Chieti, Italy. RP Quon, MJ (reprint author), NIH, Diabet Unit, Clin Invest Lab, Natl Ctr Complementary & Alternat Med, Bldg 10,Room 8C-218,10 Ctr Dr,MSC 1755, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 53 TC 23 Z9 25 U1 1 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 APR PY 2003 VL 88 IS 4 BP 1468 EP 1475 DI 10.1210/jc.2002-020933 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667BM UT WOS:000182211000009 PM 12679424 ER PT J AU Patronas, N Bulakbasi, N Stratakis, CA Lafferty, A Oldfield, EH Doppman, J Nieman, LK AF Patronas, N Bulakbasi, N Stratakis, CA Lafferty, A Oldfield, EH Doppman, J Nieman, LK TI Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CUSHINGS-DISEASE; MR; MICROADENOMAS; ADENOMAS; DIAGNOSIS; GADOLINIUM; EXPERIENCE; INJECTION; ACCURACY; HORMONE AB Recent studies show that the standard T1-weighted spin echo (SE) technique for magnetic resonance imaging (MRI) fails to identify 40% of corticotrope adenomas. We hypothesized that the superior soft tissue contrast and thinner sections obtained with spoiled gradient recalled acquisition in the steady state (SPGR) would improve tumor detection. We compared the performance of SE and SPGR MRI in 50 patients (age, 7-67 yr) with surgically confirmed corticotrope adenoma. Coronal SE and SPGR MR images were obtained before and after administration of gadolinium contrast, using a 1.5 T scanner. SE scans were obtained over 5.1 min (12-cm field of view; interleaved sections, 3 mm). SPGR scans were obtained over 3.45 min (12- or 18-cm field of view, contiguous 1- or 2-mm slices). The MRI interpretations of two radiologists were compared with findings at surgical resection. Compared with SE for detection of tumor, SPGR had superior sensitivity (80%; confidence interval, 68-91; vs. 49%; confidence interval, 34-63%), but a higher false positive rate (2% vs. 4%). We recommend the addition of SPGR to SE sequences using pituitary-specific technical parameters to improve the MRI detection of ACTH-secreting pituitary tumors. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neurosurg Branch, NIH, Bethesda, MD 20892 USA. NICHD, Dept Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,10 Ctr Dr,Room 9D42, Bethesda, MD 20892 USA. EM niemanl@nih.gov NR 23 TC 72 Z9 74 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 APR PY 2003 VL 88 IS 4 BP 1565 EP 1569 DI 10.1210/jc.2002-021438 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667BM UT WOS:000182211000025 PM 12679440 ER PT J AU Nedvidkova, J Krykorkova, I Bartak, V Papezova, H Gold, PW Alesci, S Pacak, K AF Nedvidkova, J Krykorkova, I Bartak, V Papezova, H Gold, PW Alesci, S Pacak, K TI Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-HORMONE SECRETAGOGUE; CIRCULATING GHRELIN; ACYLATED PEPTIDE; FOOD-INTAKE; HUMANS; SECRETION; ENDOCRINE; STOMACH; LIGAND; RATS AB Studies have shown that ghrelin plays a major role in energy homeostasis and modulation of feeding behavior. However, little is known about the influence of food consumption on plasma ghrelin levels in humans. Therefore, we investigated responses of plasma ghrelin to food intake, meal volume and meal nutrtional value in healthy volunteers and women with anorexia nervosa (AN). After overnight fasting, all subjects received either a standardized breakfast or fiber. Plasma ghrelin levels were measured before and after the meal. Fasting plasma ghrelin was significantly higher in AN patients than in controls (1,800.6 +/- 47.0 vs 795.9 +/- 24.3 pg/ml, P < 0.001) (606.8 +/- 15.8 vs 268.2 +/- 8.2 pmol.l, P < 0.001), and correlated negatively with percentage of body fat in both groups. Ghrelin levels markedly fell after consumption of either a standardized meal or fiber in controls, but not in anorexic women. Thus, we concluded that the acute plasma ghrelin response to food intake, which in healthy individuals is independent of meal caloric value, is impaired in women with AN. This abnormality may be part of a chronic adaptation to prolonged food restriction, which attempts to restore a normal feeding conduct by maintaining the drive to eat. C1 Charles Univ, Inst Endocrinol, Prague, Czech Republic. Charles Univ, Fac Nat Sci, Prague, Czech Republic. Charles Univ, Dept Psychiat, Prague, Czech Republic. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Messina, Dipartimento Clin Sperimentale Med & Farmacol, Messina, Italy. RP Pacak, K (reprint author), NICHD, Unit Clin Neuroendocrinol, Pediat & Reprod Endocrine Branch, NIH, Bldg 10,Room 9D 42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 24 TC 111 Z9 115 U1 1 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 APR PY 2003 VL 88 IS 4 BP 1678 EP 1682 DI 10.1210/jc.2002-021669 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667BM UT WOS:000182211000041 PM 12679456 ER PT J AU Merke, DP Fields, JD Keil, MF Vaituzis, AC Chrousos, GP Giedd, JN AF Merke, DP Fields, JD Keil, MF Vaituzis, AC Chrousos, GP Giedd, JN TI Children with classic congenital adrenal hyperplasia have decreased amygdala volume: Potential prenatal and postnatal hormonal effects SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING FACTOR; RECURRENT MAJOR DEPRESSION; SEXUAL DIMORPHISM; 21-HYDROXYLASE DEFICIENCY; ANXIETY DISORDERS; TEMPORAL-LOBE; HIPPOCAMPAL ATROPHY; EMOTIONAL MEMORY; ANOREXIA-NERVOSA; HUMAN BRAIN AB Children with classic congenital adrenal hyperplasia (CAH) have multiple endocrine imbalances, including prenatal glucocorticoid and adrenomedullary deficiency and androgen excess, with possible postnatal iatrogenic glucocorticoid excess, hyperandrogenism, and adrenomedullary hypofunction. Prenatal masculinization of the brain has been suggested in girls with classic CAH. Hormones of the hypothalamic-pituitary-adrenal axis and sex hormones interact with extrahypothalamic regulatory centers of the brain, including the amygdala and hippocampus. The amygdala is important in the processing of emotion and generation of fear, whereas the hippocampus plays an important role in memory. Chronic hypercortisolemia has been shown to be associated with hippocampal damage, while glucocorticoids and corticotropin-releasing factor play a major role in the regulation of amygdala function. We performed magnetic resonance imaging of the brain on 27 children with classic CAH and 47 sex- and age-matched controls. Volumes of the cerebrum, ventricles, temporal lobe, amygdala, and hippocampus were quantified. Females with CAH did not have brains with male-specific characteristics. In contrast, a significant decrease in amygdala volume was observed in both males and females with CAH (males, P = 0.01; females, P = 0.002). Iatrogenic effects on the hippocampus due to glucocorticoid therapy were not observed in children with CAH. These results suggest that prenatal glucocorticoid deficiency with resulting alterations in hypothalamic-pituitary-adrenal axis regulation, sex steroid excess, or some combination of these preferentially affect the growth and development of the amygdala, a structure with major functional implications that warrant further exploration. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 13S260,10 Ctr Dr,MSC 1932, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 63 TC 66 Z9 67 U1 7 U2 11 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2003 VL 88 IS 4 BP 1760 EP 1765 DI 10.1210/jc.2002-021730 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667BM UT WOS:000182211000055 PM 12679470 ER PT J AU Gunji, T Kawauchi, N Akahane, M Watanabe, K Kanamori, H Ohnishi, S AF Gunji, T Kawauchi, N Akahane, M Watanabe, K Kanamori, H Ohnishi, S TI Treatment of unresectable hepatocellular carcinoma less than 2 centimeters by transcatheter arterial chemoembolization with autologous blood clot SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE transcatheter arterial chemoembolization; hepatocellular carcinoma; autologous blood clot ID PERCUTANEOUS ETHANOL INJECTION; LONG-TERM PROGNOSIS; EMBOLIZATION; CIRRHOSIS; THERAPY AB Goals: To assess the efficacy of transcatheter arterial chemoembolization using autologous blood clot as an embolizing agent (short-TAE [S-TAE]) for the treatment of unresectable hepatocellular carcinoma less than 2 cm. Study: Twenty-eight consecutive patients with unresectable hepatocellular carcinoma less than 2 cm in diameter were treated by S-TAE alone. All patients had documented cirrhosis (Child class B:C = 20:8). S-TAE was performed by injecting a mixture of iodized oil and anticancer drugs followed by embolization of hepatic arteries with autologous blood clot. Results: A total of 147 sessions of embolization with clots were performed. S-TAE maintained patency of hepatic arteries. The overall survival rates at 1, 3, 5, and 8 years were estimated to be 89%, 52%, 34%, and 17%, respectively, which were better compared with prior records for the gelfoam method. The survival rates for Child class B patients were significantly better than that for Child class C patients (P < 0.05). The Cox proportional hazard model also demonstrated that Child staging of cirrhosis was the sole factor significantly predicting the survival (P < 0.05). Conclusions: The long-term outcomes of S-TAE for unresectable hepatocellular carcinoma less than 2 cm are satisfactory. Prognosis of these patients was significantly dependent on clinical stages of coexisting liver cirrhosis. C1 Univ Tokyo, Fac Med, Dept Internal Med 3, Tokyo 113, Japan. Univ Tokyo, Fac Med, Dept Radiol, Tokyo 113, Japan. RP Gunji, T (reprint author), NIDDK, Liver Dis Sect, Digest Dis Branch, NIH, Bldg 10,Rm 9B06,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. NR 17 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD APR PY 2003 VL 36 IS 4 BP 347 EP 351 DI 10.1097/00004836-200304000-00013 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 655WF UT WOS:000181575100013 PM 12642743 ER PT J AU Pennesi, G Mattapallil, M Sun, SH Avichezer, D Silver, PB Karabekian, Z David, CS Hargrave, PA McDowell, JH Smith, WC Wiggert, B Donoso, LA Chan, CC Caspi, RR AF Pennesi, G Mattapallil, M Sun, SH Avichezer, D Silver, PB Karabekian, Z David, CS Hargrave, PA McDowell, JH Smith, WC Wiggert, B Donoso, LA Chan, CC Caspi, RR TI A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RETINOID-BINDING-PROTEIN; PRIMERS PCR-SSP; SYMPATHETIC OPHTHALMIA; STRONG ASSOCIATION; S-ANTIGEN; DISEASE; MOLECULES; SUSCEPTIBILITY; UVEORETINITIS; EXPRESSION AB Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBP-induced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 3 10 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin, Dept Immunol, Rochester, MN USA. Univ Florida, Dept Ophthalmol, Gainesville, FL USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Wills Eye Hosp & Res Inst, Philadelphia, PA USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 52 TC 59 Z9 61 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2003 VL 111 IS 8 BP 1171 EP 1180 DI 10.1172/JCI200315155 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 668GE UT WOS:000182281300012 PM 12697736 ER PT J AU Landmesser, U Dikalov, S Price, SR McCann, L Fukai, T Holland, SM Mitch, WE Harrison, DG AF Landmesser, U Dikalov, S Price, SR McCann, L Fukai, T Holland, SM Mitch, WE Harrison, DG TI Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SMOOTH-MUSCLE CELLS; STIMULATES SUPEROXIDE PRODUCTION; ANGIOTENSIN-II; HYDROGEN-PEROXIDE; NAD(P)H OXIDASE; NADPH OXIDASE; ANION PRODUCTION; DEFICIENT MICE; ASCORBIC-ACID; KAPPA-B AB Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease. C1 Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Div Nephrol, Atlanta, GA 30322 USA. Atlanta Vet Adm Hosp, Atlanta, GA USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Med, Galveston, TX 77555 USA. RP Harrison, DG (reprint author), Emory Univ, Sch Med, Div Cardiol, 1639 Pierce Dr,319 WMB, Atlanta, GA 30322 USA. FU NHLBI NIH HHS [P01 HL058000, HL 39000 6, HL 58000, HL 59248]; NIDDK NIH HHS [DK 37175, DK 50740, R01 DK037175, R01 DK050740, R37 DK037175] NR 63 TC 976 Z9 1000 U1 4 U2 49 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 APR PY 2003 VL 111 IS 8 BP 1201 EP 1209 DI 10.1172/JCI200314172 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 668GE UT WOS:000182281300015 PM 12697739 ER PT J AU McDermott, DH Fong, AM Yang, Q Sechler, JM Cupples, LA Merrell, MN Wilson, PWF D'Agostino, RB O'Donnell, CJ Patel, DD Murphy, PM AF McDermott, DH Fong, AM Yang, Q Sechler, JM Cupples, LA Merrell, MN Wilson, PWF D'Agostino, RB O'Donnell, CJ Patel, DD Murphy, PM TI Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CORONARY-ARTERY DISEASE; CARDIAC ALLOGRAFT-REJECTION; DEFICIENT MICE; ATHEROSCLEROTIC LESIONS; REDUCES ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; TARGETED DELETION; HEART-DISEASE; RISK FACTOR AB The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Murphy, PM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Yang, Qiong/G-5438-2014; OI McDermott, David/0000-0001-6978-0867 NR 53 TC 191 Z9 199 U1 0 U2 7 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 APR PY 2003 VL 111 IS 8 BP 1241 EP 1250 DI 10.1172/JCI200316790 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 668GE UT WOS:000182281300019 PM 12697743 ER PT J AU Smith, RE Bryant, J DeCillis, A Anderson, S AF Smith, RE Bryant, J DeCillis, A Anderson, S TI Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The national surgical adjuvant breast and bowel project experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE NONLYMPHOCYTIC LEUKEMIA; NON-HODGKINS LYMPHOMA; RADIATION-THERAPY; POSTOPERATIVE RADIATION; PREMENOPAUSAL WOMEN; SECONDARY LEUKEMIA; 2ND MALIGNANCIES; INCREASED RISK; CHEMOTHERAPY; CLASSIFICATION AB Purpose: We reviewed data from all adjuvant NSABP breast cancer trials that tested regimens containing both doxorubicin (A) and cyclophosphamide (C) to characterize the incidence of subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Materials and Methods: Six complete NSABP trials have investigated AC regimens (B-15, B-16, B-18, B-22, B-23, and B-25). Six distinct AC regimens have been tested and are distinguished by differences in cyclophosphamide intensity and cumulative dose and by the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. In all regimens, A was given at 60 mg/m(2) q 21 days x 4. C was given as follows: 600 mg/m2 q 21 days x 4 ("standard AC");1,200 mg(2) q 21 days x 2;1,200 mg/m(2) q 21 days x 4; 2,400 mg/m2 q 21 days x 2; and 2,400 mg/m2 q 21 days x 4. Occurrence of AML/MDS was summarized by incidence per 1,000 patient-years at risk and by cumulative incidence. Rates were compared across regimens, by age, and by treatment with or without breast radiotherapy. Results: The incidence of AML/MDS was sharply elevated in the more intense regimens. In patients receiving two or four cycles of C at 2,400 mg/m2 with granulocyte colony-stimulating factor (G-CSF) support, cumulative incidence of AML/MDS at 5 years was 1.01 % (95% confidence interval [CI], 0.63% to 1.62%), compared with 0.21% (95% CI, 0.11 % to 0.41%) for patients treated with standard AC. Patients who received breast radiotherapy experienced more secondary AML/MDS than those who did not (RR = 2.38, P =.006), and the data indicated that G-CSF does may possibly also be independently correlated with increased risk. Conclusion: AC regimens employing intensified doses of cyclophosphamide requiring G-CSF support were characterized by increased rates of subsequent AML/MDS, although the incidence of AML/MDS was small relative to that of breast cancer relapse. Breast radiotherapy appeared to be associated with an increased risk of AML/MDS. (C) 2003 by American Society of Clinical Oncology. C1 Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Allegheny Ctr 4, Pittsburgh, PA 15212 USA. Ctr Biostat, Pittsburgh, PA USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. RP Smith, RE (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Allegheny Ctr 4, E Commons Profess Bldg,5th Floor, Pittsburgh, PA 15212 USA. OI Anderson, Stewart/0000-0001-8948-0650 FU NCI NIH HHS [U10-CA69651, U10-CA12027] NR 48 TC 173 Z9 178 U1 1 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 APR 1 PY 2003 VL 21 IS 7 BP 1195 EP 1204 DI 10.1200/JCO.2003.03.114 PG 10 WC Oncology SC Oncology GA 662XB UT WOS:000181973400002 PM 12663705 ER PT J AU Oeffinger, KC Mertens, AC Sklar, CA Yasui, Y Fears, T Stovall, M Vik, TA Inskip, PD Robison, LL AF Oeffinger, KC Mertens, AC Sklar, CA Yasui, Y Fears, T Stovall, M Vik, TA Inskip, PD Robison, LL TI Obesity in adult survivors of childhood acute lymphoblastic leukemia: A report from the childhood cancer survivor study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LONG-TERM SURVIVORS; BODY-MASS INDEX; GROWTH-HORMONE DEFICIENCY; CRANIAL IRRADIATION; YOUNG-ADULTS; PITUITARY DYSFUNCTION; RADIATION; THERAPY; WEIGHT; PREVALENCE AB Purpose: To determine whether adult survivors (greater than or equal to 18 years of age) of childhood acute lymphoblastic leukemia (ALL) are at increased risk for obesity and to assess patient and treatment variables that influence risk. Patients and Methods: A retrospective cohort of participants of the Childhood Cancer Survivor Study was used to compare 1,765 adult survivors of childhood ALL to 2,565 adult siblings of childhood cancer survivors. Body-mass index (BMI; kilograms per square meter), calculated from self-reported heights and weights, was used to determine the prevalence of being overweight (BMI, 25-29.9) or obese (BMI greater than or equal to 30.0). Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for being overweight or obese among ALL survivors relative to the sibling control group. Results: The age- and race-adjusted OR for being obese in survivors treated with cranial radiation doses greater than or equal to 20 Gy in comparison with siblings was 2.59 for females (95% CI, 1.88 to 3.55; P < .001) and 1.86 for males (95% CI, 1.33 to 2.57; P < .001). The OR for obesity was greatest among females diagnosed at 0 to 4 years of age and treated with radiation doses greater than or equal to 20 Gy (OR, 3.81; 95% CI, 2.34 to 5.99; P < .001). Obesity was not associated with treatment consisting of chemotherapy only or with cranial radiation doses of 10 to 19 Gy. Conclusion: Cranial radiotherapy greater than or equal to 20 Gy is associated with an increased prevalence of obesity, especially in females treated at a young age. It is imperative that healthcare professionals recognize this risk and develop strategies to enhance weight control and encourage longitudinal follow-up. (C) 2003 by American Society of Clinical Oncology. C1 Univ Texas, SW Med Ctr, Dept Family Practice & Community Med, Dallas, TX 75390 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. NCI, Div Canc Epidemiol & Genet, Washington, DC USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Riley Childrens Hosp, Indianapolis, IN USA. RP Oeffinger, KC (reprint author), Univ Texas, SW Med Ctr, Dept Family Practice & Community Med, 6263 Harry Hines Blvd, Dallas, TX 75390 USA. RI Yasui, Yutaka/E-2564-2015 OI Yasui, Yutaka/0000-0002-7717-8638 FU NCI NIH HHS [5U01-CA-55727-05] NR 38 TC 226 Z9 231 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 APR 1 PY 2003 VL 21 IS 7 BP 1359 EP 1365 DI 10.1200/JCO.2003.06.131 PG 7 WC Oncology SC Oncology GA 662XB UT WOS:000181973400024 PM 12663727 ER PT J AU Lewis, JH Kilgore, ML Goldman, DP Trimble, EL Kaplan, R Montello, MJ Housman, MG Escarce, JJ AF Lewis, JH Kilgore, ML Goldman, DP Trimble, EL Kaplan, R Montello, MJ Housman, MG Escarce, JJ TI Participation of patients 65 years of age or older in cancer clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOUTHWEST-ONCOLOGY-GROUP; ACUTE MYELOID-LEUKEMIA; CHEMOTHERAPY; WOMEN; UNDERREPRESENTATION; REPRESENTATION AB Purpose: Although 61% of new cases of cancer occur among the elderly, recent studies indicate that the elderly comprise only 25% of participants in cancer clinical trials. Further investigation into the reasons for low elderly participation is warranted. Our objective was to evaluate the participation of the elderly in clinical trials sponsored by the National Cancer Institute (NCI) and assess the impact of protocol exclusion criteria on elderly participation. Patients and Methods: We conducted a retrospective analysis using NCI data, analyzing patient and trial characteristics for 59,300 patients enrolled onto 495 NCI-sponsored, cooperative group trials, active from 1997 through 2000. Our main outcome measure was the proportion of elderly patients enrolled onto cancer clinical trials compared with the proportion of incident cancer patients who are elderly. Results: Overall, 32% of participants in phase II and III clinical trials were elderly, compared with 61% of patients with incident cancers in the United States who are elderly. The degree of underrepresentation was more pronounced in trials for early-stage cancers than in trials for late-stage cancers (P < .001). Furthermore, protocol exclusion criteria on the basis of organ-system abnormalities and functional status limitations were associated with lower elderly participation. We estimate that if protocol exclusions were relaxed, elderly participation in cancer trials would be 60%. Conclusion: The elderly are underrepresented in cancer clinical trials relative to their disease burden. Older patients are more likely to have medical histories that make them ineligible for clinical trials because of protocol exclusions. Insurance coverage for clinical trials is one step toward improvement of elderly access to clinical trials. Without a change in study design or requirements, this step may not be sufficient. (C) 2003 by American Society of Clinical Oncology. C1 RAND Hlth, Santa Monica, CA 90407 USA. Calif State Univ Los Angeles, Los Angeles, CA 90032 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Lewis, JH (reprint author), RAND, 1700 Main St, Santa Monica, CA 90407 USA. NR 37 TC 486 Z9 492 U1 1 U2 8 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 APR 1 PY 2003 VL 21 IS 7 BP 1383 EP 1389 DI 10.1200/JCO.2003.08.010 PG 7 WC Oncology SC Oncology GA 662XB UT WOS:000181973400028 PM 12663731 ER PT J AU Lesko, LJ Salerno, RA Spear, BB Anderson, DC Anderson, T Brazell, C Collins, J Dorner, A Essayan, D Gomez-Mancilla, B Hackett, J Huang, SM Ide, S Killinger, J Leighton, J Mansfield, E Meyer, R Ryan, SG Schmith, V Shaw, P Sistare, F Watson, M Worobec, A AF Lesko, LJ Salerno, RA Spear, BB Anderson, DC Anderson, T Brazell, C Collins, J Dorner, A Essayan, D Gomez-Mancilla, B Hackett, J Huang, SM Ide, S Killinger, J Leighton, J Mansfield, E Meyer, R Ryan, SG Schmith, V Shaw, P Sistare, F Watson, M Worobec, A TI Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: Report of the first FDA-PWG-PhRMA-DruSafe workshop SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacogenetics; pharmacogenomics; drug development process; regulatory agencies; safe harbor ID HYPERSENSITIVITY; ASSOCIATION; ABACAVIR; GENE AB The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues. C1 US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol & Biopharmaceut, Rockville, MD 20857 USA. US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Rockville, MD 20857 USA. US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Rockville, MD 20857 USA. Wyeth Res, WorldWide Regulatory Affairs, St Davids, PA USA. Abbott Labs, Pharmacogenet, Abbott Pk, IL 60064 USA. Pharmacia corp, Kalamazoo, MI USA. Pfizer Inc, Groton, CT 06340 USA. GlaxoSmithKline, Genet Res, Greenford, Middx, England. Wyeth Res, Andover, MA USA. Wyeth Res, Chazy, NY USA. US FDA, Ctr Biol Evaluat & Res, Off Therapeut, Div Clin Trial Design & Anal, Rockville, MD 20857 USA. US FDA, Ctr Devices & Radiol Hlth, Off Vitro Diagnost Device Evaluat & Safety, Rockville, MD 20857 USA. NHGRI, NIH, Gaithersburg, MD USA. Novartis, Gaithersburg, MD USA. AstraZeneca Pharmaceut, Wilmington, DE USA. GlaxoSmithKline, Res Triangle Pk, NC USA. Bristol Myers Squibb Co, Pharmacogenom & Human Genet, Princeton, NJ 08543 USA. Merck & Co Inc, Clin Genom, W Point, PA USA. RP Lesko, LJ (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol & Biopharmaceut, Rockville, MD 20857 USA. NR 21 TC 77 Z9 83 U1 0 U2 2 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 APR PY 2003 VL 43 IS 4 BP 342 EP 358 DI 10.1177/0091270003252244 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 660VX UT WOS:000181855700003 PM 12723455 ER PT J AU Jones, RW Ross, J Hoshino, Y AF Jones, RW Ross, J Hoshino, Y TI Identification of parental origin of cognate dsRNA genome segment(s) of rotavirus reassortants by constant denaturant gel electrophoresis SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE rotavirus; electrophoresis; CDGE; reassortants; diarrhea ID VACCINE DEVELOPMENT; NEUTRALIZATION; SPECIFICITIES; ANTIBODIES; SEROTYPES; VP3; INFECTION; PROTEINS; IMMUNITY; STRAINS AB Rotaviruses are the single most important etiologic agents of severe diarrhea in infants and young children worldwide. They possess a triple capsid morphology and a genome of 11 segments of double-stranded (ds) RNA. During the course of the development of various live, attenuated reassortant rotavirus vaccines, we often experienced difficulty in identifying the parental origin of certain genome segment(s) of a reassortant vaccine candidate. Various assays have been utilized for determination of the parental origin of reassortant virus genes, including polyacrylamide gel electrophoresis (PAGE), DNA and/or RNA hybridization assays and gene sequence analysis. The traditional PAGE is simple and easy to perform, however, it is common to find that certain cognate dsRNA segment(s) cannot be differentiated by this assay due to a high degree of sequence homology among different rotavirus strains. Constant denaturant gel electrophoresis (CDGE) is one of several methods that have been used to screen DNA fragments for small sequence changes or point mutations. By using the CDGE, we were successful in partially denaturing rotavirus dsRNA thereby changing the physical properties of the genome segment(s) in the gel and thus differentiating the cognate genome segment(s) of rotavirus reassortants. The CDGE provides a simple and reliable assay system for identification of parental gene origins of a rotavirus reassortant. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308,50 S Dr MSC 8026, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov NR 29 TC 15 Z9 16 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 APR PY 2003 VL 26 IS 3 BP 347 EP 354 AR PII S1386-6532(02)00086-0 DI 10.1016/S1386-6532(02)00086-0 PG 8 WC Virology SC Virology GA 659ZQ UT WOS:000181809700010 PM 12637084 ER PT J AU Oh, CK Kwon, YW Kim, YS Jang, HS Kwon, KS AF Oh, CK Kwon, YW Kim, YS Jang, HS Kwon, KS TI Expression of basic fibroblast growth factor, vascular endothelial growth factor, and thrombospondin-1 related to microvessel density in nonaggressive and aggressive basal cell carcinomas SO JOURNAL OF DERMATOLOGY LA English DT Article DE basal cell carcinoma; bFGF; VEGF; TSP-1; microvessel density ID INVASIVE BREAST-CARCINOMA; TUMOR ANGIOGENESIS; HUMAN SKIN; METASTASIS; GENE AB The aggressive forms of basal cell carcinoma (BCC) are biologically different in a number of features from their nonaggressive counterparts. The expression of basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF), and Thrombospondin-1 (TSP-1) was examined in primary culture samples of nonaggressive and aggressive BCCs. We studied the relationship between neoangiogenesis by counting microvessels, tumor aggressiveness, and the expression of three different angiogenic factors. bFGF mRNA was detectable in all BCC samples, but there was no significant difference in the levels of expression between the two types. VEGF mRNA was also detectable in all BCC samples. VEGF expression in the aggressive type was approximately 3.5-fold higher than in the nonaggressive type. TSP-1 expression was variable and not related to the type of BCC. The mean value of microvessel density (MVD) was significantly higher for the aggressive type than for the nonaggressive type. There was a significant correlation between VEGF levels and MVD. No significant relationships were found between bFGF, TSP-1 mRNA expression, and MVD. In conclusion, the results of present study suggest that VEGF expression and angiogenesis might play important roles in the progression to aggressive BCC. C1 Pusan Natl Univ, Coll Med, Dept Dermatol, Seo Ku, Pusan 602739, South Korea. NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Rockville, MD 20852 USA. Pusan Natl Univ, Inst Med Res, Pusan, South Korea. RP Oh, CK (reprint author), Pusan Natl Univ, Coll Med, Dept Dermatol, Seo Ku, 1-10 Ami Dong, Pusan 602739, South Korea. NR 22 TC 12 Z9 15 U1 0 U2 0 PU JAPANESE DERMATOLGICAL ASSOC PI TOKYO PA TAISEI-BLDG., 14-10 HONGO 3-CHOME, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 0385-2407 J9 J DERMATOL JI J. Dermatol. PD APR PY 2003 VL 30 IS 4 BP 306 EP 313 PG 8 WC Dermatology SC Dermatology GA 672RD UT WOS:000182534500004 PM 12707467 ER PT J AU Kasprzak, KS Bal, W Karaczyn, AA AF Kasprzak, KS Bal, W Karaczyn, AA TI The role of chromatin damage in nickel-induced carcinogenesis. A review of recent developments SO JOURNAL OF ENVIRONMENTAL MONITORING LA English DT Article; Proceedings Paper CT 6th International Nickel Conference CY SEP 01-06, 2002 CL MURMANSK, RUSSIA ID HUMAN PROTAMINE HP2; OXIDATIVE DNA-DAMAGE; N-TERMINAL SEQUENCE; HISTONE H2A; MASS-SPECTROMETRY; STRAND SCISSION; 2 FORMS; BINDING; NI(II); RESIDUES AB Over the last years. we have been testing a hypothesis that molecular mechanisms of nickel-induced carcinogenesis include interactions of this metal with major chromatin components: DNA, histones, and protamines. Our investigations using synthetic peptide models have resulted in identification of nickel-binding sites in core histones H3 and H2A and in protamine P2. These are: the internal -Cys(110)-AIH- motif in histone H3; the C-terminal-E-121-SHHKAKGK "tail" motif in histone H2A: and the N-terminal RTH- motif in prolamine P2. Ni(II) bound to the H3 and P2 motifs enhances oxidative DNA base damage by H2O2. In contrast, Ni(it) complex with the H2A "tail" is not redox active. Ho ever. at pH 7.4 it undergoes hydrolysis yielding a new complex. Ni(II)-SHHKAKGK, reactive with H2O2 and capable of mediating DNA oxidation. The "tail" cutting of H2A has also been observed in cells cultured with Ni(II). In Ni(II) complex with the protamine P2 peptides, H2O2 causes degradation of the metal-binding His(3) and the distant Tyr(8) residues. This site-specificity results from a long-range structuring effect of Ni(II) on its prolamine ligand. In conclusion. Ni(II) binding to some chromatin proteins in somatic and sperm cells may result in oxidative and structural damage to the proteins and DNA, These effects may alter the fidelity of DNA replication and gene expression and thus facilitate carcinogenesis, including paternally-mediated cancer in the progeny. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Room 205E, Frederick, MD 21702 USA. NR 33 TC 36 Z9 38 U1 0 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1464-0325 J9 J ENVIRON MONITOR JI J. Environ. Monit. PD APR PY 2003 VL 5 IS 2 BP 183 EP 187 DI 10.1039/b210538c PG 5 WC Chemistry, Analytical; Environmental Sciences SC Chemistry; Environmental Sciences & Ecology GA 670DT UT WOS:000182392700005 PM 12729250 ER PT J AU Salnikow, K Davidson, T Kluz, T Chen, HB Zhou, DJ Costa, M AF Salnikow, K Davidson, T Kluz, T Chen, HB Zhou, DJ Costa, M TI GeneChip analysis of signaling pathways effected by nickel SO JOURNAL OF ENVIRONMENTAL MONITORING LA English DT Article; Proceedings Paper CT 6th International Nickel Conference CY SEP 01-06, 2002 CL MURMANSK, RUSSIA ID HYPOXIA-INDUCIBLE FACTOR-1; EPITHELIAL-CELLS; TRANSFORMATION; INDUCTION; GENES; CARCINOGENICITY; MUTAGENICITY; PARTICULATE; SUBSULFIDE; TOXICITY AB The carcinogenicity of nickel compounds has been shogun in numerous epidemiological and animal Studies, Carcinogenesis is generally considered as a multistep accumulation of genetic alterations. Nickel, however, being highly carcinogenic is only a weak mutagen. We hypothesize that nickel may act by modulating signaling pathways and subsequently by reprogramming transcription factors. Insoluble nickel is considered to be more carcinogenic than Soluble. In this Study using GeneChip technology we compared changes ill gene expression caused by Soluble and insoluble nickel compounds. We found that both Soluble and insoluble nickel Compounds induce similar signaling pathways following 20 h of in vitro exposure. For example. both nickel compounds activated a number of transcription factors including hypoxia-inducible factor I (HIF-1) and p53. The induction of these important transcription factors exerts potent selective pressure leading to cell transformation. The obtained data are in agreement with Our previous observations that acute nickel exposure activates HIF-1 and p53, transcription factors and in nickel-transformed cells. the ratio of activity to p53 activity was shifted towards high HIF-I activity. The activation of the same signaling, pathways by soluble and insoluble nickel compounds suggested that both nickel Compounds have similar carcinogenic potential in vitro. C1 NYU, NIEHS, Ctr Excellence, Nelson Inst Environm Med, New York, NY 10016 USA. NYU, Sch Med, Inst Canc, New York, NY 10016 USA. RP Salnikow, K (reprint author), NYU, NIEHS, Ctr Excellence, Nelson Inst Environm Med, 550 1st Ave, New York, NY 10016 USA. RI costa, max/H-1754-2012; Zhang, Donna /B-1015-2012 FU NCI NIH HHS [CA16087]; NIEHS NIH HHS [ES00260, ES05512, ES10344] NR 29 TC 28 Z9 30 U1 0 U2 5 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1464-0325 J9 J ENVIRON MONITOR JI J. Environ. Monit. PD APR PY 2003 VL 5 IS 2 BP 206 EP 209 DI 10.1039/b210262p PG 4 WC Chemistry, Analytical; Environmental Sciences SC Chemistry; Environmental Sciences & Ecology GA 670DT UT WOS:000182392700010 PM 12729255 ER PT J AU McDermott, MM Green, D Greenland, P Liu, K Criqui, M Chan, C Guralnik, JM Pearce, WH Ridker, PM Taylor, L Rifai, N Schneider, JR Quann, M AF McDermott, MM Green, D Greenland, P Liu, K Criqui, M Chan, C Guralnik, JM Pearce, WH Ridker, PM Taylor, L Rifai, N Schneider, JR Quann, M TI Inflammatory markers, hemostatic factors, and the ankle brachial index SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Northwestern Univ, Chicago, IL 60611 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NIA, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Oregon Hlth & Sci Univ, Portland, OR USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 151 EP 151 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564300557 ER PT J AU Lawrence, WF Yabroff, KR Fleishman, JA AF Lawrence, WF Yabroff, KR Fleishman, JA TI Measuring health utilities in national data sets: A new approach to valuing the HALex. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Agcy Healthcare Res & Qual, Rockville, MD USA. NCI, Rockville, MD USA. NR 0 TC 3 Z9 3 U1 1 U2 4 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 164 EP 164 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564300614 ER PT J AU McDermott, MM Greenland, P Liu, K Guralnik, JM Criqui, MH Pearce, WH Green, D Rifai, N Ridker, PM Chan, C Taylor, LM Schneider, JR Quann, M AF McDermott, MM Greenland, P Liu, K Guralnik, JM Criqui, MH Pearce, WH Green, D Rifai, N Ridker, PM Chan, C Taylor, LM Schneider, JR Quann, M TI Inverse associations between physical activity and inflammatory markers/D-dimer in patients with peripheral arterial disease. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Northwestern Univ, Chicago, IL 60611 USA. NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 196 EP 196 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564300764 ER PT J AU Gross, CP Farrell, M Filardo, G Irwin, M Singh, H Freedman, A AF Gross, CP Farrell, M Filardo, G Irwin, M Singh, H Freedman, A TI Factors associated with women's perceived cancer risk: Results from the national health interview survey. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Yale Univ, New Haven, CT USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 265 EP 265 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564301088 ER PT J AU Gross, CP Farrell, M Filardo, G Irwin, M Singh, H Freedman, A AF Gross, CP Farrell, M Filardo, G Irwin, M Singh, H Freedman, A TI The relation between breast cancer risk and mammography utilization: Insights from the national health interview survey. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Yale Univ, Sch Med, New Haven, CT USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 265 EP 265 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564301087 ER PT J AU Goold, SD Broder, J Baum, N Danis, M AF Goold, SD Broder, J Baum, N Danis, M TI Group deliberations about healthcare tradeoffs. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2003 VL 18 SU 1 BP 274 EP 274 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 673DF UT WOS:000182564301130 ER PT J AU Chowdhury, IH Radonovich, M Mahieux, R Pise-Masison, C Muralidhar, S Brady, JN AF Chowdhury, IH Radonovich, M Mahieux, R Pise-Masison, C Muralidhar, S Brady, JN TI p53 facilitates degradation of human T-cell leukaemia virus type 1 Tax-binding protein through a proteasome-dependent pathway SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NF-KAPPA-B; TRANS-ACTIVATOR PROTEIN; WILD-TYPE P53; LEUKEMIA-VIRUS; HTLV-I; HUMAN CYTOMEGALOVIRUS; COACTIVATOR CBP; TRANSCRIPTIONAL ACTIVATION; TRANSACTIVATION FUNCTION; P53-DEPENDENT APOPTOSIS AB Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells in vivo and in vitro. The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse-chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2(.)0 to 0(.)25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transciption-dependent and independent functions of p53. C1 NCI, Basic Res Lab, Virus Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. Inst Pasteur, F-75724 Paris 15, France. RP Brady, JN (reprint author), NCI, Basic Res Lab, Virus Tumor Biol Sect, NIH, Bldg 41-B201,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 81 TC 4 Z9 4 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2003 VL 84 BP 897 EP 906 DI 10.1099/vir.0.18753-0 PN 4 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 664GN UT WOS:000182053500016 PM 12655090 ER PT J AU Kiss, A Kaposi-Novak, P Factor, V Lotz, G Halasz, J Thorgeirsson, SS Schaff, ZS AF Kiss, A Kaposi-Novak, P Factor, V Lotz, G Halasz, J Thorgeirsson, SS Schaff, ZS TI Activation of beta-catenin pathway in human hepatocellular carcinoma negatively correlates to CD-44 and AFP expression SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the European-Association-for-the-Study-of-the-Liver CY MAR 29-APR 01, 2003 CL ISTANBUL, TURKEY SP European Assoc Study Liver C1 Semmelweis Univ, Inst Pathol 2, H-1085 Budapest, Hungary. NCI, NIH, 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 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2003 VL 38 SU 2 MA 333 BP 99 EP 99 DI 10.1016/S0168-8278(03)80400-2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 666JQ UT WOS:000182174500329 ER PT J AU Wagner, M Fickert, P Zollner, G Fuchsbichler, A Silbert, D Marschall, HU Gonzalez, FJ Zatloukal, K Denk, H Trauner, M AF Wagner, M Fickert, P Zollner, G Fuchsbichler, A Silbert, D Marschall, HU Gonzalez, FJ Zatloukal, K Denk, H Trauner, M TI The role of the bile acid receptor FXR in determining ATP-binding cassette (ABC) transporter expression and liver injury in common bile duct ligated (CBDL) mice SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the European-Association-for-the-Study-of-the-Liver CY MAR 29-APR 01, 2003 CL ISTANBUL, TURKEY SP European Assoc Study Liver C1 Karl Franzens Univ Graz, Dept Med, Graz, Austria. Karl Franzens Univ Graz, Dept Pathol, Graz, Austria. Huddinge Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden. NCI, 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 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2003 VL 38 SU 2 MA 656 BP 190 EP 190 DI 10.1016/S0168-8278(03)80031-4 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 666JQ UT WOS:000182174500647 ER PT J AU Chalmers, J Todd, A Chapman, N Bellin, L Davis, S Donnan, G Frommer, M Huxley, R Lenfant, C MacMahon, S Mancia, G Mendis, S Whitworth, J Zanchetti, A AF Chalmers, J Todd, A Chapman, N Bellin, L Davis, S Donnan, G Frommer, M Huxley, R Lenfant, C MacMahon, S Mancia, G Mendis, S Whitworth, J Zanchetti, A CA Int Soc Hypertension Writing Grp TI International Society of Hypertension (ISH): Statement on blood pressure lowering and stroke prevention SO JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT World Health Organization/International-Society-of-Hypertension Meeting on Stroke and Blood Pressure CY DEC 05-07, 2002 CL MELBOURNE, AUSTRALIA SP WHO, Int Soc Hypertens DE stroke; blood pressure lowering; hypertension; prevention; treatment; International Society of Hypertension ID ISOLATED SYSTOLIC HYPERTENSION; ANTIHYPERTENSIVE DRUG-TREATMENT; CONVERTING-ENZYME-INHIBITION; TRANSIENT ISCHEMIC ATTACK; CORONARY HEART-DISEASE; LOW-DOSE ASPIRIN; RANDOMIZED TRIAL; SECONDARY PREVENTION; CARDIOVASCULAR MORBIDITY; GLOBAL BURDEN AB The ISH Statement on blood pressure lowering and stroke prevention was finalized after presentation and discussion at the World Health Organization and International Society of Hypertension (WHO-ISH) Meeting on Stroke and Blood Pressure, held in Melbourne Australia, 5-7 December 2002. The meeting was conducted under the auspice of the Austin Hospital Medical Research Foundation, Melbourne. C1 Univ Sydney, Inst Int Hlth, Writing Grp, Sydney, NSW 2042, Australia. Univ Western Australia, Perth, WA 6009, Australia. Univ Melbourne, Melbourne, Vic, Australia. NHLBI, Bethesda, MD 20892 USA. Univ Milano Bicocca, Osped San Gerardo, Monza, Italy. WHO, CH-1211 Geneva, Switzerland. Australian Natl Univ, Canberra, ACT, Australia. Univ Milan, Osped Maggiore, Milan, Italy. Ist Auxol Italiano, Milan, Italy. RP Chalmers, J (reprint author), Univ Sydney, Inst Int Hlth, Writing Grp, 144-146 Burren St, Sydney, NSW 2042, Australia. RI DONNAN, GEOFFREY/A-9947-2008; Jennings, Garry/B-3914-2009; Huxley, Rachel/J-4638-2013; Davis, Stephen/L-5260-2013; Huxley, Rachel/C-7032-2013 OI Huxley, Rachel/0000-0002-2705-6616; Davis, Stephen/0000-0003-0962-2300; Huxley, Rachel/0000-0002-2705-6616 NR 138 TC 59 Z9 64 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD APR PY 2003 VL 21 IS 4 BP 651 EP 663 DI 10.1097/01.hjh.0000052490.18130.95 PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 676KK UT WOS:000182750700002 PM 12658005 ER PT J AU Bath, P Chalmers, J Powers, W Beilin, L Davis, S Lenfant, C Mancia, G Neal, B Whitworth, J Zanchetti, A AF Bath, P Chalmers, J Powers, W Beilin, L Davis, S Lenfant, C Mancia, G Neal, B Whitworth, J Zanchetti, A CA Int Soc Hypertension Writing Grp TI International Society of Hypertension (ISH): Statement on the management of blood pressure in acute stroke SO JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT World Health Organization/International-Society-of-Hypertension Meeting on Stroke and Blood Pressure CY DEC 05-07, 2002 CL MELBOURNE, AUSTRALIA SP WHO, Int Soc Hypertens DE stroke; ischaemic stroke; primary intracerebral haemorrhage; blood pressure management; hypertension; International Society of Hypertension ID ACUTE ISCHEMIC STROKE; SPONTANEOUS INTRACEREBRAL HEMORRHAGE; PROGNOSTIC VALUE; SODIUM-NITROPRUSSIDE; HEMATOMA ENLARGEMENT; CEREBRAL INFARCTION; NITRIC-OXIDE; TRIAL; MORTALITY; FLOW AB The ISH statement on the management of blood pressure in acute stroke was finalized after presentation and discussion at the World Health Organization and International Society of Hypertension (WHO-ISH) Meeting on Stroke and Blood Pressure, held in Melbourne, Australia, 5-7 December 2002. The meeting was conducted under the auspices of the Austin Hospital Medical Research Foundation, Melbourne. C1 Univ Nottingham, Div Stroke Med, Writing Grp, Nottingham NG5 1PB, England. Univ Sydney, Sydney, NSW 2006, Australia. Washington Univ, Sch Med, St Louis, MO USA. Univ Western Australia, Perth, WA 6009, Australia. Univ Melbourne, Melbourne, Vic, Australia. NHLBI, Bethesda, MD 20892 USA. Univ Milan, Osped San Gerardo, Monza, Italy. Australian Natl Univ, Canberra, ACT, Australia. Univ Milan, Osped Maggiore, Milan, Italy. Ist Auxol Italiano, Milan, Italy. RP Bath, P (reprint author), Univ Nottingham, Div Stroke Med, Writing Grp, City Hosp Campus,Hucknall Rd, Nottingham NG5 1PB, England. RI Jennings, Garry/B-3914-2009; Davis, Stephen/L-5260-2013; OI Davis, Stephen/0000-0003-0962-2300; Bath, Philip/0000-0003-2734-5132 NR 82 TC 90 Z9 97 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD APR PY 2003 VL 21 IS 4 BP 665 EP 672 DI 10.1097/01.hjh.0000052489.18130.43 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 676KK UT WOS:000182750700003 PM 12658006 ER PT J AU Faeder, JR Hlavacek, WS Reischl, I Blinov, ML Metzger, H Redondo, A Wofsy, C Goldstein, B AF Faeder, JR Hlavacek, WS Reischl, I Blinov, ML Metzger, H Redondo, A Wofsy, C Goldstein, B TI Investigation of early events in FC epsilon RI-mediated signaling using a detailed mathematical model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASE; AFFINITY IGE RECEPTOR; BASOPHILIC LEUKEMIA-CELLS; IMMUNOGLOBULIN-E RECEPTOR; ACTIVATION LOOP TYROSINES; ANTIGEN RECEPTOR; SH2 DOMAINS; LYN KINASE; HIGH SPECIFICITY; SYK ACTIVATION AB Aggregation of FcepsilonRI on mast cells and basophils leads to autophosphorylation and increased activity of the cytosolic protein tyrosine kinase Syk. We investigated the roles of the Src kinase Lyn, the immunoreceptor tyrosine-based activation motifs (ITAMs) on the beta and gamma subunits of FcepsilonRI, and Syk itself in the activation of Syk. Our approach was to build a detailed mathematical model of reactions involving FcepsilonRI, Lyn, Syk, and a bivalent ligand that aggregates FcepsilonRI. We applied the model to experiments in which covalently cross-linked IgE dimers stimulate rat basophilic leukemia cells. The model makes it possible to test the consistency of mechanistic assumptions with data that alone provide limited mechanistic insight. For example, the model helps sort out mechanisms that jointly control dephosphorylation of receptor subunits. In addition, interpreted in the context of the model, experimentally observed differences between the beta- and gamma-chains with respect to levels of phosphorylation and rates of dephosphorylation indicate that most cellular Syk, but only a small fraction of Lyn, is available to interact with receptors. We also show that although the beta ITAM acts to amplify signaling in experimental systems where its role has been investigated, there are conditions under which the beta ITAM will act as an inhibitor. C1 Los Alamos Natl Lab, Div Theoret, Theoret Biol & Biophys Grp, Los Alamos, NM 87545 USA. Los Alamos Natl Lab, Div Theoret, Theoret Chem & Mol Phys Grp, Los Alamos, NM 87545 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. RP Goldstein, B (reprint author), Los Alamos Natl Lab, Div Theoret, Theoret Biol & Biophys Grp, MS K710, Los Alamos, NM 87545 USA. EM bxg@lanl.gov FU NIGMS NIH HHS [GM35556] NR 77 TC 96 Z9 100 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2003 VL 170 IS 7 BP 3769 EP 3781 PG 13 WC Immunology SC Immunology GA 659AL UT WOS:000181754100040 PM 12646643 ER PT J AU Kottilil, S Chun, TW Moir, S Liu, SY McLaughlin, M Hallahan, CW Maldarelli, F Corey, L Fauci, AS AF Kottilil, S Chun, TW Moir, S Liu, SY McLaughlin, M Hallahan, CW Maldarelli, F Corey, L Fauci, AS TI Innate immunity in human immunodeficiency virus infection: Effect of viremia on natural killer cell function 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 CD4(+) T-CELLS; HIV-1 INFECTION; QUANTITATIVE-ANALYSIS; REPLICATION; RECEPTORS; INDIVIDUALS; RESPONSES; DISEASE; PATHOGENESIS; PROGRESSION AB We examined the effect of viremia on cell contact and soluble factor-mediated suppression of endogenous human immunodeficiency virus (HIV) replication in CD4(+) T cells from HIV-1-infected individuals by autologous natural killer (NK) and CD8(+) T cells. NK cells suppressed HIV replication as effectively as did CD8(+) T cells. Suppression of HIV replication by NK cell culture supernatant was predominantly mediated by CC-chemokine secretion and was considerably greater in patients without viremia than in patients with viremia. Furthermore, there was an inverse correlation between the level of viremia and the ability of NK cells and NK-derived supernatants to suppress virus replication. The ability of NK cells to control HIV replication was independent of levels of interferon-gamma expression and cytolytic activity. Our results demonstrate that NK-mediated suppression of HIV replication is as potent as that of CD8(+) T cells; it is mediated predominantly by secretion of CC-chemokines, and the presence of viremia markedly impairs this NK-mediated inhibitory effect on HIV replication. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Wisconsin Ave,Bldg 10,Rm 6A08A, Bethesda, MD 20892 USA. EM Skottilil@niaid.nih.gov NR 33 TC 118 Z9 124 U1 0 U2 6 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 APR 1 PY 2003 VL 187 IS 7 BP 1038 EP 1045 DI 10.1086/368222 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 658GJ UT WOS:000181713000002 PM 12660917 ER PT J AU Aberg, JA Williams, PL Liu, T Lederman, HM Hafner, R Torriani, FJ Lennox, JL Dube, MP MacGregor, RR Currier, JS AF Aberg, JA Williams, PL Liu, T Lederman, HM Hafner, R Torriani, FJ Lennox, JL Dube, MP MacGregor, RR Currier, JS CA AIDS Clinical Trial Grp 393 Study TI A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study Team 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 PNEUMOCYSTIS-CARINII PNEUMONIA; ACTIVE ANTIRETROVIRAL THERAPY; PRIMARY PROPHYLAXIS; TOXOPLASMIC ENCEPHALITIS; HIV-1-INFECTED PATIENTS; SECONDARY PROPHYLAXIS; NATURAL-HISTORY; HIV-INFECTION; CELL COUNT; DISEASE AB The present nonrandomized prospective study evaluated whether antimycobacterial therapy for disseminated Mycobacterium avium complex ( MAC) could be withdrawn from human immunodeficiency virus-infected subjects who experienced immunologic recovery while receiving highly active antiretroviral therapy( HAART). Eligible subjects had received macrolide-based therapy for least 12 months, were asymptomatic for MAC, had received HAART for at least 16 weeks, and had CD4(+) T cell counts >100 cells/muL. Forty-eight subjects were enrolled, with a median CD4(+) T cell count of 240 cells/muL at the time of discontinuation of MAC therapy. Forty-seven subjects remained MAC free, whereas 1 subject developed localized MAC osteomyelitis. The median duration of follow-up while not receiving therapy was 77 weeks, and the incidence of MAC infection was 1.44/100 person-years (95% confidence interval, 0.04-8.01). Withdrawal of anti-MAC therapy appears to be safe in patients who have been treated with a macrolide-based regimen for at least 1 year and have an immunologic response on HAART. C1 Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA USA. Univ Calif San Diego, Dept Med, Div Infect Dis, San Diego, CA 92103 USA. Univ S Carolina, Dept Med, Div Infect Dis, Los Angeles, CA USA. Harvard Sch Publ Hlth, Boston, MA USA. Johns Hopkins Univ, Baltimore, MD USA. NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. Emory Univ, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA. Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. RP Aberg, JA (reprint author), Washington Univ, Sch Med, AIDS Clin Trials Unit, 4511 Forest Pk Ave,Ste 304, St Louis, MO 63108 USA. EM jaberg@im.wustl.edu RI Lennox, Jeffrey/D-1654-2014 OI Lennox, Jeffrey/0000-0002-2064-5565 FU NCRR NIH HHS [RR 00083, RR 00046, RR 00052]; NIAID NIH HHS [AI 27668, AI 25868, AI 27670, AI 38858, AI 32775] NR 33 TC 25 Z9 26 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2003 VL 187 IS 7 BP 1046 EP 1052 DI 10.1086/368413 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 658GJ UT WOS:000181713000003 PM 12660918 ER PT J AU Choi, EH Foster, CB Taylor, JG Erichsen, HC Chen, RA Walsh, TJ Anttila, VJ Ruutu, T Palotie, A Chanock, SJ AF Choi, EH Foster, CB Taylor, JG Erichsen, HC Chen, RA Walsh, TJ Anttila, VJ Ruutu, T Palotie, A Chanock, SJ TI Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HEPATOSPLENIC CANDIDIASIS; CELL RESPONSES; INTERLEUKIN-4; ALBICANS; CHEMOTHERAPY; IMMUNITY; CANCER AB Chronic disseminated candidiasis (CDC) is a form of Candida species infection observed primarily in patients with acute leukemia. To investigate possible genetic factors associated with CDC, we conducted a pilot study of 40 patients with both leukemia and CDC and 50 control patients with leukemia only. A common haplotype of the IL4 promoter (-1098T/-589C/ -33C) was overrepresented in patients with CDC (P = .01; odds ratio [OR], 2.16), whereas another common haplotype (-1098T/-589T/ -33T) appeared to be protective against CDC (P = .018; OR, 0.47). Genetic variants of IL4 could contribute to the development of CDC in patients with acute leukemia. C1 NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Adv Technol,NIH, Gaithersburg, MD 20892 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Cent Hosp, Dept Med, Div Hematol, Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Med, Div Infect Dis, Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Clin Chem, Helsinki, Finland. RP Chanock, SJ (reprint author), NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Adv Technol,NIH, 8717 Grovemont Circle, Gaithersburg, MD 20892 USA. EM sc83a@nih.gov RI Choi, Eun Hwa/J-5691-2012; OI Taylor, James/0000-0002-4421-1809 NR 15 TC 33 Z9 36 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 APR 1 PY 2003 VL 187 IS 7 BP 1153 EP 1156 DI 10.1086/368345 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 658GJ UT WOS:000181713000016 PM 12660931 ER PT J AU Udey, MC AF Udey, MC TI In this issue: Progress towards a more complete understanding of two important immune diseases involving skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2003 VL 120 IS 4 BP VIII EP VIII DI 10.1046/j.1523-1747.2003.12115.x PG 1 WC Dermatology SC Dermatology GA 657VQ UT WOS:000181687400001 PM 12648241 ER PT J AU Vogel, J AF Vogel, J TI The virtue of tolerance SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID GENE-THERAPY C1 NCI, Bethesda, MD 20892 USA. RP Vogel, J (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 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 APR PY 2003 VL 120 IS 4 BP XI EP XII DI 10.1046/j.1523-1747.2003.12118.x PG 2 WC Dermatology SC Dermatology GA 657VQ UT WOS:000181687400003 PM 12648242 ER PT J AU Trempus, CS Morris, RJ Bortner, CD Cotsarelis, G Faircloth, RS Reece, JM Tennant, RW AF Trempus, CS Morris, RJ Bortner, CD Cotsarelis, G Faircloth, RS Reece, JM Tennant, RW TI Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE epidermal; keratinocyte; stem cell ID EPIDERMAL STEM-CELLS; LABEL-RETAINING CELLS; HEMATOPOIETIC PROGENITOR; MONOCLONAL-ANTIBODY; GENE-EXPRESSION; BASAL CELLS; IN-VITRO; SKIN; MOUSE; DIFFERENTIATION AB It is widely believed that epithelial stem cells reside in the hair follicle bulge region. We investigated the hematopoietic stem and progenitor cell marker, CD34, as a potential marker of hair follicle bulge keratinocytes. Using a CD34-specific antibody, we identified intense membrane staining on keratinocytes in the bulge region of the mouse hair follicle. CD34 expression colocalized with both slowly cycling (label retaining) cells and keratin 15 expression. Live CD34(+) keratinocytes were positively selected using antibodies to CD34 and alpha6 integrin in combination with fluorescent activated cell sorting. Sorted cells were analyzed for DNA content, and a staining profile was generated to confirm these cells as keratinocytes. CD34 keratinocytes were predominantly in G(o)/G(1), in contrast to CD34(-) cells, which had well defined G(2)/M and S phases. In addition, CD34(+) keratinocytes were found to express alpha6 integrin more intensely than CD34(-) cells (p<0.05), identifying this population as an α6 integrin bright subset. When seeded at clonal density, CD34+ keratinocytes formed larger colonies than CD34- cells (p<0.05), indicating a higher proliferative potential. All flow-sorted cells were positive for keratin 14 expression, and negative for keratin 1, loricrin, vimentin, and CD31. The majority of CD34(+) cells (98%) were positive for keratin 6, establishing this population as basal keratinocytes of follicular origin. CD34 message was detected by reverse transcription polymerase chain reaction predominantly in the CD34(+) keratinocytes, confirming specificity of the antibody. T his work is the first to demonstrate that CD34 is a specific marker of bulge cell keratinocytes in the cutaneous epithelium. Furthermore, the use of this marker facilitates isolation of live epithelial cells with stem and progenitor cell characteristics, potentially providing a tool for the study of carcinogen target cells, gene therapy, and tissue engineering applications. C1 NIEHS, Canc Biol Grp, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Lankenau Inst Med Res, Wynnewood, PA USA. NIEHS, Traitement Signal Lab, Res Triangle Pk, NC 27709 USA. Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. RP Trempus, CS (reprint author), NIEHS, Canc Biol Grp, Natl Ctr Toxicogenom, POB 12233, Res Triangle Pk, NC 27709 USA. EM trempus@NIEHS.NIH.gov FU NCI NIH HHS [CA87780, CA45293] NR 44 TC 342 Z9 362 U1 3 U2 19 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 APR PY 2003 VL 120 IS 4 BP 501 EP 511 DI 10.1046/j.1523-1747.2003.12088.x PG 11 WC Dermatology SC Dermatology GA 657VQ UT WOS:000181687400007 PM 12648211 ER PT J AU Richard, G Brown, N Rouan, F Van der Schroeff, JG Bijlsma, E Eichenfield, LE Sybert, VP Greer, KE Hogan, P Campanelli, C Compton, JG Bale, SJ DiGiovanna, JJ Uitto, J AF Richard, G Brown, N Rouan, F Van der Schroeff, JG Bijlsma, E Eichenfield, LE Sybert, VP Greer, KE Hogan, P Campanelli, C Compton, JG Bale, SJ DiGiovanna, JJ Uitto, J TI Genetic heterogeneity in erythrokeratodermia variabilis: Novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE connexin; epidermal differentiation; erythrokeratodermia variabilis; gap junction communication; mutation ID ICHTHYOSIS-DEAFNESS SYNDROME; GAP JUNCTION PROTEIN; SKIN-DISEASE; DEFECTIVE TRAFFICKING; ECTODERMAL DYSPLASIA; CHANNELS; TERMINUS; LINKAGE; FAMILY AB Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the etiology of erythrokeratodermia variabilis. In this study, we sequenced the coding region of GJB4 in 13 unrelated erythrokeratodermia variabilis families without detectable mutations in GJB3. Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls. Mutation G12D, identified in an extended Dutch family, lies in the predicted amino-terminus and may interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. Affected individuals of two unrelated families harbored point mutations leading to amino acid substitution F137L, which was also reported in GJB3, yet the extent and severity of hyperkeratosis was milder compared to the corresponding mutation in GJB3. Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects. Nevertheless, we observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region,, which might represent either inconsequential polymorphisms or recessive mutations. In conclusion, our results demonstrate genetic heterogeneity in erythrokeratodermia variabilis, and emphasize that intercellular communication mediated by both Cx31 and Cx30.3 is crucial for epidermal differentiation. C1 Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Jefferson Med Coll, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. Red Cross Hosp, Dept Dermatol, The Hague, Netherlands. Bronovo Hosp, Dept Dermatol, The Hague, Netherlands. Juliana Childrens Hosp, Dept Dermatol, The Hague, Netherlands. Univ Amsterdam, Dept Genet, NL-1012 WX Amsterdam, Netherlands. Univ Calif San Diego, Dept Pediat Dermarol, San Diego, CA 92103 USA. Childrens Hosp, San Diego, CA USA. Univ Washington, Div Dermatol, Dept Med, Seattle, WA 98195 USA. Univ Virginia, Med Ctr, Dept Dermatol, Charlottesville, VA USA. Childrens Hosp, Westmead, NSW, Australia. Brown Univ, Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. NCI, NIH, Bethesda, MD 20892 USA. NIAMS, Genet Studies Sect, NIH, Bethesda, MD USA. MD GeneDx, Rockville, MD USA. RP Richard, G (reprint author), Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Jefferson Med Coll, Jefferson Inst Mol Med, 233 S 10th St,BLSB,Suite 409, Philadelphia, PA 19107 USA. EM Gabriele.Richard@mail.tju.edu FU NIAMS NIH HHS [K08-AR02141, P01-AR38923] NR 37 TC 63 Z9 67 U1 0 U2 3 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 APR PY 2003 VL 120 IS 4 BP 601 EP 609 DI 10.1046/j.1523-1747.2003.12080.x PG 9 WC Dermatology SC Dermatology GA 657VQ UT WOS:000181687400019 PM 12648223 ER PT J AU Remaley, AT Thomas, F Stonik, JA Demosky, SJ Bark, SE Neufeld, EB Bocharov, AV Vishnyakova, TG Patterson, AP Eggerman, TL Santamarina-Fojo, S Brewer, HB AF Remaley, AT Thomas, F Stonik, JA Demosky, SJ Bark, SE Neufeld, EB Bocharov, AV Vishnyakova, TG Patterson, AP Eggerman, TL Santamarina-Fojo, S Brewer, HB TI Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ATP binding cassette transporter; apolipoprotein A-I; high density lipoprotein ID APOLIPOPROTEIN-A-I; BINDING CASSETTE TRANSPORTER-1; PLASMA-MEMBRANE MICROSOLUBILIZATION; CELLULAR CHOLESTEROL; TANGIER-DISEASE; SECONDARY STRUCTURE; UP-REGULATION; MACROPHAGES; ABC1; PHOSPHATIDYLCHOLINE AB In order to examine the necessary structural features for a protein to promote lipid efflux by the ABCA1 transporter, synthetic peptides were tested on ABCA1-transfected cells (ABCA1 cells) and on control cells. L-37pA, an L amino acid peptide that contains two class-A amphipathic helices linked by proline, showed a 4-fold increase in cholesterol and phospholipid efflux from ABCA1 cells compared to control cells. The same peptide synthesized with a mixture of L and D amino acids was less effective than L-37pA in solubilizing dimyristoyl phosphatidyl choline vesicles and in effluxing lipids. In contrast, the 37pA peptide synthesized with all D amino acids (D-37pA) was as effective as 1-37pA. Unlike apoA-I, 1,37pA and D-37pA were also capable, although at a reduced rate, of causing lipid efflux independent of ABCA1 from control cells, Tangier disease cells, and paraformaldehyde fixed ABCA1 cells. The ability of peptides to bind to cells correlated with their lipid affinity.jlr In summary, the amphipathic helix was found to be a key structural motif for peptide-mediated lipid efflux from ABCA1, but there was no stereoselective requirement. In addition, unlike apoA-I, synthetic peptides can also efflux lipid by a passive, energy-independent pathway that does not involve ABCA1 but does depend upon their lipid affinity. C1 NHLBI, NIH, Mol Dis Branch, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, NIH, Mol Dis Branch, Bethesda, MD 20892 USA. NR 37 TC 141 Z9 142 U1 2 U2 3 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD APR PY 2003 VL 44 IS 4 BP 828 EP 836 DI 10.1194/jlr.M200495-JLR200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 667DA UT WOS:000182214500019 PM 12562845 ER PT J AU Galban, CJ Ellis, SJ Spencer, RGS AF Galban, CJ Ellis, SJ Spencer, RGS TI Experimental demonstration of quantitation errors in MR spectroscopy resulting from saturation corrections under changing conditions SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID NEGLECTING CHEMICAL-EXCHANGE; LATTICE RELAXATION-TIMES; MAGNETIC-RESONANCE SPECTROSCOPY; ONE-PULSE EXPERIMENT; IN-VIVO NMR; PITFALLS; SYSTEMS; MUSCLE; HEART AB Metabolite concentration. measurements in in vivo NMR are generally performed under partially saturated conditions, with correction for partial saturation performed after data collection using a measured saturation factor. Here, we present an experimental test of the hypothesis that quantitation errors can occur due to application of such saturation factor corrections in changing systems. Thus, this extends our previous theoretical work on quantitation errors due to varying saturation factors. We obtained results for two systems frequently studied by P-31 NMR, the ischemic rat heart and the electrically stimulated rat gastrocnemius muscle. The results are interpreted in light of previous theoretical work which defined the degree of saturation occurring in a one-pulse experiment for a system with given spin-lattice relaxation times, T(1)s, equilibrium magnetizations, M(0)s, and reaction rates. We found that (i) the assumption of constancy of saturation factors leads to quantitation errors on,the order of 40% in inorganic phosphate; (ii) the dominant contributor to the quantitation errors in inorganic phosphate is most likely changes in T-1; (iii) T-1 and M-0 changes between control and intervention periods, and chemical exchange contribute to different extents to quantitation errors in phosphocreatine and gamma-ATP; (iv) relatively small increases in interpulse delay substantially decreased quantitation errors for metabolites in ischemic rat hearts; (v) random error due to finite SNR led to approximately 4% error in quantitation, and hence was a substantially smaller contributor than were changes in saturation factors. Published by Elsevier Science (USA). C1 NIA, NIH, Baltimore, MD 21224 USA. RP Spencer, RGS (reprint author), NIA, NIH, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2003 VL 161 IS 2 BP 148 EP 153 DI 10.1016/S1090-7807(03)00033-8 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 705RY UT WOS:000184409600004 PM 12713964 ER PT J AU Marekov, LN Steinert, PM AF Marekov, LN Steinert, PM TI Charge derivatization by 4-sulfophenyl isothiocyanate enhances peptide sequencing by post-source decay matrix-assisted laser desorption/ionization time-of-flight mass spectrometry SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE peptides; charge derivatization; post-source decay; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; sequencing ID DESORPTION IONIZATION MALDI; PROTEIN IDENTIFICATION; TRYPTIC PEPTIDES; DATABASES; IONS; FRAGMENTATION; IMPROVEMENT; SPECTRA AB High-sensitivity, rapid identification of proteins in proteomic studies normally uses a combination of one- or two-dimensional electrophoresis together with mass spectrometry. The simplicity and sensitivity of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) have increased its application in recent years. The most common method of 'peptide fingerprinting' often may not provide robust identification. Normally additional sequence information by post-source decay (PSD) MALDI-TOFMS provides additional constraints for database searches to achieve highly confident results. Here we describe a derivatization procedure to facilitate the acquisition of such sequence information. Peptide digests from a skin-expressed protein were modified with 4-sulfophenyl isothiocyanate. The resulting peptides carry a fixed negative charge at the N-terminal end and the resulting PSD spectrum is dominated by C-terminal y-type ions. The sequence information in most cases can be obtained manually or with simple programming tools. Methods of optimizing the procedure and increasing the sensitivity are discussed. Copyright (C) 2003 John Wiley Sons, Ltd. C1 NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Marekov, LN (reprint author), NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. NR 29 TC 61 Z9 64 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD APR PY 2003 VL 38 IS 4 BP 373 EP 377 DI 10.1002/jms.448 PG 5 WC Biophysics; Chemistry, Organic; Spectroscopy SC Biophysics; Chemistry; Spectroscopy GA 674TY UT WOS:000182653100002 PM 12717748 ER PT J AU Park, HJ Shaukat, S Liu, XZ Hahn, SH Naz, S Ghosh, M Kim, HN Moon, SK Abe, S Tukamoto, K Riazuddin, S Kabra, M Erdenetungalag, R Radnaabazar, J Khan, S Pandya, A Usami, SI Nance, WE Wilcox, ER Riazuddin, S Griffith, AJ AF Park, HJ Shaukat, S Liu, XZ Hahn, SH Naz, S Ghosh, M Kim, HN Moon, SK Abe, S Tukamoto, K Riazuddin, S Kabra, M Erdenetungalag, R Radnaabazar, J Khan, S Pandya, A Usami, SI Nance, WE Wilcox, ER Riazuddin, S Griffith, AJ TI Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PENDRED-SYNDROME GENE; AUTOSOMAL RECESSIVE DEAFNESS; HEARING-LOSS; MOLECULAR ANALYSIS; VESTIBULAR AQUEDUCT; INNER-EAR; GJB2; EXPRESSION; CELLS; POPULATION AB Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations. C1 NIDCD, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. Univ Punjab, Ctr Excellence Mol Biol, Lahore, Pakistan. Univ Miami, Dept Otolaryngol, Miami, FL 33152 USA. Mayo Clin & Mayo Fdn, Dept Lab Med, Rochester, MN 55905 USA. NIH, Sect Human Genet, Rockville, MD USA. All India Inst Med Sci, Dept Paediat, Genet Unit, Delhi, India. Yonsei Univ, Dept Otorhinolaryngol, Seoul 120749, South Korea. Ajou Univ, Dept Otolaryngol, Suwon 441749, South Korea. Hirosaki Univ, Sch Med, Dept Otorhinolaryngol, Hirosaki, Aomori 036, Japan. Shinshu Univ, Sch Med, Dept Otorhinolaryngol, Matsumoto, Nagano 390, Japan. Maternal & Child Hlth Res Ctr, Dept Human Genet, Ulaanbaatar, Mongol Peo Rep. Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD USA. RP Griffith, AJ (reprint author), NIDCD, Sect Gene Struct & Funct, NIH, 5 Res Court,Room 2A01, Rockville, MD 20850 USA. RI Liu, Xiaoxi/D-9319-2013; naz, sadaf/F-4406-2015; OI Naz, Sadaf/0000-0002-1912-0235 FU NIDCD NIH HHS [R01 DC 04293, R01 DC 02530, R01 DC 05575] NR 40 TC 172 Z9 217 U1 1 U2 8 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD APR PY 2003 VL 40 IS 4 BP 242 EP 248 DI 10.1136/jmg.40.4.242 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 666BN UT WOS:000182155900002 PM 12676893 ER PT J AU Liao, SY Ivanov, S Ivanova, A Ghosh, S Cote, MA Keefe, K Coca-Prados, M Stanbridge, EJ Lerman, MI AF Liao, SY Ivanov, S Ivanova, A Ghosh, S Cote, MA Keefe, K Coca-Prados, M Stanbridge, EJ Lerman, MI TI Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID NONPIGMENTED CILIARY EPITHELIUM; OPEN-ANGLE GLAUCOMA; CARCINOMA; PROTEIN; CLONING AB Purpose: Carbonic anhydrase enzymes (CAs) are universally involved in many fundamental physiological processes, including acid base regulation and fluid formation and movement. In glaucoma patients, CA inhibitors are very effective in lowering intraocular pressure by reducing the rate of aqueous humour secretion mediated by the CAs in the ciliary epithelium. In this work, we investigated the expression and tissue distribution of two recently discovered CA genes CA9 (CAIX) and CA12(CAXII) in fetal, neonatal, and adult human eyes with and without glaucoma. Methods: CAIX and CAXII expression in 16 normal and 10 glaucomatous eyes, and in cultured nonpigmented ciliary epithelial cells (NPE) from normal and glaucoma eye donors was assessed by immunostaining. In addition, northern blot hybridisation was performed to assess expression of CA4, CA9, and CA12 mRNA in cultured NPE cells from normal and glaucoma donors. Results: CAXII was localised primarily to the NPE with its expression prominent during embryonic eye development but which decreased significantly in adults. CAIX expression in the NPE was very low. The epithelium of cornea and lens occasionally expressed both enzymes at low levels during development and in adult eye, and no expression was detected in the retina. The NPE from glaucoma eyes expressed higher levels of CAXII, but not CAIX, in comparison with normal eyes. This expression pattern was retained in cultured NPE cell lines. NPE cells from a glaucoma patient showed a five-fold increase in the CA12 mRNA level with no detectable expression of CA9 mRNA. Also, no expression of the CA4 gene encoding a GPI anchored plasma membrane protein was detected on these northern blots. Conclusions: Transmembrane CAIX and CAXII enzymes are expressed in the ciliary cells and, thus, may be involved in aqueous humour production. CA12 may be a targeted gene in glaucoma. C1 Univ Calif Irvine, Coll Med, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD USA. NCI, Immunobiol Lab, Frederick, MD 21701 USA. Yale Univ, Dept Ophthalmol & Visual Sci, New Haven, CT 06520 USA. Univ Calif Irvine, Coll Med, Dept Pathol, Irvine, CA 92717 USA. USN, Med Ctr, San Diego, CA 92152 USA. RP Liao, SY (reprint author), Univ Calif Irvine, Coll Med, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. FU NCI NIH HHS [CA19401, N01-CO-12400, N01-CO-56000]; NEI NIH HHS [EY04873] NR 21 TC 43 Z9 44 U1 0 U2 3 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD APR PY 2003 VL 40 IS 4 BP 257 EP 261 DI 10.1136/jmg.40.4.257 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 666BN UT WOS:000182155900004 PM 12676895 ER PT J AU Matyakhina, L Pack, S Kirschner, LS Pak, E Mannan, P Jaikumar, J Taymans, SE Sandrini, F Carney, JA Stratakis, CA AF Matyakhina, L Pack, S Kirschner, LS Pak, E Mannan, P Jaikumar, J Taymans, SE Sandrini, F Carney, JA Stratakis, CA TI Chromosome 2 (2p16) abnormalities in Carney complex tumours SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; FRAGILE SITES; ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; GENE AMPLIFICATION; CONSISTENT PATTERN; BREAST CARCINOMAS; CARDIAC MYXOMAS AB Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22-24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region, that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumours. Both thyroid and adrenal tumours constitute part of CNC indicating that the responsible gene(s) in this area may indeed be involved in both inherited and sporadic endocrine tumour pathogenesis and/or progression. C1 NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Cytogenet & Confocal Microscopy Core, NIH, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN 55905 USA. Russian Acad Sci, Inst Cytol & Genet, Siberian Dept, Novosibirsk 630090, Russia. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 48 TC 51 Z9 54 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD APR PY 2003 VL 40 IS 4 BP 268 EP 277 DI 10.1136/jmg.40.4.268 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 666BN UT WOS:000182155900006 PM 12676898 ER PT J AU Westergaard, GC Cleveland, A Trenkle, MK Lussier, ID Higley, JD AF Westergaard, GC Cleveland, A Trenkle, MK Lussier, ID Higley, JD TI CSF 5-HIAA concentration as an early screening tool for predicting significant life history outcomes in female specific-pathogen-free (SPF) rhesus macaques (Macaca mulatta) maintained in captive breeding groups SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE aggression; animal health; mortality; reproduction; rhesus macaque ID 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; CEREBROSPINAL-FLUID MONOAMINE; DIMINISHED SOCIAL COMPETENCE; NONHUMAN PRIMATE MODEL; VIOLENT OFFENDERS; FIRE SETTERS; CSF 5-HIAA; INTERINDIVIDUAL DIFFERENCES; HEALTHY-VOLUNTEERS; SEVERE AGGRESSION AB We examined relationships among cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite (5-HIAA, 5-hydroxyindoleacetic acid) and significant medical and behavioral outcomes for female rhesus macaques. Based on earlier findings with males we predicted that low CSF 5-HIAA concentrations would be associated with a range of negative life history outcomes in our captive specific-pathogen-free (SPF) breeding colony. We found that the mean CSF 5-HIAA concentration among animals that died over the course of the study period was significantly lower than among animals that survived. Further examination indicated an inverse relationship between CSF 5-HIAA concentration and number of treatments for illness, further suggesting a link between serotonergic functioning and overall animal health. Examination of behavioral data indicated that individuals with low CSF 5-HIAA concentrations were more often the targets of aggressive bouts than were individuals with high CSF 5-HIAA concentrations. Finally, we found a positive relationship between CSF 5-HIAA concentration and infant survivorship. These results suggest negative life history consequences of impaired serotonergic functioning in captive female rhesus macaques, and indicate that CSF 5-HIAA concentration sampled early in fife may provide a useful tool in facilitating colony management decisions concerning utilization of scarce and increasingly valuable non-human primate resources. C1 LABS Virginia Inc, Div Res & Dev, Yemassee, SC 29945 USA. NIAAA, Clin Studies Lab, Poclesville, MD USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res & Dev, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. FU NCRR NIH HHS [5U42 RR 05033, R24 RR 0933] NR 34 TC 14 Z9 14 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD APR PY 2003 VL 32 IS 2 BP 95 EP 104 DI 10.1034/j.1600-0684.2003.00013.x PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 674XU UT WOS:000182663500005 PM 12823632 ER PT J AU Turner, RJ AF Turner, RJ TI Understanding the biogenesis of polytopic integral membrane proteins SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Review DE translocon; membrane protein folding; transmembrane topology ID ENDOPLASMIC-RETICULUM MEMBRANE; SIGNAL-ANCHOR PROTEINS; TURN PROPENSITY SCALE; HUMAN P-GLYCOPROTEIN; TRANSMEMBRANE SEGMENTS; ER MEMBRANE; CHARGED RESIDUES; TRANSLOCON PORE; HELIX INTERACTIONS; TOPOLOGICAL RULES C1 NIDCR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), NIDCR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH,DHHS, 10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. NR 76 TC 6 Z9 6 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD APR 1 PY 2003 VL 192 IS 3 BP 149 EP 157 DI 10.1007/s00232-002-1071-z PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 664MQ UT WOS:000182065200001 PM 12820660 ER PT J AU Leapman, R AF Leapman, R TI Foreword SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Leapman, R (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2003 VL 210 BP 1 EP 4 DI 10.1046/j.1365-2818.2003.01169.x PN 1 PG 4 WC Microscopy SC Microscopy GA 666RE UT WOS:000182189600001 ER PT J AU Leapman, RD AF Leapman, RD TI Detecting single atoms of calcium and iron in biological structures by electron energy-loss spectrum-imaging SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article; Proceedings Paper CT International Workshop on Strategies and Advances in Atomic-Level Spectroscopy and Analysis (SALSA) CY MAY 05-09, 2002 CL GUADELOUPE, GUADELOUPE DE calcium; detection limits; electron energy-loss spectroscopy; iron; macromolecular assembly; scanning transmission electron microscope; spectrum-imaging ID LOSS SPECTROSCOPY; ELEMENTAL ANALYSIS; DETECTION LEVEL; EELS; RESOLUTION; MICROANALYSIS; MICROSCOPY; MACROMOLECULES; SIGNAL AB As techniques for electron energy-loss spectroscopy (EELS) reach a higher degree of optimization, experimental detection limits for analysing biological structures are approaching values predicted by the physics of the electron scattering. Theory indicates that it should be possible to detect a single atom of certain elements like calcium and iron contained in a macromolecular assembly using a finely focused probe in the scanning transmission electron microscope (STEM). To test this prediction, EELS elemental maps have been recorded with the spectrum-imaging technique in a VG Microscopes HB501 STEM coupled to a Gatan Enfina spectrometer, which is equipped with an efficient charge-coupled device (CCD) array detector. By recording spectrum-images of haemoglobin adsorbed onto a thin carbon film, it is shown that the four heme groups in a single molecule can be detected with a signal-to-noise ratio of similar to10:1. Other measurements demonstrate that calcium adsorbed onto a thin carbon film can be imaged at single atom sensitivity with a signal-to-noise ratio of similar to5:1. Despite radiation damage due to the necessarily high electron dose, it is anticipated that mapping single atoms of metals and other bound elements will find useful applications in characterizing large protein assemblies. C1 NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), NIH, Div Bioengn & Phys Sci, ORS, Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 47 Z9 48 U1 0 U2 8 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 APR PY 2003 VL 210 BP 5 EP 15 DI 10.1046/j.1365-2818.2003.01173.x PN 1 PG 11 WC Microscopy SC Microscopy GA 666RE UT WOS:000182189600002 PM 12694411 ER PT J AU Sun, Y Lu, X Gershengorn, MC AF Sun, Y Lu, X Gershengorn, MC TI Thyrotropin-releasing hormone receptors - similarities and differences SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Symposium on G Protein-Coupled Receptor Signalling in Neuroendocrine Systems held at the 5th International Congress of Neuroendocrinology CY AUG 31-SEP 04, 2002 CL BRISTOL, ENGLAND ID CENTRAL-NERVOUS-SYSTEM; RAT PITUITARY-CELLS; AGONIST-STIMULATED INTERNALIZATION; CONSTITUTIVELY ACTIVE MUTANTS; MESSENGER-RIBONUCLEIC-ACID; HETEROTRIMERIC G-PROTEINS; TRH RECEPTOR; PHOSPHOLIPASE-C; GH3 CELLS; SIGNAL-TRANSDUCTION AB dThyrotropin-releasing hormone (TRH) initiates its effects by interacting with cell-surface membrane receptors. Two G protein-coupled receptors for TRH, TRH receptor type 1 (TRH-R1) and TRH receptor type 2 (TRH-R2), have been cloned from mammals. In this review, we compare TRH-R1 and TRH-R2 with regard to their tissue distribution, binding affinities for TRH and TRH analogs, basal and activated signaling activities and characteristics of internalization. TRH-R1 and TRH-R2 are distributed differently in the brain and peripheral tissues, but exhibit indistinguishable binding affinities for TRH and TRH analogs. Although they both can be stimulated by TRH to similar maximal signaling levels, TRH-R2 exhibits higher basal signaling activity and is more rapidly internalized than TRH-R1. These differences in signaling and internalization properties are probably important in the distinct parts that TRH-R1 and TRH-R2 may play in mammalian physiology. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDKD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 82 TC 101 Z9 105 U1 2 U2 8 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD APR PY 2003 VL 30 IS 2 BP 87 EP 97 DI 10.1677/jme.0.0300087 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 668XD UT WOS:000182319700002 PM 12683933 ER PT J AU Aguilera, G Volpi, S Rabadan-Diehl, C AF Aguilera, G Volpi, S Rabadan-Diehl, C TI Transcriptional and post-transcriptional mechanisms regulating the rat pituitary vasopressin V1b receptor gene SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Symposium on G Protein-Coupled Receptor Signalling in Neuroendocrine Systems held at the 5th International Congress of Neuroendocrinology CY AUG 31-SEP 04, 2002 CL BRISTOL, ENGLAND ID TRANSLATIONAL REGULATION; CHRONIC STRESS; POLY(A) TAIL; ADRENAL AXIS; GAGA FACTOR; EXPRESSION; PROMOTER; CLONING; RESPONSIVENESS; ORGANIZATION AB The number of V1b vasopressin receptors (V1bR) in the anterior pituitary plays an important role during adaptation of the hypothalamic-pituitary-adrenal axis to stress in rats. Regulation of V1bR expression involves transcriptional and translational mechanisms. One of the elements mediating transcriptional activation of the rat V1bR gene is a long stretch of GAGA repeats (GAGA box) in the promoter located near the transcription start point capable of binding a protein complex of 127 kDa present in pituitary nuclear extracts. There is a lack of correlation between changes in V1bR mRNA and the number of VP binding sites, suggesting that V1bR expression depends on the efficiency of V1b R mRNAtranslation into protein. Two mechanisms by which the 5' untranslated region (5'-UTR) of the rat V1bR mRNA can mediate either inhibition or activation of V1bR mRNA translation have been identified. First, upstream open reading frames (ORF) present in the 5'-UTR repress translation of the major ORF encoding the V1b receptor, and secondly, an internal ribosome entry site (IRES) activates V1bR translation. Stimulation of IRES activity through protein kinase C-mediated pathways results in V1bR mRNA translation increasing V1bR protein levels. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary vasopressin receptors according to physiological demand. C1 NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, NIH Bldg 10 Rm 10N262, Bethesda, MD 20892 USA. NR 48 TC 12 Z9 12 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD APR PY 2003 VL 30 IS 2 BP 99 EP 108 DI 10.1677/jme.0.0300099 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 668XD UT WOS:000182319700003 PM 12683934 ER PT J AU Nowak, JZ Sedkowska, P Zawilska, JB Gozes, I Brenneman, DE AF Nowak, JZ Sedkowska, P Zawilska, JB Gozes, I Brenneman, DE TI Antagonism of VIP-stimulated cyclic AMP formation in chick brain SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT 12th Annual Meeting of the European-Neuropeptide-Club (ENC) CY MAY 22-25, 2002 CL OLSZTYN, POLAND SP European Neuropeptide Club DE VIP; VIP antagonist; PACAP; PACAP antagonist; chick cerebral cortex; cyclic AMP (cAMP) ID VASOACTIVE-INTESTINAL-PEPTIDE; CYCLASE-ACTIVATING POLYPEPTIDE; MOLECULAR-CLONING; CEREBRAL-CORTEX; NERVOUS-SYSTEM; PACAP; RECEPTOR; RAT; OCTACOSAPEPTIDE; NEUROENDOCRINE AB Of eight peptides tested (0.01-5 muM), only two, that is, pituitary adenylate cyclase-activating polypeptide (PACAP27) and chicken vasoactive intestinal peptide (cVIP), potently stimulated cyclic AMP (cAMP) production in cerebral cortical slices of the chick. Mammalian VIP (mViP) showed some activity only at the highest dose tested, whereas truncated forms of PACAP or VIP, that is, PACAP6-27, cVIP6-28, and mVIP6-28, or hybrid compounds, that is, neurotensin6-11-cVIP7-28 (NT-cVIP) and rieurotensin6-11-mVIP7-28 (NT-mVIP), were inactive. Thirty-minute preincubation of chick cortical slices with 5 W PACAP6-27, NT-cVIP, or NT-mVIP competitively antagonized the cAMP effects of cVIP (0.03-1 muM), with the truncated form of PACAP being the best antagonist. Preincubation of slices with 5 muM mVIP6-28 also produced a significant inhibition of the cVIP (0.1-1 muM)-induced increase in cAMP production; however its action was independent of the concentration of cVIP. In contrast to mVIP6-28, cVIP6-28 showed no antagonistic activity against the full-length peptide. In parallel experiments, 30-min pretreatment of cortical slices with 5 muM PACAP6-27 significantly antagonized the PACAP38-evoked increase in cAMP formation, whereas mVIP6-28 or the NT-mVIP hybrid was ineffective. It has been concluded that in the chick brain, PACAP and cVIP stimulate cAMP biosynthesis via PAC(1) and VPAC-type receptors, respectively, and PACAP6-27 seems to be the most potent, yet PACAP/VIP receptor-nonselective antagonist. Unlike truncated PACAP, the NT-VIP hybrid peptides tested may represent VPAC-type receptor-selective blocking activity. C1 Polish Acad Sci, Inst BIogen Amines, PL-90950 Lodz, Poland. Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NICHHD, Dev Neurobiol Lab, Sect Dev & Mol Pharmacol, NIH, Bethesda, MD 20892 USA. RP Nowak, JZ (reprint author), Polish Acad Sci, Inst BIogen Amines, P-225, PL-90950 Lodz, Poland. NR 32 TC 8 Z9 8 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR PY 2003 VL 20 IS 2 BP 163 EP 171 DI 10.1385/JMN:20:2:163 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 688YZ UT WOS:000183466000009 PM 12794310 ER PT J AU Hardy, J AF Hardy, J TI The relationship between amyloid and tau SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE amyloid; plaques; tangles; tau; genetic; Alzheimer's disease; Pick's disease ID FAMILIAL ALZHEIMERS-DISEASE; PRECURSOR PROTEIN GENE; LEWY BODIES; LOCUS; MUTATIONS; MICE AB Based on genetic findings, the relationship between the APP/Abeta and tau/tangle pathologies are discussed. It is argued that APP/Abeta is upstream of tau/tangle in the Alzheimer pathogenesis, and that the relationship between the pathologies are promiscuous in two ways: first, APP/Abeta can equally be seen to be upstream of synuclein/Lewy bodies in cell death pathways, and second, tau pathology can be initiated by genetic lesions in other pathways. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,6C103, Bethesda, MD 20892 USA. RI Hardy, John/C-2451-2009 NR 18 TC 46 Z9 49 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR PY 2003 VL 20 IS 2 BP 203 EP 206 DI 10.1385/JMN:20:2:203 PG 4 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 688YZ UT WOS:000183466000013 PM 12794314 ER PT J AU von Sternberg, R Cumberlidge, N AF von Sternberg, R Cumberlidge, N TI Autapomorphies of the endophragmal system in trichodactylid freshwater crabs (Crustacea : Decapoda : Eubrachyura) SO JOURNAL OF MORPHOLOGY LA English DT Article DE freshwater crabs; Trichodactylidae; Eubrachyura; endophragmal system; sella turcica; interosternites; junction plate ID BRACHYURA AB An examination of the thoracic endophragmal system in trichodactylid freshwater crabs revealed several derived features that appear restricted to this family. Trichodactylids have a highly reduced sella turcica with a rim-like overall configuration; as a consequence of sella turcica reduction the median septum is dorsoventrally diminished and exposed along its length. In addition, interosternite 7/8 is medially erased with the remnants restricted to the lateral regions of the sternum. The configurations of the sella turcica and interosternite 7/8 in trichodactylids underscore the monophyly of this family. The Dilocarcininae is characterized by having interosternites 5/6 through 7/8 restricted to the lateral sectors of the sternum, the lateral remnants of interosternite 4/5 forming prominent, rib-like ridges oriented diagonally to the longitudinal axis of the crab, and the median septum forming with interosternite 4/5 a Y-shaped pattern. These autapomorphies of the endophragmal system separate the trichodactylids from all other eubrachyurans and emphasize the morphological distinctness of the group. A description of the trichodactylid endophragmal junction plate is also provided. (C) 2003 Wiley-Liss, Inc. C1 Smithsonian Inst, Dept Syst Biol, NHB 163, Washington, DC 20013 USA. No Michigan Univ, Dept Biol, Marquette, MI 49855 USA. RP von Sternberg, R (reprint author), NIH, NLM, Natl Ctr Biotechnol Informat, GenBank, Bethesda, MD 20894 USA. EM Sternber@ncbi.nlm.nih.gov; Sternberg.Richard@nmnh.si.edu NR 29 TC 6 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-2525 EI 1097-4687 J9 J MORPHOL JI J. Morphol. PD APR PY 2003 VL 256 IS 1 BP 23 EP 28 DI 10.1002/jmor.10072 PG 6 WC Anatomy & Morphology SC Anatomy & Morphology GA 655NU UT WOS:000181559600003 PM 12616572 ER PT J AU Southwick, SM Axelrod, SR Wang, S Yehuda, R Morgan, CA Charney, D Rosenheck, R Mason, JW AF Southwick, SM Axelrod, SR Wang, S Yehuda, R Morgan, CA Charney, D Rosenheck, R Mason, JW TI Twenty-four-hour urine cortisol in combat veterans with PTSD and comorbid borderline personality disorder SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER C1 VA Connecticut Healthcare Syst, Clin Neurosci Div, Natl Ctr PTSD 116A, West Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. NIA, Baltimore, MD 21224 USA. Bronx Vet Adm Med Ctr, Dept Psychiat, Bronx, NY USA. NIMH, Bethesda, MD 20892 USA. VA Connecticut Healthcare Syst, NE Program Evaluat Ctr, West Haven, CT 06516 USA. RP Southwick, SM (reprint author), VA Connecticut Healthcare Syst, Clin Neurosci Div, Natl Ctr PTSD 116A, 950 Campbell Ave, West Haven, CT 06516 USA. NR 7 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD APR PY 2003 VL 191 IS 4 BP 261 EP 262 DI 10.1097/00005053-200304000-00009 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 668NL UT WOS:000182300000008 PM 12695738 ER PT J AU Klein, DC Ganguly, S Coon, SL Shi, Q Gaildrat, P Morin, F Weller, JL Obsil, T Hickman, A Dyda, F AF Klein, DC Ganguly, S Coon, SL Shi, Q Gaildrat, P Morin, F Weller, JL Obsil, T Hickman, A Dyda, F TI 14-3-3 proteins in pineal photoneuroendocrine transduction: How many roles? SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 9th Triennial Meeting of the European-Pineal-and-Biological-Rhythm-Society CY JUL 18-22, 2002 CL ABERDEEN, SCOTLAND SP European Pineal & Biol Rhythm Soc DE 14-3-3; pineal; N-acetyltransferase; signal transduction; melatonin; serotonin ID ADRENAL CHROMAFFIN CELLS; TRYPTOPHAN-HYDROXYLASE ACTIVITY; CALCIUM-DEPENDENT EXOCYTOSIS; MULTIPLE SIGNALING PATHWAYS; CORTICAL ACTIN NETWORK; TYROSINE-HYDROXYLASE; KINASE-C; ACTIVATOR PROTEIN; CATECHOLAMINE SECRETION; MELATONIN SYNTHESIS AB Recent studies suggest that a common theme links the diverse elements of pineal photoneuroendocrine transduction-regulation via binding to 14-3-3 proteins . The elements include photoreception, neurotransmission, signal transduction and the synthesis of melatonin from tryptophan. We review general aspects of 14-3-3 proteins and their biological function as binding partners, and also focus on their roles in pineal photoneuroendocrine transduction. C1 NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NIH 49 6A82, Bethesda, MD 20892 USA. RI Obsil, Tomas/B-7142-2012 OI Obsil, Tomas/0000-0003-4602-1272 NR 53 TC 24 Z9 25 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD APR PY 2003 VL 15 IS 4 BP 370 EP 377 DI 10.1046/j.1365-2826.2003.01000.x PG 8 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 652UE UT WOS:000181398300009 PM 12622836 ER PT J AU Falcon, J Gothilf, Y Coon, SL Boeuf, G Klein, DC AF Falcon, J Gothilf, Y Coon, SL Boeuf, G Klein, DC TI Genetic, temporal and developmental differences between melatonin rhythm generating systems in the teleost fish pineal organ and retina SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 9th Triennial Meeting of the European-Pineal-and-Biological-Rhythm-Society CY JUL 18-22, 2002 CL ABERDEEN, SCOTLAND SP European Pineal & Biol Rhythm Soc DE fish; retina; pineal organ; melatonin; arylalkylamine N-acetyltransferase ID EUROPEAN SEA BASS; N-ACETYLTRANSFERASE; TROUT RETINA; ZEBRAFISH; OPSIN; PHOTORECEPTORS; N-ACETYLTRANSFERASE-2; EXPRESSION; GLAND; PIKE AB Complete melatonin rhythm generating systems, including photodetector, circadian clock and melatonin synthesis machinery, are located within individual photoreceptor cells in two sites in Teleost fish: the pineal organ and retina. In both, light regulates daily variations in melatonin secretion by controlling the activity of arylalkylamine N -acetyltransferase (AANAT). However, in each species examined to date, marked differences exist between the two organs which may involve the genes encoding the photopigments, genes encoding AANAT, the times of day at which AANAT activity and melatonin production peak and the developmental schedule. We review the fish pineal and retinal melatonin rhythm generating systems and consider the evolutional pressures and other factors which led to these differences. C1 CNRS, Lab Arago, UMR 7628, F-66651 Banyuls sur Mer, France. Univ Paris 06, F-66651 Banyuls sur Mer, France. Tel Aviv Univ, George S Wise Fac Life Sci, Dept Zool, IL-69978 Tel Aviv, Israel. NIH, Dev Neurobiol Lab, Bethesda, MD 20892 USA. RP Falcon, J (reprint author), CNRS, Lab Arago, UMR 7628, BP 44, F-66651 Banyuls sur Mer, France. RI FALCON, Jack/I-5302-2013 OI FALCON, Jack/0000-0002-7572-6581 NR 29 TC 64 Z9 67 U1 0 U2 10 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD APR PY 2003 VL 15 IS 4 BP 378 EP 382 DI 10.1046/j.1365-2826.2003.00993.x PG 5 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 652UE UT WOS:000181398300010 PM 12622837 ER PT J AU Chalela, JA Ezzeddine, M Latour, L Warach, S AF Chalela, JA Ezzeddine, M Latour, L Warach, S TI Reversal of perfusion and diffusion abnormalities after intravenous thrombolysis for a lacunar infarction SO JOURNAL OF NEUROIMAGING LA English DT Article DE lacunar infarct; thrombolysis; DWI lesion reversal ID ACUTE ISCHEMIC-STROKE AB Perfusion and diffusion magnetic resonance imaging (MRI) have been used to guide therapy in patients with large vessel occlusions. In an analogous fashion, the authors used perfusion and diffusion MRI to demonstrate a perfusion deficit and a matching diffusion lesion in a patient with lacunar infarct. Following thrombolytic therapy, the authors observed a reversal of the perfusion deficit, the diffusion lesion, and clinical recovery. This case suggests that perfusion and diffusion MRI may be informative in patients with lacunar infarction who are candidates for thrombolysis. C1 Natl Inst Neurol Disorders & Stroke, NIH, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Chalela, JA (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Sect Stroke Diagnost & Therapeut, 10 Ctr Dr,Room B1D733,MSC 1063, Bethesda, MD 20892 USA. EM chalelaj@ninds.nih.gov NR 7 TC 14 Z9 15 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD APR PY 2003 VL 13 IS 2 BP 152 EP 154 DI 10.1177/1051228403251260 PG 3 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 876CT UT WOS:000225474200009 PM 12722498 ER PT J AU Itoh, H Nakahara, H Hikosaka, O Kawagoe, R Takikawa, Y Aihara, K AF Itoh, H Nakahara, H Hikosaka, O Kawagoe, R Takikawa, Y Aihara, K TI Correlation of primate caudate neural activity and saccade parameters in reward-oriented behavior SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID NIGRA PARS RETICULATA; BASAL GANGLIA; EYE-MOVEMENTS; FUNCTIONAL-PROPERTIES; SUPERIOR COLLICULUS; OCULOMOTOR FUNCTIONS; SUBTHALAMIC NUCLEUS; AUDITORY RESPONSES; MONKEY; NEURONS AB Changes in the reward context are associated with changes in neuronal activity in the basal ganglia as well as changes in motor outputs. A typical example is found in the caudate (CD) projection neurons and saccade parameters. It raised the possibility that the changes in CD neuronal activity contribute to the changes in saccade parameters. To examine this possibility, we calculated the correlation coefficients (CORs) of the firing rates of each neuron with saccade parameters ( peak saccade velocity and latency) on a trial-by-trial basis. We then calculated the mean CORs separately for two CD populations: reward-enhanced type neurons (RENs) that showed enhanced activity and reward-depressed type neurons (RDNs) that showed depressed activity when reward was expected. The activity of RENs was positively correlated with the saccadic peak velocity and negatively correlated with the saccade latency. The activity of RDNs was not significantly correlated with the saccade parameters. We further analyzed the CORs for RENs, a major type of CD neurons. First, we examined the time courses of the CORs using a moving time window (duration: 200 ms). The positive correlation with the saccade velocity and the negative correlation with the saccade latency were present not only in the peri-saccadic period but also during the pre- and postcue periods. Second, we asked whether the CORs with the saccade parameters were direction-selective. A majority of RENs were more active before contralateral saccades (contralateral-preferring neurons) and their activity was correlated more strongly with contralateral saccades than with ipsilateral saccades. A minority of RENs, ipsilateral-preferring neurons, showed no such preference. These results are consistent with the hypothesis that CD neuronal activity exerts facilitatory effects on contralateral saccades and that the effects start well before saccade execution. Furthermore, a multiple regression analysis indicated that changes in activity of some, but not all, CD neurons could be explained by changes in saccade parameters; a major determinant was reward context ( presence or absence of reward). These results suggest that, while a majority of CD neurons receive reward-related signals, only some of them can make a significant contribution to change saccadic outputs based on expected reward. C1 Univ Tokyo, Dept Math Engn & Informat Phys, Tokyo 1138656, Japan. RIKEN, Brain Sci Inst, Lab Math Neurosci, Saitama 3510198, Japan. Japan Adv Inst Sci & Technol, Sch Knowledge Sci, Ishikawa 9231292, Japan. Juntendo Univ, Dept Physiol, Sch Med, Tokyo 1138421, Japan. Jap Sci & Technol Corp, Core Res Evolut Sci & Technol Program, Saitama 3320012, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. RI Nakahara, Hiroyuki/N-5411-2015; OI Nakahara, Hiroyuki/0000-0001-6891-1175; Itoh, Hideaki/0000-0001-8623-2408 NR 34 TC 44 Z9 45 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2003 VL 89 IS 4 BP 1774 EP 1783 DI 10.1152/jn.00630.2002 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 665MR UT WOS:000182125300005 PM 12686566 ER PT J AU Slutsky, I Wess, J Gomeza, J Dudel, J Parnas, I Parnas, H AF Slutsky, I Wess, J Gomeza, J Dudel, J Parnas, I Parnas, H TI Use of knockout mice reveals involvement of M-2-muscarinic receptors in control of the kinetics of acetylcholine release SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID FROG NEUROMUSCULAR-JUNCTION; MOTOR-NERVE TERMINALS; G-PROTEIN MODULATION; TRANSMITTER RELEASE; NEUROTRANSMITTER RELEASE; CALCIUM CHANNELS; TIME-COURSE; N-TYPE; SYNAPTIC TRANSMISSION; MUSCARINIC RECEPTORS AB We have previously suggested that presynaptic M-2-muscarinic receptors (M2R) are involved in the control of the time course of evoked acetylcholine release in the frog neuromuscular junction. The availability of knockout mice lacking functional M2R (M-2-KO) enabled us to address this issue in a more direct way. Using the phrenic diaphragm preparation, we show that in wild-type (WT) mice experimental manipulations known to affect Ca2+ entry and removal, greatly affected the amount of acetylcholine released ( quantal content). However, the time course of release remained unaltered under all these experimental treatments. On the other hand, in the M-2-KO mice, similar experimental treatments affected both the quantal content and the time course of release. In general, a larger quantal content was accompanied by a longer duration of release. Similarly, the rise time of the postsynaptic current produced by axon stimulation was sensitive to changes in [Ca2+](o) or [Mg2+](o) in M-2-KO mice but not in WT mice. Measurements of Ca2+ currents revealed that the shorter rise time of the postsynaptic current seen in high [Mg2+](o) in M-2-KO mice was not produced by a shorter wave of the presynaptic Ca2+ current. These results support our earlier findings and provide direct evidence for the major role that presynaptic M-2-muscarinic receptors play in the control of the time course of evoked acetylcholine release under physiological conditions. C1 Hebrew Univ Jerusalem, Dept Neurobiol, Otto Loewi Minerva Ctr Cellular & Mol Neurobiol, IL-91904 Jerusalem, Israel. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Munich, Lehrstuhl Zellulare Physiol, D-80336 Munich, Germany. RP Parnas, H (reprint author), Hebrew Univ Jerusalem, Dept Neurobiol, Otto Loewi Minerva Ctr Cellular & Mol Neurobiol, IL-91904 Jerusalem, Israel. OI Slutsky, Inna/0000-0002-0700-2266 NR 73 TC 37 Z9 39 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2003 VL 89 IS 4 BP 1954 EP 1967 DI 10.1152/jn.00668.2002 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 665MR UT WOS:000182125300023 PM 12686574 ER PT J AU Chen, WG West, AE Tao, X Corfas, G Szentirmay, MN Sawadogo, M Vinson, C Greenberg, ME AF Chen, WG West, AE Tao, X Corfas, G Szentirmay, MN Sawadogo, M Vinson, C Greenberg, ME TI Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE upstream stimulatory factor; USF1; USF2; activity-dependent transcription; brain-derived neurotrophic factor; BDNF; calcium; neural plasticity; activity-dependent neural development ID MAJOR LATE PROMOTER; FACTOR-DEPENDENT MECHANISM; ELEMENT-BINDING PROTEIN; CLASS-I MHC; FACTOR USF; GENE-EXPRESSION; MESSENGER-RNAS; CALCIUM REGULATION; SIGNALING PATHWAY; SYNAPTIC ACTIVITY AB To identify molecular mechanisms that control activity-dependent gene expression in the CNS, we have characterized the factors that mediate activity-dependent transcription of BDNF promoter III. We report the identification of a Ca2+-responsive E-box element, CaRE2, within BDNF promoter III that binds upstream stimulatory factors 1 and 2 ( USF1/2) and show that USFs are required for the activation of CaRE2-dependent transcription from BDNF promoter III. We find that the transcriptional activity of the USFs is regulated by Ca2+-activated signaling pathways in neurons and that the USFs bind to the promoters of a number of neuronal activity-regulated genes in vivo. These results suggest a new function for the USFs in the regulation of activity-dependent transcription in neurons. C1 Harvard Univ, Childrens Hosp, Sch Med, Div Neurosci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Greenberg, ME (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Div Neurosci, 300 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA79579]; NICHD NIH HHS [HD18655]; NINDS NIH HHS [NS28829-07] NR 69 TC 110 Z9 113 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 1 PY 2003 VL 23 IS 7 BP 2572 EP 2581 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 665ET UT WOS:000182107200009 PM 12684442 ER PT J AU Polster, BM Basanez, G Young, M Suzuki, M Fiskum, G AF Polster, BM Basanez, G Young, M Suzuki, M Fiskum, G TI Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Bax; BH3; Bid; brain mitochondria; cytochrome c; dibucaine; propranolol; apoptosis; permeability transition ID AMYOTROPHIC-LATERAL-SCLEROSIS; AMPHIPHILIC DRUG-INHIBITION; FOCAL CEREBRAL-ISCHEMIA; BCL-2 FAMILY-MEMBERS; NEURONAL DEATH; PERMEABILITY TRANSITION; MEMBRANE FLUIDITY; LOCAL-ANESTHETICS; NERVOUS-SYSTEM; SIGNAL PEPTIDE AB BH3 (Bcl-2 homology 3)-only proteins of the Bcl-2 family activate Bax or Bak during apoptosis to promote the release of pro-death factors sequestered in the mitochondrial intermembrane space. Previous results demonstrated that a synthetic BH3 peptide mimics the ability of the BH3-only protein Bid to promote Bax insertion and cytochrome c (cyt c) release from neural cell mitochondria. However, the BH3 peptide was deficient in promoting cyt c release from mitochondria without associated Bax, such as adult rat brain mitochondria. This study tested the hypothesis that the amphiphilic membrane-active cationic drugs dibucaine and propranolol block BH3 peptide-initiated cyt c efflux by preventing the integration of Bax into the mitochondrial outer membrane. BH3 peptide-initiated release of cyt c from GT1-7 neural cell mitochondria was inhibited by dibucaine and propranolol at concentrations of 100-300 muM. Recombinant Bax (100 nM) alone did not release cyt c from adult rat brain mitochondria; however, when BH3 peptide or caspase-8 cleaved Bid (cBid) was added, robust cyt c release was achieved that was inhibited completely by 200 muM dibucaine or propranolol. These drugs at similar concentrations also inhibited release of entrapped 10 kDa dextrans from protein-free liposomes treated with Bax and cBid. Contrary to the hypothesis that dibucaine and propranolol act by inhibiting the insertion of Bax into the mitochondrial outer membrane, membrane insertion of Bax was not inhibited in mitochondria or liposomes, indicating a mechanism of drug action downstream from this event. These results suggest that dibucaine and propranolol inhibit Bax-induced permeability changes through a direct interaction with the lipid membrane and present a novel target for the development of neuroprotective, antiapoptotic therapeutics. C1 Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. Univ Basque Country, Unidad Biofis, Ctr Mixto Consejo Super Invest Cient Univ Pais Va, E-48080 Bilbao, Spain. Univ Basque Country, Dept Bioquim & Biol Mol, E-48080 Bilbao, Spain. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Fiskum, G (reprint author), Univ Maryland, Sch Med, Dept Anesthesiol, Med Sci Teaching Facil 5-34,685 W Baltimore St, Baltimore, MD 21201 USA. EM gfisk001@umaryland.edu RI Basanez, Gorka/L-9509-2014 OI Basanez, Gorka/0000-0002-7475-7861 FU NINDS NIH HHS [NS-34152] NR 59 TC 55 Z9 58 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 1 PY 2003 VL 23 IS 7 BP 2735 EP 2743 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 665ET UT WOS:000182107200026 PM 12684459 ER PT J AU Chefer, VI Zakharova, I Shippenberg, TS AF Chefer, VI Zakharova, I Shippenberg, TS TI Enhanced responsiveness to novelty and cocaine is associated with decreased basal dopamine uptake and release in the nucleus accumbens: Quantitative microdialysis in rats under transient conditions SO JOURNAL OF NEUROSCIENCE LA English DT Article DE individual differences in response to novelty; dopamine; dopamine uptake and release; nucleus accumbens; cocaine; transient no net flux microdialysis ID EXTRACELLULAR DOPAMINE; TRANSPORTER ACTIVITY; AMPHETAMINE; INHIBITION; LOCOMOTOR; VULNERABILITY; ABSTINENCE; ACTIVATION; CLEARANCE; PREDICTS AB Male rats were screened for their response to a novel environment and designated as high responders (HRs) or low responders (LRs). They then received daily injections of saline or cocaine ( 20 mg/kg, i.p.). Basal and cocaine-evoked extracellular dopamine (DA(ext)) levels as well as basal DA uptake rate and cocaine-evoked inhibition of uptake in the nucleus accumbens were determined on abstinence day 3 using quantitative microdialysis under transient conditions. The kinetics of uptake, dopamine transporter (DAT) expression, and [H-3](-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate ([H-3]WIN35428) binding were also examined. The locomotor activating effects of cocaine and the magnitude of behavioral sensitization were greater in HRs. Saline-treated HRs had lower basal uptake than LRs. DA uptake after cocaine challenge was also lower in these animals. Although basal DA(ext) did not differ, cocaine-evoked DA(ext) was greater in HRs. The K-m and V-max of DA uptake were higher in naive HRs than LRs, as were the K-d and B-max of [H-3]WIN35428 binding. DAT protein expression did not differ. Previous cocaine exposure decreased basal DA uptake. It increased cocaine-evoked DA(ext) and decreased the cocaine-induced inhibition of uptake, especially in HRs, indicating greater DA release during cocaine challenge in this phenotype. We hypothesize that lower basal uptake in HRs results from a decrease in DAT binding affinity that is compensated for, in part, by an increased number of plasma membrane binding sites. Basal uptake, but not DA(ext), was lower in HRs, indicating lower basal DA release in HRs. The finding that cocaine-evoked DA(ext) is higher in naive and cocaine-exposed HRs suggests that the greater responsiveness of DA neurons in HRs may underlie the enhanced behavioral responses that characterize this phenotype. C1 NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, NIH,Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 57 Z9 59 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 APR 1 PY 2003 VL 23 IS 7 BP 3076 EP 3084 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 665ET UT WOS:000182107200061 PM 12684494 ER PT J AU Seth, P Diaz, F Major, EO AF Seth, P Diaz, F Major, EO TI Advances in the biology of JC virus and induction of progressive multifocal leukoencephalopathy SO JOURNAL OF NEUROVIROLOGY LA English DT Review DE demyelination; human polyomavirus; JC infection; PML therapy; viral pathogenesis ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN POLYOMAVIRUS JC; CENTRAL-NERVOUS-SYSTEM; HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN NEUROTROPIC VIRUS; HIV-INFECTED PATIENTS; NUCLEAR FACTOR-I; CEREBROSPINAL-FLUID; GLIAL-CELLS; HUMAN BRAIN AB Since the initial description of progressive multifocal leukoencephalopathy (PML) in 1958, clinical and basic science investigators have demonstrated a growing interest in the area of neurovirology, with a recent focus on polyomaviruses. In this review, the authors present an overview of the biological properties of the human polyomavirus, JC virus (JCV), and its association with PML as the etiologic agent. Additionally, the authors provide a discussion of the current understanding of JCV molecular pathogenesis and therapeutic strategies. C1 NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Room 5W21,36 Convent Dr, Bethesda, MD 20892 USA. NR 102 TC 21 Z9 22 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD APR PY 2003 VL 9 IS 2 BP 236 EP 246 DI 10.1080/13550280390194019 PG 11 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 671LQ UT WOS:000182466600011 PM 12707854 ER PT J AU Michel, RB Brechbiel, MW Mattes, MJ AF Michel, RB Brechbiel, MW Mattes, MJ TI A comparison of 4 radionuclides conjugated to antibodies for single-cell kill SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE radioimmunotherapy; Auger electrons; micrometastases; CD20; major histocompatibility complex class II ID ELECTRON-EMITTING RADIONUCLIDES; NON-HODGKINS-LYMPHOMA; MONOCLONAL-ANTIBODY; RADIOLABELED ANTIBODIES; DOSE-RATE; RADIATION; CYTOTOXICITY; RADIOIMMUNOTHERAPY; INTERNALIZATION; XENOGRAFTS AB We previously found that Ga-67 was more potent and more specific in single-cell kill than other Auger electron emitters and P-particle emitters, using an anti-CD74 antibody (Ab) (major histocompatibility complex [MHC] class 11 invariant chain). Because anti-CD74 Abs follow an unusual processing pathway, with rapid delivery in very large amounts to lysosomes, it was important to determine if similar results would be obtained with other, more typical Abs. Methods: Target cells were Raji B-lymphoma cells, and the Abs tested were antimature MHC class 11 antigen (lacking the invariant chain) and anti-CD20, both of which react with high-density antigens. Labeling was with I-125 or I-131, by conventional iodination; with In-111 using the chelator benzyl-diethylenetriaminepentaacetic acid; or with Ga-67 using the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid. Abs were incubated with the cells for 2 cl, uptake of radioactivity was assayed at various times, and toxicity was assayed primarily by a clonogenic assay. The fraction surviving was plotted versus cumulative disintegrations per cell to determine relative potency. Results: The ranking of the radionuclides for potency was I-131 > Ga-67 > I-125 > In-111. Ga-67 was approximately 2- to 3-fold more potent than In-111. This was very similar to previous results with anti-CD74. Dosimetry calculations were generally consistent with the level of toxicity observed. In previous studies of nonspecific toxicity, the order of ranking was the same. Conclusion: The subcellular location of the bound Ab (whether on the cell surface or the cytoplasm) does not appear to be an important variable in the choice of radionuclide for single-cell kill. Ga-67 is a promising radionuclide for killing micrometastases, for high-density target antigens, but methods for achieving higher specific activity are required to fully exploit this approach. Each of the 4 radionuclides tested has certain advantages, and further studies are required to select the optimal radionuclide for a particular purpose. C1 Ctr Mol Med & Immunol, Belleville, NJ 07109 USA. NIH, Bethesda, MD 20892 USA. RP Mattes, MJ (reprint author), Ctr Mol Med & Immunol, 520 Belleville Ave, Belleville, NJ 07109 USA. FU NCI NIH HHS [CA 87059] NR 24 TC 34 Z9 34 U1 0 U2 10 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD APR PY 2003 VL 44 IS 4 BP 632 EP 640 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 664PB UT WOS:000182068500028 PM 12679410 ER PT J AU Schmidt, BL Tambeli, CH Levine, JD Gear, RW AF Schmidt, BL Tambeli, CH Levine, JD Gear, RW TI Adaptations in nucleus accumbens circuitry during opioid withdrawal associated with persistence of noxious stimulus-induced antinociception in the rat SO JOURNAL OF PAIN LA English DT Article DE analgesia; delta-opioid receptor; mu-opioid receptor; morphine; pain; capsaicin ID JAW-OPENING REFLEX; VENTROLATERAL ORBITAL CORTEX; PERIAQUEDUCTAL GRAY-MATTER; ANTERIOR PRETECTAL NUCLEUS; SOMATOSTATIN ANALOGS; LOCOMOTOR-ACTIVITY; INDUCED ANALGESIA; MORPHINE PELLETS; SUCROSE DRINKING; RECEPTORS AB We studied adaptations in nucleus accumbens opioidergic circuitry mediating noxious stimulus-induced antinociception (NSIA) in rats withdrawing from chronic morphine administration. Although the magnitude of NSIA in withdrawing rats was similar to that observed in naive rats despite the tolerance of withdrawing rats to the antinociceptive effects of acutely administered morphine, the involvement of nucleus accumbens opioid receptors in NSIA in withdrawing rats was different from previous observations in both naive and tolerant rats. In withdrawing rats intra-accumbens administration of the mu-opioid receptor antagonist Cys(2), Tyr(3), Orn(5), Pen(7) amide (CTOP), but not the delta-receptor antagonist naltrindole, blocked NSIA. Both antagonists blocked NSIA in the naive state, but neither was effective in tolerant rats. Also, intra-accumbens administration of the mu-agonist [D-Ala(2), N-Me-Phe(4)-Gly(5)-ol]-enkephalin (DAMGO) alone was sufficient to induce antinociception in withdrawing rats, whereas a combination of both mu- and delta-receptor agonists (ie, DAMGO and D-Pen(25)-enkephalin [DPDPE], respectively) is required to induce antinociception in naive rats. The delta- agonist DPDPE was without effect in the withdrawing rat, alone or when combined with DAMGO. Thus, although the magnitude of NSIA does not differ significantly among the 3 states, it is mediated by both mu- and delta-receptors in the naive rat, mu- but not delta-receptors in the withdrawing rat, and neither receptor type in the morphine tolerant rat. These changes may result from different degrees of tolerance, with delta-receptors being the most sensitive; however, it is not known how these changes occur without affecting the magnitude of the resultant antinociception. (C) 2003 by the American Pain Society. C1 Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Grad Program Oral Biol, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Neurosci, San Francisco, CA 94143 USA. Univ Campinas, Fac Dent Piracicaba, Campinas, SP, Brazil. RP Gear, RW (reprint author), Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, C-522,Box 0440, San Francisco, CA 94143 USA. RI Tambeli, Claudia/D-4356-2012; OI Schmidt, Brian/0000-0002-2409-8984 FU NIDCR NIH HHS [K16 DE00386] NR 38 TC 8 Z9 8 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2003 VL 4 IS 3 BP 141 EP 147 DI 10.1054/jpai.2003.12 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 672WU UT WOS:000182546700004 PM 14622711 ER PT J AU Agrawal, M AF Agrawal, M TI Voluntariness in clinical research at the end of life SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article; Proceedings Paper CT Meeting on the Ethics of End-of-Life Research CY SEP 12-13, 2002 CL NIH CAMPUS, BETHESDA, MARYLAND SP NINR, Off Rare Dis HO NIH CAMPUS DE voluntariness; vulnerability; coercion; exploitation; end of life ID INFORMED CONSENT; FUNCTIONAL STATUS; ADULTS AB Voluntariness is a requirement that is frequently voiced in research ethics but is poorly understood. This article seeks to clarify voluntariness and assess its significance in clinical research at the end of life. First, what voluntariness is and why we consider it important is considered. Next, where voluntafiness fits in the overall context Of making clinical research ethical is clarified. Finally, the murky terms "vulnerability, " "exploitation, " and "coercion " are clarified and their relationship to voluntariness examined. The danger of using some of these terms is that they carry a lot of moral weight and labeling patients as "vulnerable " or "coerced" can close off conversation because they are reflexively associated with unethical research. Finally, correctly characterized threats to voluntafiness are examined and ways to ameliorate them are presented. (C) 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier All rights reserved. C1 Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Agrawal, M (reprint author), Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bldg 10,Room 1C116,10 Ctr Dr, Bethesda, MD 20892 USA. NR 22 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD APR PY 2003 VL 25 IS 4 BP S25 EP S32 DI 10.1016/S0885-3924(03)00057-5 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 666HJ UT WOS:000182171300018 PM 12691694 ER PT J AU Casarett, DJ Knebel, A Helmers, K AF Casarett, DJ Knebel, A Helmers, K TI Ethical challenges of palliative care research SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Editorial Material C1 Univ Penn, Div Geriatr, Philadelphia, PA 19104 USA. Philadelphia Vet Adm Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. NINR, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Casarett, DJ (reprint author), Univ Penn, Div Geriatr, 3615 Chestnut St, Philadelphia, PA 19104 USA. NR 8 TC 18 Z9 18 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD APR PY 2003 VL 25 IS 4 BP S3 EP S5 DI 10.1016/S0885-3924(03)00058-7 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 666HJ UT WOS:000182171300015 PM 12723543 ER PT J AU Shi, Q Savage, JE Hufeisen, SJ Rauser, L Grajkowska, E Ernsberger, P Wroblewski, JT Nadeau, JH Roth, BL AF Shi, Q Savage, JE Hufeisen, SJ Rauser, L Grajkowska, E Ernsberger, P Wroblewski, JT Nadeau, JH Roth, BL TI L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NUTRITION EXAMINATION SURVEY; VASCULAR ENDOTHELIAL-CELLS; CEREBELLAR GRANULE CELLS; 3RD NATIONAL-HEALTH; MESSENGER-RNA; ALZHEIMERS-DISEASE; MICE LACKING; DEVELOPMENTAL REGULATION; SYNAPTIC PLASTICITY AB Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that L-homocysteine sulfinic acid (L-HCSA), L-homocysteic acid, L-cysteine sulfinic acid, and L-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Galpha(qi9)) and 2) inhibited the forskolin-induced cAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, L-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when L-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed. C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, RM W438, Cleveland, OH 44106 USA. RI Roth, Bryan/F-3928-2010; Ernsberger, Paul/O-2702-2014 OI Ernsberger, Paul/0000-0003-2372-2500 FU NHLBI NIH HHS [HL58982]; NIMH NIH HHS [MHN80002, K02MH01366]; NINDS NIH HHS [NS37436] NR 73 TC 76 Z9 80 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2003 VL 305 IS 1 BP 131 EP 142 DI 10.1124/jpet.102.047092 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662VW UT WOS:000181970400016 PM 12649361 ER PT J AU Kozikowski, AP Johnson, KM Deschaux, O Bandyopadhyay, BC Araldi, GL Carmona, G Munzar, P Smith, MP Balster, RL Beardsley, PM Tella, SR AF Kozikowski, AP Johnson, KM Deschaux, O Bandyopadhyay, BC Araldi, GL Carmona, G Munzar, P Smith, MP Balster, RL Beardsley, PM Tella, SR TI Mixed cocaine agonist/antagonist properties of (+)-methyl 4 beta-(4-chlorophenyl)-1-methylpiperidine-3 alpha-carboxylate, piperidine-based analog of cocaine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROGRESSIVE RATIO SCHEDULE; TRANSPORTER KNOCKOUT MICE; DISCRIMINATIVE-STIMULUS; INTRAVENOUS COCAINE; DOPAMINE-TRANSPORTER; SEEKING BEHAVIOR; SEROTONIN; ABUSE; PHARMACOLOGY; FLUOXETINE AB The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4beta( 4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylic acid [(+)CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence. C1 Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA. Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Drug Discovery Program, Washington, DC 20007 USA. NIDA, Behav Neurosci Branch, Preclin Pharmcol Sect, NIH, Baltimore, MD USA. Biostream Therapeut Inc, Cambridge, MA USA. Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. Virginia Commonwealth Univ, Inst Drug & Alcohol Studies, Richmond, VA USA. RP Johnson, KM (reprint author), Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA. RI Johnson, Kenneth/E-7944-2014 FU NIMH NIH HHS [N01MH80005] NR 45 TC 9 Z9 9 U1 2 U2 4 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 APR PY 2003 VL 305 IS 1 BP 143 EP 150 DI 10.1124/jpet.102.046318 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662VW UT WOS:000181970400017 PM 12649362 ER PT J AU Sprague, JE Banks, ML Cook, VJ Mills, EM AF Sprague, JE Banks, ML Cook, VJ Mills, EM TI Hypothalamic-pituitary-thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID BROWN ADIPOSE-TISSUE; MDMA INDUCED HYPERTHERMIA; INDUCED DOPAMINE RELEASE; UNCOUPLING PROTEIN-3; BODY-TEMPERATURE; RAT; NOREPINEPHRINE; NEUROTOXICITY; HORMONE; THERMOGENESIS AB An acute and potentially life-threatening complication associated with the recreational use of the 3,4-methylenedioxymethamphetamine ( MDMA, Ecstasy) is hyperthermia. In the present study, Sprague-Dawley rats treated with MDMA ( 40 mg/kg s.c.) responded with a significant increase ( maximal at 1 h) in rectal and skeletal muscle temperatures that lasted for at least 3 h post-treatment. Hypophysectomized ( HYPO) and thyroparathyroidectomized ( TX) animals treated with MDMA ( 40 mg/kg s.c.) did not become hyperthermic and in fact displayed a significant hypothermia. The HYPO and TX animals were also resistant to the serotonergic neurotoxic effects of MDMA assessed by serotonin measurements 4 to 7 days later in the striatum and hippocampus. MDMA ( 40 mg/kg s.c.) induced a significant increase in thyroxine levels 1 h post-treatment. Thyroid hormone replacement in TX animals returned the hyperthermic response seen after MDMA. Prazosin, an alpha(1)-antagonist (0.2 mg/kg i.p.), administered 30 min before MDMA significantly attenuated the MDMA-induced increase in rectal temperature, but had no effect on skeletal muscle temperature. Cyanopindolol, a beta(3)-antagonist (4 mg/kg s.c.), administered 30 min before MDMA (40 mg/kg s.c.) significantly attenuated the increase in skeletal muscle temperature, but had no effect on the rise in rectal temperature. The combination of prazosin and cyanopindolol resulted in an abolishment of MDMA-induced hyperthermia. The mechanisms of thermogenesis induced by MDMA seem to result from an interaction between the hypothalamic-pituitary-thyroid axis and the sympathetic nervous system, wherein mechanisms leading to core and skeletal muscle hyperthermia after MDMA exposure seem to be differentially regulated by alpha(1)- and beta(3)-adrenergic receptors. C1 Ohio No Univ, Raabe Coll Pharm, Dept Pharmaceut & Biomed Sci, Ada, OH 45810 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Sprague, JE (reprint author), Ohio No Univ, Raabe Coll Pharm, Dept Pharmaceut & Biomed Sci, Ada, OH 45810 USA. RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 NR 40 TC 61 Z9 64 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 APR PY 2003 VL 305 IS 1 BP 159 EP 166 DI 10.1124/jpet.102.044982 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662VW UT WOS:000181970400019 PM 12649364 ER PT J AU Liu, YX Qin, LY Li, GR Zhang, W An, LJ Liu, B Hong, JS AF Liu, YX Qin, LY Li, GR Zhang, W An, LJ Liu, B Hong, JS TI Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; INJURY FOLLOWING TRANSIENT; NECROSIS-FACTOR-ALPHA; GUINEA-PIG BRAIN; NITRIC-OXIDE; REACTIVE OXYGEN; FOCAL ISCHEMIA; NEURODEGENERATIVE DISEASES; INTRANIGRAL INJECTION; GLUTAMATE TOXICITY AB Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1-10 muM) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or beta-amyloid peptide ( 1-42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Dalian Univ Technol, Dept Bioengn, Dalian, Peoples R China. RP Hong, JS (reprint author), NIEHS, Lab Pharmacol & Chem, MD-F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. RI liu, Bin/A-7695-2009 NR 57 TC 137 Z9 147 U1 2 U2 6 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 APR PY 2003 VL 305 IS 1 BP 212 EP 218 DI 10.1124/jpet.102.043166 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662VW UT WOS:000181970400026 PM 12649371 ER PT J AU Yu, AM Idle, JR Krausz, KW Kupfer, A Gonzalez, FJ AF Yu, AM Idle, JR Krausz, KW Kupfer, A Gonzalez, FJ TI Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MONOAMINE-OXIDASE-A; PARKINSONS-DISEASE; N-METHYLATION; UDP-GLUCURONYLTRANSFERASE; MONOCLONAL-ANTIBODIES; LIVER-MICROSOMES; HUMAN BRAIN; METABOLISM; RAT; IDENTIFICATION AB The psychotropic beta-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K-cat (min(-1)) and K-m (muM) values for harmaline were: CYP1A1, 10.8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Bern, Dept Clin Pharmacol, Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Rm 2A19A, Bethesda, MD 20892 USA. NR 54 TC 81 Z9 81 U1 1 U2 6 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 APR PY 2003 VL 305 IS 1 BP 315 EP 322 DI 10.1124/jpet.102.047050 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662VW UT WOS:000181970400039 PM 12649384 ER PT J AU Losi, G Prybylowski, K Fu, ZY Luo, JH Wenthold, RJ Vicini, S AF Losi, G Prybylowski, K Fu, ZY Luo, JH Wenthold, RJ Vicini, S TI PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID D-ASPARTATE RECEPTOR; POSTSYNAPTIC DENSITY; PROTEIN FAMILY; MOUSE-BRAIN; SYNAPSES; EXPRESSION; SUBUNITS; DIFFERENTIATION; CELLS; MECHANISMS AB We transfected a green fluorescent protein-tagged PSD-95 (TISD-95gfp) into cultured rat cerebellar granule cells (CGCs) to investigate the role of PSD-95 in excitatory synapse maturation. Cells were grown in low potassium to favour functional synapse formation in vitro. Transfected cells displayed clear clusters of PSD-95gfp, often at the extremities of the short dendritic trees. We recorded NMDA and AMPA miniature excitatory postsynaptic currents (NMDA- and AMPA-mESPCs) in the presence of TTX and bicuculline. At days in vitro (DIV) 7-8 PSD-95gfp-transfected cells had NMDA-mEPSCs with faster decay and smaller amplitudes than matching controls. In contrast, AMPA-mEPSC frequencies and amplitudes were increased. Whole-cell current density and ifenprodil sensitivity were reduced in PSD-95gfp cells, indicating a reduction of NR2B subunits containing NMDA receptors. No changes were observed compared to control when cells were transfected with cDNA for PSD-95gfp with palmitoylation site mutations that prevent targeting to the synapse. Overexpression of the NMDA receptor NR2A subunit, but not the NR2B subunit, prevented NMDA-mEPSC amplitude reduction when cotransfected with PSD-95gfp. PSD-959fp overexpression produced faster NMDA-mEPSC decay when transfected alone or with either NR2 subunit. Surface staining of the epitope-tagged NR2 subunits revealed that colocalization with PSD-95gfp was higher for flag-tagged NR2A subunit clusters than for flag-tagged NR2B subunit clusters. These data suggest that PSD-95 overexpression in CGCs favours synaptic maturation by allowing synaptic insertion of NR2A and depressing expression of NR2B subunits. C1 Georgetown Univ, Dept Physiol & Biophys, Washington, DC 20057 USA. NIDCD, Neurochem Lab, NIH, Bethesda, MD USA. Zhejiang Univ, Neurobiol Lab, Hangzhou 310027, Peoples R China. RP Vicini, S (reprint author), Georgetown Univ, Dept Physiol & Biophys, Box 571460,Bldg Room 225, Washington, DC 20057 USA. OI Losi, Gabriele/0000-0001-7796-9299; LOSI, GABRIELE/0000-0002-4931-6167 FU NIMH NIH HHS [MH01680, MH58946] NR 30 TC 53 Z9 59 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 APR 1 PY 2003 VL 548 IS 1 BP 21 EP 29 DI 10.1113/jphysiol.2002.034918 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 690VH UT WOS:000183570800002 PM 12576494 ER PT J AU George, SZ Hicks, GE Nevitt, MA Cauley, JA Vogt, MT AF George, SZ Hicks, GE Nevitt, MA Cauley, JA Vogt, MT TI The relationship between lumbar lordosis and radiologic variables and lumbar lordosis and clinical variables in elderly, African-American women SO JOURNAL OF SPINAL DISORDERS & TECHNIQUES LA English DT Article; Proceedings Paper CT ISSLS 2002 Meeting CY 2002 CL CLEVELAND, OHIO SP ISSLS DE African-American women; lordosis; radiologic; disability; symptoms ID LOW-BACK-PAIN; SPINAL SAGITTAL CONFIGURATION; STANDING LATERAL RADIOGRAPHS; DEGENERATIVE SPONDYLOLISTHESIS; CLASSIFICATION APPROACH; ADULT VOLUNTEERS; RELIABILITY; MOBILITY; BALANCE; FRACTURES AB Several authors have hypothesized that there is a link between lumbar lordosis and low back pain. These relationships have not been previously described in a sample consisting exclusively of elderly, African-American women. The purpose of this study was to describe the relationship between lumbar lordosis and radiologic variables and lumbar lordosis and clinical variables in elderly, African-American women. A total of 475 African-American women enrolled in the multicenter Study of Osteoporotic Fractures participated in this ancillary, cross-sectional, study of lumbar lordosis. These women received lumbar spine radiographs and completed a questionnaire on low back pain and its impact on their daily lives. Lumbar lordosis tertiles were created based on radiographic measurements. Comparisons were made between the tertiles for differences in radiologic and clinical variables. Significant differences (p < 0.0025) were observed between the lordosis tertiles and the presence of spondylolisthesis, intervertebral disc space, and vertebral wedging. No significant differences were observed between the lordosis tertiles for the occurrence of low back pain, symptoms associated with low back pain, and disability experienced from low back pain. The degree of lumbar lordosis was associated with radiologic variables but was not associated with symptoms or decreased function from low back pain. These findings question the clinical utility of the lumbar lordosis measurement in elderly, African-American women. C1 Univ Florida, Brooks Ctr Rehabil Study, Ctr Pain Res & Behav Hlth, Hlth Sci Ctr, Gainesville, FL 32610 USA. NIA, Clin Res Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Orthopaed Surg, Pittsburgh, PA 15260 USA. RP George, SZ (reprint author), Univ Florida, Brooks Ctr Rehabil Study, Ctr Pain Res & Behav Hlth, Hlth Sci Ctr, POB 100165, Gainesville, FL 32610 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 48 TC 5 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1536-0652 J9 J SPINAL DISORD TECH JI J. Spinal Disord. Tech. PD APR PY 2003 VL 16 IS 2 BP 200 EP 206 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 664HM UT WOS:000182055700014 PM 12679677 ER PT J AU Sherwood, JT Schomisch, SJ Thompson, DR George, DT Cmolik, BL AF Sherwood, JT Schomisch, SJ Thompson, DR George, DT Cmolik, BL TI Aortomyoplasty: Hemodynamics and comparison to the intraaortic balloon pump SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE counterpulsation; aortomyoplasty; electrical stimulation; heart-assist device; heart failure; hemodynamics ID DESCENDING THORACIC AORTOMYOPLASTY; CANINE SKELETAL-MUSCLE; LATISSIMUS-DORSI; HEART-FAILURE; AORTIC COUNTERPULSATION; CARDIAC-ASSIST; SUBENDOCARDIAL ISCHEMIA; DYNAMIC AORTOMYOPLASTY; OXYGEN CONSUMPTION; BLOOD-FLOW AB Background. Aortomyoplasty (AMP), a procedure in which the latissimus dorsi muscle (LDM) is wrapped around the aorta and stimulated during diastole, is a potential method of chronic counterpulsation. Counterpulsation by the intraaortic balloon pump (LABP) is a proven treatment for ischemic coronary syndrome and heart failure but cannot be used chronically. This study examined the long-term potential of a unique AMP configuration and compared its performance to the LABP. Materials and methods. AMP was done using a wringer configuration (AMP-W) in nine dogs. Six and 12 months later, acute hemodynamic augmentation was evaluated by measuring differences in mean diastolic aortic pressure (mDAP), peak left ventricular pressure (pLVP), and the endocardial viability ratio (EVR) between stimulated and unstimulated beats. Results. The diastolic augmentation obtained by AMP-W at 6 months and by AMP-W and LABP at 12 months was statistically significant. Additionally, the enhancements in EVR (16.1 +/- 4.3%), mDAP (8.6 +/- 2.5%), and pLVP (-1.8 +/- 1.0%) at 6 months were similar to those in EVR (19.1 +/- 5.2%), mDAP (13.1 +/- 3.6%), and pLVP (-0.8 +/- 1.3%) at 12 months. Most importantly, the augmentation obtained by AMP-W at 12 months was similar to that of the IABP: EVR (17.1 +/- 5.9%), mDAP (13.4 +/- 6.7%), and pLVP (-1.5 +/- 0.8%). Conclusions. AMP-W is a safe, robust procedure, capable of providing counterpulsation equivalent to the LABP, 12 months following surgery. The potential for AMP-W to offer chronic counterpulsation and to benefit the ischemic heart should be investigated further. (C) 2003 Elsevier Science (USA). C1 Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Toledo, Sch Med, Toledo, OH 43606 USA. NHLBI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Cmolik, BL (reprint author), Univ Hosp Cleveland, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM blc3@po.cwru.edu NR 35 TC 4 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD APR PY 2003 VL 110 IS 2 BP 315 EP 321 DI 10.1006/jsre.2002.6569 PG 7 WC Surgery SC Surgery GA 687BU UT WOS:000183356600001 PM 12788660 ER PT J AU Greenhill, LL Jensen, PS Abikoff, H Blumer, JL DeVeaugh-Geiss, J Fisher, C Hoagwood, K Kratochvil, CJ Lahey, BB Laughren, T Leckman, J Petti, TA Pope, K Shaffer, D Vitiello, B Zeanah, C AF Greenhill, LL Jensen, PS Abikoff, H Blumer, JL DeVeaugh-Geiss, J Fisher, C Hoagwood, K Kratochvil, CJ Lahey, BB Laughren, T Leckman, J Petti, TA Pope, K Shaffer, D Vitiello, B Zeanah, C TI Developing strategies for psychopharmacological studies in preschool children SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE preschool children; clinical trials; ethics; diagnosis ID YOUNG-CHILDREN; DISORDER AB Objective: To identify the obstacles and special challenges-ethical, practical, scientific, and regulatory-faced by investigators who attempt to conduct psychopharmacological studies in preschoolers. Method: In a workshop held at the 47th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, featuring interactive sessions designed to elicit discussion of the theory and feasibility of research in this young population, several key domains were identified: diagnosis and assessment, ethics, research design, special considerations for preschoolers, regulatory/industry issues, and education/training. Results: A Pediatric Psychopharmacology Initiative is needed to consolidate recommendations from this and other workshops and current federal, research, and regulatory committees. A scholarly review and a guide for institutional review boards and investigators should be prepared on issues related to preschoolers. Developmental specialists provide valuable expertise that can strengthen studies of pediatric psychopharmacology. "N of 1" case studies can provide valuable information to clinicians. Only preschoolers with severe symptoms that occur in several interpersonal contexts should be entered into trials. Indications for the study of symptom complexes (e.g., aggression) rather than specific diagnoses should be examined and considered for regulatory activities. Psychopharmacology practice parameters for preschoolers are needed. Conclusions: With preschoolers being increasingly treated with psychopharmacological agents, the need for investigations to address the safety and efficacy of these medications is becoming a central issue for researchers from many disciplines. C1 New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NYU, Ctr Child Study, New York, NY 10012 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Fordham Univ, Bronx, NY 10458 USA. Univ Nebraska, Lincoln, NE 68583 USA. Univ Chicago, Chicago, IL 60637 USA. Yale Univ, New Haven, CT 06520 USA. Indiana Univ, Bloomington, IN 47405 USA. NIMH, Bethesda, MD 20892 USA. Tulane Univ, New Orleans, LA 70118 USA. US FDA, Rockville, MD 20857 USA. RP Greenhill, LL (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr, New York, NY 10032 USA. EM LarryLGreenhill@cs.com OI Jensen, Peter/0000-0003-2387-0650 FU NIMH NIH HHS [U01-MH50453, U01-MH50461, MH50467] NR 19 TC 25 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD APR PY 2003 VL 42 IS 4 BP 406 EP 414 DI 10.1097/01.CHI.0000064812.95464.FA PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 658DN UT WOS:000181706500006 PM 12649627 ER PT J AU Brockow, K Akin, C Huber, M Metcalfe, DD AF Brockow, K Akin, C Huber, M Metcalfe, DD TI Assessment of the extent of cutaneous involvement in children and adults with mastocytosis: Relationship to symptomatology, tryptase levels, and bone marrow pathology SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID MAST-CELL DISEASE; RECEPTOR-ALPHA CHAIN; SYSTEMIC MASTOCYTOSIS; URTICARIA-PIGMENTOSA; SKIN; PLASMA; BLOOD AB Background. Cutaneous involvement occurs in most patients with systemic mastocytosis. Objective: We sought to determine whether the extent of cutaneous involvement is predictive of systemic disease. Methods: In a prospective survey of 48 adults and 19 children, the extent and density of cutaneous lesions were compared with patient history, symptoms, internal organ involvement, serum total mast cell tryptase level, and bone marrow pathology. Results: Cutaneous lesions in children were of a greater mean and maximum diameter, but similar in extent and density compared with lesions in adults. In adults with skin lesions, the extent of lesions correlated to disease duration. Adults with extensive cutaneous disease experienced more pruritus and flushing. Fatigue, splenomegaly, and hepatomegaly were more frequent in adults without cutaneous involvement; and in those with a greater density of lesions and disease duration. Increased tryptase levels were found in children and adults with systemic disease and correlated to skin lesion density and bone marrow pathology. Conclusion: An examination of the extent and density of cutaneous lesions in adults helps identify those with more extensive extracutaneous disease and, thus, requiring a more thorough evaluation. (J Am Acad Dermatol 2003;48:508-16.). C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, NIH, Lab Allerg Dis, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 20 TC 53 Z9 53 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2003 VL 48 IS 4 BP 508 EP 516 DI 10.1067/njd.2003.98 PG 9 WC Dermatology SC Dermatology GA 662NK UT WOS:000181953500003 PM 12664011 ER PT J AU O'Reilly, F Feldman, E Yang, J Hwu, P Turner, ML AF O'Reilly, F Feldman, E Yang, J Hwu, P Turner, ML TI Recurring cutaneous eruption in a patient with metastatic renal cell carcinoma being treated with high-dose interleukin 2 SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID FIXED DRUG ERUPTION C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. RP Turner, ML (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2003 VL 48 IS 4 BP 602 EP 604 DI 10.1067/mjd.2003.204 PG 3 WC Dermatology SC Dermatology GA 662NK UT WOS:000181953500018 PM 12664026 ER PT J AU Bhathena, SJ Ali, AA Haudenschild, C Latham, P Ranich, T Mohamed, AI Hansen, CT Velasquez, MT AF Bhathena, SJ Ali, AA Haudenschild, C Latham, P Ranich, T Mohamed, AI Hansen, CT Velasquez, MT TI Dietary flaxseed meal is more protective than soy protein concentrate against hypertriglyceridemia and steatosis of the liver in an animal model of obesity SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE cholesterol; flaxseed; fatty liver; hypertriglyceridemia; plasma lipids; soy protein ID CARDIOVASCULAR RISK-FACTORS; NONALCOHOLIC FATTY LIVER; HYPERCHOLESTEROLEMIC ATHEROSCLEROSIS; DEFATTED FLAXSEED; DIABETES-MELLITUS; SOYBEAN FOODS; CORPULENT RAT; SERUM-LIPIDS; BLOOD-LIPIDS; ISOFLAVONES AB Objective: Soy protein and flaxseed meal have been reported to have beneficial effects on many chronic diseases in humans and animals. The primary objective of the study was to evaluate the beneficial effects of soy protein and flaxseed meal on hypertriglyceridemia and liver steatosis associated with obesity and diabetes. We compared the effects of dietary soy protein and flaxseed meal with that of casein on plasma and liver lipids in a genetic model of obesity, type II diabetes and insulin resistance, namely the SHR/N-cp rat. Methods: Lean and obese phenotypes of SHR/-cp rats were fed AIN 93 diets containing 20% of energy from casein (control), soy protein concentrate or flaxseed meal for six months. Plasma was analyzed for total cholesterol, LDL cholesterol, triglycerde and total protein. Liver was analyzed for steatosis by light microscopy after staining samples with Hematoxylin-Eosin and Oil-Red-O. Results: In lean rats soy protein and flaxseed meal significantly decreased plasma total cholesterol (26.0% and 20.3% respectively) compared to casein. In obese rats flaxseed meal had significant cholesterol lowering effect compared to control rats (41%). Soy protein significantly lowered both plasma LDL-cholesterol and HDL-cholesterol in lean phenotypes while in obese phenotypes flaxseed meal significantly lowered LDL-cholesterol and HDL-cholesterol compared to casein-fed rats. Flaxseed meal also significantly lowered plasma triglyceride in both lean and obese rats compared to casein fed rats (33.7% and 37% respectively). There was significantly greater fat accumulation in fivers of obese rats than lean rats (200%) regardless of dietary protein type. Flaxseed meal significantly lowered fat deposition in fivers of both lean and obese rats compared to rats fed casein or soy protein. Dietary component(s) present in flaxseed meal or soy protein responsible for hypolipidemic effects is not clear. Conclusions: The marked hypotriglyceridemic and hypocholesterolemic effects of flaxseed meal may have important therapeutic implications in patients with hypertriglyceridemia and hypercholesterolemia and deserve further study in humans with these disorders. Flaxseed meal supplementation may provide a new therapeutic strategy to reduce hypertriglyceridemia and fatty liver. C1 USDA ARS, Beltsville Human Nutr Res Ctr, Phytonutr Lab, Beltsville, MD 20705 USA. NIH, Anim Genet Resource, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Dept Expt Pathol, Rockville, MD USA. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. Virginia State Univ, Petersburg, VA USA. Ain Shams Univ, Dept Food Sci, Cairo, Egypt. RP Bhathena, SJ (reprint author), USDA ARS, Beltsville Human Nutr Res Ctr, Phytonutr Lab, Bldg 307,Room 315, Beltsville, MD 20705 USA. OI Latham, Patricia/0000-0003-2782-9444 NR 50 TC 39 Z9 40 U1 0 U2 5 PU AMER COLL NUTRITION PI NEW YORK PA C/O HOSP. JOINT DIS. 301 E. 17TH ST., NEW YORK, NY 10003 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD APR PY 2003 VL 22 IS 2 BP 157 EP 164 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 664YR UT WOS:000182093200008 PM 12672712 ER PT J AU Mehta, KM Simonsick, EM Penninx, BWJH Schulz, R Rubin, SM Satterfield, S Yaffe, K AF Mehta, KM Simonsick, EM Penninx, BWJH Schulz, R Rubin, SM Satterfield, S Yaffe, K TI Prevalence and correlates of anxiety symptoms in well-functioning older adults: Findings from the health aging and body composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Meeting of the Gerontological-Society-of-America CY NOV, 2001 CL CHICAGO, ILLINOIS SP Gerontol Soc Amer DE anxiety symptoms; anxiety disorders; aged 65 and older ID DEPRESSIVE SYMPTOMS; RISK-FACTORS; PHYSICAL-DISABILITY; ELDERLY POPULATION; LATER LIFE; COMMUNITY; WOMEN; ASSOCIATION; HYPERTENSION; MORTALITY AB OBJECTIVES: To determine the prevalence and correlates of anxiety symptoms in the absence of depression, in older black and white people. DESIGN: Cross-sectional study. SETTING: Baseline assessment of a biracial cohort of community-resident well-functioning men and women aged 70 to 79 participating in the Health Aging and Body Composition study. PARTICIPANTS: Three thousand forty-one participants (mean age 74, 52% women, 58% white). MEASUREMENTS: Participants were asked about three major anxiety symptoms (feeling fearful, tense/keyed-up, or shaky/nervous) derived from the Hopkins Symptom Checklist. Participants were considered to have anxiety symptoms if they reported feeling at least two anxiety symptoms "a little" or one symptom "quite a bit" in the past week. Logistic regression models were used to identify demographic, psychosocial, and health-related correlates of anxiety symptoms. RESULTS: Anxiety symptoms occurred in 15% of older people without depression and 43% of those with depression. Of nondepressed older people, women were more likely to have anxiety symptoms than men (P < .01), especially white women (20% prevalence). After multivariate adjustment, the chronic conditions of urinary incontinence (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-1.9), hearing impairment (OR = 1.4, 95% CI = 1.0-2.1), hypertension (OR = 1.3, 95% CI = 1.0-1.7) and poor sleep (OR = 1.7, 95% CI = 1.3-2.4) were associated with a higher prevalence of anxiety symptoms. Persons with poorer psychosocial functioning, low personal mastery (OR = 2.0, 95% CI = 1.6-2.5) and the need for more emotional support (OR = 2.2, 95% CI = 1.7-2.8), also had higher rates of anxiety symptoms. CONCLUSION: Anxiety symptoms are common in depressed and nondepressed older people. Given the high prevalence and coexistence with depressive symptoms, it will be important to conduct longitudinal studies that assess depressive and anxiety symptoms to clarify the direction and influence and disentangle the health-related consequences of these two conditions. C1 Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Tennessee, Dept Prevent Med, Coll Med, Memphis, TN 38163 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. RP Mehta, KM (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. FU NIA NIH HHS [K23-AG00888, N01-AG62103, N01-AG62101, N01-AG62106, P30 AG 15272, T32-AG00212-08] NR 46 TC 67 Z9 68 U1 3 U2 7 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 APR PY 2003 VL 51 IS 4 BP 499 EP 504 DI 10.1046/j.1532-5415.2003.51158.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 659XD UT WOS:000181803000008 PM 12657069 ER PT J AU Simonsick, EM AF Simonsick, EM TI Fitness and cognition: Encouraging findings and methodological considerations for future work SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID EXERCISE C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. RP Simonsick, EM (reprint author), NIA, Gerontol Res Ctr, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 5 TC 6 Z9 7 U1 1 U2 1 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 APR PY 2003 VL 51 IS 4 BP 570 EP 571 DI 10.1046/j.1532-5415.2003.51170.x PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 659XD UT WOS:000181803000022 PM 12657084 ER PT J AU Agelli, M Porter, K McQuillan, G Kington, R AF Agelli, M Porter, K McQuillan, G Kington, R TI Factors associated with consent in the adults participating in the 1999-2000 National Health and Nutrition Examination Survey (NHANES) SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 NCI, NIH, Bethesda, MD 20892 USA. NCHS, CDC, Hyattsville, MD USA. NIH OD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P327 BP S152 EP S152 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100371 ER PT J AU Agelli, M Clegg, L AF Agelli, M Clegg, L TI Primary Merkel cell carcinoma: Incidence trends, epidemiology, and predictors of survival. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P188 BP S107 EP S107 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100234 ER PT J AU Atkinson, H Cesari, M Penninx, B Buchanan, C Fried, L Guralnik, J Williamson, JD AF Atkinson, H Cesari, M Penninx, B Buchanan, C Fried, L Guralnik, J Williamson, JD TI Predictors of functional decline in older women with concurrent cognitive decline. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RI Cesari, Matteo/A-4649-2008 OI Cesari, Matteo/0000-0002-0348-3664 NR 0 TC 0 Z9 0 U1 0 U2 0 PU 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 APR PY 2003 VL 51 IS 4 SU S MA P389 BP S172 EP S173 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100433 ER PT J AU Barron, JS Simonsick, EM Fleg, JL Metter, EJ AF Barron, JS Simonsick, EM Fleg, JL Metter, EJ TI Fitness and strength among older american workers and risk of retirement SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Johns Hopkins Univ, Div Geriatr Med & Gerontol, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P320 BP S149 EP S150 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100364 ER PT J AU Boyd, CM Ostir, GV Xue, Q Guralnik, J Fried, L AF Boyd, CM Ostir, GV Xue, Q Guralnik, J Fried, L TI The association between hospitalization and change in physical performance among disabled older women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Johns Hopkins Univ, Ctr Aging & Hlth, Div Geriatr Med & Gerontol, Baltimore, MD 21218 USA. Univ Texas, Med Branch, Dept Internal Med, Sealy Ctr Aging, Galveston, TX 77550 USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P190 BP S107 EP S108 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100236 ER PT J AU Buchanan, CK Fitzpatrick, A Dekosky, S Nahin, R Williamson, JD AF Buchanan, CK Fitzpatrick, A Dekosky, S Nahin, R Williamson, JD TI Association of walking speed with cognitive performance in non-demented adults age >= 75 years. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Wake Forest Univ, Sch Med, Roena Kulynych Dementia Res Ctr, Internal Med Sect Geriatr, Winston Salem, NC 27109 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. NIH, Natl Ctr Complmentary & Alternat Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P216 BP S116 EP S117 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100262 ER PT J AU Chodosh, J Seeman, TE Keeler, E Sewall, A Hirsch, SH Guralnik, JM Reuben, DB AF Chodosh, J Seeman, TE Keeler, E Sewall, A Hirsch, SH Guralnik, JM Reuben, DB TI Does cognitive decline in high functioning older persons affect hospital utilization? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 VA GLAHS, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. Sewall Inc, Bethesda, MD USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P83 BP S72 EP S72 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100129 ER PT J AU de Rekeneire, N Shorr, R Kuller, L Schwartz, A Harris, T AF de Rekeneire, N Shorr, R Kuller, L Schwartz, A Harris, T TI Diabetes, hyperglycemia and inflammation in the elderly. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 NIA, Bethesda, MD 20892 USA. Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2003 VL 51 IS 4 SU S MA A24 BP S35 EP S35 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100025 ER PT J AU Gray, SL Penninx, B Blough, D Artz, M Guralnik, J Wallace, R Buchner, D LaCroix, A AF Gray, SL Penninx, B Blough, D Artz, M Guralnik, J Wallace, R Buchner, D LaCroix, A TI Benzodiazepine use and physical performance in community dwelling older women. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Univ Washington, Sch Pharm, Seattle, WA 98195 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. NIA, Epidemiol & Demog Sect, Bethesda, DC USA. Univ Iowa, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. CDC, Phys Act & Hlth Branch, Atlanta, GA 30333 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 APR PY 2003 VL 51 IS 4 SU S MA P452 BP S194 EP S194 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100497 ER PT J AU Hu, P Bretsky, P Crimmins, EM Guralnik, JM Reuben, DB Seeman, TE AF Hu, P Bretsky, P Crimmins, EM Guralnik, JM Reuben, DB Seeman, TE TI The effects of serum beta-carotene levels on decline of cognitive function in high-functioning older persons with or without apolipoprotein E4 alleles. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Univ Calif Los Angeles, Sch Med, Div Geriatr Med, Los Angeles, CA USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ So Calif, Andrus Gerontol Ctr, Los Angeles, CA USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P445 BP S192 EP S192 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100490 ER PT J AU Leveille, SG Fried, LP Guralnik, JM AF Leveille, SG Fried, LP Guralnik, JM TI Pain-related disability among older women: Findings from the Women's Health and Aging Study. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA A27 BP S36 EP S36 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100028 ER PT J AU Lin, EE Galban, C Taub, D Kasper, C Ling, SM AF Lin, EE Galban, C Taub, D Kasper, C Ling, SM TI Muscle IL-1 in a rodent model of papain-induced osteoarthritis of the knee: A mechanism for muscle malfunction? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Johns Hopkins Univ, Baltimore, MD USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P550 BP S228 EP S228 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100595 ER PT J AU Miller, RR Zhang, Y Silliman, RA Kelly-Hayes, M Leveille, S Murabito, J Kiel, DP O'Connor, G Felson, DT AF Miller, RR Zhang, Y Silliman, RA Kelly-Hayes, M Leveille, S Murabito, J Kiel, DP O'Connor, G Felson, DT TI Impact of medical conditions upon functional recovery in elders. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Boston Med Ctr, Geriatr Sect, Boston, MA USA. Boston Med Ctr, Clin Epidemiol Unit, Boston, MA USA. Harvard Univ, Sch Med, Div Aging, Boston, MA 02115 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA A26 BP S36 EP S36 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100027 ER PT J AU Perera, S Studenski, S Guralnik, JM AF Perera, S Studenski, S Guralnik, JM TI Effect of transient and persistent functional decline on survival in community-dwelling elders. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Univ Kansas, Med Ctr, Ctr Aging, Kansas City, KS 66103 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RI Perera, Subashan/D-7603-2014 NR 0 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2003 VL 51 IS 4 SU S MA P490 BP S207 EP S207 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100535 ER PT J AU Williamson, JD AF Williamson, JD TI The Ginkgo Evaluation of Memory Study (GEMS): Design, baseline and 1-year follow-up data. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MARYLAND SP American Geriatr Soc C1 Wake Forest Univ, Bowman Gray Sch Med, Roena Kulynych Dementia Res Ctr, Winston Salem, NC 27103 USA. Univ Washington, Seattle, WA 98195 USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2003 VL 51 IS 4 SU S MA P250 BP S127 EP S127 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 667VP UT WOS:000182255100294 ER PT J AU Cogdill, KW AF Cogdill, KW TI Information needs and information seeking in primary care: a study of nurse practitioners SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID NONPHYSICIAN CLINICIAN; MEDICAL INFORMATION; FAMILY PHYSICIANS; QUESTIONS; KNOWLEDGE; PREFERENCES; INTERNISTS; EDUCATION AB Objective: The objective was to understand the information-related behavior of nurse practitioners (NPs), a population of clinicians responsible for an increasing proportion of primary care. Methods: Two phases of data collection addressed seven research questions. The initial phase of data collection was a questionnaire sent to 300 NPs, who were asked to report their experiences of needing information as a result of patient encounters as well as their experiences of seeking information. The second phase of data collection entailed a series of interviews with twenty NPs following their encounters with patients to collect data on instances of information needs and information seeking. Results: NPs most frequently needed information related to drug therapy and diagnosis. NPs with a master's degree were found to perceive information needs more frequently than their colleagues who had not received a master's degree. The information resources NPs used most frequently were consultations with colleagues, drug reference manuals, and textbooks and protocol manuals. NPs were more likely to pursue needs related to drug therapy with a print resource and needs related to diagnosis with a colleague. The generalizability of a need emerged as a negative predictor of information seeking. Conclusions: This study has addressed a number of questions about the information-related behavior of NPs in primary care practices and led to the development of a temporal model of information seeking in these settings. Results of this research underscore the importance of access to information resources in primary care practices. This study's findings also support the development of educational and outreach programs to promote evidence-based decision making among primary care clinicians. C1 Natl Lib Med, Natl Network Lib Med, Natl Network Off, Bethesda, MD 20894 USA. RP Cogdill, KW (reprint author), Natl Lib Med, Natl Network Lib Med, Natl Network Off, Bethesda, MD 20894 USA. OI Cogdill, Keith/0000-0002-9863-1657 NR 30 TC 57 Z9 60 U1 4 U2 14 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD APR PY 2003 VL 91 IS 2 BP 203 EP 215 PG 13 WC Information Science & Library Science SC Information Science & Library Science GA 703KW UT WOS:000184279400011 PM 12883577 ER PT J AU Lindberg, DAB AF Lindberg, DAB TI Frances Humphrey Howard, 1914-2002 - Obituary SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Biographical-Item C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Lindberg, DAB (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD APR PY 2003 VL 91 IS 2 BP 269 EP 269 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 703KW UT WOS:000184279400024 ER PT J AU Ward, BM Weisberg, AS Moss, B AF Ward, BM Weisberg, AS Moss, B TI Mapping and functional analysis of interaction sites within the cytoplasmic domains of the vaccinia virus A33R and A36R envelope proteins SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIN-BASED MOTILITY; TO-CELL SPREAD; EXTRACELLULAR VIRUS; TAIL FORMATION; CONTAINING MICROVILLI; INTRACELLULAR MOVEMENT; F12L PROTEIN; PLAQUE SIZE; GENE; SURFACE AB Incorporation of the vaccinia virus A36R protein into the outer membrane of intracellular enveloped virions (IEV) is dependent on expression of the A33R protein. Possible interactions of the 200-amino-acid cytoplasmic domain of the A36R protein with itself or with the cytoplasmic domain of the A33R, A34R, B5R, or F12L IEV membrane protein was investigated by using the yeast two-hybrid system. A strong interaction was detected only between the cytoplasmic domains of the A36R and A33R proteins. Upon further analyses, the interaction site was mapped to residues 91 to 111 of the A36R protein. To investigate the role of the A36R:A33R interaction during viral infection, five recombinant vaccinia viruses containing B5R-GFP as a marker were constructed. Four had the full-length A36R gene replaced with various-length C-terminal truncations of A36R, of which two contained residues 91 to 111 and two were missing this region. The fifth recombinant virus had an A33R gene with most of the 40-amino-acid cytoplasmic tail deleted. Residues 91 to III of A36R and the cytoplasmic tail of A33R were required for a strong interaction between the two proteins during viral infection and for maximal amounts of A36R protein on IEV. Mutants lacking these regions of A33R or A36R formed IEV that exhibited only short sporadic intracellular movement, displayed no actin tails, and formed small plaques on cell monolayers equivalent to those of an A36R deletion mutant and smaller than those formed by point mutations that specifically abrogate actin tail formation. The A33R interaction site of the A36R protein is highly conserved among orthopoxviruses and may overlap binding sites for cellular proteins needed for microtubular movement and actin tail formation. C1 NIH, Viral Dis Lab, NIAID, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIH, Viral Dis Lab, NIAID, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 49 TC 30 Z9 33 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 APR PY 2003 VL 77 IS 7 BP 4113 EP 4126 DI 10.1128/JVI.77.7.4113-4126.2003 PG 14 WC Virology SC Virology GA 657QM UT WOS:000181677900022 PM 12634370 ER PT J AU Nakamura, H Lu, M Gwack, Y Souvlis, J Zeichner, SL Jung, JU AF Nakamura, H Lu, M Gwack, Y Souvlis, J Zeichner, SL Jung, JU TI Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator SO JOURNAL OF VIROLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; SITE-SPECIFIC RECOMBINATION; INTERFERON REGULATORY FACTOR; POLYADENYLATED NUCLEAR-RNA; LYMPHOMA CELL-LINE; HERPESVIRUS HUMAN-HERPESVIRUS-8 GENOME; LYTIC SWITCH PROTEIN; DNA-SEQUENCES; 2-MU CIRCLE; TRANSCRIPTIONAL ACTIVATION AB An important step in the herpesvirus life cycle is the switch from latency to lytic reactivation. In order to study the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), we developed a gene expression system in KSHV-infected primary effusion lymphoma cells. This system uses Flp-mediated efficient recombination and tetracycline-inducible expression. The Rta transcriptional activator, which acts as a molecular switch for lytic reactivation of KSHV, was efficiently integrated downstream of the Flp recombination target site, and its expression was tightly controlled by tetracycline. Like stimulation with tetradecanoyl phorbol acetate (TPA), the ectopic expression of Rta efficiently induced a complete cycle of viral replication, including a well-ordered program of KSHV gene expression and production of infectious viral progeny. A striking feature of Rta-mediated lytic gene expression was that Rta induced KSHV gene expression in a more powerful and efficient manner than TPA stimulation, indicating that Rta plays a central, leading role in KSHV lytic gene expression. Thus, our streamlined gene expression system provides a novel means not only to study the effects of viral gene products on overall KSHV gene expression and replication, but also to understand the natural viral reactivation process. C1 Harvard Univ, Sch Med, NERPRC, Div Tumor Virol,Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Jung, JU (reprint author), Harvard Univ, Sch Med, NERPRC, Div Tumor Virol,Dept Microbiol & Mol Genet, 1 Pine Hill Dr, Southborough, MA 01772 USA. EM zeichner@nih.gov; jae_jung@hms.harvard.edu FU NCI NIH HHS [CA82057, CA86841, CA91819, R01 CA082057, R01 CA091819]; NCRR NIH HHS [K26 RR000168, P51 RR000168, RR00168]; NIAID NIH HHS [AI38131] NR 96 TC 158 Z9 163 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 APR PY 2003 VL 77 IS 7 BP 4205 EP 4220 DI 10.1128/JVI.77.7.4205-4220.2003 PG 16 WC Virology SC Virology GA 657QM UT WOS:000181677900030 PM 12634378 ER PT J AU Cho, Y Basta, S Chen, WS Bennink, JR Yewdell, JW AF Cho, Y Basta, S Chen, WS Bennink, JR Yewdell, JW TI Heat-aggregated noninfectious influenza virus induces a more balanced CD8(+)-T-lymphocyte immunodominance hierarchy than infectious virus SO JOURNAL OF VIROLOGY LA English DT Article ID MHC CLASS-I; HISTOCOMPATIBILITY COMPLEX-MOLECULES; EXOGENOUS SOLUBLE-ANTIGEN; TOXIC LYMPHOCYTES-T; DENDRITIC CELLS; SURFACE-ANTIGEN; PEPTIDE; RESPONSES; EPITOPE; ROLES AB CD8(+)-T-cell (TCD8+) responses to infectious viruses are characterized by an immunodominance hierarchy in which the majority of TCD8+ respond to one or a few immunodominant determinants, with a minority of TCD8+ responding to a number of subdominant determinants. It is now well established that exogenous antigens are capable of inducing TCD8+ to such immunodominant determinants, but the diversity of the response and the nature of the immunodominance hierarchy have not been examined. We addressed this issue by characterizing TCD8+ responses to influenza virus preparations rendered inert by incubation for 10 min at 100degreesC, as first reported by Speidel et al. (Eur. J. Immunol. 27:2391-2399, 1997). Extending these findings, we show that the primary TCD8+ response to boiled virus can be sufficiently robust to be detected ex vivo by intracellular cytokine staining and that the response encompasses many of the peptides recognized by TCD8+ induced by infectious virus. Importantly, the immunodominance hierarchy elicited was leveled, and we were unable to detect TCD8+ that were specific for boiled virus. We used peritoneal exudate cells as antigen-presenting cells in vitro, and a number of observations indicated that boiled virus is processed via a phagocytic route that is likely to be endosomal in nature. These findings suggest that the repertoires of immunogenic peptides generated by endosomes and cytosolic processes overlap to a surprising degree. Furthermore, they demonstrate that the form of antigen administered can influence immunodominance hierarchies and that exogenous-antigen vaccines can induce broad and balanced TCD8+ responses. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Rm 211,Bldg 4,4 Ctr Dr,MSC 0440, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Chen, Weisan/E-7828-2012 NR 40 TC 16 Z9 18 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2003 VL 77 IS 8 BP 4679 EP 4684 DI 10.1128/JVI.77.8.4679-4684.2003 PG 6 WC Virology SC Virology GA 662VU UT WOS:000181970200021 PM 12663774 ER PT J AU Nascimbeni, M Mizukoshi, E Bosmann, M Major, ME Mihalik, K Rice, CM Feinstone, SM Rehermann, B AF Nascimbeni, M Mizukoshi, E Bosmann, M Major, ME Mihalik, K Rice, CM Feinstone, SM Rehermann, B TI Kinetics of CD4(+) and CD8(+) memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees SO JOURNAL OF VIROLOGY LA English DT Article ID EX-VIVO ANALYSIS; B VIRUS; IMMUNE-RESPONSE; IN-VIVO; IMMUNOLOGICAL SIGNIFICANCE; CIRCULATING LYMPHOCYTES; PROTECTIVE IMMUNITY; VIRAL CLEARANCE; CTL RESPONSES; HUMAN LIVER AB The immunological correlates of hepatitis C virus (HCV)-specific immunity are not well understood. Antibodies to HCV structural proteins do not appear to play a key role in clearance of the virus and do not persist after recovery. Here, we studied the kinetics of the cellular immune responses of three HCV-recovered chimpanzees during rechallenge with increasing doses of homologous HCV. Although HCV envelope antibodies remained undetectable throughout the rechallenge, all animals mounted rapid HCV-specific T-cell responses. The pattern of the cellular immune response in blood and liver correlated with the virological outcome. The animal that most rapidly cleared circulating HCV as determined by nested reverse transcription-PCR (RT-PCR) displayed the most vigorous and sustained response of gamma interferon (IFN-gamma)-producing and proliferating CD4(+) T cells in the blood. Vigorous CD4(+) T-cell proliferation during viremia was followed by an increased frequency and a phenotypic and functional change of the tetramer(+) CD8(+) T-cell population. The second animal cleared HCV initially with strong peripheral and intrahepatic CD4(+) T-cell responses but experienced low-level HCV recrudescence 12 weeks later, when HCV-specific T cells became undetectable. The third animal maintained minute amounts of circulating HCV, detectable only by nested RT-PCR, in the face of a weak IFN-gamma(+) T-cell response. Collectively, the results suggest protective rather than sterilizing immunity after recovery from hepatitis C. The rate of HCV clearance following reexposure depends on the cellular immune response, the quality and quantity of which may vary among chimpanzees that recovered from HCV infection. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Res, Bethesda, MD 20892 USA. Rockefeller Univ, Ctr Study Hepatitis C, New York, NY 10021 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Room 9B16, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA85883-01, R01 CA085883] NR 65 TC 139 Z9 141 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2003 VL 77 IS 8 BP 4781 EP 4793 DI 10.1128/JVI.77.8.4781-4793.2003 PG 13 WC Virology SC Virology GA 662VU UT WOS:000181970200032 PM 12663785 ER PT J AU Hu, JJ Switzer, WM Foley, BT Robertson, DL Goeken, RA Korber, BT Hirsch, VM Beer, BE AF Hu, JJ Switzer, WM Foley, BT Robertson, DL Goeken, RA Korber, BT Hirsch, VM Beer, BE TI Characterization and comparison of recombinant simian immunodeficiency virus from drill (Mandrillus leucophaeus) and mandrill (Mandrillus sphinx) isolates SO JOURNAL OF VIROLOGY LA English DT Article ID AFRICAN-GREEN MONKEYS; WILD-CAPTURED CHIMPANZEE; CROSS-SPECIES TRANSMISSION; RED-CAPPED MANGABEY; PRIMATE LENTIVIRUS; NATURAL INFECTION; HIGHLY DIVERGENT; MOLECULAR CHARACTERIZATION; SEROEPIDEMIOLOGIC SURVEY; CERCOPITHECUS-LHOESTI AB Since simian immunodeficiency virus (SIV) was found to be the source of the human AIDS pandemic, a major goal has been to characterize the diversity of SIV strains in the wild and to assess their potential for crossover into humans. In the present study, SIV was isolated from a seropositive drill (Mandrillus leucophaeus) and three seropositive mandrills (Mandrillus sphinx) by using macaque peripheral blood mononuclear cells (PBMC). Full-length sequences were obtained from a drill and mandrill and designated SIVdrl1FAO and SIVmnd5440, respectively. A 182-bp fragment of the pol genes of the two remaining mandrill SIV isolates was also analyzed. Phylogenetic analyses demonstrated that SIVdrl1FAO formed a monophyletic clade with SIVmnd5440 and SIVmndM14, recently designated SIVmnd type 2. Both the SIVdrl and SIVmnd type 2 genomes carried a vpx gene and appeared to share a common ancestor with SIVrcm in the 5' region of the genome and with SIVmndGB1 (type 1) in the 3' region of the genome. A statistically significant recombination breakpoint was detected at the beginning of envelope, suggesting that the viruses were descendents of the same recombinant. Phylogenetic analysis of vpx and vpr genes demonstrated that the vpx genes formed a monophyletic cluster that grouped with vpr from SIVagm. In addition, both SIVdrl1FAO and SIVmnd5440 replicated in human PBMC and therefore could pose a risk of transmission to the human population. C1 NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, HIV & Retrovirol Branch, Div AIDS STD & TB Lab Res, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. Los Alamos Natl Lab, Grp T10, Los Alamos, NM 87545 USA. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. RP Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. OI Foley, Brian/0000-0002-1086-0296; Korber, Bette/0000-0002-2026-5757 NR 56 TC 45 Z9 45 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2003 VL 77 IS 8 BP 4867 EP 4880 DI 10.1128/JVI.77.8.4867-4880.2003 PG 14 WC Virology SC Virology GA 662VU UT WOS:000181970200040 PM 12663793 ER PT J AU Wolff, L Koller, R Hu, XR Anver, MR AF Wolff, L Koller, R Hu, XR Anver, MR TI A Moloney murine leukemia virus-based retrovirus with 4070A long terminal repeat sequences induces a high incidence of myeloid as well as lymphoid neoplasms SO JOURNAL OF VIROLOGY LA English DT Article ID MYC TRANSGENIC MICE; MOLECULAR-CLONING; 3' END; C-MYB; INTEGRATION; FRIEND; REGIONS; TUMORS; LOCUS; LYMPHOMAGENESIS AB Retroviruses can be used to accelerate hematopoietic cancers predisposed to neoplastic disease by prior genetic manipulations such as in transgenic or knockout mice. The virus imparts a second neoplastic "hit," providing evidence that the initial hit is transforming. In the present study, a unique retrovirus was developed that can induce a high incidence of myeloid disease and has a broad host range. This agent is a Moloney murine leukemia virus (Mo-MuLV)-based virus that has most of the U3 region of the long terminal repeat (LTR) replaced with that of retrovirus 4070A. Like Mo-MuLV, this virus, called MOL4070LTR, is NB-tropic and not restricted by Fv1 allelles. MOL4070LTR causes myeloid leukemias in ca. 50% of mice, a finding in contrast to Mo-MuLV, which induces almost exclusively lymphoid disease. The data suggest that the LTR of the 4070A virus expands the tissue tropism of the disease to the myeloid lineage. Interesting, MCF recombinant envelope was expressed in the lymphoid but not the myeloid neoplasms of BALB/c mice. This retrovirus has the potential for accelerating myeloid disease in genetically engineered mice. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Rm 4124,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-12400] NR 33 TC 34 Z9 34 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2003 VL 77 IS 8 BP 4965 EP 4971 DI 10.1128/JVI.77.8.4965-4971.2003 PG 7 WC Virology SC Virology GA 662VU UT WOS:000181970200049 PM 12663802 ER PT J AU Meissner, HI Rimer, BK Davis, WW Eisner, EJ Siegler, IC AF Meissner, HI Rimer, BK Davis, WW Eisner, EJ Siegler, IC TI Another round in the mammography controversy SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID BREAST-CANCER; SCREENING MAMMOGRAPHY; DECISION-MAKING; CONSEQUENCES; GUIDELINES; ADOPTION; DEBATE AB Purpose: The October 2001 publication of a meta-analysis questioning the scientific basis for recommending screening mammography sparked yet a new flame of controversy about this issue. We conducted a national survey in March 2002 to provide information about women's perspectives on the issues, including the evidence regarding the efficacy of mammography and, ultimately, their intentions to continue screening. Methods: We added 12 questions to a national telephone omnibus survey in March 2002 to assess women's reactions to the ongoing debate. Responses were collected over three waves of the twice-weekly survey to obtain data from 733 women between the ages of 40 and 69. The sample was weighted to the U.S. population for census region, age, race, ethnicity, and educational attainment. Results: Consistent with prior studies, most women were getting regular mammograms (78%) (95% confidence interval [CI] 75%-81%), >90% believed that mammography is effective in detecting breast cancer (95%) (95% CI 93%-97%) and in reducing breast cancer mortality (93%) (95% CI 91%-96%), and only about 22% (95% CI 19%-25%) said they were confused. Logistic regression analyses revealed sociodemographic differences among women who had heard about the controversy and who reported some confusion about mammograms. Women with lower levels of education, younger women, and those residing in nonmetropolitan areas were significantly less likely to be aware of the controversy. Although a majority of women said they were not confused about mammography, minority women and women with lower education levels were more likely to report being confused. There were no significant demographic differences in intentions to get future mammograms. Women who were concerned about getting breast cancer were much more likely to be planning to have future mammograms than women who were not at all concerned (odds ratio [OR] 3.63; 95% CI 2.37, 5.56). Likewise, respondents who said that they had enough information to make decisions whether to get future mammograms were much more likely to plan on getting screened than women who said they did not have enough information (OR 2.47; 95% CI 1.14, 5.40). Conclusions: These results do not suggest that controversy leads to lower rates of adherence. They do indicate that some women lack the information needed to make informed decisions about mammography. C1 NCI, Appl Canc Screening Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Off Commun, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. RP Meissner, HI (reprint author), NCI, Appl Canc Screening Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Suite 4102,6130 Execut Blvd, Bethesda, MD 20892 USA. FU NCI NIH HHS [P01CA72099] NR 35 TC 21 Z9 21 U1 1 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD APR PY 2003 VL 12 IS 3 BP 261 EP 276 DI 10.1089/154099903321667609 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 679CR UT WOS:000182903700008 PM 12804357 ER PT J AU Lim, MK Suh, CH Kim, HJ Kim, ST Lee, JS Kang, MH Kim, JH Lee, JH AF Lim, MK Suh, CH Kim, HJ Kim, ST Lee, JS Kang, MH Kim, JH Lee, JH TI Fire-related post-traumatic stress disorder: Brain H-1-MR spetroscopic findings SO KOREAN JOURNAL OF RADIOLOGY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; HIPPOCAMPAL VOLUME; N-ACETYLASPARTATE; MR SPECTROSCOPY; ABNORMALITIES; METABOLITE; PTSD AB Objective: To investigate the MR imaging and H-1-MR spectroscopic findings of acute fire-related post-traumatic stress disorder (PTSD). Materials and Methods: Sixteen patients (M:F=10:6; mean age, 16 years) with fire-related PTSD underwent MR imaging and H-1-MR spectroscopy, and for 2 control purposes, the procedures were repeated in eight age-matched normal volunteers. In all patients and controls, the regions of interest where data were acquired at MRS were the basal ganglia (BG), frontal periventricular white matter (FWM), and parietal periventricular white matter (PWM). Results: In all patients with PTSD, MR images appeared normal. In contrast, MRS showed that in the BG, NAA/Cr ratios were significantly lower in patients than in volunteers. This decrease did not, however, show close correlation with the severity of the neuropsychiatric symptoms. In patients, neither NAA/Cr ratios in FWM nor PWM, nor Cho/Cr ratios in all three regions, were significantly different from those in the control group. Conclusion: Decreased NAA/Cr ratios in the BG, as seen at H-1-MRS, might be an early sign of acute fire-related PTSD. C1 Inha Univ Hosp, Coll Med, Dept Psychiat, Inchon 400103, South Korea. Inha Univ Hosp, Coll Med, Dept Radiol, Inchon 400103, South Korea. Gachon Med Sch, Dept Radiol, Inchon, South Korea. NINDS, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), Inha Univ Hosp, Coll Med, Dept Psychiat, 7-206 3rd St,Shinheung Dong, Inchon 400103, South Korea. NR 22 TC 10 Z9 10 U1 1 U2 1 PU KOREAN RADIOLOGICAL SOC PI SEOUL PA 121-8 YANGJAE-DONG, SEOCHO-GU, SEOUL 137-130, SOUTH KOREA SN 1229-6929 J9 KOREAN J RADIOL JI Korean J. Radiol. PD APR-JUN PY 2003 VL 4 IS 2 BP 79 EP 84 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 699FJ UT WOS:000184045800002 PM 12845302 ER PT J AU Hardy, J Cookson, MR Singleton, A AF Hardy, J Cookson, MR Singleton, A TI Genes and parkinsonism SO LANCET NEUROLOGY LA English DT Review ID ALPHA-SYNUCLEIN AGGREGATION; UBIQUITIN-PROTEIN LIGASE; EARLY-ONSET PARKINSONISM; HYDROLASE L1 GENE; NEURODEGENERATIVE DISEASE; SUBSTANTIA-NIGRA; PARK6-LINKED PARKINSONISM; JUVENILE PARKINSONISM; FAMILIAL AGGREGATION; PATHOGENIC MUTATIONS AB Genetic studies in families with mendelian inheritance of Parkinson's disease (PD) have reported the cloning of several disease-associated genes. These studies of rare familial forms of the disease have cast doubt on our understanding of the role of genetics in typical PD and have complicated the classification of the disorder. However, this genetic information might help us to construct a hypothesis for the pathogenetic processes that underlie PD. In this review we describe the molecular genetics of PD as currently understood to help explain the pathways that underlie neurodegeneration. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Cookson@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 NR 102 TC 77 Z9 81 U1 0 U2 6 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD APR PY 2003 VL 2 IS 4 BP 221 EP 228 DI 10.1016/S1474-4422(03)00350-8 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 658NH UT WOS:000181726700017 PM 12849210 ER PT J AU Westergaard, GC Chavanne, TJ Lussier, ID Houser, L Cleveland, A Suomi, SJ Higley, JD AF Westergaard, GC Chavanne, TJ Lussier, ID Houser, L Cleveland, A Suomi, SJ Higley, JD TI Left-handedness is correlated with CSF monoamine metabolite and plasma cortisol concentrations, and with impaired sociality, in free-ranging adult male rhesus macaques (Macaca mulatta) SO LATERALITY LA English DT Article ID CEREBROSPINAL-FLUID MONOAMINE; HAND PREFERENCE; 5-HYDROXYINDOLEACETIC ACID; AMINE METABOLITES; NONHUMAN-PRIMATES; VIOLENT OFFENDERS; FIRE SETTERS; INTERINDIVIDUAL DIFFERENCES; CEREBRAL LATERALIZATION; BIOLOGICAL MECHANISMS AB In this research we examined biological and behavioural correlates of handedness in free-ranging adult male rhesus macaques (Macaca mulatta). Specifically, we examined relationships between handedness and cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma concentrations of the hormones cortisol and adrenocorticotropin (ACTH), and multiple indices of social behaviour, including occurrences of proximity to other animals, grooming, submission, and aggression. We determined handedness through systematic observation of animals reaching for food in their unrestricted home environment. The frequency of right- versus left-hand use was significantly positively correlated with CSF 5-HIAA, CSF MHPG, and plasma cortisol concentrations, and with social proximity and the frequency and duration of bouts in which animals received grooming. The frequency of right- versus left-hand use was significantly negatively correlated with the frequency of submissive behaviour, and with the frequency and intensity of bouts in which animals received aggression. We conclude that handedness is associated with an array of biological and behavioural processes in free-ranging adult male rhesus macaques and that left-handedness may be used to identify individuals at increased risk for impaired functioning of the serotonin, norepinephrine, and hypothalamic-pituitary-adrenal systems, and for social isolation and susceptibility to violent attack. C1 Labs Virginia Inc, Div Res & Dev, Yemassee, SC 29945 USA. NICHHD, Bethesda, MD 20892 USA. NIAAA, Bethesda, MD USA. RP Westergaard, GC (reprint author), Labs Virginia Inc, Div Res & Dev, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. NR 64 TC 21 Z9 21 U1 1 U2 6 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1357-650X J9 LATERALITY JI Laterality PD APR PY 2003 VL 8 IS 2 BP 169 EP 187 DI 10.1080/13576500244000148 PG 19 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA 675EB UT WOS:000182679100005 PM 15513221 ER PT J AU Lamb, ME Garretson, ME AF Lamb, ME Garretson, ME TI The effects of interviewer gender and child gender on the informativeness of alleged child sexual abuse victims in forensic interviews SO LAW AND HUMAN BEHAVIOR LA English DT Article DE forensic interview; gender; interview protocol ID INVESTIGATIVE UTTERANCE TYPES; FACIAL EXPRESSION; EYEWITNESS TESTIMONY; QUESTION TYPE; COMMUNICATION; RESPONSES; SUGGESTIBILITY; CONTRADICTIONS; WITNESSES; STRESSFUL AB Most students of forensic interviews have focused on the interrogatory techniques used to elicit information from alleged child abuse victims. We asked how the gender of the interviewer and the gender of the child affected this process. Forensic investigators in three countries used either the NICHD structured interview protocol or local standard interview practices to interview 672 alleged victims who ranged in age from 4 to 14 years. Analyses of the interviews showed significant effects of gender on both the interviewers' behavior and the amount of information provided by children. Female interviewers asked boys more invitations, as well as absolutely and proportionally more suggestive questions, than they did girls, whereas male interviewers interviewed boys and girls similarly. Children's responses varied depending on their gender and age, the gender of the interviewer, and the type of question asked. Girls of all ages provided more information in response to directive questions posed by female rather than male interviewers whereas boys did not respond differently to male and female interviewers. The oldest girls provided more information in response to option-posing questions posed by male interviewers. More information was provided by the younger children in response to suggestive prompts from interviewers of the opposite gender. The gender-of-interviewer effects were attenuated in protocol-guided interviews. C1 NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, Rockledge 1 Ctr Suite 8048,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 72 TC 21 Z9 22 U1 1 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-7307 J9 LAW HUMAN BEHAV JI Law Hum. Behav. PD APR PY 2003 VL 27 IS 2 BP 157 EP 171 DI 10.1023/A:1022595129689 PG 15 WC Law; Psychology, Social SC Government & Law; Psychology GA 649JP UT WOS:000181204900003 PM 12733419 ER PT J AU Greiner, RS Catalan, JN Moriguchi, T Salem, N AF Greiner, RS Catalan, JN Moriguchi, T Salem, N TI Docosapentaenoic acid does not completely replace DHA in n-3 FA-deficient rats during early development SO LIPIDS LA English DT Article; Proceedings Paper CT 5th Congress of the Interntional-Society-for-the-Study-of-Fatty-Acids-and-Lipids CY MAY 07-11, 2002 CL MONTREAL, CANADA SP Int Soc Study Fatty Acids & Lipids ID ESSENTIAL FATTY-ACIDS; LINOLENIC ACID; DOCOSAHEXAENOIC ACID; BRAIN LIPIDS; ALPHA; DESATURATION; MEMBRANES; GROWTH AB The reciprocal replacement of DHA by docosapentaenoic acid (DPAn-6) was studied in rats that consumed an n-3 FA-deficient or n-3 FA-adequate diet. Dams were fed the two experimental diets from weaning and throughout pregnancy and lactation. Their pups were then fed the respective diets after weaning. Cortex FA analysis was performed at various times (0, 5, 10, 20, 50, and 91 d) after birth to determine whether DPAn-6 completely replaced DHA in the n-3-deficient group. Cortical DHA levels were significantly lower (average 86%) in the n-3-deficient rats. DPAn-6 increased significantly in the n-3-deficient rats starting with a 6.5-fold increase at day 0 up to a 54-fold increase at day 91 compared with the n-3-adequate group. However, this significant increase did not completely replace the loss of DHA at postnatal days 5, 10, and 20 in which there was still an 11.5, 10.3, and 8.0% deficit in the sum of DHA and DPAn-6, respectively, in the n-3-deficient group. Once docosatetraenoic (DTA) and arachidonic acids (AA) were included in the sum (DHA + DPAn-6 + DTA + AA), the levels between the two groups were similar. These results suggest that not only DPAn-6 but also other n-6 FA, including DTA and AA, replace DHA in n-3-deficient rats. The lack of total 22-carbon (22C) FA in the brain during the rapid membrane biogenesis that occurs during early development could be a factor in the nervous system functional deficits associated with n-3 FA deficiency. C1 NIAAA, Lab Mem Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Salem, N (reprint author), 12420 Parklawn Dr,Room 1-14, Rockville, MD 20852 USA. NR 26 TC 54 Z9 55 U1 0 U2 4 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD APR PY 2003 VL 38 IS 4 BP 431 EP 435 DI 10.1007/s11745-003-1080-2 PG 5 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 690YE UT WOS:000183577400018 PM 12848290 ER PT J AU Mitchell, DC Niu, SL Litman, BJ AF Mitchell, DC Niu, SL Litman, BJ TI Enhancement of G protein-coupled signaling by DHA phospholipids SO LIPIDS LA English DT Article; Proceedings Paper CT 5th Congress of the Interntional-Society-for-the-Study-of-Fatty-Acids-and-Lipids CY MAY 07-11, 2002 CL MONTREAL, CANADA SP Int Soc Study Fatty Acids & Lipids ID CHAIN PHOSPHATIDYLCHOLINE VESICLES; POLYUNSATURATED FATTY-ACIDS; HIGHER-ORDER ANALYSIS; ROD OUTER SEGMENT; CYTOPLASMIC LOOP; ANISOTROPY DECAY; METARHODOPSIN-II; MOLECULAR ORDER; RHESUS-MONKEYS; LEARNING-TASKS AB The effect of phospholipid acyl chain and cholesterol composition on G protein-coupled signaling was studied in native rod outer segment (ROS) disk and reconstituted membranes by measuring several steps in the visual transduction pathway. The cholesterol content of disk membranes was varied from 4 to 38 mol% cholesterol with methyl-beta-cyclodextrin. The visual signal transduction system [rhodopsin, G protein (G(t)), and phosphodiesterase (PDE)] was reconstituted with membranes containing various levels of phospholipid acyl chain unsaturation, with and without cholesterol. ROS membranes from rats raised on n-3 fatty acid-deficient and -adequate diets were also studied. The ability of rhodopsin to form the active metarhodopsin II conformation and bind G(t) was diminished by a reduction in the level of DHA (22:6n-3) acyl chains or an increase in membrane cholesterol. DHA acyl chain containing phospholipids minimized the inhibitory effects of cholesterol on the rate of rhodopsin-G(t) coupling. The activity of PDE, which is a measure of the integrated signal response, was reduced in membranes lacking or deficient in DHA acyl chains. PDE activity in membranes containing docosapentaenoic acid (DPA, 22:5n-6) acyl chains, which replace DHA in n-3 fatty acid deficiency, was 50% lower than in DHA-containing membranes. Our results indicate that efficient and rapid propagation of G protein-coupled signaling is optimized by DHA phospholipid acyl chains. C1 NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Pk Bldg,Room 158, MSC 8115,12420 Parklawn Dr, Bethesda, MD 20892 USA. EM litman@helix.nih.gov NR 48 TC 63 Z9 65 U1 1 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD APR PY 2003 VL 38 IS 4 BP 437 EP 443 DI 10.1007/s11745-003-1081-1 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 690YE UT WOS:000183577400019 PM 12848291 ER PT J AU Gawrisch, K Eldho, NV Holte, LL AF Gawrisch, K Eldho, NV Holte, LL TI The structure of DHA in phospholipid membranes SO LIPIDS LA English DT Article; Proceedings Paper CT 5th Congress of the Interntional-Society-for-the-Study-of-Fatty-Acids-and-Lipids CY MAY 07-11, 2002 CL MONTREAL, CANADA SP Int Soc Study Fatty Acids & Lipids ID MOLECULAR-DYNAMICS SIMULATIONS; DIUNSATURATED ACYL CHAIN; DOCOSAHEXAENOIC ACID; ARACHIDONIC-ACID; LIPID BILAYER; FATTY-ACIDS; H-2 NMR; CONFORMATIONAL-ANALYSIS; MODEL DIACYLGLYCEROLS; PHYSICAL-PROPERTIES AB Early experiments and molecular simulations of PUFA favored a rigid arrangement of double bonds in U-shaped or extended conformations such as angle-iron or helical. Although results of recent solid-state NMR measurements and molecular simulations have confirmed the existence of these structural motifs, they portray an image of DHA (22:6n-3) as a highly flexible molecule with rapid transitions between large numbers of conformers on the time scale from picoseconds to hundreds of nanoseconds. The low barriers to torsional rotation about C-C bonds that link the cis-locked double bonds with the methylene carbons between them are responsible for this unusual flexibility. Both the amplitude and frequency of motion increase toward the terminal methyl group of DHA. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Rm 150, Rockville, MD 20852 USA. NR 49 TC 53 Z9 56 U1 1 U2 15 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD APR PY 2003 VL 38 IS 4 BP 445 EP 452 DI 10.1007/s11745-003-1082-0 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 690YE UT WOS:000183577400020 PM 12848292 ER PT J AU Kim, HY Akbar, M Lau, A AF Kim, HY Akbar, M Lau, A TI Effects of docosapentaenoic acid on neuronal apoptosis SO LIPIDS LA English DT Article; Proceedings Paper CT 5th Congress of the Interntional-Society-for-the-Study-of-Fatty-Acids-and-Lipids CY MAY 07-11, 2002 CL MONTREAL, CANADA SP Int Soc Study Fatty Acids & Lipids ID POLYUNSATURATED FATTY-ACIDS; DOCOSAHEXAENOIC ACID; GLIOMA-CELLS; RAT-BRAIN; PHOSPHATIDYLSERINE; ACCUMULATION; DEFICIENCY AB We previously established that n-3 FA status in membrane phospholipids influences the biosynthesis and accumulation of PS in neuronal tissues. We also demonstrated that neuronal apoptosis under adverse conditions is prevented by DHA enrichment in a PS-dependent manner. In this study, we examined the effect of a structural analog of DHA, docosapentaenoic acid (22:5n-6, DPA), which accumulates in neuronal membranes during n-3 FA deficiency. We observed that enrichment of neuronal cells with DPA increased the total PS content in comparison to nonenriched control. However, the increase was significantly less than that observed in DHA-enriched cells, primarily due to the fact that the 18:0,22:5n-6 species was not accumulated as effectively as 18:0,22:6n-3 in PS. As was the case with DHA, DPA enrichment also protected against cell death induced by staurosporine treatment in Neuro 2A cells, but to a lesser extent. These data indicate that provision of DPA in place of DHA is sufficient neither for fully supporting PS accumulation nor for cell survival. The in vitro interaction between Raf-1 and membrane was affected not only by the PS content but also by the fatty acyl composition in PS. The reduction of PS concentration as well as the substitution of 18:0,22:6 with 16:0,18:1 in the liposome considerably reduced the interaction with Raf-1. These data suggest that depletion of DHA from neuronal tissues may have a compounding effect on Raf-1 translocation in growth factor signaling. The fact that DPA cannot fully support the protective role played by DHA may provide a basis for the adverse effect of n-3 FA deficiency on neuronal development and function. C1 NIAAA, Sect Mass Spectrometry, LMBB, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, LMBB, NIH, 12420 Parklawn Dr,Rm 158, Rockville, MD 20852 USA. NR 23 TC 26 Z9 27 U1 1 U2 6 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD APR PY 2003 VL 38 IS 4 BP 453 EP 457 DI 10.1007/s11745-003-1083-z PG 5 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 690YE UT WOS:000183577400021 PM 12848293 ER PT J AU Son, NH Joyce, B Hieatt, A Chrest, FJ Yanovski, J Weng, NP AF Son, NH Joyce, B Hieatt, A Chrest, FJ Yanovski, J Weng, NP TI Stable telomere length and telomerase expression from naive to memory B-lymphocyte differentiation SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article; Proceedings Paper CT 3rd Conference on Immunology and Ageing in Europe CY APR, 2002 CL PALERMO, ITALY DE telomere; telomerase; naive and memory B cells; aging AB Telomere length and telomerase activity play important roles in regulating replicative lifespan of cells. The length of telomeres also serves as a marker for the replicative history and for the remaining replicative potential of cells. Differential telomere length has been reported in human naive and memory T cells but not in naive versus memory B-lymphocytes. We report here an analysis of telomere length and induced telomerase expression in naive (CD27(-)) and memory (CD27(+)) B cells from normal adults. Although both naive and memory B cells lose telomere repeats with age, there is no consistent difference in telomere length between these two B cell subsets. Furthermore, both naive and memory B cells are capable of inducing telomerase activity at similar levels after in vitro stimulation independent of donor's age. Finally, there is a slow increase of memory B cells in peripheral blood with age. Together, these findings suggest that B cells are capable of maintaining telomere length during differentiation from naive to memory B cells and this ability is maintained through age. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. NIA, Flowcytometry Unit, Res Resource Branch, NIH, Baltimore, MD USA. NICHD, DEB, UGO, NIH, Bethesda, MD USA. RP Weng, NP (reprint author), NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. OI Yanovski, Jack/0000-0001-8542-1637 NR 20 TC 24 Z9 25 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD APR PY 2003 VL 124 IS 4 BP 427 EP 432 DI 10.1016/S0047-6374(03)00018-6 PG 6 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 680GJ UT WOS:000182967700010 PM 12714249 ER PT J AU Spoudeas, HA Charmandari, E Brook, CGD AF Spoudeas, HA Charmandari, E Brook, CGD TI Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE HPA axis function; post-irradiation effects; posterior fossa tumours ID GROWTH-HORMONE DEFICIENCY; CHILDRENS CANCER GROUP; LONG-TERM SURVIVORS; BRAIN-TUMORS; CRANIOSPINAL IRRADIATION; ADJUVANT CHEMOTHERAPY; RADIATION-THERAPY; SHORT SYNACTHEN; FOLLOW-UP; RADIOTHERAPY AB Background. The evolution of anterior pituitary deficits after treatment for pituitary tumours has been largely attributed to local irradiation, but may be influenced as much by tumour mass or surgery. Other than growth hormone (GH) insufficiency, the late endocrinopathies after survival from non-central brain tumours have been little documented. The aim of this study was to investigate the hypothalamic-pituitary-adrenal (HPA) axis in long-term survivors of cranial irradiation for childhood posterior fossa tumours. Procedure. We studied long-term data in patients treated prepubertally for posterior fossa brain tumours and systematically referred by radiation oncologists for growth and pubertal monitoring to the London Centre for Paediatric Endocrinology over the last 25 years. They must have undergone HPA axis assessment twice, first prepubertally at documentation of growth failure, and second at completion of growth and puberty. Data on sixteen patients (12 males, 4 females; median age: 5.7 years, range: 2.5-8.8 years), who had undergone excision surgery with high dose cranial irradiation and/or chemotherapy for childhood posterior fossa tumours, were examined. Patients were followed for a median of 11.0 (range: 6.8-21.4) years after radiotherapy. HPA axis assessment was under-taken with the insulin-induced hypoglycaemia test (ITT). Basal thyroid, cortisol and gonadal function tests were undertaken annually throughout the follow-up period and any deficits replaced. Results. At each ITT, all patients mounted an inadequate GH response. By the end of the follow-up period all patients remained severely GH deficient, two (12.5%) had partial ACTH insufficiency, one (6.3%) had secondary hypothyroidism but none were gonadotropin deficient or hyperprolactinaemic. Conclusions. Unlike the severe, evolving multiple pituitary deficits after treatment of pituitary or central tumours in adults, these findings in children with posterior fossa tumours suggest that, with the exception of GH, neurotoxicity due to irradiation per se is associated with a low prevalence of anterior pituitary hormone deficiencies, even at a long follow-up. Since the children in this study were selected for assessment on the basis of growth failure, the high prevalence of GH insufficiency at first testing is to be expected; however, the early onset (within 1-3 years of irradiation) and permanence we have identified supports the view that GH is the most sensitive hormone to radiation injury. C1 UCL, London Ctr Paediat Endocrinol, London, England. RP Charmandari, E (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM charmane@mail.nih.gov RI Charmandari, Evangelia/B-6701-2011 NR 40 TC 36 Z9 38 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD APR PY 2003 VL 40 IS 4 BP 224 EP 229 DI 10.1002/mpo.10267 PG 6 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 646AE UT WOS:000181012000004 PM 12555249 ER PT J AU Cooper, LA Gonzales, JJ Gallo, JJ Rost, KM Meredith, LS Rubenstein, LV Wang, NY Ford, DE AF Cooper, LA Gonzales, JJ Gallo, JJ Rost, KM Meredith, LS Rubenstein, LV Wang, NY Ford, DE TI The acceptability of treatment for depression among African-American, Hispanic, and white primary care patients SO MEDICAL CARE LA English DT Article; Proceedings Paper CT 12th International-National-Institute-of-Mental-Health Conference on Mental Health Problems in the General Health Sector CY JUL 13-14, 1998 CL BALTIMORE, MARYLAND SP Int Natl Inst Mental Hlth DE depression; patient attitudes; ethnic minorities; disparities; African Americans; Hispanics ID MENTAL-HEALTH-CARE; MAJOR DEPRESSION; QUALITY IMPROVEMENT; SERVICE UTILIZATION; MEXICAN-AMERICANS; ATTITUDE-CHANGE; UNITED-STATES; PREFERENCES; DISORDERS; PREVALENCE AB BACKGROUND. Ethnic minority patients are less likely than white patients to receive guideline-concordant care for depression. It is uncertain whether racial and ethnic differences exist in patient beliefs, attitudes, and preferences for treatment. METHODS. A telephone survey was conducted of 829 adult patients (659 non-Hispanic whites, 97 African Americans, 73 Hispanics) recruited from primary care offices across the United States who reported 1 week or more of depressed mood or loss of interest within the past month and who met criteria for Major Depressive Episode in the past year. Within this cohort, we examined differences among African Americans, Hispanics, and whites in acceptability of antidepressant medication and acceptability of individual counseling. RESULTS. African Americans (adjusted OR, 0.30; 95% CI 0.19-0.48) and Hispanics (adjusted OR, 0.44; 95% CI, 0.26-0.76) had lower odds than white persons of finding antidepressant medications acceptable. African Americans had somewhat lower odds (adjusted OR, 0.63; 95% CI, 0.35-1.12), and Hispanics had higher odds (adjusted OR, 3.26; 95% CI, 1.08-9.89) of finding counseling acceptable than white persons. Some negative beliefs regarding treatment were more prevalent among ethnic minorities; however adjustment for these beliefs did not explain differences in acceptability of treatment for depression. CONCLUSIONS. African Americans are less likely than white persons to find antidepressant medication acceptable. Hispanics are less likely to find antidepressant medication acceptable, and more likely to find counseling acceptable than white persons. Racial and ethnic differences in beliefs about treatment modalities were found, but did not explain differences in the acceptability of depression treatment. Clinicians should consider patients' cultural and social context when negotiating treatment decisions for depression. Future research should identify other attitudinal barriers to depression care among ethnic minority patients. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. NIMH, Rockville, MD 20857 USA. Univ Penn, Dept Family Med, Philadelphia, PA 19104 USA. Univ Colorado, Hlth Sci Ctr, Dept Family Med, Denver, CO 80202 USA. RAND Corp, Hlth Program, Santa Monica, CA USA. VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Cooper, LA (reprint author), Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-500, Baltimore, MD 21205 USA. OI Wang, Nae-Yuh/0000-0001-6513-9730 FU NIMH NIH HHS [MH5443, MH5444, MH57992] NR 43 TC 370 Z9 371 U1 4 U2 16 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 APR PY 2003 VL 41 IS 4 BP 479 EP 489 DI 10.1097/00005650-200304000-00004 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 663LE UT WOS:000182006400004 PM 12665712 ER PT J AU Galban, S Fan, JS Martindale, JL Cheadle, C Hoffman, B Woods, MP Temeles, G Brieger, E Decker, J Gorospe, M AF Galban, S Fan, JS Martindale, JL Cheadle, C Hoffman, B Woods, MP Temeles, G Brieger, E Decker, J Gorospe, M TI von Hippel-Lindau protein-mediated repression of tumor necrosis factor alpha translation revealed through use of cDNA arrays SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CARCINOMA CELLS; FACTOR MESSENGER-RNA; SUPPRESSOR GENE-PRODUCT; CYCLIN D1; PROSTAGLANDIN A(2); HUMAN TISSUES; TNF-ALPHA; EXPRESSION; HYPOXIA AB Based on evidence that the von Hippel-Lindau (VHL) tumor suppressor protein is associated with polysomes and interacts with translation regulatory factors, we set out to investigate the potential influence of pVHL on protein translation. To this end, renal cell carcinoma (RCC) cells that either lacked pVHL or expressed pVHL through stable transfection were used to prepare RNA from cytosolic (unbound) and polysome-bound fractions. Hybridization of cDNA arrays using RNA from each fraction revealed a subset of transcripts whose abundance in polysomes decreased when pVHL function was restored. The tumor necrosis factor alpha (TNF-alpha) mRNA was identified as one of the transcripts that preferentially associated with polysomes in pVHL-deficient cells. Additional evidence that the TNF-alpha mRNA was a target of translational repression by pVHL was obtained from reporter gene assays, which further revealed that pVHL's inhibitory influence on protein synthesis occurred through the TNF-alpha-3'-untranslated region. Our findings uncover a novel function for the pVHL tumor suppressor protein as regulator of protein translation. C1 NIA, LCMB, GRC, IRP,NIH, Baltimore, MD 21224 USA. NIA, Intramural Res Program, DNA Array Unit, NIH, Baltimore, MD USA. Message Pharmaceut Inc, Malvern, PA 19355 USA. Univ Mainz, Sch Med, Dept Otorhinolaryngol, D-55101 Mainz, Germany. Biosci Inst, D-55128 Ingelheim, Germany. RP Gorospe, M (reprint author), NIA, LCMB, GRC, IRP,NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov NR 60 TC 60 Z9 61 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 APR PY 2003 VL 23 IS 7 BP 2316 EP 2328 DI 10.1128/MCB.23.7.2316-2328.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 658QJ UT WOS:000181731400009 PM 12640117 ER PT J AU Shack, S Wang, XT Kokkonen, GC Gorospe, M Longo, DL Holbrook, NJ AF Shack, S Wang, XT Kokkonen, GC Gorospe, M Longo, DL Holbrook, NJ TI Caveolin-induced activation of the phosphatidylinositol 3-kinase/Akt pathway increases arsenite cytotoxicity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CISPLATIN-INDUCED APOPTOSIS; GROWTH-FACTOR RECEPTOR; MAP KINASE CASCADE; NEUTRAL SPHINGOMYELINASE; SIGNAL-TRANSDUCTION; SCAFFOLDING DOMAIN; CELLULAR-RESPONSE; OXIDATIVE STRESS; PLASMA-MEMBRANE; CELLS AB The inhibitory effect of caveolin on the cellular response to growth factor stimulation is well established. Given the significant overlap in signaling pathways involved in regulating cell proliferation and stress responsiveness, we hypothesized that caveolin would also affect a cell's ability to respond to environmental stress. Here we investigated the ability of caveolin-1 to modulate the cellular response to sodium arsenite and thereby alter survival of the human cell lines 293 and HeLa. Cells stably transfected with caveolin-1 were found to be much more sensitive to the toxic effects of sodium arsenite than either untransfected parental cells or parental cells transfected with an empty vector. Unexpectedly, the caveolin-overexpressing cells also exhibited a significant activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which additional studies suggested was likely due to decreased neutral sphingomyelinase activity and ceramide synthesis. In contrast to its extensively documented antiapoptotic influence, the elevated activity of Akt appears to be important in sensitizing caveolin-expressing cells to arsenite-induced toxicity, as both pretreatment of cells with the PI3K inhibitor wortmannin and overexpression of a dominant-negative Akt mutant markedly improved the survival of arsenite-treated cells. This death-promoting influence of the PI3K/Akt pathway in caveolin-overexpressing cells appeared not to be unique to sodium arsenite, as wortmannin pretreatment also resulted in increased survival in the presence of H2O2. In summary, our results indicate that caveolin-induced upregulation of the PI3K/Akt signaling pathway, which appears to be a death signal in the presence of arsenite and H2O2, sensitizes cells to environmental stress. C1 Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06511 USA. NIA, Lab Cell & Mol Biol, IRP, NIH, Baltimore, MD 21224 USA. NIA, Immunol Lab, IRP, NIH, Baltimore, MD 21224 USA. Yale Univ, Sch Med, Sect Geriatr, New Haven, CT 06511 USA. RP Holbrook, NJ (reprint author), Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, 300 George St,Room 8100, New Haven, CT 06511 USA. EM Nikki.Holbrook@yale.edu NR 44 TC 64 Z9 67 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 APR PY 2003 VL 23 IS 7 BP 2407 EP 2414 DI 10.1128/MCB.23.7.2407-2414.2003 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 658QJ UT WOS:000181731400016 PM 12640124 ER PT J AU Swanson, MJ Qiu, HF Sumibcay, L Krueger, A Kim, SJ Natarajan, K Yoon, S Hinnebusch, AG AF Swanson, MJ Qiu, HF Sumibcay, L Krueger, A Kim, SJ Natarajan, K Yoon, S Hinnebusch, AG TI A multiplicity of coactivators is required by Gcn4p at individual promoters in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; HISTONE ACETYLTRANSFERASE COMPLEXES; EUKARYOTIC TRANSLATION INITIATION; NUCLEOSOME-REMODELING COMPLEX; AMINO-ACID BIOSYNTHESIS; YEAST SWI/SNF COMPLEX; SACCHAROMYCES-CEREVISIAE; IN-VIVO; GENE-EXPRESSION AB Transcriptional activators interact with multisubunit coactivators that modify chromatin structure or recruit the general transcriptional machinery to their target genes. Budding yeast cells respond to amino acid starvation by inducing an activator of amino acid biosynthetic genes, Gcn4p. We conducted a comprehensive analysis of viable mutants affecting known coactivator subunits from the Saccharomyces Genome Deletion Project for defects in activation by Gcn4p in vivo. The results confirm previous findings that Gcn4p requires SAGA, SWI/SNF, and SRB mediator (SRB/MED) and identify key nonessential subunits of these complexes required for activation. Among the numerous histone acetyltransferases examined, only that present in SAGA, Gcn5p, was required by Gcn4p. We also uncovered a dependence on CCR4-NOT, RSC, and the Pan complex. In vitro binding experiments suggest that the Gcn4p activation domain interacts specifically with CCR4-NOT and RSC in addition to SAGA, SWI/SNF, and SRB/MED. Chromatin immunoprecipitation experiments show that Mbf1p, SAGA, SWI/SNF, SRB/MED, RSC, CCR4-NOT, and the Paf1 complex all are recruited by Gcn4p to one of its target genes (ARG1) in vivo. We observed considerable differences in coactivator requirements among several Gcn4p-dependent promoters; thus, only a subset of the array of coactivators that can be recruited by Gcn4p is required at a given target gene in vivo. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6A-B1A-13, Bethesda, MD 20892 USA. NR 139 TC 101 Z9 104 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2003 VL 23 IS 8 BP 2800 EP 2820 DI 10.1128/MCB.23.8.2800-2820.2003 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 664EZ UT WOS:000182049900015 PM 12665580 ER PT J AU Nie, ZQ Yan, ZJ Chen, EH Sechi, S Ling, C Zhou, SL Xue, YT Yang, DF Murray, D Kanakubo, E Cleary, ML Wang, WD AF Nie, ZQ Yan, ZJ Chen, EH Sechi, S Ling, C Zhou, SL Xue, YT Yang, DF Murray, D Kanakubo, E Cleary, ML Wang, WD TI Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SWI-SNF COMPLEX; TRANSCRIPTIONAL ACTIVATION; NUCLEOSOME; GENES; PROTEIN; BRG1; MLL; FUSION; ENL; PURIFICATION AB The SWI/SNF family of chromatin-remodeling complexes has been discovered in many species and has been shown to regulate gene expression by assisting transcriptional machinery to gain access to their sites in chromatin. Several complexes of this family have been reported for humans. In this study, two additional complexes are described that belong to the same SWI/SNF family. These new complexes contain as many as eight subunits identical to those found in other SWI/SNF complexes, and they possess a similar ATP-dependent nucleosome disruption activity. But unlike known SWI/SNFs, the new complexes are low in abundance and contain an extra subunit conserved between human and yeast SWI/SNF complexes. This subunit, ENL, is a homolog of the yeast SWI/SNF subunit, ANC1/TFG3. Moreover, ENL is a fusion partner for the gene product of MLL that is a common target for chromosomal translocations in human acute leukemia. The resultant MLL-ENL fusion protein associates and cooperates with SWI/SNF complexes to activate transcription of the promoter of HoxA7, a downstream target essential for oncogenic activity of MLL-ENL. Our data suggest that human SWI/SNF complexes show considerable heterogeneity, and one or more may be involved in the etiology of leukemia by cooperating with MLL fusion proteins. C1 NIA, Genet Lab, TRIAD Ctr, NIH, Baltimore, MD 21224 USA. NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. RP Wang, WD (reprint author), NIA, Genet Lab, TRIAD Ctr, NIH, 333 Cassell Dr,Room 4000, Baltimore, MD 21224 USA. NR 48 TC 61 Z9 66 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 APR PY 2003 VL 23 IS 8 BP 2942 EP 2952 DI 10.1128/MCB.23.8.2942-2952.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 664EZ UT WOS:000182049900026 PM 12665591 ER PT J AU Levi, G Puche, AC Mantero, S Barbieri, O Trombino, S Paleari, L Egeo, A Merlo, GR AF Levi, G Puche, AC Mantero, S Barbieri, O Trombino, S Paleari, L Egeo, A Merlo, GR TI The Dlx5 homeodomain gene is essential for olfactory development and connectivity in the mouse SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; MESSENGER-RNA EXPRESSION; EXTRA-TOES XT; MICE LACKING; HOMEOBOX GENES; MUTANT MICE; CALRETININ-IMMUNOREACTIVITY; GABAERGIC INTERNEURONS; TYROSINE-HYDROXYLASE; GLOMERULAR FORMATION AB The distalless-related homeogene Dlx5 is expressed in the olfactory placodes and derived tissues and in the anterior-basal forebrain. We investigated the role of Dlx5 in olfactory development. In Dlx5(-/-) mice, the olfactory bulbs (OBs) lack glomeruli, exhibit disorganized cellular layers, and show reduced numbers of TH- and GAD67-positive neurons. The olfactory epithelium in Dlx5(-/-) mice is composed of olfactory receptor neurons (ORNs) that appear identical to wild-type ORNs, but their axons fail to contact the OBs. We transplanted Dlx5(-/-) OBs into a wild-type newborn mouse; wild-type ORN axons enter the mutant 013 and form glomeruli, but cannot rescue the lamination defect or the expression of TH and GAD67. Thus, the absence of Dlx5 in the OB does not per se prevent ORN axon ingrowth. In conclusion, Dlx5 plays major roles in the connectivity of ORN axons and in the differentiation of OB interneurons. (C) 2003 Elsevier Science (USA). All rights reserved. C1 CNRS, Lab Physiol Gen & Comparee, UMR 8572, Museum Natl Hist Nat, Paris, France. Natl Canc Inst, IST, Lab Mol Morphogenesis, Genoa, Italy. Univ Maryland, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Univ Genoa, Dept Oncol Biol & Genet, IST, Genoa, Italy. DTI, Ctr Biotecnol Avanzate, I-16132 Genoa, Italy. RP Merlo, GR (reprint author), CNR, ITB, Via Fratelli Cervi 93, I-20090 Milan, Italy. RI Barbieri, Ottavia/E-8768-2011; Levi, Giovanni/B-4416-2013; OI Mantero, Stefano/0000-0003-0608-2724 FU Telethon [GP0218Y01, TCP99003] NR 82 TC 51 Z9 54 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD APR PY 2003 VL 22 IS 4 BP 530 EP 543 DI 10.1016/S1044-7431(02)00041-6 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 676YQ UT WOS:000182780500009 PM 12727448 ER PT J AU Angeloni, D Duh, FM Moody, M Dean, M Zabarovsky, ER Sentchenko, V Braga, E Lerman, MI AF Angeloni, D Duh, FM Moody, M Dean, M Zabarovsky, ER Sentchenko, V Braga, E Lerman, MI TI C to A single nucleotide polymorphism in intron 18 of the human MST1R (RON) gene that maps at 3p21.3 SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE alternative splicing; breast cancer; MST1R (RON); Center d'Etude du Polymorphisme Humain (CEPH); single nucleotide polymorphism (SNP); single strand conformation polymorphism (SSCP) ID RECEPTOR TYROSINE KINASE; SPLICING VARIANT; OVEREXPRESSION; CARCINOMA; PROTEIN AB The MST1R (RON) gene, that maps at 3p21.3, encodes a protein tyrosine kinase receptor comprised of an extra-cellular domain that contains the ligand binding pocket and an intracellular region where the kinase domain is located. It controls cell survival and motility programs related to invasive growth. With the single strand conformation polymorphism (SSCP) method, a C to A nucleotide polymorphism (SNP) was found in intron 18 of the gene. The SNP has a frequency of 0.28 among African-American, 0.25 among Caucasian CEPH and 0.09 among Asian healthy individuals. During these studies, an alternatively spliced cDNA of MST1R, lacking exon 19, was also found that may result from this change. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21702 USA. Karolinska Inst, MTC, S-17177 Stockholm, Sweden. Karolinska Inst, CGR, S-17177 Stockholm, Sweden. RP Angeloni, D (reprint author), Scuola Superlore St Anna, Piazza Martiri Liberta,33, I-56100 Pisa, Italy. RI Zabarovsky, Eugene/A-6645-2010; Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU PHS HHS [N01-C0-56000, N01-C0-12400] NR 10 TC 7 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD APR-JUN PY 2003 VL 17 IS 2-3 BP 55 EP 57 DI 10.1016/S0890-8508(02)00115-9 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 692JH UT WOS:000183657600001 PM 12788025 ER PT J AU Puertollano, R van der Wel, NN Greene, LE Eisenberg, E Peters, PJ Bonifacino, JS AF Puertollano, R van der Wel, NN Greene, LE Eisenberg, E Peters, PJ Bonifacino, JS TI Morphology and dynamics of clathrin/GGA1-coated carriers budding from the trans-Golgi network SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTORS; PLASMA-MEMBRANE; LIVING CELLS; GGA PROTEINS; ENDOPLASMIC-RETICULUM; ENDOSOME TRANSPORT; SECRETORY VESICLES; AP-1 COMPLEX; VHS DOMAINS; CLATHRIN AB Sorting of transmembrane proteins and their ligands at various compartments of the endocytic and secretory pathways is mediated by selective incorporation into clathrin-coated intermediates. Previous morphological and biochemical studies have shown that these clathrin-coated intermediates consist of spherical vesicles with a diameter of 60-100 nm. Herein, we report the use of fluorescent imaging of live cells to demonstrate the existence of a different type of transport intermediate containing associated clathrin coats. Clathrin and the adaptors GGA1 and adaptor protein-1, labeled with different spectral variants of the green fluorescent protein, are shown to colocalize to the trans-Golgi network and to a population of vesicles and tubules budding from it. These intermediates are highly pleiomorphic and move toward the peripheral cytoplasm for distanced of up to 10 mum with average speeds of -1 mum/s. The labeled clathrin and GGA1 cycle on and off membranes with half-times of 10-20 s, independently of vesicle budding. Our observations indicate the existence of a novel type of trans-Golgi network-derived carriers containing associated clathrin, GGA1 and adaptor protein-1 that are larger than conventional clathrin-coated vesicles, and that undergo long-range translocation in the cytoplasm before losing their coats. C1 Netherlands Canc Inst, Div Tumor Biol, Amsterdam, Netherlands. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NHLBI, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 43 TC 89 Z9 92 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD APR PY 2003 VL 14 IS 4 BP 1545 EP 1557 DI 10.1091/mbc.02-07-0109 PG 13 WC Cell Biology SC Cell Biology GA 666PG UT WOS:000182185200025 PM 12686608 ER PT J AU Amundson, SA Lee, RA Koch-Paiz, CA Bittner, ML Meltzer, P Trent, JM Fornace, AJ AF Amundson, SA Lee, RA Koch-Paiz, CA Bittner, ML Meltzer, P Trent, JM Fornace, AJ TI Differential responses of stress genes to low dose-rate gamma irradiation SO MOLECULAR CANCER RESEARCH LA English DT Article ID IONIZING-RADIATION; CELL-CYCLE; GENOTOXIC STRESS; CDNA MICROARRAY; RATE DEPENDENCE; MESSENGER-RNA; L5178Y CELLS; DNA-REPAIR; EXPRESSION; INDUCTION AB In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, Div Basic Sci, NIH, Room 5C09,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 35 TC 164 Z9 177 U1 1 U2 3 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 APR PY 2003 VL 1 IS 6 BP 445 EP 452 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 668YU UT WOS:000182325600005 PM 12692264 ER PT J AU Shami, PJ Saavedra, JE Wang, LY Bonifant, CL Diwan, BA Singh, SV Gu, YJ Fox, SD Buzard, GS Citro, ML Waterhouse, DJ Davies, KM Ji, XH Keefer, LK AF Shami, PJ Saavedra, JE Wang, LY Bonifant, CL Diwan, BA Singh, SV Gu, YJ Fox, SD Buzard, GS Citro, ML Waterhouse, DJ Davies, KM Ji, XH Keefer, LK TI JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GLUTATHIONE TRANSFERASE; IN-VITRO; REFINEMENT; APOPTOSIS; COMPLEX; CONJUGATE; SUBSTRATE; MOLECULES; FAMILY; ACID AB We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O-2-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O-2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1 -yl]diazen-1-ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC50 of 0.2-0.5 mum. After 5 days of exposure to 0.5 mum JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5-1 mum resulted in apoptosis induction in a concentration-and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 mumol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by similar to50% when the mice received i.v. injections three times/week with 4 mumol/ kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents. C1 SLC VA Med Ctr, Salt Lake City, UT 84148 USA. Univ Utah, Dept Internal Med, Div Med Oncol, Salt Lake City, UT 84112 USA. Natl Canc Inst Frederick, Sci Applicat Int Corp, Frederick, MD USA. Natl Canc Inst Frederick, Analyt Chem Lab, Frederick, MD USA. Univ Pittsburgh, Inst Canc, Dept Pharmacol, Pittsburgh, PA 15213 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. Natl Canc Inst, Lab Comparat Carcinogenesis, Frederick, MD USA. RP Shami, PJ (reprint author), SLC VA Med Ctr, Box 151M,500 Foothill Blvd, Salt Lake City, UT 84148 USA. RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012; Keefer, Larry/N-3247-2014 OI Ji, Xinhua/0000-0001-6942-1514; Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-12400]; NIEHS NIH HHS [ES09140] NR 30 TC 96 Z9 104 U1 1 U2 10 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 APR PY 2003 VL 2 IS 4 BP 409 EP 417 PG 9 WC Oncology SC Oncology GA 668UT UT WOS:000182312100008 PM 12700285 ER PT J AU Knopp, MV von Tengg-Kobligk, H Choyke, PL AF Knopp, MV von Tengg-Kobligk, H Choyke, PL TI Functional magnetic resonance imaging in oncology for diagnosis and therapy monitoring SO MOLECULAR CANCER THERAPEUTICS LA English DT Review ID CONTRAST-ENHANCED MRI; TUMOR MICROCIRCULATION; RADIATION-THERAPY; CERVICAL-CANCER; DYNAMIC MRI; BREAST; CARCINOMA; AGENTS; ANGIOGENESIS; CHEMOTHERAPY AB Functional magnetic resonance imaging is rapidly evolving as a capable noninvasive assessment tool for oncology to improve diagnosis and to monitor therapy. Current clinical techniques are based on microcirculation imaging using extracellular low molecular weight contrast agents such as gadopentetate dimeglumine and analogues. The temporal evolution of the enhancement visualizes the angiogenic properties of lesions with regard to vascular density and permeability, heterogeneity, and changes during therapy C1 Ohio State Univ, Univ Hosp, Dept Radiol, Columbus, OH 43210 USA. Diagnost Radiol Dept, Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Knopp, MV (reprint author), Ohio State Univ, Univ Hosp, Dept Radiol, 163 Means Hall,1654 Upham Dr, Columbus, OH 43210 USA. EM Knopp-1@medctr.osu.edu RI von Tengg-Kobligk, Hendrik/A-1420-2017 OI von Tengg-Kobligk, Hendrik/0000-0003-3207-3223 NR 38 TC 53 Z9 58 U1 0 U2 4 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 APR PY 2003 VL 2 IS 4 BP 419 EP 426 PG 8 WC Oncology SC Oncology GA 668UT UT WOS:000182312100009 PM 12700286 ER PT J AU Lahusen, T De Siervi, A Kunick, C Senderowicz, AM AF Lahusen, T De Siervi, A Kunick, C Senderowicz, AM TI Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential SO MOLECULAR CARCINOGENESIS LA English DT Article DE paullones; alsterpaullone; flavopiridol; apoptosis; mitochondrial potential; cyclin-dependent kinases; cell cycle; cyclin D3; caspases ID BREAST-CARCINOMA CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHASE-I TRIAL; CYTOCHROME-C; REFRACTORY NEOPLASMS; GROWTH-INHIBITION; ANTICANCER DRUGS; HUMAN CANCER; IAP-FAMILY; DEATH AB The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethyl ketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Preincubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting. Published 2003 Wiley-Liss, Inc.(dagger). C1 Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Hamburg, Inst Farm, Hamburg, Germany. RP Senderowicz, AM (reprint author), Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Room 211,30 Convent Dr, Bethesda, MD 20892 USA. NR 74 TC 48 Z9 50 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD APR PY 2003 VL 36 IS 4 BP 183 EP 194 DI 10.1002/nc.10114 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 664ZA UT WOS:000182094100003 PM 12669310 ER PT J AU Ritchie, JWA Shi, YB Hayashi, Y Baird, FE Muchekehu, RW Christie, GR Taylor, PM AF Ritchie, JWA Shi, YB Hayashi, Y Baird, FE Muchekehu, RW Christie, GR Taylor, PM TI A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID AMINO-ACID-TRANSPORT; XENOPUS OOCYTES; CELLS; IDENTIFICATION; PROTEIN; ACTIVATION; BINDING; GENE; TRIIODOTHYRONINE; IODOTHYRONINE AB Thyroid hormones (THs) must be taken up by target cells to act at the genomic level through binding to nuclear thyroid hormone receptors (TRs). Extensive study has been made of mechanisms by which TH-bound TRs regulate transcription, yet little is known about the critical upstream step, i.e. how THs enter the cell. Growing evidence suggests that saturable transport mechanisms mediate the greater part of TH movement across the plasma membrane and have important roles in the regulation of TH bioavailability. For example, System L is a multifunctional transport system serving as a plasma membrane transporter of THs and amino acids in mammalian cells. We have used two complementary systems, the Xenopus oocyte (which has negligible basal System L activity) and the mammalian BeWo cell line (which has System L activity for TH transport), to investigate the role of this representative TH transporter in nuclear action of THs. We demonstrate that overexpression of System L in Xenopus oocytes increases both cytoplasmic and nuclear delivery of THs from external medium and also enhances transcriptional activation by TRs. Conversely, blocking endogenous System L activity in BeWo cells with specific inhibitors reduces both TH uptake and TR function. These results indicate that plasma membrane TH transporters such as System L may have important roles in gene regulation by TRs. C1 Univ Dundee, Sch Life Sci, Dundee DD1 5EH, Scotland. Univ Dundee, Div Mol Physiol, Dundee DD1 5EH, Scotland. Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Environm Med Res Inst, Nagoya, Aichi 4648601, Japan. RP Taylor, PM (reprint author), Univ Dundee, Sch Life Sci, MSI WTB Complex, Dundee DD1 5EH, Scotland. RI Taylor, Peter/A-4667-2010; Ritchie, James/B-9377-2013; OI Hayashi, Yoshitaka/0000-0002-7557-4303 NR 41 TC 33 Z9 36 U1 0 U2 4 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 APR PY 2003 VL 17 IS 4 BP 653 EP 661 DI 10.1210/me.2002-0179 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 661GC UT WOS:000181882000012 PM 12554788 ER PT J AU Payami, H Nutt, J Gancher, S Bird, T McNeal, MG Seltzer, WK Hussey, J Lockhart, P Gwinn-Hardy, K Singleton, AA Singleton, AB Hardy, J Farrer, M AF Payami, H Nutt, J Gancher, S Bird, T McNeal, MG Seltzer, WK Hussey, J Lockhart, P Gwinn-Hardy, K Singleton, AA Singleton, AB Hardy, J Farrer, M TI SCA2 may present as levodopa-responsive parkinsonism SO MOVEMENT DISORDERS LA English DT Article DE parkinsonism; SCA2 mutation; levodopa ID SPINOCEREBELLAR ATAXIA TYPE-2; DISEASE; EXPANSION AB Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. (less than or equal to31 repeats is normal, 32-35 is borderline, greater than or equal to36 is pathogenic). The expanded allele segregated with neurological signs in one kindred. The absence of borderline mutations in the normal population, and the co-segregation of the expanded allele with neurological signs in one kindred suggest that SCA2 mutations may be responsible for a subset of familial parkinsonism. (C) 2002 Movement Disorder Society. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Kaiser Permanente, Portland, OR USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. Oregon Hlth Sci Univ, Dept Mol Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Med Genet, Portland, OR 97201 USA. Athena Diagnost Inc, Worcester, MA USA. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. NINDS, Neurogenet Lab, Bethesda, MD 20892 USA. Wadsworth Ctr, Albany, NY 12208 USA. RP Payami, H (reprint author), Wadsworth Ctr, 120 New Scotland Ave, Albany, NY 12208 USA. RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lockhart, Paul/E-7753-2011; OI Lockhart, Paul/0000-0003-2531-8413; Gwinn, Katrina/0000-0002-8277-651X FU NCRR NIH HHS [5M01 RR00334]; NIA NIH HHS [AG0817]; NINDS NIH HHS [NS40256, R01 NS36960] NR 10 TC 45 Z9 46 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2003 VL 18 IS 4 BP 425 EP 429 DI 10.1002/mds.10375 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 667ZH UT WOS:000182264800011 PM 12671950 ER PT J AU Kreitman, RJ AF Kreitman, RJ TI Taming ricin toxin SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID VASCULAR LEAK SYNDROME; PHASE-I; A-CHAIN; ENDOTHELIAL-CELLS; IMMUNOTOXINS; RESISTANT; LEUKEMIA; LYMPHOMA; TRIAL C1 NCI, Div Canc Biol, Mol Biol Lab, Clin Immunotherapy Sect,NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Div Canc Biol, Mol Biol Lab, Clin Immunotherapy Sect,NIH, Bethesda, MD 20892 USA. NR 12 TC 9 Z9 9 U1 0 U2 1 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 APR PY 2003 VL 21 IS 4 BP 372 EP 374 DI 10.1038/nbt0403-372 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 664VH UT WOS:000182082400016 PM 12665820 ER PT J AU Kamada, H Tsutsumi, Y Sato-Kamada, K Yamamoto, Y Yoshioka, Y Okamoto, T Nakagawa, S Nagata, S Mayumi, T AF Kamada, H Tsutsumi, Y Sato-Kamada, K Yamamoto, Y Yoshioka, Y Okamoto, T Nakagawa, S Nagata, S Mayumi, T TI Synthesis of a poly(vinylpyrrolidone-co-dimethyl maleic anhydride) co-polymer and its application for renal drug targeting SO NATURE BIOTECHNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; ORGANIC ANION TRANSPORTER; POLYETHYLENE-GLYCOL; ANTITUMOR-ACTIVITY; MOLECULAR DESIGN; THROMBOPOIETIC ACTIVITY; SUPEROXIDE-DISMUTASE; SOLID TUMORS; RAT-KIDNEY; INTERLEUKIN-6 AB We have synthesized a polymeric drug carrier, polyvinylpyrrolidone-co-dimethyI maleic anhydride [poly(VP-co-DMMAn)], for use in renal drug delivery. About 80% of the 10-kDa poly(VP-co-DMMAn) selectively accumulated in the kidneys 24 h after intravenous administration to mice. Although this accumulated poly(VP-co-DMMAn) was gradually excreted in the urine, about 40% remained in the kidneys 96 h after treatment. Poly(VP-co-DMMAn) was taken up by the renal proximal tubular epithelial cells and no cytotoxicity was noted. Higher doses did not produce toxicity in the kidneys or other tissues. In contrast, polyvinylpyrroliclone of the same molecular weight did not show any tissue-specific distribution. Poly(VP-co-DMMAn)-modified superoxide dismutase accumulated in the kidneys after intravenous administration and accelerated recovery from acute renal failure in a mouse model. In contrast, polyvinylpyrrolidone-modified superoxide dismutase and native superoxide dismutase were not as effective. Thus, poly(VP-co-DMMAn) is a useful candidate as a targeting carrier for renal drug delivery systems. C1 Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Suita, Osaka 5650871, Japan. NCI, Div Basic Sci, Mol Biol Lab, Ira Pastans Lab,NIH, Bethesda, MD 20892 USA. RP Tsutsumi, Y (reprint author), Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan. OI Kamada, Haruhiko/0000-0002-2478-3818 NR 29 TC 68 Z9 71 U1 1 U2 12 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 APR PY 2003 VL 21 IS 4 BP 399 EP 404 DI 10.1038/nbt798 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 664VH UT WOS:000182082400021 PM 12612587 ER PT J AU Yamanaka, K Ishikawa, H Megumi, Y Tokunaga, F Kanie, M Rouault, TA Morishima, I Minato, N Ishimori, K Iwai, K AF Yamanaka, K Ishikawa, H Megumi, Y Tokunaga, F Kanie, M Rouault, TA Morishima, I Minato, N Ishimori, K Iwai, K TI Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2 SO NATURE CELL BIOLOGY LA English DT Article ID IRON-REGULATORY PROTEIN-2; BINDING PROTEIN; MESSENGER-RNA; HIF-ALPHA; DEGRADATION; METABOLISM; DISEASE; RING; UBIQUITYLATION; HYDROXYLATION AB The ubiquitin system is involved in several basic cellular functions(1-3). Ubiquitination is carried out by a cascade of three reactions catalysed by the El, E2 and E3 enzymes. Among these, the E3 ubiquitin-protein ligases have a pivotal role in determining the specificity of the system by recognizing the target substrates through defined targeting motifs(1-3). Although RING finger proteins constitute an important family of E3 ligases(4), only a few post-transcriptional modifications, including phosphorylation(1), proline hydroxylation(5,6) and glycosylation(7), are known to function as recognition signals for E3. Iron regulatory protein 2 (IRP2), a modulator of iron metabolism, is regulated by iron-induced ubiquitination and degradation(8). Here we show that the RING finger protein HOIL-1 functions as an E3 ligase for oxidized IRP2, suggesting that oxidation is a specific recognition signal for ubiquitination. The oxidation of IRP2 is generated by haem, which binds to IRP2 in iron-rich cells, and by oxygen, indicating that the iron sensing of IRP2 depends on the synthesis and availability of haem. C1 Kyoto Univ, Grad Sch Engn, Dept Mol Engn, Sakyo Ku, Kyoto 6068501, Japan. Kyoto Univ, Grad Sch Biostudies, Dept Mol & Syst Biol, Sakyo Ku, Kyoto 6068501, Japan. Osaka City Univ, Grad Sch Med, Dept Mol Cell Biol, Abeno Ku, Osaka 5458585, Japan. Japan Sci & Technol Corp, JST, CREST, Kawaguchi, Saitama 3320012, Japan. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Yamanaka, K (reprint author), Kyoto Univ, Grad Sch Engn, Dept Mol Engn, Sakyo Ku, Kyoto 6068501, Japan. RI Yamanaka, Koji/H-5806-2011; Ishikawa, Haruto/B-1562-2012; Ishimori, Koichiro/S-1247-2016 OI Yamanaka, Koji/0000-0003-4655-0035; Ishikawa, Haruto/0000-0001-6362-5719; Ishimori, Koichiro/0000-0002-5868-0462 NR 25 TC 117 Z9 123 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD APR PY 2003 VL 5 IS 4 BP 336 EP 340 DI 10.1038/ncb952 PG 5 WC Cell Biology SC Cell Biology GA 664UR UT WOS:000182080700017 PM 12629548 ER PT J AU Puls, I Jonnakuty, C LaMonte, BH Holzbaur, ELF Tokito, M Mann, E Floeter, MK Bidus, K Drayna, D Oh, SJ Brown, RH Ludlow, CL Fischbeck, KH AF Puls, I Jonnakuty, C LaMonte, BH Holzbaur, ELF Tokito, M Mann, E Floeter, MK Bidus, K Drayna, D Oh, SJ Brown, RH Ludlow, CL Fischbeck, KH TI Mutant dynactin in motor neuron disease SO NATURE GENETICS LA English DT Article ID FAST AXONAL-TRANSPORT; DROSOPHILA-MELANOGASTER; P150(GLUED) COMPONENT; CYTOPLASMIC DYNEIN; SWISS-MODEL; COMPLEX AB Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower m neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is p dicted to distort the folding of dynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show the dysfunction of dynactin-mediated transport can lead to human motor neuron disease. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. NINDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. NINDS, Electromyography Sect, NIH, Bethesda, MD 20892 USA. NIDCD, Sect Syst Biol Commun Disorders, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. Massachusetts Gen Hosp, Day Neuromuscular Res Lab, Charlestown, MA 02129 USA. RP Puls, I (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 15 TC 550 Z9 567 U1 2 U2 20 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 APR PY 2003 VL 33 IS 4 BP 455 EP 456 DI 10.1038/ng1123 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 662CM UT WOS:000181928600011 PM 12627231 ER PT J AU Cooper, MK Wassif, CA Krakowiak, PA Taipale, J Gong, RY Kelley, RI Porter, FD Beachy, PA AF Cooper, MK Wassif, CA Krakowiak, PA Taipale, J Gong, RY Kelley, RI Porter, FD Beachy, PA TI A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis SO NATURE GENETICS LA English DT Article ID LEMLI-OPITZ-SYNDROME; A REDUCTASE-ACTIVITY; FLOOR PLATE; INHIBITION; FIBROBLASTS; CYCLOPAMINE; BINDING; CYCLODEXTRINS; INDUCTION; PROTEINS AB Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus. C1 Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Howard Hughes Med Inst, Baltimore, MD 21205 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Kennedy Krieger Inst, Baltimore, MD 21205 USA. RP Beachy, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. OI Wassif, Christopher/0000-0002-2524-1420 NR 30 TC 204 Z9 208 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2003 VL 33 IS 4 BP 508 EP 513 DI 10.1038/ng1134 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 662CM UT WOS:000181928600023 PM 12652302 ER PT J AU Green, P Ewing, B Miller, W Thomas, PJ Green, ED AF Green, P Ewing, B Miller, W Thomas, PJ Green, ED CA NISC Comparative Sequencing Progr TI Transcription-associated mutational asymmetry in mammalian evolution SO NATURE GENETICS LA English DT Article ID COUPLED REPAIR; SUBSTITUTION PATTERNS; BASE-COMPOSITION; STRAND SYMMETRY; DNA; RATES; GENES; REPLICATION; SEQUENCE; PSEUDOGENES AB Although mutation is commonly thought of as a random process, evolutionary studies show that different types of nucleoticle substitution occur with widely varying rates that presumably reflect biases intrinsic to mutation and repair mechanisms(1-4). A strand asymmetry(5,6), the occurrence of particular substitution types at higher rates than their complementary types, that is associated with DNA replication has been found in bacteria(7) and mitochondria(8). A strand asymmetry that is associated with transcription and attributable to higher rates of cytosine deamination on the coding strand has been observed in enterobacteria(9-11). Here, we describe a qualitatively different transcription-associated strand asymmetry in mammals, which may be a byproduct of transcription-coupled repair(12) in germline cells. This mutational asymmetry has acted over long periods of time to produce a compositional asymmetry, an excess of G+T over A+C on the coding strand, in most genes. The mutational and compositional asymmetries can be used to detect the orientations and approximate extents of transcribed regions. C1 Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. RP Green, P (reprint author), Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. NR 30 TC 180 Z9 190 U1 0 U2 7 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 APR PY 2003 VL 33 IS 4 BP 514 EP 517 DI 10.1038/ng1103 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 662CM UT WOS:000181928600024 PM 12612582 ER PT J AU Mascola, JR Montefiori, DC AF Mascola, JR Montefiori, DC TI HIV-1: nature's master of disguise SO NATURE MEDICINE LA English DT Editorial Material ID PERSISTENT INFECTION; VIRUS VARIANTS; NEUTRALIZATION AB HIV-1 readily mutates to escape the immune response, evolving in ways that allow it to persist in the host. New findings reveal that HIV-1 protects itself from antibodies by putting up a shield of constantly shifting sugar moieties. This shield may be contributing to the poor performance of candidate HIV-1 vaccines. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 32 Z9 33 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 APR PY 2003 VL 9 IS 4 BP 393 EP 394 DI 10.1038/nm0403-393 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 663CD UT WOS:000181987400021 PM 12669056 ER PT J AU Ye, QH Qin, LX Forgues, M He, P Kim, JW Peng, AC Simon, R Li, Y Robles, AI Chen, YD Ma, ZC Wu, ZQ Ye, SL Liu, YK Tang, ZY Wang, XW AF Ye, QH Qin, LX Forgues, M He, P Kim, JW Peng, AC Simon, R Li, Y Robles, AI Chen, YD Ma, ZC Wu, ZQ Ye, SL Liu, YK Tang, ZY Wang, XW TI Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning SO NATURE MEDICINE LA English DT Article ID PRIMARY LIVER-CANCER; HUMAN BREAST-CANCER; INTRAHEPATIC METASTASIS; BONE SIALOPROTEIN; TUMOR PROGRESSION; OSTEOPONTIN; IDENTIFICATION; MICROARRAY; PROTEIN; MODEL AB Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the expression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC. C1 NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Fudan Univ, Liver Canc Inst, Shanghai 200433, Peoples R China. Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. NCI, Biometr Res Branch, Rockville, MD USA. EMMES Corp, Rockville, MD USA. NHGRI, Canc Genet Lab, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 NR 45 TC 506 Z9 580 U1 4 U2 41 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 APR PY 2003 VL 9 IS 4 BP 416 EP 423 DI 10.1038/nm843 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 663CD UT WOS:000181987400031 PM 12640447 ER PT J AU Basta, M Van Goor, F Luccioli, S Billings, EM Vortmeyer, AO Baranyi, L Szebeni, J Alving, CR Carroll, MC Berkower, I Stojilkovic, SS Metcalfe, DD AF Basta, M Van Goor, F Luccioli, S Billings, EM Vortmeyer, AO Baranyi, L Szebeni, J Alving, CR Carroll, MC Berkower, I Stojilkovic, SS Metcalfe, DD TI F(ab)'(2)-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins SO NATURE MEDICINE LA English DT Article ID DOSE INTRAVENOUS IMMUNOGLOBULIN; IMMUNE GLOBULIN; COMPLEMENT; RECEPTORS; ASTHMA; PATHOGENESIS; MODULATION; ACTIVATION; COMPONENTS; FRAGMENTS AB High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)'(2)-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)'(2)-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)'(2). This binding could interfere with the role of C3a and C5a in inflammation. C1 NINDS, Neuronal Excitabil Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NHLBI, Computat Biophys Sect, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Membrane Biochem, Silver Spring, MD USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. US FDA, Immunoregulat Lab, Off Vaccines, Ctr Biol, Bethesda, MD 20014 USA. RP Basta, M (reprint author), NINDS, Neuronal Excitabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. OI Basta, Milan/0000-0001-5958-9241 NR 38 TC 138 Z9 142 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2003 VL 9 IS 4 BP 431 EP 438 DI 10.1038/nm836 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 663CD UT WOS:000181987400033 PM 12612546 ER PT J AU Tomaru, U Yamano, Y Nagai, M Maric, D Kaumaya, PTP Biddison, W Jacobson, S AF Tomaru, U Yamano, Y Nagai, M Maric, D Kaumaya, PTP Biddison, W Jacobson, S TI Detection of virus-specific T cells and CD8(+) T-cell epitopes by acquisition of peptide-HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections SO NATURE MEDICINE LA English DT Article ID NEUROLOGICAL DISEASE; LYMPHOCYTES; MEMORY; HTLV-1; MYELOPATHY; HAM/TSP; LOAD AB Antigen-specific CD8(+) T cells acquire peptide-major histocompatibility complex (MHC) clusters through T-cell receptor (TCR)-mediated endocytosis after specific antigen stimulation. We generated an antigen-presenting cell (APC) expressing human leukocyte antigen (HLA)-A*201 coupled to the enhanced green fluorescent protein (GFP), which delivered GFP to an antigen-specific T cell when pulsed with antigenic peptide. We quantitatively identified human T-cell lymphotropic virus type I ( HTLV-I) Tax(11-19) peptide-specific T-cell populations in peripheral blood mononuclear cells (PBMCs) from patients with HTLV-I-associated neurologic disease and defined a new CD8(+) T-cell epitope in the HTLV-I envelope region. Acquisition of peptide-HLA-GFP complexes by antigen-specific T cells could distinguish, with respect to phenotype and perforin production, T cells from the chronic viral infections cytomegalovirus and HTLV-I. This approach will be a powerful tool in understanding the role of antigen-specific T-cell responses in health and disease. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Kagoshima Univ, Fac Med, Dept Internal Med 3, Kagoshima 890, Japan. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 21 TC 39 Z9 44 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2003 VL 9 IS 4 BP 469 EP 475 DI 10.1038/nm845 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 663CD UT WOS:000181987400039 PM 12652294 ER PT J AU Wulfkuhle, JD Liotta, LA Petricoin, EF AF Wulfkuhle, JD Liotta, LA Petricoin, EF TI Proteomic applications for the early detection of cancer SO NATURE REVIEWS CANCER LA English DT Review ID LASER CAPTURE MICRODISSECTION; PROTEIN IDENTIFICATION TECHNOLOGY; ARTIFICIAL NEURAL NETWORKS; IMAGING MASS-SPECTROMETRY; PROSTATE-SPECIFIC ANTIGEN; IMMOBILIZED PH GRADIENTS; BREAST DUCTAL CARCINOMA; OVARIAN-CANCER; GENE-EXPRESSION; ANTIBODY ARRAYS AB The ability of physicians to effectively treat and cure cancer is directly dependent on their ability to detect cancers at their earliest stages. Proteomic analyses of early-stage cancers have provided new insights into the changes that occur in the early phases of tumorigenesis and represent a new resource of candidate biomarkers for early-stage disease. Studies that profile proteomic patterns in body fluids also present new opportunities for the development of novel, highly sensitive diagnostic tools for the early detection of cancer. C1 NCI FDA Clin Proteom Program, Off Director, Ctr Biol Evaluat & Res, FDA, Bethesda, MD 20892 USA. NCI, NCI FDA Clin Proteom Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), NCI FDA Clin Proteom Program, Off Director, Ctr Biol Evaluat & Res, FDA, Bethesda, MD 20892 USA. NR 82 TC 518 Z9 554 U1 13 U2 96 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 APR PY 2003 VL 3 IS 4 BP 267 EP 275 DI 10.1038/nrc.1043 PG 9 WC Oncology SC Oncology GA 664NB UT WOS:000182066200012 PM 12671665 ER PT J AU Hussain, SP Hofseth, LJ Harris, CC AF Hussain, SP Hofseth, LJ Harris, CC TI Radical causes of cancer SO NATURE REVIEWS CANCER LA English DT Review ID NITRIC-OXIDE SYNTHASE; HEPATITIS-B-VIRUS; ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR GENE; CERVICAL INTRAEPITHELIAL NEOPLASIA; INFLAMMATORY BOWEL-DISEASE; OXIDATIVE DNA-DAMAGE; HUMAN BREAST-CANCER; P53 MUTATION LOAD; CELL-CYCLE ARREST AB Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals - such as antioxidant scavengers and enzymes - and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov NR 179 TC 846 Z9 883 U1 4 U2 53 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 APR PY 2003 VL 3 IS 4 BP 276 EP 285 DI 10.1038/ncr1046 PG 10 WC Oncology SC Oncology GA 664NB UT WOS:000182066200013 PM 12671666 ER PT J AU Dancey, J Sausville, EA AF Dancey, J Sausville, EA TI Issues and progress with protein kinase inhibitors for cancer treatment SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; C-RAF KINASE; LYMPHOCYTE-PROLIFERATION ASSAYS; SIGNAL-TRANSDUCTION PATHWAY; DRUG-INDUCED APOPTOSIS; ISIS-5132 CGP 69846A; HUMAN LEUKEMIA-CELLS; PHASE-I TRIAL; TYROSINE KINASE AB Identification of the key roles of protein kinases in cancer has led to extensive efforts to develop kinase inhibitors for the treatment of a wide range of cancers, and more than 30 such agents are now in clinical trials. Here, we consider the crucial issues in the development of kinase inhibitors for cancer, and discuss strategies to address the challenges raised by these issues in the light of preclinical and clinical experiences so far. C1 NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Investigat Drug Branch, Rockville, MD 20852 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Rockville, MD 20852 USA. RP Dancey, J (reprint author), NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Investigat Drug Branch, 6130 Execut Blvd,Room 7131, Rockville, MD 20852 USA. NR 150 TC 382 Z9 392 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD APR PY 2003 VL 2 IS 4 BP 296 EP 313 DI 10.1038/nrd1066 PG 18 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 661LV UT WOS:000181892800020 PM 12669029 ER PT J AU Savonenko, AV Xu, GM Price, DL Borchelt, DR Markowska, AL AF Savonenko, AV Xu, GM Price, DL Borchelt, DR Markowska, AL TI Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP(SWE) SO NEUROBIOLOGY OF DISEASE LA English DT Article DE place discrimination; water maze; longitudinal; cross-sectional; memory; beta-amyloid; aging ID AMYLOID PRECURSOR PROTEIN; INBRED MOUSE STRAINS; TRAIT LOCI ANALYSES; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; SPATIAL MEMORY; DOWN-SYNDROME; SINGLE-GENE; F1 HYBRIDS; PLUS-MAZE AB Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-amyloid (Abeta), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the "Swedish" variant of APP (APP(SWE)) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of Abeta1-42 in brain increases with aging from low levels (2-10 pmol/g) at 6-14 months of age to relatively high levels (60-100 pmol/g) at 24-26 months, when deposits of Abeta were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human Abeta (60-100 pmol/g). Thus, the expression of APPSWE at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Dept Psychol, Baltimore, MD 21218 USA. Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Borchelt, DR (reprint author), NIA, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG05146] NR 44 TC 51 Z9 52 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD APR PY 2003 VL 12 IS 3 BP 194 EP 211 DI 10.1016/S0969-9961(02)00012-8 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 679YG UT WOS:000182949100004 PM 12742740 ER PT J AU Bymaster, FP McKinzie, DL Felder, CC Wess, J AF Bymaster, FP McKinzie, DL Felder, CC Wess, J TI Use of M-1-M-5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system SO NEUROCHEMICAL RESEARCH LA English DT Article DE acetylcholine; gene targeting; knockout mice; muscarinic agonists; muscarinic receptors; xanomeline ID ACETYLCHOLINE-RECEPTOR; HUMAN IRIS; NEURONS; LACKING; SUBTYPES; RAT; HYPERACTIVITY; LOCALIZATION; STIMULATION; HIPPOCAMPUS AB In this review we report recent findings on the physiological role of the five known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting technology. Using knockout mice for each mAChRs subtype, the role of mAChRs subtypes in a number of physiological functions was confirmed and new activities were discovered. The M, mAChRs modulate neurotransmitter signaling in cortex and hippocampus. The M-3 mAChRs are involved in exocrine gland secretion, smooth muscle contractility, pupil dilation, food intake, and weight gain. The role of the M-5 mAChRs involves modulation of central dopamine function and the tone of cerebral blood vessels. mAChRs of the M-2 subtype mediate muscarinic agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release in several brain regions. M-4 mAChRs modulate dopamine activity in motor tracts and act as inhibitory autoreceptors in striatum. Thus, as elucidated by gene targeting technology, mAChRs have widespread and manifold functions in the periphery and brain. C1 Eli Lilly & Co, Lilly Res Lab, Lilly Corp Ctr, Neurosci Res Div, Indianapolis, IN 46285 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Bymaster, FP (reprint author), Eli Lilly & Co, Lilly Res Lab, Lilly Corp Ctr, Neurosci Res Div, Indianapolis, IN 46285 USA. NR 42 TC 110 Z9 115 U1 1 U2 5 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD APR PY 2003 VL 28 IS 3-4 BP 437 EP 442 DI 10.1023/A:1022844517200 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 655LZ UT WOS:000181555000008 PM 12675128 ER PT J AU Brenneman, DE Phillips, TM Hauser, J Hill, JM Spong, CY Gozes, I AF Brenneman, DE Phillips, TM Hauser, J Hill, JM Spong, CY Gozes, I TI Complex array of cytokines released by vasoactive intestinal peptide SO NEUROPEPTIDES LA English DT Article DE interleukin-3; granulocyte colony stimulating factor; tumor necrosis factor-alpha; macrophage colony stimulating factor; interleukin-6 ID CYCLASE-ACTIVATING POLYPEPTIDE; NECROSIS-FACTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; CULTURED RAT ASTROCYTES; NEURONAL DEATH; NEONATAL RAT; SPINAL-CORD; TNF-ALPHA; NEUROPROTECTIVE PEPTIDE; INFLAMMATORY CYTOKINES AB A complex mixture of five cytokines has been shown to be released by vasoactive intestinal peptide (VIP). Cytokines were measured in paired samples of culture medium and astroglial cytosol by capillary electrophoresis. This is the first description of VIP-mediated release for TNF-alpha, IL-3, G-CSF and M-CSF from astrocyte cultures. Kinetic studies after VIP treatment demonstrated a gradual but incomplete depletion of cytosolic cytokine levels, with differences observed among the cytokines. Significant increases in release were apparent within 15-30 min for all cytokines. As the recognized VIP receptors (VPAC1 and VPAC2) are linked to adenylate cyclase and also interact with pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), both this homologous peptide and 8-bromo cAMP were investigated and compared to VIP-mediated release. Treatment with 1 mM 8-bromo cAMP produced cytokine release similar in amount to 0.1 nM PACAP-38, but significantly less (<50%) in comparison to 0.1 nM VIP. PACAP-38 and VIP exhibited similar EC50's for the release of G-CSF and TNF-α; however, the maximal release was 4-6 times greater for VIP than for PACAP-38. This similarity in potency suggested a VPAC-like receptor; however, the greater efficacy for VIP in comparison to PACAP-38, combined with a lack of cAMP production at subnanomolar concentrations of VIP, suggested a mechanism not currently associated with VPAC receptors. For M-CSF, IL-3 and IL-6, the EC50's of VIP were 3-30 times more potent than those of PACAP-38 in producing release. These studies suggested that multiple mechanisms mediate cytokine release in astrocytes: (1) a low efficacy release produced by PACAP-38 that is cAMP-mediated and (2) a high efficacy, VIP-preferring mechanism that was not linked to cAMP. In summary, subnanomolar concentrations of VIP released a complex array of cytokines from astrocytes that may contribute to the mitogenic and neurotrophic properties of this neuropeptide in the central nervous system. (C) 2003 Published by Elsevier Science Ltd. C1 NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIH, Ultramicro Analyt Immunochem Resource, Div Bioengn & Phys Sci, Off Res Serv,Off Director, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Brenneman, DE (reprint author), Johnson & Johnson Pharmaceut Res & Dev, Drug Discovery, CNS Biol R3014, LLC Welsh & McKean Rd, Spring House, PA 19477 USA. NR 54 TC 42 Z9 44 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD APR PY 2003 VL 37 IS 2 BP 111 EP 119 DI 10.1016/S0143-4179(03)00022-2 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 685AL UT WOS:000183238600005 PM 12747943 ER PT J AU Jagoda, EM Kiesewetter, DO Shimoji, K Ravasi, L Yamada, M Gomeza, J Wess, J Eckelman, WC AF Jagoda, EM Kiesewetter, DO Shimoji, K Ravasi, L Yamada, M Gomeza, J Wess, J Eckelman, WC TI Regional brain uptake of the muscarinic ligand, [F-18]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in M1, M3 and M4 receptor knockout mice SO NEUROPHARMACOLOGY LA English DT Article DE muscarinic receptors; KO mice; cerebral blood flow; saturability ID ACETYLCHOLINE-RECEPTOR; AUTORADIOGRAPHIC DISTRIBUTION; ALZHEIMERS-DISEASE; BINDING-SITES; RAT-BRAIN; COMPETITION; SELECTIVITY; SUBTYPES; LACKING; YOUNG AB A muscarinic receptor radioligand, 3-(3-(3-fluoropropyl)thio) -1,2,5,thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (fP-TZTP) radiolabeled with the positron emitting radionuclide F-18 ([F-18]FP-TZTP) displayed regional brain distribution consistent with M2 receptor densities in rat brain. The purpose of the present study is to further elucidate the subtype selectivity of [F-18]FP-TZTP using genetically engineered mice which lacked functional M1, M2, M3, or M4 muscarinic receptors. Using ex vivo autoradiography, the regional brain localization of [F-18]FP-TZTP in M2 knockout (M2 KO) was significantly decreased (51.3 to 61.4%; P<0.01) when compared to the wild-type (WT) mice in amygdala, brain stem, caudate putamen, cerebellum, cortex, hippocampus, hypothalamus, superior colliculus, and thalamus. In similar studies with M1KO, M3KO and M4KO compared to their WT mice, [F-18]FP-TZTP uptakes in the same brain regions were not significantly decreased at P<0.01. However, in amygdala and hippocampus small decreases of 19.5% and 22.7%, respectively, were observed for M1KO vs WT. mice at P<0.05. Given the fact that large decreases in [F-18]FP-TZTP brain uptakes were seen only in M2 KO vs. WT mice, we conclude that [F-18]FP-TZTP preferentially labels M2 receptors in vivo. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIH, PET Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, PET Dept, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 23 Z9 23 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2003 VL 44 IS 5 BP 653 EP 661 DI 10.1016/S0028-3908(03)00050-9 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 665UZ UT WOS:000182140800011 PM 12668051 ER PT J AU Hall, FS Sora, I Uhl, GR AF Hall, FS Sora, I Uhl, GR TI Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE transgenic mice; dopamine transporter; vesicular monoamine transporter; ethanol; reward ID ALCOHOL-PREFERRING RATS; VENTRAL TEGMENTAL AREA; FAWN-HOODED RAT; ELEVATES EXTRACELLULAR DOPAMINE; DRD2 VARIANT SER311CYS; NONPREFERRING NP RATS; SPRAGUE-DAWLEY RATS; RECEPTOR GENE DRD2; SEROTONIN-TRANSPORTER; NUCLEUS-ACCUMBENS AB Several lines of evidence suggest that monoaminergic systems, especially dopaminergic and serotoninergic systems, modulate ethanol consumption. Humans display significant differences in expression of the vesicular and plasma membrane monoamine transporters important for monoaminergic functions, including the vesicular monoamine transporter (VMAT2, SLC18A2) and dopamine transporter (DAT SLC6A3). In addition, many ethanol effects differ by sex in both humans and animal models. Therefore, ethanol consumption and preference were compared in male and female wild-type mice, and knockout (KO) mice with deletions of genes for DAT and VMAT2, Voluntary ethanol (2-32%v/v) and water consumption were compared in two-bottle preference tests in wild-type (+/+) vs heterozygous VMAT2 KO mice (+/-) and in wild-type (+/+) vs heterozygous (+/-) or homozygous (-/-) DAT KO mice. Deletions of either the DAT or VMAT2 genes increased ethanol consumption in male KO mice, although these effects were highly dependent on ethanol concentration, while female DAT KO mice had higher ethanol preferences. Thus, lifetime reductions in the expression of either DAT or VMAT2 increase ethanol consumption, dependent on sex. C1 NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. Tokyo Metropolitan Inst Psychiat, Psychopharmacol Lab, Tokyo, Japan. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 112 TC 37 Z9 38 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2003 VL 28 IS 4 BP 620 EP 628 DI 10.1038/sj.npp.1300070 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 664MB UT WOS:000182063900002 PM 12655306 ER PT J AU Johansson, C Willeit, M Smedh, C Ekholm, J Paunio, T Kieseppa, T Lichtermann, D Praschak-Rieder, N Neumeister, A Nilsson, LG Kasper, S Peltonen, L Adolfsson, R Schalling, M Partonen, T AF Johansson, C Willeit, M Smedh, C Ekholm, J Paunio, T Kieseppa, T Lichtermann, D Praschak-Rieder, N Neumeister, A Nilsson, LG Kasper, S Peltonen, L Adolfsson, R Schalling, M Partonen, T TI Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE seasonal affective disorder; seasonality; morningness-eveningness; CLOCK; period2; period3; NPAS2 ID SINGLE-NUCLEOTIDE POLYMORPHISMS; SLEEP PHASE SYNDROME; DEPRESSION; GENES; LIGHT; TIME; ASSOCIATION; MORNINGNESS; EVENINGNESS; MPER1 AB Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness-eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n = 177) and diurnal preference (n = 92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case-control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 47 1 Leu/Ser (chi(2) = 9.90, Bonferroni corrected P=0,035), indicating a recessive effect of the leucine allele on disease susceptibility (chi(2) = 6.61, Bonferroni corrected P = 0.050). Period3 647 Val/Gly was associated with self reported morningness-eveningness scores (n = 92, one-way ANOVA F = 4.99, Bonferroni corrected P = 0.044), with higher scores found in individuals with at least one glycine allele (t = 3.1, Bonferroni corrected P = 0.013). A second, population-based sample of individuals selected for high (n = 127) or low (n = 98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case-control material (n = 177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference. C1 Karolinska Hosp, Neurogenet Unit, S-17176 Stockholm, Sweden. Karolinska Inst, Dept Mol Med, Neurogenet Unit, Stockholm, Sweden. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Umea Univ, Dept Clin Sci, Div Psychiat, Umea, Sweden. Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland. Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA USA. Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden. RP Johansson, C (reprint author), Karolinska Hosp, Neurogenet Unit, CMM L8-00, S-17176 Stockholm, Sweden. RI Partonen, Timo/G-1105-2012; Hertzman Johansson, Carolina/D-6570-2013; OI Partonen, Timo/0000-0003-1951-2455; Hertzman Johansson, Carolina/0000-0002-7787-0608; Adolfsson, Rolf/0000-0001-9785-8473 NR 34 TC 189 Z9 195 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2003 VL 28 IS 4 BP 734 EP 739 DI 10.1038/sj.npp.1300121 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 664MB UT WOS:000182063900015 PM 12655319 ER PT J AU Stapleton, JM Gilson, SF Wong, DF Villemagne, VL Dannals, RF Grayson, RF Henningfield, JE London, ED AF Stapleton, JM Gilson, SF Wong, DF Villemagne, VL Dannals, RF Grayson, RF Henningfield, JE London, ED TI Intravenous nicotine reduces cerebral glucose metabolism: A preliminary study SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE addiction; brain imaging; drug abuse; fluorodeoxyglucose; nicotine; positron emission tomography ID CIGARETTE-SMOKING; BLOOD-FLOW; RAT-BRAIN; AWAKE RAT; SMOKERS; ACTIVATION; ABUSE; NONSMOKERS; TOBACCO; PET AB Nicotine is self-administered by smoking tobacco products, and enhances positive mood (at least in smokers). Since most drugs of abuse decrease regional cerebral metabolic rate(s) for glucose (rCMRglc) in human subjects, we posited that administration of nicotine would similarly reduce rCMRglc. Positron emission tomography (PET) with [F-18]fluorodeoxyglucose was used to assess the effects of intravenous nicotine ( 1.5mg) on cerebral glucose metabolism in six healthy male volunteers (21-38 years of age). Two PET assays (placebo and nicotine) were performed, and subjective self-reports of mood and feeling state were collected. Data were analyzed using analysis of variance, Nicotine reduced global glucose metabolism (by 9.51% of placebo control), with reductions in most of the 30 individual regions tested. Nine regions had bilateral effects that reached statistical significance (p < 0.05, uncorrected for the number of regions tested), although the statistical model used did not separate these effects from a global effect. The subjects reported both positive and negative effects of nicotine on mood/feeling state. The widespread decreases in cerebral metabolism are consistent with the many effects of nicotine on cognition and mood. The findings indicate that nicotine resembles other drugs of abuse in reducing brain metabolism, perhaps by a common mechanism. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Anesthesiol, Baltimore, MD 21205 USA. RP London, ED (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza,Box 60, Los Angeles, CA 90024 USA. NR 40 TC 27 Z9 29 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2003 VL 28 IS 4 BP 765 EP 772 DI 10.1038/sj.npp.1300106 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 664MB UT WOS:000182063900019 PM 12655323 ER PT J AU Nelson, PG Jia, M Li, MX AF Nelson, PG Jia, M Li, MX TI Protein kinases and Hebbian function SO NEUROSCIENTIST LA English DT Article DE protein kinases; neuromuscular junction; Hebbian synapse; phosphorylation; A kinase anchoring proteins ID NEUROMUSCULAR-JUNCTION; SYNAPSE ELIMINATION; ACETYLCHOLINE-RECEPTORS; AMPA RECEPTORS; MUSCLE-CELLS; NR1 SUBUNIT; IN-VITRO; PHOSPHORYLATION; ACTIVATION; THROMBIN AB The Hebb synapse, in which the strength of synapses is affected by activity in presynaptic and postsynaptic nerve cells, is a widely used model for developmental and learning-related neuroplasticity. Presynaptic and postsynaptic firing that is correlated in time is postulated to increase synaptic strength while activity in presynaptic and postsynaptic neurons that is not correlated results in weakening. The authors describe a cell biologic, mechanistic model for activity-dependent modification of synapse strength that selectively weakens inactive inputs to activated targets. Differentially localized protein kinase A and protein kinase C molecules are activated by spike and synaptic activity. Subsequent kinase-specific phosphorylation and stabilization or destabilization of synaptic receptors are molecular and cell biologic substrates of the Hebb synapse. C1 NICHHD, Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 30 TC 5 Z9 5 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD APR PY 2003 VL 9 IS 2 BP 110 EP 116 DI 10.1177/1073858403252226 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 661QJ UT WOS:000181901000010 PM 12708615 ER PT J AU Radzius, A Gallo, JJ Epstein, DH Gorelick, DA Cadet, JL Uhl, GE Moolchan, ET AF Radzius, A Gallo, JJ Epstein, DH Gorelick, DA Cadet, JL Uhl, GE Moolchan, ET TI A factor analysis of the Fagerstrom Test for Nicotine Dependence (FTND) SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID TOLERANCE QUESTIONNAIRE; PREVALENCE; SMOKING AB Psychometric study of the Fagerstrom Test for Nicotine Dependence (FTND) provides insight into its structure and the dimensions of nicotine addiction it assesses. We evaluated the factor structure of the FTND in 541 research volunteers, most with histories of polysubstance use. Tetrachoric and phi correlation techniques were utilized and promax- and varimax-rotated solutions are reported. Two factors were found. Factor 1 was defined by questions regarding time to first cigarette in after waking, which cigarette is most preferred, and prominence of morning smoking. Factor 2 was defined by questions regarding difficulty refraining from smoking, amount smoked, and smoking while ill. The question "How soon on waking do you smoke your first cigarette?" loaded substantially on both Factor 2 and Factor 1. Repeating the analyses after stratification by gender did not change the results. The factor structure from our sample population was similar to results reported by previous studies with different types of populations. We propose that Factor 1 assesses the degree of urgency to restore nicotine levels to a given threshold after nighttime abstinence, whereas Factor 2 reflects the persistence with which nicotine levels are maintained at about that threshold during waking hours. Thus, the FTND may assess distinguishable self-reportable pharmacological dimensions of nicotine addiction. These two dimensions may provide indirect assessment of a smoker's daily nicotine intake. Testing this hypothesis requires correlation of biomarkers and responses to specific items of the FTND. C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. Univ Penn, Dept Family Practice & Community Med, Philadelphia, PA 19104 USA. RP Radzius, A (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 45 Z9 46 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD APR PY 2003 VL 5 IS 2 BP 255 EP 260 DI 10.1080/1462220031000073289 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 716HC UT WOS:000185021900017 PM 12745499 ER PT J AU Ma, Y Kiesewetter, DO Lang, LX Der, M Huang, B Carson, RE Eckelman, WC AF Ma, Y Kiesewetter, DO Lang, LX Der, M Huang, B Carson, RE Eckelman, WC TI Determination of [F-18]FCWAY, [F-18]FP-TZTP, and their metabolites in plasma using rapid and efficient liquid-liquid and solid phase extractions SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article ID 5-HT1A ANTAGONISTS; RAT HEPATOCYTES; IDENTIFICATION; WAY-100635; AGONIST AB Liquid-liquid and solid phase extraction methods were developed for the accurate and rapid quantitation of radioactive components in human plasma following injection of two PET ligands. A solid phase extraction (SPE) method was developed for the determination of the 5HT(1A) receptor ligand [N-{2-[4-(2-methoxyphenyl) piperazino]ethyl}-N-(2-pyridinyl) trans-4-[F-18]fluorocyclohexanecarboxamide (FC-WAY). and its acidic metabolite. 4-[F-18]fluorocyclohexane carboxylic acid (FC). In both cases, the extraction method was much faster and easier to use. yet provided results comparable to HPLC and TLC methods. In addition, an easy to perform two-step liquid-liquid extraction was developed for quantitation of 3-(3-((3-[F-18]fluoropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([F-18]FP-TZTP). a selective M2 muscarinic agonist. C1 NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Ma, Y (reprint author), NIH, PET Dept, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 13 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD APR PY 2003 VL 30 IS 3 BP 233 EP 240 DI 10.1016/S0969-8051(02)00452-3 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 681MX UT WOS:000183040900003 PM 12745014 ER PT J AU Del Parigi, A Chen, KW Salbe, AD Reiman, EM Tataranni, PA AF Del Parigi, A Chen, KW Salbe, AD Reiman, EM Tataranni, PA TI Are we addicted to food? SO OBESITY RESEARCH LA English DT Article ID DOPAMINE NEURONS; OBESITY; REWARD; RESPONSES; HUMANS; GENE; MECHANISMS; COMPULSION; SATIATION; CHOCOLATE C1 NIH, Clin Diabet & Nutr Sect, Phoenix, AZ 85016 USA. Good Samaritan Hosp, PET Res Ctr, Phoenix, AZ USA. RP Del Parigi, A (reprint author), NIH, Clin Diabet & Nutr Sect, 4212 N 16th St,Rm 541, Phoenix, AZ 85016 USA. RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 NR 31 TC 40 Z9 41 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD APR PY 2003 VL 11 IS 4 BP 493 EP 495 DI 10.1038/oby.2003.68 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 666UV UT WOS:000182195600001 PM 12690075 ER PT J AU Wong, TY Klein, R Sharrett, AR Manolio, TA Hubbard, LD Marino, EK Kuller, L Burke, G Tracy, RP Polak, JF Gottdiener, JS Siscovick, DS AF Wong, TY Klein, R Sharrett, AR Manolio, TA Hubbard, LD Marino, EK Kuller, L Burke, G Tracy, RP Polak, JF Gottdiener, JS Siscovick, DS TI The prevalence and risk factors of retinal microvascular abnormalities in older persons - The cardiovascular health study SO OPHTHALMOLOGY LA English DT Article ID MIDDLE-AGED PERSONS; ATHEROSCLEROSIS RISK; BLOOD-PRESSURE; COMMUNITIES; DISEASE; RETINOPATHY; HYPERTENSION; STROKE; ARTERY; ADULTS AB Purpose: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons. Design and Participants: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities. Methods: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations. Main Outcome Measures: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis. Results: The prevalence of retinal microvascular abnormalities was 8.3% for retinopathy, 9.6% for focal arteriolar narrowing, and 7.7% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis. Conclusions: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis. C1 Natl Univ Singapore, Singapore 119260, Singapore. Singapore Eye Res Inst, Singapore 119260, Singapore. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Univ Vermont, Coll Med, Dept Pathol, Colchester, VT USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Georgetown Univ Hosp, Div Cardiol, Washington, DC 20007 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA USA. RP Wong, TY (reprint author), Natl Univ Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. OI Klein, Ronald/0000-0002-4428-6237 FU NHLBI NIH HHS [HC-97-06] NR 40 TC 166 Z9 178 U1 0 U2 5 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 APR PY 2003 VL 110 IS 4 BP 658 EP 666 DI 10.1016/S0161-6420(02)01931-0 PG 9 WC Ophthalmology SC Ophthalmology GA 673EE UT WOS:000182566600022 PM 12689883 ER PT J AU Leethanakul, C Knezevic, V Patel, V Amornphimoltham, P Gillespie, J Shillitoe, EJ Emko, P Park, MH Emmert-Buck, MR Strausberg, RL Krizman, DB Gutkind, JS AF Leethanakul, C Knezevic, V Patel, V Amornphimoltham, P Gillespie, J Shillitoe, EJ Emko, P Park, MH Emmert-Buck, MR Strausberg, RL Krizman, DB Gutkind, JS TI Gene discovery in oral squamous cell carcinoma through the Head and Neck Cancer Genome Anatomy Project: confirmation by microarray analysis SO ORAL ONCOLOGY LA English DT Article DE oral epithelium; oral cancer; LCM; gene expression; cDNA microarrays; CGAP ID LASER-CAPTURE MICRODISSECTION; S-TRANSFERASE-PI; CDNA LIBRARIES; EXPRESSION; CONSTRUCTION; INTERLEUKIN-4; CADHERIN; RECEPTOR; CAVITY; LUNG AB The near completion of the human genome project and the recent development of novel, highly sensitive high-throughput techniques have now afforded the unique opportunity to perform a comprehensive molecular characterization of normal, precancerous, and malignant cells, including those derived from squamous carcinomas of the head and neck (HNSCC). As part of these efforts, representative cDNA libraries from patient sets, comprising of normal and malignant squamous epithelium, were generated and contributed to the Head and Neck Cancer Genome Anatomy Project (HN-CGAP). Initial analysis of the sequence information indicated the existence of many novel genes in these libraries [Oral Oncol 36 (2000) 474]. In this study, we surveyed the available sequence information using bioinformatic tools and identified a number of known genes that were differentially expressed in normal and malignant epithelium. Furthermore, this effort resulted in the identification of 168 novel genes. Comparison of these clones to the human genome identified clusters in loci that were not previously recognized as being altered in HNSCC. To begin addressing which of these novel genes are frequently expressed in HNSCC, their DNA was used to construct an oral-cancer-specific microarray, which was used to hybridize alpha-P-33 dCTP labeled cDNA derived from five HNSCC patient sets. Initial assessment demonstrated 10 clones to be highly expressed (>2-fold) in the normal squamous epithelium, while 14 were highly represented in the malignant counterpart, in three of the five patient sets, thus suggesting that a subset of these newly discovered transcripts might be highly expressed in this tumor type. These efforts, together with other multi-institutional genomic and proteomic initiatives are expected to contribute to the complete understanding of the molecular pathogenesis of HNSCCs, thus helping to identify new markers for the early detection of preneoplastic lesions and novel targets for pharmacological intervention in this disease. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. NCI, Canc Genome Anat Project, Off Director, NIH,Adv Technol Ctr, Gaithersburg, MD 20877 USA. Sci Applicat Int Corp, NCI, Bethesda, MD 20892 USA. SUNY Syracuse, Upstate Med Univ, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. SUNY Syracuse, Upstate Med Univ, Dept Otolaryngol & Commun Sci, Syracuse, NY 13210 USA. NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. Canc Genome Off, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 25 TC 47 Z9 50 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD APR PY 2003 VL 39 IS 3 BP 248 EP 258 AR PII S1368-8375(02)00107-0 DI 10.1016/S1368-8375(02)00107-0 PG 11 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 658UG UT WOS:000181738400006 PM 12618197 ER PT J AU Rao, MR Levine, RJ Wasif, NK Clemens, JD AF Rao, MR Levine, RJ Wasif, NK Clemens, JD TI Reliability of maternal recall and reporting of child births and deaths in rural Egypt SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID PREGNANCY-RELATED EVENTS; MEDICAL RECORDS; MORTALITY; COMPLETENESS; ACCURACY; WOMEN AB Demographic indicators such as fertility rates and infant mortality rates are often measured in census surveys by interviewing mothers to obtain their pregnancy histories and child deaths. The validity of such surveys depends upon accurate recall of histories, truthful reporting of events and understanding of the questions posed. To measure the reliability of maternal reporting, two census surveys conducted in a rural Egyptian population were compared. Women between 15 and 55 years of age residing in 20 villages were asked their histories of live births, stillbirths and child deaths. An identical set of questions was posed 2 years later. Twice-monthly home visits were conducted in the intervening 2-year interval to identify accurately any new births, stillbirths and deaths occurring in the population. The maternal reports from the first census were combined with the prospectively identified births, stillbirths and deaths and compared with the maternal reports from the second census. For 1502 women, the discrepancies in the total number of births, stillbirths and child deaths reported between the two surveys were 0.6%, 4% and 0.6% respectively. However, when the consistency of responses was analysed, the proportion of women with discordant responses was 10%, 6% and 7% for the same measures. These results suggest that, despite the large number of births and deaths that women may experience in developing countries, maternal interviews provide reliable responses that can be used to estimate mortality and fertility rates in settings where vital records are incomplete or unreliable. C1 NICHHD, Epidemiol Branch, DESPR, NIH, Bethesda, MD 20892 USA. UTAS, Assiut, Egypt. RP Rao, MR (reprint author), NICHHD, Epidemiol Branch, DESPR, NIH, 6100 Execut Blvd 7B03, Bethesda, MD 20892 USA. NR 26 TC 10 Z9 10 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD APR PY 2003 VL 17 IS 2 BP 125 EP 131 DI 10.1046/j.1365-3016.2003.00482.x PG 7 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 664BU UT WOS:000182042500004 PM 12675778 ER PT J AU Mannes, AJ Martin, BM Yang, HYT Keller, JM Lewin, S Gaiser, RR Iadarola, MJ AF Mannes, AJ Martin, BM Yang, HYT Keller, JM Lewin, S Gaiser, RR Iadarola, MJ TI Cystatin C as a cerebrospinal fluid biomarker for pain in humans SO PAIN LA English DT Article DE proteomics; cerebrospinal fluid; cystatin C; surface enhanced laser desorption ionization; matrix-assisted laser desorption ionization time of flight; mass spectrometry; subtraction cloning; labor ID IMMUNOREACTIVE BETA-ENDORPHIN; P-LIKE IMMUNOREACTIVITY; RAT SPINAL-CORD; SUBSTANCE-P; POSTOPERATIVE PAIN; PROJECTION NEURONS; SEQUENCE-ANALYSIS; GENE-EXPRESSION; MESSENGER-RNA; DORSAL HORN AB Through a process of subtraction cloning and differential hybridization, we previously identified several new genes whose expression was induced by peripheral inflammation. One of these coded for cystatin C, a secreted cysteine protease inhibitor in the cystatin superfamily. We hypothesized that, concurrent with increased expression in dorsal horn, increased secretion would elevate the cystatin C content in cerebrospinal fluid (CSF) during active pain states. Alterations were assessed by immunoassay and by surface enhanced laser desorption ionization (SELDI) mass spectrometry with either reverse phase or immobilized anti-cystatin C antibody surfaces using CSF from ten age-matched obstetrical patients at term. Five control subjects were scheduled for an elective caesarian section and were not in pain. Another five subjects were in labor for 8.9 +/- 1 h and were in severe pain as assessed with a visual analog scale and the McGill short form questionnaire. The level of cystatin C as measured by immunoassay in the non-pain patients was 2.77 +/- 0.75 mug/ml and in the pain patients 5.36 +/- 0.92 mug/ml (P < 0.02). The elevation occurred without significant change in total CSF protein or beta-endorphin content. The cystatin C increase also was detectable by SELDI with either raw CSF or after antibody capture. These data are consistent with our previous animal study and the idea that persistent pain induces the synthesis and release of cystatin C in dorsal spinal cord, the surplus of which overflows into the CSF. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. NIMH, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. Hosp Univ Penn, Dept Anesthesiol, Philadelphia, PA 19104 USA. RP Mannes, AJ (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bldg 49,Room 1A08,49 Convent Dr,MSC-4410, Bethesda, MD 20892 USA. OI Mannes, Andrew/0000-0001-5834-5667 NR 40 TC 47 Z9 50 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD APR PY 2003 VL 102 IS 3 BP 251 EP 256 DI 10.1016/S0304-3959(02)00403-7 PG 6 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 667GF UT WOS:000182222400006 PM 12670666 ER PT J AU Fallon, EM Tanofsky-Kraff, M Freedman, RJ Semega-Janneh, M Elberg, J Wentz, R Cohen, ML Young-Hyman, D Yanovski, SZ Yanovski, JA AF Fallon, EM Tanofsky-Kraff, M Freedman, RJ Semega-Janneh, M Elberg, J Wentz, R Cohen, ML Young-Hyman, D Yanovski, SZ Yanovski, JA TI Quality of life in obese African American and Caucasian adolescents SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHHD, Dev Endocrinol Branch, NIH, Unit Growth & Obes, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 14 BP 3A EP 3A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900015 ER PT J AU Jackson, SH Alicea, C AF Jackson, SH Alicea, C TI M-CSF primes dendritic cell precursors to secrete IL-10 SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 70 BP 13A EP 13A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900071 ER PT J AU Liu, YS Miller, BA Barnes, J AF Liu, YS Miller, BA Barnes, J TI Interferon-gamma augments p38 and JNK MAP kinases through blocking MKP-1 induction in lipopolysaccharide-stimulated macrophages SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIA, Lab Cellular Mol Biol, Stress Signaling Unit, Baltimore, MD 21224 USA. Ohio State Univ, Childrens Hosp, Childrens Res Inst, Ctr Dev Pharmacol & Toxicol, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 85 BP 15A EP 15A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900086 ER PT J AU Taylor, SK Melchionda, F Fry, TJ Mackall, CL AF Taylor, SK Melchionda, F Fry, TJ Mackall, CL TI Dendritic cell-based vaccination for HY-specific immune response generation: Modified female DCs versus male DC endogenous expression SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Baylor Coll Med, Houston, TX 77030 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 91 BP 16A EP 16A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900092 ER PT J AU Frattarelli, DAC Reinheimer, G Aranda, JV AF Frattarelli, DAC Reinheimer, G Aranda, JV TI Stable pulmonary function tests in asthma camp attendees SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Hosp Michigan, NIH, PPRU, Div Clin Pharmacol, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 98 BP 17A EP 17A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900099 ER PT J AU Batista, DL Mansell, A Steele, D Vanvleet, M Alario, AJ AF Batista, DL Mansell, A Steele, D Vanvleet, M Alario, AJ TI Is Montelukast effective in the treatment of young children wheezing with a viral illness? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 120 BP 21A EP 22A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900121 ER PT J AU McBride, KL Lewin, M Fernbach, S Pignatelli, R Combes, A Menesses, A Ho, T Bezold, L Lam, W Kaplan, N Towbin, J Belmont, J AF McBride, KL Lewin, M Fernbach, S Pignatelli, R Combes, A Menesses, A Ho, T Bezold, L Lam, W Kaplan, N Towbin, J Belmont, J TI Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Baylor Coll Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Div Cardiol, Houston, TX 77030 USA. NIEHS, Biostat Branch, Environm Dis & Med Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 215 BP 38A EP 38A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900216 ER PT J AU Bell, MJ Hallenbeck, JM Gallo, V AF Bell, MJ Hallenbeck, JM Gallo, V TI Cytokine response after experimental intrauterine inflammation SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Res Inst, Ctr Neurosci Res, Washington, DC USA. NINDS, Stroke Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 341 BP 61A EP 61A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900342 ER PT J AU Snider, LA Morse, LC Swedo, SE AF Snider, LA Morse, LC Swedo, SE TI Association of episodic handwriting deterioration in school children with motor tic disorders SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 375 BP 66A EP 66A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900376 ER PT J AU Kaler, SG Bochey, ME AF Kaler, SG Bochey, ME TI Skewed X-chromosome inactivation in PHACE syndrome suggests a X-linked dominant gene SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, NIH, Lab Clin Genom, Unit Pediat Genet, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 464 BP 82A EP 82A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900465 ER PT J AU Lozano, EA Hoke, TR Thompson, WR AF Lozano, EA Hoke, TR Thompson, WR TI Rapid initiation of mechanical ventricular support for fulminant myocarditis in children SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Baylor Coll Med, Lillie Frank Abercrombie Sect Pediat Cardiol, Houston, TX 77030 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 713 BP 125A EP 125A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900714 ER PT J AU Feuillan, P Calis, K Hill, S Robey, PG Collins, MT AF Feuillan, P Calis, K Hill, S Robey, PG Collins, MT TI Letrozole treatment of precocious puberty in girls with the McCune-Albright Syndrome SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, DEB, Bethesda, MD USA. NIDCR, Bethesda, MD USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 778 BP 136A EP 136A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900779 ER PT J AU Elberg, J Fallon, EM McDuffie, JR Steinberg, EN Yanovski, JA AF Elberg, J Fallon, EM McDuffie, JR Steinberg, EN Yanovski, JA TI Comparison of body fat measurements by pencil beam DXA (QDR 2000), array beam DXA (QDR 4500A), and air displacement plethysmography in children and adolescents SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, NIH, Dev Endocrinol Branch, Unit Growth & Obes, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 802 BP 141A EP 141A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900803 ER PT J AU Bauer, AJ Stergiopoulos, SG Sandrini, F Griffin, KJ Sarlis, NJ Stratakis, CA AF Bauer, AJ Stergiopoulos, SG Sandrini, F Griffin, KJ Sarlis, NJ Stratakis, CA TI Characterization of protein kinase A (PKA) and the PKA-type 1-alpha regulatory subunit (PRKAR1A) gene in human thyroid tumor cell lines SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Dev Endocrinol Branch, Sect Genet & Metab, Bethesda, MD USA. Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. NIDDK, Clin Endocrinol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 823 BP 144A EP 144A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900824 ER PT J AU Batista, DL Keil, M Stratakis, CA AF Batista, DL Keil, M Stratakis, CA TI Determinants of height and bone maturation in children with Cushing syndrome: The National Institute of Health series SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHHD, Dev Endocrinol Branch, Unit Genet & Endocrinol, Bethesda, MD 20892 USA. Brown Univ, Sch Med, Div Pediat Ambulatory Med, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 827 BP 145A EP 145A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900828 ER PT J AU Cohen, ML Tanofsky-Kraff, M Steinberg, EN Elberg, J Semega-Janneh, M Yanovski, S Yanovski, J AF Cohen, ML Tanofsky-Kraff, M Steinberg, EN Elberg, J Semega-Janneh, M Yanovski, S Yanovski, J TI A longitudinal study of the associations between body size changes, depressive symptomatology, and disordered eating symptomatology in children SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHHD, Dev Endocrinol Branch, NIH, Unit Growth & Obes, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 845 BP 148A EP 148A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900846 ER PT J AU Nwosu, BU Coco, M Yanovski, JA Baron, J AF Nwosu, BU Coco, M Yanovski, JA Baron, J TI Does a maximum stimulated growth hormone of 7-10 ng/ml indicate partial growth hormone derficiency? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 843 BP 148A EP 148A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900844 ER PT J AU Nilsson, O Falk, J Ritzen, ME Baron, J Savendahl, L AF Nilsson, O Falk, J Ritzen, ME Baron, J Savendahl, L TI Raloxifene acts as an estrogen agonist on the rabbit growth plate SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 864 BP 151A EP 152A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900865 ER PT J AU Griffin, KJ Kirschner, LS Stergiopoulos, SG Lenherr, SM Claflin, ES Matyakhina, L Bauer, AJ Carney, JA Stratakis, CA AF Griffin, KJ Kirschner, LS Stergiopoulos, SG Lenherr, SM Claflin, ES Matyakhina, L Bauer, AJ Carney, JA Stratakis, CA TI A transgenic mouse model for Carney complex expressing an antisense construct to PRKAR1A SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Ohio State Univ, Columbus, OH 43210 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Mayo Clin, Rochester, MN USA. NICHD, Dev Endocrinol Branch, UGEN, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 874 BP 153A EP 153A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900875 ER PT J AU Chen, AM Rogan, W AF Chen, AM Rogan, W TI DDT use for malaria control might increase non-malarial infant deaths SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 907 BP 159A EP 159A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900908 ER PT J AU Ross, JA Mertens, AC Xiang, Y Klebanoff, M Olshan, AF AF Ross, JA Mertens, AC Xiang, Y Klebanoff, M Olshan, AF TI Sulpha-based medication use during pregnancy and reproductive outcomes in the National Collaborative Perinatal Project (NCPP) SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Univ Minnesota, Minneapolis, MN 55455 USA. NICHHD, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 918 BP 161A EP 161A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900919 ER PT J AU Llanos, AR Mena, P Valenzuela, A Salem, N Uauy, R AF Llanos, AR Mena, P Valenzuela, A Salem, N Uauy, R TI LCP metabolism and endogenous bioequivalence of intermediates in the formation of DHA and AA using deuterated precursors SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 INTA Univ Chile, Santiago, Chile. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 950 BP 167A EP 167A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897900951 ER PT J AU Thronberry, J El-Khorazaty, MN El-Mohandes, AAE Johnson, AA Joseph, JG Subramanian, KNS Keily, M AF Thronberry, J El-Khorazaty, MN El-Mohandes, AAE Johnson, AA Joseph, JG Subramanian, KNS Keily, M CA NIH DC Initiative Reduce Infant TI Acceptability of audio computer-assisted self-interview (A-CASI) among minority women receiving prenatal care in Washington, DC SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Res Triangle Inst, Rockville, MD USA. George Washington Univ, Washington, DC 20052 USA. Howard Univ, Washington, DC 20059 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Georgetown Univ, Washington, DC 20057 USA. NICHHD, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1080 BP 190A EP 190A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901081 ER PT J AU Saluja, G Brenner, RA Smith, GS Schroeder, T AF Saluja, G Brenner, RA Smith, GS Schroeder, T TI Circumstances of swimming pool drownings in youth aged 5-24, 1995-1998 SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. Liberty Mutual, Ctr Safety Res, Boston, MA USA. Consumer Prod Safety Commiss, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1129 BP 199A EP 199A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901130 ER PT J AU Mirza, NM Kadow, K Palmer, M Yanovski, JA AF Mirza, NM Kadow, K Palmer, M Yanovski, JA TI Clinical correlates of obesity in Latino children and adolescents SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NIH, DEB, Unit Growth & Obes, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1188 BP 209A EP 209A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901189 ER PT J AU Steinberg, E Tanofsky-Kraff, M Cohen, M Elberg, J Freedman, R Parikh, S Semega-Janneh, M Yanovski, S Yanovski, J AF Steinberg, E Tanofsky-Kraff, M Cohen, M Elberg, J Freedman, R Parikh, S Semega-Janneh, M Yanovski, S Yanovski, J TI Differences in parent and child reports of children's eating and weight control behaviors SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIH, Unit Growth & Obes, Bethesda, MD 20892 USA. NIH, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1185 BP 209A EP 209A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901186 ER PT J AU Perrin, EM Murphy, ML Casey, J Pichichero, ME Runyan, DK Swedo, SE AF Perrin, EM Murphy, ML Casey, J Pichichero, ME Runyan, DK Swedo, SE TI A prospective study of the neuropsychiatric sequelae of Streptococcal infection SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. Elmwood Pediat Grp, Rochester, NY USA. NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1226 BP 216A EP 216A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901227 ER PT J AU Frattarelli, DAC Aranda, JV AF Frattarelli, DAC Aranda, JV TI Scaling in a children's hospital SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Hosp Michigan, NIH PPRU, Div Clin Pharmacol, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1298 BP 228A EP 228A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901299 ER PT J AU Cabral, WA Marini, JC AF Cabral, WA Marini, JC TI High proportion of osteoblasts heterozygous for type I collagen mutations is compatible with normal skeletal function: Implications for cell therapy SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Sect Connect Tissue Disorders, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1475 BP 258A EP 258A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901475 ER PT J AU Goker-Alpan, O Orvisky, E Lwin, A Schiffman, R Sidransky, E AF Goker-Alpan, O Orvisky, E Lwin, A Schiffman, R Sidransky, E TI Divergent phenotypes associated with genotype L444P/L444P: The role of modifiers in Gaucher disease SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIMH, NSB, NIH, Bethesda, MD 20892 USA. NHGRI, MGB, NIH, Bethesda, MD 20892 USA. NINDS, DMNB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1473 BP 258A EP 258A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901473 ER PT J AU Goker-Alpan, O Tayebi, N Kishani, P Rosenbaum, H Sidransky, E AF Goker-Alpan, O Tayebi, N Kishani, P Rosenbaum, H Sidransky, E TI Renal involvement in Gaucher disease: Different mechanisms with different outcomes SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIMH, NSB, NIH, Bethesda, MD 20892 USA. NHGRI, MGB, NIH, Bethesda, MD 20892 USA. Duke Univ, Durham, NC 27706 USA. Rambam Med Ctr, Haifa, Israel. NR 0 TC 0 Z9 0 U1 1 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1472 BP 258A EP 258A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901472 ER PT J AU Letocha, AD Reynolds, J Reing, CM Chernoff, EJ Troendle, J Hill, S Gerber, L Marini, JC AF Letocha, AD Reynolds, J Reing, CM Chernoff, EJ Troendle, J Hill, S Gerber, L Marini, JC TI Controlled trial of pamidronate in children with types III and IV OI SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, NIH, Sect Connect Tissue Disorders, Bethesda, MD USA. NICHD, NIH, Biometry & Math Stat Branch, Bethesda, MD USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. INOVA Fairfax Hosp, Dept Orthoped, Fairfax, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1476 BP 258A EP 259A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901476 ER PT J AU Lacbawan, FL Davis, RL Collins, GH Kent, P Holohan, PD Shrimpton, AE Muenke, M Krasnewich, D AF Lacbawan, FL Davis, RL Collins, GH Kent, P Holohan, PD Shrimpton, AE Muenke, M Krasnewich, D TI Neuroserpinopathy: A conformational neurodegenerative disorder in children and adults SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Syracuse, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1485 BP 260A EP 260A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901485 ER PT J AU Karl, JC Taylor, SK Fry, TJ Mackall, CL AF Karl, JC Taylor, SK Fry, TJ Mackall, CL TI Expansion, maturation, and functional characterization of murine dendritic cells for tumor immunotherapy SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Amer Pediat Soc Pediat Res, Student Res Program, The Woodlands, TX USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1571 BP 275A EP 275A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901570 ER PT J AU Liu, YS Li, J Lorenzini, A Sinogeeva, N Chen, PL Gorospe, M Cristofalo, VJ AF Liu, YS Li, J Lorenzini, A Sinogeeva, N Chen, PL Gorospe, M Cristofalo, VJ TI Constitutively active Raf induces growth arrest in WI-38 normal human lung fibroblasts: The effects of active Raf on chromosomal structure and gene expression profiles SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NIA, Intramural Res Program, Lab Cellular Mol Biol, Baltimore, MD 21224 USA. Lankenau Inst Med Res, Wynnewood, PA USA. Ohio State Univ, Childrens Hosp, Childrens Res Inst, Ctr Dev Pharmacol & Toxicol, Columbus, OH 43210 USA. RI Lorenzini, Antonello/G-4463-2012; LORENZINI, ANTONELLO/E-6582-2016 OI LORENZINI, ANTONELLO/0000-0001-9615-9697 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1572 BP 275A EP 275A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901571 ER PT J AU Sutton, JF Stacey, M Kearns, WG Young, NS Liu, JM AF Sutton, JF Stacey, M Kearns, WG Young, NS Liu, JM TI Increased risk for aplastic anemia and myelodysplastic syndrome in individuals lacking GSTT1 gene SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. Eastern Virginia Med Sch, Ctr Pediat Res, Norfolk, VA 23501 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1599 BP 280A EP 280A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901598 ER PT J AU Velazquez, I Alter, BP AF Velazquez, I Alter, BP TI Comparison of liver tumors associated with androgen use in non-Fanconi's anemia (FA) and Fanconi's anemia patients SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Clin Genet Branch, Rockville, MD USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1665 BP 292A EP 292A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901664 ER PT J AU Raju, TNK AF Raju, TNK TI The battling snakes: Should Caduceus continue to be the symbol of medicine? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, NIH, CRMC, Pregnancy & Perinatol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1738 BP 304A EP 304A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901737 ER PT J AU Lulic, M Ergun, H Frattarelli, DAC Tutag-Lehr, V Aranda, JV AF Lulic, M Ergun, H Frattarelli, DAC Tutag-Lehr, V Aranda, JV TI Vancomycin elimination in intrauterine growth retardation SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Hutzel Hosp, Dept Pharm, Detroit, MI 48201 USA. Childrens Hosp Michigan, NIH PPRU, Div Clin Pharmacol, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1807 BP 317A EP 317A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901806 ER PT J AU Chowers, Y Kirschner, J Keller, N Barshak, I Tal, R Bar-Meir, S Schneerson, R Passwell, JH AF Chowers, Y Kirschner, J Keller, N Barshak, I Tal, R Bar-Meir, S Schneerson, R Passwell, JH TI IgG polysaccharide antibodies derived from immune sera inhibit the uptake of Shigella organisms into gastro-intestinal epithelial cells and inhibit their provoked inflammatory response SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Weizmann Inst Sci, IL-76100 Rehovot, Israel. NICHD, Lab Dev & Mol Immunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1853 BP 325A EP 325A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901852 ER PT J AU Veasy, LG Tani, LY Daly, JA Miner, LJ Bale, JF Korgenski, K Kaplan, EL Musser, JM Hill, HR AF Veasy, LG Tani, LY Daly, JA Miner, LJ Bale, JF Korgenski, K Kaplan, EL Musser, JM Hill, HR TI Temporal association of mucoid strains of streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA. Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA. Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. Univ Minnesota, Minneapolis, MN 55455 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1881 BP 329A EP 330A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901880 ER PT J AU Mirochnick, M Bryson, Y Stek, A Mofenson, L Connor, J Watts, H Huang, S Hughes, M Cunningham-Schrader, B Purdue, L Asfaw, Y Smith, E AF Mirochnick, M Bryson, Y Stek, A Mofenson, L Connor, J Watts, H Huang, S Hughes, M Cunningham-Schrader, B Purdue, L Asfaw, Y Smith, E TI Pharmacokinetics (PK) of nelfinavir (NFV) and its M8 metabolite in pregnant HIV-infected women and their infants: PACTG 353 SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Univ So Calif, Med Ctr, Los Angeles, CA 90089 USA. NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. SDAC, Boston, MA USA. FSTRF, Buffalo, NY USA. PACTG Ops, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1891 BP 331A EP 331A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901890 ER PT J AU Domachowske, JB Bonville, CA Rosenberg, HF AF Domachowske, JB Bonville, CA Rosenberg, HF TI Microarray analysis of pulmonary gene expression patterns using a mouse model of acute, severe bronchiolitis SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 SUNY Upstate Med Univ, Syracuse, NY USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1915 BP 335A EP 336A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901914 ER PT J AU Bonville, CA Rosenberg, HF Domachowske, JB AF Bonville, CA Rosenberg, HF Domachowske, JB TI Successful therapeutic intervention for severe bronchiolitis using pharmacologic blockade of chemokine receptor-1 (CCR1) in combination with antiviral therapy SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 SUNY Upstate Med Univ, Syracuse, NY USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 1917 BP 336A EP 336A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897901916 ER PT J AU Laptook, AR O'Shea, TM Shankaran, S Bhaskar, B AF Laptook, AR O'Shea, TM Shankaran, S Bhaskar, B TI Extremely low birth weight infants (ELBW, BW < 1000 gm) with normal head ultrasounds (HUS) have poor early neurodevelopment (ND) SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2003 BP 351A EP 351A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902001 ER PT J AU Vohr, BR Wright, LL Perritt, R Poole, K AF Vohr, BR Wright, LL Perritt, R Poole, K TI Motherhood >= 30 years, multiples and extremely low birth weight SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2156 BP 380A EP 380A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902154 ER PT J AU Llanos, AR Mena, P Valenzuela, A Salem, N Uauy, R AF Llanos, AR Mena, P Valenzuela, A Salem, N Uauy, R TI Effect of IUGR on the formation of DHA and AA from deuterated precursors SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 INTA Univ Chile, Santiago, Chile. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2205 BP 389A EP 389A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902203 ER PT J AU Curtis, J Kim, G Wehr, NB Levine, RL AF Curtis, J Kim, G Wehr, NB Levine, RL TI Identification of the group B streptcoccal pulmonary hypertensive factor SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Natl Naval Med Res Inst, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Biochem Lab, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD USA. RI Levine, Rodney/D-9885-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2213 BP 391A EP 391A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902211 ER PT J AU Benjamin, DK Delong, ER Steinbach, WJ Cotten, CM Walsh, TJ Clark, RH AF Benjamin, DK Delong, ER Steinbach, WJ Cotten, CM Walsh, TJ Clark, RH TI Empirical therapy for neonatal candidemia: Evaluation of 21,233 blood cultures SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Duke Univ, Durham, NC 27706 USA. Duke Clin Res Inst, Durham, NC USA. Pediatrix, Neonatol, Ft Lauderdale, FL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2245 BP 396A EP 396A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902243 ER PT J AU Hintz, SR Kendrick, DE Stoll, BJ Vohr, BR Fanaroff, AA Donovan, EF Poole, WK Blakely, ML Wright, LL AF Hintz, SR Kendrick, DE Stoll, BJ Vohr, BR Fanaroff, AA Donovan, EF Poole, WK Blakely, ML Wright, LL CA NICHD Neonatal Res Network TI Long-term neurodevelopmental outcome of extremely low birth weight (ELBW) infants after necrotizing enterocolitis SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Stanford Univ, Stanford, CA 94305 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Emory Univ, Atlanta, GA 30322 USA. Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Univ Texas, Houston, TX 77030 USA. NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2252 BP 398A EP 398A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902250 ER PT J AU Thomas, RL Aranda, JV Van Overmeire, B Hamre, M AF Thomas, RL Aranda, JV Van Overmeire, B Hamre, M TI A meta-analysis comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus (PDA) SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Wayne State Univ, Sch Med, Detroit, MI 48202 USA. Childrens Hosp Michigan, NIH, NICHD, Pharmaceut Res Unit, Detroit, MI 48201 USA. Univ Antwerp Hosp, Antwerp, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2368 BP 419A EP 419A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902366 ER PT J AU Shankaran, S Das, A Bauer, CR Bada, H Lester, B Wright, L Poole, K AF Shankaran, S Das, A Bauer, CR Bada, H Lester, B Wright, L Poole, K TI Fetal origin in childhood disease: Is intra-uterine growth restriction in term infants associated with risk of childhood hypertension? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2378 BP 420A EP 420A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902376 ER PT J AU Bada, HS Das, A Bauer, CR Shankaran, S Lester, BM Gard, C Wright, LL Smeriglio, V LaGasse, L AF Bada, HS Das, A Bauer, CR Shankaran, S Lester, BM Gard, C Wright, LL Smeriglio, V LaGasse, L TI Intrauterine growth restriction: Legal and illegal drug use and population attributable risk SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2385 BP 421A EP 422A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902383 ER PT J AU Heller, CD O'Shea, M Wrage, L Poole, K AF Heller, CD O'Shea, M Wrage, L Poole, K TI Human milk intake and the risk of retinopathy of prematurity in extremely low birth weight infants SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Wake Forest Univ, Winston Salem, NC 27109 USA. NICHD, Neonatal Res Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2396 BP 424A EP 424A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902394 ER PT J AU Blakely, ML Tyson, JE McDonald, SA Lally, KP Poole, K Stoll, BJ Stevenson, DK Wright, LL AF Blakely, ML Tyson, JE McDonald, SA Lally, KP Poole, K Stoll, BJ Stevenson, DK Wright, LL TI Outcome of extremely low birth weight (ELBW) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) treated with initial laparotomy (lap) or peritoneal drainage SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2472 BP 437A EP 437A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902470 ER PT J AU Truong, HHM Sim, M Dillon, M Uittenbogaart, C Dickover, R Plaeger, S Bryson, Y AF Truong, HHM Sim, M Dillon, M Uittenbogaart, C Dickover, R Plaeger, S Bryson, Y TI Immune activation during late pregnancy and postpartum as measured by elevated serum beta 2-microglobulin correlates with increases in HIV RNA and CD4/CD8 T cells SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2475 BP 438A EP 438A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902473 ER PT J AU Vohr, BR Poindexter, BB Dusick, AM McKinley, LT Wright, LL Langer, J Poole, K AF Vohr, BR Poindexter, BB Dusick, AM McKinley, LT Wright, LL Langer, J Poole, K TI Effects of human milk (HM) in the NICU on the developmental outcome and growth of ELBW infants at 18 months of age SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2487 BP 440A EP 440A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902485 ER PT J AU Shankaran, S Langer, J Kazzi, SN Laptook, A Walsh, M AF Shankaran, S Langer, J Kazzi, SN Laptook, A Walsh, M TI Cumulative hours of exposure to hypocarbia and hyperoxia as risk factors for periventricular leukomalacia (PVL) in low birth weight (LBW) infants SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2541 BP 450A EP 450A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902539 ER PT J AU Cotton, RB Sundell, H Zeldin, DC Morrow, JD Roberts, LJ Hazinski, TA Law, AB Steele, S AF Cotton, RB Sundell, H Zeldin, DC Morrow, JD Roberts, LJ Hazinski, TA Law, AB Steele, S TI Inhaled nitric oxide (NO) attenuates hyperoxic lung injury in lambs SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Vanderbilt Univ, Nashville, TN USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2615 BP 463A EP 463A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902613 ER PT J AU El-Mohandes, AAE El-Khorazaty, MN Kiely, M Johnson, AA Subramanian, KNS Joseph, JG AF El-Mohandes, AAE El-Khorazaty, MN Kiely, M Johnson, AA Subramanian, KNS Joseph, JG TI Assessment of levels of nicotine exposure during pregnancy among high-risk minority women in Washington, DC SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 George Washington Univ, Washington, DC 20052 USA. Res Triangle Inst, Rockville, MD USA. NICHHD, Rockville, MD USA. Howard Univ, Washington, DC 20059 USA. Georgetown Univ, Washington, DC 20057 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2682 BP 475A EP 475A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902680 ER PT J AU El-Mohandes, AAE El-Khorazaty, MN Kiely, M Joseph, JG Subramanian, KNS Johnson, AA AF El-Mohandes, AAE El-Khorazaty, MN Kiely, M Joseph, JG Subramanian, KNS Johnson, AA CA DC Initiative Reduce Infant TI Project DC-hope of the NIH-DC initiative to reduce infant mortality: An integrated community intervention to improve pregnancy outcomes SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 George Washington Univ, Washington, DC 20052 USA. Res Triangle Inst, Rockville, MD USA. NICHHD, Rockville, MD USA. Childrens Hosp, Natl Med Ctr, Washington, DC 20010 USA. Georgetown Univ, Washington, DC 20057 USA. Howard Univ, Washington, DC 20059 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2683 BP 475A EP 475A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902681 ER PT J AU El-Mohandes, AAE El-Khorazaty, MN Kiely, M Johnson, AA Joseph, JG Subramanian, KNS AF El-Mohandes, AAE El-Khorazaty, MN Kiely, M Johnson, AA Joseph, JG Subramanian, KNS CA NIH-DC Initiat Reduce Infant Mortal TI Audio computer-assisted self-interview (A-CASI) as a screening tool for risk factors in minority women receiving prenatal care SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 George Washington Univ, Washington, DC 20052 USA. Res Triangle Inst, Rockville, MD USA. NICHHD, Rockville, MD USA. Howard Univ, Washington, DC 20059 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Georgetown Univ, Washington, DC 20057 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2681 BP 475A EP 475A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902679 ER PT J AU Kiely, M El-Mohandes, AAE El-Khorazaty, MN Johnson, AA Subramanian, KNS Joseph, JG AF Kiely, M El-Mohandes, AAE El-Khorazaty, MN Johnson, AA Subramanian, KNS Joseph, JG TI Evaluation of methodologies identifying smokers and levels of smoking during pregnancy among high risk minority women in DC SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHHD, Rockville, MD USA. George Washington Univ, Washington, DC 20052 USA. Res Triangle Inst, Rockville, MD USA. Georgetown Univ, Washington, DC 20057 USA. Howard Univ, Washington, DC 20059 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 2739 BP 485A EP 485A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897902737 ER PT J AU Yang, ZW Zheng, SP Asico, LD Yu, PY Bek, M Sibley, DR Jose, PA AF Yang, ZW Zheng, SP Asico, LD Yu, PY Bek, M Sibley, DR Jose, PA TI Regulation of reactive oxygen species production by phospholipase D and D-5 dopamine receptors SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Georgetown Univ, Med Ctr, Dept Pediat & Physiol & Biophys, Washington, DC 20007 USA. NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3005 BP 531A EP 531A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903002 ER PT J AU Lester, BM Das, A LaGasse, LL Seifer, R Bauer, CR Shankaran, S Bada, H Messinger, D Wright, LL Smeriglio, V Poole, K AF Lester, BM Das, A LaGasse, LL Seifer, R Bauer, CR Shankaran, S Bada, H Messinger, D Wright, LL Smeriglio, V Poole, K TI Prenatal cocaine exposure and 7-year outcome: IQ and special education SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHD, Neonatal Res Network, Bethesda, MD USA. NIDA, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3020 BP 534A EP 534A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903017 ER PT J AU Grabill, CM Silva, A Koretsky, A Rouault, TA AF Grabill, CM Silva, A Koretsky, A Rouault, TA TI MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3100 BP 548A EP 548A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903097 ER PT J AU Urs, J Frattarelli, DAC Gates, D Biglin, K Lieh-Lai, M Aranda, JV AF Urs, J Frattarelli, DAC Gates, D Biglin, K Lieh-Lai, M Aranda, JV TI Patterns of near miss medication errors in an inpatient pharmacy SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Hosp Michigan, Div Med Educ, Detroit, MI 48201 USA. Childrens Hosp Michigan, NIH PPRU, Div Clin Pharmacol, Detroit, MI 48201 USA. Childrens Hosp Michigan, Dept Pharm, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3162 BP 558A EP 559A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903159 ER PT J AU Ergun, H Frattarelli, DAC Aravind, MK Aranda, JV AF Ergun, H Frattarelli, DAC Aravind, MK Aranda, JV TI Characterization of the role of physiochemical factors in the hydrolysis of dipyrone SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Hosp Michigan, Div Clin Pharmacol, NIH PPRU, Detroit, MI 48201 USA. Ankara Univ, Dept Pharmacol & Clin Pharmacol, TR-06100 Ankara, Turkey. NR 0 TC 0 Z9 0 U1 1 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3178 BP 561A EP 561A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903174 ER PT J AU Mirza, NM Palmer, M Kadow, K Yanovski, JA AF Mirza, NM Palmer, M Kadow, K Yanovski, JA TI Does body size matter to Latino children and adolescents? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT Annual Meeting of the Pediatric-Academic-Society CY MAY 03-06, 2003 CL SEATTLE, WASHINGTON SP Pediat Acad Soc, Amer Pediat Soc, Soc Pediat Res, Ambulatory Pediat Assoc, Tulane Univ Hlth Sci Ctr, Ctr Continuing Educ C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NIH, DEB, Unit Growth & Obes, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 SU S MA 3272 BP 577A EP 578A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 661PA UT WOS:000181897903268 ER PT J AU Nelson, KB Grether, JK Dambrosia, JM Walsh, E Kohler, S Satyanarayana, G Nelson, PG Dickens, BF Phillips, TM AF Nelson, KB Grether, JK Dambrosia, JM Walsh, E Kohler, S Satyanarayana, G Nelson, PG Dickens, BF Phillips, TM TI Neonatal cytokines and cerebral palsy in very preterm infants SO PEDIATRIC RESEARCH LA English DT Article ID BIRTH-WEIGHT INFANTS; ENDOTHELIAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; PERIVENTRICULAR LEUKOMALACIA; INFLAMMATORY CYTOKINES; RISK; LESIONS; CHORIOAMNIONITIS; PREMATURITY; INFECTION AB To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of I I cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-alpha, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children. C1 NINDS, Neuroepidemiol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, Oakland, CA 94612 USA. Calif Dept Hlth Serv, Environm Hlth Invest Branch, Oakland, CA 94612 USA. George Washington Univ, Med Ctr, Immunochem Lab, Washington, DC 20037 USA. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIH, DBEPS, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NIH, Ctr Clin, Room 5S221, Bethesda, MD 20892 USA. NR 30 TC 104 Z9 106 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD APR PY 2003 VL 53 IS 4 BP 600 EP 607 DI 10.1203/01.PDR.0000056802.22454.AB PG 8 WC Pediatrics SC Pediatrics GA 661NU UT WOS:000181897300013 PM 12612192 ER PT J AU Gubbins, PO Melchert, RB McConnell, SA Franks, AM Penzak, SR Gurley, BJ AF Gubbins, PO Melchert, RB McConnell, SA Franks, AM Penzak, SR Gurley, BJ TI Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using primary human hepatocytes SO PHARMACOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY NOV 04-09, 2000 CL LOS ANGELES, CALIFORNIA SP Amer Coll Clin Pharmacy DE itraconazole; interleukin 6; drug metabolism ID CYTOCHROME-P-450 ENZYMES; DRUG-METABOLISM; PRIMARY CULTURE; EXPRESSION; PHARMACOKINETICS; CYTOKINES; SERUM; INDUCTION; RECEPTOR; MYELOMA AB A potential cytokine-drug interaction between interleukin 6 (IL-6) and itraconazole (ITZ) was studied using human hepatocytes in primary culture. Cultures from 5 adult males (mean age 42 15 years) who had not received any medicines known to interact with CYP3A4 were studied. Cultures were exposed to ITZ 500 ng/ml, and the effects of 120 mug/ml cimetidine, 50 ng/ml human IL-6, or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h. Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC and normalized to total cellular protein. Mean intracellular concentrations between groups were compared using one-way Anova (f test; p <0.10) and corresponding Bonferroni versus control test for multiple comparisons (p < 0.02). Mean intracellular ITZ concentrations between the groups were similar at all time points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6 did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent metabolism. C1 Univ Arkansas Med Sci, Coll Pharm, Dept Pharm Practice, Little Rock, AR 72257 USA. Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, Little Rock, AR 72257 USA. NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Lab, Bethesda, MD USA. RP Gubbins, PO (reprint author), Univ Arkansas Med Sci, Coll Pharm, Dept Pharm Practice, 4301 W Markham,Slot 522, Little Rock, AR 72257 USA. EM Gubbinspaulo@uams.edu OI Melchert, Russell/0000-0003-4813-6911 NR 23 TC 2 Z9 2 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0031-7012 J9 PHARMACOLOGY JI Pharmacology PD APR PY 2003 VL 67 IS 4 BP 195 EP 201 DI 10.1159/000068401 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 656XL UT WOS:000181636300003 PM 12595750 ER PT J AU Dimmock, JR Jha, A Zello, GA Allen, TM Santos, CL Balzarini, J De Clercq, E Manavathu, EK Stables, JP AF Dimmock, JR Jha, A Zello, GA Allen, TM Santos, CL Balzarini, J De Clercq, E Manavathu, EK Stables, JP TI Cytotoxic 4 '-aminochalcones and related compounds SO PHARMAZIE LA English DT Article ID MALEAMIC ACIDS; INVIVO AB A series of 4'-aminochalcones 1 and related maleamic acids 2 and Schiff bases 3 were designed and synthesized as candidate cytotoxic agents. The atomic charges on different atoms of representative compounds were calculated. Evaluation of the enones 1-3 against human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells revealed that approximately 40% of the IC(50) values generated were less than 10 muM. In some cases cytotoxicity was correlated with the Hammett sigma values of the aryl substituents and less frequently with the aryl Hansch pi values. Evidence was obtained that in general these compounds displayed selective toxicity for certain malignant cells and were well tolerated in mice. This study has revealed various directions whereby the project may be amplified in the future with a view to finding compounds with increased cytotoxicity to tumour cells. C1 Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2M7, Canada. Rega Inst, Louvain, Belgium. Wayne State Univ, Dept Med, Detroit, MI 48202 USA. NINDS, Bethesda, MD 20892 USA. RP Dimmock, JR (reprint author), Univ Saskatchewan, Coll Pharm & Nutr, 110 Sci Pl, Saskatoon, SK S7N 5C9, Canada. RI Jha, Amitabh/B-5452-2010 OI Jha, Amitabh/0000-0002-6305-0721 NR 27 TC 25 Z9 25 U1 0 U2 3 PU GOVI-VERLAG PHARMAZEUTISCHER VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCCARL MANNICH STR 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD APR PY 2003 VL 58 IS 4 BP 227 EP 232 PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 669YZ UT WOS:000182380600001 PM 12749401 ER PT J AU Yoon, TJ Hearing, VJ AF Yoon, TJ Hearing, VJ TI Co-culture of mouse epidermal cells for studies of pigmentation SO PIGMENT CELL RESEARCH LA English DT Article DE melanocyte; keratinocyte; co-culture; pigment; mutant ID SERUM-FREE CULTURE; HUMAN MELANOCYTES; KERATINOCYTES CONTROL; ULTRAVIOLET-RADIATION; MELANOMA-CELLS; DIFFERENTIATION; MELANOGENESIS; GROWTH; PROLIFERATION; EXPRESSION AB Interactions between melanocytes and keratinocytes in the skin suggest bi-directional interchanges between these two cell types. Thus, melanocytes cultured alone may not accurately reflect the physiology of the skin and the effects of physiological regulators in vivo, because they do not consider possible interactions with keratinocytes. As more and more pigment genes are identified and cloned, the characterization of their functions becomes more of a challenge, particularly with respect to their roles in the processing and transport of melanosomes and their transfer to keratinocytes. Immortalized melanocytes mutant at these loci are now being routinely generated from mice, but interestingly, successful co-culture of murine melanocytes and keratinocytes is very difficult compared with their human counterparts. Thus, we have now optimized co-culture conditions for murine melanocytes and keratinocytes so that pigmentation and the effects of specific mutations can be studied in a more physiologically relevant context. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bldg 37,Room 1B22, Bethesda, MD 20892 USA. NR 37 TC 10 Z9 13 U1 1 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD APR PY 2003 VL 16 IS 2 BP 159 EP 163 DI 10.1034/j.1600-0749.2003.00028.x PG 5 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 652HK UT WOS:000181373600009 PM 12622793 ER PT J AU Borzychowski, AM Chantakru, S Minhas, K Paffaro, VA Yamada, AT He, H Korach, KS Croy, BA AF Borzychowski, AM Chantakru, S Minhas, K Paffaro, VA Yamada, AT He, H Korach, KS Croy, BA TI Functional analysis of murine uterine natural killer cells genetically devoid of oestrogen receptors SO PLACENTA LA English DT Article ID METRIAL GLAND-CELLS; INTERFERON-GAMMA CONTRIBUTES; MESSENGER RIBONUCLEIC-ACIDS; PREGNANT MOUSE UTERUS; ESTROGEN-RECEPTOR; MENSTRUAL-CYCLE; GROWTH-FACTOR; MICE; PROGESTERONE; DIFFERENTIATION AB Uterine Natural Killer (uNK) cell differentiation in vivo requires oestrogen (E) priming prior to progesterone (P). Hybridomas between uNK precursor and SP2/0 cells express message for E receptor (ER)alpha but nor PR. However, mature, rodent and human uNK cells lack these receptors. To functionally assess requirements for uNK cell expression of ERalpha, or ERbeta during precursor differentiation, marrow was transplanted from either ERalphadegrees(/)degrees (alphaERKO) or ERbetadegrees(/)degrees (betaERKO) mice into alymphoid RAG-2degrees(/)degrees/gammacdegrees(/)degrees females. Recipients were mated and their implantation sites were examined by light microscopy, morphometry and ultrastructure. High numbers of uNK cells were established from each donor strain. Graft-derived uNK cells were similar in number and morphology to uNK cells of normal mice, suggesting that neither alpha- nor beta-ER is required for uNK precursor cell differentiation. Induction of spiral artery modification in the transplant recipients indicated that graft-derived uNK cells had functional properties. A novel technique for rapid isolation of highly purified uNK cells from normal mice using Dolichos biflorus agglutinin (DBA) lectin-conjugated magnetic beads was employed to obtain RNA. Expression of alpha- and beta-ER was absent by RT-PCR from NK cells isolated from the uterus, supporting the conclusions from the in vivo study. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Guelph, Ontario Vet Coll, Dept Biomed Sci, Guelph, ON N1G 2W1, Canada. NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Estadual Campinas, Inst Biol, BR-13083970 Campinas, SP, Brazil. RP Croy, BA (reprint author), Univ Guelph, Ontario Vet Coll, Dept Biomed Sci, Room 2604,Bldg 40, Guelph, ON N1G 2W1, Canada. RI Yamada, Aureo/F-7752-2012; OI Yamada, Aureo/0000-0003-3620-9685; Korach, Kenneth/0000-0002-7765-418X NR 53 TC 21 Z9 21 U1 0 U2 6 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD APR PY 2003 VL 24 IS 4 BP 403 EP 411 DI 10.1053/plac.2002.0924 PG 9 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 672MW UT WOS:000182525500015 PM 12657515 ER PT J AU Junicke, H Hart, JR Kisko, J Glebov, O Kirsch, IR Barton, JK AF Junicke, H Hart, JR Kisko, J Glebov, O Kirsch, IR Barton, JK TI A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIIMINE COMPLEXES; PROSTATE-CANCER; CELL-LINES; REPAIR; INTERCALATOR; INSTABILITY; DEFECTS AB A rhodium(III) complex, rac-[Rh(bpy)(2)phzi](3+) (bpy, 2,2'-bipyridine; phzi, benzo[a]phenazine-5,6-quinone diimine) has been designed as a sterically demanding intercalator targeted to destabilized mismatched sites in double-helical DNA. The complex is readily synthesized by condensation of the phenazine quinone with the corresponding diammine complex. Upon photoactivation, the complex promotes direct strand scission at single-base mismatch sites within the DNA duplex. As with the parent mismatch-specific reagent, [Rh(bpy)(2)(chrysi)](3+) [chrysene-5,6-quinone diimine (chrysi)], mismatch selectivity depends on the helix destabilization associated with mispairing. Unlike the parent chrysi complex, the phzi analogue binds and cleaves with high affinity and efficiency. The specific binding constants for CA, CC, and CT mismatches within a 31-mer oligonucleotide duplex are 0.3, 1, and 6 x 10(7) M-1, respectively; site-specific photocleavage is evident at nanomolar concentrations. Moreover, the specificity, defined as the ratio in binding affinities for mispaired vs. well paired sites, is maintained. The increase in affinity is attributed to greater stability in the mismatched site associated with stacking by the heterocyclic aromatic ligand. The high-affinity complex is also applied in the differential cleavage of DNA obtained from cell lines deficient in mismatch repair vs. those proficient in mismatch repair. Agreement is found between photocleavage by the mismatch-specific probes and deficiency in mismatch repair. This mismatch-specific targeting, therefore, offers a potential strategy for new chemotherapeutic design. C1 CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. NCI, Genet Branch, Canc Res Ctr, Natl Naval Med Ctr, Gaithersburg, MD 20899 USA. RP Barton, JK (reprint author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. OI Hart, Jonathan/0000-0002-3905-225X FU NIGMS NIH HHS [R01 GM033309, GM33309, R37 GM033309] NR 21 TC 66 Z9 68 U1 2 U2 8 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 APR 1 PY 2003 VL 100 IS 7 BP 3737 EP 3742 DI 10.1073/pnas.0537194100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400039 PM 12610209 ER PT J AU Burchmore, RJS Rodriguez-Contreras, D McBride, K Barrett, MP Modi, G Sacks, D Landfear, SM AF Burchmore, RJS Rodriguez-Contreras, D McBride, K Barrett, MP Modi, G Sacks, D Landfear, SM TI Genetic characterization of glucose transporter function in Leishmania mexicana SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GREEN FLUORESCENT PROTEIN; PROMASTIGOTES; AMASTIGOTES; EXPRESSION; MUTANTS; STAGE; IDENTIFICATION; CULTIVATION; METABOLISM; INDUCTION AB Both insect and mammalian life cycle stages of Leishmania mexicana take up glucose and express all three isoforms encoded by the LmGT glucose transporter gene family. To evaluate glucose transporter function in intact parasites, a null mutant line has been created by targeted disruption of the LmGT locus that encompasses the LmGT1, LmGT2, and LmGT3 genes. This Deltalmgt null mutant exhibited no detectable glucose transport activity. The growth rate of the Deltalmgt knockout in the promastigote stage was reduced to a rate comparable with that of WT cells grown in the absence of glucose. Deltalmgt cells also exhibited dramatically reduced infectivity to macrophages, demonstrating that expression of LmGT isoforms is essential for viability of amastigotes. Furthermore, WT L. mexicana were not able to grow as axenic culture form amastigotes if glucose was withdrawn from the medium, implying that glucose is an essential nutrient in this life cycle stage. Expression of either LmGT2 or LmGT3, but not of LmGT1, in Deltalmgt null mutants significantly restored growth as promastigotes, but only LmGT3 expression substantially rescued amastigote growth in macrophages. Subcellular localization of the three isoforms was investigated in Deltalmgt cells expressing individual LmGT isoforms. Using anti-DeltamGT antiserum and GFP-tagged LmGT fusion proteins, LmGT2 and LmGT3 were localized to the cell body, whereas LmGT1 was localized specifically to the flagellum. These results establish that each glucose transporter isoform has distinct biological functions in the parasite. C1 Univ Glasgow, Inst Biomed & Life Sci, Div Infect & Immun, Glasgow G12 8QQ, Lanark, Scotland. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. RP Landfear, SM (reprint author), Univ Glasgow, Inst Biomed & Life Sci, Div Infect & Immun, Joseph Black Bldg, Glasgow G12 8QQ, Lanark, Scotland. RI Burchmore, Richard/A-1896-2011; OI Landfear, Scott/0000-0002-1643-6664; Barrett, Mike/0000-0001-9447-3519; Burchmore, Richard/0000-0003-1663-9004 FU NIAID NIH HHS [AI25920, R01 AI025920] NR 43 TC 88 Z9 94 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 1 PY 2003 VL 100 IS 7 BP 3901 EP 3906 DI 10.1073/pnas.0630165100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400068 PM 12651954 ER PT J AU Mullen, GED Kennedy, MN Visintin, A Mazzoni, A Leifer, CA Davies, DR Segal, DM AF Mullen, GED Kennedy, MN Visintin, A Mazzoni, A Leifer, CA Davies, DR Segal, DM TI The role of disulfide bonds in the assembly and function of MD-2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TOLL-LIKE RECEPTOR-4; CONFERS LIPOPOLYSACCHARIDE RESPONSIVENESS; SIGNAL-TRANSDUCTION; QUALITY-CONTROL; PROTEINS; TLR4; RECOGNITION; ACTIVATION; IMMUNITY; MOLECULE AB MD-2 is a secreted glycoprotein that binds to the extracellular domain of Toll-like receptor 4 (TLR4) and is required for the activation of TLR4 by lipopolysaccharide (LPS). The protein contains seven Cys residues and consists of a heterogeneous collection of disulfide-linked oligomers. To investigate the role of sulfhydryls in MD-2 structure and function, we created 17 single and multiple Cys substitution mutants. All of the MD-2 mutant proteins, including one totally lacking Cys residues, were secreted and stable. SDS/PAGE analyses indicated that most Cys residues could participate in oligomer formation and that no single Cys residue was required for oligomerization. Of the single Cys substitutions, only C95S and C1055 failed to confer LIPS responsiveness on TLR4 when mutant and TLR4 were cotransfected into cells expressing an NF-kappaB reporter plasmid. Surprisingly, substitution of both C95 and C105 partially restored activity. Structural analyses revealed that C95 and C105 formed an intrachain disulfide bond, whereas C95 by itself produced an inactive dimer. In contrast to the cotransfection experiments, only WT MD-2 conferred responsiveness to LIPS when secreted proteins were added directly to TLR4 reporter cells. Our data are consistent with a model in which most, possibly all sulfhydryls lie on the surface of a stable MD-2 core structure where they form both intra- and interchain disulfide bridges. These disulfide bonds produce a heterogeneous array of oligomers, including some species that can form an active complex with TLR4. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 23 TC 56 Z9 62 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 1 PY 2003 VL 100 IS 7 BP 3919 EP 3924 DI 10.1073/pnas.0630495100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400071 PM 12642668 ER PT J AU Rhee, J Inoue, Y Yoon, JC Puigserver, P Fan, ML Gonzalez, FJ Spiegelman, BM AF Rhee, J Inoue, Y Yoon, JC Puigserver, P Fan, ML Gonzalez, FJ Spiegelman, BM TI Regulation of hepatic fasting response by PPAR gamma coactivator-1 alpha (PGC-1): Requirement for hepatocyte nuclear factor 4 alpha in gluconeogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; TRANSCRIPTION FACTOR FKHR; MITOCHONDRIAL BIOGENESIS; DEHYDROGENASE GENE; ACCESSORY FACTOR; FACTOR-IV; EXPRESSION; INSULIN; ALPHA AB The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4alpha in the liver, we show here that PGC-1alpha completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4alpha is absent. It is also shown that PGC-1alpha can induce genes of beta-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4alpha. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4alpha-binding sites that function robustly only when HNF4alpha is coactivated by PGC-1alpha. These data illustrate the involvement of PGC-1alpha in several aspects of the hepatic fasting response and show that HNF4alpha is a critical component of PGC-1alpha-mediated gluconeogenesis. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Lab Metab, Bethesda, MD 20892 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NIDDK NIH HHS [R01 DK061562, DK 61562] NR 41 TC 342 Z9 352 U1 4 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 APR 1 PY 2003 VL 100 IS 7 BP 4012 EP 4017 DI 10.1073/pnas.0730870100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400087 PM 12651943 ER PT J AU Liu, YQ Zhou, JZ Omelchenko, MV Beliaev, AS Venkateswaran, A Stair, J Wu, LY Thompson, DK Xu, D Rogozin, IB Gaidamakova, EK Zhai, M Makarova, KS Koonin, EV Daly, MJ AF Liu, YQ Zhou, JZ Omelchenko, MV Beliaev, AS Venkateswaran, A Stair, J Wu, LY Thompson, DK Xu, D Rogozin, IB Gaidamakova, EK Zhai, M Makarova, KS Koonin, EV Daly, MJ TI Transcriptome dynamics of Deinococcus radiodurans recovering from ionizing radiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESCHERICHIA-COLI; NUDIX HYDROLASES; GENE-EXPRESSION; STRAND BREAKS; DNA-BINDING; GENOME; PROTEIN; REPAIR; RECA; RECOMBINATION AB Deinococcus radiodurans R1 (DEIRA) is a bacterium best known for its extreme resistance to the lethal effects of ionizing radiation, but the molecular mechanisms underlying this phenotype remain poorly understood. To define the repertoire of DEIRA genes responding to acute irradiation (15 kGy), transcriptome dynamics were examined in cells representing early, middle, and late phases of recovery by using DNA microarrays covering approximate to94% of its predicted genes. At least at one time point during DEIRA recovery, 832 genes (28% of the genome) were induced and 451 genes (15%) were repressed 2-fold or more. The expression patterns of the majority of the induced genes resemble the previously characterized expression profile of recA after irradiation. DEIRA recA, which is central to genomic restoration after irradiation, is substantially up-regulated on DNA damage (early phase) and down-regulated before the onset of exponential growth (late phase). Many other genes were expressed later in recovery, displaying a growth-related pattern of induction. Genes induced in the early phase of recovery included those involved in DNA replication, repair, and recombination, cell wall metabolism, cellular transport, and many encoding uncharacterized proteins. Collectively, the microarray data suggest that DEIRA cells efficiently coordinate their recovery by a complex network, within which both DNA repair and metabolic functions play critical roles. Components of this network include a predicted distinct ATP-dependent DNA ligase and metabolic pathway switching that could prevent additional genomic damage elicited by metabolism-induced free radicals. C1 Oak Ridge Natl Lab, Div Environm Sci, Oak Ridge, TN 37831 USA. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. Michigan State Univ, Ctr Microbial Ecol, E Lansing, MI 48824 USA. NIH, Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Zhou, JZ (reprint author), Oak Ridge Natl Lab, Div Environm Sci, POB 2008, Oak Ridge, TN 37831 USA. RI Beliaev, Alexander/E-8798-2016 OI Beliaev, Alexander/0000-0002-6766-4632 NR 48 TC 211 Z9 229 U1 4 U2 19 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 APR 1 PY 2003 VL 100 IS 7 BP 4191 EP 4196 DI 10.1073/pnas.0630387100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400118 PM 12651953 ER PT J AU Friedman-Hill, SR Robertson, LC Desimone, R Ungerleider, LG AF Friedman-Hill, SR Robertson, LC Desimone, R Ungerleider, LG TI Posterior parietal cortex and the filtering of distractors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SPATIAL SELECTIVE ATTENTION; POSITRON-EMISSION-TOMOGRAPHY; RESPONSE CHANNEL ACTIVATION; UNILATERAL VISUAL NEGLECT; INFERIOR TEMPORAL CORTEX; EXTRASTRIATE AREA V4; DIRECTED ATTENTION; BALINTS-SYNDROME; SINGLE NEURONS; NEURAL SYSTEMS AB Neural systems for visual processing can focus attention on behaviorally relevant objects, filtering out competing distractors: Neurophysiological studies in animals and brain imaging studies in humans suggest that such filtering depends on top-down inputs to extrastriate visual areas, originating in structures important for attentional control. To test whether the posterior parietal cortex may be a necessary source of signals that filter distractors, we measured the ability of a patient with bilateral parietal lesions to discriminate the features of a target surrounded by distractors of variable contrast. In the presence of distractors, the patient was impaired at discriminating both grating orientation and faces, and the magnitude of the impairment increased with distractor salience. These attentional deficits are remarkably similar to those caused by damage to monkey extrastriate regions V4 and/or TEO, which are thought to be recipients of top-down attentional feedback. In contrast to the effects of V4 and TEO lesions, however, the parietal lesions impaired performance even with widely spaced targets and distractors, a finding consistent with the projections of parietal cortex to visual processing areas covering a wide range of receptive field sizes and eccentricities. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. Dept Vet Affairs, Med Res Serv, Martinez, CA 94553 USA. RP Friedman-Hill, SR (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM friedmas@intra.nimh.nih.gov NR 85 TC 92 Z9 95 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 1 PY 2003 VL 100 IS 7 BP 4263 EP 4268 DI 10.1073/pnas.0730772100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 664JR UT WOS:000182058400130 PM 12646699 ER PT J AU Cao, H Lu, PH Sheng, ZH AF Cao, H Lu, PH Sheng, ZH TI Functions of glia in synaptogenesis and synaptic neurotransmission SO PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS LA Chinese DT Article DE glia cells; build synapse; synaptic neurotransmission ID CULTURED HIPPOCAMPAL-NEURONS; GLUTAMATE RECEPTORS; ASTROCYTES; CELLS; RELEASE; TRANSMISSION; SYNAPSES; WAVES AB More and more researches show that glial cells not only provide an ideal environment for neuronal cell but help neurons to build synapse and enhance synaptic efficacy directly. In addition, glial cells can release chemical transmitters and are intimately involved in the active control of neuronal activity and synaptic neurotransmission. C1 Shanghai Med Univ 2, Dept Neurobiol, Shanghai 200025, Peoples R China. NIH, Synapt Funct Unit, Bethesda, MD 20892 USA. NR 20 TC 1 Z9 1 U1 0 U2 0 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1000-3282 J9 PROG BIOCHEM BIOPHYS JI Prog. Biochem. Biophys. PD APR PY 2003 VL 30 IS 2 BP 167 EP 170 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 676QZ UT WOS:000182764700001 ER PT J AU Ahram, M Flaig, MJ Gillespie, JW Duray, PH Linehan, WM Ornstein, DK Niu, SL Zhao, YM Petricoin, EF Emmert-Buck, MR AF Ahram, M Flaig, MJ Gillespie, JW Duray, PH Linehan, WM Ornstein, DK Niu, SL Zhao, YM Petricoin, EF Emmert-Buck, MR TI Evaluation of ethanol-fixed, paraffin-embedded tissues for proteomic applications SO PROTEOMICS LA English DT Article DE ethanol fixation; laser capture microdissection; prostate cancer; tissue staining ID DIFFERENTIALLY EXPRESSED GENES; TRANSITIONAL-CELL CARCINOMAS; IMMUNOHISTOCHEMICAL DEMONSTRATION; MOLECULAR CLASSIFICATION; PROSTATE-CANCER; FIXATION; IDENTIFICATION; FORMALIN; PROTEIN; KERATINS AB We previously reported that ethanol fixation and paraffin embedding of tissues produce excellent histomorphology and good preservation of macromolecules. Here, we present a detailed evaluation of ethanol-fixed tissues for proteomic initiatives. When proteins were extracted from ethanol-fixed, paraffin-embedded prostate tissue, resolved by two-dimensional gel electrophoresis (2-DE), and stained by standard methods, several hundred protein molecules could be detected and successfully analyzed by mass spectrometry. Protein profiles obtained from ethanol-fixed tissues were highly similar to those observed from frozen tissues, in contrast to the poor protein recovery from formalin-fixed material. The protein content of specific cells that were microdissected from ethanol-fixed tissue sections using laser capture microdissection could also be successfully analyzed by 2-DE. We observed that eosin staining of tissue sections had a detrimental effect on protein separation,,whereas hematoxylin staining had minimal consequence. In order to illustrate the applicability of ethanol-fixed tissues for proteomic discovery studies, we compared the protein profiles of patient-matched, normal prostatic epithelial cells and invasive adenocarcinoma cells obtained from ethanol-fixed, paraffin-embedded tissues. A number of differentially expressed proteins was discovered and identified by mass spectrometry. Immunohistochemical analyses performed on ethanol-fixed tissue sections were in agreement with the proteomic discovery findings. In light of these results, we conclude that ethanol-fixed tissues can be successfully utilized for proteomic analyses. C1 NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Urol, Chapel Hill, NC USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75235 USA. US FDA, Tissue Proteom Unit, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Pathol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 2A33, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA85146] NR 25 TC 122 Z9 132 U1 0 U2 6 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 APR PY 2003 VL 3 IS 4 BP 413 EP 421 DI 10.1002/pmic.200390056 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 666WQ UT WOS:000182199800005 PM 12687609 ER PT J AU Pezawas, L Wittchen, HU Pfister, H Angst, J Lieb, R Kasper, S AF Pezawas, L Wittchen, HU Pfister, H Angst, J Lieb, R Kasper, S TI Recurrent brief depressive disorder reinvestigated: a community sample of adolescents and young adults SO PSYCHOLOGICAL MEDICINE LA English DT Article ID EARLY DEVELOPMENTAL-STAGES; GENERAL HEALTH-CARE; SUICIDAL-BEHAVIOR; MAJOR DEPRESSION; PSYCHOLOGICAL-PROBLEMS; CLINICAL-FEATURES; AFFECTIVE-ILLNESS; MENTAL-DISORDERS; PREVALENCE; TRIAL AB Background. This article presents prospective lower bound estimations of findings on prevalence, incidence, clinical correlates, severity markers, co-morbidity and course stability of threshold and subthreshold recurrent brief depressive disorder (RBD) and other mood disorders in a community sample of 3021 adolescents. Method. Data were collected at baseline (age 14-17) and at two follow-up interviews within an assessment was based on the Munich Composite observation period of 42 months. Diagnostic International Diagnostic Interview (M-CIDI). Results. Our data suggest that RBD is a prevalent (2(.)6%) clinical condition among depressive disorders (21(.)3 %) being at least as prevalent as dysthymia (2(.)3 %) in young adults over lifetime. Furthermore, RBD is associated with significant clinical impairment sharing many features with major depressive disorder (MDD). Suicide attempts were reported in 7(.)8 % of RBD patients, which was similar to MDD (11(.)9 %). However, other features, like gender distribution or co-morbidity patterns, differ essentially from MDD. Furthermore, the lifetime co-occurrence of MDD and RBD or combined depression represents a severe psychiatric condition. Conclusions. This study provides further independent support for RBD as a clinically significant syndrome that could not be significantly explained as a prodrome or residual of major affective disorders. C1 NIMH, CBDB, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Gen Psychiat, A-1010 Vienna, Austria. Tech Univ Dresden, D-8027 Dresden, Germany. Max Planck Inst Psychiat, Dept Clin Psychol & Epidemiol, D-80804 Munich, Germany. Univ Zurich, Univ Hosp Psychiat, Zurich, Switzerland. RP Pezawas, L (reprint author), NIMH, CBDB, NIH, 10 Ctr Dr 4S235, Bethesda, MD 20892 USA. RI Wittchen, Hans-Ulrich/A-8507-2014; OI Pezawas, Lukas/0000-0002-1329-6352; Wittchen, Hans-Ulrich/0000-0002-6311-7711 NR 50 TC 20 Z9 22 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD APR PY 2003 VL 33 IS 3 BP 407 EP 418 DI 10.1017/S0033291702006967 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 671TB UT WOS:000182479200004 PM 12701662 ER PT J AU Daly, RC Su, TP Schmidt, PJ Pagliaro, M Pickar, D Rubinow, DR AF Daly, RC Su, TP Schmidt, PJ Pagliaro, M Pickar, D Rubinow, DR TI Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE methyltestosterone; anabolic steroids; aggression; thyroid; mood ID SPATIAL COGNITION; CONTROLLED TRIAL; HAND PREFERENCE; HUMAN-PLASMA; TESTOSTERONE; RADIOIMMUNOASSAY; MEN; HORMONES; CORTICOTROPIN; CORTISOL AB Objective: Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms. Method: Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined. Results: Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p < 0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r = 0.5,p = 0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r = 0.52,p = 0.02). Hormonal changes did not correlate with plasma MT levels. Conclusions: Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes. Published by Elsevier Science Ltd. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. RP Daly, RC (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Rm 3N238,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. NR 48 TC 51 Z9 52 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD APR PY 2003 VL 28 IS 3 BP 317 EP 331 DI 10.1016/S0306-4530(02)00025-2 PG 15 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 657BE UT WOS:000181644900007 PM 12573299 ER PT J AU Mattson, BJ Williams, SE Rosenblatt, JS Morrell, JI AF Mattson, BJ Williams, SE Rosenblatt, JS Morrell, JI TI Preferences for cocaine- or pup-associated chambers differentiates otherwise behaviorally identical postpartum maternal rats SO PSYCHOPHARMACOLOGY LA English DT Article DE maternal behavior; conditioned place preference; cocaine locomotor activity; maternal aggression; postpartum period ID CONDITIONED PLACE PREFERENCE; SPRAGUE-DAWLEY RATS; MEDIAL PREOPTIC AREA; INDIVIDUAL-DIFFERENCES; FEMALE RATS; LOCOMOTOR-ACTIVITY; FLIGHT RESPONSES; ADULT RATS; NOVELTY; REINFORCEMENT AB Rationale and objectives: Our previous work uncovered a differential preference of maternal female rats for cues associated with pups versus cues associated with cocaine at three different postpartum time points. Our current study examines the preference for these cues in conjunction with an assessment of the capacity to express the maternal behavior at one of these time points. We examined dams at day 10 postpartum using a procedure that included two additional controls, and a complete assessment of the expression of maternal behavior and locomotor activity. Methods: A conditioned place-preference procedure was used to determine the preference for cocaine- or pup-associated cues. The two controls were (1) a preconditioning test to verify no initial chamber preference and (2) a separate control group of postpartum day-10 dams exposed to chambers and cues but not to unconditioned stimuli. The expression of maternal behavior was determined by measurement of maternal nest building, retrieval of pups to the nest, grooming, crouching over pups, nursing, and maternal aggression. Locomotor activity was measured with an automated apparatus. Results: Dams conditioned with cocaine or pups showed a preference for either the cocaine-associated chamber or the pup-associated chamber, confirming the existence of two similar-sized preference groups at this time point. Regardless of preference, dams had equal and robust expression of maternal behavior and similar locomotor capacity. The pre-conditioning test showed no initial chamber preferences and did not alter the conditioned preference response. The use of unconditioned stimuli in the place-preference conditioning procedure was effective and necessary for the preference response. Conclusion: Our current study has revealed that differences in the motivational state of the maternal dam emerge even while the expression of maternal behavior is constant and substantial. The data suggest that the difference in preference is a very specific appetitive response that is not linked to expression of maternal behavior or locomotor capacity. C1 NIDA, Behav Neurosci Branch, Baltimore, MD 21224 USA. Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. RP Mattson, BJ (reprint author), NIDA, Behav Neurosci Branch, Bldg C,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [R01 DA014025-01A2, R01 DA014025]; NIGMS NIH HHS [5 S06 GM 08223-15] NR 59 TC 49 Z9 49 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2003 VL 167 IS 1 BP 1 EP 8 DI 10.1007/s00213-002-1351-4 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 676QG UT WOS:000182763000001 PM 12607073 ER PT J AU Panlilio, LV Katz, JL Pickens, RW Schindler, CW AF Panlilio, LV Katz, JL Pickens, RW Schindler, CW TI Variability of drug self-ad ministration in rats SO PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Society-for-Neuroscience CY NOV 10-15, 2001 CL SAN DIEGO, CA SP Soc Neurosci DE titration; regulation; cocaine; remifentanil; food ID NUCLEUS-ACCUMBENS DOPAMINE; CARROLL 2001; ADMINISTERED COCAINE; INTRAVENOUS COCAINE; D-AMPHETAMINE; SATIETY THRESHOLD; ACCESS CONDITIONS; SET-POINT; BEHAVIOR; HEROIN AB Rationale: Although temporal patterns of drug self-administration in animals are known to be highly regular, this regularity has rarely been quantified or systematically compared across reinforcers. Objectives: Over a range of unit doses, this study assessed: (1) the within-subject variability of inter-infusion intervals (latencies); (2) the estimated whole-body drug level at the time of self-infusion; (3) the within-subject variability of these drug levels; and (4) the statistical dependence between successive latencies, to determine whether regularity is maintained by compensatory, moment-to-moment adjustment of latencies. Methods: Rats were trained with cocaine (10-1000 mug/kg per infusion, IV), remifentanil (an ultra-short acting opioid; 0.25-32 mug/kg per infusion, IV), or food (20-180 mg/delivery). Results: Within subjects, latencies were most consistent from infusion to infusion at unit doses on the descending limb of the dose-response curve. However, the drug level at the time an infusion was initiated was actually least consistent at these doses. Sequential latencies showed only a weak autocorrelation for both drugs. Conclusion: These results suggest that highly consistent response patterns are not simply a product of precise titration of drug levels. The weak autocorrelation between sequential latencies suggests that temporal regularity of responding is not maintained through compensatory adjustments of post-infusion pauses. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIDA, Medicat Discovery Res Branch, NIH, DHHS, Baltimore, MD 21224 USA. Virginia Commonwealth Univ, Richmond, VA 23298 USA. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lpanlili@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 55 TC 44 Z9 44 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2003 VL 167 IS 1 BP 9 EP 19 DI 10.1007/s00213-002-1366-x PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 676QG UT WOS:000182763000002 PM 12644888 ER PT J AU Pierce, DA Sharp, GB Mabuchi, K AF Pierce, DA Sharp, GB Mabuchi, K TI Joint effects of radiation and smoking on lung cancer risk among atomic bomb survivors SO RADIATION RESEARCH LA English DT Article ID MORTALITY; EXPOSURE AB Results are given on the joint effect of radiation exposure and cigarette smoking on lung cancer risks among A-bomb survivors, based on 592 cases through 1994. Information on smoking was derived from mail surveys and clinical interviews of 45,113 persons in the Radiation Effects Research Foundation cohort. Radiation and smoking effects on lung cancer are found to be significantly sub-multiplicative and quite consistent with additivity. The smoking relative risk, previously very low in studies of this cohort, is now similar to that found in Western populations. This increase is likely to be related to the scarcity of cigarettes during and after the war. The smoking relative risk depends little on sex. After adjusting for smoking, the radiation-related risks relative to background rates for nonsmokers are similar to those for other solid cancers: a sex-averaged ERR/Sv of about 0.9 with a female:male sex ratio of about 1.6. Adjusting for smoking removes a spuriously large female:male ratio in radiation relative risk due to confounding between sex and smoking level. The adjustment also removes an artifactual age-at-exposure effect in the radiation relative risk, opposite in direction to other cancers, which is due to birth cohort variation in lung cancer rates. (C) 2003 by Radiation Research Society. C1 Radiat Effects Res Fdn, Dept Stat, Hiroshima 732, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima 732, Japan. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pierce, DA (reprint author), Radiat Effects Res Fdn, Dept Stat, 5-2 Hijiyama Pk, Hiroshima 732, Japan. NR 13 TC 84 Z9 91 U1 1 U2 3 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 APR PY 2003 VL 159 IS 4 BP 511 EP 520 DI 10.1667/0033-7587(2003)159[0511:JEORAS]2.0.CO;2 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 663MU UT WOS:000182010000009 PM 12643796 ER PT J AU Wu, PK Ringeisen, BR Krizman, DB Frondoza, CG Brooks, M Bubb, DM Auyeung, RCY Pique, A Spargo, B McGill, RA Chrisey, DB AF Wu, PK Ringeisen, BR Krizman, DB Frondoza, CG Brooks, M Bubb, DM Auyeung, RCY Pique, A Spargo, B McGill, RA Chrisey, DB TI Laser transfer of biomaterials: Matrix-assisted pulsed laser evaporation (MAPLE) and MAPLE Direct Write SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID THIN-FILMS; BIODEGRADABLE POLYMERS; ELECTROCHEMICAL BIOSENSOR; SOFT LITHOGRAPHY; DEPOSITION; SURFACES; ABLATION; PROTEINS; GLUCOSE; DNA AB Two techniques for transferring biomaterial using a pulsed laser beam were developed: matrix-assisted pulsed laser evaporation (MAPLE) and MAPLE direct write (MDW). MAPLE is a large-area vacuum based technique suitable for coatings, i.e., antibiofouling, and MDW is a localized deposition technique capable of fast prototyping of devices, i.e., protein or tissue arrays. Both techniques have demonstrated the capability of transferring large (mol wt >100 kDa) molecules in different forms, e.g., liquid and gel, and preserving their functions. They can deposit patterned films with spatial accuracy and resolution of tens of mum and layering on a variety of substrate materials and geometries. MDW can dispense volumes less than 100 pl, transfer solid tissues, fabricate a complete device, and is computed aided design/computer aided manufacturing compatible. They are noncontact techniques and can be integrated with other sterile processes. These attributes are substantiated by films and arrays of biomaterials, e.g., polymers, enzymes, proteins, eucaryotic cells, and tissue, and a dopamine sensor. These examples, the instrumentation, basic mechanisms, a comparison with other techniques, and future developments are discussed. (C) 2003 American Institute of Physics. C1 USN, Res Lab, Washington, DC 20375 USA. NCI, Ctr Adv Technol, Gaithersburg, MD 20877 USA. Good Samaritan Hosp, Johns Hopkins Orthopaed, Baltimore, MD 21239 USA. So Oregon Univ, Dept Phys, Ashland, OR 97520 USA. RP Wu, PK (reprint author), USN, Res Lab, 4555 Overlook Ave SW, Washington, DC 20375 USA. NR 66 TC 96 Z9 97 U1 0 U2 17 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD APR PY 2003 VL 74 IS 4 BP 2546 EP 2557 DI 10.1063/1.1544081 PG 12 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 660JA UT WOS:000181829000043 ER PT J AU Zeuner, RA Klinman, DM Illei, G Yarboro, C Ishii, KJ Gursel, M Verthelyi, D AF Zeuner, RA Klinman, DM Illei, G Yarboro, C Ishii, KJ Gursel, M Verthelyi, D TI Response of peripheral blood mononuclear cells from lupus patients to stimulation by CpG oligodeoxynucleotides SO RHEUMATOLOGY LA English DT Article DE SLE; innate immune system; CpG oligodeoxynucleotide; toll-like receptor; dendritic cells ID NATURAL-KILLER-CELLS; STRANDED DNA ANTIBODIES; SEX-HORMONE LEVELS; DENDRITIC CELLS; CYTOKINE PRODUCTION; REVISED CRITERIA; BACTERIAL-DNA; IFN-ALPHA; IN-VITRO; T-CELLS AB Objectives. Increased levels of hypomethylated CpG-containing DNA in sera from patients with systemic lupus erythematosus (SLE) may contribute to the initiation and/or perpetuation of the disease. This study characterizes the in vitro response of peripheral blood mononuclear cells (PBMC) from SLE patients to CpG DNA. Methods. Secretion of cytokines and IgM, cell proliferation and up-regulation of co-stimulatory molecules were evaluated in PBMC from SLE patients (n = 24) and normal controls (n = 24) after stimulation with synthetic oligodeoxynucleotides (ODN) containing CpG motifs. Results. Up-regulation of co-stimulatory molecules and the secretion of interferon-alpha and interleukin-6 (IL-6) in response to CpG ODN was significantly reduced in monocytes and dendritic cells from SLE patients. Secretion of interferon-gamma by natural killer (NK) cells was also reduced. In contrast, the IgM and IL-10 response of B cells to CpG ODN was normal. Conclusion. Monocytes, dendritic cells and NK cells from SLE patients respond abnormally to CpG ODN stimulation, which may contribute to the cytokine imbalance observed in SLE. C1 US FDA, Sect Retroviral Res, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NIAMS, NIH, Bethesda, MD USA. Univ Kiel, Med Clin 2, D-24098 Kiel, Germany. RP Klinman, DM (reprint author), US FDA, Sect Retroviral Res, Ctr Biol Evaluat & Res, Bldg 29A,Room 3D10, Bethesda, MD 20892 USA. RI Gursel, Mayda /H-1812-2012; Ishii, Ken/B-1685-2012; OI Ishii, Ken/0000-0002-6728-3872; Gursel, Mayda/0000-0003-0044-9054 NR 29 TC 20 Z9 22 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD APR PY 2003 VL 42 IS 4 BP 563 EP 569 DI 10.1093/rheumatology/keg191 PG 7 WC Rheumatology SC Rheumatology GA 666YK UT WOS:000182203900010 PM 12649404 ER PT J AU Scarabino, T Bertolino, A Burroni, M Popolizio, T Duyn, J Weinberger, DR Salvolini, U AF Scarabino, T Bertolino, A Burroni, M Popolizio, T Duyn, J Weinberger, DR Salvolini, U TI White matter lesions in phenylketonuria: Evaluation with magnetic resonance Imaging and magnetic resonance spectroscopy SO RIVISTA DI NEURORADIOLOGIA LA English DT Article DE phenylketonuria; phenylalanine; magnetic resonance imaging (MRI); proton magnetic resonance spectroscopic imaging (1H-MRSI) ID PHENYLALANINE; BRAIN; HYPERPHENYLALANINEMIA AB Phenylketonuria (PKU) is a congenital metabolic autosomic recessive disease, caused by a deficit in the liver of phenyl-alanine hydroxylase, the enzyme responsible for conversion of phenyl-alanine (PHE) into tyrosine. Reduction of this enzymatic activity is responsible for increased phenyl-alanine in blood and tissues and, above all, in brain. Accumulation of PHE causes neural damage which produces a typical clinical picture with mental retardation, psychiatric symptoms and epilepsy. It is now possible to diagnose this disease early (with neonatal screening), before irreversible clinical symptoms reflecting central nervous system injury appear. Early diagnosis allows timely onset of therapy (the only possible) consisting of a special diet with reduced intake of PHE (integrated with a mix of aminoacids) whose objective is to keep levels of PHE low in the blood (3-6 mg/dl). Magnetic Resonance Imaging (MRI) is the elective diagnostic tool to evaluate in vivo the involvement of the brain in PKU. Previous MRI morphological studies in patients with PKU have reported various focal symmetrical lesions in periventricular white matter (especially parieto-occipital) of patients with PKU with PHE blood values higher than 10 mg/dl. These lesions, whose importance is not yet clear, seem to represent a reversible structural alteration of myelin, since they regress if blood PHE decreases. Proton magnetic resonance spectroscopy (H-1-MRS) can measure in vivo brain metabolites which could help determine the nature of white matter lesions. In particular, changes in NAA (a marker of neuronal integrity) or mI (a potential astrocytic marker) could point to possible neurochemical dysfunction, whereas Cho levels may parallel the degree of the tissue myelination. The purpose of the present study was to evaluate morphologically and biochemically the regional specificity of white matter lesions with structural MRI and with H-1-MRSI. The study included 12 patients with PKU ten to 42 years of age. All patients underwent structural MRI scans while eight of them were also studied with H-1-MRSI. Structural MRI lesions in white matter were analyzed both qualitatively (signal intensity) and quantitatively (location and extension). H-1-MRSI metabolites were measured as the ratio of the area under each peak: NAA/Cr, NAA/Cho, Cho/Cr. Analysis of location and extension of the lesion on structural MRI data showed limited involvement of parieto-occipital white matter in three cases (with isointense or vaguely hypointense lesions in T1, and moderately hyperintense lesions in T2); medium involvement in six cases (with fairly hypointense or isointense lesions in T1, fairly or moderately hyperintense lesions in T2); serious involvement in three cases (with isointense or fairly hypointense lesions in T1, and fairly hyperintense lesions in T2). As for H-1-MRSI data, ANOVA showed a significant reduction of NAA/Cho and increase in Cho/Cr in white matter lesions, but no change in NAA/Cr. No correlation was found between clinical parameters and morphological or spectroscopic data. In conclusion, our morphological MRI data confirmed the presence of multiple signal alterations, focal and symmetrical, in deep periventricular white matter (especially posterior), with occasional involvement of subcortical white matter. However, these lesions do not seem to be strongly predictive of clinical outcome. H-1-MRSI data suggest increased Cho levels in white matter lesions. Since Cho is thought to reflect membrane turnover, these data may support the demyelinating nature of lesions, consistent with earlier post mortem studies. C1 Casa Sollievo Sofferenza Sci Inst, Dept Neuroradiol, San Giovanni Rotondo, Italy. Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Bari, Italy. Gen Hosp, Dept Neuropsychiat, Fano, Italy. NIH, Lab Diagnost Radiol Res, Bethesda, MD USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD USA. Univ Ancona, Dept Neuroradiol, Ancona, Italy. RI Duyn, Jozef/F-2483-2010; Bertolino, Alessandro/O-6352-2016 OI Bertolino, Alessandro/0000-0002-1251-1380 NR 19 TC 0 Z9 0 U1 1 U2 2 PU EDIZIONI CENTAURO PI BOLOGNA PA VIA DEL PRATELLO, 8, 40122 BOLOGNA, ITALY SN 1120-9976 J9 RIV NEURORADIOL JI Riv. Neuroradiol. PD APR PY 2003 VL 16 IS 2 BP 251 EP 261 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 713DZ UT WOS:000184842000003 ER PT J AU Ingjaldsson, JT Thayer, JF Laberg, JC AF Ingjaldsson, JT Thayer, JF Laberg, JC TI Preattentive processing of alcohol stimuli SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE preattentive processing; cue reactivity; automatic analysis ID COMPULSIVE DRINKING SCALE; COLOR-NAMING TASK; CONDITIONED ABSTINENCE; RESPONSES; BEHAVIOR; RECOMMENDATIONS; REACTIVITY; ADDICTION; ATTENTION; DRINKERS AB An experiment was conducted to test the automatic analysis of briefly presented alcohol stimuli in alcohol-dependent individuals. Alcoholics and controls were exposed to four different conditions: two brief (30 ms) and two long (130 ms) exposure conditions, each containing alcoholic and non-alcoholic pictures. Heart rate (HR) interbeat intervals were recorded and phasic cardiac responses assessed. Alcoholics had a stronger initial HR deceleration after exposure to masked alcohol slides compared with masked control slides, indicating a preattentive analysis of alcohol stimuli. This initial HR deceleration in the masked condition suggests an automatic attentional focusing to degraded alcohol cues. No such attentional effect was found when the pictures were presented unmasked and were clearly perceived. The implication of these results for the understanding of relapse in addictive behavior is discussed. C1 Univ Bergen, Dept Clin Psychol, N-5015 Bergen, Norway. NIA, Gerontol Res Ctr, Baltimore, MD USA. Univ Bergen, Dept Psychosocial Sci, Bergen, Norway. RP Ingjaldsson, JT (reprint author), Univ Bergen, Dept Clin Psychol, Christiegate 12, N-5015 Bergen, Norway. NR 41 TC 12 Z9 12 U1 1 U2 1 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD APR PY 2003 VL 44 IS 2 BP 161 EP 165 DI 10.1111/1467-9450.00334 PG 5 WC Psychology, Multidisciplinary SC Psychology GA 677FJ UT WOS:000182796000011 PM 12778984 ER PT J AU McKeown, RE Weed, DL Kahn, JP Stoto, MA AF McKeown, RE Weed, DL Kahn, JP Stoto, MA TI American College of Epidemiology ethics guidelines: Foundations and dissemination SO SCIENCE AND ENGINEERING ETHICS LA English DT Article; Proceedings Paper CT Meeting of the AAAS-Office-of-Research-Integrity (ORI) CY APR 10-11, 2000 CL WASHINGTON, D.C. SP AAS, Office Res Integrity DE ethics guidelines; epidemiology; public health; professional virtues; values; responsibility; research ethics ID MEDICATION-FREE RESEARCH; DEVELOPING-COUNTRIES; CONSENT; WORLD AB Epidemiology is a core science of public health, focusing on research related to the distribution and determinants of both positive and adverse health states and events and on application of knowledge gained to improve public health. The American College of Epidemiology (ACE) is a professional organization devoted to the professional practice of epidemiology. As part of that commitment, and in response to concerns for more explicit attention to core values and duties of epidemiologists in light of emerging issues and increased scrutiny of epidemiology, the College developed, adopted, and published a set of Ethics Guidelines. The structure of the ACE ethics guidelines is in four parts: (1) a brief statement of core values and duties of epidemiologists, coupled with the virtues important to professional practice; (2) concise statements of key duties and obligations; (3) exposition of the duties and obligations with more applications; and (4) a brief summary and conclusion. The Guidelines have been published on the ACE website and in the official College journal Annals of Epidemiology. The guidelines contain (and maintain) core elements that define the discipline of epidemiology and its fundamental duties, but they are also intended to be dynamic and evolving, responsive to a changing professional and social environment. C1 Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. NCI, Off Prevent Oncol, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. UMH Twin Cities, Ctr Bioeth, Minneapolis, MN USA. RAND Corp, Ctr Domest & Int Hlth Secur, Arlington, VA USA. RP McKeown, RE (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. NR 27 TC 4 Z9 5 U1 0 U2 1 PU OPRAGEN PUBLICATIONS PI GUILDFORD PA PO BOX 54, GUILDFORD GU1 2YF, SURREY, ENGLAND SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD APR PY 2003 VL 9 IS 2 BP 207 EP 214 DI 10.1007/s11948-003-0008-y PG 8 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 682GZ UT WOS:000183084500008 PM 12774653 ER PT J AU Tosato, G AF Tosato, G TI Introduction: Herpesviruses in hematology SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NCI, CCR, ETIB, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, CCR, ETIB, 9000 Rockville Pike,MSSC-1907,10 Ctr Dr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2003 VL 40 IS 2 BP 105 EP 106 DI 10.1053/shem.2003.50017 PG 2 WC Hematology SC Hematology GA 668UL UT WOS:000182311500001 ER PT J AU Cohen, JI AF Cohen, JI TI Benign and malignant Epstein-Barr virus-associated B-cell lymphoproliferative diseases SO SEMINARS IN HEMATOLOGY LA English DT Article ID CYTOTOXIC T-CELLS; INDUCED INFECTIOUS-MONONUCLEOSIS; ORGAN TRANSPLANT RECIPIENTS; APLASTIC-ANEMIA; GENE-PRODUCT; HEMOPHAGOCYTIC SYNDROME; HODGKINS-DISEASE; ENCODING GENE; PREVENTION; EBV C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Room 11N214,10 Ctr Dr, Bethesda, MD 20892 USA. NR 69 TC 24 Z9 25 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2003 VL 40 IS 2 BP 116 EP 123 DI 10.1053/shem.2003.50018 PG 8 WC Hematology SC Hematology GA 668UL UT WOS:000182311500003 PM 12704588 ER PT J AU Aoki, Y Tosato, G AF Aoki, Y Tosato, G TI Pathogenesis and manifestations of human herpesvirus-8 associated disorders SO SEMINARS IN HEMATOLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; PRIMARY EFFUSION LYMPHOMA; ENDOTHELIAL GROWTH-FACTOR; MULTICENTRIC CASTLEMANS-DISEASE; FACTOR/VASCULAR PERMEABILITY FACTOR; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; RESEMBLING KAPOSIS-SARCOMA; NON-HODGKIN-LYMPHOMA; EPSTEIN-BARR VIRUS; HIV-TAT PROTEIN C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aoki, Y (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,12N226 MSC1907, Bethesda, MD 20892 USA. NR 87 TC 18 Z9 21 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2003 VL 40 IS 2 BP 143 EP 153 DI 10.1053/shem.2003.50014 PG 11 WC Hematology SC Hematology GA 668UL UT WOS:000182311500006 PM 12704591 ER PT J AU Little, RF Yarchoan, R AF Little, RF Yarchoan, R TI Treatment of gammaherpesvirus-related neoplastic disorders in the immunosuppressed host SO SEMINARS IN HEMATOLOGY LA English DT Review ID EPSTEIN-BARR-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMA; CENTRAL-NERVOUS-SYSTEM; MULTICENTRIC CASTLEMANS-DISEASE; ACTIVE ANTIRETROVIRAL THERAPY; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; PRIMARY EFFUSION LYMPHOMA; BONE-MARROW TRANSPLANTATION C1 NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Little, RF (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bldg 10,Room 10S255,MSC 1868, Bethesda, MD 20892 USA. NR 105 TC 3 Z9 3 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2003 VL 40 IS 2 BP 163 EP 171 DI 10.1053/shem.2003.50016 PG 9 WC Hematology SC Hematology GA 668UL UT WOS:000182311500008 PM 12704593 ER PT J AU Owen, RG Treon, SP Al-Katib, A Fonseca, R Greipp, PR McMaster, ML Morra, E Pangalis, GA Miguel, JFS Branagan, AR Dimopoulos, MA AF Owen, RG Treon, SP Al-Katib, A Fonseca, R Greipp, PR McMaster, ML Morra, E Pangalis, GA Miguel, JFS Branagan, AR Dimopoulos, MA TI Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus panel recommendations from the second international workshop on Waldenstrom's macroglobulinemia SO SEMINARS IN ONCOLOGY LA English DT Review ID IGM MONOCLONAL GAMMOPATHY; B-CELL LYMPHOMA; PROGNOSTIC FACTORS; CHROMOSOMAL-ABNORMALITIES; CLINICAL COURSE; SCORING SYSTEM; FEATURES; MYELOMA; PROPOSAL; CLASSIFICATION C1 Harvard Univ, Sch Med, Waldenstroms Macroglobulinemia Program, Dana Farber Canc Inst, Boston, MA 02115 USA. Leeds Gen Infirm, Leeds, W Yorkshire, England. Van Elslander Canc Ctr, Grosse Point Woods, MI USA. Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. Niguardia CaGranda Hosp, Milan, Italy. Univ Salamanca, E-37008 Salamanca, Spain. Univ Athens, Athens, Greece. RP Owen, RG (reprint author), Harvard Univ, Sch Med, Waldenstroms Macroglobulinemia Program, Dana Farber Canc Inst, LG100,44 Binney St, Boston, MA 02115 USA. OI Fonseca, Rafael/0000-0002-5938-3769; Branagan, Andrew/0000-0002-3868-9267 NR 41 TC 407 Z9 428 U1 0 U2 16 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2003 VL 30 IS 2 BP 110 EP 115 DI 10.1053/sonc.2003.50082 PG 6 WC Oncology SC Oncology GA 673VY UT WOS:000182602000002 PM 12720118 ER PT J AU McMaster, ML AF McMaster, ML TI Familial Waldenstrom's macroglobulinemia SO SEMINARS IN ONCOLOGY LA English DT Review ID MONOCLONAL GAMMOPATHY; POPULATION; CANCER; IGM; RELATIVES; DISEASE; HISTORY; RISK C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP McMaster, ML (reprint author), Execut Plaza S,Room 7010,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. NR 37 TC 35 Z9 37 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2003 VL 30 IS 2 BP 146 EP 152 DI 10.1053/sonc.2003.50063 PG 7 WC Oncology SC Oncology GA 673VY UT WOS:000182602000009 PM 12720125 ER PT J AU Liu, HJ Jamison, D Li, XJ Ma, EJ Yin, YP Detels, R AF Liu, HJ Jamison, D Li, XJ Ma, EJ Yin, YP Detels, R TI Is syndromic management better than the current approach for treatment of STDs in China? Evaluation of the cost-effectiveness of syndromic management for male STD patients SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED DISEASES AB Background: The syndromic treatment approach has not been evaluated in sexually transmitted disease (STD) clinics in China. Goal. The goal was to evaluate and compare the validity and cost-effectiveness of syndromic management with current STD management for men in clinics in Hefei, China. Study Design: Diagnostic accuracy, treatment appropriateness, costs, and effectiveness of current clinical procedures and syndromic management were compared for 406 men attending four STD clinics. Results: A modified World Health Organization (WHO) syndromic algorithm for urethral discharge yielded 100% sensitivity and a 69% positive predictive value (PPV). A syndromic algorithm for genital ulcers correctly treated all syphilis patients, with a 25% PPV. The average cost (in $US) per correct treatment by the current approach was $323.48 for urethritis and $85.65 for syphilis. For the syndromic approach, the average cost per correct treatment was $3.15 for urethritis and $13.54 for syphilis. Conclusion: Syndromic management can provide better treatment for men with STDs at significantly lower cost in resource-poor settings such as China. C1 Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. Fogarty Int Ctr, NIH, Bethesda, MD USA. Hefei Antiepidem Stn, Anhui, Peoples R China. Natl Ctr STD & Leprosy Control, Nanjing, Peoples R China. RP Detels, R (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Box 951772, Los Angeles, CA 90095 USA. FU FIC NIH HHS [1TW00013] NR 13 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD APR PY 2003 VL 30 IS 4 BP 327 EP 330 DI 10.1097/00007435-200304000-00010 PG 4 WC Infectious Diseases SC Infectious Diseases GA 663DE UT WOS:000181990300010 PM 12671553 ER PT J AU Hashimoto, RF Dougherty, ER Brun, M Zhou, ZZ Bittner, ML Trent, JM AF Hashimoto, RF Dougherty, ER Brun, M Zhou, ZZ Bittner, ML Trent, JM TI Efficient selection of feature sets possessing high coefficients of determination based on incremental determinations SO SIGNAL PROCESSING LA English DT Article DE coefficient of determination; feature selection; gene microarray; optimal classifier ID GENE-EXPRESSION AB Feature selection is problematic when the number of potential features is very large. Absent distribution knowledge, to select a best feature set of a certain size requires that all feature sets of that size be examined. This paper considers the question in the context of variable selection for prediction based on the coefficient of determination (CoD). The CoD varies between 0 and 1, and measures the degree to which prediction is improved by using the features relative to prediction in the absence of the features. It examines the following heuristic: if we wish to find feature sets of size m with CoD exceeding 8, what is the effect of only considering a feature set if it contains a subset with CoD exceeding lambda < delta? This means that if the subsets do not possess sufficiently high CoD, then it is assumed that the feature set itself cannot possess the required CoD. As it stands, the heuristic cannot be applied since one would have to know the CoDs beforehand. It is meaningfully posed by assuming a prior distribution on the CoDs. Then one can pose the question in a Bayesian framework by considering the probability P(theta > delta \ max{theta(1), theta(2),..., theta(v)} < lambda), where theta is the CoD of the feature set and theta(1), theta(2),..., theta(v) are the CoDs of the subsets. Such probabilities allow a rigorous analysis of the following decision procedure: the feature set is examined if max{theta(1),theta(2),...,theta(v)} greater than or equal to lambda. Computational saving increases as lambda increases, but the probability of missing desirable feature sets increases as the increment delta-lambda decreases; conversely, computational saving goes down as lambda decreases, but the probability of missing desirable feature sets decreases as theta-lambda increases. The paper considers various loss measures pertaining to omitting feature sets based on the criteria. After specializing the matter to binary features, it considers a simulation model, and then applies the theory in the context of microarray-based genomic CoD analysis. It also provides optimal computational algorithms. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. Univ Sao Paulo, Inst Matemat & Estatist, Deptm Ciencia Computacao, Sao Paulo, Brazil. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Dougherty, ER (reprint author), Texas A&M Univ, Dept Elect Engn, 3128 TAMU, College Stn, TX 77843 USA. RI Hashimoto, Ronaldo/B-6544-2013 OI Hashimoto, Ronaldo/0000-0002-6399-8790 NR 16 TC 9 Z9 9 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-1684 J9 SIGNAL PROCESS JI Signal Process. PD APR PY 2003 VL 83 IS 4 BP 695 EP 712 DI 10.1016/S0165-1684(02)00468-1 PG 18 WC Engineering, Electrical & Electronic SC Engineering GA 653BP UT WOS:000181415600002 ER PT J AU Kuznetsov, VA AF Kuznetsov, VA TI Family of skewed distributions associated with the gene expression and proteome evolution SO SIGNAL PROCESSING LA English DT Article DE gene expression; protein domains; evolution; birth-death stochastic processes; Pareto distribution; Waring distribution ID TRANSCRIPTIONAL REGULATION; METABOLIC NETWORKS; SIZE DISTRIBUTION; SMALL-WORLD; GENOMES; CELLS; DNA; PROTEINS; BEHAVIOR; MODEL AB We study statistical distributions appearing in various genome-related phenomena, including the distribution of the transcript copy number in the transcriptome of eukaryotic cells and the distribution of the number of proteins containing a protein domain in proteomes of species. We found that the empirical distributions for all studied data sets are well fitted by a family of Pareto-like distribution functions whose shape depends in a predictable manner on the sample size. Such distributions are generated as limiting distributions in a Markov random process where the birth and death intensities are linear functions of events. We also propose a novel model of progressive evolution of a population in terms of the increase of the numbers of distinct components and their links in the system and we study evolution of the probability distribution of these links. Estimating two unknown parameters of this model allows us to describe the progressive evolution of the number of distinct protein domain sets and the number of proteins containing a given protein domain in the proteomes of 70 fully sequenced genome organisms. This model also predicts trends in proteome complexity evolution. Published by Elsevier Science B.V. C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Kuznetsov, VA (reprint author), NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NR 41 TC 22 Z9 23 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-1684 J9 SIGNAL PROCESS JI Signal Process. PD APR PY 2003 VL 83 IS 4 BP 889 EP 910 DI 10.1016/S0165-1684(02)00481-4 PG 22 WC Engineering, Electrical & Electronic SC Engineering GA 653BP UT WOS:000181415600015 ER PT J AU Garroutte, EM Goldberg, J Beals, J Herrell, R Manson, SM AF Garroutte, EM Goldberg, J Beals, J Herrell, R Manson, SM CA AI-SUPERPFP Team TI Spirituality and attempted suicide among American Indians SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; religion; spirituality; suicide; American Indians; measurement ID INTERNATIONAL DIAGNOSTIC INTERVIEW; RELIGIOUS INVOLVEMENT; BOARDING SCHOOL; RISK-FACTORS; ADOLESCENTS; DEPRESSION; PREVENTION; DURKHEIM; IDEATION AB American Indians exhibit suicide-related behaviors at rates much higher than the general population. This study examines the relation of spirituality to the lifetime prevalence of attempted suicide in a probability sample of American Indians. Data were derived from a cross-sectional sample of 1456 American Indian tribal members (age range 15-57 yr) who were living on or near their Northern Plains reservations between 1997 and 1999. Data were collected by personal interviews. Commitment to Christianity was assessed using a measure of beliefs. Commitment to tribal cultural spirituality (or forms of spirituality deriving from traditions that predate European contact) was assessed using separate measures for beliefs and spiritual orientations. Results indicated that neither commitment to Christianity nor to cultural spirituality, as measured by beliefs, was significantly associated with suicide attempts (P-trend for Christianity= 0.22 and P-trend for cultural spirituality= 0.85). Conversely, commitment to cultural spirituality, as measured by an index of spiritual orientations, was significantly associated with a reduction in attempted suicide (P-trend = 0.01). Those with a high level of cultural spiritual orientation had a reduced prevalence of suicide compared with those with low level of cultural spiritual orientation. (OR=0.5, 95% CI=0.3, 0.9). This result persisted after simultaneous. adjustment for age, gender, education, heavy alcohol use, substance abuse and psychological distress. These results are consistent with anecdotal reports suggesting the effectiveness of American Indian suicide-prevention programs emphasizing orientations related to cultural spirituality. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Boston Coll, Dept Sociol, Chestnut Hill, MA 02467 USA. Washington Univ, St Louis, MO 63130 USA. Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. NIH, Bethesda, MD 20892 USA. RP Garroutte, EM (reprint author), Boston Coll, Dept Sociol, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. FU NIMH NIH HHS [R01 MH48174, P01 MH42473] NR 63 TC 52 Z9 54 U1 0 U2 14 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 APR PY 2003 VL 56 IS 7 BP 1571 EP 1579 AR PII S0277-9536(02)00157-0 DI 10.1016/S0277-9536(02)00157-0 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 655QZ UT WOS:000181565300017 PM 12614706 ER PT J AU Zheng, G Gastwirth, JL AF Zheng, G Gastwirth, JL TI Fisher information in ordered randomly censored data with applications to characterization problems SO STATISTICA SINICA LA English DT Article DE factorization; Fisher information; hazard function; Koziol-Green model; order statistics; time-dependent; Weibull family ID KOZIOL-GREEN MODEL; SAMPLE AB The proportional hazards model of Koziol-Green is often considered in survival analysis. If the lifetime and censoring random variables axe independent, the Koziol-Green model implies that the variable indicating whether the observation is censored or not does not contain Fisher information about the parameters of the underlying lifetime distribution. The Koziol-Green model, however, is not uniquely characterized by this result on the lack of Fisher information in the censoring indicator. Given the ordered randomly censored lifetimes with corresponding indicators, we obtain a necessary and sufficient condition, weaker than the Koziol-Green model, which ensures that a set of any number of censoring indicators does not contain Fisher information about the parameters of the lifetime distribution. Under this weaker condition, the results are applied to characterize the Weibull distribution within the class of scale parameter families of lifetime distributions and the factorization of the hazard function in terms of the Fisher information in randomly censored data. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 19 TC 6 Z9 6 U1 0 U2 2 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD APR PY 2003 VL 13 IS 2 BP 507 EP 517 PG 11 WC Statistics & Probability SC Mathematics GA 673QE UT WOS:000182591000015 ER PT J AU Necela, BM Cidlowski, JA AF Necela, BM Cidlowski, JA TI Development of a flow cytometric assay to study glucocorticoid receptor-mediated gene activation in living cells SO STEROIDS LA English DT Article DE glucocorticoid receptor; flow cytometry; reporter gene; activation; GFP ID CREB-BINDING-PROTEIN; FACTOR-KAPPA-B; HORMONE RECEPTORS; EXPRESSION; TRANSCRIPTION; MECHANISMS; COACTIVATOR; ANTAGONISTS; COREPRESSOR; MODULATION AB A flow cytometry-based reporter gene assay was developed and utilized to measure glucocorticoid receptor (GR)-mediated gene activation at the single cell level in living cells. A reporter gene was generated that contains two copies of the glucocorticoid response element and an E1b TATA box upstream of a destabilized enhanced green fluorescent protein. Glucocorticoid activation of the reporter gene in Cos-1 and HTC cell lines was measured in vivo by flow cytometry and was shown to be dose dependent, leading to an increase in total fluorescence of the cell population. Flow cytometric analysis indicated this increase in total fluorescence per sample resulted from an increase in the number of cells expressing the activated green fluorescent protein (GFP) reporter as well as an overall increase in the mean GFP fluorescence within cells. Activation of reporter gene activity was time dependent occurring as early as 1-2 h after dexamethasone addition. Activation of the reporter gene was specific as it exhibited different sensitivities to a range of glucocorticoids and activation could be blocked with glucocorticoid receptor antagonists. Coexpression of the coactivator SRC-1a or P65 subunit of NF-kappa B with GR led to enhancement or repression, respectively. Taken together, these data suggest the reporter-based flow cytometry assay is an effective method for analyzing glucocorticoid receptor-mediated gene expression at the single cell level in living cells. Published by Elsevier Science Inc. C1 NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Bldg 101,MD F3-07, Res Triangle Pk, NC 27709 USA. NR 35 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD APR PY 2003 VL 68 IS 4 BP 341 EP 350 DI 10.1016/S0039-128X(03)00032-1 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 691KU UT WOS:000183606100005 PM 12787895 ER PT J AU Goldstein, LB Matchar, DB Hoff-Lindquist, J Samsa, GP Horner, RD AF Goldstein, LB Matchar, DB Hoff-Lindquist, J Samsa, GP Horner, RD TI Veterans Administration Acute Stroke (VASt) Study - Lack of race/ethnic-based differences in utilization of stroke-related procedures or services SO STROKE LA English DT Article DE health services; racial differences; stroke ID TRANSIENT ISCHEMIC ATTACKS; CAROTID ENDARTERECTOMY; RACIAL-DIFFERENCES; DECISION-MAKING; HEALTH-CARE; DISEASE; RACE; ATHEROSCLEROSIS; ANGIOGRAPHY; SURGERY AB Background and Purpose-Race/ethnic-based disparities in the utilization of health-related services have been reported. Data collected as part of the Veterans Administration Acute Stroke Study (VASt) were analyzed to determine whether similar differences were present in patients admitted to Veterans Administration (VA) hospitals with acute ischemic stroke. Methods-VASt prospectively identified stroke patients admitted to 9 geographically separated VA hospitals between April 1995 and March 1997. Demographic characteristics and all inpatient diagnostic tests/procedures were recorded. Frequencies were compared with chi(2) tests. Results-Of 1073 enrolled patients, 775 (white, n=520; nonwhite, n=255, including 226 blacks and 28 Hispanic-Americans) with ischemic stroke were admitted from home. Mean ages (71.0+/-0.6 versus 71.9+/-0.4 years; P=0.25) and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) stroke types (atherothrombotic, 12.9% versus 13.3%; cardioembolic, 16.5% versus 18.0%; lacunar, 26.4% versus 27.1%; other, 1.4% versus 2.0%; unclassified, 42.9% versus 39.6%; P=0.89) for whites versus nonwhites were similar. There were no race/ethnic-based differences in the utilization of brain CT (91.0% versus 92.2%; P=0.58), MRI (36.2% versus 41.6%; P=0.14), transthoracic (52.5% versus 53.7%; P=0.75) or transesophageal echocardiography (10.2% versus 10.6%; P=0.86), 24-hour ECG (3.3% versus 1.6%; P=0.17), carotid ultrasound (64.0% versus 62.0%; P=0.57), carotid endarterectomy (1.5% versus 0.8%; P=0.38), rehabilitation evaluations (71.0% versus 76.5%; P=0.11), speech therapy (9.6% versus 12.6%; P=0.21), recreational therapy (3.1% versus 2.0%; P=0.37), or occupational therapy (16.0% versus 19.6%; P=0.20) for whites versus nonwhites, respectively. Angiography was performed less frequently (3.1% versus 8.5%; P=0.01) and ECG more frequently (81.6% versus 73.5%; P=0.01) in nonwhites. The proportions of patients discharged functionally independent were also similar (52% of whites and 50% of nonwhites had discharge Rankin Scale scores of 0, 1, or 2; P=0.63). Conclusions-Aside from cerebral angiography and ECG, there were no race/ethnic-based disparities in the utilization of a variety of stroke-related procedures and services. The difference in the use of angiography is unlikely to be related to a difference in screening for carotid endarterectomy because there was no difference in the frequency of carotid ultrasonography. The reason ECG was obtained more frequently in nonwhites is uncertain. C1 Duke Univ, Med Ctr, Ctr Clin Hlth Policy Res,Dept Med, Stroke Policy Program,Duke Ctr Cerebrovasc Dis, Durham, NC 27710 USA. Vet Affairs Med Ctr, Durham, NC USA. Duke Univ, Dept Neurol, Durham, NC 27710 USA. Duke Univ, Dept Gen Internal Med, Durham, NC 27710 USA. NINDS, Off Minor Hlth & Res, Bethesda, MD 20892 USA. RP Goldstein, LB (reprint author), Duke Univ, Med Ctr, Ctr Clin Hlth Policy Res,Dept Med, Stroke Policy Program,Duke Ctr Cerebrovasc Dis, Box 3651, Durham, NC 27710 USA. FU NINDS NIH HHS [K24 NS02165] NR 36 TC 41 Z9 41 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2003 VL 34 IS 4 BP 999 EP 1003 DI 10.1161/01.STR.0000063364.88309.27 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 663PQ UT WOS:000182014300042 PM 12649513 ER PT J AU Horner, RD Swanson, JW Bosworth, HB Matchar, DB AF Horner, RD Swanson, JW Bosworth, HB Matchar, DB CA VAST Study Team TI Effects of race and poverty on the process and outcome of inpatient rehabilitation services among stroke patients SO STROKE LA English DT Article DE outcome; rehabilitation; stroke ID TRIAL AB Background and Purpose-The greater mortality and residual physical impairments among black stroke patients may be attributable to differential utilization of rehabilitation services. This report examines, within an equal-access healthcare system, racial differences in time to initiation of stroke rehabilitation services and in the trajectory of physical function recovery. Methods-This study was a secondary analysis of data from an inception cohort of 1073 stroke patients hospitalized between April 1995 and March 1997 and followed up for up to 1 year. Inpatient data came from medical record reviews; follow-up data came from telephone interviews at 1, 6, and 12 months after stroke. The study included consecutive acute ischemic or intracerebral hemorrhagic stroke patients from 9 VA medical centers. The main outcome measures were time to initiation of inpatient rehabilitation services and ability to perform activities of daily living. Results-There were no racial differences in receipt of inpatient rehabilitation services (blacks, 76%; whites, 70%) or in the proportion of patients referred within 3 days of admission (blacks, 43.5%; whites, 42.0%). Among patients who experienced delay in initiation of rehabilitation, only low-income blacks experienced worse functional recovery over 12 months. Conclusions-Low-income black stroke patients who experience delay in initiation of inpatient rehabilitation have a worse trajectory of functional recovery in the first year after stroke. Poverty-associated factors in the postdischarge setting may explain this phenomenon. C1 Duke Univ, Med Ctr, Epidemiol Res & Informat Ctr, Durham, NC USA. Duke Univ, Med Ctr, Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. Duke Univ, Ctr Clin Hlth Policy Res, Durham, NC USA. RP Horner, RD (reprint author), NINDS, NSC Bldg,Rm 2149,6001 Execut Blvd, Rockville, MD 20852 USA. NR 16 TC 62 Z9 63 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2003 VL 34 IS 4 BP 1027 EP 1031 DI 10.1161/01.STR.0000060028.60365.5D PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 663PQ UT WOS:000182014300048 PM 12624220 ER PT J AU Sun, PD AF Sun, PD TI Conserved in structure but diverse in recognition SO STRUCTURE LA English DT Editorial Material ID CRYSTAL-STRUCTURE; COMPLEX AB The crystal structure of BMP7 in complex with the type 11 activin receptor shows a different receptor binding site on the ligand compared to that observed in the TGF-beta3 and receptor complex. The result highlights the potential diversity in ligand recognition among members of the TGF-beta superfamily. C1 NIAID, Struct Immunol Sect, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 3 TC 5 Z9 5 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD APR PY 2003 VL 11 IS 4 BP 362 EP 363 AR PII S0969-2126(03)00053-4 DI 10.1016/S0969-2126(03)00053-4 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 673QJ UT WOS:000182591400003 PM 12679011 ER PT J AU Yang, W AF Yang, W TI Pruning DNA: Structure-specific endonucleases (XPF/Rad1/Mus81) SO STRUCTURE LA English DT Editorial Material ID FLAP ENDONUCLEASE-1; REPAIR PROTEINS; REPLICATION; DOMAINS; BINDING; FAMILY; FEN-1 AB The crystal structure of Hef endonuclease, an archaeal member of the XPF/Rad1/Mus81 family, reveals a type 11 restriction enzyme-like active site and a bifurcated dimer interface essential for DNA cleavage. These findings provide a focal point for future study of this family of structure-specific endonucleases. C1 NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Lab Mol Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 15 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD APR PY 2003 VL 11 IS 4 BP 365 EP 366 AR PII S0969-2126(03)00059-5 DI 10.1016/S0969-2126(03)00059-5 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 673QJ UT WOS:000182591400006 PM 12679014 ER PT J AU Kang, BS Cooper, DR Jelen, F Devedjiev, Y Derewenda, U Dauter, Z Otlewski, J Derewenda, ZS AF Kang, BS Cooper, DR Jelen, F Devedjiev, Y Derewenda, U Dauter, Z Otlewski, J Derewenda, ZS TI PDZ tandem of human syntenin: Crystal structure and functional properties SO STRUCTURE LA English DT Article DE PDZ; syndecan; merlin; schwannoma; cancer; crystallography; calorimetry ID STRUCTURE REFINEMENT; PROTEIN; DOMAINS; BINDING; INTERACTS; MEMBRANE; RECOGNITION; CYTOSKELETON; ASSOCIATION; CASK/LIN-2 AB Syntenin, a 33 kDa protein, interacts with several cell membrane receptors and with merlin, the product of the causal gene for neurofibromatosis type II. We report a crystal structure of the functional fragment of human syntenin containing two canonical PDZ domains, as well as binding studies for full-length syntenin, the PDZ tandem, and isolated PDZ domains. We show that the functional properties of syntenin are a result of independent interactions with target peptides, and that each domain is able to bind peptides belonging to two different classes: PDZ1 binds peptides from classes I and III, while PDZ2 interacts with classes I and II. The independent binding of merlin by PDZ1 and syndecan-4 by PDZ2 provides direct evidence for the coupling of syndecan-mediated signaling to actin regulation by merlin. C1 Univ Virginia, Ctr Canc, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. Univ Wroclaw, Inst Biochem & Mol Biol, Lab Prot Engn, PL-50137 Wroclaw, Poland. NCI, Synchrotron Radiat Res Stn, Macromol Crystallog Lab, Brookhaven Natl Lab, Upton, NY 11973 USA. RP Derewenda, ZS (reprint author), Univ Virginia, Ctr Canc, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RI Otlewski, Jacek/B-6340-2008 NR 49 TC 71 Z9 74 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD APR PY 2003 VL 11 IS 4 BP 459 EP 468 DI 10.1016/S0969-2126(03)00052-2 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 673QJ UT WOS:000182591400015 PM 12679023 ER PT J AU Cendales, LC Swanson, SJ Kirk, AD Mannon, RB Hale, DA AF Cendales, LC Swanson, SJ Kirk, AD Mannon, RB Hale, DA TI Delayed autotransplantation of a solitary kidney facilitated by pump perfusion preservation SO SURGERY LA English DT Article C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. RP Hale, DA (reprint author), Rm 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 4 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD APR PY 2003 VL 133 IS 4 BP 438 EP 439 DI 10.1067/msy.2003.129 PG 2 WC Surgery SC Surgery GA 674MN UT WOS:000182640700015 PM 12717362 ER PT J AU Chefer, SI London, ED Koren, AO Pavlova, OA Kurian, V Kimes, AS Horti, AG Mukhin, AG AF Chefer, SI London, ED Koren, AO Pavlova, OA Kurian, V Kimes, AS Horti, AG Mukhin, AG TI Graphical analysis of 2-[F-18]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain SO SYNAPSE LA English DT Article DE positron emission tomography; nonhuman primates; radioligand; in vivo binding ID PET; RADIOLIGAND; TRACER AB External imaging of nicotinic acetylcholine receptors (nAChRs) using techniques such as PET would help to clarify the roles of these receptors in the physiology and pathology of brain function. Here we report the results of quantitative PET studies of cerebral nAChRs with 2-[F-18]fluoro-A-85380 (2-[F-18]FA) in rhesus monkeys. Data from dynamic PET scans were analyzed using graphical methods. Binding potential (BP) values of 2.0, 0.4, 0.3, and 0.03 observed in the thalamus (Th), cortex (Cx), striatum (Str), and cerebellum (Cb), respectively, were consistent with the pattern of alpha(4)beta(2), nAChR distribution in monkey brain. The high value of 2-[F-18]FA-specific binding in the rhesus monkey Th and low level of that in Cb compared with nonspecific accumulation of radioactivity in these structures allowed use of Cb as a reference region for calculation of BP and volume of distribution of specific binding (VDsb) in Th by graphical methods, both with and without the plasma input function. In contrast, estimation of 2[F-18]FA specific binding in low-receptor-density regions such as Cx and Str required assessment of nondisplaceable volume of distribution (VDnd) in a separate study and measurement of nonmetabolized radioligand concentrations in the plasma. For accurate quantitation of 2-[F-18]FA-specific binding by graphical analysis, PET studies should last up to 7 h due to the slow kinetics of 2[F-18]FA brain distribution. Further, to avoid substantial underestimation in measured BP values the doses of administered 2-[F-18]FA should not exceed 0.1 nmol/kg body weight. The findings suggest that 2-[F-18]FA is a promising ligand for quantitation of nAChRs in human brain. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Mukhin, AG (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 21 TC 63 Z9 63 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 APR PY 2003 VL 48 IS 1 BP 25 EP 34 DI 10.1002/syn.10180 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 650DQ UT WOS:000181247700004 PM 12557269 ER PT J AU Podruchny, TA Connolly, C Bokde, A Herscovitch, P Eckelman, WC Kiesewetter, DO Sunderland, T Carson, RE Cohen, RM AF Podruchny, TA Connolly, C Bokde, A Herscovitch, P Eckelman, WC Kiesewetter, DO Sunderland, T Carson, RE Cohen, RM TI In vivo muscarinic 2 receptor imaging in cognitively normal young and older volunteers SO SYNAPSE LA English DT Article DE PET; brain imaging; cholinergic ID POSITRON EMISSION TOMOGRAPHY; AGE-RELATED-CHANGES; ALZHEIMERS-DISEASE; HUMAN-BRAIN; ACETYLCHOLINE-RECEPTORS; REGIONAL DISTRIBUTION; CHOLINERGIC SYSTEM; AGING HUMAN; BINDING; SUBTYPES AB The precise effects of normal aging on the cholinergic system are unknown, as both in vitro and PET studies have shown conflicting results. In vivo determination of muscarinic receptor distribution and density has been hampered by both poor subtype selectivity and/or blood-brain barrier permeability of known ligands. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3-[F-18]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ((FP)-F-18-TZTP) suggested the use of (FP)-F-18-TZTP to selectively quantify M2 receptors in humans. In this study, we used (FP)-F-18-TZTP to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 +/- 5.5 years) and 20 healthy older subjects (mean age = 62.1 +/- 7.7 years). Corrections for subject motion during the 120-min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (V-T) of (FP)-F-18-TZTP. Within both groups of subjects, volumes of distribution (K-1/k(2)) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of (FP)-F-18-TZTP throughout much of the cerebellum, cortex, and subcortex (Global Gray V-T = 742 +/- 163 in older subjects and 645 +/- 74 in younger subjects, P < 0.03). Across all subjects (FP)-F-18-TZTP, regional, and Global Gray distribution volumes were significantly correlated to age (Global Gray V-T, r = 0.41, P < 0.01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation for the data. C1 NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Munich, Alzheimer Mem Ctr, Dementia & Neuroimaging Res Sect, D-80336 Munich, Germany. Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, D-80336 Munich, Germany. NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Cohen, RM (reprint author), NIMH, Geriatr Psychiat Branch, NIH, Bldg 10,Room 3N228,MSC 1275,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 43 TC 38 Z9 38 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD APR PY 2003 VL 48 IS 1 BP 39 EP 44 DI 10.1002/syn.10165 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 650DQ UT WOS:000181247700006 PM 12557271 ER PT J AU Woodcock, HL Hodoscek, M Sherwood, P Lee, YS Schaefer, HF Brooks, BR AF Woodcock, HL Hodoscek, M Sherwood, P Lee, YS Schaefer, HF Brooks, BR TI Exploring the quantum mechanical/molecular mechanical replica path method: a pathway optimization of the chorismate to prephenate Claisen rearrangement catalyzed by chorismate mutase SO THEORETICAL CHEMISTRY ACCOUNTS LA English DT Article; Proceedings Paper CT Symposium on Methods and Applications of Combined Quantum Mechanical and Molecular Mechanical Potentials held at the 222nd American-Chemical-Society National Meeeting CY AUG 26-30, 2001 CL CHICAGO, ILLINOIS SP Amer Chem Soc DE quantum mechanical/molecular mechanical; replica path method; chorismate mutase ID COMBINED QM/MM SIMULATION; BACILLUS-SUBTILIS; TRANSITION-STATE; ACTIVE-SITE; ENZYME; ENERGY; STABILIZATION; MUTAGENESIS; POTENTIALS; EXCHANGE AB A replica path method has been developed and extended for use in complex systems involving hybrid quantum/classical (quantum mechanical/molecular mechanical) coupled potentials. This method involves the definition of a reaction path via replication of a set of macromolecular atoms. An "important" subset of these replicated atoms is restrained with a penalty function based on weighted root-mean-square rotation/translation best-fit distances between adjacent (i +/- 1) and next adjacent (i +/- 2) pathway steps. An independent subset of the replicated atoms may be treated quantum mechanically using the computational engine Gamess-UK. This treatment can be performed in a highly parallel manner in which many dozens of processors can be efficiently employed. Computed forces may be projected onto a reference pathway and integrated to yield a potential of mean force (PMF). This PMF, which does not suffer from large errors associated with calculated potential-energy differences, is extremely advantageous. As an example, the QM/MM replica path method is applied to the study of the Claisen rearrangement of chorismate to prephenate which is catalyzed by the Bacillus subtilis isolated, chorismate mutase. Results of the QM/MM pathway minimizations yielded an activation enthalpy DeltaH(daggerdagger) of 14.9 kcal/mol and a reaction enthalpy of -19.5 kcal/mol at the B3LYP/6-31G(d) level of theory. The resultant pathway was compared and contrasted with one obtained using a forced transition approach based on a reaction coordinate constrained repeated walk procedure (DeltaH(daggerdagger) 20.1 kcal/mol, DeltaH(rxn) = -20.1 kcal/mol, RHF/4-31G). The optimized replica pat results compare favorably to the experimental activation enthalpy of 12.7 +/- 0.4 kcal/mol. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Georgia, Ctr Computat Quantum Chem, Athens, GA 30602 USA. Natl Inst Chem, SI-1000 Ljubljana, Slovenia. CLRC, Daresbury Lab, Warrington WA4 4AD, Cheshire, England. NIH, Ctr Mol Modeling, CIT, Bethesda, MD 20892 USA. RP Woodcock, HL (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Woodc, Henry/D-9275-2011; Sherwood, Paul/B-9033-2012; OI Sherwood, Paul/0000-0002-4611-5052; Woodcock, Henry/0000-0003-3539-273X NR 40 TC 80 Z9 80 U1 2 U2 11 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1432-881X J9 THEOR CHEM ACC JI Theor. Chem. Acc. PD APR PY 2003 VL 109 IS 3 BP 140 EP 148 DI 10.1007/s00214-002-0421-3 PG 9 WC Chemistry, Physical SC Chemistry GA 681LY UT WOS:000183038700007 ER PT J AU Bauer, AK Faiola, B Abernethy, DJ Marchan, R Pluta, LJ Wong, VA Gonzalez, FJ Butterworth, BE Borghoff, SJ Everitt, JI Recio, L AF Bauer, AK Faiola, B Abernethy, DJ Marchan, R Pluta, LJ Wong, VA Gonzalez, FJ Butterworth, BE Borghoff, SJ Everitt, JI Recio, L TI Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE benzene; bone marrow; genotoxicity; hematotoxicity; leukemia; mEH; micronuclei ID LUNG-CANCER RISK; BONE-MARROW; GENETIC POLYMORPHISMS; EXPOSURE; METABOLITES; EXPRESSION; LEUKEMIA; WORKERS; CHINA; HEMATOTOXICITY AB Enzymes involved in benzene metabolism are likely geneticdeterminants of benzene-induced toxicity. Polymorphisms in human microsomal epoxide hydrolase (mEH) are associated with an increased risk of developing leukemia, specifically those associated with benzene. This study was designed to investigate the importance of mEH in benzene-induced toxicity. Male and female mEH-deficient (mEH(-/-)) mice and background mice (129/Sv) were exposed to inhaled benzene (0, 10, 50, or 100 ppm) 5 days/week, 6 h/day, for a two-week duration. Total white blood cell counts and bone marrow cell counts were used to assess hematotoxicity and myelotoxicity. Micronucleated peripheral blood cells were counted to assess genotoxicity, and the p21 mRNA level in bone marrow cells was used as a determinant of the p53-regulated DNA damage response. Male mEH(-/-) mice did not have any significant hematotoxicity or myelotoxicity at the highest benzene exposure compared to the male 129/Sv mice. Significant hematotoxicity or myelotoxicity did not occur in the female mEH(-/-) or 129/Sv mice. Male mEH(-/-) mice were also unresponsive to benzene-induced genotoxicity compared to a significant induction in the male 129/Sv mice. The female mEH(-/-) and 129/Sv mice were virtually unresponsive to benzene-induced genotoxicity. While p21 mRNA expression was highly induced in male 129/Sv mice after exposure to 100-ppm benzene, no significant alteration was observed in male mEH(-/-) mice. Likewise, p21 mRNA expression in female mEH(-/-) mice was not significantly induced upon benzene exposure whereas a significant induction was observed in female 129/Sv mice. Thus mEH appears to be critical in benzene-induced toxicity in male, but not female, mice. C1 Chem Ind Inst Toxicol, Ctr Hlth Res, Res Triangle Pk, NC 27709 USA. NCI, Bethesda, MD 20892 USA. RP Bauer, AK (reprint author), NIEHS, Pulm Pathobiol Lab, E214,Bldg 101,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Everitt, Jeffrey/0000-0003-0273-6284 FU NIEHS NIH HHS [1F32 ES11424-01, F32 ES011424-01] NR 47 TC 26 Z9 27 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2003 VL 72 IS 2 BP 201 EP 209 DI 10.1093/toxsci/kfg024 PG 9 WC Toxicology SC Toxicology GA 662DP UT WOS:000181931200005 PM 12655032 ER PT J AU Dill, JA Fuciarelli, AF Lee, KM Mellinger, KM Chan, PC Burka, LT Roycroft, JH AF Dill, JA Fuciarelli, AF Lee, KM Mellinger, KM Chan, PC Burka, LT Roycroft, JH TI Single administration toxicokinetic studies of decalin (decahydronaphthalene) in rats and mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE decalin (decahydronaphthalene); decalone; decalol; alpha(2u)-globulin; toxicokinetics ID ALPHA-2U-GLOBULIN NEPHROPATHY; D-LIMONENE; KIDNEYS; ALPHA(2U)-GLOBULIN; NEPHROTOXICITY; PATHOBIOLOGY; PROTEINS; BINDING AB Decalin (decahydronaphthalene) is an industrial solvent known to cause alpha(2u)-globulin nephropathy in male rats. Studies were conducted using decalin (mixture of cis and trans isomers) to (1) characterize systemic elimination of decalin in rats and mice and (2) evaluate disposition of decalin, its metabolites, and kidney alpha(2u)-globulin in young and old rats of both sexes following a single 6-h whole-body inhalation exposure at up to 400 ppm decalin. Additionally, a separate group of young male F344/N rats were administered either cis- or trans-decalin iv at doses up to 20 mg/kg to assess disposition of each isomer, its metabolites, and kidney alpha(2u)-globulin. Decalin was eliminated from blood in a dose-dependent manner, regardless of sex, age, or species. C-0 and AUC(x) increased supra-proportionally with exposure concentration. Mice were more efficient in eliminating decalin than rats at lower exposure concentrations, but nonlinear elimination kinetics were more noticeable at 400 ppm. Sex differences in blood decalin elimination were observed in rats; females had a consistently higher AUCx at all exposure concentrations. There was a dose-dependent increase in kidney decalin, decalone, and alpha(2u)-globulin in male rats exposed to decalin. Kidney a,,-globulin and decalone concentrations in old male rats were substantially lower than those in young males, but were similar to those observed in all (young and old) females. Compared to old males and all females, young male rats had significantly lower urinary decalol concentrations, but higher kidney decalin, decalone, and a,,-globulin concentrations. Administration of decalin to male rats as either the cis or trans isomer revealed that more cis-decalone is produced per unit dose as compared to trans-decalone, and that more trans-decalin accumulated in the kidney (as alpha(2u)-globulin-ligand complexes) compared to cis-decalin. These patterns of isomer-specific metabolism were also reflected in the cis/trans ratios of decalin in blood, as well as urinary decalol metabolites. The ratio of alpha(2u)-globulin to the total amount of decalin plus decalone measured in the male rat kidney was approximately 1.0. Therefore, alpha(2u)-globulin was a key, factor in the accumulation of decalin and decalone in kidneys of young male rats, decalin and decalone were practically absent in all females and in old males. C1 Battelle Mem Inst, Toxicol NW, Richland, WA 99352 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Dill, JA (reprint author), Battelle Mem Inst, Toxicol NW, MS K4-16,POB 999, Richland, WA 99352 USA. FU NIEHS NIH HHS [N01-ES-55392] NR 26 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2003 VL 72 IS 2 BP 210 EP 222 DI 10.1093/toxsci/kfg027 PG 13 WC Toxicology SC Toxicology GA 662DP UT WOS:000181931200006 PM 12660358 ER PT J AU Dill, JA Lee, KM Renne, RA Miller, RA Fuciarelli, AF Gideon, KM Chan, PC Burka, LT Roycroft, JH AF Dill, JA Lee, KM Renne, RA Miller, RA Fuciarelli, AF Gideon, KM Chan, PC Burka, LT Roycroft, JH TI alpha(2u)-Globulin nephropathy and carcinogenicity following exposure to decalin (decahydronaphthalene) in F344/N rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE decalin (decahydronaphthalene); 2-decalone; decalol; alpha(2u)-globulin; hyaline droplet; cell proliferation; hyperplasia; nephropathy; toxicity; carcinogenicity; sex; F344/N ID ALPHA-2U-GLOBULIN; KIDNEYS; NEPHROTOXICITY; MECHANISMS; TOXICITY; TISSUE; MICE AB Decalin (decahydronaphthalene) is a widely used industrial solvent known to cause male rat-specific alpha(2u)-globulin nephropathy. In this project, 13-week and two-year inhalation studies of decalin were conducted consecutively in both sexes of F344/N rats. The key objectives were to (1) characterize the 13-week toxicity of decalin in rats, with an emphasis on nephropathy in males; (2) compare the kidney concentrations of decalin, 2-decalone, and alpha(2u)-globulin in males over 2 to 13 weeks of decalin exposure; and (3) correlate male rat nephropathy observed in the 13-week study with renal carcinogenicity in the two-year study. F344 rats (M/F) were exposed via whole-body inhalation to 0, 25, 50, 100, 200, or 400 ppm decalin for 13 weeks. Urine was collected at weeks 2 and 6 for creatinine and decalol analyses and at week 12 for clinical urinalysis. Right kidneys were collected from male rats at weeks 2 and 6 and from both sexes at week 13, homogenates were prepared using the whole kidney, and these homogenates were analyzed for alpha(2u)-globulin, decalin, and 2-decalone. Left kidneys were evaluated for histopathology and cell proliferation utilizing a proliferating cell nuclear antigen technique and counting proximal renal tubular epithelial cells to determine cell labeling indices. Necropsies and histopathologic evaluations were performed at week 13. Decalin exposure caused increases in kidney weight, urinalysis parameters (protein, AST, LDH), kidney alpha(2u)-globulin concentration, and proximal convoluted renal tubular cell proliferation in males. These changes were accompanied by microscopic lesions (accumulation of hyaline droplets in cortical tubules, regeneration of proximal tubular epithelium, and granular casts in medullary tubules) clearly linked to alpha(2u)-globulin nephropathy. Both decalin and 2-decalone were related to increased alpha(2u)-globulin in male kidneys. Kidney concentrations of decalin, 2-decalone, and alpha(2u)-globulin in exposed females were negligible, while females excreted greater amounts of decalol metabolites in urine than males at weeks 2 and 6. There were no exposure-related microscopic lesions in females. For chronic exposure, F344 rats were exposed via whole-body inhalation to 0, 25, 50 (males only), 100, or 400 ppm decalin for two years. Chronic exposure induced a spectrum of nonneoplastic and neoplastic lesions in the renal cortex of males, ranging from regenerative lesions of chronic nephropathy to tubular carcinomas. Incidences of renal tubular adenoma, tubular carcinoma, combined tubular adenomas and carcinomas, cortical tubular hyperplasia, hyaline droplet accumulation, hyperplasia of pelvic epithelium, and mineralization in renal papilla were increased in exposed males compared to controls. There was a clear increase in the mean severity of chronic nephropathy in decalin-exposed males. It was concluded that the carcinogenic effect on the renal cortical epithelium of male rats exposed to decalin was related to increased turnover of this epithelium, resulting from the cytotoxic effects of alpha(2u)-globulin accumulation in the renal cortical tubular cell cytoplasm. C1 Battelle Mem Inst, Toxicol NW, Richland, WA 99352 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Dill, JA (reprint author), Battelle Mem Inst, Toxicol NW, MS K4-16,POB 999, Richland, WA 99352 USA. FU NIEHS NIH HHS [N01-ES-55392] NR 36 TC 9 Z9 10 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2003 VL 72 IS 2 BP 223 EP 234 DI 10.1093/toxsci/kfg028 PG 12 WC Toxicology SC Toxicology GA 662DP UT WOS:000181931200007 PM 12660359 ER PT J AU Dekundy, A Kaminski, RM Turski, WA AF Dekundy, A Kaminski, RM Turski, WA TI Dizocilpine improves beneficial effects of cholinergic antagonists in anticholinesterase-treated mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE anticholinesterase; NMDA antagonist; atropine; mecamylamine; mice; seizures; lethality; nicotinic; muscarinic ID PROTEIN-KINASE-C; ACETYLCHOLINE-RECEPTORS; CHEMICAL WARFARE; INDUCED SEIZURES; BRAIN-DAMAGE; SOMAN; ORGANOPHOSPHATE; CARBAMATE; ATROPINE; AGENTS AB Mice were administered anticholinesterase pesticides dichlorvos (DDVP) or methomyl (MET). Both DDVP and MET induced dose-dependent seizures and lethality in mice. The muscarinic antagonist atropine (ATR, 1.8 mg/kg) did not prevent seizures but diminished the lethality induced by DDVP or MET. The nicotinic antagonist mecamylamine (MEC, 1 mg/kg) affected neither DDVP-induced seizures nor DDVP- and MET-induced lethality, but diminished MET-induced seizures. At a higher dose (10 mg/ kg), MEC attenuated seizures produced by MET, but not DDVP, and decreased lethality of both anticholinesterases. The N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801, 1 mg/kg) prevented DDVP-, but not MET-induced seizures. MK-801 did not affect DDVP- or MET-induced lethality. Concurrent administration of ATR and MK-801 prevented the occurrence of DDVP- but not MET-induced seizures. MK-801 coadministered with ATR enhanced its protective effect against DDVP- or MET-induced lethality in mice. Coinjection of MEC (at both doses studied) and MK-801 completely prevented seizures produced by both acetylcholinesterase (ACNE) inhibitors. Coadministration of MEC (1 mg/kg) and MK-801 protected mice against DDVP or MET lethality. MK-801 administered along with MEC at 10 mg/kg enhanced antilethal effects of the nicotinic antagonist in DDVP- or MET-treated mice. With respect to the mechanism underlying anticholinesterase-induced neurotoxicity, muscarinic and nicotinic, as well as NMDA receptors, seem to play major roles. The results suggest that combined treatment with cholinergic and NMDA antagonists might be beneficial in anticholinesterase-induced poisonings. C1 Inst Agr Med, Dept Toxicol, PL-20950 Lublin, Poland. Med Univ, Dept Pharmacol & Toxicol, PL-20090 Lublin, Poland. RP Kaminski, RM (reprint author), NINDS, NIH, 49 Convent Dr,MSC 4457,Bldg 49,Rm 5A75, Bethesda, MD 20892 USA. NR 37 TC 12 Z9 16 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2003 VL 72 IS 2 BP 289 EP 295 DI 10.1093/toxsci/kfg013 PG 7 WC Toxicology SC Toxicology GA 662DP UT WOS:000181931200015 PM 12660363 ER PT J AU Brown, P AF Brown, P TI Variant CJD transmission through blood: risks to predictors and "predictees" SO TRANSFUSION LA English DT Editorial Material ID DISEASE; VCJD C1 NIH, Bethesda, MD 20892 USA. RP Brown, P (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 16 Z9 16 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 APR PY 2003 VL 43 IS 4 BP 425 EP 427 DI 10.1046/j.1537-2995.2003.t01-1-00351.x PG 3 WC Hematology SC Hematology GA 664RQ UT WOS:000182075000003 PM 12662273 ER PT J AU Moncada, V Bolan, C Yau, YY Leitman, SF AF Moncada, V Bolan, C Yau, YY Leitman, SF TI Analysis of PBPC cell yields during large-volume leukapheresis of subjects with a poor mobilization response to filgrastim SO TRANSFUSION LA English DT Article ID COLONY-STIMULATING FACTOR; BLOOD PROGENITOR CELLS; PERIPHERAL-BLOOD; STEM-CELLS; CD34(+) CELLS; G-CSF; TRANSPLANTATION; LYMPHOMA; CHEMOTHERAPY AB BACKGROUND: The circulating CD34 count is a reliable predictor of peripheral blood progenitor cell (PBPC) yields in subjects with a vigorous mobilization response to G-CSF, however, the value of this parameter in poor mobilizers is uncharacterized. STUDY DESIGN AND METHODS: Consecutive PBPC prdcedures (n = 81) with preapheresis CD34 counts less than 20 per muL (poor mobilizers) were compared with an equal number of good mobilizers (preapheresis CD34 counts greater than or equal to20/muL). G-CSF was administered at standard doses (10 mug/kg/day). RESULTS: CD34 yields correlated strongly with preapheresis CD34 counts in both good and poor mobilizers and were higher in allogeneic than autologous donors. For a standard 75-kg recipient, a CD34 cell dose of greater than 2 x 10(6) per kg was never achieved in less than two 15-L procedures if the preapheresis CD34 count was less than 8 per muL. Preapheresis WBC and MNC counts were lower in poor than in good mobilizers (28.4 vs. 43.0 and 3.25 vs. 5.01 x 10(3)/muL, respectively, p < 0.0001). Total WBC counts correlated more strongly with preapheresis CD34 counts, total CD34 yields, and CD34 yields per L processed in good mobilizers (R = 0.50, R = 0.44, and R = 0.42, respectively) than in poor mobilizers (R = 0.22, R = 0.02, and R = 0.01, respectively), whereas total MNC counts correlated more strongly with these parameters in poor (R 0.38, R = 0.23, and R = 0.27, respectively) than in good mobilizers (R = 0.04, R = 0.13, and R = 0.16, respectively). CONCLUSION: CD34 cell yields correlate strongly with preapheresis CD34 counts. Based on this analysis, a CD34 count greater than or equal to 8 per muL is the threshold for performing PBPC collections in our institution. C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RP Bolan, C (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. NR 18 TC 40 Z9 41 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 APR PY 2003 VL 43 IS 4 BP 495 EP 501 DI 10.1046/j.1537-2995.2003.00361.x PG 7 WC Hematology SC Hematology GA 664RQ UT WOS:000182075000013 PM 12662283 ER PT J AU Raben, N Nagaraju, K Lee, A Lu, N Rivera, Y Jatkar, T Hopwood, JJ Plotz, PH AF Raben, N Nagaraju, K Lee, A Lu, N Rivera, Y Jatkar, T Hopwood, JJ Plotz, PH TI Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice SO TRANSGENIC RESEARCH LA English DT Article DE antibodies; lysosomal disorder; tetracycline inducible system; tolerance; transgenic/knockouts ID DISEASE TYPE-II; HEMATOPOIETIC STEM-CELLS; GLYCOGENOSIS TYPE-II; POMPE-DISEASE; HEMOPHILIA-A; RABBIT MILK; FACTOR-VIII; LONG-TERM; HEPATOCYTE TRANSPLANTATION; REPLACEMENT THERAPY AB When knockout mice are used to test the efficacy of recombinant human proteins, the animals often develop antibodies to the enzyme, precluding long-term pre-clinical studies. This has been a problem with a number of models, for example, the evaluation of gene or enzyme replacement therapies in a knockout model of glycogen storage disease type II (GSDII; Pompe syndrome). In this disease, the lack of acid alpha-glucosidase (GAA) results in lysosomal accumulation of glycogen, particularly in skeletal and cardiac muscle. Here, we report that in a GAA-deficient mouse model of GSDII, low levels of transgene-encoded human GAA expressed in skeletal muscle or liver dramatically blunt or abolish the immune response to human recombinant protein. Of two low expression transgenic lines, only the liver-expressing line exhibited a profound GAA deficiency in skeletal muscle and heart indistinguishable from that in the original knockouts. The study suggests that the induction of tolerance in animal models of protein deficiencies could be achieved by restricting the expression of a gene of interest to a particular, carefully chosen tissue. C1 NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Womens & Childrens Hosp, Dept Chem Pathol, Adelaide, SA 5006, Australia. RP Raben, N (reprint author), NIAMS, Arthrit & Rheumatism Branch, NIH, 9000 Rockville Pike,Clin Ctr Bld 10-9N244, Bethesda, MD 20892 USA. NR 36 TC 24 Z9 24 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD APR PY 2003 VL 12 IS 2 BP 171 EP 178 DI 10.1023/A:1022998010833 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 660UR UT WOS:000181852600004 PM 12739885 ER PT J AU Crook, ME Akyurek, LM AF Crook, ME Akyurek, LM TI Gene transfer strategies to inhibit neointima formation SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID MUSCLE CELL-PROLIFERATION; DEPENDENT KINASE INHIBITORS; IN-VIVO; EXPRESSION; DELIVERY; THERAPY; VITRO; ANGIOPLASTY; ARTERIES; DISEASE AB Vascular smooth muscle cell (VSMC) proliferation after arterial injury results in neointima formation and plays an important role in the pathogenesis of restenosis after angioplasty, in-stent restenosis, vascular bypass graft occlusion, and allograft vasculopathy. Major progress has been made recently in elucidating the cellular and molecular mechanisms underlying neointima formation. However, no known curative treatment currently exists. In cases in which pharmacologic and surgical interventions have had limited success, gene therapy remains a potential strategy for the treatment of such vascular proliferative diseases. To date, recombinant adenoviral vectors continue to be the most efficient methods of gene transfer into the arterial wall. However, concerns over the safety of using viral vectors in a clinical situation have inspired the considerable progress that has been made in improving both viral and nonviral modes of gene transfer This review discusses some of the recent insights and outstanding progress in vascular gene therapeutic approaches to inhibit neointima both from a biologic and therapeutic perspective. (C) 2003, Elsevier Science Inc. C1 Univ Gothenburg, Dept Anat & Cell Biol, SE-40530 Gothenburg, Sweden. Univ Gothenburg, Wallenberg Lab, SE-40530 Gothenburg, Sweden. Natl Heart Lung & Blood Inst, Cardiovasc Biol Branch, Bethesda, MD USA. RP Akyurek, LM (reprint author), Univ Gothenburg, Dept Anat & Cell Biol, Medicinaregatan 3-5,Box 420, SE-40530 Gothenburg, Sweden. NR 39 TC 17 Z9 24 U1 1 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD APR PY 2003 VL 13 IS 3 BP 102 EP 106 AR PII S1050-1738(02)00255-4 DI 10.1016/S1050-1738(02)00255-4 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 664CY UT WOS:000182045200002 PM 12691673 ER PT J AU Makarova, KS Wolf, YI Koonin, EV AF Makarova, KS Wolf, YI Koonin, EV TI Potential genomic determinants of hyperthermophily SO TRENDS IN GENETICS LA English DT Article ID REVERSE GYRASE; GENE-TRANSFER; PROTEIN; CLASSIFICATION; EVOLUTION; DATABASE; ARCHAEAL; CONTEXT; DNA; INFORMATION AB We searched for genes that could be important for hyperthermophily using a flexible approach to phyletic pattern analysis. We identified 290 clusters of orthologous groups of proteins (COGs) that are preferentially present in archaeal and bacterial hyperthermophiles. Of these, 58 COGs include proteins from at least one bacterium and two archaea, and these were considered to be the best candidates for a specific association with the hyperthermophilic phenotype. Detailed sequence and genome-context analysis of these COGs led to functional predictions for several previously uncharacterized protein families, including a novel group of putative molecular chaperones and a unique transcriptional regulator. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 30 TC 57 Z9 60 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD APR PY 2003 VL 19 IS 4 BP 172 EP 176 DI 10.1016/S0168-9525(03)00047-7 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 674ET UT WOS:000182625000002 PM 12683966 ER PT J AU Sandor, M Weinstock, JV Wynn, TA AF Sandor, M Weinstock, JV Wynn, TA TI Response to Doenhoff: Granulomas: these gizmos are cool! SO TRENDS IN IMMUNOLOGY LA English DT Letter ID SCHISTOSOMA-MANSONI; MICE; INFECTION; IMMUNOPATHOLOGY; DEFICIENT; MEN C1 Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Med Sci Ctr, Madison, WI 53706 USA. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. NIAID, Schistosomiasis Immunol & Pathol Unit, Immunobiol Sect, Parasit Dis Lab,NIH, Bethesda, MD 20892 USA. RP Sandor, M (reprint author), Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Med Sci Ctr, Room 5468,1300 Univ Ave, Madison, WI 53706 USA. RI Wynn, Thomas/C-2797-2011 NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD APR PY 2003 VL 24 IS 4 BP 169 EP 170 DI 10.1016/S1471-4906(03)00054-1 PG 2 WC Immunology SC Immunology GA 676DD UT WOS:000182735900006 ER PT J AU Bhandoola, A Rosenberg, AS Singer, A AF Bhandoola, A Rosenberg, AS Singer, A TI CD4(+) T-cell responses to self-peptide-MHC SO TRENDS IN IMMUNOLOGY LA English DT Letter C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. US FDA, Div Therapeut Prot, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD APR PY 2003 VL 24 IS 4 BP 171 EP 171 DI 10.1016/S1471-4906(03)00061-9 PG 1 WC Immunology SC Immunology GA 676DD UT WOS:000182735900007 PM 12697444 ER PT J AU Gerdeman, GL Partridge, JG Lupica, CR Lovinger, DM AF Gerdeman, GL Partridge, JG Lupica, CR Lovinger, DM TI It could be habit forming: drugs of abuse and striatal synaptic plasticity SO TRENDS IN NEUROSCIENCES LA English DT Review ID LONG-TERM DEPRESSION; VENTRAL TEGMENTAL AREA; BRAIN REWARD AREAS; NUCLEUS-ACCUMBENS; DORSAL STRIATUM; BASAL GANGLIA; CORTICOSTRIATAL SYNAPSES; DOPAMINE-RECEPTORS; CHOLINERGIC INTERNEURONS; BEHAVIORAL SENSITIZATION AB Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction. C1 Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. NIAAA, Lab Mol Physiol, Rockville, MD 20852 USA. Div Intramural Clin & Basic Res, Rockville, MD 20852 USA. NIDA, Sect Cellular Neurophysiol, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. RP Gerdeman, GL (reprint author), Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. NR 89 TC 295 Z9 312 U1 2 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD APR PY 2003 VL 26 IS 4 BP 184 EP 192 DI 10.1016/S0166-2236(03)00065-1 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 671ZR UT WOS:000182496100008 PM 12689769 ER PT J AU van Hooft, JA Yakel, JL AF van Hooft, JA Yakel, JL TI 5-HT3 receptors in the CNS: 3B or not 3B? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Article ID SEROTONIN 5-HT3; NICOTINIC ACETYLCHOLINE; NERVE-TERMINALS; ION-CHANNEL; SUBUNIT; EXPRESSION; INTERNEURONS; COMPLEXES; CALCIUM; RELEASE AB 5-HT3 receptors are widely distributed in the CNS and PNS where they participate in a variety of physiological processes. Native 5-HT3 receptors in the CNS display functional and pharmacological heterogeneity, suggesting the existence of multiple receptor subunits. However, recent evidence suggests that of the two known subunits only the 5-HT3A receptor subunit (and not the 5-HT3B receptor subunit) is functionally present in the CNS. The molecular makeup of the 5-HT3 receptor therefore remains an open question. C1 Univ Amsterdam, Swammerdam Inst Life Sci, Neurobiol Sect, NL-1090 GB Amsterdam, Netherlands. NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), Univ Amsterdam, Swammerdam Inst Life Sci, Neurobiol Sect, POB 94084, NL-1090 GB Amsterdam, Netherlands. NR 20 TC 31 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2003 VL 24 IS 4 BP 157 EP 160 DI 10.1016/S0165-6147(03)00051-8 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 676ZU UT WOS:000182783100003 PM 12707000 ER PT J AU Soldatov, MM AF Soldatov, MM TI Ca2+ channel moving tail: link between Ca2+-induced inactivation and Ca2+-signal transduction SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID CA2+-DEPENDENT INACTIVATION; ALPHA(1C) SUBUNIT; CALCIUM-CHANNEL; CA2+-SENSITIVE INACTIVATION; MOLECULAR DETERMINANTS; CALMODULIN COMPLEX; OPEN PROBABILITY; BINDING; TRANSLOCATION; INHIBITION AB Ca2+-induced inactivation is an important property of L-type voltage-gated Ca2+ channels. However, the underlying mechanisms are not yet understood well. There is general agreement that calmodulin (CaM) binds, in a Ca2+-dependent manner, to C-terminal motifs LA and IQ of the pore-forming alpha1c-subunit and acts as a sensor that conveys Ca2+-induced inactivation. New data indicate that both Ca2+-induced inactivation and Ca2+ signal transduction depend on the voltage-gated mobility of the C-terminal tail of the alpha1c-subunit. It is proposed that LA is a Ca2+-sensitive lock for the mechanism of slow voltage-dependent inactivation of the channel. A Ca2+-dependent switch of CaM from LA to 10 removes CaM from the inner mouth of the pore and thus eliminates slow inactivation by facilitating the constriction of the pore. The mobile tail then shuttles the Ca2+-CaM-IQ complex to a downstream target of the Ca2+ signaling cascade, where Ca2+ is released as an activating stimulus. Apo-CaM rebinds to LA and returns to the pore for a new cycle of Ca2+ signal transduction. C1 NIA, NIH, Baltimore, MD 21224 USA. RP Soldatov, MM (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2003 VL 24 IS 4 BP 167 EP 171 DI 10.1016/S0165-6147(03)00065-8 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 676ZU UT WOS:000182783100005 ER PT J AU Nabel, GJ AF Nabel, GJ TI Vaccine for AIDS and Ebola virus infection SO VIRUS RESEARCH LA English DT Article; Proceedings Paper CT 12th International Congress of Virology CY JUL 27-AUG 01, 2002 CL PARIS, FRANCE DE HIV; AIDS; immunodeficiency; Ebola virus; filovirus; hemorrhagic fever ID ENVELOPE GLYCOPROTEIN; GENETIC IMMUNIZATION; GP41; RESPONSES; DISEASES; ENTRY; DNA AB Ebola virus and HIV present challenges for vaccine development because natural immunity to these viruses is difficult to find, and there are no immune correlates of protection in humans. Modern molecular genetic, virologic and immune analyses have been used to rationally identify promising approaches based on animal model and human clinical studies. Improved vaccine candidates have been defined for HIV, and a promising Ebola vaccine have conferred protection in non-human primates. Further evaluation in humans will allow an assessment of their potential efficacy and point the way to the development of more successful vaccines. Published by Elsevier Science B.V. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. NR 27 TC 12 Z9 13 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD APR PY 2003 VL 92 IS 2 BP 213 EP 217 DI 10.1016/S0168-1702(02)00354-4 PG 5 WC Virology SC Virology GA 669EX UT WOS:000182339900012 PM 12686432 ER PT J AU Lin, J Dong, HF Oppenheim, JJ Howard, OM AF Lin, J Dong, HF Oppenheim, JJ Howard, OM TI Effects of astragali radix on the growth of different cancer cell lines SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article ID CHINESE MEDICINAL HERBS; UP-REGULATION; APOPTOSIS; POLYSACCHARIDES; MEMBRANACEUS; FLAVONOIDS; CARCINOMA; SELENIUM; ROOTS; MICE AB AIM: To investigate the inhibitory effect of a Chinese herb medicine Astragali radix (AR) on growth of different cancer cell lines. METHODS: To observe the in vitro effects of AR on tumor cell proliferation by trypan blue exclusion, MTS method and tritium thymidine incorporation assay. Apoptosis was detected by DNA ladder method. RESULTS: The inhibition rates of AR on the cell respiration of AGS, KATOIII, HT29, MDA231, MEL7 and MEL14 were 68.25%, 62.36%, 22.8%, 27.69%, 2.85% and 5.14% respectively at the concentration of 100 ug/ml; it inhibited AGS DNA synthesis by 87.33% at the concentration of 50 ug/ml. The inhibitory effect on AGS was time-and dose-dependent. AR did not induce apoptosis in AGS cells. CONCLUSION: AR specifically inhibits gastric cancer cells growth in vitro and the mechanism is mainly cytostatic but not cytotoxic or inducing apoptosis. C1 Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Gastroenterol, Shanghai 200021, Peoples R China. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Lin, J (reprint author), Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Gastroenterol, Shanghai 200021, Peoples R China. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 31 TC 27 Z9 28 U1 0 U2 8 PU W J G PRESS PI BEIJING PA PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD APR PY 2003 VL 9 IS 4 BP 670 EP 673 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 671MR UT WOS:000182469000008 PM 12679907 ER PT J AU Engelholm, LH List, K Netzel-Arnett, S Cukierman, E Mitola, DJ Aaronson, H Kjoller, L Larsen, JK Yamada, KM Strickland, DK Holmbeck, K Dano, K Birkedal-Hansen, H Behrendt, N Bugge, TH AF Engelholm, LH List, K Netzel-Arnett, S Cukierman, E Mitola, DJ Aaronson, H Kjoller, L Larsen, JK Yamada, KM Strickland, DK Holmbeck, K Dano, K Birkedal-Hansen, H Behrendt, N Bugge, TH TI uPARAP/Endo 180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion SO JOURNAL OF CELL BIOLOGY LA English DT Article DE cell adhesion; integrin; matrix internalization; matrix metallo-proteinase; uPAR ID RECEPTOR-ASSOCIATED PROTEIN; PLASMINOGEN-ACTIVATOR RECEPTOR; UROKINASE RECEPTOR; MANNOSE RECEPTOR; LECTIN RECEPTOR; PHAGOCYTOSIS; BINDING; INTERNALIZATION; DOMAIN; CELLS AB The uptake and lysosomal degradation of collagen by fibroblasts constitute a major pathway in the turnover of connective tissue. However, the molecular mechanisms governing this pathway are poorly understood. Here, we show that the urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180, a novel mesenchymally expressed member of the macrophage mannose receptor family of endocytic receptors, is a key player in this process. Fibroblasts from mice with a targeted deletion in the uPARAP/Endo180 gene displayed a near to complete abrogation of collagen endocytosis. Furthermore, these cells had diminished initial adhesion to a range of different collagens, as well as impaired migration on fibrillar collagen. These studies identify a central function of uPARAP/Endo180 in cellular collagen interactions. C1 NIDCR, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Ctr Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Matrix Metalloprot Unit, NIH, Bethesda, MD 20892 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Finsen Lab, Copenhagen, Denmark. Amer Red Cross, Dept Vasc Biol, Rockville, MD 20855 USA. RP Bugge, TH (reprint author), NIDCR, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Ctr Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805; Engelholm, Lars/0000-0002-6616-1232 NR 28 TC 94 Z9 99 U1 0 U2 5 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 MAR 31 PY 2003 VL 160 IS 7 BP 1009 EP 1015 DI 10.1083/jcb.200211091 PG 7 WC Cell Biology SC Cell Biology GA 663MA UT WOS:000182008300006 PM 12668656 ER PT J AU Peaire, AE Takeshima, T Johnston, JM Isoe, K Nakashima, K Commissiong, JW AF Peaire, AE Takeshima, T Johnston, JM Isoe, K Nakashima, K Commissiong, JW TI Production of dopaminergic neurons for cell therapy in the treatment of Parkinson's disease SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE neuronal progenitor; dopaminergic neuron; Parkinson's disease; expansion; cell therapy; neuronal aggregates ID NEURAL PRECURSOR CELLS; HUMAN SUBSTANTIA-NIGRA; CENTRAL-NERVOUS-SYSTEM; STEM-CELLS; IN-VITRO; SONIC HEDGEHOG; VENTRAL MESENCEPHALON; SUSPENSION GRAFTS; TYPE-1 ASTROCYTES; FLOOR PLATE AB Dopaminergic cell therapy is a potential viable treatment for Parkinson's disease. However, lack of a well-characterized cell preparation of known phenotypic composition containing a high percentage of dopaminergic neurons, has prevented a definitive, controlled, pilot clinical trial from being conducted. We report the successful in vitro expansion of rat E12 mesencephalic progenitors to produce 5-fold the normal number of dopaminergic neurons. The expanded neurons (MAP2+) were detached, resuspended, and formed into small aggregates of 10-200 neurons containing 25-50% of dopaminergic neurons (TH+) that will likely be optimal for use in successful cell therapy. After storage in DPBS, in 0 mM Ca2+ for up to 24 h at room temperature, aggregated cells were still 90% viable. These results demonstrate that it might be feasible to use a similar protocol to expand human dopaminergic progenitors in vitro. If successful, the requisite large numbers of dopaminergic neurons required to conduct a pilot clinical trial for Parkinson's disease will be produced in vitro. Indications are that the cells can be maintained at optimal viability for the duration of the neural transplantation procedure, under real operating conditions. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Prescient NeuroPharma Inc, Cell Biol, Toronto, ON M9W 4Y9, Canada. NINDS, NTU, LMCN, NIH, Bethesda, MD 20892 USA. Tottori Univ, Fac Med, Div Neurol, Inst Neurol Sci, Yonago, Tottori 683, Japan. RP Commissiong, JW (reprint author), Prescient NeuroPharma Inc, Cell Biol, 96 Skyway Ave, Toronto, ON M9W 4Y9, Canada. NR 55 TC 11 Z9 12 U1 0 U2 0 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 MAR 30 PY 2003 VL 124 IS 1 BP 61 EP 74 DI 10.1016/S0165-0270(02)00364-3 PG 14 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 661CZ UT WOS:000181874800004 PM 12648765 ER PT J AU Ou, W Silver, J AF Ou, W Silver, J TI Role of a conserved amino-terminal sequence in the ecotropic MLV receptor mCAT1 SO VIROLOGY LA English DT Article DE cationic amino acid transporter; subcellular localization; mitochondrial-targeting peptide ID NUCLEAR-LOCALIZATION SIGNAL; RETROVIRUS RECEPTOR; MURINE RETROVIRUSES; FLUORESCENT PROTEIN; ACID TRANSPORTERS; MITOCHONDRIA; SUBUNIT; IDENTIFICATION; PALMITOYLATION; TRANSLOCATION AB The amino-terminus of mCAT1 and homologous proteins is predicted to form a positively charged, amphipathic alpha helix on the cytoplasmic side of the plasma membrane. Peptides with similar sequence motifs often provide membrane anchors, protein-protein interaction domains, or intracellular transport-targeting signals. Deleting most of the cytoplasmic N-terminal sequence of mCAT1 led to reduced expression on the cell surface and accumulation in the endoplasmic reticulum but did not abrogate receptor function. Surprisingly, when the N-terminal 36 or 18 amino acids of mCAT1 were fused to green fluorescent protein (gfp), gfp accumulated almost exclusively in mitochondria. Mitochondrial targeting depended on arginines at positions 15 and 16 and was inhibitable by downstream transmembrane sequences. Although the full-length mCAT1 was not detected in mitochondria, the mitochondrial-targeting property of the N-terminal sequence fused to gfp is conserved in orthologous and paralogous proteins that diverged similar to80 million years ago, suggesting a conserved biological function. We propose that the conserved N-terminal motif of CAT proteins provides a regulatable signal for transport to, or retention in, different cell membrane compartments. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Silver, J (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 336, Bethesda, MD 20892 USA. OI Silver, Jonathan/0000-0001-9231-6368 NR 39 TC 8 Z9 8 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 MAR 30 PY 2003 VL 308 IS 1 BP 101 EP 113 DI 10.1016/S0042-6822(02)00086-7 PG 13 WC Virology SC Virology GA 669EV UT WOS:000182339700010 PM 12706094 ER PT J AU Ambrose, Z Thompson, J Larsen, K Kuller, L Panicali, DL Clements, JD Agy, M Montefiori, DC Hu, SL Bosch, ML AF Ambrose, Z Thompson, J Larsen, K Kuller, L Panicali, DL Clements, JD Agy, M Montefiori, DC Hu, SL Bosch, ML TI Evidence for immune-mediated reduction of viral replication in Macaca nemestrina mucosally immunized with inactivated SHIV89.6 SO VIROLOGY LA English DT Article DE macaque; SHIV; HIV; mucosal; immunity; vaccine; prime-boost; immunization ID SIMIAN IMMUNODEFICIENCY VIRUS; HEAT-LABILE ENTEROTOXIN; VAGINAL CHALLENGE; RHESUS MACAQUES; AIDS VACCINE; ESCHERICHIA-COLI; PERSISTENT INFECTION; CHIMERIC VIRUS; PROTECTION; SIV AB Although most HIV-1 infections worldwide result from heterosexual transmission, most vaccine candidates have focused on induction of systemic immunity and protection. We hypothesized that combining systemic priming with mucosal boosting would induce mucosal immunity that would protect from intravaginal challenge. Macaques were primed systemically with recombinant vaccinia viruses and boosted mucosally using inactivated SHIV89.6 plus adjuvant. Other animals received protein boosts with adjuvant alone. Priming and boosting induced antiviral IgG and IgA antibodies. Such antibodies were induced to a lesser degree in animals receiving boosts alone. Anti-SHIV T cell responses were induced only in the prime-boost animals. Immunized animals and controls were challenged intravaginally with SHIV89.6 and significant reductions in proviral and viral RNA loads were observed in the prime-boost animals. The boost-only animals did not have significant viral load reductions. These data suggest that cellular immunity was required for protection from intravaginal challenge. This immunization regimen provides a promising lead for vaccine development. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Washington, Sch Publ Hlth & Community Med, Dept Pathobiol, Seattle, WA 98195 USA. Univ Washington, Sch Pharm, Washington Reg Primate Res Ctr, Dept Pharmaceut, Seattle, WA 98195 USA. Tulane Univ, Dept Microbiol & Immunol, New Orleans, LA 70112 USA. Therion Biol, Cambridge, MA 02142 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Bosch, ML (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 NR 47 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2003 VL 308 IS 1 BP 178 EP 190 DI 10.1016/S0042-6822(03)00027-8 PG 13 WC Virology SC Virology GA 669EV UT WOS:000182339700017 PM 12706101 ER PT J AU Tran, SD Pillemer, SR Dutra, A Barrett, AJ Brownstein, MJ Key, S Pak, E Leakan, RA Kingman, A Yamada, KM Baum, BJ Mezey, E AF Tran, SD Pillemer, SR Dutra, A Barrett, AJ Brownstein, MJ Key, S Pak, E Leakan, RA Kingman, A Yamada, KM Baum, BJ Mezey, E TI Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study SO LANCET LA English DT Article ID HEMATOPOIETIC STEM-CELLS; OSTEOGENESIS IMPERFECTA; MESENCHYMAL CELLS; TRANSPLANTS; CHILDREN; FUSION AB Background Adult bone marrow-derived (BMD) cells could be used to repair damaged organs and tissues, but the intrinsic plasticity of these cells has been questioned by results of in-vitro studies suggesting that such cells might fuse with other cells giving the appearance of differentiation. We aimed to determine whether fusion events are important in vivo. Methods To test whether BMD cells can colonise an epithelial tissue and differentiate there without fusion, we did in-situ hybridisation with Y and X chromosome probes labelled with 35-sulphur or digoxigenin, or labelled fluorescently. We did immunohistochemistry with anticytokeratin 13 along with fluorescence in-situ hybridisation to identify Y-chromosome positive buccal epithelial cells in cheek scrapings obtained from five females who had received either a bone-marrow transplant or an allogeneic mobilised peripheral-blood progenitor-cell transplant (enriched in CD34+ cells) from male donors. Findings When examined 4-6 years after male-to-female marrow-cell transplantation, all female recipients had Y-chromosome-positive buccal cells (0.8-12.7%). In more than 9700 cells studied, we detected only one XXXY-positive cell (0.01%) and one XXY cell (0.01%), both of which could have arisen when an XY cell fused with an XX cell. Interpretation Male BMD cells migrate into the cheek and differentiate into epithelial cells, an occurrence that does not depend on fusion of BMD cells to recipient cells. This finding might be an example of transdifferentiation of haemopoietic or stromal progenitor cells. Plasticity of BMD cells could be useful in regenerative medicine. C1 NIDCR, NIH, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD USA. NIDCR, Biostat Core, NIH, Bethesda, MD USA. NHGRI, Cytogenet Core, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Basic Neurosci Programme, NIH, Bethesda, MD 20892 USA. RP Tran, SD (reprint author), NIDCR, NIH, Gene Therapy & Therapeut Branch, 10 Ctr Dr,Room 1N113,MSC 1190, Bethesda, MD 20892 USA. EM stran@dir.nidcr.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 NR 18 TC 114 Z9 124 U1 0 U2 4 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAR 29 PY 2003 VL 361 IS 9363 BP 1084 EP 1088 DI 10.1016/S0140-6736(03)12894-2 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 660ZD UT WOS:000181865200010 PM 12672312 ER PT J AU Blair, RJR AF Blair, RJR TI Facial expressions, their communicatory functions and neuro-cognitive substrates SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE facial expressions; amygdala; communication; psychopath; autism ID BILATERAL AMYGDALA DAMAGE; TEMPORAL VISUAL-CORTEX; FUSIFORM FACE AREA; PREFRONTAL CORTEX; HUMAN-BRAIN; SELECTIVE IMPAIRMENT; SOCIAL INFORMATION; AUTISTIC-CHILDREN; SMILE PRODUCTION; EMOTIONAL FACES AB Human emotional expressions serve a crucial communicatory role allowing the rapid transmission of valence information from one individual to another. This paper will review the literature on the neural mechanisms necessary for this communication: both the mechanisms involved in the production of emotional expressions and those involved in the interpretation of the emotional expressions of others. Finally, reference to the neuro-psychiatric disorders of autism, psychopathy and acquired sociopathy will be made. In these conditions, the appropriate processing of emotional expressions is impaired. In autism, it is argued that the basic response to emotional expressions remains intact but that there is impaired ability to represent the referent of the individual displaying the emotion. In psychopathy, the response to fearful and sad expressions is attenuated and this interferes with socialization resulting in an individual who fails to learn to avoid actions that result in harm to others. In acquired sociopathy, the response to angry expressions in particular is attenuated resulting in reduced regulation of social behaviour. C1 NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv,NIH, Room 206,MSC 2670,15K N Dr, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov NR 166 TC 233 Z9 236 U1 15 U2 61 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 29 PY 2003 VL 358 IS 1431 BP 561 EP 572 DI 10.1098/rstb.2002.1220 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 662GY UT WOS:000181940000012 PM 12689381 ER PT J AU Basu, NK Kole, L Owens, IS AF Basu, NK Kole, L Owens, IS TI Evidence for phosphorylation requirement for human bilirubin UDP-glucuronosyltransferase (UGT1A1) activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE UDP-glucuronosyltransferase; bilirubin; phosphorylation; PKC; curcumin; calphostin-C ID GENE-COMPLEX; HUMAN LIVER; I PATIENT; CURCUMIN; CELLS; IDENTIFICATION; EXPRESSION; APOPTOSIS; LOCUS; COLON AB Our discovery of rapid down-regulation of human bilirubin UDP-glucuronosyltransferase (UGT) in colon cell lines that was transient and irreversible following curcumin- and calphostin-C-treatment, respectively, suggested phosphorylation event(s) were involved in activity. Likewise, bilirubin-UGT1A1 expressed in COS-1 cells was inhibited by curcumin and calphostin-C. Because calphostin-C is a highly specific protein kinase C (PKC) inhibitor, we examined and found 4 to 5 predicted PKC phosphorylation sites in 11 UGTs examined. UGT1A1 incorporated [P-33]orthophosphate, which was inhibited by calphostin-C. Also triple mutant, T75A/T112A/S435G-UGT1A1, at predicted PKC sites failed to incorporate [P-33]orthophosphate. Individual or double mutants exhibited dominant-negative, additive, or no effect, while the triple mutant retained 10-15% activity towards bilirubin and two xenobiotics. Compared to wild-type, S435G and T112A/S435G shifted pH-optimum for eugenol, but not for bilirubin or anthra-flavic acid, toward alkaline and acid conditions, respectively. This represents the first evidence that a UGT isozyme requires phosphorylation for activity. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Owens, IS (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 19 TC 34 Z9 36 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 28 PY 2003 VL 303 IS 1 BP 98 EP 104 DI 10.1016/S0006-291X(03)00241-9 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 665LK UT WOS:000182122000016 PM 12646172 ER PT J AU Majumdar, A Puri, N Cuenoud, B Natt, F Martin, P Khorlin, A Dyatkina, N George, AJ Miller, PS Seidman, MM AF Majumdar, A Puri, N Cuenoud, B Natt, F Martin, P Khorlin, A Dyatkina, N George, AJ Miller, PS Seidman, MM TI Cell cycle modulation of gene targeting by a triple helix-forming oligonucleotide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERSTRAND CROSS-LINKS; NUCLEOTIDE EXCISION-REPAIR; NUCLEOSOME CORE PARTICLES; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; IN-VIVO; STRANDED DNA; 3RD STRAND; PSORALEN; CHROMATIN AB Successful gene-targeting reagents must be functional under physiological conditions and must bind chromosomal target sequences embedded in chromatin. Triple helix-forming oligonucleotides (TFOs) recognize and bind specific sequences via the major groove of duplex DNA and may have potential for gene targeting in vivo. We have constructed chemically modified, psoralen-linked TFOs that mediate site-specific mutagenesis of a chromosomal gene in living cells. Here we show that targeting efficiency is sensitive to the biology of the cell, specifically, cell cycle status. Targeted mutagenesis was variable across the cycle with the greatest activity in S phase. This was the result of differential TFO binding as measured by cross-link formation. Targeted cross-linking was low in quiescent cells but substantially enhanced in S phase cells with adducts in similar to20-30% of target sequences. 75-80% of adducts were repaired faithfully, whereas the remaining adducts were converted into mutations (>5% mutation frequency). Clones with mutations could be recovered by direct screening of colonies chosen at random. These results demonstrate high frequency target binding and target mutagenesis by TFOs in living cells. Successful protocols for TFO-mediated manipulation of chromosomal sequences are likely to reflect a combination of appropriate oligonucleotide chemistry and manipulation of the cell biology. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Novartis, Horsham RH12 4AB, W Sussex, England. Novartis Pharma Ltd, CH-4002 Basel, Switzerland. Qiagen, Alameda, CA 94501 USA. Genelabs Inc, Redwood City, CA 94063 USA. ATCC, Manassas, VA 20108 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Seidman, MM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI George, Andrew/0000-0002-2866-0241 NR 70 TC 62 Z9 63 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 MAR 28 PY 2003 VL 278 IS 13 BP 11072 EP 11077 DI 10.1074/jbc.M211837200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660VU UT WOS:000181855400028 PM 12538585 ER PT J AU Liu, XB Singh, BB Ambudkar, IS AF Liu, XB Singh, BB Ambudkar, IS TI TRPC1 is required for functional store-operated Ca2+ channels - Role of acidic amino acid residues in the S5-S6 region SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED CALCIUM-CHANNEL; CATION CHANNELS; PORE PROPERTIES; GLAND CELLS; C-TERMINUS; ENTRY; RELEASE; PROTEIN; FAMILY; INFLUX AB The exact role of TRPC1 in store-operated calcium influx channel (SOCC) function is not known. We have examined the effect of overexpression of full-length TRPC1, depletion of endogenous TRPC1, and expression of TRPC1 in which the proposed pore region (S5-S6, amino acids (aa) 557-620) was deleted or modified by site-directed mutagenesis on thapsigargin- and carbachol-stimulated SOCC activity in HSG. cells. TRPC1 overexpression induced channel activity that was indistinguishable from the endogenous SOCC activity. Transfection with antisense hTRPC1 decreased SOCC activity although characteristics of SOCC-mediated current, I-SOC, were not altered. Expression of TRPC1Delta567-793, but not TRPC1Delta664-793, induced a similar decrease in SOCC activity. Furthermore, TRPC1Delta567-793 was coimmunoprecipitated with endogenous TRPC1. Simultaneous substitutions of seven acidic as in the S5-S6 region (Asp --> Asn and Glu --> Gln) decreased SOCC-mediated Ca2+, but not Na+, current and induced a left shift in E-rev. Similar effects were induced by E576K or D581K, but not D581N or E615K, substitution. Furthermore, expressed TRPC1 proteins interacted with each other. Together, these data demonstrate that TRPC1 is required for generation of functional SOCC in HSG cells. We suggest that TRPC1 monomers co-assemble to form SOCC and that specific acidic as residues in the proposed pore region of TRPC1 contribute to Ca2+ influx. C1 NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N-113, Bethesda, MD 20892 USA. OI Singh, Brij/0000-0003-0535-5997 NR 37 TC 115 Z9 124 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 MAR 28 PY 2003 VL 278 IS 13 BP 11337 EP 11343 DI 10.1074/jbc.M213271200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660VU UT WOS:000181855400061 PM 12536150 ER PT J AU Wess, J Duttaroy, A Gomeza, J Zhang, WL Yamada, M Felder, CC Bernardini, N Reeh, PW AF Wess, J Duttaroy, A Gomeza, J Zhang, WL Yamada, M Felder, CC Bernardini, N Reeh, PW TI Muscarinic receptor subtypes mediating central and peripheral antinociception studied with muscarinic receptor knockout mice: A review SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT 1st International Symposium on Non-neuronal Acetylcholine CY JUL 06, 2002 CL SAN FRANCISCO, CALIFORNIA DE analgesia; C-fibers; CGRP; gene targeting; knockout mice; muscarine; nociceptors; muscarinic receptors; oxotremorine; pain sensitivity ID ISOLATED RAT SKIN; ACETYLCHOLINE-RECEPTORS; M2; LOCALIZATION; NOCICEPTORS; BRAIN AB To gain new insight into the physiological and pathophysiological roles of the muscarinic cholinergic system, we generated mutant mouse strains deficient in each of the five muscarinic acetylcholine receptor subtypes (M-1-M-5). In this chapter, we review a set of recent studies dealing with the identification of the muscarinic receptor subtypes mediating muscarinic agonist-dependent analgesic effects by central and peripheral mechanisms. Most of these studies were carried out with mutant mouse strains lacking M-2 or/and M-4 muscarinic receptors. It is well known that administration of centrally active muscarinic agonists induces pronounced analgesic effects. To identify the muscarinic receptors mediating this activity, wild-type and muscarinic receptor mutant mice were injected with the non-subtype-selective muscarinic agonist, oxotremorine (s.c., i.t., and i.c.v.), and analgesic effects were assessed in the tail-flick and hot-plate tests. These studies showed that M-2 receptors play a key role in mediating the analgesic effects of oxotremorine, both at the spinal and supraspinal level. However, studies with M-2/M-4 receptor double KO mice indicated that M-4 receptors also contribute to this activity. Recent evidence suggests that activation of muscarinic receptors located in the skin can reduce the sensitivity of peripheral nociceptors. Electrophysiological and neurochemical studies with skin preparations from muscarinic receptor mutant mice indicated that muscarine-induced peripheral antinociception is mediated by M-2 receptors. Since acetylcholine is synthesized and released by different cell types of the skin, it is possible that non-neuronally released acetylcholine plays a role in modulating peripheral nociception. Our results highlight the usefulness of muscarinic receptor mutant mice to shed light on the functional roles of acetylcholine released from both neuronal and non-neuronal cells. Published by Elsevier Science Inc. C1 NIDDKD, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Univ Erlangen Nurnberg, Inst Physiol & Expt Pathophysiol, D-91054 Erlangen, Germany. RP Wess, J (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Signaling Sect, Bldg 8A,Room B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. RI Reeh, Peter/J-8981-2012 OI Reeh, Peter/0000-0002-4367-094X NR 21 TC 53 Z9 56 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAR 28 PY 2003 VL 72 IS 18-19 BP 2047 EP 2054 DI 10.1016/S0024-3205(03)00082-1 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 656KM UT WOS:000181607000006 PM 12628455 ER PT J AU Chernyavsky, AI Nguyen, VT Arredondo, J Ndoye, A Zia, S Wess, J Grando, SA AF Chernyavsky, AI Nguyen, VT Arredondo, J Ndoye, A Zia, S Wess, J Grando, SA TI The M-4 muscarinic receptor-selective effects on keratinocyte crawling locomotion SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT 1st International Symposium on Non-neuronal Acetylcholine CY JUL 06, 2002 CL SAN FRANCISCO, CALIFORNIA DE M-4 muscarinic receptor; keratinocyte motility; knockout mouse ID ACETYLCHOLINE; ANTAGONIST; MIGRATION; CELLS AB We have investigated how the cholinergic system of epidermal keratinocytes (KC) controls migratory function of these cells. Several molecular subtypes of muscarinic acetylcholine receptors (mAChRs) have been detected in KC. Early results suggested that M-4 is the predominant mAChR regulating cell motility. To determine muscarinic effects on lateral migration of KC, we used an agarose gel keratinocyte outgrowth system (AGKOS) which provides for measurements of the response of large cell populations (> 10(4) cells). Muscarine produced a dose-dependent stimulatory effect on cell migration (p < 0.05). This activity was abolished by atropine, which decreased migration distance when given alone. To identify the mAChR subtype(s) mediating these muscarinic effects, we substituted atropine with subtype-selective antagonists. Tropicamide (M-4-selective) was more effective at decreasing the migration distance than pirenzepine and 4-DAMP at nanomolar concentrations. We then compared lateral migration of KC obtained from M-4 mAChR knockout mice with that of wild-type murine KC, using AGKOS. In the absence of M-4 mAChR, the migration distance of KC was significantly (p < 0.05) decreased. These results indicate that the M-4 MAChR plays a central role in mediating cholinergic control of keratinocyte migration by endogenous acetylcholine produced by these cells. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. NIDDK, Mol Signaling Sect, LBC, NIH, Bethesda, MD USA. RP Grando, SA (reprint author), Univ Calif Davis, Dept Dermatol, 4860 Y St,3400, Sacramento, CA 95817 USA. FU NIGMS NIH HHS [GM62136] NR 12 TC 10 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAR 28 PY 2003 VL 72 IS 18-19 BP 2069 EP 2073 DI 10.1016/S0024-3205(03)00085-7 PG 5 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 656KM UT WOS:000181607000009 PM 12628458 ER PT J AU Lovekamp-Swan, T Jetten, AM Davis, BJ AF Lovekamp-Swan, T Jetten, AM Davis, BJ TI Dual activation of PPAR alpha and PPAR gamma by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE ovary; aromatase; peroxisome proliferator-activated receptor; phthalates; estrogen (granulosa cell) ID MESSENGER-RIBONUCLEIC-ACID; RECEPTOR-ALPHA; GENE-EXPRESSION; PEROXISOME PROLIFERATORS; SUPPRESSES ESTRADIOL; TISSUE DISTRIBUTION; AROMATASE; INDUCTION; DIETHYLHEXYLPHTHALATE; LOCALIZATION AB Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid metabolism and cell differentiation. The plasticizer di-(2-ethylhexyl) plithalate is a peroxisome proliferator, and its active metabolite monci-(2-ethythexyl) plithalate (MEHP) activates PPARalpha and PPARgamma in cell transactivation assays. MEHP is a female reproductive toxicant and decreases activity, mRNA, and protein levels of aromatase, the rate-limiting enzyme that converts testosterone to estradiol in ovarian granulosa cells. To test the hypothesis that MEHP suppresses aromatase through PPAR pathways, granulosa cells were cultured with MEHP (50 muM) or selective activators of PPARgamma or PPARalpha for 48 h and gene expression was analyzed by real time RT-PCR. Both PPARalpha and PPARgamma activators significantly decreased aromatase mRNA and estradiol production like MEHP. The PPARgamma-selective antagonist GR 259662 partially blocked the suppression of aromatase by MEHP, suggesting that MEHP acts through PPARgamma, but not exclusively. MEHP and the PPARalpha-selective agonist GW 327647 induced expression of 17beta-hydroxysteroid dehydrogenase IV, a known PPARalpha-regulated gene, and induction was maintained with addition of the PPARgamma-selective antagonist. PPARalpha-selective activation also induced expression of aryl hydrocarbon receptor (AhR), CYP1B1, and epoxide hydrolase in the granulosa cell. These data support a model in which MEHP activates both PPARalpha and PPARgamma to suppress aromatase and alter other genes related to metabolism and differentiation in the granulosa cell. Published by Elsevier Science Ireland Ltd. C1 NIEHS, Lab Womens Hlth, Res Triangle Pk, NC 27709 USA. NIEHS, Cell Biol Sect, Div Intramural Res, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Davis, BJ (reprint author), NIEHS, Lab Womens Hlth, POB 12233,MD-A2-01, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 33 TC 106 Z9 112 U1 2 U2 11 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 28 PY 2003 VL 201 IS 1-2 BP 133 EP 141 AR PII S0303-7207(02)00423-9 DI 10.1016/S0303-7207(02)00423-9 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 674QF UT WOS:000182646900014 PM 12706301 ER PT J AU Yamakawa, H Phillips, MI Saavedra, JM AF Yamakawa, H Phillips, MI Saavedra, JM TI Intracisternal administration of angiotensin II AT(1) receptor antisense oligodeoxynucleotides protects against cerebral ischemia in spontaneously hypertensive rats SO REGULATORY PEPTIDES LA English DT Article DE renin-angiotensin system; stroke; brain ischemia; genetic hypertension; cerebral blood flow ID MESSENGER-RNA; PASTE STANDARDS; BLOOD-FLOW; BRAIN; OLIGONUCLEOTIDES; AUTORADIOGRAPHY; CALIBRATION; INFARCTION; INHIBITION; ANTAGONIST AB Pharmacological blockade of peripheral and brain Angiotensin II (Ang II) AT(1) receptors protects against brain ischemia. To clarify the protective role of brain AT(1) receptors, we examined the effects of specific antisense oligodeoxynucleotides (AS-ODN) targeted to AT(1) receptor mRNA administered intracisternally to spontaneously hypertensive rats (SHRs), 4 and 7 days before middle cerebral artery (MCA) occlusion, and we determined the infarct size and tissue swelling 24 h after surgery. A single intracistemal injection of AT(1) mRNA receptor antisense oligodeoxynucleotides reduced systemic blood pressure for 5 days and AT(1) receptor binding for at least 4 days in the area postrema and the nucleus of the solitary tract. A similar injection of scrambled oligodeoxynucleotides (SC-ODN) was without effect. Both blood pressure and AT(1) receptor binding returned to normal 7 days after antisense receptor mRNA administration. Both the infarction size and the tissue swelling after middle cerebral artery occlusion were reduced when the antisense oligodeoxynucleotide was administered 7 days, but not 4 days, before the operation. We conclude that 4 to 5 days of decrease in brain AT(1) receptor binding by a single administration of an AT(1) receptor mRNA oligodeoxynucleotide are sufficient to significantly protect the brain against ischemia resulting from total occlusion of a major cerebral vessel. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Pharmacol Sect, IRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, IRP, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. NR 24 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD MAR 28 PY 2003 VL 111 IS 1-3 BP 117 EP 122 AR PII S0167-0115(02)00264-1 DI 10.1016/S0167-0115(02)00264-1 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 656RF UT WOS:000181621700016 PM 12609758 ER PT J AU Lum, L Yao, SQ Mozer, B Rovescalli, A Von Kessler, D Nirenberg, M Beachy, PA AF Lum, L Yao, SQ Mozer, B Rovescalli, A Von Kessler, D Nirenberg, M Beachy, PA TI Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells SO SCIENCE LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCAN; DOUBLE-STRANDED-RNA; CUBITUS INTERRUPTUS; TRANSCRIPTIONAL REGULATION; TOUT-VELU; WINGLESS; GENE; PROTEIN; INTERFERENCE; SUPPRESSOR AB Classical genetic screens can be limited by the selectivity of mutational targeting, the complexities of anatomically based phenotypic analysis, or difficulties in subsequent gene identification. Focusing on signaling response to the secreted morphogen Hedgehog (Hh), we used RNA interference (RNAi) and a quantitative cultured cell assay to systematically screen functional roles of all kinases and phosphatases, and subsequently 43% of predicted Drosophila genes. Two gene products reported to function in Wingless (Wg) signaling were identified as Hh pathway components: a cell surface protein (Daily-like protein) required for Hh signal reception, and casein kinase 1alpha, a candidate tumor suppressor that regulates basal activities of both Hh and Wg pathways. This type of cultured cell-based functional genomics approach may be useful in the systematic analysis of other biological processes. C1 Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Beachy, PA (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. NR 37 TC 359 Z9 376 U1 2 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 28 PY 2003 VL 299 IS 5615 BP 2039 EP 2045 DI 10.1126/science.1081403 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 660LG UT WOS:000181834200046 PM 12663920 ER PT J AU Barros, SA Tennant, RW Cannon, RE AF Barros, SA Tennant, RW Cannon, RE TI Molecular structure and characterization of a novel murine ABC transporter, Abca13 SO GENE LA English DT Article DE ATP-binding cassette transporter; genomic structure; murine Abca13; post-transcriptional splicing ID ATP-BINDING CASSETTE; STEROL-DEPENDENT REGULATION; INTRAHEPATIC CHOLESTASIS; CHOLESTEROL TRANSPORT; GENE; PROMOTER; SEQUENCE; PROTEIN; IDENTIFICATION; TRAFFICKING AB We report the isolation and structural characterization of the full-length gene and cDNA for a novel mouse ATP-binding cassette (ABC) transporter, Abca13. The mRNA, isolated from mouse kidney, is 6.7 kb in size and encodes a protein consisting of 2143 amino acids with a predicted molecular weight of 240 kDa. The Abca13 gene consists of 44 exons which span 360 kb of genomic sequence. Abca13 has been mapped to mouse chromosome 11.a2, revealing the human orthologue highly conserved on a syntenic region of human chromosome 7p12. The deduced mouse Abca13 protein shows highest amino acid sequence homology to human ABCA 1 (50%), ABCA4 (50%), and ABCA 12 (56%). Analysis of the putative Abca13 promoter region revealed potential transcription factor binding sites associated with myeloid- and lymphoid-derived cell types. mRNA transcript levels were highest in mouse submaxillary gland, epididymus, ovary, and thymus; with lower levels in a variety of other tissues. An alternative transcript was discovered in mouse kidney devoid of exon 11. The removal of exon I I by post-transcriptional splicing causes a frameshift in the open reading frame and results in a premature termination codon. We hypothesize that the excision of exon I I may serve as a regulatory mechanism in kidney, and perhaps other tissues as well. The molecular characterization of the mouse Abca13 gene will establish the foundation for future functional studies of the human ABCA13 transporter. Published by Elsevier Science B.V. C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27514 USA. RP Cannon, RE (reprint author), NIEHS, Natl Ctr Toxicogenom, POB 12233,MD F1-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 35 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAR 27 PY 2003 VL 307 BP 191 EP 200 DI 10.1016/S0378-1119(03)00465-7 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 677EC UT WOS:000182793100020 PM 12706902 ER PT J AU Koonin, EV AF Koonin, EV TI Swift publication would reward good reviewers SO NATURE LA English DT Letter C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 3 Z9 3 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 MAR 27 PY 2003 VL 422 IS 6930 BP 374 EP 374 DI 10.1038/422374c PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 659WV UT WOS:000181801200017 PM 12660754 ER PT J AU Mattson, MP AF Mattson, MP TI Neurobiology - Ballads of a protein quartet SO NATURE LA English DT Editorial Material ID ALZHEIMERS-DISEASE; BETA-APP; PRESENILINS; NOTCH C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 11 TC 11 Z9 16 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 MAR 27 PY 2003 VL 422 IS 6930 BP 385 EP 387 DI 10.1038/422385a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 659WV UT WOS:000181801200027 PM 12660764 ER PT J AU Walsh, TJ AF Walsh, TJ TI Caspofungin versus amphotericin B for invasive candidiasis - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RANDOMIZED TRIAL; CANDIDEMIA; FLUCONAZOLE C1 NCI, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 27 PY 2003 VL 348 IS 13 BP 1288 EP 1288 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 659RG UT WOS:000181790800021 ER PT J AU Tycko, R AF Tycko, R TI Insights into the amyloid folding problem from solid-state NMR SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; ATOMIC-FORCE MICROSCOPY; C-13 CHEMICAL-SHIFTS; BETA-SHEET STRUCTURE; X-RAY-DIFFRACTION; ALZHEIMERS-DISEASE; FIBRIL FORMATION; SECONDARY-STRUCTURE; IN-VITRO; ROTATING SOLIDS C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM tycko@helix.nih.gov NR 98 TC 161 Z9 163 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 25 PY 2003 VL 42 IS 11 BP 3151 EP 3159 DI 10.1021/bi0237378p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 658GY UT WOS:000181714300001 PM 12641446 ER PT J AU Vasan, RS Sullivan, LM Roubenoff, R Dinarello, CA Harris, T Benjamin, EJ Sawyer, DB Levy, D Wilson, PWF D'Agostino, RB AF Vasan, RS Sullivan, LM Roubenoff, R Dinarello, CA Harris, T Benjamin, EJ Sawyer, DB Levy, D Wilson, PWF D'Agostino, RB TI Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction - The Framingham Heart Study SO CIRCULATION LA English DT Article DE cytokines; interleukin-6; tumor necrosis factor-alpha; C-reactive protein; heart failure ID TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; IDIOPATHIC DILATED CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; CORONARY-ARTERY DISEASE; BLOOD MONONUCLEAR-CELLS; FACTOR-ALPHA; CIRCULATING LEVELS; CYTOKINES; INTERLEUKIN-6 AB Background-Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with worse functional status and adverse prognosis. It is unclear whether cytokine levels can predict the incidence of CHF in asymptomatic individuals. Methods and Results-We investigated the relations of serum interleukin-6 (IL-6), C-reactive protein (CRP), and spontaneous production of tumor necrosis factor-alpha (TNFalpha) by peripheral blood mononuclear cell (PBMC) to CHF incidence among 732 elderly Framingham Study subjects (mean age 78 years, 67% women) free of prior myocardial infarction and CHF. On follow-up (mean 5.2 years), 56 subjects ( 35 women) developed CHF. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60 (PBMC TNFalpha) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration (P=0.04, and 0.03, respectively, for trend). A serum CRP level greater than or equal to5 mg/dL was associated with a 2.8-fold increased risk of CHF (P=0.02). Subjects with elevated levels of all 3 biomarkers (serum IL-6 and PBMC TNFalpha >median values, CRPgreater than or equal to5 mg/dL) had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34 to 12.37], P=0.01) compared with the other subjects. Conclusions-In our elderly, community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, was associated with increased risk of CHF in people without prior myocardial infarction. Additional epidemiological investigations are warranted to confirm the contribution of inflammation to the pathogenesis of CHF in the general population. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Myocardial Biol Unit, Boston, MA 02118 USA. Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Dept Math Stat, Boston, MA 02215 USA. Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@fram.nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL04334, N01-HC-25195]; NIA NIH HHS [AG15797, Y01-AG-4-0245]; NIAID NIH HHS [AI-15614]; NIDDK NIH HHS [DK02120] NR 39 TC 391 Z9 411 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 25 PY 2003 VL 107 IS 11 BP 1486 EP 1491 DI 10.1161/01.CIR.0000057810.48709.F6 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 659EM UT WOS:000181764600008 PM 12654604 ER PT J AU Fox, CS Vasan, RS Parise, H Levy, D O'Donnell, CJ D'Agostino, RB Benjamin, EJ AF Fox, CS Vasan, RS Parise, H Levy, D O'Donnell, CJ D'Agostino, RB Benjamin, EJ TI Mitral annular calcification predicts cardiovascular morbidity and mortality - The Framingham Heart Study SO CIRCULATION LA English DT Article DE calcium; echocardiography; cardiovascular diseases; mortality ID CORONARY-ARTERY CALCIFICATION; BEAM COMPUTED-TOMOGRAPHY; AORTIC-VALVE SCLEROSIS; STAGE RENAL-DISEASE; RISK-FACTORS; MYOCARDIAL-INFARCTION; ANULAR CALCIUM; OLDER ADULTS; ATRIAL-FIBRILLATION; MEDIA THICKNESS AB Background-Mitral annular calcification (MAC) has been associated with stroke in longitudinal, community-based cohorts and cardiovascular disease (CVD) outcomes in many small retrospective studies. Prospective data are limited on the relation of MAC with CVD morbidity and mortality. Methods and Results-We examined the association between MAC assessed by M-mode echocardiography and the incidence of CVD, CVD death, and all-cause death over 16 years of follow-up in the Framingham Heart Study subjects who attended a routine examination between 1979 and 1981. Cox proportional hazards models were used to estimate hazard ratios (HRs) associated with the presence of MAC for each outcome. Of 1197 (445 male, 752 female) subjects who had adequate echocardiographic assessment, 14% had MAC. There were 307 incident CVD events and 621 deaths. In multivariable adjusted analyses, MAC was associated with an increased risk of incident CVD (HR, 1.5; 95% CI, 1.1, 2.0), CVD death (HR, 1.6; 95% CI, 1.1, 2.3), and all-cause death (HR, 1.3; 95% CI, 1.04, 1.6). For each 1-mm increase in MAC, the risk of incident CVD, CVD death, and all-cause death increased by approximate to 10%. Conclusions-The independent association of MAC with incident CVD and CVD death underscores that cardiac calcification is a marker of increased CVD risk. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@fram.nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1K24HL04334, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 39 TC 151 Z9 157 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 25 PY 2003 VL 107 IS 11 BP 1492 EP 1496 DI 10.1161/01.CIR.0000058168.26163.BC PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 659EM UT WOS:000181764600009 PM 12654605 ER PT J AU Zochodne, DW Max, MB AF Zochodne, DW Max, MB TI An old acquaintance - Opioids in neuropathic pain SO NEUROLOGY LA English DT Editorial Material ID POSTHERPETIC NEURALGIA; MORPHINE; EFFICACY; TRIAL C1 Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. Natl Inst Dental & Craniofacial Res, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. Dept Hlth & Human Serv, Bethesda, MD USA. RP Zochodne, DW (reprint author), Univ Calgary, Dept Clin Neurosci, Room 182A,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. NR 13 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 25 PY 2003 VL 60 IS 6 BP 894 EP 895 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 679YB UT WOS:000182948600002 PM 12654949 ER EF