FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Thorpy, M Ehrenberg, BL Hening, WA Mahowald, M Malow, BA Phillips, B Richardson, C Wellbery, C Hallett, M Kiley, IP McCutcheon, C Rogus, S AF Thorpy, M Ehrenberg, BL Hening, WA Mahowald, M Malow, BA Phillips, B Richardson, C Wellbery, C Hallett, M Kiley, IP McCutcheon, C Rogus, S CA Natl Heart, Lung, & Blood Inst TI Restless legs syndrome: Detection and management in primary care SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID PRAMIPEXOLE; AKATHISIA; DISEASE; IRON AB Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. Patients with RLS have an irresistible urge to move their legs, which is usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. It is estimated that between 2 and 15 percent of the population may experience symptoms of RLS, Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency. neurologic lesions, pregnancy and uremia. RLS also may occur secondarily to the use of certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions that may be used as a basis to assess the likelihood of RLS is included in this article. Pharmacologic treatment of RLS includes dopaminergic agents, opioids, benzodiazepines and anticonvulsants. The primary cam physician plays a central role in the diagnosis and management of RLS. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Rogus, S (reprint author), NHLBI, NIH, Room 4A-16,31 Ctr Dr,MSC 2480, Bethesda, MD 20892 USA. NR 30 TC 24 Z9 24 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JUL 1 PY 2000 VL 62 IS 1 BP 108 EP 114 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 335FH UT WOS:000088232800011 ER PT J AU Capristo, E Addolorato, G Mingrone, G De Gaetano, A Greco, AV Tataranni, PA Gasbarrini, G AF Capristo, E Addolorato, G Mingrone, G De Gaetano, A Greco, AV Tataranni, PA Gasbarrini, G TI Changes in body composition, substrate oxidation, and resting metabolic rate in adult celiac disease patients after a 1-y gluten-free diet treatment SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE celiac disease; fat mass; fat-free mass; resting metabolic rate; substrate oxidation; body composition; gluten-free diet ID INFLAMMATORY BOWEL-DISEASE; INDUCED THERMOGENESIS; NUTRITIONAL-STATUS; PREVALENCE; DIAGNOSIS; SPECTRUM; ICEBERG; SPRUE AB Background: The incidence of celiac disease has been on the rise in both Europe and the United States. Celiac disease patients are at high risk of undernutrition because of nutrient malabsorption. Objective: The aim of the present study was to evaluate changes in body composition and energy metabolism in a group of patients with celiac disease before and after consumption of a gluten-free diet (GFD). Design: Body composition (by anthropometry and isotopic dilution), resting metabolic rate (RMR), and substrate oxidation rates (by indirect calorimetry) were assessed in 39 adult celiac disease patients (16 men and 23 women) with a mean (+/-SD) age of 29.9 +/- 7.6 y, weight of 58.3 +/- 6.6 kg, and percentage body fat of 20.1 +/- 6.7%. and in 63 (29 men and 34 women) age- and height matched control subjects (age: 33.2 +/- 8.1 y; weight: 66.8 +/- 6.6 kg; and percentage body fat: 25.4 +/- 3.7%). Celiac disease patients were studied twice, at diagnosis and 1 y after treatment with a GFD. Results: Before treatment, celiac disease patients had a lower body weight (P < 0.05) and a higher carbohydrate oxidation rate (P < 0.01) than did control subjects. Carbohydrate oxidation rates correlated positively with fecal lipid loss in untreated celiac disease patients (r = 0.80, P < 0.0001). After the CFD, percentage body fat was higher in celiac disease patients than in control subjects (P < 0.01), and lipid intakes tended to be higher than before treatment. Conclusions: This longitudinal study showed that the GFD treatment significantly increased body fat stores. Untreated patients preferentially utilized carbohydrates as a fuel substrate, probably as a consequence of both lipid malabsorption and a high carbohydrate intake, and lipid utilization increased with the restoration of the intestinal mucosa. C1 Univ Cattolica Sacro Cuore, Inst Internal Med, Dept Internal Med, CNR,Ctr Fisiopatol Shock, I-00168 Rome, Italy. NIDDKD, Clin Diabet & Nutr Ctr, NIH, Phoenix, AZ 85016 USA. RP Capristo, E (reprint author), Univ Cattolica Sacro Cuore, Inst Internal Med, Dept Internal Med, CNR,Ctr Fisiopatol Shock, Largo A Gemelli 8, I-00168 Rome, Italy. EM e.capristo@tin.it OI Addolorato, Giovanni/0000-0002-1522-9946 NR 39 TC 38 Z9 38 U1 3 U2 9 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2000 VL 72 IS 1 BP 76 EP 81 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 328VG UT WOS:000087871100013 PM 10871564 ER PT J AU Loria, CM Klag, MJ Caulfield, LE Whelton, PK AF Loria, CM Klag, MJ Caulfield, LE Whelton, PK TI Vitamin C status and mortality in US adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE ascorbic acid; antioxidants; mortality; cancer; cardiovascular disease; smoking; NHANES II; second National Health and Nutrition Examination Survey; adults ID UNITED-STATES; ASCORBIC-ACID; BETA-CAROTENE; ANTIOXIDANT; SMOKERS; CANCER; POPULATION; DISEASE; PLASMA; DAMAGE AB Background: Low vitamin C status may increase the risk of mortality from cancer and cardiovascular disease. Objective: The objective was to test whether an association existed between serum ascorbate concentrations and mortality and whether the association was modified by cigarette smoking status or sex. Design: Serum ascorbate concentrations were measured in adults as part of the second National Health and Nutrition Examination Survey (1976-1980). Vital status was ascertained 12-16 y later. Results: The relative risk (RR) of death, adjusted for potential confounders, was estimated by using Cox proportional hazards models. Men in the lowest (<28.4 mu mol/L) compared with the highest (greater than or equal to 73.8 mu mol/L) serum ascorbate quartile had a 57% higher risk of dying from any cause (RR: 1.57; 95% CI: 1.21, 2.03) and a 62% higher risk of dying from cancer (RR: 1.62; 95% CI: 1.01, 2.59). In contrast, there was no increased risk among men in the middle 2 quartiles for these outcomes and no increased risk of cardiovascular disease mortality in any quartile. There was no association between serum ascorbate quartile and mortality among women. These findings were consistent when analyses were limited to nonsmokers or further to adults who never smoked, suggesting that the observed relations were not due to cigarette smoking. Conclusions: These data suggest that men with low serum ascorbate concentrations may have an increased risk of mortality, probably because of an increased risk of dying from cancer. In contrast, serum ascorbate concentrations were not related to mortality among women. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA. RP Loria, CM (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8150, Bethesda, MD 20892 USA. NR 37 TC 65 Z9 68 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2000 VL 72 IS 1 BP 139 EP 145 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 328VG UT WOS:000087871100021 PM 10871572 ER PT J AU Hediger, ML Overpeck, MD Ruan, WJ Troendle, JF AF Hediger, ML Overpeck, MD Ruan, WJ Troendle, JF TI Early infant feeding and growth status of US-born infants and children aged 4-71 mo: analyses from the third National Health and Nutrition Examination Survey, 1988-1994 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE breast-feeding; growth; infants; young children; weight; length; midupper arm circumference; triceps skinfold thickness; third National Health and Nutrition Examination; Survey; NHANES III ID FORMULA-FED INFANTS; BREAST-FED INFANTS; GESTATIONAL-AGE; UNITED-STATES; BIRTH-WEIGHT; ASSOCIATION; ADIPOSITY; PROTEIN; CURVES; LIFE AB Background: There is controversy over what growth references to use in evaluating breast-fed infants and concern about whether never-breast-fed infants are at risk of overweight in childhood. Objective: The objective of this study was to determine whether infants who are exclusively breast-fed for 4 mo differ in average size from infants who are fed in other ways and whether such differences persist through age 5 y. Design: Data from the third National Health and Nutrition Examination Survey (NHANES III) were linked to birth certificates of US-born infants and children. Feeding groups were defined on the basis of feeding patterns over the first 4 mo of life: exclusively breast-fed for 4 mo, partially breast-fed, breastfed for <4 mo, and never breast-fed. Growth status, indexed as internally derived z scores (SD units) for weight, length (height), weight-for-length (height), midupper arm circumference, and triceps skinfold thickness, was compared among feeding groups. Results: The final sample consisted of 5594 non-Hispanic white, non-Hispanic black, and Mexican American infants and children aged 4-71 mo. Of these, 21% were exclusively breast-fed for 4 mo, 10% were partially breast-fed, 24% were breast-fed for <4 mo, and 45% were never breast-fed. At 8-11 mo, infants who were exclusively breast-fed ford, mo had adjusted mean z scores for weight (-0.21; -0.2 kg), weight-for-length (-0.27), and midupper arm circumference (-0.15) that differed significantly from zero (P < 0.05). By 12-23 mo, the differences had dissipated; there were no significant differences subsequent to 5 y. Triceps skinfold thickness was not related to early infant feeding. Conclusion: Infants who were exclusively breast-fed for 4 mo weighed less at 8-11 mo than did infants who were fed in other ways, but there were few other significant differences in growth status through age 5 y associated with early infant feeding. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Overpeck, MD (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bldg 6100,Room 7B03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 43 TC 76 Z9 81 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2000 VL 72 IS 1 BP 159 EP 167 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 328VG UT WOS:000087871100024 PM 10871575 ER PT J AU Sandler, DP AF Sandler, DP TI John Snow and modern-day environmental epidemiology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Sandler, Dale/0000-0002-6776-0018 NR 14 TC 4 Z9 4 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2000 VL 152 IS 1 BP 1 EP 3 DI 10.1093/aje/152.1.1 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 331TV UT WOS:000088035500001 PM 10901322 ER PT J AU Auvinen, A Linet, MS Hatch, EE Kleinerman, RA Robison, LL Kaune, WT Misakian, M Niwa, S Wacholder, S Tarone, RE AF Auvinen, A Linet, MS Hatch, EE Kleinerman, RA Robison, LL Kaune, WT Misakian, M Niwa, S Wacholder, S Tarone, RE TI Extremely low-frequency magnetic fields and childhood acute lymphoblastic leukemia: An exploratory analysis of alternative exposure metrics SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; child; electromagnetic fields; environmental exposure; leukemia, lymphocytic, acute ID RESIDENTIAL EXPOSURE; CHILDREN; CANCER; RISK; APPLIANCES; INDEXES; CANADA; TUMORS; 50-HZ AB Data collected by the National Cancer institute-Children's Cancer Group were utilized to explore various metrics of magnetic field levels and risk of acute lymphoblastic leukemia (ALL) in children. Cases were aged 0-14 years, were diagnosed with ALL during 1989-1993, were registered with the Children's Cancer Group, and resided in one home for at least 70 percent of the 5 years immediately prior to diagnosis. Controls were identified by using random digit dialing and met the same residential requirements. With 30-second ("spot") measurements and components of the 24-hour measurement obtained in the subject's bedroom, metrics evaluated included measures of central tendency, peak exposures, threshold values, and measures of short-term temporal variability. Measures of central tendency and the threshold measures showed good-to-high correlation, but these metrics correlated less well with the others. Small increases in risk (ranging from 1.02 to 1.69 for subjects in the highest exposure category) were associated with some measures of central tendency, but peak exposures, threshold values, measures of short-term variability, and spot measurements demonstrated little association with risk of childhood ALL. In general, risk estimates were slightly higher for the nighttime (10 p.m.-6 a.m.) interval than for the corresponding 24-hour period. C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Radiat & Nucl Safety Author, Helsinki, Finland. Childrens Canc Grp, Arcadia, CA USA. EM Factors, Richland, WA USA. Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. Westat Inc, Rockville, MD USA. RP Linet, MS (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Execut Blvd,Room EPS 7054, Bethesda, MD 20892 USA. OI Kleinerman, Ruth/0000-0001-7415-2478; Auvinen, Anssi/0000-0003-1125-4818 NR 38 TC 24 Z9 25 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2000 VL 152 IS 1 BP 20 EP 31 DI 10.1093/aje/152.1.20 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 331TV UT WOS:000088035500005 PM 10901326 ER PT J AU Zheng, T Holford, TR Tessari, J Mayne, ST Owens, PH Ward, B Carter, D Boyle, P Dubrow, R Archibeque-Engle, S Zahm, SH AF Zheng, T Holford, TR Tessari, J Mayne, ST Owens, PH Ward, B Carter, D Boyle, P Dubrow, R Archibeque-Engle, S Zahm, SH TI Breast cancer risk associated with congeners of polychlorinated biphenyls SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; case-control studies; polychlorinated biphenyls; women's health ID ENVIRONMENTAL ORGANOCHLORINE EXPOSURE; ADIPOSE-TISSUE; RESIDUES; SERUM; PESTICIDES; PCBS; WOMEN AB Experimental studies show that hormonal and nonhormonal activities of polychlorinated biphenyls (PCBs) are structure dependent, suggesting that the breast cancer risk associated with PCBs may vary according to specific PCB congeners, In 1994-1997, the authors conducted a case-control study of Connecticut women to investigate whether breast cancer risk is associated with body burden of PCBs and Varies by PCB congeners. A total of 304 breast cancer cases and 186 controls aged 40-79 years were recruited into the study. Fresh breast adipose tissue was analyzed for PCBs. The age- and lipid-adjusted geometric mean tissue levels of total PCBs were not significantly different (p = 0.46) far the cases (478.6 parts per billion) and controls (494.1 parts per billion). The covariate-adjusted odds ratio was 0.7 (95% confidence interval: 0.4, 1.1) for ail study participants when the third tertile was compared with the lowest tertile. No individual congeners or groups of congeners were associated with a significantly increased risk of breast cancer. Further stratification by type of breast disease; menopausal, parity, and lactation status; and body size also showed no significant association with body levels of PCBs. These results suggest that environmental exposure to PCBs may not substantially affect breast cancer risk. C1 Yale Univ, Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA. Yale Univ, Yale Canc Ctr, New Haven, CT USA. Colorado State Univ, Dept Environm Hlth, Ft Collins, CO 80523 USA. European Inst Oncol, Div Epidemiol & Stat, Milan, Italy. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zheng, T (reprint author), 129 Church St,Suite 700-703, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA-62986] NR 24 TC 56 Z9 57 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2000 VL 152 IS 1 BP 50 EP 58 DI 10.1093/aje/152.1.50 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 331TV UT WOS:000088035500008 PM 10901329 ER PT J AU Newes-Adeyi, G Maxwell, JP AF Newes-Adeyi, G Maxwell, JP TI Preventive care-seeking among inner-city African American pregnant women SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article ID ADEQUATE PRENATAL-CARE; REDUCING INFANT-MORTALITY; HEALTHY START PROGRAM; LOW-INCOME WOMEN; KEEPING APPOINTMENTS; CASE-MANAGEMENT; BALTIMORE CITY; PUBLIC-HEALTH; COMMUNITY; BARRIERS AB Objective: To describe the demographic, psychosocial, and situational characteristics of low-income, inner-city, African American pregnant women and their participation in a comprehensive low-birthweight (LBW) prevention program, Methods: Data (n = 945) were obtained from structured interviews, activity logs, and vital statistics, Results: Many participants' circumstances were economically and psychosocially stressful. The majority of activities participated in required effort. Stressful circumstances did not affect women's participation levels in either effort acts or traditional prenatal care health education. Conclusions: (a) Inner-city, poor women living in stressful circumstances will participate in LBW-prevention programs; (b) traditional LBW-preventive education can be linked with addressing pregnant women's psychosocial needs. C1 NICHD, DESPR, NIH, Bethesda, MD 20892 USA. Greater Washington Res Ctr, Washington, DC USA. RP Newes-Adeyi, G (reprint author), Jovid Fdn, 5335 Wisconsin Ave NW,Suite 440, Washington, DC 20015 USA. NR 38 TC 0 Z9 0 U1 1 U2 2 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD JUL-AUG PY 2000 VL 24 IS 4 BP 254 EP 267 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 330GP UT WOS:000087954700002 ER PT J AU Moore, SR Parascandola, J AF Moore, SR Parascandola, J TI The other pharmacists in the American Civil War SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Letter C1 Univ N Carolina, US Publ Hlth Serv, Chapel Hill, NC 27599 USA. Natl Lib Med, Rockville, MD 20857 USA. RP Moore, SR (reprint author), Univ N Carolina, US Publ Hlth Serv, Chapel Hill, NC 27599 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUL 1 PY 2000 VL 57 IS 13 BP 1276 EP 1276 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 331GU UT WOS:000088010600017 PM 10902070 ER PT J AU Fang, BS Sneller, MC Straus, SE Frenkel, L Dale, JK Rick, ME AF Fang, BS Sneller, MC Straus, SE Frenkel, L Dale, JK Rick, ME TI Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE autoimmune lymphoproliferative syndrome; factor VIII inhibitor; bleeding disorder ID FAS GENE-MUTATIONS; LYMPHOCYTE; APOPTOSIS; THERAPY; DISEASE AB The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII, ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.(1) C1 NIH, Warren Grant Magnuson Clin Ctr, Hematol Serv, Bethesda, MD 20892 USA. NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Invest, NIH, Bethesda, MD 20892 USA. Scott & White Clin, San Antonio, TX USA. RP Rick, ME (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Hematol Serv, Bldg 10,Room 2C 390,10 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 11 Z9 11 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 2000 VL 64 IS 3 BP 214 EP 217 DI 10.1002/1096-8652(200007)64:3<214::AID-AJH14>3.0.CO;2-T PG 4 WC Hematology SC Hematology GA 325HR UT WOS:000087670600014 PM 10861820 ER PT J AU Hudson, LD AF Hudson, LD TI Breaking away from home SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID PELIZAEUS-MERZBACHER-DISEASE; PROTEOLIPID PROTEIN GENE; MAJOR CAUSE; DUPLICATIONS C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Hudson, LD (reprint author), Bldg 36,Room 5D02,36 Convent Dr MSC 4160, Bethesda, MD 20892 USA. NR 12 TC 2 Z9 2 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2000 VL 67 IS 1 BP 1 EP 3 DI 10.1086/302982 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 347JY UT WOS:000088926900001 PM 10827110 ER PT J AU Zhang, WH Bailey-Wilson, JE Li, WD Wang, XQ Zhang, CL Mao, XH Liu, ZH Zhou, CN Wu, M AF Zhang, WH Bailey-Wilson, JE Li, WD Wang, XQ Zhang, CL Mao, XH Liu, ZH Zhou, CN Wu, M TI Segregation analysis of esophageal cancer in a moderately high-incidence area of northern China SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FAMILIAL AGGREGATION; SHANXI-PROVINCE; LINXIAN; STOMACH; TRIAL AB In order to explore the mode of inheritance of esophageal cancer in a moderately high-incidence area of northern China, we conducted a pedigree survey on 225 patients affected by esophageal cancer in Yangquan, Shanxi Province. Segregation analysis was performed using the REGTL program of S.A.G.E. The results showed that Mendelian autosomal recessive inheritance of a major gene that influences susceptibility to esophageal cancer provided the best fit to the data. In the best-fitting recessive model, the frequency of the disease allele was .2039. There was a significant sex effect on susceptibility to the disease. The maximum cumulative probability of esophageal cancer among males with the AA genotype was 100%, but, among females, it was 63.5%. The mean age at onset for both men and women was 62 years. The age-dependent penetrances for males with the AA genotype by the ages of 60 and 80 years were 41.6% and 95.2%, respectively, whereas, for females, they were 26.4% and 60.5%, respectively. Incorporating environmental risk factors-such as cigarette smoking, pipe smoking, alcohol drinking, eating hot food, and eating pickled vegetables-into the models did not provide significant improvement of the fit of the models to these data. The results suggest a major locus underlying susceptibility to esophageal cancer with sex-specific penetrance. C1 Chinese Acad Med Sci, Inst Canc, Natl Lab Mol Oncol, Beijing 100021, Peoples R China. NHGRI, NIH, Baltimore, MD USA. Canc Inst Yangquan City, Yangquan City, Shanxi Province, Peoples R China. RP Wu, M (reprint author), Chinese Acad Med Sci, Inst Canc, Natl Lab Mol Oncol, Chaoyang Qu,POB 2258, Beijing 100021, Peoples R China. OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NCRR NIH HHS [1 P41 RR03655, P41 RR003655] NR 29 TC 55 Z9 63 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2000 VL 67 IS 1 BP 110 EP 119 DI 10.1086/302970 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 347JY UT WOS:000088926900014 PM 10841811 ER PT J AU Martin, ER Monks, SA Warren, LL Kaplan, NL AF Martin, ER Monks, SA Warren, LL Kaplan, NL TI A test for linkage and association in general pedigrees: The pedigree disequilibrium test SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID TRANSMISSION/DISEQUILIBRIUM TEST; SIBSHIP TEST AB Family-based tests of linkage disequilibrium typically are based on nuclear-family data including affected individuals and their parents or their unaffected siblings. A limitation of such tests is that they generally are not valid tests of association when data from related nuclear families from larger pedigrees are used. Standard methods require selection of a single nuclear family from any extended pedigrees when testing for linkage disequilibrium. Often data are available for larger pedigrees, and it would be desirable to have a valid test of linkage disequilibrium that can use all potentially informative data. In this study, we present the pedigree disequilibrium test (PDT) for analysis of linkage disequilibrium in general pedigrees. The PDT can use data from related nuclear families from extended pedigrees and is valid even when there is population substructure. Using computer simulations, we demonstrated validity of the test when the asymptotic distribution is used to assess the significance, and examined statistical power. Power simulations demonstrate that, when extended pedigree data are available, substantial gains in power can be attained by use of the PDT rather than existing methods that use only a subset of the data. Furthermore, the PDT remains more powerful even when there is misclassification of unaffected individuals. Our simulations suggest that there may be advantages to using the PDT even if the data consist of independent families without extended family information. Thus, the PDT provides a general test of linkage disequilibrium that can be widely applied to different data structures. C1 Duke Univ, Med Ctr, Dept Med, Ctr Human Genet, Durham, NC 27710 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Martin, ER (reprint author), Duke Univ, Med Ctr, Dept Med, Ctr Human Genet, Box 3468, Durham, NC 27710 USA. NR 13 TC 485 Z9 494 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2000 VL 67 IS 1 BP 146 EP 154 DI 10.1086/302957 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 347JY UT WOS:000088926900017 PM 10825280 ER PT J AU Ojo, AO Leichtman, AB Punch, JD Hanson, JA Dickinson, DM Wolfe, RA Port, FK Agodoa, LY AF Ojo, AO Leichtman, AB Punch, JD Hanson, JA Dickinson, DM Wolfe, RA Port, FK Agodoa, LY TI Impact of pre-existing donor hypertension and diabetes mellitus on cadaveric renal transplant outcomes SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE marginal donor kidney; kidney transplantation; graft survival; recipient survival; center effect ID DELAYED GRAFT FUNCTION; QUALITY-OF-LIFE; ALLOGRAFT SURVIVAL; ACUTE REJECTION; RISK-FACTORS; ORGAN; KIDNEY; RECIPIENTS; OLDER; AGE AB Hypertension (HTN) and diabetes mellitus (DOM) predispose to systemic atherosclerosis with renal involvement. The prevalence of HTN and DM in cadaveric renal donors (affected donors) and the results of transplantation are unknown. We investigated these issues with national data from the US Renal Data System. A total of 4,035 transplants from affected donors were matched 1:1 with unaffected controls according to donor age and race, recipient race, and year of transplantation. Graft and patient survival were estimated. Among the 25,039 solitary renal transplantations performed between July 1, 1994, and June 30, 1997, cadaveric renal transplants from donors with HTN accounted for 15%, and donors with DM, 2%, Programs with 1-year cadaveric renal graft survival rates greater than 90% had 50% less affected donors compared with programs having 1-year cadaveric renal graft survival rates of 85% or less. Compared with donor-age-matched controls, transplants from affected donors were at minimally increased risk for primary nonfunction, delayed graft function, and acute rejection. Three-year graft survival rates were 71% in affected donor organs and 75% in controls (P = 0.001). Compared with controls, duration of HTN was an independent risk factor for graft survival (3-year graft survival rates, 75% versus 65%; relative risk = 1.36 for HTN >10 years; P < 0.001). A substantial fraction of cadaveric renal donors have preexisting HTN, Programs transplanting fewer affected donor kidneys had better than average results. Because the negative impact of donor HTN and DM on transplant outcome was of moderate degree except when the duration of donor HTN was greater than 10 years, use of affected donors should not be discouraged, but graft and patient survival analyses should account for their presence. (C) 2000 by the National Kidney Foundation, Inc. C1 Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Univ Michigan, Renal Res & Educ Assoc, Ann Arbor, MI USA. NIDDKD, US Renal Data Syst, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Ojo, AO (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, Div Nephrol, TC 3914,Box 0364, Ann Arbor, MI 48109 USA. NR 35 TC 55 Z9 55 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2000 VL 36 IS 1 BP 153 EP 159 DI 10.1053/ajkd.2000.8288 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 331FM UT WOS:000088007700021 PM 10873885 ER PT J AU Culleton, BF Larson, MG Parfrey, PS Kannel, WB Levy, D AF Culleton, BF Larson, MG Parfrey, PS Kannel, WB Levy, D TI Proteinuria as a risk factor for cardiovascular disease and mortality in older people: A prospective study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID DEPENDENT DIABETES-MELLITUS; URINARY ALBUMIN EXCRETION; STAGE RENAL-DISEASE; 10-YEAR FOLLOW-UP; ESSENTIAL-HYPERTENSION; VASCULAR-DISEASE; NONDIABETIC SUBJECTS; ENDOTHELIAL DYSFUNCTION; PROGNOSTIC-SIGNIFICANCE; INSULIN-RESISTANCE AB BACKGROUND: The prognostic significance of proteinuria in older people is not well defined. We examined the associations between proteinuria and incident coronary heart disease, cardiovascular mortality, and all-cause mortality in older people. SUBJECTS AND METHODS: Casual dipstick proteinuria was determined in 1,045 men (mean [+/- SD] age 68 +/- 7 years) and 1,541 women (mean age 69 +/- 7 years) attending the 15th biennial examination of the Framingham Heart Study. Participants were divided by grade of proteinuria: none (85.3%), trace (10.2%), and greater-than-trace (4.5%). Cox proportional hazards analyses were used to determine the relations of baseline proteinuria to the specified outcomes, adjusting for other risk factors, including serum creatinine level. RESULTS: During 17 years of follow-up, there were 455 coronary heart disease events, 412 cardiovascular disease deaths, and 1,214 deaths. In men, baseline proteinuria was associated with all-cause mortality (hazards ratio [HR] = 1.3, 95% confidence interval [CI] 1.0 to 1.7 for trace proteinuria; HR = 1.3, 95% CI 1.0 to 1.8 for greater-than-trace proteinuria; P for trend = 0.02). In women, trace proteinuria was associated with cardiovascular disease death (HR = 1.6, 95% CI 1.1 to 2.4), and all-cause mortality (HR = 1.4, 95% CI 1.1 to 1.7). CONCLUSION: Proteinuria is a significant, although relatively weak, risk factor for all-cause mortality in men and women, and for cardiovascular disease mortality in women. Am J Med. 2000;109:1-8. (C) 2000 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. Mem Univ Newfoundland, Div Nephrol, St Johns, NF, Canada. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 57 TC 97 Z9 98 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2000 VL 109 IS 1 BP 1 EP 8 DI 10.1016/S0002-9343(00)00444-7 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 343PA UT WOS:000088709700001 PM 10936471 ER PT J AU Maymon, E Romero, R Pacora, P Gomez, R Athayde, N Edwin, S Yoon, BH AF Maymon, E Romero, R Pacora, P Gomez, R Athayde, N Edwin, S Yoon, BH TI Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE matrix metalloproteinase 8; parturition; premature rupture of fetal membranes; intra-amniotic infection; neutrophil collagenase; forebag ID FETAL MEMBRANES; POLYMORPHONUCLEAR LEUKOCYTES; TERM; INTERLEUKIN-8; INHIBITORS AB OBJECTIVES: The mechanisms by which microbial invasion of the amniotic cavity leads to membrane weakening and rupture are poorly understood. Recently. endogenous host enzymes have been implicated in this process. Matrix metalloproteinases are a family of potent enzymes that degrade components of the extracellular matrix. Collagen type I provides the main tensile strength of the fetal membranes. Matrix metalloproteinase 8 (MMP-8), or neutrophil collagenase, degrades interstitial collagens, acting preferentially on collagen type I. This study was undertaken (1) to determine whether MMP-8 is present in amniotic fluid and whether its concentrations are changed in preterm and term labor and membrane rupture with and without intra-amniotic infection and (2) to determine whether the amniotic fluid concentrations of MMP-8 in labor at term are different in the lower and upper uterine compartments. STUDY DESIGN: A cross-sectional study was conducted and transabdominal amniocentesis was performed in women in the following categories: (1) midtrimester (n = 25), (2) preterm labor in the presence and absence of microbial invasion of the amniotic cavity (n = 86), (3) preterm premature rupture of the membranes in the presence and absence of microbial invasion of the amniotic cavity (n = 51), (4) term patients in labor and not in labor (n = 51), and (5) term premature rupture of membranes (n = 20). Additional paired samples of amniotic fluid were retrieved by transabdominal amniocentesis (upper compartment) and transvaginal amniocentesis (lower or forebag compartment) from 14 term patients (28 samples) in spontaneous labor with intact membranes. Amniotic fluid MMP-8 concentrations were determined with a sensitive and specific immunoassay. RESULTS: MMP-8 was detected in 95.4% (249/261) of all samples. (1) Spontaneous human parturition was associated with a significant increase in amniotic fluid concentrations of MMP-8 in both term and preterm gestation. Term (no labor median, 3.3 ng/mL; range, <0.06-38.6 ng/mL; vs labor median, 16.6 ng/mL; range, 0.33-1650 ng/mL; P < .05). Patients with preterm labor who delivered preterm (in the absence of microbial invasion of the amniotic cavity) had a significantly higher median amniotic fluid MMP-8 concentration than those with preterm labor who delivered at term (preterm labor, term delivery median, 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm labor, preterm delivery median, 32.5 ng/mL; range. <0.06-6006.6 ng/mL; P < .003). (2) Spontaneous rupture of membranes in preterm gestation but not in term gestation was associated with elevated amniotic fluid concentrations of MMP-8. Preterm gestation (preterm labor, intact membranes median. 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm premature rupture of membranes median, 35.1 ng/mL; range, 0.71-1184.1 ng/mL; P < .05). Term gestation (intact membranes median, 3.3 ng/mL; range, 0.24-38.6 ng/mL; vs rupture of membranes median, 5.6 ng/mL; range, 0.22-19.8 ng/mL; P = .9). (3) Microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid MMP-8 concentration in patients with preterm labor and intact membranes, as well as in patients with preterm premature rupture of membranes. Preterm labor (no microbial invasion of the amniotic cavity, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL; vs microbial invasion of the amniotic cavity median, 208.1 ng/mL; range, 4.2-14,600 ng/mL; P < .001). Preterm premature rupture of membranes (no microbial invasion of the amniotic cavity median, 35.1 ng/mL; range, 0.71-1184.1 ng/mL; vs microbial invasion of the amniotic cavity median, 317.9 ng/mL; range, 2.16-14,500 ng/mL; P < .01). (4) The median amniotic fluid MMP-8 concentrations were significantly higher in fluid obtained from the forebag compartment than in that obtained from the upper compartment (median, 66.2 ng/mL; range, 7.4-170 ng/mL; vs median, 13.3 ng/mL; range, 2-170 ng/mL; respectively; P < .01). CONCLUSIONS: These data suggest a role for a specific interstitial collagenase (MMP-8) in microbial invasion of the amniotic cavity, preterm membrane rupture, and term and preterm labor. The higher concentration of MMP-8 in fluid bathing the cervical region may explain the predilection for membrane rupture to occur close to the lower pole of the uterus. C1 Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, NICHHD,Perinatol Res branch, Detroit, MI 48201 USA. NICHHD, Perinatal Res Branch, Bethesda, MD 20892 USA. Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. RP Maymon, E (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, NICHHD,Perinatol Res branch, 4707 St Antoine Blvd, Detroit, MI 48201 USA. RI Yoon, Bo Hyun/H-6344-2011 NR 25 TC 123 Z9 128 U1 0 U2 7 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2000 VL 183 IS 1 BP 94 EP 99 DI 10.1067/mob.2000.105344 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 340ZA UT WOS:000088565500017 PM 10920315 ER PT J AU Watts, DH Lambert, JS Stiehm, ER Bethel, J Whitehouse, J Fowler, MG Read, J AF Watts, DH Lambert, JS Stiehm, ER Bethel, J Whitehouse, J Fowler, MG Read, J CA Pediat AIDS Clin Trials Grp 185 Study TI Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of <= 500/mu L SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE postpartum complications; human immunodeficiency virus-infected women ID INTRAVENOUS IMMUNOGLOBULIN; ANTIBIOTIC-PROPHYLAXIS; BACTERIAL VAGINOSIS; CESAREAN-SECTION; RISK-FACTORS; ENDOMETRITIS; TRANSMISSION; ZIDOVUDINE; PREGNANCY; MORBIDITY AB OBJECTIVE: We sought to describe rates of and risk factors for complications by delivery mode among human immunodeficiency virus-infected women with CD4 counts of less than or equal to 500/mu L. STUDY DESIGN: Complication rates were calculated by delivery mode, as follows: planned cesarean delivery performed without labor or rupture of membranes, other cesarean delivery performed after labor or rupture of membranes, or vaginal delivery. Risk factors were evaluated. RESULTS: Major complications in the planned cesarean delivery (n = 37), other cesarean delivery (n = 95), and vaginal delivery (n = 365) groups were amnionitis or endometritis (16%, 27%, and 7%, respectively), wound infection (5%, 8%, and <1%, respectively), and transfusion (8%, 6%, and 3%, respectively). Any peripartum infection occurred among 16 (18%) of those with a CD4 count of <200/mu L and 43 (13%) with a CD4 count of greater than or equal to 200/mu L (P = .17). On multivariate analyses, factors associated with amnionitis-endometritis were cesarean delivery and African American race, and a factor associated with transfusion was third-trimester anemia. CONCLUSION: Endometritis and wound infection occurred more frequently among human immunodeficiency virus-infected women after cesarean than among women undergoing vaginal delivery; however, complication rates overall were within the range reported in human immunodeficiency virus-negative women, Measures to decrease complications in human immunodeficiency virus-infected women, such as greater use of prophylactic antibiotics, should be assessed. C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Rockville, MD USA. Univ Calif Los Angeles, Los Angeles, CA USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. RP Watts, DH (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, 6100 Execut Blvd,4B11, Bethesda, MD 20892 USA. NR 25 TC 36 Z9 41 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2000 VL 183 IS 1 BP 100 EP 107 DI 10.1067/mob.2000.105423 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 340ZA UT WOS:000088565500018 PM 10920316 ER PT J AU Gifford, RW August, PA Cunningham, G Green, LA Lindheimer, MD McNellis, D Roberts, JM Sibai, BM Taler, SJ AF Gifford, RW August, PA Cunningham, G Green, LA Lindheimer, MD McNellis, D Roberts, JM Sibai, BM Taler, SJ CA Natl High Blood Pressure Educ Pro TI Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE eclampsia; hypertension; preeclampsia; pregnancy; treatment ID RANDOMIZED CONTROLLED TRIAL; LOW-DOSE ASPIRIN; LONG-TERM PROGNOSIS; MONITORED OUTPATIENT MANAGEMENT; GESTATIONAL HYPERTENSION REMOTE; INTRAUTERINE GROWTH-RETARDATION; ELEVATED LIVER-ENZYMES; ACUTE-RENAL-FAILURE; V KOROTKOFF SOUNDS; SEVERE PREECLAMPSIA AB This report updates the 1990 "National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy" acid focuses on classification, pathophysiologic features, and management of the hypertensive disorders of pregnancy. Through a combination of evidence-based medicine and consensus this report updates contemporary approaches to hypertension control during pregnancy by expanding on recommendations made in "The Sixth Report of the Joint National Committee on Prevention, Detection. Evaluation. and Treatment of High Blood Pressure." The recommendations to use Korotkoff phase V for determination of diastolic pressure and to eliminate edema as a criterion for diagnosing preeclampsia are discussed. In addition, the use as a diagnostic criterion of blood pressure increases of 30 mm Hg systolic or 15 mm Hg diastolic with blood pressure <140/90 mm Hg has not been recommended, because available evidence shows that women with blood pressures fitting this description are not more likely to have adverse outcomes. Management distinctions are made between chronic hypertension that is present before pregnancy and hypertension that occurs as part of the pregnancy-specific condition of preeclampsia, as well as management considerations for women with comorbid conditions. A discussion of the pharmacologic treatment of hypertension during pregnancy includes recommendations for specific agents. The use of low-dose aspirin, calcium, or other dietary supplements in the prevention of preeclampsia is described, and expanded sections on counseling women for future pregnancies and recommendations for future research are included. C1 NHLBI, Natl High Blood Pressure Educ Program, Off Prevent Educ & control, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Dept Hypertens & Nephrol, Cleveland, OH 44195 USA. Cornell Univ, New York Presbyterian Hosp, Weill Med Col, Div Hypertens, New York, NY USA. Univ Texas, SW Med Ctr, Dept Obstet & Gynecol, Dallas, TX 75235 USA. Univ Michigan, Dept Family Med, Ann Arbor, MI 48109 USA. Univ Chicago, Chicago, IL 60637 USA. NICHHD, Pregnancy & Perinatol Branch, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Magee Womens Hosp, Pittsburgh, PA 15213 USA. Magee Womens Res Inst, Pittsburgh, PA USA. Univ Tennessee, Div Maternal & Fetal Med, Memphis, TN USA. Mayo Clin, Div Hypertens & Internal Med, Rochester, MN USA. Prospect Associates Inc, Silver Spring, MD USA. RP Gifford, RW (reprint author), NHLBI, Natl High Blood Pressure Educ Program, Off Prevent Educ & control, NIH, 31 Ctr Dr,MSC 2480, Bethesda, MD 20892 USA. NR 202 TC 1153 Z9 1241 U1 8 U2 65 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2000 VL 183 IS 1 BP S1 EP S22 DI 10.1067/mob.2000.107928 PG 22 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 340ZA UT WOS:000088565500048 ER PT J AU Robinson, MR Reed, G Csaky, KG Polis, MA Whitcup, SM AF Robinson, MR Reed, G Csaky, KG Polis, MA Whitcup, SM TI Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CYSTOID MACULAR EDEMA; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MAINTENANCE THERAPY; INTRAVENOUS CIDOFOVIR; DEFICIENCY-SYNDROME; CLINICAL RESEARCH; CMV RETINITIS; AIDS; INITIATION; INFECTION AB PURPOSE: To investigate the clinical features associated with immune recovery in human immunodeficiency virus (HIV)-infected patients with cytomegalovirus retinitis who are taking highly active antiretroviral therapy. METHODS: Sixteen patients were evaluated prospectively at the National Eye Institute, Bethesda, Maryland. Evaluation included a medical history and a complete ophthalmologic examination. The examination included best corrected visual acuity score measured by means of logarithmic charts, slit-lamp biomicroscopy, dilated retinal examination, retinal photography, and fluorescein angiography. Immune-recovery uveitis was defined as the ocular inflammation associated with clinical immune the presence of moderate to severe macular edema on fluorescein angiography and vitreous haze (P less than or equal to .001). CONCLUSIONS: Immune-recovery uveitis is an important cause of visual morbidity in HIV-infected patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Although immune recovery associated with highly active antiretroviral therapy has allowed some patients to discontinue specific anticytomegalovirus therapy, the rejuvenated immune response can be associated with sight-threatening inflammation. Published by Elsevier Science Inc. C1 NEI, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10N112,10 Ctr Dr MSC 1863, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 36 TC 60 Z9 68 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUL PY 2000 VL 130 IS 1 BP 49 EP 56 DI 10.1016/S0002-9394(00)00530-4 PG 8 WC Ophthalmology SC Ophthalmology GA 355UN UT WOS:000089407100007 PM 11004259 ER PT J AU Wiener, SM Hoyt, RF Deleonardis, JR Clevenger, RR Jeffries, KR Nagashima, K Mandel, M Owens, J Eckhaus, M Lutz, RJ Safer, B AF Wiener, SM Hoyt, RF Deleonardis, JR Clevenger, RR Jeffries, KR Nagashima, K Mandel, M Owens, J Eckhaus, M Lutz, RJ Safer, B TI Manometric changes during retrograde biliary infusion in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE drug delivery; polarized epithelia; tight junction; cholestasis ID BILE-DUCT LIGATION; GENE-TRANSFER; HEPATOCELLULAR-CARCINOMA; RAT-LIVER; IN-VIVO; CHOLESTASIS; COMPLEX; HEPATOBILIARY; CANALICULI; JUNCTIONS AB The manometric, ultrastructural, radiographic, and physiological consequences of retrograde biliary infusion were determined in normostatic and cholestatic mice. Intraluminal biliary pressure changed as a function of infusion volume, rate, and viscosity. Higher rates of constant infusion resulted in higher peak intraluminal biliary pressures. The pattern of pressure changes observed was consistent with biliary ductular and/or canalicular filling followed by leakage at a threshold pressure. Retrograde infusion with significant elevations in pressure led to paracellular leakage of lanthanum chloride, radiopaque dye, and [C-14] sucrose with rapid systemic redistribution via sinusoidal and subsequent hepatic venous drainage. Chronic extrahepatic bile duct obstruction resulted in significantly smaller peak intrabiliary pressures and lower levels of paracellular leakage. These findings indicate that under both normostatic and cholestatic conditions elevated intrabiliary volumes/pressures result in an acute pressure-dependent physical opening of tight junctions, permitting the movement of infusate from the intrabiliary space into the subepithelial tissue compartment. Control of intraluminal pressure may potentially permit the selective delivery of macromolecules >18-20 Angstrom in diameter to specific histological compartments. C1 NHLBI, Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell & Mol Struct, Frederick Canc Res & Dev Ctr, Frederick, MD 21270 USA. NIH, Pathol Serv, Diagnost & Surg Sect, Vet Resources Program,Natl Ctr Res Resources, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Wiener, SM (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit GRJ 722, 55 Fruit St, Boston, MA 02114 USA. NR 37 TC 13 Z9 13 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUL PY 2000 VL 279 IS 1 BP G49 EP G66 PG 18 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 333RN UT WOS:000088144700007 PM 10898746 ER PT J AU Zhou, YY Wang, SQ Zhu, WZ Chruscinski, A Kobilka, BK Ziman, B Wang, S Lakatta, EG Cheng, HP Xiao, RP AF Zhou, YY Wang, SQ Zhu, WZ Chruscinski, A Kobilka, BK Ziman, B Wang, S Lakatta, EG Cheng, HP Xiao, RP TI Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiology SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE excitation-contraction coupling; beta-adrenergic signaling ID RABBIT VENTRICULAR MYOCYTES; MICE; CELLS AB Rapid development of transgenic and gene-targeted mice and acute genetic manipulation via gene transfer vector systems have provided powerful tools for cardiovascular research. To facilitate the phenotyping of genetically engineered murine models at the cellular and subcellular levels and to implement acute gene transfer techniques in single mouse cardiomyocytes, we have modified and improved current enzymatic methods to isolate a high yield of high-quality adult mouse myocytes (5.3 +/- 0.5 x 10(5) cells/left ventricle, 83.8 +/- 2.5% rod shaped). We have also developed a technique to culture these isolated myocytes while maintaining their morphological integrity for 2-3 days. The high percentage of viable myocytes after 1 day in culture (72.5 +/- 2.3%) permitted both physiological and biochemical characterization. The major functional aspects of these cells, including excitation-contraction coupling and receptor-mediated signaling, remained intact, but the contraction kinetics were significantly slowed. Furthermore, gene delivery via recombinant adenoviral infection was highly efficient and reproducible. In adult beta(1)/beta(2)-adrenergic receptor (AR) double-knockout mouse myocytes, adenovirus-directed expression of either beta(1) -or beta(2)-AR, which occurred in 100% of cells, rescued the functional response to beta-AR agonist stimulation. These techniques will permit novel experimental settings for cellular genetic physiology. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Stanford Univ, Med Ctr, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 24 TC 209 Z9 219 U1 0 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2000 VL 279 IS 1 BP H429 EP H436 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 336LE UT WOS:000088302100049 PM 10899083 ER PT J AU Frank, SM Raja, SN Bulcao, C Goldstein, DS AF Frank, SM Raja, SN Bulcao, C Goldstein, DS TI Age-related thermoregulatory differences during core cooling in humans SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE epinephrine; heat production; norepinephrine regulation; temperature vasoconstriction ID OLDER MEN; BODY-COMPOSITION; COLD EXPOSURES; RESPONSES; TEMPERATURE; YOUNG; VASOCONSTRICTION; HYPOTHERMIA; ARTERIES AB The current study assessed sympathetic neuronal and vasomotor responses, total body oxygen consumption, and sensory thermal perception to identify thermoregulatory differences in younger and older human subjects during core cooling. Cold fluid (40 ml/kg, 4 degrees C) was given intravenously over 30 min to decrease core temperature (Tc) in eight younger (age 18-23) and eight older (age 55-71) individuals. Compared with younger subjects, the older subjects had significantly lower Tc thresholds for vasoconstriction (35.5 +/- 0.3 vs. 36.2 +/- 0.2 degrees C, P = 0.03), heat production (35.2 +/- 0.4 vs. 35.9 +/- 0.1 degrees C, P = 0.04), and plasma norepinephrine (NE) responses (35.0 vs. 36.0 degrees C, P < 0.05). Despite a lower Tc nadir during cooling, the maximum intensities of the vasoconstriction (P = 0.03) and heat production (P = 0.006) responses were less in the older compared with the younger subjects, whereas subjective thermal comfort scores were similar. Plasma NE concentrations increased fourfold in the younger but only twofold in the older subjects at maximal Tc cooling. The vasomotor response for a given change in plasma NE concentration was decreased in the older group (P = 0.01). In summary, aging is associated with 1) a decreased Tc threshold and maximum response intensity for vasoconstriction, total body oxygen consumption, and NE release, 2) decreased vasomotor responsiveness to NE, and 3) decreased subjective sensory thermal perception. C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. McGill Univ, Sch Med, Montreal, PQ H2X 3R2, Canada. RP Frank, SM (reprint author), Johns Hopkins Hosp, Dept Anesthesiol & Crit Care Med, Carnegie 280,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCRR NIH HHS [5-MO1-RR-00722]; NINDS NIH HHS [NS-26363] NR 36 TC 66 Z9 69 U1 4 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUL PY 2000 VL 279 IS 1 BP R349 EP R354 PG 6 WC Physiology SC Physiology GA 334DX UT WOS:000088171400043 PM 10896899 ER PT J AU Ecelbarger, CA Kim, GH Terris, J Masilamani, S Mitchell, C Reyes I Verbalis, JG Knepper, MA AF Ecelbarger, CA Kim, GH Terris, J Masilamani, S Mitchell, C Reyes, I Verbalis, JG Knepper, MA TI Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE immunoblotting; sodium transporters; collecting duct; Brattleboro rat; aldosterone ID CORTICAL COLLECTING TUBULES; WATER CHANNEL; BRATTLEBORO RAT; V-2 RECEPTOR; TRANSCRIPTIONAL REGULATION; ADRENOCORTICAL FUNCTION; ALPHA-SUBUNITS; GAMMA-SUBUNITS; BETA-SUBUNITS; MESSENGER-RNA AB Sodium transport is increased by vasopressin in the cortical collecting ducts of rats and rabbits. Here we investigate, by quantitative immunoblotting, the effects of vasopressin on abundances of the epithelial sodium channel (ENaC) subunits (alpha, beta, and gamma) in rat kidney. Seven-day infusion of 1-deamino-[8-D-arginine]-vasopressin (dDAVP) to Brattleboro rats markedly increased whole kidney abundances of band gamma-ENaC (to 238% and 288% of vehicle, respectively), whereas alpha-ENaC was more modestly, yet significantly, increased (to 142% of vehicle). Similarly, 7-day water restriction in Sprague-Dawley rats resulted in significantly increased abundances of beta- and gamma- but no significant change in alpha-ENaC. Acute administration of dDAVP (2 nmol) to Brattleboro rats resulted in modest, but significant, increases in abundance for all ENaC subunits, within 1 h. In conclusion, all three subunits of ENaC are upregulated by vasopressin with temporal and regional differences. These changes are too slow to play a major role in the short-term action of vasopressin to stimulate sodium reabsorption in the collecting duct. Long-term increases in ENaC abundance should add to the short-term regulatory mechanisms (undefined in this study) to enhance sodium transport in the renal collecting duct. C1 Georgetown Univ, Div Endocrinol, Washington, DC 20007 USA. NHLBI, Lab Kidney & Electrolyte Metab, Bethesda, MD 20892 USA. RP Ecelbarger, CA (reprint author), Georgetown Univ, Div Endocrinol, Bldg D,Rm 232,4000 Reservoir Rd NW, Washington, DC 20007 USA. EM ecelbarc@gunet.georgetown.edu FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NIDDK NIH HHS [K01-DK-02672-01, DK-38094] NR 52 TC 168 Z9 170 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2000 VL 279 IS 1 BP F46 EP F53 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 333RM UT WOS:000088144600004 PM 10894786 ER PT J AU Blazer, DG Hybels, CF Simonsick, EM Hanlon, JT AF Blazer, DG Hybels, CF Simonsick, EM Hanlon, JT TI Marked differences in antidepressant use by race in an elderly community sample: 1986-1996 SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID OLDER ADULTS; DRUG-USE; DEPRESSED OUTPATIENTS; PRESCRIBING PATTERNS; HEALTH-SERVICES; PRIMARY-CARE; POPULATION; PRESCRIPTION; MEDICATIONS; SYMPTOMS AB Objective: Prescriptions of antidepressant medications have increased significantly over the past 15 years across the life cycle. One overall correlate of medication use in older adults is race, with African Americans using fewer medications than whites. Given the frequency of depressive symptoms among elderly populations, as well as the increased potential for adverse side effects from antidepressants, the relative contribution of race in the use of antidepressants is critical for determining well-designed studies. The authors analyzed data from a community-based cohort of elders followed for 10 years to determine the association of race to the use of antidepressants between 1986 and 1996, with control for known correlates of depression in late life. Method: Information on antidepressant use and demographic and health characteristics were obtained from a stratified, probability-based sample of 4,162 elders (equally distributed between African American and white community-dwelling subjects) in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. Results: A total of 4.6% of whites and 2.3% of African Americans used antidepressants in 1986. Approximately 14.3% of whites and 5.0% of African Americans used antidepressants in 1996. In controlled analyses, the prevalence odds ratio for antidepressant use in whites, compared to African Americans, was 1.76 in 1986 and 3.77 in 1996. Conclusions: African American elders are much less likely to take antidepressants, and the difference in use increased over the 10 years of the survey. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Study Aging, Durham, NC 27710 USA. NIA, Demog Biometry & Epdemiol Program, Bethesda, MD 20892 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. RP Blazer, DG (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Study Aging, Box 3003, Durham, NC 27710 USA. FU NIA NIH HHS [AG-12765, AG-15432, AG-12102] NR 34 TC 107 Z9 107 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2000 VL 157 IS 7 BP 1089 EP 1094 DI 10.1176/appi.ajp.157.7.1089 PG 6 WC Psychiatry SC Psychiatry GA 329WJ UT WOS:000087931200010 PM 10873916 ER PT J AU Hall, GW Carriero, NJ Takushi, RY Montoya, ID Preston, KL Gorelick, DA AF Hall, GW Carriero, NJ Takushi, RY Montoya, ID Preston, KL Gorelick, DA TI Pathological gambling among cocaine-dependent outpatients SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 59th Annual Scientific Meeting of the College-on-Problems-of-Drug-Dependence CY JUN 14-19, 1997 CL NASHVILLE, TENNESSEE SP Coll Problems Drug Dependence ID ADDICTION SEVERITY INDEX; METHADONE PATIENTS; SUBSTANCE-ABUSERS; GAMBLERS; DEMOGRAPHICS; ALCOHOLICS; MISUSERS; VETERANS; SEEKING AB Objective: The authors investigated the occurrence of pathological gambling among cocaine-dependent outpatients, its influence on short-term outcome of treatment, and comparative characteristics of patients with and without pathological gambling. Method: The subjects were 313 cocaine-dependent (200 also opiate-dependent) outpatients in clinical trials of medication for cocaine dependence. Pathological gambling (DSM-III-R criteria) was assessed with the Diagnostic Interview Schedule, and sociodemographic and socioeconomic characteristics were determined with the Addiction Severity Index. Outcome was defined as time in treatment (proportion of maximum scheduled time) and proportion of cocaine-positive urine samples during treatment. Results: Pathological gambling had a lifetime occurrence rate of 8.0% and a current (past month) occurrence of 3.8%. Onset preceded the onset of cocaine dependence in 72.0% of the patients (and preceded onset of opiate dependence in 44.4%). Patients with pathological gambling (lifetime or current) did not differ significantly from other patients in length of treatment or proportion of cocaine-positive urine samples. Those with lifetime pathological gambling were significantly more likely to have tobacco dependence (84.0% versus 61.1%) and antisocial personality disorder (56.0% versus 19.8%), to be unemployed (84.0% versus 49.3%), to have recently engaged in illegal activity for profit (64.0% versus 38.5%), and to have been incarcerated (62.5% versus 33.9%). Conclusions: Pathological gambling is substantially more prevalent among cocaine-dependent outpatients than in the general population. Patients with pathological gambling differ from other cocaine-dependent outpatients in some sociodemographic characteristics but not in short-term outcome of treatment for cocaine dependence. C1 NIDA, IRP, Baltimore, MD 21224 USA. Howard Univ, Dept Social Work Direct Serv, Washington, DC 20059 USA. Howard Univ, Dept Psychol, Washington, DC 20059 USA. RP Gorelick, DA (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 34 TC 47 Z9 47 U1 1 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2000 VL 157 IS 7 BP 1127 EP 1133 DI 10.1176/appi.ajp.157.7.1127 PG 7 WC Psychiatry SC Psychiatry GA 329WJ UT WOS:000087931200016 PM 10873922 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI Ignore AIDS and it will bury the rest of you SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Non Book Collect, Hist Med Div, Bethesda, MD 20894 USA. RP Theerman, P (reprint author), Natl Lib Med, Non Book Collect, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2000 VL 90 IS 7 BP 1028 EP 1028 DI 10.2105/AJPH.90.7.1028 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 327TR UT WOS:000087810000004 PM 10897176 ER PT J AU Auerbach, JD Coates, TJ AF Auerbach, JD Coates, TJ TI HIV prevention research: Accomplishments and challenges for the third decade of AIDS SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SEXUALLY-TRANSMITTED DISEASES; INJECTION-DRUG USERS; YOUNG GAY; MEN; INTERVENTION; INFECTION; ZIDOVUDINE; REDUCTION; BEHAVIOR; PROGRAM AB The past 2 decades have taught us that HIV prevention can work. We now have evidence from places as diverse as Senegal, Thailand, Uganda, and Australia that concerted HIV prevention efforts at the national level have resulted in the maintenance of low seroprevalence rates where they otherwise would have been expected to rise. We are beginning to Observe declining rates of HIV prevalence acid incidence in places and populations with historically high rates-for example, injection drug users in New York City. This trend points to the long-term impact of prevention efforts in those communities.(1,2) The best of these efforts have been based on sound scientific research. As we move into the third decade of the AIDS epidemic, it is important to restate principles, acknowledge advances, and identify challenges and future directions in HIV prevention research. C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. Univ Calif San Francisco, AID Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. RP Auerbach, JD (reprint author), NIH, Off AIDS Res, Bldg 2,Room 4E30,2 Ctr Dr, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH42459] NR 31 TC 72 Z9 74 U1 0 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2000 VL 90 IS 7 BP 1029 EP 1032 DI 10.2105/AJPH.90.7.1029 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 327TR UT WOS:000087810000005 PM 10897177 ER PT J AU Marcus, M Freed, JR Coulter, ID Der-Martirosian, C Cunningham, W Andersen, R Garcia, I Schneider, DA Maas, WR Bozzette, SA Shapiro, MF AF Marcus, M Freed, JR Coulter, ID Der-Martirosian, C Cunningham, W Andersen, R Garcia, I Schneider, DA Maas, WR Bozzette, SA Shapiro, MF TI Perceived unmet need for oral treatment among a national population of HIV-positive medical patients: Social and clinical correlates SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HEALTH-CARE; DENTAL-CARE; ACCESS; INFECTION; SERVICES; SAMPLES AB Objectives. This study examines social, behavioral, and clinical correlates of perceived unmet need for oral health care for people with HIV infection, Methods. Baseline in-person interviews with 2864 individuals were conducted with the HIV Cast and Services Utilization Study cohort, a nationally representative probability sample of HIV-infected persons in medical care. Bivariate and logistic regression analyses were conducted with unmet need in the last 6 months as the dependent variable and demographic, social, behavioral, and disease characteristics as independent variables. Results. We estimate that 19.3% of HIV-infected medical patients (n = 44550) had a perceived unmet need for dental care in the last 6 months. The odds of having unmet dental needs were highest for those on Medicaid in states without dental benefits (odds ratio [OR] = 2.21), for others with no dental insurance (OR = 2.26), for those with incomes under $5000 (OR = 2.20), and for those with less than a high school education (OR = 1.83). Low CD4 count was not significant. Conclusions. Perceived unmet need was related more to social and economic factors than to stage of infection. An expansion of dental benefits for those on Medicaid might reduce unmet need for dental care. C1 Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. Agcy Healthcare Res & Qual, Atlanta, GA USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. RAND Corp, Santa Monica, CA USA. RP Marcus, M (reprint author), Univ Calif Los Angeles, Sch Dent, 10833 Le Conte Ave,Box 951668, Los Angeles, CA 90095 USA. FU AHRQ HHS [HS08578] NR 19 TC 29 Z9 29 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2000 VL 90 IS 7 BP 1059 EP 1063 DI 10.2105/AJPH.90.7.1059 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 327TR UT WOS:000087810000011 PM 10897183 ER PT J AU Leung, DYM Chrousos, GP AF Leung, DYM Chrousos, GP TI Is there a role for glucocorticoid receptor beta in glucocorticoid-dependent asthmatics? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID STEROID-RESISTANT ASTHMA; BINDING-AFFINITY; RT-PCR; ISOFORM; EXPRESSION; MECHANISMS; GENE C1 Univ Colorado, Hlth Sci Ctr, Natl Jewish Med & Res Ctr, Dept Pediat,Div Pediat Allergy Immunol, Denver, CO 80206 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Leung, DYM (reprint author), Univ Colorado, Hlth Sci Ctr, Natl Jewish Med & Res Ctr, Dept Pediat,Div Pediat Allergy Immunol, 1400 Jackson St,Room K926, Denver, CO 80206 USA. NR 19 TC 21 Z9 22 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL PY 2000 VL 162 IS 1 BP 1 EP 3 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 333JH UT WOS:000088126800001 PM 10903210 ER PT J AU Devouassoux-Shisheboran, M Hayashi, T Linnoila, RI Koss, MN Travis, WD AF Devouassoux-Shisheboran, M Hayashi, T Linnoila, RI Koss, MN Travis, WD TI A clinicopathologic study of 100 cases of pulmonary sclerosing hemangioma with immunohistochemical studies - TTF-1 is expressed in both round and surface cells, suggesting an origin from primitive respiratory epithelium SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE sclerosing hemangioma; lung, sclerosing pneumocytoma; thyroid transcription factor-1; epithelial membrane antigen; tumorlet; surfactant ID TRANSCRIPTION FACTOR-I; HUMAN-LUNG; PROGESTERONE RECEPTORS; INTERMEDIATE FILAMENTS; PROTEIN-B; FETAL; MESOTHELIOMA; CARCINOMAS; ANTIBODIES; DIAGNOSIS AB Pulmonary sclerosing hemangioma (SH) is a lung neoplasm of uncertain histogenesis that is composed of two major cell types: surface and round cells. The authors studied 100 cases of pulmonary SH that presented as a peripheral (95%), solitary (96%) mass of less than 3 cm in diameter (74%) in asymptomatic patients who were mostly women (83%) with a mean age of 46.2 years. Immunohistochemistry of multiple epithelial, mesothelial, pneumocyte, neuroendocrine, and mesenchymal markers was performed on 47 cases to investigate the histogenesis of this neoplasm. Both surface and round cells stained with epithelial membrane antigen (EMA) and thyroid transcription factor-1 (TTF-1) in more than 90% of cases; however, the round cells were uniformly negative for pancytokeratin and positive for cytokeratin-7 and CAM5.2 in only 31% and 17% of cases, respectively. Surfactant proteins A and B as well as Clara cell antigen were positive in varying numbers of surface cells but they were negative in the round cells. Neuroendocrine cells either as isolated scattered cells or as a tumorlet within the center of SH were detected (chromogranin, Leu-7, synaptophysin positive) in three cases. The expression of TTF-1 in the absence of surfactant proteins A and B and Clara cell antigens in the round cells of SH suggests that they are derived from primitive respiratory epithelium. The alveolar pneumocytes and neuroendocrine cells map either represent phenotypic differentiation of a primitive respiratory epithelial component or they may correspond to non-neoplastic entrapped or hyperplastic elements. The concomitant positivity of both cell types in SH for TTF-1 and EMA, and the negativity of round cells for pancytokeratin and neuroendocrine markers, provide useful clues not only for histogenesis but also for the diagnosis of this lung neoplasm. C1 Armed Forces Inst Pathol, Dept Pulm Pathol, Washington, DC 20306 USA. Hop Croix Rousse, Hospices Civils Lyon, Dept Pathol, Lyon, France. Nagasaki Univ Hosp, Dept Pathol, Nagasaki, Japan. NCI, Cell & Canc Biol Dept, Med Branch, NIH, Rockville, MD USA. RP Travis, WD (reprint author), Armed Forces Inst Pathol, Dept Pulm & Med Pathol, Bldg 54,Room M003B,6825 NW 16th St, Washington, DC 20306 USA. NR 45 TC 141 Z9 183 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUL PY 2000 VL 24 IS 7 BP 906 EP 916 DI 10.1097/00000478-200007000-00002 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 329WU UT WOS:000087932100002 PM 10895813 ER PT J AU Kau, ASM Reider, EE Payne, L Meyer, WA Freund, L AF Kau, ASM Reider, EE Payne, L Meyer, WA Freund, L TI Early behavior signs of psychiatric phenotypes in fragile X syndrome SO AMERICAN JOURNAL ON MENTAL RETARDATION LA English DT Article ID MALES; CHILDREN; GAZE AB Whether preschool males with fragile X syndrome can be distinguished from those with idiopathic developmental delay in the four problem behavior areas associated with the fragile X phenotypes Nas examined, Males with fragile X (n = 41) and age- and IQ-matched controls (n = 16) were rated by their mothers on the Dimensions of Temperament Scale-Revised, the Child Behavior Checklist, and the Aberrant Behavior Checklist-Community. The fragile X group showed deficits in motor skills, increased initial avoidance, decreased social withdrawal, deficits in attention, increased hyperactivity, and positive mood. They were distinguished from controls on all of these variables except hyperactivity and attention. When maternal characteristics were controlled for, the fragile X group showed a significantly higher level of generalized activity level than did controls. C1 Krieger Inst, Dept Psychiat, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NICHHD, Bethesda, MD USA. RP Kau, ASM (reprint author), Krieger Inst, Dept Psychiat, 1750 E Fairmont Ave,4th Floor, Baltimore, MD 21231 USA. FU NICHD NIH HHS [HD 33175-04] NR 37 TC 30 Z9 30 U1 1 U2 3 PU AMER ASSOC MENTAL RETARDATION PI WASHINGTON PA 444 N CAPITOL ST, NW, STE 846, WASHINGTON, DC 20001-1512 USA SN 0895-8017 J9 AM J MENT RETARD JI Am. J. Ment. Retard. PD JUL PY 2000 VL 105 IS 4 BP 286 EP 299 DI 10.1352/0895-8017(2000)105<0286:EBSOPP>2.0.CO;2 PG 14 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 336XR UT WOS:000088328700007 PM 10934570 ER PT J AU Sampson, ML Csako, G Remaley, AT AF Sampson, ML Csako, G Remaley, AT TI Dual HDL/total cholesterol test: a single-tube, homogeneous assay for sequential measurement of HDL cholesterol and total cholesterol SO ANNALS OF CLINICAL BIOCHEMISTRY LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE AB The quantitation of cholesterol in lipoprotein subfractions is valuable in estimating the risk for coronary artery disease, but requires multiple tests. We describe a relatively simple procedure, referred to as the dual HDL/total cholesterol (DHT) assay, which allows the sequential measurement of HDL cholesterol (HDL-C) and total cholesterol (total-C) in a single tube. HDL-C is first measured using a homogeneous assay that utilizes an anti-apolipoprotein B [apo(B)] antibody, which sterically blocks the enzymatic measurement of cholesterol on the non-HDL subfractions. Next, deoxycholate is added, which disrupts the antibody-apo(B) complex and allows the subsequent enzymatic measurement of the remaining cholesterol in the non-I-IDL subfractions. The DHT assay has an acceptable analytical performance and yields results similar to standard methods: for HDL-C, y(DHT)=0.98x+ 0.19, r=0.90; for total-C, y(DHT)= 1.11x-0.09, r=0.99. In summary, the DI-IT assay is a homogeneous assay for both HDL-C and total-C, and provides a simple and cost-effective method for screening for hyperlipidaemia. C1 NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. NR 12 TC 1 Z9 1 U1 0 U2 0 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0004-5632 J9 ANN CLIN BIOCHEM JI Ann. Clin. Biochem. PD JUL PY 2000 VL 37 BP 479 EP 487 DI 10.1258/0004563001899672 PN 4 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 330UM UT WOS:000087979600008 PM 10902864 ER PT J AU Devereux, RB Roman, MJ O'Grady, MJ Fabsitz, RR Rhoades, ER Crawford, A Howard, BV Lee, ET Welty, TK AF Devereux, RB Roman, MJ O'Grady, MJ Fabsitz, RR Rhoades, ER Crawford, A Howard, BV Lee, ET Welty, TK TI Differences in echocardiographic findings and systemic hemodynamics among non-diabetic American Indians in different regions: The Strong Heart Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE American Indians; echocardiography; left ventricle; aorta; cardiac output ID LEFT-VENTRICULAR MASS; PRESSURE-OVERLOAD HYPERTROPHY; AGED 45-74 YEARS; CARDIOVASCULAR-DISEASE; RISK-FACTORS; ARTERIAL-HYPERTENSION; SHORTENING RELATIONS; MORTALITY; CHILDREN; ADULTS AB PURPOSE: This study was undertaken to determine whether differences in left ventricular (LV) and systemic hemodynamic findings exist between American Indians in different regions that might contribute to known differences in cardiovascular morbidity rates among American Indians. METHODS: We compared echocardiography results in 290 non-diabetic Strong Heart Study (SHS) participants in Arizona, 595 in Oklahoma and 572 in North/South Dakota (ND/SD). RESULTS: Participants in the 3 regions were similar in age and gender but those in Arizona had the highest body mass indices and lowest heart rates while those in ND/SD had the lowest diastolic blood pressures (BP). In analyses that adjusted for significant covariates, ND/SD participants had larger aortic (Ao) anular, Ao root, and LV chamber size as well as higher cardiac output and lower peripheral resistance, whereas Arizona participants had increased LV wall thickness and mass and reduced LV myocardial contractility. These findings may contribute to the known high rates of cardiovascular events in ND/SD Indians and to the proportionately higher rate of cardiovascular death than of non-fatal cardiovascular events that has been recently documented in Arizona Indians. CONCLUSIONS: Application of echocardiography to non-diabetic SHS participants reveals that LV chamber and arterial size are larger in ND/SD Indians and that LV wall thicknesses and mass are higher and LV myocardial contractility lower in Arizona Indians, possibly contributing to the higher than expected rates of cardiovascular morbidity and mortality among Indians in Arizona. Ann Epidemiol 2000;10:324-332. Published by Elsevier Science Inc. C1 New York Presbyterian Hosp, Weill Cornell Med Ctr, Div Cardiol, New York, NY 10021 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Aberdeen Area Indian Hlth Serv, Rapid City, SD USA. NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. Medlant Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Weill Cornell Med Ctr, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. FU NHLBI NIH HHS [U01-HL41654, U01-HL41652, U01-HL41642] NR 37 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUL PY 2000 VL 10 IS 5 BP 324 EP 332 DI 10.1016/S1047-2797(00)00059-4 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 341ZM UT WOS:000088620900009 PM 10942881 ER PT J AU Taaffe, DR Villa, ML Holloway, L Marcus, R AF Taaffe, DR Villa, ML Holloway, L Marcus, R TI Bone mineral density in older non-Hispanic Caucasian and Mexican-American women: relationship to lean and fat mass SO ANNALS OF HUMAN BIOLOGY LA English DT Article ID GROWTH-HORMONE SECRETION; POSTMENOPAUSAL WOMEN; HIP FRACTURE; BODY-FAT; PHYSICAL-ACTIVITY; ELDERLY MEN; OSTEOPOROTIC FRACTURES; REPRODUCTIVE FACTORS; PREMENOPAUSAL WOMEN; CIGARETTE-SMOKING AB Primary objective: The prevalence of osteoporotic fracture is higher in non-Hispanic Caucasian (NI-IC) than Mexican-American (MA) women in the USA. The present study examined bone mineral density (BMD) in these two ethnic groups and the association between BMD and body composition. Research design: Cross-sectional, Subjects: Sixty-two NHC and 54 MA women, aged 60 86 years, with a body mass index (kg m(-2)) of < 30. Methods: BMD (g cm(-2)) of the spine (L2-4), hip (femoral neck, trochanter, Ward's triangle) and whole body was determined by dual-energy X-ray absorptiometry (DXA). Bone mineral-free lean mass (LM) and fat mass (FM) and several ratios of body fat distribution were also assessed by DXA. Results: There was no difference in age (NHC, 69.5 +/- 0.7; MA 69.5 +/- 0.9 years; mean +/- SEM) or body mass, but MA women were shorter with a higher truncal adiposity (p < 0.001). There was no significant difference in BMD between groups, however, adjusting for height resulted in higher hip and whole body BMD in MA women (p< 0.01). When volumetric bone density was calculated (bone mineral apparent density; BMAD, g cm(-3)), a trend for higher values in MA women was observed at the femoral neck (p = 0.018). LM contributed independently to BMD at the spine and hip in NHC women, with FM also contributing at the femoral neck. In MA women, LM was an independent contributor to lumbar spine and trochanter BMD, and both LM and FM contributed to whole body BMD, However, the effects of LM and FM were removed in both groups when BMD was adjusted for body or bone size, the only exception being at the trochanter in NHC women. Conclusions: These results indicate that MA women have higher bone density at the proximal femur than NHC women, which may partially account for their lower rate of hip fracture. Further, differences in bone density between the two ethnic groups do not appear to be dependent on soft-tissue composition. C1 Aging Study Unit, Palo Alto, CA USA. Stanford Univ, Stanford, CA 94305 USA. RP Taaffe, DR (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. NR 64 TC 30 Z9 30 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0301-4460 J9 ANN HUM BIOL JI Ann. Hum. Biol. PD JUL-AUG PY 2000 VL 27 IS 4 BP 331 EP 344 PG 14 WC Anthropology; Biology; Public, Environmental & Occupational Health SC Anthropology; Life Sciences & Biomedicine - Other Topics; Public, Environmental & Occupational Health GA 339NQ UT WOS:000088483900001 PM 10942342 ER PT J AU Hallett, M AF Hallett, M TI How does botulinum toxin work? SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID WRITERS CRAMP; INJECTION; STIMULATION; INHIBITION; DYSTONIA; MUSCLES; REFLEX C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 14 TC 37 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2000 VL 48 IS 1 BP 7 EP 8 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 330JP UT WOS:000087959200003 PM 10894209 ER PT J AU Goldstein, DS Tack, G Li, ST AF Goldstein, DS Tack, G Li, ST TI Sympathetic innervation and function in reflex sympathetic dystrophy SO ANNALS OF NEUROLOGY LA English DT Article ID NERVE GROWTH-FACTOR; HUMAN FOREARM; PLASMA DIHYDROXYPHENYLALANINE; UNAFFECTED LIMBS; NEUROPATHIC PAIN; NOREPINEPHRINE; RATS; 6-FLUORODOPAMINE; EXISTENCE; CATECHOLS AB Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining; the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of N-13-ammonia was used to assess local perfusion, and 6-[F-18]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. N-13-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[F-18]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[F-18]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydrophenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Univ Nijmegen Hosp, Div Gen Internal Med, NL-6500 HB Nijmegen, Netherlands. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 44 TC 36 Z9 36 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2000 VL 48 IS 1 BP 49 EP 59 DI 10.1002/1531-8249(200007)48:1<49::AID-ANA8>3.0.CO;2-T PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 330JP UT WOS:000087959200009 PM 10894215 ER PT J AU Pratley, RE Caviness, J AF Pratley, RE Caviness, J TI Weight loss in Huntington's disease - Reply SO ANNALS OF NEUROLOGY LA English DT Letter C1 NIDDKD, US Dept HHS, NIH, Phoenix, AZ 85016 USA. RP Pratley, RE (reprint author), NIDDKD, US Dept HHS, NIH, Phoenix, AZ 85016 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2000 VL 48 IS 1 BP 130 EP 131 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 330JP UT WOS:000087959200029 ER PT J AU Mankani, MH Dufresne, CR AF Mankani, MH Dufresne, CR TI Verrucous malformations: Their presentation and management SO ANNALS OF PLASTIC SURGERY LA English DT Article ID HEMANGIOMA AB Verrucous hemangiomas are a distinct subset of vascular malformations that have not been described extensively in the plastic surgery literature. They are characterized by reactive epidermal acanthosis, papillomatosis, hyperkeratosis, and extension into the subcutaneous tissues. In response to injury, infection. or subtotal resection, they enlarge and become increasingly keratotic. In light of contemporary definitions of hemangiomas and malformations, the authors recommended that these lesions be renamed verrucous malformations. The authors review their evaluation and treatment of 6 patients with this lesion and offer an algorithm that emphasizes excision over ablative therapy. Of the 6 patients, 3 patients had failed either cryotherapy or laser removal by a nonsurgeon, with a consequent increase in lesion size and discomfort. The lesions were all subsequently excised. Because of the size and location of the verrucous malformations, staged removal was required in 3 patients. Patients have been followed for as long as 7 years. A single recurrence was controlled with reexcision. Excision of verrucous malformations, rather than laser ablation or cryosurgery, is supported by the authors' favorable results. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20817 USA. Georgetown Univ, Div Plast Surg, Washington, DC USA. RP Mankani, MH (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, 9000 Rockville Pike,Bldg 30,Room 228, Bethesda, MD 20817 USA. NR 15 TC 14 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD JUL PY 2000 VL 45 IS 1 BP 31 EP 36 DI 10.1097/00000637-200045010-00006 PG 6 WC Surgery SC Surgery GA 333GW UT WOS:000088123400006 PM 10917095 ER PT J AU Jaretzki, A Barohn, RJ Ernstoff, RM Kaminski, HJ Keesey, JC Penn, AS Sanders, DB AF Jaretzki, A Barohn, RJ Ernstoff, RM Kaminski, HJ Keesey, JC Penn, AS Sanders, DB CA Task Force Med Sci Advisory Board TI Myasthenia gravis: Recommendations for clinical research standards (Reprinted from Neurology, vol 55, pg 16-23, 2000) SO ANNALS OF THORACIC SURGERY LA English DT Reprint ID LONG-TERM CORRELATION; THYMIC CARCINOMA; DOUBLE-BLIND; THYMECTOMY; THYMOMA; DISEASE; AZATHIOPRINE; SEVERITY; QUALITY; PATIENT C1 Columbia Presbyterian Med Ctr, Dept Surg, New York, NY 10032 USA. Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75235 USA. William Beaumont Hosp, Serv Neurol, Royal Oak, MI 48072 USA. Case Western Reserve Univ, Univ Hosp Cleveland, Dept Vet Affairs Med Ctr, Dept Neurol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Univ Hosp Cleveland, Dept Vet Affairs Med Ctr, Dept Neurosci, Cleveland, OH 44106 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. NINDS, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Jaretzki, A (reprint author), Myasthenia Gravis Fdn Amer Inc, 123 W Madison,Suite 800, Chicago, IL 60602 USA. NR 52 TC 160 Z9 167 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2000 VL 70 IS 1 BP 327 EP 334 DI 10.1016/S0003-4975(00)01595-2 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 336TB UT WOS:000088318100088 ER PT J AU Ascher, E Scheinman, M Hingorani, A Seth, P Marella, VK Jacob, T AF Ascher, E Scheinman, M Hingorani, A Seth, P Marella, VK Jacob, T TI Effect of p53 gene therapy combined with CTLA4Ig selective immunosuppression on prolonged neointima formation reduction in a rat model SO ANNALS OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Joint Annual Meeting of the Society-for-Vascular-Surgery, North-American-Chapter / International-Society-for-Cardiovascular-Surgery CY JUN 07-10, 1998 CL SAN DIEGO, CALIFORNIA SP Soc Vasc Surg, N Amer Chapter, Int Soc Cardiovasc Surg ID MUSCLE CELL-PROLIFERATION; DEPENDENT KINASE INHIBITOR; ARTERIAL INJURY; IN-VIVO; CAROTID ARTERIES; EXPRESSION; TRANSPLANTATION; VECTOR; APOPTOSIS; INDUCTION AB In a previous study, we have demonstrated a significant reduction of neointimal formation following adenovirus-mediated gene transfer of p53 to the injured rat carotid artery. The purpose of this study was to determine if the effect of p53 gene in reducing neointimal formation would still be present up to 8 weeks after arterial injury and whether it could be enhanced by adding immunosuppression. Cytotoxic T lymphocyte-associated antigen-4 Ig (CTLA4Ig), a novel immunosuppressive agent, is a recombinant soluble protein that blocks T cell-dependent immune response. Animals were divided into eight groups (n = 6 in each). In vivo gene transfer was used in isolated segments of balloon-injured rat carotid arteries. Genetically modified adenovirus encoding for wild-type p53 protein was applied at 8 x 10(10) pfu/ml. Control rats received adenovirus null at the same concentration. A daily dose of 300 mu g of CTLA4Ig was given intraperitoneally, either once, twice, or three times. Expression of p53 was determined by Western blot analysis. Neointimal formation was assessed at 4 or 8 weeks by harvesting carotid arteries and determining the intima/media (I/M) ratio cross-sectional area measurements. p53 expression was confirmed by Western blot analysis. We concluded that adenovirus-mediated p53 gene transfer significantly decreases the formation of neointima up to 8 weeks following rat carotid injury. However, there is loss of effectiveness on neointimal formation inhibition as time elapses. When CTLA4Ig is added, there is significant improvement in results, with sustained neointimal formation inhibition at 8 weeks after the procedure. DOI: 10.1007/s100169910077. C1 Maimonides Med Ctr, Div Vasc Surg, Brooklyn, NY 11219 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Ascher, E (reprint author), Maimonides Med Ctr, Div Vasc Surg, 4802 10th Ave, Brooklyn, NY 11219 USA. NR 26 TC 18 Z9 22 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0890-5096 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JUL PY 2000 VL 14 IS 4 BP 385 EP 392 DI 10.1007/s100169910077 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 333TA UT WOS:000088145800013 PM 10943792 ER PT J AU Sandor, V Robbins, AR Robey, R Myers, T Sausville, E Bates, SE Sackett, DL AF Sandor, V Robbins, AR Robey, R Myers, T Sausville, E Bates, SE Sackett, DL TI FR901228 causes mitotic arrest but does not alter microtubule polymerization SO ANTI-CANCER DRUGS LA English DT Article DE histone deacetylase inhibitors; microtubules; mitosis; prometaphase ID CHROMOBACTERIUM-VIOLACEUM NO-968; VERTEBRATE SOMATIC-CELLS; INSTITUTE DRUG SCREEN; BREAST-CANCER; DEPSIPEPTIDE; EXPRESSION; INHIBITORS; DISCOVERY; AGENTS; CYCLE AB FR901228, a natural cyclic depsipeptide, shows high cytotoxicity against human cancer cell lines (low nM IC50 values). Cells exposed to FR901228 arrest with G(1) or G(2)/M DNA content; S phase is depleted. G(2)/M cells include cells arrested in mitosis. We wished to understand the mitotic arrest by this compound. Mitotic arrest is often due to interference with microtubules and COMPARE testing in the NCI drug screen indicated a possible taxane-like mechanism, Testing of FR901228 for tubulin binding or alteration of in vitro MT assembly failed to reveal any effect. Likewise, examination of cellular microtubules following exposure to FR901228 did not reveal any change, Similar G(2)/M accumulation was observed in MCF7, MCF10 and PC3 cells. About 50% of G(2)/M cells were mitotic and contained microtubule spindles. Mitotic cells peaked at about 14-16 h drug exposure and declined to near 0% by 24-30 h. The block was at prometaphase, with numerous chromosomes unattached to the spindle. We conclude that FR901228 induces formation of aberrant spindles probably by Interfering with chromosome attachment, causing mitotic accumulation without affecting mitotic microtubules. C1 NCI, DTP Clin Trials Unit, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Sackett, DL (reprint author), NCI, DTP Clin Trials Unit, Dev Therapeut Program, NIH, Bldg 12A,Room 2041,12 S Dr,MSC 5626, Bethesda, MD 20892 USA. NR 24 TC 40 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD JUL PY 2000 VL 11 IS 6 BP 445 EP 454 DI 10.1097/00001813-200007000-00005 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 347AW UT WOS:000088904900005 PM 11001385 ER PT J AU Harris, SR Panaro, NJ Thorgeirsson, UP AF Harris, SR Panaro, NJ Thorgeirsson, UP TI Oxidative stress contributes to the anti-proliferative effects of flavone acetic acid on endothelial cells SO ANTICANCER RESEARCH LA English DT Article DE FAA; endothelium; proliferation; superoxide; apoptosis ID MITOCHONDRIAL ELECTRON-TRANSPORT; NECROSIS-FACTOR-ALPHA; TUMOR BLOOD-FLOW; NITRIC-OXIDE; FLAVONE-8-ACETIC ACID; PEROXYNITRITE; MICE AB The synthetic flavonoid flavone acetic acid (FAA) has anti-tumor activity against a variety of transplanted tumors in mice through mechanisms which likely involve effects on tumor vasculature and the host immune system. The aims of the present in vitro study were to compare the sensitivity of tumor and endothelial cells to FAA treatment and to assess if nitric oxide and superoxide are involved in the FAA-mediated suppression of cell proliferation. FAA at 1 mM concentration was approximately two times move effective in suppressing proliferation of endothelial than tumor cells. The antiproliferative effect of 1 mM FAA on endothelial cells was partially blocked by inhibitors to various superoxide-producing enzymes (xanthine oxidase, cyclooxygenase, poly-ADP-ribose polymerase, ribonucleotide reductase) and completely inhibited by the direct scavengers of superoxide lucigenin and Tiron. In contrast, inhibitors of nitric oxide were unable to prevent the effects of PAA on proliferation. FAA induced apoptosis of endothelial cells, which was not affected by inhibitors of nitric oxide or superoxide. Our data imply that FAA inhibits proliferation of endothelial cells by a superoxide-dependent mechanism and induces apoptosis by a nitric oxide and superoxide-independent mechanism. C1 NCI, Tumor Biol & Carcinogenesis Sect, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, UP (reprint author), NCI, Tumor Biol & Carcinogenesis Sect, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci,NIH, Bldg 37,Room 2A-19,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 11 Z9 11 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 2000 VL 20 IS 4 BP 2249 EP 2254 PG 6 WC Oncology SC Oncology GA 340WT UT WOS:000088559700001 PM 10953282 ER PT J AU D'Ambrosio, SM Gibson-D'Ambrosio, R Milo, GE Casto, B Kelloff, GJ Steele, VE AF D'Ambrosio, SM Gibson-D'Ambrosio, R Milo, GE Casto, B Kelloff, GJ Steele, VE TI Differential response of normal, premalignant and malignant human oral epithelial cells to growth inhibition by chemopreventive agents SO ANTICANCER RESEARCH LA English DT Article DE chemoprevention; oral cancer; retinoids; non-retinoids; growth inhibition ID ABERRANT CRYPT FOCI; CANCER CHEMOPREVENTION; RETINOIC ACID; ALPHA-DIFLUOROMETHYLORNITHINE; CARCINOMA-CELLS; APOPTOSIS; HEAD; NECK; PREVENTION; CONVERSION AB Squamous cell carcinoma (SCC) of the oral cavity is a multistep process, progressing through a series of discrete, irreversible and complementary alterations in genes that control cell growth, death, and differentiation. In the premalignant state, the oral mucosa progresses through various grades of epithelial dysplasia, with the potential to convert to SCC. Chemopreventive strategies are designed to suppress, reverse, or prevent the formation of premalignant lesions and their subsequent progression to SCC. In the present study, we determined the growth inhibitory effect of 21 chemopreventive agents in a cell culture model using normal, premalignant, and malignant human oral mucosal cell fines. There were significant differences in the growth inhibitory responses of these cell lines to selected retinoids and non-retinoid analogs. Among the retinoids tested, the synthetic retinamides, as a class, showed selective growth inhibition of both premalignant and malignant cells compared to normal human oral epithelial cells in culture. Within the retinamide class, 2CPR exhibited the greatest selectivity in the growth inhibition of premalignant and malignant cells. Among the non-retinoids analyzed, DFMO was a moderate to potent inhibitor of malignant and premalignant oral cell growth, respectively, and stimulated normal oral cell growth at low concentrations. Using this in vitro approach, we have identified several potential chemopreventive agents for oral cancer as selective growth inhibitors of premalignant and malignant human oral mucosa cells. C1 Ohio State Univ, Sch Med & Publ Hlth, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NCI, Rockville, MD 20852 USA. RP D'Ambrosio, SM (reprint author), Ohio State Univ, Sch Med & Publ Hlth, 400 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [N01-CN-85144]; NIDCR NIH HHS [1P01-DE12704] NR 41 TC 26 Z9 26 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 2000 VL 20 IS 4 BP 2273 EP 2280 PG 8 WC Oncology SC Oncology GA 340WT UT WOS:000088559700004 PM 10953285 ER PT J AU Holaday, SK Martin, BM Fletcher, PL Krishna, NR AF Holaday, SK Martin, BM Fletcher, PL Krishna, NR TI NMR solution structure of butantoxin SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE butantoxin; 2D-NMR; solution structure; potassium channels ID NUCLEAR-MAGNETIC-RESONANCE; 3-DIMENSIONAL SOLUTION STRUCTURE; SCORPION PANDINUS IMPERATOR; CHANNEL BLOCKING TOXIN; POTASSIUM CHANNEL; K+ CHANNELS; HIGH-AFFINITY; COUPLING-CONSTANTS; VENOM; SELECTIVITY AB The NMR structure of a new toxin, butantoxin (BuTX), which is present in the venoms of the three Brazilian scorpions Tityus serrulatus, Tityus bahiensis, and Tityus stigmurus, has been investigated. This toxin was shown to reversibly block the Shaker B potassium channels (K-d similar to 660 nM) and inhibit the proliferation of T-cells and the interleukin-2 production of antigen-stimulated T-helper cells. BuTX is a 40 amino acid basic protein stabilized by the four disulfide bridges: Cys2-Cys5, Cys10-Cys31, Cys16-Cys36, and Cys20-Cys38, The latter three are conserved among all members of the short-chain scorpion toxin family, while the first is unique to BuTX The three-dimensional structure of BuTX was determined using H-1-NMR spectroscopy. NOESY, phase sensitive COSY (PH-COSY), and amide hydrogen exchange data were used to generate constraints for molecular modeling calculations. Distance geometry and simulated annealing calculations were performed to generate a family of 49 structures free of constraint violations. The secondary structure of BuTX consists of a short 21/2 turn alpha-helix (Glu15-Phe23) and a beta-sheet. The beta-sheet is composed of two well-defined antiparallel strands (Gly29-Met32 and Lys35-Cys38) connected by a type-I' beta-turn (Asn33-Asn34), Residues Cys5-Ala9 form a quasi-third strand of the beta-sheet, The N-terminal C2-C5 disulfide bridge unique to this toxin does not appear to confer stability to the protein. (C) 2000 Academic Press. C1 Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. NIMH, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. E Carolina Univ, Sch Med, Dept Microbiol & Immunol, Greenville, NC 27858 USA. RP Krishna, NR (reprint author), Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. NR 50 TC 25 Z9 28 U1 1 U2 3 PU ACADEMIC PRESS INC 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 JUL 1 PY 2000 VL 379 IS 1 BP 18 EP 27 DI 10.1006/abbi.2000.1858 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 329WR UT WOS:000087931900003 PM 10864437 ER PT J AU Sommerfelt, K Andersson, HW Sonnander, K Ahlsten, G Ellertsen, B Markestad, T Jacobsen, G Hoffman, HJ Bakketeig, L AF Sommerfelt, K Andersson, HW Sonnander, K Ahlsten, G Ellertsen, B Markestad, T Jacobsen, G Hoffman, HJ Bakketeig, L TI Cognitive development of term small for gestational age children at five years of age SO ARCHIVES OF DISEASE IN CHILDHOOD LA English DT Article DE small for gestational age; socioeconomic status; preschool; cognitive ID LOW-BIRTH-WEIGHT; INTRAUTERINE GROWTH; RISK-FACTORS; SOCIAL RISK; INFANTS; LIFE; INTELLIGENCE; ABILITIES; BEHAVIOR; BABIES AB Aim-To assess the relative significance for cognitive development of small for gestational age, parental demographic factors, and factors related to the child rearing environment. Methods-IQ of a population based cohort of 338 term infants who were small for gestational age (SGA) and without major handicap, and a random control sample of 335 appropriate for gestational age (AGA) infants were compared at 5 years of age. Results-The mean non-verbal IQ was four points lower, while the mean verbal IQ was three points lower for the children in the SGA group. The results were not confounded by parental demographic or child rearing factors. However, parental factors, including maternal non-verbal problem solving abilities, and child rearing style, accounted for 20% of the variance in non-verbal IQ, while SGA versus AGA status accounted for only 2%. The comparable numbers for verbal IQ were 30 and 1%. Furthermore, we found no evidence that the cognitive development of SGA children was more sensitive to a non-optimal child rearing environment than that of AGA children. Maternal smoking at conception was associated with a reduction in mean IQ comparable to that found for SGA status, and this effect was the same for SGA and AGA children. The cognitive function of asymmetric SGA was comparable to that of symmetric SGA children. Conclusions-Our findings indicate that child cognitive development is strongly associated with parental factors, but only marginally associated with intrauterine growth retardation. C1 Univ Bergen, Haukeland Sykehus, Barnekliniken, Dept Pediat, N-5021 Bergen, Norway. Univ Bergen, Dept Biol & Med Psychol, N-5020 Bergen, Norway. Univ Trondheim, Dept Psychol, N-7034 Trondheim, Norway. Univ Trondheim, Dept Community Med & Gen Practice, N-7034 Trondheim, Norway. Univ Uppsala, Dept Neurosci & Psychiat, S-75105 Uppsala, Sweden. Univ Uppsala, Dept Pediat, S-75105 Uppsala, Sweden. NIDCD, NIH, Stat & Data Syst Branch, Bethesda, MD USA. RP Sommerfelt, K (reprint author), Univ Bergen, Haukeland Sykehus, Barnekliniken, Dept Pediat, N-5021 Bergen, Norway. FU NICHD NIH HHS [N01-HD-1-3127] NR 45 TC 59 Z9 63 U1 2 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-9888 J9 ARCH DIS CHILD JI Arch. Dis. Child. PD JUL PY 2000 VL 83 IS 1 BP 25 EP 30 DI 10.1136/adc.83.1.25 PG 6 WC Pediatrics SC Pediatrics GA 332HC UT WOS:000088067400006 PM 10868995 ER PT J AU Stock, RP Olvera, A Scarfi, S Sanchez, R Ramos, MA Boffa, LC Benatti, U Landt, O Alagon, A AF Stock, RP Olvera, A Scarfi, S Sanchez, R Ramos, MA Boffa, LC Benatti, U Landt, O Alagon, A TI Inhibition of neomycin phosphorotransferase expression in Entamoeba histolytica with antisense peptide nucleic acid (PNA) oligomers SO ARCHIVES OF MEDICAL RESEARCH LA English DT Article; Proceedings Paper CT 14th Seminar on Amebiasis CY NOV 27-30, 2000 CL Mexico City, MEXICO SP IPN, Ctr Invest & Estudios Avanzados, Consejo Nacl Ciencia & Technol, Colegio Nacl, Inst Mexicano Seguro Social, Secretaria Salud, Univ Nacl Autonoma Mexico DE Entamoeba histolytica; PNA; antisense; neomycin C1 Univ Nacl Autonoma Mexico, Inst Biotechnol, Cuernavaca 62210, Morelos, Mexico. Univ Genoa, Ist Policattedra Chim Biol, Genoa, Italy. Natl Canc Inst, Genoa, Italy. TIB MOLBIOL, Berlin, Germany. RP Alagon, A (reprint author), Univ Nacl Autonoma Mexico, Inst Biotechnol, Av Univ 2001, Cuernavaca 62210, Morelos, Mexico. EM alagon@ibt.unam.mx RI Ramos, Marco/D-5438-2012 OI Ramos, Marco/0000-0002-8950-2079 NR 5 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0188-4409 J9 ARCH MED RES JI Arch. Med. Res. PD JUL-AUG PY 2000 VL 31 IS 4 SU S BP S271 EP S272 DI 10.1016/S0188-4409(00)00114-4 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 371RU UT WOS:000165192600113 PM 11070312 ER PT J AU Wong, ML Sternberg, EM AF Wong, ML Sternberg, EM TI Immunological assays for understanding neuroimmune interactions SO ARCHIVES OF NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BRAIN-BARRIER; INTERLEUKIN-1; PITUITARY; CELLS AB The human nervous system, particularly the central nervous system (CNS), enjoys a status of immune privilege owing to the restricted access of cells and molecules originating from the immune system. This protection from immune damage is particularly important for preservation of the CNS, since mature brain cells are terminally differentiated and are not normally replaced after death. There is now new evidence for the presence of stem cells in the brain that may be the source for neuronal cells in adulthood. This phenomenon appears to be very limited and does not compensate for the neuronal loss that occurs during pathological processes.' Thus, the brain, unlike other organs that are composed of cell types that have the capacity to divide, is particularly vulnerable to immune-mediated damage. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Wong, ML (reprint author), Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Gonda Goldschmeid Neurosci Genet Res Ctr, 3357B,695 Charles E Young Dr S,Box 951761, Los Angeles, CA 90095 USA. RI Wong, Ma-Li/D-7903-2011 NR 8 TC 8 Z9 9 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JUL PY 2000 VL 57 IS 7 BP 948 EP 952 DI 10.1001/archneur.57.7.948 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 333TB UT WOS:000088145900006 PM 10891976 ER PT J AU Griffith, AJ Gebarski, SS Shepard, NT Kileny, PR AF Griffith, AJ Gebarski, SS Shepard, NT Kileny, PR TI Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article; Proceedings Paper CT 22nd Midwinter Meeting of the Association-for-Research-in-Otolaryngology CY FEB 13-18, 1999 CL ST PETERSBURG, FLORIDA SP Assoc Res Otolaryngol ID HEARING-LOSS; GENE; COLLAGEN; LOCUS; STICKLER; DEFECT; FAMILY; MICE AB Background: Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1. Objective: To determine the auditory and vestibular phenotypes associated with a COL11A1 splicing. Design: Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems. Subjects: Three affected individuals from a family cosegregating Marshall syndrome and a COL11A1 splice site mutation. Results: The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems. Computed tomography detected no malformations of temporal bone structures. Conclusions: The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system. The onset and degree of hearing loss associated with COL11A1 mutations are useful clinical features to differentiate Marshall syndrome from the phenotypically similar Stickler syndrome. C1 Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Griffith, AJ (reprint author), NIDCD, Neurootol Branch, NIH, 5 Res Ct,Room 2A-02, Rockville, MD 20850 USA. FU NCRR NIH HHS [M01-RR00042] NR 22 TC 11 Z9 11 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD JUL PY 2000 VL 126 IS 7 BP 891 EP 894 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 332ZV UT WOS:000088105000011 PM 10889003 ER PT J AU Compton, CC Fielding, LP Burgart, LJ Conley, B Cooper, HS Hamilton, SR Hammond, MEH Henson, DE Hutter, RVP Nagle, RB Nielsen, ML Sargent, DJ Taylor, CR Welton, M Willett, C AF Compton, CC Fielding, LP Burgart, LJ Conley, B Cooper, HS Hamilton, SR Hammond, MEH Henson, DE Hutter, RVP Nagle, RB Nielsen, ML Sargent, DJ Taylor, CR Welton, M Willett, C TI Prognostic factors in colorectal cancer - College of American Pathologists Consensus Statement 1999 SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT XXXVth Conference of the College-of-American-Pathologists CY JUN 10-13, 1999 CL CHICAGO, ILLINOIS SP Coll Amer Pathologists ID CELL NUCLEAR ANTIGEN; NUCLEOLAR ORGANIZER REGIONS; LYMPH-NODE METASTASIS; NEGATIVE COLON-CANCER; K-RAS MUTATION; LONG-TERM PROGNOSIS; DNA FLOW-CYTOMETRY; LARGE BOWEL-CANCER; RECTAL-CANCER; MULTIVARIATE-ANALYSIS AB Background.-Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and Methods,-The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and Conclusions-Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). Factors in category IIB included the following: histologic type, histologic features associated with microsatellite instability (MSI) (ie, host lymphoid response to tumor and medullary or mucinous histologic type), high degree of MSI (MSI-H), loss of heterozygosity at 18q (DCC gene allelic loss), and tumor border configuration (infiltrating vs pushing border). Factors grouped in category III included the following: DNA content, all other molecular markers except loss of heterozygosity 18q/DCC and MSI-H, perineural invasion, microvessel density, tumor cell-associated proteins or carbohydrates, peritumoral fibrosis, peritumoral inflammatory response, focal neuroendocrine differentiation, nuclear organizing regions, and proliferation indices. Category IV factors included tumor size and gross tumor configuration. This report records findings and recommendations of the consensus conference group, organized according to structural guidelines defined herein. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. York Hosp, York, PA USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. St Barnabas Med Ctr, Livingston, NJ USA. Univ Arizona, Tucson, AZ USA. Kansas Pathol Consultants, Wichita, KS USA. Univ So Calif, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Compton, CC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg,Room 256,55 Fruit St, Boston, MA 02114 USA. OI Sargent, Daniel/0000-0002-2684-4741 NR 213 TC 640 Z9 676 U1 0 U2 22 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUL PY 2000 VL 124 IS 7 BP 979 EP 994 PG 16 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900008 PM 10888773 ER PT J AU Bostwick, DG Grignon, DJ Hammond, MEH Amin, MB Cohen, M Crawford, D Gospadarowicz, M Kaplan, RS Miller, DS Montironi, R Pajak, TF Pollack, A Srigley, JR Yarbro, JW AF Bostwick, DG Grignon, DJ Hammond, MEH Amin, MB Cohen, M Crawford, D Gospadarowicz, M Kaplan, RS Miller, DS Montironi, R Pajak, TF Pollack, A Srigley, JR Yarbro, JW TI Prognostic factors in prostate cancer - College of American Pathologists Consensus Statement 1999 SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT XXXVth Conference of the College-of-American-Pathologists CY JUN 10-13, 1999 CL CHICAGO, ILLINOIS SP Coll Amer Pathologists ID SEMINAL-VESICLE INVOLVEMENT; POSITIVE SURGICAL MARGINS; EXTERNAL-BEAM RADIOTHERAPY; NEEDLE-BIOPSY SPECIMENS; RADICAL PROSTATECTOMY; PERINEURAL INVASION; CLINICAL STAGE; NEUROENDOCRINE DIFFERENTIATION; GLEASON SCORE; NUCLEAR ROUNDNESS AB Background.-Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in prostate cancer and stratified them into categories reflecting the strength of published evidence and taking into account the expert opinions of the Prostate Working Group members. Materials and Methods.-Factors were ranked according to the previous College of American Pathologists categorical rankings: category I, factors proven to be of prognostic importance and useful in clinical patient management; category II, factors that have been extensively studied biologically and clinically but whose importance remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected pertaining to existing prognostic factors, and (3) improving patient care. Results and Conclusions.-Factors ranked in category I included preoperative serum prostate-specific antigen level, TNM stage grouping, histologic grade as Gleason score, and surgical margin status. Category II factors included tumor volume, histologic type, and DNA ploidy. Factors in category III included perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc). C1 Bostwick Labs, Richmond, VA USA. Wayne State Univ, Detroit, MI USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Emory Univ, Atlanta, GA 30322 USA. Univ Iowa, Iowa City, IA USA. Univ Colorado, Denver, CO 80202 USA. Univ Toronto, Toronto, ON, Canada. NCI, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Ancona, Ancona, Italy. Amer Coll Radiol, Philadelphia, PA USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. McMaster Univ, Hamilton, ON, Canada. Amer Joint Comm Canc, Chicago, IL USA. RP Bostwick, DG (reprint author), Care of Schramm J, Coll Amer Pathologists, 325 Waukegan Rd, Northfield, IL 60093 USA. NR 102 TC 203 Z9 210 U1 0 U2 4 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUL PY 2000 VL 124 IS 7 BP 995 EP 1000 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900009 PM 10888774 ER PT J AU Pajak, TF Clark, GM Sargent, DJ McShane, LM Hammond, MEH AF Pajak, TF Clark, GM Sargent, DJ McShane, LM Hammond, MEH TI Statistical issues in tumor marker studies SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT XXXVth Conference of the College-of-American-Pathologists CY JUN 10-13, 1999 CL CHICAGO, ILLINOIS SP Coll Amer Pathologists ID PROGNOSIS; CANCER AB Context.- Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. Objective.-To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. Results.-Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. Conclusion.-Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources. C1 Amer Coll Radiol, Philadelphia, PA 19107 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. RP Pajak, TF (reprint author), Amer Coll Radiol, 1101 Market St, Philadelphia, PA 19107 USA. OI Sargent, Daniel/0000-0002-2684-4741 NR 8 TC 26 Z9 27 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUL PY 2000 VL 124 IS 7 BP 1011 EP 1015 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900012 PM 10888777 ER PT J AU Winer, KK Merke, DP AF Winer, KK Merke, DP TI Picture of the month - Autoimmune polyglandular syndrome type 1 SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID SYNDROME TYPE-I; DISEASE TYPE-I C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Winer, KK (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2000 VL 154 IS 7 BP 745 EP 746 PG 2 WC Pediatrics SC Pediatrics GA 332LE UT WOS:000088075100017 PM 10891030 ER PT J AU Mudd, SH Finkelstein, JD Refsum, H Ueland, PM Malinow, MR Lentz, SR Jacobsen, DW Brattstrom, L Wilcken, B Wilcken, DEL Blom, HJ Stabler, SP Allen, RH Selhub, J Rosenberg, IH AF Mudd, SH Finkelstein, JD Refsum, H Ueland, PM Malinow, MR Lentz, SR Jacobsen, DW Brattstrom, L Wilcken, B Wilcken, DEL Blom, HJ Stabler, SP Allen, RH Selhub, J Rosenberg, IH TI Homocysteine and its disulfide derivatives - A suggested consensus terminology SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE homocysteine; homocystine; disulfide; hyperhomocysteinemia; tHcy ID CARDIOVASCULAR-DISEASE; PLASMA HOMOCYSTEINE; RISK FACTOR C1 NIMH, DIRP, LMB, Bethesda, MD 20892 USA. Vet Adm Med Ctr, Washington, DC 20422 USA. George Washington Univ, Washington, DC USA. Univ Bergen, LOCUS Homocystein & Related Vitamins, Bergen, Norway. Oregon Reg Primate Res Ctr, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Cleveland Clin Fdn, Lerner Res Inst, Cleveland, OH 44195 USA. Cty Hosp, Dept Med, Kalmar, Sweden. New Childrens Hosp, Sydney, NSW, Australia. Univ New S Wales, Prince Wales Hosp, Dept Cardiovasc Med, Sydney, NSW, Australia. Univ Nijmegen Hosp, Dept Pediat, NL-6500 HB Nijmegen, Netherlands. Univ Colorado, Hlth Sci Ctr, Div Hematol, Denver, CO USA. Tufts Univ, USDA, Human Nutr Res Ctr, Boston, MA 02111 USA. RP Mudd, SH (reprint author), NIMH, DIRP, LMB, Bldg 36,Room 1B-08,36 Convent Dr MSC 4034, Bethesda, MD 20892 USA. RI Ueland, Per/C-7340-2013; Refsum, Helga/A-4073-2010 NR 18 TC 142 Z9 154 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2000 VL 20 IS 7 BP 1704 EP 1706 PG 3 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 334DC UT WOS:000088169600004 PM 10894806 ER PT J AU Potter, K Butler, JJ Horton, WE Spencer, RGS AF Potter, K Butler, JJ Horton, WE Spencer, RGS TI Response of engineered cartilage tissue to biochemical agents as studied by proton magnetic resonance microscopy SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CANINE ARTICULAR-CARTILAGE; ANTERIOR CRUCIATE LIGAMENT; SELF-DIFFUSION; CHONDROCYTES; MATRIX; WATER; ACID; NMR; OSTEOARTHRITIS; INTERLEUKIN-1 AB Objective, To test the hypothesis that magnetic resonance imaging (MRI) results correlate with the biochemical composition of cartilage matrix and can therefore be used to evaluate natural tissue development and the effects of biologic interventions. Methods. Chondrocytes harvested from day-16 chick embryo sterna were inoculated into an MRI-compatible hollow-fiber bioreactor, The tissue that formed over a period of 2-4 weeks was studied biochemically, histologically, and with MRI. Besides natural development, the response of the tissue to administration of retinoic acid, interleukin-1 beta (IL-1 beta), and daily dosing with ascorbic acid was studied. Results. Tissue wet and dry weight, glycosaminoglycan (GAG) content, and collagen content all increased with development time, while tissue hydration decreased. The administration of retinoic acid resulted in a significant reduction in tissue wet weight, proteoglycan content, and cell number and an increase in hydration as compared with controls. Daily dosing with ascorbic acid increased tissue collagen content significantly compared with controls, while the administration of IL-1 beta resulted in increased proteoglycan content. The water proton longitudinal and transverse relaxation rates correlated well with GAG and collagen concentrations of the matrix as well as with tissue hydration. In contrast, the magnetization transfer value for the tissue correlated only with total collagen, Finally, the self-coefficient of water correlated with tissue diffusion hydration. Conclusion. Parameters derived from MR images obtained noninvasively can be used to quantitatively assess the composition of cartilage tissue generated in a bioreactor. We conclude that MRI is a promising modality for the assessment of certain biochemical properties of cartilage in a wide variety of settings. C1 NIA, Gerontol Res Ctr, Nucl Magnet Resonance Unit, Intramural Res Program,NIH, Baltimore, MD 21224 USA. NICHHD, NIH, Bethesda, MD 20892 USA. NE Ohio Univ, Coll Med, Rootstown, OH 44272 USA. RP Spencer, RGS (reprint author), NIA, Gerontol Res Ctr, Nucl Magnet Resonance Unit, Intramural Res Program,NIH, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 65 Z9 68 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUL PY 2000 VL 43 IS 7 BP 1580 EP 1590 DI 10.1002/1529-0131(200007)43:7<1580::AID-ANR23>3.3.CO;2-7 PG 11 WC Rheumatology SC Rheumatology GA 332LX UT WOS:000088076700023 PM 10902763 ER PT J AU Jones, LN Watts, NR Booy, FP Steven, AC Parry, DAD AF Jones, LN Watts, NR Booy, FP Steven, AC Parry, DAD TI Intermediate filament structure: Hard alpha-keratin SO ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES LA English DT Article; Proceedings Paper CT 9th Congress of the Asian-Australasian-Association-of-Animal-Production-Societies/23rd Biennial Conference of the Australian-Society-of-Animal-Production CY JUL 03-07, 2000 CL UNIV NEW S WALES, SYDNEY, AUSTRALIA SP Asian Australasian Assoc Anim Prod Soc, Australian Soc Anim Prod HO UNIV NEW S WALES C1 CSIRO, Text & Fibre Technol, Geelong, Vic 3216, Australia. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. Massey Univ, Dept Phys, Palmerston North, New Zealand. RP Jones, LN (reprint author), CSIRO, Text & Fibre Technol, POB 21, Geelong, Vic 3216, Australia. NR 5 TC 1 Z9 1 U1 1 U2 2 PU ASIAN-AUSTRALASIAN ASSOC ANIMAL PRODUCTION SOCIETIES PI SUWON PA COLLEGE AGRICULTURE LIFE SCIENCES, DEPT ANIMAL SCIENCE TECHNOLOGY, SUWON 441-744, SOUTH KOREA SN 1011-2367 J9 ASIAN AUSTRAL J ANIM JI Asian Australas. J. Anim. Sci. PD JUL PY 2000 VL 13 SU S BP 120 EP 120 PG 1 WC Agriculture, Dairy & Animal Science SC Agriculture GA 397JF UT WOS:000166692000054 ER PT J AU Thomas, TL Hooper, TI Camarca, M Murray, J Sack, D Mole, D Spiro, RT Horn, WG Garland, FC AF Thomas, TL Hooper, TI Camarca, M Murray, J Sack, D Mole, D Spiro, RT Horn, WG Garland, FC TI A method for monitoring the Health of US Navy submarine crewmembers during periods of isolation SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Article DE submariners; health; epidemiology; surveillance ID MORTALITY AB Background: With the expansion of the manned space program, an essential consideration in planning is the medical support necessary for long-term missions, information on analogous populations serving in isolated and/or contained environments may be useful in predicting health risks for astronauts. Methods: The present study evaluates rates of health events that occur in a highly screened, healthy military population during periods of isolation. A centralized database was designed to collect medical encounter data from U.S. Navy submarines and contains demographic information, crew rosters for each patrol, medical encounter notes, accident reports, medical evacuation reports, vital signs and laboratory data. The population included in the present analysis is composed of crewmembers aboard 136 submarine patrols between January 1, 1997 and December 31, 1998. Results: A total of 2044 initial visits to medical staff and 973 re-visits for the same condition were recorded during these patrols. Potentially mission-impacting medical events reported among crewmembers were rare (i.e., among a crew of 10 individuals, only 1-2 medical Events would be expected to occur during a 100 d-mission). The most common category of medical events was injury, followed by respiratory illnesses (URIs), skin problems (minor infections, ingrown toenail), symptoms and ill-defined conditions, digestive disorders, infectious conditions, sensory organ problems (ear and eye), and musculoskeletal conditions. C1 Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Div Epidemiol & Biostat, Bethesda, MD 20814 USA. USN, Bur Med & Surg, Washington, DC USA. USN, Ctr Environm Hlth, Norfolk, VA USA. COMSUBLANT, Force Med, Norfolk, VA USA. COMSUBPAC, Force Med, Pearl River, NY USA. USN, Submarine Med Res Lab, Groton, CT USA. Naval Hlth Res Ctr, San Diego, CA USA. RP Thomas, TL (reprint author), NCI, Radiat Epidemiol Branch, NIH, EPS-7100,6120 Execut Blvd, Rockville, MD 20852 USA. NR 12 TC 9 Z9 10 U1 1 U2 5 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD JUL PY 2000 VL 71 IS 7 BP 699 EP 705 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA 329RE UT WOS:000087921000006 PM 10902933 ER PT J AU Chappell, LL Deal, KA Dadachova, E Brechbiel, MW AF Chappell, LL Deal, KA Dadachova, E Brechbiel, MW TI Synthesis, conjugation, and radiolabeling of a novel bifunctional chelating agent for Ac-225 radioimmunotherapy applications SO BIOCONJUGATE CHEMISTRY LA English DT Article ID MONOCLONAL-ANTIBODIES; PHARMACOKINETICS; LYMPHOMA; THERAPY; ACID; IMMUNOREACTIVITY; RADIONUCLIDES; DERIVATIVES; CHEMISTRY; COMPLEXES AB Ac-225 (t(1/2) = 10 days) is an alternative alpha-emitter that has been proposed for radioimmunotherapy (RIT) due to its many favorable properties, such as half-life and mode of decay. The factor limiting use of Ac-225 in RIT is the lack of an acceptably stable chelate for in vivo applications. Herein is described the first reported bifunctional chelate for (225)AC that has been evaluated for stability for in vivo applications. The detailed synthesis of a bifunctional chelating agent 2-(4-isothiocyanatobenzyl)-1,4,7,10,13,16- hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid (HEHA-NCS) is reported. This ligand was conjugated to three monoclonal antibodies, CC49, T101, and BL-3 with chelate-to-protein ratios between 1.4 and 2. The three conjugates were radiolabeled with Ac-225, and serum stability study of the [(225)AC]-BL-3-HEHA conjugate was performed. C1 NCI, Radioimmune & Inorgan Chem Sect, DCS, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, DCS, NIH, Bethesda, MD 20892 USA. RI Dadachova, Ekaterina/I-7838-2013 NR 43 TC 29 Z9 30 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUL-AUG PY 2000 VL 11 IS 4 BP 510 EP 519 DI 10.1021/bc990153f PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 337RZ UT WOS:000088376600010 PM 10898572 ER PT J AU Wheelan, SJ Marchler-Bauer, A Bryant, SH AF Wheelan, SJ Marchler-Bauer, A Bryant, SH TI Domain size distributions can predict domain boundaries SO BIOINFORMATICS LA English DT Article ID PROTEIN; DATABASE; IDENTIFICATION AB Motivation: The sizes of protein domains observed in the 3D-structure database follow a surprisingly narrow distribution. Structural domains are furthermore formed from a single-chain continuous segment in over 80% of instances. These observations imply that some choices of domain boundaries on an otherwise uncharacterized sequence are more likely than others, based solely on the size and segment number of predicted domains. This property might be used to guess the locations of protein domain boundaries. Results: To test this possibility we enumerate putative domain boundaries and calculate their relative likelihood under a probability model that considers only the size and segment number of predicted domains. We ask in a cross-validated test using sequences with known 3D structure, whether the most likely guesses agree with the observed domain structure. We find that domain boundary predictions are surprisingly successful for sequences up to 400 residues long and that guessing domain boundaries in this way can improve the sensitivity of threading analysis. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Bryant, SH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Marchler-Bauer, Aron/A-9681-2009; OI Marchler-Bauer, Aron/0000-0003-1516-0712 NR 19 TC 115 Z9 118 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL PY 2000 VL 16 IS 7 BP 613 EP 618 DI 10.1093/bioinformatics/16.7.613 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 368DF UT WOS:000090101900005 PM 11038331 ER PT J AU Lee, BM Kim, HS Jeohn, GH AF Lee, BM Kim, HS Jeohn, GH TI Inducible nitric oxide synthase mRNA is upregulated in skin tumors of v-Ha-ras transgenic TG-AC mice treated with 12-o-tetradecanoylphorbol-13-acetate SO BIOLOGICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE TPA; inducible nitric oxide synthase; transgenic mice ID L-ARGININE; EXPRESSION; MELANOMA; CANCER; PROLIFERATION; MACROPHAGES; ACTIVATION; METABOLISM; PROMOTION; GROWTH AB The correlation between the steady-state level of inducible nitric oxide synthase (iNOS) mRNA and skin tumors induced following treatment with 12-o-tetradecanoylpharbol-13-acetate (TPA) was investigated in transgenic TG-AC mice, which carry the v-aa-ras oncogene fused to the promoter of the mouse embryonic alpha-like, zeta-globin gene. In animals treated with TPA (2.5 mu g x 2/week, for 2 weeks), the increase of iNOS mRNA was locally confined only to the regions of papillomas, but not to the skin tissues surrounding the papillomas, However, the tissues surrounding the papillomas showed only a minor increase in the steady-state level of iNOS mRNA, These data suggest that iNOS gene expressions may underlie tumorigenesis during TPA promotion in TC-AC mice. C1 Sungkyunkwan Univ, Coll Pharm, Div Toxicol, Suwon 440746, Kyunggi Do, South Korea. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Lee, BM (reprint author), Sungkyunkwan Univ, Coll Pharm, Div Toxicol, Chunchun Dong 300, Suwon 440746, Kyunggi Do, South Korea. EM bmlee@skku.ac.kr NR 29 TC 2 Z9 3 U1 0 U2 0 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0918-6158 J9 BIOL PHARM BULL JI Biol. Pharm. Bull. PD JUL PY 2000 VL 23 IS 7 BP 826 EP 829 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 331XF UT WOS:000088043400007 PM 10919360 ER PT J AU Hagiwara, K McMenamin, MG AF Hagiwara, K McMenamin, MG TI Wrapper arms strategy to construct multicomponent plasmids using three-piece ligation SO BIOTECHNIQUES LA English DT Article ID GENES C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP McMenamin, MG (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 2C22,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2000 VL 29 IS 1 BP 34 EP + PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 333QP UT WOS:000088141000004 PM 10907071 ER PT J AU Spring, KR AF Spring, KR TI Scientific imaging with digital cameras SO BIOTECHNIQUES LA English DT Article AB The new BioImaging column of BioTechniques will feature short articles devoted to microscopy and digital imaging. The subject matter will address details of the methods used to produce images of cells and tissues at any magnification and resolution, and might include "tricks-of-the-trade", novel methods of specimen preparation, practices of image collection, tips on the digital manipulation and publication of images and historical perspectives. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Spring, KR (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 14 Z9 15 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2000 VL 29 IS 1 BP 70 EP + PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 333QP UT WOS:000088141000012 PM 10907079 ER PT J AU Kim, HJ Tisdale, JF Wu, T Takatoku, M Sellers, SE Zickler, P Metzger, ME Agricola, BA Malley, JD Kato, I Donahue, RE Brown, KE Dunbar, CE AF Kim, HJ Tisdale, JF Wu, T Takatoku, M Sellers, SE Zickler, P Metzger, ME Agricola, BA Malley, JD Kato, I Donahue, RE Brown, KE Dunbar, CE TI Many multipotential gene-marked progenitor or stem cell clones contribute to hematopoiesis in nonhuman primates SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; IMMUNE-DEFICIENT MICE; BLOOD CD34(+) CELLS; PERIPHERAL-BLOOD; IN-VIVO; RETROVIRAL VECTORS; W/WV MICE; MOUSE; TRANSDUCTION; ENGRAFTMENT AB Retroviral Insertion site analysis was used to track the contribution of retrovirally transduced primitive progenitors to hematopoiesis after autologous transplantation in the rhesus macaque model. CD34-enriched mobilized peripheral blood cells were transduced with retroviral marking vectors containing the neo gene and were reinfused after total body irradiation. High-level gene transfer efficiency allowed insertion site analysis of individual myeloid and erythroid colony-forming units (CFU) and of highly purified B- and T-lymphoid populations in 2 animals. At multiple time points up to 1 year after transplantation, retroviral insertion sites were identified by performing inverse polymerase chain reaction and sequencing vector-containing CFU or more than 99% pure T- and B-cell populations. Forty-eight unique insertion sequences were detected in the first animal and also in the second animal, and multiple clones contributed to hematopoiesis at 2 or more time points. Multipotential clones contributing to myeloid and lymphoid lineages were identified. These results support the concept that hematopoiesis in large animals is polyclonal and that individual multipotential stem or progenitor cells can contribute to hematopoiesis for prolonged periods. Gene transfer to long-lived, multipotent clones is shown and is encouraging for human gene therapy applications. (Blood. 2000; 96:1-8) (C) 2000 by The American Society of Hematology. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Biotechnol Res Labs, Shiga, Japan. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 44 TC 85 Z9 86 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 JUL 1 PY 2000 VL 96 IS 1 BP 1 EP 8 PG 8 WC Hematology SC Hematology GA 327UX UT WOS:000087813200001 PM 10891424 ER PT J AU Salcedo, R Ponce, ML Young, HA Wasserman, K Ward, JM Kleinman, HK Oppenheim, JJ Murphy, WJ AF Salcedo, R Ponce, ML Young, HA Wasserman, K Ward, JM Kleinman, HK Oppenheim, JJ Murphy, WJ TI Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression SO BLOOD LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; X-C CHEMOKINE; CHEMOTACTIC PROTEIN-1; CXC CHEMOKINES; ACTIVATING FACTOR; T-LYMPHOCYTES; GRO-ALPHA; IN-VIVO; JE GENE; RECRUITMENT AB Although several CXC chemokines have been shown to induce angiogenesis and play roles in tumor growth, to date, no member of the CC chemokine family has been reported to play a direct role in angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotaxis of human endothelial cells at nanomolar concentrations. This chemotactic response was inhibited by a monoclonal antibody to MCP-1, MCP-1 also induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and the matrigel plug assays. As expected, the angiogenic response induced by MCP-1 was accompanied by an inflammatory response. With the use of a rat aortic sprouting assay in the absence of leukocytic infiltrates, we ruled out the possibility that the angiogenic effect of MCP-1 depended on leukocyte products. Moreover, the direct effect of MCP-1 on angiogenesis was consistent with the expression of CCR2, the receptor for MCP-1, on endothelial cells. Assessment of supernatant from a human breast carcinoma cell line demonstrated the production of MCP-1. Treatment of immunodeficient mice bearing human breast carcinoma cells with a neutralizing antibody to MCP-1 resulted in significant increases in survival and inhibition of the growth of lung micrometastases. Taken together, our data indicate that MCP-1 can act as a direct mediator of angiogenesis, As a chemokine that is abundantly produced by some tumors, it can also directly contribute to tumor progression. Therefore, therapy employing antagonists of MCP-1 in combination with other inhibitors of angiogenesis may achieve more comprehensive inhibition of tumor growth. (Blood. 2000;96:34-40) (C) 2000 by The American Society of Hematology. C1 Frederick Canc Res & Dev Ctr, Div Basic Sci, Expt Immunol Lab, Mol Immunoregulat Lab, Frederick, MD USA. Frederick Canc Res & Dev Ctr, SAIC, Intramural Res Support Program, Frederick, MD USA. Frederick Canc Res & Dev Ctr, Off Lab Anim Resources, Vet & Tumor Pathol Sect, Frederick, MD USA. Natl Inst Dent & Craniofacial Res, Cell Biol Sect, Bethesda, MD USA. RP Murphy, WJ (reprint author), NCI, LLB, DBS, Frederick Canc Res & Dev Ctr, Bldg 567,Rm 209, Frederick, MD 21702 USA. NR 40 TC 541 Z9 573 U1 3 U2 19 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 JUL 1 PY 2000 VL 96 IS 1 BP 34 EP 40 PG 7 WC Hematology SC Hematology GA 327UX UT WOS:000087813200006 PM 10891427 ER PT J AU Bishop, MR Tarantolo, SR Geller, RB Lynch, JC Bierman, PJ Pavletic, ZS Vose, JM Kruse, S Dix, SP Morris, ME Armitage, JO Kessinger, A AF Bishop, MR Tarantolo, SR Geller, RB Lynch, JC Bierman, PJ Pavletic, ZS Vose, JM Kruse, S Dix, SP Morris, ME Armitage, JO Kessinger, A TI A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; PERIPHERAL-BLOOD; PROGENITOR CELLS; HEMATOLOGICAL MALIGNANCIES; MONONUCLEAR-CELLS; GROWTH-FACTORS; G-CSF; RECOVERY; ENGRAFTMENT AB Blood stem cell transplantation (BSCT) results in rapid hematopoietic recovery in both the allogeneic and autologous transplant settings. Because of the large numbers of progenitor cells in mobilized blood, the administration of growth factors after transplantation may not provide further acceleration of hematopoietic recovery. A randomized, double-blind, placebo-controlled study was performed to determine the effects of filgrastim (granulocyte colony-stimulating factor; G-CSF) administration on hematopoietic recovery after allogeneic BSCT. Fifty-four patients with hematologic malignancies undergoing a related, HLA-matched allogeneic BSCT were randomly assigned to receive daily filgrastim at 10 mu g/kg or placebo starting on the day of transplantation. A minimum of 3 x 10(6) CD34(+) cells/kg in the allograft was required for transplantation. All patients received a standard preparative regimen and a standard regimen for the prevention of graft-versus-host disease (GVHD). The median time to achieve an absolute neutrophil count greater than 0.5 x 10(9)/L was 11 days (range, 9-20 days) for patients who received filgrastim compared with 15 days (range, 10-22 days) for patients who received placebo (P = .0082). The median time to achieve a platelet count greater than 20 x 10(9)/L was 13 days (range, 8-35 days) for patients who received filgrastim compared with 15.5 days (range, 8-42 days) for patients who received placebo (P = .79). There were no significant differences for red blood cell transfusion independence,the incidence of acute GVHD, or 100-day mortality between the groups. The administration of filgrastim appears to be a safe and effective supportive-care measure following allogeneic BSCT. (Blood. 2000;96:80-85) (C) 2000 by The American Society of Hematology. C1 Univ Nebraska, Med Ctr, Dept Med, Omaha, NE 68105 USA. Oncol & Hematol Associates, Blood & Marrow Transplant Program, Kansas City, MO USA. St Lukes Hosp Kansas City, Kansas City, MO USA. Univ Nebraska, Med Ctr, Dept Prevent & Societal Med, Omaha, NE USA. RP Bishop, MR (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Bethesda, MD 20892 USA. NR 36 TC 69 Z9 69 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 JUL 1 PY 2000 VL 96 IS 1 BP 80 EP 85 PG 6 WC Hematology SC Hematology GA 327UX UT WOS:000087813200013 PM 10891434 ER PT J AU Nicot, C Mahieux, R Takemoto, S Franchini, G AF Nicot, C Mahieux, R Takemoto, S Franchini, G TI Bcl-X-L is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples SO BLOOD LA English DT Article ID VIRUS TYPE-I; NF-KAPPA-B; CELL LEUKEMIA-LYMPHOMA; T-CELL; TAX-PROTEIN; CONSTITUTIVE ACTIVATION; MOLECULAR MECHANISMS; ANTISENSE INHIBITION; ARSENIC TRIOXIDE; INTERFERON-ALFA AB Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell lymphocytic leukemia (ATLL), whereas HTLV-II has not been associated with hematopoietic malignancies. The control of apoptotic pathways has emerged as a critical step in the develop ment of many cancer types. As a result, the underlying mechanism of long-term survival of HTLV-I and HTLV-II was studied in infected T cells in vitro and in ex vivo ATLL samples. Results Indicate that HTLV-I- and HTLV-II-infected T cells in vitro express high levels of the antiapoptotic protein Eel compared with other human leukemic T cell lines or uninfected peripheral blood mononuclear cells. The levels of proapoptotic proteins Bax, BAD, and Bak were not significantly altered. HTLV-I and HTLV-II viral transactivators, Tax1 and Tax2, are known to increase expression of cellular genes. These proteins were tested for increased transcription from the human Bcl2 and Bcl-X-L promoters. Whereas no effect was observed on the Bcl2 promoter, both Tax1 and Tax2 increased transcription of the Bcl-X-L promoter in T cells, although Taxi appeared to be more efficient than Tax2. The biological significance of these observations was validated by the finding of an increased expression of Bcl-X-L in ex vivo ATLL cells, especially from patients unresponsive to various chemotherapy regimens. Altogether, these data suggest that overexpression of Bcl-X-L in vivo may be in part responsible for the resistance of ATLL cells to chemotherapy. In addition, inefficient activation of the Bcl-X-L promoter by Tax2 may result in a shorter survival time of HTLV-II-infected cells in vivo and a diminished risk of leukemia development. (Blood. 2000;96:275-281) (C) 2000 by The American Society of Hematology. C1 NCI, Basic Res Lab, Div Basic Sci, Lab Receptor Biol & Gene Express,NIH, Bethesda, MD 20892 USA. RP Nicot, C (reprint author), NCI, Basic Res Lab, Div Basic Sci, Lab Receptor Biol & Gene Express,NIH, 9000 Rockville Pike,Bldg 41,Rm C303, Bethesda, MD 20892 USA. OI Takemoto, Shigeki/0000-0003-4130-074X NR 63 TC 85 Z9 87 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2000 VL 96 IS 1 BP 275 EP 281 PG 7 WC Hematology SC Hematology GA 327UX UT WOS:000087813200041 PM 10891462 ER PT J AU Migliaccio, S Newbold, RR Teti, A Jefferson, WJ Toverud, SU Taranta, A Bullock, BC Suggs, CA Spera, G Korach, KS AF Migliaccio, S Newbold, RR Teti, A Jefferson, WJ Toverud, SU Taranta, A Bullock, BC Suggs, CA Spera, G Korach, KS TI Transient estrogen exposure of female mice during early development permanently affects osteoclastogenesis in adulthood SO BONE LA English DT Article DE estrogens; development; bone turnover; osteoclasts; mice ID OSTEOBLAST-LIKE CELLS; PREVENTS BONE LOSS; ACID-PHOSPHATASE; SKELETAL DEVELOPMENT; OVARIECTOMIZED RATS; TARTRATE-RESISTANT; PRENATAL EXPOSURE; RESPONSE ELEMENT; RECEPTOR GENE; ANIMAL-MODEL AB Estrogens modulate bone tissue turnover in both experimental animal models and postmenopausal women. Our previous studies have shown that exposure to diethylstilbestrol (DES) during the perinatal period increases peak bone mass in female mice in adulthood. We investigated whether developmental DES exposure can influence bone mass by affecting osteoclastogenesis, Female mice were injected with 100 mu g/kg body weight DES from days 9-16 of gestation or, alternatively, pups received neonatal injections of 2 mu g of DES from days 1-5 of life. Animals were weaned at 21 days of age and effects of estrogen on bone cells were evaluated in adulthood. A significant increase in bone mass in female mice was already observed at 2 months, with a maximal effect in older animals. Bone sections from DFS-treated animals showed a significant decrease in osteoclast number and tartrate-resistant acid phosphatase (TRAP) enzymatic activity as compared with controls. To verify the importance of the estrogen surge at puberty in this event, a group of control and DFS-treated mice were ovariectomized at 17 days to prevent puberty, and potential effect on osteoclastic cells was evaluated in adulthood. As expected, ovariectomy induced an increase of TRAP-positive cells. DES treatment blunted the ovariectomized-dependent increase of the total number of osteoclastic cells, suggesting a role of developmental DES exposure in the process of bone-cell imprinting. Our data indicate, for the first time, that transient changes in estrogen levels during development modulate bone turnover and osteoclastogenesis likely participating in bone-cell imprinting during early phases of bone development, and that this effect could be induced by direct alteration of bone microenvironment, (Bone 27:47-52; 2000) (C) 2000 by Elsevier Science Inc. All rights reserved. C1 Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. Univ Rome La Sapienza, Dept Histol & Med Embryol, Rome, Italy. Univ Rome La Sapienza, Dept Med Physiopathol, Rome, Italy. NIEHS, Reprod Toxicol Grp, Toxicol Branch, Environm Toxicol Program,Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. Univ N Carolina, Sch Med & Dent, Chapel Hill, NC USA. Ist Dermopat Immacolata, Rome, Italy. NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Comparat Med, Winston Salem, NC 27103 USA. RP Migliaccio, S (reprint author), Univ Aquila, Dept Expt Med, Via Vetoio Coppito 2, I-67100 Laquila, Italy. OI Migliaccio, Silvia/0000-0002-4563-6630; Korach, Kenneth/0000-0002-7765-418X; Teti, Anna Maria/0000-0002-5887-4419 NR 48 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2000 VL 27 IS 1 BP 47 EP 52 DI 10.1016/S8756-3282(00)00286-6 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337TF UT WOS:000088377200007 PM 10865208 ER PT J AU Roh, JY Yee, C Lazarova, Z Hall, RP Yancey, KB AF Roh, JY Yee, C Lazarova, Z Hall, RP Yancey, KB TI The 120-kDa soluble ectodomain of type XVII collagen is recognized by autoantibodies in patients with pemphigoid and linear IgA dermatosis SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE basement membrane; bullous pemphigoid antigen; cicatricial pemphigoid; human keratinocyte; linear IgA dermatosis; pemphigoid gestationis ID BULLOUS DERMATOSIS; EXTRACELLULAR DOMAIN; BASEMENT-MEMBRANE; BP180 ECTODOMAIN; LAMINA-LUCIDA; ANTIGEN; KERATINOCYTES; ANTIBODIES; EPITOPES; PROTEIN AB Background Type XVII collagen promotes adhesion of basal keratinocytes to epidermal basement membrane, and is the target of disease in patients with certain inherited or acquired blistering diseases. Two forms of type XVII collagen are produced by cultured human keratinocytes: a 180-kDa full-length, transmembrane protein, and a recently identified 120-kDa soluble fragment that corresponds to its collagenous ectodomain. Objectives We aimed to determine the incidence and pattern of reactivity of autoantibodies against the 180- and 120-kDa forms of type XVII collagen in sera from 40 patients with bullous pemphigoid (BP), pemphigoid gestationis or cicatricial pemphigoid (CP), as well as six patients with linear IgA dermatosis (LAD). Methods Various immunochemical techniques were used. Results These studies found that the 120-kDa fragment of type XVII collagen was bound by circulating autoantibodies in 13 of 38 patients with BP or CP and all six patients with LAD. While many pemphigoid sera had specific reactivity against one but not both forms of this protein, autoantibodies from patients with LAD bound only the soluble ectodomain. Conclusions These findings are consistent with the presence of both neoepitopes and cross-reactive epitopes on the ectodomain of type XVII collagen. The finding that sera from patients with LAD showed specific reactivity to epidermal basement membrane suggests that such neoepitopes are present in human skin and that their targeting by autoantibodies may contribute to disease pathogenesis. C1 NCI, Dermatol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Dept Med, Div Dermatol, Durham, NC 27706 USA. RP Yancey, KB (reprint author), NCI, Dermatol Branch, Div Clin Sci, NIH, Bldg 10,Room 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 27 TC 20 Z9 20 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JUL PY 2000 VL 143 IS 1 BP 104 EP 111 DI 10.1046/j.1365-2133.2000.03598.x PG 8 WC Dermatology SC Dermatology GA 331HK UT WOS:000088012700017 PM 10886143 ER PT J AU Xiong, KM Li, CY Weight, FF AF Xiong, KM Li, CY Weight, FF TI Inhibition by ethanol of rat P2X(4) receptors expressed in Xenopus oocytes SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE ATP; ethanol; ion channel; receptor; purinoceptor; oocyte ID FAST SYNAPTIC TRANSMISSION; LOCUS-CERULEUS NEURONS; ATP-ACTIVATED CURRENT; MAMMALIAN NEURONS; ION-CHANNEL; ADENOSINE 5'-TRIPHOSPHATE; SYMPATHETIC NEURONS; GANGLION NEURONS; SENSORY NEURONS; BRAIN AB 1 The effect of ethanol on the function of P2X(4) receptors expressed in Xenopus oocytes was studied using two-electrode voltage-clamp recording. 2 The amplitude of current activated by 1 mu M ATP was decreased by ethanol in a concentration-dependent manner over the concentration range 1-500 mM. The concentration of ethanol that produced 50% inhibition (IC50) of current activated by 1 mu M ATP was 58 mM. 3 Ethanol inhibition of ATP-activated current was not dependent on membrane potential from - 60 to + 20 mV, and ethanol did not change the reversal potential of ATP-activated current. 4 Ethanol, 50 mM, shifted the ATP concentration-response curve to the right, increasing the EC50 for ATP from 9.1 to 16.0 mu M, but did not reduce the maximal response to ATP. 5 The results suggest that ethanol may inhibit P2X(4) receptors by decreasing the apparent affinity of the binding site for ATP. 6 Since the P2X(4) receptor is the most abundant P2X subunit in the brain, these receptors could be important effecters of ethanol action in the central nervous system. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Xiong, KM (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, 12501 Washington Ave, Rockville, MD 20582 USA. NR 42 TC 35 Z9 39 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUL PY 2000 VL 130 IS 6 BP 1394 EP 1398 DI 10.1038/sj.bjp.0703439 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 337VZ UT WOS:000088383500027 PM 10903981 ER PT J AU Li, CS Hueber, FM Hotton, CL AF Li, CS Hueber, FM Hotton, CL TI A neotype for Drepanophycus spinaeformis Goppert 1852 SO CANADIAN JOURNAL OF BOTANY-REVUE CANADIENNE DE BOTANIQUE LA English DT Article DE Drepanophycus; neotype; lycopsid; cauline sporangia; Lower Devonian; Canada AB The species Drepanophycus spinaeformis Goppert 1852 was described as a fossil plant closely allied with the fucoid algae. Many years later the type, a single figured specimen, was lost along with its associated collection. Subsequent studies described and assigned additional fossils to the species and redefined it as a land plant, a lycopsid. Through all of the descriptions and assignments of specimens to the species, no single specimen was designated as the type to bear the name in the absence of a holotype. The purpose of this paper is to designate a specimen as the neotype, the bearer of the name, and to emend the taxonomic description of the species. C1 Smithsonian Inst, Dept Paleobiol, Washington, DC 20560 USA. Chinese Acad Sci, Inst Bot, Dept Paleobot, Lab Systemat & Evolutionary Bot, Beijing 100093, Peoples R China. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Hueber, FM (reprint author), Smithsonian Inst, Dept Paleobiol, MRC 121, Washington, DC 20560 USA. NR 28 TC 18 Z9 19 U1 0 U2 4 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0008-4026 J9 CAN J BOT JI Can. J. Bot.-Rev. Can. Bot. PD JUL PY 2000 VL 78 IS 7 BP 889 EP 902 PG 14 WC Plant Sciences SC Plant Sciences GA 343GZ UT WOS:000088694700005 ER PT J AU Frisch, M Hjalgrim, H Jaeger, AB Biggar, RJ AF Frisch, M Hjalgrim, H Jaeger, AB Biggar, RJ TI Changing patterns of tonsillar squamous cell carcinoma in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE human papillomaviruses; oral neoplasms; tobacco smoking; tonsillar neoplasms; tonsillectomy ID HUMAN-PAPILLOMAVIRUS INFECTION; PHARYNGEAL CANCER; NECK-CANCER; ORAL CAVITY; HEAD; DNA; ASSOCIATION; SMOKING; REGION; HPV AB Objective: Tonsillar squamous cell carcinoma (SCC) may differ etiologically from other oral cancers. The aim of this study was to provide a detailed description of the incidence patterns of tonsillar SCC in the United States. Methods: Population-based incidence data from the Connecticut Tumor Registry (period 1945-1994) and from the SEER program (period 1973-1995) were used to calculate age-standardized (US 1970) and age-specific incidence rates and confidence intervals (CIs). Linear regression was used to evaluate trends. Results: The incidence of tonsillar SCC increased fourfold among white women in Connecticut during 1945-1994 but remained rather constant in white men. During 1973-1995, incidence rates per million person-years were considerably higher in blacks (31.6; 95% CI: 29.0-34.4 in men, and 9.6; 95% CI: 8.3-10.9 in women) than whites (14.8; 95% CI: 14.3-15.3 in men, and 6.1; 95% CI: 5.8-6.4 in women). Men, but not women, who were younger than 60 years experienced significant annual increases in tonsillar SCC incidence during 1973-1995 (2.7% in blacks and 1.9% in whites). No similar increases occurred for oral SCC at non-tonsillar sites. Conclusion: Incidence rates of tonsillar SCC vary considerably by sex, race and time in a way that cannot be explained by changes in tonsillectomy practices alone. Changes in environmental risk factors, including changes in smoking patterns and an increase in oral human papillomavirus infections, may have contributed. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. RP Frisch, M (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 35 TC 113 Z9 114 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2000 VL 11 IS 6 BP 489 EP 495 DI 10.1023/A:1008918223334 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 348PR UT WOS:000088994400002 PM 10880031 ER PT J AU Fennell, TR MacNeela, JP Morris, RW Watson, M Thompson, CL Bell, DA AF Fennell, TR MacNeela, JP Morris, RW Watson, M Thompson, CL Bell, DA TI Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: Effects of glutathione S-transferase T1-null and M1-null genotypes SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN ERYTHROCYTES; 2-CYANOETHYLENE OXIDE; GENETIC-POLYMORPHISM; CYTOCHROME-P450 2E1; MOLECULAR DOSIMETRY; ALKYLATING-AGENTS; BLADDER-CANCER; M1 GSTM1; WORKERS; METABOLISM AB Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents. Both ACN and EO undergo conjugation with glutathione, The objectives of this study were to examine the relationship between cigarette smoking and hemoglobin adducts derived from ACN and EO and to investigate whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of these agents. The hemoglobin adducts N-(2-cyanoethyl)valine (CEVal), which is formed from ACN, and N-(2-hydroxyethyl)valine (HEVal), which is formed from EO, and GST genotypes were determined in blood samples obtained from 16 nonsmokers and 32 smokers tone to two packs/day), Smoking information was obtained by questionnaire, and plasma cotinine levels were determined by immunoassay, Glutathione transferase null genotypes (GSTM1 and GSTT1 were determined by PCR, Both CEVal and HEVal levels increased with increased cigarette smoking dose (both self-reported and cotinine-based), CEVal and HEVal levels mere also correlated, GSTM1 and GSTT1 genotypes had little effect on CEVal concentrations. GSTM1 null genotypes had no significant impact on HEVal. However, HEVal levels mere significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The ratio of HEVal:CEVal was also elevated in GSTT1-null smokers (1.50 +/- 0.57 versus 0.88 +/- 0.24; P = 0.0002). The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%. C1 Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Analyt Sci Inc, Durham, NC 27713 USA. RP Fennell, TR (reprint author), Chem Ind Inst Toxicol, POB 12137,6 Davis Dr, Res Triangle Pk, NC 27709 USA. RI Fennell, Tim/D-9936-2013 NR 63 TC 51 Z9 58 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2000 VL 9 IS 7 BP 705 EP 712 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 334ZQ UT WOS:000088217100012 PM 10919741 ER PT J AU Ozbal, CC Skipper, PL Yu, MC London, SJ Dasari, RR Tannenbaum, SR AF Ozbal, CC Skipper, PL Yu, MC London, SJ Dasari, RR Tannenbaum, SR TI Quantification of (7S,8R)-dihydroxy-(9R,10S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene adducts in human serum albumin by laser-induced fluorescence: Implications for the in vivo metabolism of benzo[a]pyrene SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ANTI-DIOL EPOXIDE; OPTICAL ENANTIOMERS; DNA ADDUCTS; MOUSE SKIN; 7,8-DIOL-9,10-EPOXIDES; CYTOCHROME-P450; CARCINOGENESIS; HYDROLASE; ENZYMES; MICE AB The ubiquitous environmental carcinogen benzo[a]pyrene (BaP) is metabolized in vivo in humans to its ultimate carcinogenic form of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). Mouse skin tumorigenicity studies indicate that the (7R,8S,9S,10R) enantiomer of BPDE, (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(7R,SS,9S,10R)BPDE], is a potent tumor initiator, whereas the (7S,8R,9R,10S) enantiomer of BPDE, (7S,8R)-dihydroxy-(9R,10S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(7S,8R,9R,10S)-BPDE], may act as a tumor promoter. In vitro experiments have shown that human liver microsomes are capable of metabolizing BaP to both the (7R,8S,9S,10R) and (7S,8R,9R,10S) enantiomers of BPDE. However, the metabolism of BaP to (7S,8R,9R,10S)-BPDE has not been demonstrated in humans in vivo. The adducts formed between human serum albumin (HSA) and the (7S,8R,9R,10R) and (7R,8S,9S,10R) enantiomers of BPDE have been described previously. (7S,8R,9R,10S)-BPDE forms a stable adduct at histidine(146) of HSA, whereas (7R,8S,9R,10R)-BPDE forms a relatively unstable ester adduct at aspartate(187) or glutamate(188) of HSA. Using high-performance liquid chromatography with laser-induced fluorescence (LIF) detector, we quantified the level of (7S,8R,9R,10S)-BPDE adducts at histidine(146) in HSA isolated from 63 healthy males who were population control subjects for an ongoing case-control study of bladder cancer. By design, roughly half of the participants were lifelong nonsmokers (n = 35), whereas the remaining 28 participants were current smokers of varying intensities. HP-BPDE adducts were detected in 60 of the 63 samples (95%) by HPLC-LIF. Adduct levels ranged from undetectable (<0.04 fmol/mg HSA) to 0.77 fmol/mg HSA. The samples had a mean and median (7S,8R,9R,10S)-BPDE-HSA adduct level of 0.22 and 0.16 fmol of adduct/mg albumin, respectively. Mean adduct levels did not differ between smokers and nonsmokers (P = 0.72). Occupational exposure to polycyclic aromatic hydrocarbons was unrelated to adduct level (P = 0.62). Intake frequencies of two food items showed statistically significant associations with adduct levels. Consumption of sweet potatoes was negatively related to adduct level (P 0.029), whereas intake of grapefruit juice was positively related to adduct level (P = 0.045). None of the three indices of residential ambient air pollution under study showed a statistically significant association with adduct levels. C1 MIT, Div Bioengn & Environm Hlth, Cambridge, MA 02139 USA. MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Tannenbaum, SR (reprint author), MIT, Div Bioengn & Environm Hlth, Bldg 56-731,77 Massachusetts Ave, Cambridge, MA 02139 USA. OI London, Stephanie/0000-0003-4911-5290 FU NCI NIH HHS [R35 CA53890]; NIEHS NIH HHS [P01 ES05622, P30 ES07048] NR 31 TC 17 Z9 18 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 JUL PY 2000 VL 9 IS 7 BP 733 EP 739 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 334ZQ UT WOS:000088217100016 PM 10919745 ER PT J AU Bergmann-Leitner, ES Abrams, SI AF Bergmann-Leitner, ES Abrams, SI TI Influence of interferon gamma on modulation of Fas expression by human colon carcinoma cells and their subsequent sensitivity to antigen-specific CD8(+) cytotoxic T lymphocyte attack SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE human; CTL; Fas; interferon gamma; tumor immunity ID MEDIATED CYTOTOXICITY; PEPTIDE VACCINATION; APOPTOSIS; CD4(+); DEATH; CTL; MECHANISMS; RESPONSES; PROTEASE; CANCER AB The inability of certain neoplastic populations to undergo Fas-mediated death by immune effector mechanisms may confer a selective survival advantage, which may contribute to tumor escape. In this study, we examined the role of Fas-mediated lysis in a human-antigen (Ag)-specific cytotoxic T lymphocyte (CTL)/colon carcinoma cell model, and the regulation of the lytic phenotype by interferon gamma (IFN gamma). Previously, we have identified mutated ras peptides reflecting the valine-for-glycine substitution at position 12 as unique HLA-A2-restricted, CD8(+) CTL neo-epitopes. Peptide-specific CTL, established from both normal and carcinoma-bearing individuals, lysed in vitro a HLA-A2(+) primary colon adenocarcinoma cell line, SW480, harboring the naturally occurring ras mutation. Pretreatment of SW480 cells with IFN gamma, was necessary to promote efficient Ag-specific CTL killing, although the mechanisms by which IFN gamma influenced the lytic outcome remains to be elucidated. Here, we show, by phenotypic analysis of SW480 cells, a significant up-regulation of HLA-A2, ICAM-1 and Fas molecules after IFN gamma pretreatment, which paralleled their sensitivity to lysis with anti-Fas stimuli. Moreover, nearly half of the lytic response to IFN gamma-treated SW480 cells was inhibited by neutralizing anti-Fas or anti-Fasligand (FasL) mAb, revealing for the first time an important functional role for Fas/FasL interactions in carcinoma cell killing by human Ag-specific CTL, mAb against HLA-A2, ICAM-1, the alpha beta T cell receptor (TCR) and Fas molecules inhibited lysis; however, if these CTL were preactivated to express functional Fast and then used as effecters; only anti-Fas mAb efficiently blocked lysis. IFN gamma also increased pro-caspase-3 protein expression and its subsequent activation in SW480 cells following Ag-specific CTL attack. Peptide-based caspase inhibitors blocked both caspase-3 activation and CTL-mediated lysis. Overall, these data suggested that IFN gamma (a) facilitated both Ag-dependent and Ag-independent events as a prerequisite for efficient CTL/target interactions, Fast up-regulation and triggering of Fas-dependent, as well as Fas-independent lysis (perforin); and (b) enhanced or restored a Fas-sensitive phenotype in SW480 cells, reflecting modulation of cell-surface and intracellular elements of the Fas pathway. Thus, IFN gamma may play an important role in the regulation of a human neoplastic cell death phenotype, which may have implications for our understanding of the processes of both tumor evasion and tumor regression following Ag-specific CTL attack. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B46,10 Ctr Dr, Bethesda, MD 20892 USA. RI Bergmann-Leitner, Elke/B-3548-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956 NR 37 TC 27 Z9 28 U1 0 U2 3 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 JUL PY 2000 VL 49 IS 4-5 BP 193 EP 207 DI 10.1007/s002620000105 PG 15 WC Oncology; Immunology SC Oncology; Immunology GA 336RE UT WOS:000088316100003 PM 10941902 ER PT J AU McGinn, CJ Pestalozzi, BC Drake, JC Glennon, MC Kunugi, K Otterson, G Allegra, CJ Johnston, PG Kinsella, TJ AF McGinn, CJ Pestalozzi, BC Drake, JC Glennon, MC Kunugi, K Otterson, G Allegra, CJ Johnston, PG Kinsella, TJ TI Cell cycle regulation of the G(0)/G(1) transition in 5-fluorouracil-sensitive and -resistant human colon cancer cell lines SO CANCER JOURNAL LA English DT Article DE colon cancer; cell cycle; G(0) phase; G(1) phase; fluorouracil ID THYMIDYLATE SYNTHASE GENE; COLORECTAL-CARCINOMA; TRANSCRIPTION FACTOR; DNA-SYNTHESIS; EXPRESSION; INHIBITOR; SYNTHETASE; PROTEIN; P21; FLUOROURACIL AB PURPOSE Resistance to 5-fluorouracil (5-FU) has been associated with thymidylate synthase (TS) gene amplification and increased TS protein levels. Increased TS protein expression has also been found to be a significant independent prognostic factor for disease-free survival and overall survival in patients treated with adjuvant 5-FU-based chemotherapy. In these studies and in our prior preclinical studies, TS has been considered a marker of proliferative capacity. The purpose of the current study was to further evaluate the association between TS levels and cell cycle regulation, by investigating cell cycle kinetics in a 5-FU-resistant cell line with constitutive overexpression of TS. The influence of increased TS levels on cell cycle progression may provide insight into methods to overcome 5-FU resistance. MATERIALS 5-FU-sensitive NCI H630(WT) and 5-FU-resistant NCl H630(R1) (with 15- to 20-fold higher TS protein levels) were utilized in this investigation to determine the influence of constitutive overexpression of TS on cell cycle kinetics. RESULTS There was no apparent influence of increased TS levels on cell cycle distribution during asynchronous growth, and both cell lines reach plateau growth phase in 120 hours, arresting in G(0)/G(1), as determined by flow cytometry, In the H630(WT) cells, this G(0)/G(2) arrest was associated with a 14- to 17-fold reduction in TS activity and protein levels (using the TS-106 monoclonal antibody), whereas in the H630(R1) cells, only a two- to fivefold reduction was noted. Flow cytometry analysis utilizing Ki-67 indicated that there was no evidence of a G(0) population in the confluent H630(R1), whereas 26% +/- 7% of confluent H630(WT) cells were Ki-67 negative (G(0)) and the remainder had low Ki-67 signal intensity. Analysis of pRb phosphorylation and p16 and p21 expression suggested that the arrest point for both cell lines was before the point at which Rb phosphorylation takes place, yet the confluent H630(R1) cells had threefold higher p21 than confluent H630(WT) cells. DISCUSSION These data suggest that the 5-N-resistant H630(R1) cell lines arrest at a later point in G(0)/G(1) and have a potentially greater capacity for proliferation. C1 Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. NCI, Med Branch, Bethesda, MD 20892 USA. Queens Univ, Dept Oncol, Belfast, Antrim, North Ireland. Case Western Reserve Univ, Dept Radiat Oncol, Cleveland, OH 44106 USA. RP Kinsella, TJ (reprint author), Univ Hosp Cleveland, Dept Radiat Oncol, 11100 Euclid Ave,LTR 6068, Cleveland, OH 44106 USA. FU NCI NIH HHS [CA50595] NR 47 TC 7 Z9 7 U1 0 U2 2 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PONE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. Sci. Am. PD JUL-AUG PY 2000 VL 6 IS 4 BP 234 EP 242 PG 9 WC Oncology SC Oncology GA 368MB UT WOS:000090119800007 PM 11038143 ER PT J AU Hansen, LA Woodson, RL Holbus, S Strain, K Lo, YC Yuspa, SH AF Hansen, LA Woodson, RL Holbus, S Strain, K Lo, YC Yuspa, SH TI The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors SO CANCER RESEARCH LA English DT Article ID FACTOR-ALPHA; TRANSGENIC MICE; EGF-RECEPTOR; TARGETED DISRUPTION; V-RAS(HA) ONCOGENE; CELL-PROLIFERATION; HAIR FOLLICLE; SENCAR MICE; IN-VITRO; EXPRESSION AB Previous studies using keratinocytes from epidermal growth factor receptor (EGFR)-deficient mice revealed that the ECFR is not required for papilloma formation initiated by a mutant ras(Ha) gene, although the tumors that develop are very small (A, A. Dlugosz et at, Cancer Res., 57: 3180-3188, 1997), The current study used a combination of bromodeoxyuridine pulse-chase, proliferating cell nuclear antigen distribution, and differentiation marker analysis to reveal the following: (a) the EGFR was required to maintain the proliferative population in the basal cell compartment of papillomas; (b) in the absence of EGFR, cycling tumor cells migrated into the suprabasal compartment and initiated the differentiation program prematurely; and (c) these changes were associated with cell cycle arrest. Further analysis of v-ras(Ha)-transformed EGFR-deficient keratinocytes in vitro indicated that such cells migrated more on and attached less to extracellular matrix components. Together, these studies reveal that an essential function for the EGFR pathway in squamous tumors is to maintain a proliferative pool of basal cells and prevent premature terminal differentiation. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Hansen, LA (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, 37-3B25,37 Convent Dr, Bethesda, MD 20892 USA. NR 41 TC 59 Z9 61 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3328 EP 3332 PG 5 WC Oncology SC Oncology GA 334AF UT WOS:000088162400003 PM 10910032 ER PT J AU Hussain, SP Amstad, P Raja, K Ambs, S Nagashima, M Bennett, WP Shields, PG Ham, AJ Swenberg, JA Marrogi, AJ Harris, CC AF Hussain, SP Amstad, P Raja, K Ambs, S Nagashima, M Bennett, WP Shields, PG Ham, AJ Swenberg, JA Marrogi, AJ Harris, CC TI Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: A cancer-prone chronic inflammatory disease SO CANCER RESEARCH LA English DT Article ID NITRIC-OXIDE SYNTHASE; KI-RAS MUTATIONS; TUMOR-SUPPRESSOR GENE; COLORECTAL-CANCER; DNA-DAMAGE; CHROMOSOMAL INSTABILITY; LIPID-PEROXIDATION; BOWEL-DISEASE; EXPRESSION; CARCINOMA AB Ulcerative colitis (UC) is a chronic inflammatory disease that produces reactive oxygen and nitrogen species and increases the risk of colorectal cancer (CRC), The p53 tumor suppressor gene is frequently mutated in UC-associated dysplastic lesions and CRC, We are exploring the hypothesis that p53 mutations In the nontumorous colonic tissue in noncancerous UC cases indicate genetic damage from exposure to exogenous and endogenous carcinogens and may identify individuals at increased cancer risk, We are reporting, fur the first time, the frequency of specific p53 mutated alleles in nontumorous colon tissue from donors either with or without UC by using a highly sensitive genotypic mutation assay, Higher p53 mutation frequencies of both G:C to A:T transitions at the CpG site of codon 248 and C:C to T:A transitions at codon 247 were observed in colon From UC cases when compared with normal adult controls (P = 0.001 and P = 0.001, respectively), in the UC cases, higher p53 codon 247 and 248 mutation frequencies were observed in the inflamed lesional regions when compared with the nonlesional regions of their colon (P < 0.001 and P = 0.001), The colonic nitric oxide synthase-2 activity was higher in UC cases than in non-UC adult controls (P = 0.02), Our data are consistent with the hypothesis that a higher Frequency of p53 mutant cells can be generated under oxidative stress in people with UC, The increased frequency of specific p.53 mutated alleles in noncancerous UC colon tissue may confer susceptibility to the development of CRO in an inflammatory microenvironment. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 2C05, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 NR 55 TC 303 Z9 309 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 JUL 1 PY 2000 VL 60 IS 13 BP 3333 EP 3337 PG 5 WC Oncology SC Oncology GA 334AF UT WOS:000088162400004 PM 10910033 ER PT J AU Salnikow, K Su, WC Blagosklonny, MV Costa, M AF Salnikow, K Su, WC Blagosklonny, MV Costa, M TI Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism SO CANCER RESEARCH LA English DT Article ID OXIDATIVE STRESS; MAMMALIAN-CELLS; FREE-RADICALS; GENE; GENERATION; COBALT(II); RESPONSES; DAMAGE; INVIVO; IONS AB Nickel (Ni2+) and cobalt (Co2+) mimic hypoxia and were used as a tool to study the role of oxygen sensing and signaling cascades in the regulation of hypoxia-inducible gene expression. These metals can produce oxidative stress; therefore, it was conceivable that reactive oxygen species (ROS) may trigger signaling pathways resulting in the activation of the hypoxia-inducible factor (HIF)-1 transcription factor and up-regulation of hypoxia-related genes. We found that the exposure of A549 cells to Co2+ or Ni2+ produced oxidative stress, and although Co2+ was a more potent producer of ROS than Ni2+, both metals equally increased the expression of Cap43, a hypoxia-regulated gene. The coadministration of hydrogen peroxide with metals induced more ROS; however, this did not further increase the expression of Cap43 mRNA, The free radical scavenger 2-mercaptoethanol completely suppressed ROS generation by CoCl2 and NiCl2 but did not diminish the induced Cap43 gene expression. The activity of the HIF-1 transcription factor as assessed in transient transfection assays was stimulated by Ni2+, hypoxia, and desferrioxamine, but this activation was not diminished when oxidative stress was attenuated nor was HIF-dependent transcription enhanced by hydrogen peroxide. We conclude that ROS are produced during the exposure of cells to metals that mimic hypoxia, but the formation of ROS was not involved in the activation of HIF-1-dependent genes. C1 NYU, Sch Med, Nelson Inst Environm Med, New York, NY 10016 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Salnikow, K (reprint author), NYU, Sch Med, Nelson Inst Environm Med, 57 Old Forge Rd, Tuxedo Park, NY 10987 USA. RI costa, max/H-1754-2012 FU NCI NIH HHS [CA16037]; NIEHS NIH HHS [ES00260, ES05512] NR 27 TC 147 Z9 155 U1 3 U2 17 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 JUL 1 PY 2000 VL 60 IS 13 BP 3375 EP 3378 PG 4 WC Oncology SC Oncology GA 334AF UT WOS:000088162400012 PM 10910041 ER PT J AU Mei, JM Hord, NG Winterstein, DF Donald, SP Phang, JM AF Mei, JM Hord, NG Winterstein, DF Donald, SP Phang, JM TI Differential formation of beta-catenin/lymphoid enhancer factor-1 DNA binding complex induced by nitric oxide in mouse colonic epithelial cells differing in adenomatous polyposis coli (Apc) genotype SO CANCER RESEARCH LA English DT Article ID RABBIT ARTICULAR CHONDROCYTES; FIBROBLAST GROWTH-FACTOR; E-CADHERIN; SMALL-INTESTINE; CATENIN; EXPRESSION; ADHESION; SYNTHASE; DISEASE; TRANSCRIPTION AB increased cytoplasmic beta-catenin levels and the associated nuclear beta-catenin/T-cell factor (Tcf)-lymphoid enhancer factor (I,EF) complex formation have been frequently found in colon cancer, In this context, overproduction of nitric oxide (NO) attributable to inflammatory stimuli in diseases such as ulcerative colitis and Crohn's disease may contribute to colonic carcinogenesis. Therefore, we examined the modulation by NO of cytoplasmic beta-catenin levels and the formation of the nuclear beta-catenin/LEF-1 DNA binding complex in conditionally immortalized mouse colonic epithelial cells that differed in adenomatous polyposis coli (Apc) genotype, namely young adult mouse colon (YAMC; Apc(+/+)) and immortal mouse colon epithelium (IMCE; Apc-(Min/+)). Unlike most colon canter cell lines, this pair of cell lines has either nondetectable or low basal level of beta-catenin when they are cultured under non-permissive and nonproliferative conditions. Using electrophoretic mobility shift assays, se found that NO-releasing agents (E)-methyl-2-[(E)-hydroxy- imino]-5-nitro-6-methoxy-3-hexeneamide and S-nitroso-N-acetylpenicillamine greatly enhanced the formation of beta-catenin/LEF-1 DNA binding complex in a concentration- and time-dependent fashion in YAMC and IMCE cells, Significantly, IMCE cells showed a markedly greater amount of nuclear beta-catenin/LEF-1 DNA binding complex in response to NO. Super shift by anti-beta-catenin antibody confirmed the presence of beta-catenin in the complex. Western blot analysis of the soluble cytoplasmic fractions demonstrated that these NO donors caused differential accumulation of cytoplasmic beta-catenin in YAMC and LR ICE. In conclusion, this study indicates that the defective beta-catenin degradation machinery attributable to Apc(Min/+) mutation in LR;ICE cells not only affects basal levels but also contributes to NO-induced dysregulation of cytoplasmic beta-catenin and nuclear beta-catenin/LEF-1 DNA binding complex formation. C1 NCI, Div Basic Sci, Basic Res Lab, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. RP Mei, JM (reprint author), NCI, Div Basic Sci, Basic Res Lab, Metab & Canc Susceptibil Sect, Room 12-90,Bldg 560, Frederick, MD 21702 USA. NR 29 TC 12 Z9 12 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3379 EP 3383 PG 5 WC Oncology SC Oncology GA 334AF UT WOS:000088162400013 PM 10910042 ER PT J AU Blagosklonny, MV Bishop, PC Robey, R Fojo, T Bates, SE AF Blagosklonny, MV Bishop, PC Robey, R Fojo, T Bates, SE TI Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE PATHWAY; RAF-1/BCL-2 PHOSPHORYLATION; LEUKEMIA-CELLS; APOPTOSIS; TAXOL; DEATH; DIFFERENTIATION; PROLIFERATION; PACLITAXEL; INHIBITION AB Lack of selectivity in the killing of tumor and normal cells is a major obstacle in cancer therapy. By inhibiting normal but not autonomous cell growth, we exploited the differences in cell cycle regulation to achieve a selective protection of nonautonomous cells against paclitaxel and other microtubule-active drugs. Tubulin polymerization, a primary effect of paclitaxel, can be dissociated from Eel-a, phosphorylation and cytotoxicity in HL-60 cells. Growth arrest prevented paclitaxel-induced Bcl-2 phosphorylation and apoptosis without affecting paclitaxel-induced tubulin polymerization, We abrogated the effects of paclitaxel on MCF-10A immortalized breast cells, while preserving its effects on MCF-7 cancer cells. Unlike MCF-7 cells, MCF-10A cells were arrested by epidermal growth factor withdrawal, precluding paclitaxel-induced Bcl-2 phosphorylation, Furthermore, the inhibition of the epidermal growth factor receptor kinase with low doses of AG1478 arrested growth of MCF-10A but not MCF-7 cells. Pretreatment with AG1478 did not affect paclitaxel-induced Bcl-2/Raf-1 phosphorylation in MCF-7 but abrogated such phosphorylation in MCF-10A. Exploitation of growth factor dependency may allow the protection of normal cells from microtubule-active drugs. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. NR 26 TC 42 Z9 42 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3425 EP 3428 PG 4 WC Oncology SC Oncology GA 334AF UT WOS:000088162400022 PM 10910051 ER PT J AU Simeonova, PP Wang, SY Toriuma, W Kommineni, V Matheson, J Unimye, N Kayama, F Harki, D Ding, M Vallyathan, V Luster, MI AF Simeonova, PP Wang, SY Toriuma, W Kommineni, V Matheson, J Unimye, N Kayama, F Harki, D Ding, M Vallyathan, V Luster, MI TI Arsenic mediates cell proliferation and gene expression in the bladder epithelium: Association with activating protein-1 transactivation SO CANCER RESEARCH LA English DT Article ID DRINKING-WATER; URINARY-BLADDER; C-JUN; DIMETHYLARSINIC ACID; HUMAN KERATINOCYTES; CANCER MORTALITY; GROWTH-FACTORS; IN-VITRO; EXPOSURE; SKIN AB Although the mechanism of action has not yet been defined, epidemiological studies have demonstrated an association between elevated arsenic levels in drinking water and the incidence of urinary bladder transitional cell carcinomas, rn the current studies, we demonstrate that mice exposed to 0.01% sodium arsenite in drinking water develop hyperplasia of the bladder urothelium within 4 weeks of exposure. This was accompanied by the accumulation of inorganic trivalent arsenic, and to a lesser extent dimethylarsinic acid, in bladder tissue, as well as a persistent increase in DNA binding of the activating protein (AP)-1 transcription factor. AP-I transactivation by arsenic also occurred in bladders of transgenic mice containing an AP-I luciferase reporter, Consistent with these in vivo observations, arsenite increased cell proliferation and AP-1 DNA binding in a human bladder epithelial cell line, Gene expression studies using RNase protection assays, reverse transcription-PCR, and cDNA microarrays indicated that arsenite alters the expression of a number of genes associated with cell growth, such as c-fos, c-jun, and EGR-1, as well as cell arrest, such as GADD153 and GADD45, The proliferation-enhancing effect of arsenic on uroepithelial cells likely contributes to its ability to cause cancer. C1 NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, NIH, Morgantown, WV 26505 USA. Tanabe Seiyaku Co Ltd, Toda, Saitama 335, Japan. W Virginia Univ, Med Ctr, Dept Urol, Morgantown, WV 26505 USA. Tako Chuo Hosp, Chiba, Japan. RP Simeonova, PP (reprint author), NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, NIH, 1095 Willowdale Rd, Morgantown, WV 26505 USA. NR 44 TC 148 Z9 152 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3445 EP 3453 PG 9 WC Oncology SC Oncology GA 334AF UT WOS:000088162400026 PM 10910055 ER PT J AU Heidel, SM MacWilliams, PS Baird, WM Dashwood, WM Buters, JTM Gonzalez, FJ Larsen, MC Czuprynski, CJ Jefcoate, CR AF Heidel, SM MacWilliams, PS Baird, WM Dashwood, WM Buters, JTM Gonzalez, FJ Larsen, MC Czuprynski, CJ Jefcoate, CR TI Cytochrome P4501B1 mediates induction of bone marrow cytotoxicity and preleukemia cells in mice treated with 7,12-dimethylbenz[a]anthracene SO CANCER RESEARCH LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; CHILDHOOD-CANCER; LUNG-CANCER; DNA-ADDUCTS; BENZOPYRENE; APOPTOSIS; EXPRESSION; METABOLISM; MUTATIONS; EXPOSURE AB Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) through many environmental pollutants, especially cigarette smoke. These chemicals cause a variety of tumors and immunotoxic effects, as a consequence of bioactivation by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but is also a physiological regulator, as evidenced by linkage of CYP1B1 deficiency to congenital human glaucoma. This investigation demonstrates that CYP1B1 null mice are almost completely protected from the acute bone marrow cytotoxic and preleukemic effects of the prototypic PAH 7,12-dimethylbenz[a]anthracene (DMBA), CYP1B1 null mice did not produce the appreciable amounts of bone marrow DMBA dihydrodiol epoxide DNA adducts present in wild-type mice, despite comparable hepatic inductions of the prominent PAM-metabolizing P-450 cytochrome, CYP1A1. Wild-type mice constitutively expressed low levels of bone marrow CYP1B1. These findings suggest that CYP1B1 is responsible for the formation of DMBA dihydrodiol epoxides in the bone marron. Furthermore, this study substantiates the importance of DMBA dihydrodiol epoxide generation at the site of cancer initiation and suggests that tissue-specific constitutive CYP1B1 expression may contribute to cancer susceptibility in the human population. C1 Univ Wisconsin, Med Sci Ctr, Dept Pharmacol, Madison, WI 53706 USA. Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. Univ Wisconsin, Environm Hlth Sci Ctr, Madison, WI 53706 USA. Oregon State Univ, Ctr Environm Hlth Sci, Corvallis, OR 97331 USA. Tech Univ Munich, Int Toxicol & Environm Hlth, D-80636 Munich, Germany. NCI, Bethesda, MD 20892 USA. RP Jefcoate, CR (reprint author), Univ Wisconsin, Med Sci Ctr, Dept Pharmacol, 1300 Univ Ave, Madison, WI 53706 USA. RI Buters, Jeroen/G-5070-2011 FU NIEHS NIH HHS [1F32-ES05827, ES07015, ES09090] NR 42 TC 71 Z9 80 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3454 EP 3460 PG 7 WC Oncology SC Oncology GA 334AF UT WOS:000088162400027 PM 10910056 ER PT J AU Bennett, LM McAllister, KA Malphurs, J Ward, T Collins, NK Seely, JC Gowen, LC Koller, BH Davis, BJ Wiseman, RW AF Bennett, LM McAllister, KA Malphurs, J Ward, T Collins, NK Seely, JC Gowen, LC Koller, BH Davis, BJ Wiseman, RW TI Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER SUSCEPTIBILITY; DNA-DAMAGE RESPONSE; FOLLOW-UP; BRCA1-DEFICIENT MICE; EMBRYONIC LETHALITY; TUMOR-FORMATION; MEIOTIC CELLS; GENE-PRODUCT; IN-UTERO; RISK AB Women who inherit mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are predisposed to the development of breast and ovarian cancer. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALBlc(B1+/-) mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129(B2+/-) mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES), Beginning at 3 weeks of age, BALB/c(B1+/-), 129(B2+/-), and wild-type female mice were fed a control diet or a diet containing 640 ppb DES for 26 weeks. DES treatment caused vaginal epithelial hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and Fibrosis, as well as oviductal smooth muscle hypertrophy. The severity of the DES response was mouse strain specific. The estrogen-responsive 129/SvEv strain exhibited an extreme response in the reproductive tract, whereas the effect in BALB/cJ and C3H/HeN((MMTV-)) mice was less severe. The Brca1 and Brca2 genetic alterations influenced the phenotypic response of BALB/cJ and 129/SvEv inbred strains, respectively, to DES in the mammary gland and ovary. The mammary duct branching morphology was inhibited in DES-treated BALB/c(B1+/-) mice compared with similarly treated BALB/c(B1+/+) littermates. In addition, the majority of BALB/c(B1+/-) mice had atrophied ovaries, whereas wild-type littermates were largely diagnosed with arrested follicular development, The mammary ductal architecture in untreated 129(B2+/-) mice revealed a subtle inhibited branching phenotype that was enhanced with DES treatment. However, no significant differences were observed in ovarian pathology between 129(B2+/+) and 129(B2+/-) mice. These data suggest that estrogenic compounds may modulate mammary gland or ovarian morphology in BALB/c(B1+/-) and 129(B2+/-) mice. These observations are consistent with the hypothesis that compromised DNA repair processes in cells harboring Brca1 or Brca2 mutations lead to inhibited growth and differentiation compared with the proliferative response of wild-type cells to DES treatment. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Pathco Inc, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. RP Bennett, LM (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Mail Drop C4-06,Bldg 101,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Bennett3@niehs.nih.gov FU NIEHS NIH HHS [N01-ES-65399] NR 70 TC 33 Z9 34 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2000 VL 60 IS 13 BP 3461 EP 3469 PG 9 WC Oncology SC Oncology GA 334AF UT WOS:000088162400028 PM 10910057 ER PT J AU Kobayashi, H Carrasquillo, JA Paik, CH Waldmann, TA Tagaya, Y AF Kobayashi, H Carrasquillo, JA Paik, CH Waldmann, TA Tagaya, Y TI Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15 SO CANCER RESEARCH LA English DT Article ID PHASE-I TRIAL; FUSION TOXIN DAB486IL-2; T-CELL; IL-2 RECEPTOR; BETA-CHAIN; THERAPY; PROTEIN; CANCER; IDENTIFICATION; PROLIFERATION AB Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors that share beta and gamma c subunits of their receptors on T/NK-cells, Although these two cytokines share receptor components, the IL-15R alpha molecule is expressed constitutively by various tissue cells, whereas the IL-2R alpha expression is mostly restricted to activated mononuclear cells. Consequently, we postulated that the biodistribution of IL-15 might be different from that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL-15 in pharmacokinetics, biodistribution, and their tumor-targeting abilities. It found that only IL-2 showed specific binding to a protein, alpha(2)-macroglobulin, which may be the reason that IL-2 displays longer blood clearance than IL-15. Upon injection of these cytokines into mice, we observed that IL-15 accumulated significantly more than IL-2 in kidney, spleen, and bone. These are all tissues that express IL-15 receptor alpha but not IL-2 receptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells transfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting that the expression of the alpha chains is sufficient to define specific biodistribution of IL-2 and IL-15, although these cytokines share the beta and gamma c molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent. C1 NCI, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NCI, Warren G Magnuson Clin Ctr, Metab Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. RP Carrasquillo, JA (reprint author), NCI, Dept Nucl Med, NIH, Bldg 10,Room 1C-496,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 33 TC 30 Z9 35 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 JUL 1 PY 2000 VL 60 IS 13 BP 3577 EP 3583 PG 7 WC Oncology SC Oncology GA 334AF UT WOS:000088162400042 PM 10910071 ER PT J AU Hansen, LA Sigman, CC Andreola, F Ross, SA Kelloff, GJ De Luca, LM AF Hansen, LA Sigman, CC Andreola, F Ross, SA Kelloff, GJ De Luca, LM TI Retinoids in chemoprevention and differentiation therapy SO CARCINOGENESIS LA English DT Review ID ACUTE PROMYELOCYTIC LEUKEMIA; ACID RECEPTOR-ALPHA; PML-RAR-ALPHA; ARYL-HYDROCARBON RECEPTOR; FEMALE SENCAR MICE; GROWTH-FACTOR-BETA; BREAST-CANCER; VITAMIN-A; MALIGNANT CONVERSION; 9-CIS-RETINOIC ACID AB Retinoids are essential for the maintenance of epithelial differentiation. As such, they play a fundamental role in chemoprevention of epithelial carcinogenesis and in differentiation therapy. Physiological retinoic acid is obtained through two oxidation steps from dietary retinol, i.e. retinol-->retinal-->retinoic acid. The latter retinal-->retinoic acid step is irreversible and eventually marks disposal of this essential nutrient, through cytochrome P450-dependent oxidative steps. Mutant mice deficient in aryl hydrocarbon receptor (AHR) accumulate retinyl palmitate, retinol and retinoic acid. This suggests a direct connection between the AHR and retinoid homeostasis. Retinoids control gene expression through the nuclear retinoic acid receptors (RARs) alpha, beta and gamma and 9-cis-retinoic acid receptors alpha, beta and gamma, which bind with high affinity the natural ligands all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoids are effective chemopreventive agents against skin, head and neck, breast, liver and other forms of cancer. Differentiation therapy of acute promyelocytic leukemia (APL) is based on the ability of retinoic acid to induce differentiation of leukemic promyelocytes. Patients with relapsed, retinoid-resistant APL are now being treated with arsenic oxide, which results in apoptosis of the leukemic cells. Interestingly, induction of differentiation in promyelocytes and consequent remission of APL following retinoid therapy depends on expression of a chimeric PML-RAR alpha fusion protein resulting from a t(15;17) chromosomal translocation, This protein functions as a dominant negative against the function of both PML and RARs and its overexpression is able to recreate the phenotypes of the disease in transgenic mice. The development of new more effective and less toxic retinoids, alone or in combination with other drugs, may provide additional avenues for cancer chemoprevention and differentiation therapy. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Food Safety & Appl Nutr, OSN, Washington, DC 20204 USA. RP De Luca, LM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 115 TC 199 Z9 212 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2000 VL 21 IS 7 BP 1271 EP 1279 DI 10.1093/carcin/21.7.1271 PG 9 WC Oncology SC Oncology GA 336QD UT WOS:000088313700001 PM 10874003 ER PT J AU Newbold, RR Hanson, RB Jefferson, WN Bullock, BC Haseman, J McLachlan, JA AF Newbold, RR Hanson, RB Jefferson, WN Bullock, BC Haseman, J McLachlan, JA TI Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol SO CARCINOGENESIS LA English DT Article ID FEMALE MICE; NEOPLASTIC TRANSFORMATION; NEONATAL EXPOSURE; PRENATAL EXPOSURE; UTERINE-TUMORS; CARCINOGENESIS; MOUSE; ADENOCARCINOMA; ESTRADIOL; ESTROGENS AB Prenatal exposure to diethylstilbestrol (DES) is associated with reproductive tract abnormalities, subfertility and neoplasia in experimental animals and humans. Studies using experimental animals suggest that the carcinogenic effects of DES may he transmitted to succeeding generations, To further evaluate this possibility and to determine if there is a sensitive window of exposure, outbred CD-1 mice were treated with DES during three developmental stages: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 mu g/kg maternal body weight) during major organogenesis; group II was treated once on day 18 of gestation (1000 mu g/kg maternal body weight) just prior to birth; and group III was treated on days 1-5 of neonatal life (0.002 mu g/pup/day). DES-exposed female mice (F-1) were raised to maturity and bred to control males to generate DES-lineage (Fz) descendants. The Fz males obtained from these matings are the subjects of this report; results in Fz females have been reported previously [Newbold ct al, (1998) Carcinogenesis, 19, 1655-1663], Reproductive performance of FZ males when bred to control females was not different from control males. However, in DES Fz males killed at 17-24 months, an increased incidence of proliferative lesions of the rete testis and tumors of the reproductive tract was observed. Since these increases were seen in all DES treatment groups, all exposure periods were considered susceptible to perturbation by DES, These data suggest that, while fertility of the DES Fz mice appeared unaltered, increased susceptibility for tumors is transmitted from the DES 'grandmothers' to subsequent generations. C1 NIEHS, Environm Toxicol Program, Toxicol Lab, Reprod Toxicol Grp,Dev Endocrinol Sect, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Dis & Med Program, Biostat Branch, Res Triangle Pk, NC 27709 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. RP Newbold, RR (reprint author), NIEHS, Environm Toxicol Program, Toxicol Lab, Reprod Toxicol Grp,Dev Endocrinol Sect, Res Triangle Pk, NC 27709 USA. NR 57 TC 111 Z9 121 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2000 VL 21 IS 7 BP 1355 EP 1363 DI 10.1093/carcin/21.7.1355 PG 9 WC Oncology SC Oncology GA 336QD UT WOS:000088313700012 PM 10874014 ER PT J AU Gomez-Angelats, M Bortner, CD Cidlowski, JA AF Gomez-Angelats, M Bortner, CD Cidlowski, JA TI Cell volume regulation in immune cell apoptosis SO CELL AND TISSUE RESEARCH LA English DT Review DE apoptosis; cell volume; lymphocyte; ion channels; glucocorticoids; Fas ID PROTEIN-KINASE-C; INDUCED THYMOCYTE APOPTOSIS; GATED POTASSIUM CHANNEL; FAS-MEDIATED APOPTOSIS; AMINO-ACID-TRANSPORT; HUMAN T-CELLS; ANISOTONIC MEDIA; TYROSINE PHOSPHORYLATION; DEPENDENT ACTIVATION; HUMAN-LYMPHOCYTES AB The loss of cell volume is an early and fundamental feature of programmed cell death or apoptosis; however, the mechanisms responsible for cell shrinkage during apoptosis are poorly understood. The loss of cell volume is not a passive component of the apoptotic process, and a number of experimental findings from different laboratories highlight the importance of this process as an early and necessary regulatory event in the signaling of the death cascade. Additionally, the loss of intracellular ions, particularly potassium, has been shown to play a primary role in cell shrinkage, caspase activation, and nuclease activity during apoptosis. Thus, an understanding of the role that ion channels and plasma membrane transporters play in cellular signaling during apoptosis may have important physiological implications for immune cells, especially lymphocyte function. Furthermore, this knowledge may also have an impact on the design of therapeutic strategies for a variety of diseases of the immune system in which apoptosis plays a central role, such as oncogenic processes or immune system disorders. The present review summarizes our appreciation of the mechanisms underlying the early loss of cell volume during apoptosis and their association with down-stream events in lymphocyte apoptosis. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 80 TC 53 Z9 53 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD JUL PY 2000 VL 301 IS 1 BP 33 EP 42 DI 10.1007/s004410000216 PG 10 WC Cell Biology SC Cell Biology GA 334JM UT WOS:000088183400005 PM 10928279 ER PT J AU Mattson, MP Culmsee, C Yu, ZF AF Mattson, MP Culmsee, C Yu, ZF TI Apoptotic and antiapoptotic mechanisms in stroke SO CELL AND TISSUE RESEARCH LA English DT Review DE calcium; free radicals; ischemia; neurotrophic factor; NF-kappa B; Par-4 ID FOCAL CEREBRAL-ISCHEMIA; AMYLOID BETA-PEPTIDE; FIBROBLAST GROWTH-FACTOR; TRANSIENT FOREBRAIN ISCHEMIA; DELAYED NEURONAL DEATH; PROTECTS HIPPOCAMPAL-NEURONS; MITOCHONDRIAL PERMEABILITY TRANSITION; MANGANESE SUPEROXIDE-DISMUTASE; METABOLIC EXCITOTOXIC INSULTS; TROPHIC FACTOR WITHDRAWAL AB Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be a prominent form of neuronal death in chronic neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Recent findings also implicate apoptosis in neuronal degeneration after ischemic brain injury in animal models of stroke. Activation of both apoptotic and antiapoptotic signaling cascades occurs in neurons in animal and cell culture models of stroke. Apoptotic cascades involve: increased levels of intracellular oxyradicals and calcium; induction of expression of proteins such as Par-4 (prostate apoptosis response-it), which act by promoting mitochondrial dysfunction and suppressing antiapoptotic mechanisms; mitochondrial membrane depolarization, calcium uptake, and release of factors (e.g., cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation; activation of cysteine proteases of the caspase family, activation of transcription factors such as AP-1 that may induce expression of "killer genes." Antiapoptotic signaling pathways are activated by neurotrophic factors, certain cytokines, and increases in oxidative and metabolic stress. Such protective pathways include: activation of the transcription factors (e.g., nuclear factor-kappa B, NF-kappa B) that induce expression of stress proteins, antioxidant enzymes, and calcium-regulating proteins; phosphorylation-mediated modulation of ion channels and membrane transporters; cytoskeletal alterations that modulate calcium homeostasis; and modulation of proteins that stabilize mitochondrial function (e.g., Bcl-2). Intervention studies in experimental stroke models have identified a battery of approaches of potential benefit in reducing neuronal death in stroke patients, including administration of antioxidants, calcium-stabilizing agents, caspase inhibitors, and agents that activate NF-kappa B. Interestingly, recent studies suggest novel dietary approaches (e.g., food restriction and supplementation with antioxidants) that may reduce brain damage following stroke. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, GRC4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 126 TC 206 Z9 221 U1 3 U2 12 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD JUL PY 2000 VL 301 IS 1 BP 173 EP 187 DI 10.1007/s004419900154 PG 15 WC Cell Biology SC Cell Biology GA 334JM UT WOS:000088183400016 PM 10928290 ER PT J AU An, WG Schulte, TW Neckers, LM AF An, WG Schulte, TW Neckers, LM TI The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210(bcr-abl) and v-src proteins before their degradation by the proteasome SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID TYROSINE KINASE-ACTIVITY; ROUS-SARCOMA VIRUS; CELL-FREE SYSTEM; PH(1)-POSITIVE LEUKEMIA-CELLS; RAT-KIDNEY CELLS; HERBIMYCIN-A; TRANSFORMING PROTEIN; BCR-ABL; PROGESTERONE-RECEPTOR; HETEROPROTEIN COMPLEX AB Several important signaling proteins including transcription factors and protein kinases depend on heat shock protein (Hsp)-90 for stability. p210(bcr-abl), a protein expressed in chronic myelogenous leukemia, is functionally inhibited by the benzoquinone ansamycin herbimycin A. Benzoquinone ansamycins also bind to and inhibit the activity of Hsp90. We now demonstrate that p210(bcr-abl) is complexed with Hsp90 and its cochaperone p23 in K562 chronic myelogenous leukemia cells. Brief exposure to the benzoquinone ansamycin Hsp90 inhibitor geldanamycin (GA) decreases the association of p210(bcr-abl) With Hsp90 and p23 and increases its association with the chaperones Hsp70 and p60(Hop). GA has a similar effect on chaperone association with v-src, another Hsp90-dependent oncogenic kinase. Loss of Hsp90/p23 association and acquisition of Hsp70/p60(Hop) association of both p210(bcr-abl) and v-src precede GA-induced degradation of these kinases. GA-induced degradation is mediated by the proteasome because proteasome inhibitors block the effects of GA, causing both p210(bcr-abl) and v-src to accumulate in a detergent-insoluble cellular fraction. Both p210(bcr-abl) and v-src are more susceptible to GA-induced degradation than are their normal cellular counterparts, c-abl and c-src. C1 NCI, Dept Cell & Canc Biol, Med Branch, NIH, Rockville, MD 20850 USA. RP Neckers, LM (reprint author), NCI, Dept Cell & Canc Biol, Med Branch, NIH, Rockville, MD 20850 USA. NR 53 TC 214 Z9 222 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD JUL PY 2000 VL 11 IS 7 BP 355 EP 360 PG 6 WC Cell Biology SC Cell Biology GA 337XD UT WOS:000088387700002 PM 10939589 ER PT J AU Carroll, RE Matkowsky, KA Tretiakova, MS Battey, JF Benya, RV AF Carroll, RE Matkowsky, KA Tretiakova, MS Battey, JF Benya, RV TI Gastrin-releasing peptide is a mitogen and a morphogen in murine colon cancer SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID CELL LUNG-CANCER; HUMAN BREAST-CANCER; BOMBESIN-LIKE PEPTIDES; SWISS 3T3 CELLS; EPITHELIAL-CELLS; RECEPTOR EXPRESSION; ANTAGONIST RC-3095; COLORECTAL-CANCER; PROTEIN-KINASE; GROWTH-FACTORS AB Little is known about the factors involved in regulating the appearance, or differentiation, of solid tumors including those arising from the colon. We herein demonstrate that the mitogen gastrin-releasing peptide (GRP) is a morphogen, critically important in regulating the differentiation of murine colon cancer. Although epithelial cells lining the mouse colon do not normally express GRP and its receptor (GRP-R), both are aberrantly expressed by all better differentiated cancers in wild-type C57BL/6J mice treated with the carcinogen azoxymethane, Whereas small tumors in both wild-type and GRP-R-deficient (i.e., GRP-R-/-) mice are histologically similar, larger tumors become better differentiated in the former but degenerate into more poorly differentiated mucinous adenocarcinomas in the latter. This alteration in phenotype is attributable to GRP increasing focal adhesion kinase expression in GRP-R-expressing tumors. Consistent with GRP acting as a mitogen, GRP/GRP-R coexpressing tumors in wild-type animals also contain more proliferating cells than those occurring in GRP-R-/- mice. Yet tumors are similarly sized in animals of either genotype receiving azoxymethane for identical times, a finding attributable to the significantly higher number of apoptotic cells detected in GRP/GRP-R coexpressing cancers. Thus, these findings indicate that although GRP is a mitogen, aberrant expression does not result in increased tumor growth. Rather, the mitogenic properties of GRP are subordinate to it acting as a morphogen, where it and its receptor are critically involved in regulating colon cancer histological progression by promoting a well-differentiated phenotype. C1 Univ Illinois, Dept Med, Chicago, IL 60612 USA. Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. Chicago Vet Adm Med Ctr, W Side Div, Chicago, IL 60612 USA. NIDOCD, NIH, Bethesda, MD 20892 USA. RP Benya, RV (reprint author), Univ Illinois, Dept Med, 840 S Wood St M-C 787, Chicago, IL 60612 USA. FU NCI NIH HHS [CA-80360]; NIDDK NIH HHS [DK-51168] NR 53 TC 29 Z9 29 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD JUL PY 2000 VL 11 IS 7 BP 385 EP 393 PG 9 WC Cell Biology SC Cell Biology GA 337XD UT WOS:000088387700005 PM 10939592 ER PT J AU Rand, RP Parsegian, VA Rau, DC AF Rand, RP Parsegian, VA Rau, DC TI Intracellular osmotic action SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE water; osmotic stress; channels; enzymes; DNA; actin ID PROBING ALAMETHICIN CHANNELS; WATER-SOLUBLE POLYMERS; HYDRATION CHANGES; PROTEIN SOLVATION; VOLUME CHANGES; DNA-BINDING; BOUND WATER; STRESS; FORCES; MOLECULES AB Water often acts as a critical reactant in cellular reactions. Its role can be detected by modulating water activity with osmotic agents. We describe the principles behind this 'osmotic stress' strategy, and survey the ubiquity of water effects on molecular structures that have aqueous, solute-excluding regions. These effects are seen with single-functioning molecules such as membrane channels and solution enzymes, as well as in the molecular assembly of actin, the organization of DNA and the specificity of protein/DNA interactions. C1 Brock Univ, Dept Biol Sci, St Catharines, ON L2S 3A1, Canada. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Rand, RP (reprint author), Brock Univ, Dept Biol Sci, St Catharines, ON L2S 3A1, Canada. NR 41 TC 39 Z9 41 U1 1 U2 9 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2000 VL 57 IS 7 BP 1018 EP 1032 DI 10.1007/PL00000742 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 342MN UT WOS:000088648600005 PM 10961342 ER PT J AU Ellis, CA Clark, G AF Ellis, CA Clark, G TI The importance of being K-Ras SO CELLULAR SIGNALLING LA English DT Review DE Ras; oncogene; signalling; cancer ID NIH 3T3 CELLS; PROTEIN-KINASE KINASE; GDP DISSOCIATION STIMULATOR; GUANINE-NUCLEOTIDE EXCHANGE; COLON EPITHELIAL-CELLS; HA-RAS; N-RAS; PLASMA-MEMBRANE; IN-VIVO; SIGNAL-TRANSDUCTION AB The ras genes give rise to a family of related proteins that have strong transforming potential. Typical in vitro studies fail to discriminate between the transforming activity of the Ras proteins. Although activating mutations in ras genes are commonly found in human disease, they are not evenly distributed between the different ras members. Instead, they are concentrated in k-ras. With the absence of evidence to suggest that k-ras DNA is more prone to mutation than h-ras DNA, this imbalance in mutational frequency suggests a special biological role for the K-Ras protein in vivo. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. RP Clark, G (reprint author), NCI, Dept Cell & Canc Biol, NIH, 9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 154 TC 107 Z9 115 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD JUL PY 2000 VL 12 IS 7 BP 425 EP 434 DI 10.1016/S0898-6568(00)00084-X PG 10 WC Cell Biology SC Cell Biology GA 357AM UT WOS:000089476400001 PM 10989276 ER PT J AU Huxlin, KR Saunders, RC Marchionini, D Pham, HA Merigan, WH AF Huxlin, KR Saunders, RC Marchionini, D Pham, HA Merigan, WH TI Perceptual deficits after lesions of inferotemporal cortex in macaques SO CEREBRAL CORTEX LA English DT Article ID INFERIOR TEMPORAL CORTEX; RHESUS-MONKEYS; FOVEAL PRESTRIATE; VISUAL DISCRIMINATION; CORTICAL CONNECTIONS; AREA TEO; STIMULI; IMPAIRMENTS; NEURONS; LOBE AB This study used a novel approach to examine a much studied question, the nature of visual deficits caused by lesions of the inferotemporal cortex (IT). Unlike many previous studies of IT lesions, we de-emphasized early, non-specific disruptions of testing caused by the lesions, and instead concentrated on permanent changes in thresholds. This approach produced unexpected results that suggest a re-evaluation of the traditional view of the role of the IT cortex in shape perception and such related visual abilities as perceptual invariances, visual grouping, the visibility of illusory contours and the performance of oddity discriminations. In addition, the measurement of stable, post-lesion hue discrimination thresholds gave us a different perspective on the severity of color vision deficits which result from lesions of the IT cortex. We found that shape distortion thresholds were not permanently elevated by IT lesions and, indeed, showed no greater transitory disruption than did other visual abilities. This result is inconsistent with the common view that IT is critical to shape discriminations. Two other visual abilities that would be expected to be disrupted by IT lesions - the visual grouping of misoriented line segments and shape invariances (failure of irrelevant stimulus changes to disrupt shape distortion thresholds) - were not affected by IT lesions. However, shape discriminations based on illusory contours and some oddity discriminations were severely and permanently affected. Our results also showed that IT lesions caused permanent, moderate to large impairments of color vision, but not color blindness. Bilateral damage to area TEO caused no disruption of performance on any of the above discriminations. Our results suggest that the IT cortex in macaques may be critical to the visibility of illusory contours and the performance of some oddity discriminations, that it plays some role in color perception, but that it is not essential for shape, grouping discriminations or perceptual shape invariances. C1 Univ Rochester, Med Ctr, Dept Ophthalmol, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Ctr Visual Sci, Rochester, NY 14642 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Huxlin, KR (reprint author), Univ Rochester, Med Ctr, Dept Ophthalmol, Box 314, Rochester, NY 14642 USA. EM huxlin@cvs.rochester.edu FU NEI NIH HHS [EY08898] NR 49 TC 65 Z9 65 U1 1 U2 1 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 JUL PY 2000 VL 10 IS 7 BP 671 EP 683 DI 10.1093/cercor/10.7.671 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 333RB UT WOS:000088142400004 PM 10906314 ER PT J AU Quintanilla-Vega, B Hoover, DJ Bal, W Silbergeld, EK Waalkes, MP Anderson, LD AF Quintanilla-Vega, B Hoover, DJ Bal, W Silbergeld, EK Waalkes, MP Anderson, LD TI Lead interaction with human protamine (HP2) as a mechanism of male reproductive toxicity SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID HUMAN-SPERM PROTAMINES; ZINC-FINGER PROTEINS; DNA STRAND BREAKS; P2 PROTAMINES; METAL-BINDING; IN-SITU; CHROMATIN; EXPOSURE; DECONDENSATION; DENATURATION AB During spermatogenesis, histones are replaced by protamines, which condense and protect sperm DNA. In humans, zinc contributes to sperm chromatin stability and binds to protamine P2 (HP2). Chemical interactions with nuclear protamines, which prevent normal sperm chromatin condensation, may induce changes in the sperm genome and thus affect fertility and offspring development. Since lead has a high affinity for zinc-containing proteins, we investigated lead interactions with HP2 as a novel mechanism of its toxicity to sperm. UV/vis and CD spectroscopy results indicated that HP2 binds Pb2+ at two different sites, causing a conformational change in the protein. They also provided evidence that thiol groups are primarily involved in Zn2+ and Pb2+ binding to HP2 and that HP2 may have additional binding sites for Pb2+ not related to Zn2+. HP2 affinities for Pb2+ and Zn2+ were very similar, suggesting that Pb2+ can compete with or replace Zn2+ in HP2 in vivo. This interaction of lead with HP2 resulted in a dose-dependent decrease in the extent of HPS-DNA binding, although lead interaction with DNA also contributed to this effect. Therefore, the ability of lead to decrease the level of HP2-DNA interaction may result in alterations to sperm chromatin condensation, and thus in reduced fertility. C1 IPN, CINVESTAV, Secc Toxicol Ambiental, Mexico City 07360, DF, Mexico. NIEHS, NCI, Res Triangle Pk, NC 27709 USA. Univ Maryland, Sch Med, Program Human Hlth & Environm, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Univ Wroclaw, Fac Chem, PL-50138 Wroclaw, Poland. NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. RP Quintanilla-Vega, B (reprint author), IPN, CINVESTAV, Secc Toxicol Ambiental, Ave IPN 2508, Mexico City 07360, DF, Mexico. NR 54 TC 45 Z9 48 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JUL PY 2000 VL 13 IS 7 BP 594 EP 600 DI 10.1021/tx000017v PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 336QB UT WOS:000088313500009 PM 10898591 ER PT J AU Bal, W Liang, RT Lukszo, J Lee, SH Dizdaroglu, M Kasprzak, KS AF Bal, W Liang, RT Lukszo, J Lee, SH Dizdaroglu, M Kasprzak, KS TI Ni(II) specifically cleaves the C-terminal tail of the major variant of histone H2A and forms an oxidative damage mediating complex with the cleaved-off octapeptide SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DNA-BASE DAMAGE; CHROMATOGRAPHY-MASS-SPECTROMETRY; MALE F344 RATS; CHROMATIN CONDENSATION; DEOXYRIBONUCLEIC-ACID; NICKEL CARCINOGENESIS; STRAND SCISSION; BINDING; PROTEIN; NUCLEOSOME AB The acetyl-TESHHK-amide peptide, modeling a part of the C-terminal "tail" of histone H2A, was found previously by us to undergo at pH 7.4 a Ni(II)-assisted hydrolysis of the E-S peptide bond with formation of a stronger Ni(II) complex with the SHHK-amide product [Bal, W., et al. (1998) Chem. Res. Toxicol. 11, 1014-1023]. To further characterize the hydrolysis and test the resulting Ni(II) complex for redox activity, bovine histone H2A and three peptides were investigated: acetyl-LLGKVTIAQGGVLPNIQAVLLPKKTESHHKAKGK (H2A(34)), modeling the entire "C-tail" of H2A; SHHKAKGK (H2A(8)), modeling the cutoff product of hydrolysis; and acetyl-KTESHKAKGK (H2A(10)), modeling a putative Ni(II) binding site in a minor variant H2A.4 of human histone H2A. The Ni(II)-assisted hydrolysis of H2A and H2A(34) was found to proceed approximately 7-fold faster than that of the Ni(II)- acetyl-TESHHK-amide complex under comparable conditions. In both cases, the Ni(II) complex with H2A(8) was the smaller product of the hydrolysis, indicating a high site specificity of the reaction. Of three other metals tested with H2A(34), only Cu(II) cleaved the E-S bond, although much less efficiently than Ni(II); Co(II) and Zn(II) had no effect whatsoever. The H2A(10) peptide appeared to be fully resistant to hydrolytic cleavage and did not exhibit any redox activity versus H2O2 in the presence of Ni(II) at pH 7.4. Likewise, redox-inactive was the Ni(II)-H2A(34) complex. In contrast, the Ni(II)-H2A(8) complex promoted oxidative damage of pUC19 DNA by H2O2, evidenced by a significant increase in the number of single strand breaks and nucleobase modifications typical for a hydroxyl radical-like species attack on DNA. Interestingly, instead of 8-oxopurines, the corresponding formamidopyrimidines were the major products of the damage. The difference in redox activity between the Ni(II)-H2A(34) and Ni(II)-H2A8 complexes is most likely associated with their different geometries: octahedral and square planar, respectively. Incubation of the Ni(II)-H2A8 complex with H2O2 also resulted in degradation of the peptide ligand, especially at its Ser and His residues. Thus, binding of Ni(II) to the ESHHK motif of the histone H2A C-tail is damaging to the histone C-terminal tail and to histone-associated DNA. The results support a dual mechanism of Ni(II)-induced carcinogenesis, including both genotoxic and epigenetic effects. C1 NCI, KSK, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. NIAID, Chem Sci & Technol Lab, Rockville, MD 20852 USA. Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland. RP Bal, W (reprint author), NCI, KSK, Comparat Carcinogenesis Lab, FCRDC, Bldg 538,Rm 205, Frederick, MD 21702 USA. RI Jerzykiewicz, Lucjan/I-2325-2013 OI Jerzykiewicz, Lucjan/0000-0001-9756-7035 NR 54 TC 95 Z9 96 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JUL PY 2000 VL 13 IS 7 BP 616 EP 624 DI 10.1021/tx0000441 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 336QB UT WOS:000088313500012 PM 10898594 ER PT J AU Saavedra, J Keefer, L AF Saavedra, J Keefer, L TI NO better pharmaceuticals SO CHEMISTRY IN BRITAIN LA English DT Article ID NITRIC-OXIDE DONORS; PULMONARY-HYPERTENSION; CEREBRAL VASOSPASM; IN-VIVO; ADDUCT; DELIVERY; REVERSAL C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. RP Saavedra, J (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. NR 20 TC 14 Z9 14 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD,, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0009-3106 J9 CHEM BRIT JI Chem. Br. PD JUL PY 2000 VL 36 IS 7 BP 30 EP 33 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 334AD UT WOS:000088162200061 ER PT J AU Suizzo, MA AF Suizzo, MA TI The social-emotional and cultural contexts of cognitive development: Neo-Piagetian perspectives SO CHILD DEVELOPMENT LA English DT Editorial Material AB The neo-Piagetian research on individual differences in cognitive development reviewed by Larivee, Normandeau, and Parent suggests that Piaget's theory can be used to explain variability in development. My commentary explores this question further through a discussion of two additional sources of variation in children's cognitive development: social-emotional context and cultural meanings. C1 NICHHD, Child & Family Res Sect, Bethesda, MD 20892 USA. RP Suizzo, MA (reprint author), NICHHD, Child & Family Res Sect, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM ms497y@nih.gov NR 19 TC 9 Z9 9 U1 2 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2000 VL 71 IS 4 BP 846 EP 849 DI 10.1111/1467-8624.00191 PG 4 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 356KZ UT WOS:000089443600004 PM 11016549 ER PT J AU Appelbaum, M Batten, DA Belsky, J Boller, K Friedman, S Phillips, D Booth, CL Spieker, SJ Bradley, R Caldwell, B Brownell, C Campbell, S Burchinal, P Cox, M Clarke-Stewart, A Hirsh-Pasek, K Weinraub, M Huston, A Knoke, B Wallner-Allen, KE Marshall, N McCartney, K O'Brien, M Tresch-Owen, M Pianta, R Vandell, DL AF Appelbaum, M Batten, DA Belsky, J Boller, K Friedman, S Phillips, D Booth, CL Spieker, SJ Bradley, R Caldwell, B Brownell, C Campbell, S Burchinal, P Cox, M Clarke-Stewart, A Hirsh-Pasek, K Weinraub, M Huston, A Knoke, B Wallner-Allen, KE Marshall, N McCartney, K O'Brien, M Tresch-Owen, M Pianta, R Vandell, DL CA Natl Inst Child Hlth Human Dev Ear TI The relation of child care to cognitive and language development SO CHILD DEVELOPMENT LA English DT Article ID EARLY INTERVENTION; LOW-INCOME; ACADEMIC-ACHIEVEMENT; MATERNAL EMPLOYMENT; QUALITY; MOTHER; FAMILIES; AGE; EXPERIENCES; PERFORMANCE AB Children from 10 sites in the United States were followed from birth to age 3 to determine how experiences in child care relate to cognitive and language development (Ns varied between 595 and 856, depending on the assessment). Multiple assessments of family and child care environments and of cognitive and language competence were collected. Analyses that adjusted for maternal vocabulary score, family income, child gender, observed quality of the home environment, and observed maternal cognitive stimulation indicated that the overall quality of child care, and language stimulation in particular, was consistently but modestly related to cognitive and language outcomes at ages 15, 24, and 36 months. The effect sizes for high (top quartile) versus low (bottom quartile) quality ranged from .18 to .48. After adjusting for child care quality, cumulative experience in center-based care was associated with better outcomes than was participation in other types of care. The amount of time children spent in care was not related to outcomes. Children in exclusive maternal care did not differ systematically from children in child care. Tests for lagged relations of earlier child care experiences to later performance (adjusting for current child care) showed that language stimulation predicted subsequent cognitive and language performance 9 to 12 months later. Although children in center care at age 3 performed better than children in other types of care, earlier experience in child care homes was associated with better performance at age 3 than was experience in other types of care. The relations of child care variables to outcomes did not vary consistently as a function of family income, quality of home environment, child gender, or ethnic group. C1 NICHHD, Ctr Res Mothers & Childrens, Rockville, MD 20852 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Vanderbilt Univ, Nashville, TN USA. Penn State Univ, University Pk, PA 16802 USA. Univ Washington, Seattle, WA 98195 USA. Univ Arkansas, Little Rock, AR 72204 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Calif Irvine, Irvine, CA USA. Temple Univ, Philadelphia, PA 19122 USA. Univ Texas, Austin, TX 78712 USA. Res Triangle Inst, Raleigh, NC USA. Wellesley Coll, Wellesley, MA 02181 USA. Univ New Hampshire, Durham, NH 03824 USA. Univ Kansas, Lawrence, KS 66045 USA. Univ Texas, Dallas, TX 75230 USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Wisconsin, Madison, WI USA. RP Friedman, S (reprint author), NICHHD, Ctr Res Mothers & Childrens, 6100 Execut Blvd, Rockville, MD 20852 USA. EM friedmas@exchange.nih.gov RI Marshall, Nancy/C-3428-2012 NR 100 TC 236 Z9 242 U1 12 U2 46 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2000 VL 71 IS 4 BP 960 EP 980 PG 21 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 356KZ UT WOS:000089443600015 ER PT J AU Plehn-Dujowich, D Bell, P Ishov, AM Baumann, C Maul, GG AF Plehn-Dujowich, D Bell, P Ishov, AM Baumann, C Maul, GG TI Non-apoptotic chromosome condensation induced by stress: delineation of interchromosomal spaces SO CHROMOSOMA LA English DT Article ID PROLIFERATION-RELATED ANTIGEN; NUCLEAR DOMAIN-10 ND10; HIGHER-ORDER STRUCTURE; COILED BODIES; CELL-CYCLE; INSITU HYBRIDIZATION; GENE-EXPRESSION; KI-67 DETECTS; HEAT-SHOCK; CHROMATIN AB Chromosomes are known to occupy distinct territories, suggesting the existence of definite borders. Visualization of these borders requires chromatin condensation like that seen in prophase cells. We developed a novel method to induce chromosome condensation in all cells regardless of cell cycle stage using a complex set of stresses. The cells were not apoptotic, as indicated by the absence of DNA damage, maintenance of the intact lamina and scaffold attachment factor A, and by the continuation of metabolic processes as well as proliferative capacity. That the appearance of chromosome condensation did not represent a premature mitotic event was shown by the absence of fibrillarin and Ki67 envelopment of chromosomes, continued protein synthesis and the reversibility of chromosome condensation. That chromosome condensation was achieved was demonstrated by the removal of chromatin from the nuclear envelope and chromosome painting. Specific genetic sites known to be at the surface of chromosomes retained their positions as shown by in situ hybridization. Stress-induced chromosome condensation was used to Drove that specific nuclear domains such as ND10 are inter-chromosomally located and that green fluorescent protein-tagged ND10-associated proteins are useful markers for chromosomal boundaries after adenovirus 5 track formation in vivo. From these observations we conclude that chromosomal territories appear to have boundaries that exclude developing macromolecular aggregates. C1 Wistar Inst, Philadelphia, PA 19104 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Maul, GG (reprint author), Wistar Inst, 3601 Spruce St, Philadelphia, PA 19104 USA. RI Ishov, Alexander/E-4912-2010 FU NIAID NIH HHS [AI 41136]; NICHD NIH HHS [HD 34612]; NIGMS NIH HHS [GM 57599] NR 69 TC 25 Z9 25 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD JUL PY 2000 VL 109 IS 4 BP 266 EP 279 DI 10.1007/s004120000073 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 339UR UT WOS:000088496700006 PM 10968255 ER PT J AU Reischl, IG Dubois, GR Peiritsch, S Brown, KS Wheat, L Woisetschlager, M Mudde, GC AF Reischl, IG Dubois, GR Peiritsch, S Brown, KS Wheat, L Woisetschlager, M Mudde, GC TI Regulation of Fc epsilon RI expression on human monocytic cells by ligand and IL-4 SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE cell line; Fc epsilon RI; human; IgE; IL-4; monocytes; regulation; transfection ID AFFINITY IGE RECEPTOR; EPIDERMAL LANGERHANS CELLS; IMMUNOGLOBULIN-E; HUMAN BASOPHILS; GAMMA-CHAIN; MAST-CELLS; SIGNAL-TRANSDUCTION; MESSENGER-RNA; SERUM IGE; IN-VIVO AB Background The Fc epsilon RI subunit composition and kinetic of expression differ between antigen-presenting cells and mast cells. Up to now, there has been no human in vitro model available that mimics the characteristics on monocytes. Objective The characterization of a natural human monocytic cell line (THP1), which expresses Fc epsilon RI, and the comparison to primary human monocytes and other monocytic cell lines, which only express Fc epsilon RI after transfection with the human Fc epsilon RI alpha-chain gene. Methods Surface receptor expression was characterized by flow cytometry, the human Fc epsilon RI alpha-chain gene was introduced by electroporation, and induction of Fc epsilon RI alpha-chain message was detected by semiquantitative RT PCR. Results Here we show that the parental human cell line THP1, but none of the other cell lines tested, displays surface Fc epsilon RI in response to IL-4 or incubation with receptor ligand (IgE, antibody). Transfection of Fc epsilon RI alpha-chain resulted in receptor expression on all cell lines, all of which increased surface Fc epsilon RI in the presence of IgE. Only the THP1-alpha transfectant, however, further increased receptor levels in response to IL-4, resulting from mRNA induction for the Fc epsilon RI-alpha, but not the beta- or gamma-subunit. Conclusion Based on THP1, U937 and HL60 and their alpha-chain transfectants we present a model system for the study of Fc epsilon RI regulation and signalling on human cells. THP1 in particular, due to its responsiveness to both ligand and IL-4, even without prior manipulation, is ideally suited to address questions on Fc epsilon RI modulation in an 'allergic environment'. C1 Novartis Res Inst, Dept Immunol, A-1235 Vienna, Austria. RP Reischl, IG (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 9N256, Bethesda, MD 20892 USA. NR 36 TC 17 Z9 17 U1 1 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD JUL PY 2000 VL 30 IS 7 BP 1033 EP 1040 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 334CP UT WOS:000088167800018 PM 10848927 ER PT J AU Rider, LG Artlett, CM Foster, CB Ahmed, A Neeman, T Chanock, SJ Jimenez, SA Miller, FW AF Rider, LG Artlett, CM Foster, CB Ahmed, A Neeman, T Chanock, SJ Jimenez, SA Miller, FW CA Childhood Myositis Heterogeneity C TI Polymorphisms in the IL-1 receptor antagonist gene VNTR are possible risk factors for juvenile idiopathic inflammatory myopathies SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE IL-1 receptors (genetics); polymorphism; genetic risk factor; myositis; juvenile dermatomyositis ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; GRAVES-DISEASE; BOWEL-DISEASE; INTERLEUKIN-1; DERMATOMYOSITIS; ASSOCIATION; SUSCEPTIBILITY; SEVERITY AB Although HLA-DRB1 and -DQA1 alleles have been associated with adult and juvenile idiopathic inflammatory myopathies (JIIM), they only partially account for the genetic risk for these autoimmune disorders. Because IL-1 alpha and IL-1 beta, and the anti-inflammatory competitive inhibitor, IL-1 receptor antagonist (IL-1Ra), have been implicated in the pathogenesis of myositis, we assessed the role of variable number tandem repeat (VNTR) polymorphisms of the IL-1Ra gene (IL-1RN) in the aetiology of JIIM: IL-1RN VNTR polymorphisms were performed on 250 JIIM patients and 471 race-matched controls and were correlated with clinical characteristics. The IL-1RN A1 allele, associated with increased proinflammatory activity, was found to be a risk factor for Caucasians with JIIM (96.0% carriage rate versus 90.2% in race-matched controls, P-corr = 0.037, odds ratio (OR) = 2.5, confidence interval (CI) = 1.1-5.8), but not for African-Americans, in whom the A3 allele was a possible risk factor (7.0% versus 1.1% in race-matched controls, P-corr = 0.07, OR = 6.5, CI = 1.1-40.3). IL-1RN genotypes did not correlate with circulating levels of IL-1Ra, which were higher in patients than in controls. The polymorphic IL-1RN locus could be the first non-MHC genetic risk factor identified for JIIM, and different alleles may confer susceptibility for different ethnic groups. C1 US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD 20892 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Div Rheumatol, Philadelphia, PA 19107 USA. NCI, Paediat Oncol Branch, Bethesda, MD 20892 USA. Specialty Labs, Santa Monica, CA USA. US FDA, Div Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Rider, LG (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Bldg 29B,Room 2G11,HFM-561,8800 Rockville Pike, Bethesda, MD 20892 USA. OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 34 TC 41 Z9 49 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2000 VL 121 IS 1 BP 47 EP 52 DI 10.1046/j.1365-2249.2000.01266.x PG 6 WC Immunology SC Immunology GA 328NH UT WOS:000087856600008 PM 10886238 ER PT J AU Davis, TA Maloney, DG Grillo-Lopez, AJ White, CA Williams, ME Weiner, GJ Dowden, S Levy, R AF Davis, TA Maloney, DG Grillo-Lopez, AJ White, CA Williams, ME Weiner, GJ Dowden, S Levy, R TI Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a SO CLINICAL CANCER RESEARCH LA English DT Article ID RECOMBINANT ALPHA-INTERFERON; MONOCLONAL-ANTIBODY THERAPY; B-CELL LYMPHOMA; ANTITUMOR-ACTIVITY; TRIAL; INVIVO; IDEC-C2B8; IDIOTYPE; CYTOTOXICITY; AUGMENTATION AB Rituximab and IFN have each demonstrated single-agent activity in patients with low-grade non-Hodgkins lymphoma (NHL), A single-arm, multicenter, Phase II trial was conducted to assess the safety and efficacy of combination therapy with rituximab and IFN-alpha-2a in 38 patients with relapsed or refractory, low-grade or follicular, B-cell NHL, IFN-alpha-2a [2,5 or 5 million units (MIU)I was administered s,c., three times weekly for 12 weeks. Starting on the fifth week of treatment, rituximab was administered by i,v, infusion (375 mg/m(2)) weekly for 4 doses. All 38 patients received four complete infusions of rituximab and were evaluable for efficacy, although 11 patients (29%) did not receive all 36 injections of IFN, The mean number of IFN-alpha-2a injections was 31 doses; the mean total units received were 141 MIU (maximum, 180 MIU), The study treatment was reasonably well tolerated with no unexpected toxicities stemming from the combination therapy. No grade 4 events were reported. Frequent adverse events during the treatment period included asthenia (35 of 38 patients), chills (31 of 38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and myalgia (22 of 38), The overall response rate was 45% (17 of 38 patients); 11% had a complete response, and 34% had a partial response. The Kaplan-Meier estimates for the median response duration and the median time to progression in responders are 22.3 and 25.2 months, respectively. Further follow-up is needed to determine whether this treatment combination leads to a significantly longer time to progression than single-agent treatment with rituximab. C1 NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD 20852 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. IDEC Pharmaceut COrp, San Diego, CA 92121 USA. Univ Virginia, Hlth Sci Ctr, Charlottesville, VA 22908 USA. Univ Iowa, Iowa City, IA 52242 USA. Stanford Univ, Ctr Med, Stanford, CA 94305 USA. RP Davis, TA (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Execut Plaza N 715,6130 Execut Blvd, Rockville, MD 20852 USA. NR 62 TC 96 Z9 101 U1 0 U2 1 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 JUL PY 2000 VL 6 IS 7 BP 2644 EP 2652 PG 9 WC Oncology SC Oncology GA 333TU UT WOS:000088147500008 PM 10914705 ER PT J AU Breathnach, OS Georgiadis, MS Schuler, BS Pizzella, P Llorens, V Kasturi, V Steinberg, SM O'Neil, K Takimoto, CH Johnson, BE AF Breathnach, OS Georgiadis, MS Schuler, BS Pizzella, P Llorens, V Kasturi, V Steinberg, SM O'Neil, K Takimoto, CH Johnson, BE TI Phase II trial of paclitaxel by 96-hour continuous infusion in combination with cisplatin for patients with advanced non-small cell lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; CLINICAL-TRIALS; 3-HOUR INFUSION; BREAST-CANCER; LINES; TAXOL; CARBOPLATIN; TOXICITY; EXPOSURE; SCHEDULE AB Our purpose was to determine the antitumor efficacy and safety profile of the combination of paclitaxel administered by 96-h continuous i,v, infusion followed by bolus cisplatin in patients with untreated advanced non-small cell lung cancer (NSCLC), Fifty-eight patients with untreated advanced or recurrent NSCLC were enrolled between October 1995 and December 1998, The median patient age was 60 years (age range, 34-75 years). Twenty-four patients were female. The majority of patients (n = 52) had an Eastern Cooperative Oncology Group performance status of 0/1, Twelve patients had stage IIIB NSCLC, 43 had stage IV disease, and 3 had recurrent disease after prior resection, Seven patients had received cranial irradiation for brain metastases, and 5 patients had received bone irradiation before enrollment. Patients,were treated with paclitaxel (120 mg/m(2)/96 h) by continuous i,v, infusion followed by cisplatin (80 mg/m(2)) on day 5, Therapy was administered every 3 weeks as tolerated until disease progression or a maximum of six cycles. A total of 264 cycles of therapy were administered. Twenty-nine patients received all six cycles, Forty-six patients had measurable disease, with 20 patients achieving a partial response, and no complete responses were seen (overall response rate, 43%; 95% confidence interval, 29-60%), The median progression-free survival was 5.5 months. At a median potential follow-up of 27.2 months, the median survival for all 58 enrolled patients was 8.5 months, and the actuarial 1-year survival was 37% (95% confidence interval, 25.9-50.5%). This is the most extensive evaluation of prolonged continuous infusional paclitaxel in patients,vith advanced-stage cancer. In contrast to predictions from in vitro cytotoxicity models, the regimen does not appear to be obviously superior to shorter infusion times in the clinical setting. Additional trials of this regimen in patients with NSCLC are therefore of low priority. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Natl Naval Med Ctr, Med Branch, Bethesda, MD 20889 USA. NCI, Natl Naval Med Ctr, Biostat & Data Management Sect, Bethesda, MD 20889 USA. NCI, Natl Naval Med Ctr, Div Clin Sci, Bethesda, MD 20889 USA. Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. Natl Naval Med Ctr, Dept Pulm Med, Bethesda, MD 20889 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Dana 1234,44 Binney St, Boston, MA 02115 USA. NR 37 TC 9 Z9 10 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 JUL PY 2000 VL 6 IS 7 BP 2670 EP 2676 PG 7 WC Oncology SC Oncology GA 333TU UT WOS:000088147500011 PM 10914708 ER PT J AU Beers, R Chowdhury, P Bigner, D Pastan, I AF Beers, R Chowdhury, P Bigner, D Pastan, I TI Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display SO CLINICAL CANCER RESEARCH LA English DT Article ID MIMICKING SOMATIC HYPERMUTATION; AFFINITY MATURATION; HUMAN TUMORS; IN-VITRO; MUTAGENESIS; SELECTION; LIBRARY; DOMAINS; SITE AB Recombinant immunotoxins are fusion proteins composed of Fv regions of antibodies and bacterial or plant toxins that are being developed for the targeted therapy of cancer, MR1(Fv)-PE38 is a single-chain recombinant immunotoxin that targets a mutant form of the epidermal growth factor receptor (EGFR), EGFRvIII, that is frequently overexpressed in malignant glioblastomas. We have used random complementarity determining region (CDR) mutagenesis to obtain mutants of MR1(Fv) with an increased affinity for EGFRvIII and an increased activity when converted to a recombinant immunotoxin. Initially, nine residues of heavy chain CDR3 were randomly mutagenized, and several mutants with increased binding affinity were isolated. All mutations were located at amino acids 98 and 99, which correspond to a DNA hot spot, a DNA sequence that mutates at high frequency during natural antibody maturation. A specific region of variable region of antibody light chain CDR3 was mutagenized that corresponded to a hot spot and a mutant (MR1-1) with an additional increase in affinity, and cytotoxic activity was isolated. These studies show that targeting hot spots in the CDRs of Fvs is an effective approach to obtaining Fvs with increased affinity. The increased affinity of MR1-1(FV) makes it an attractive candidate for the targeted therapy of glioblastomas. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 28 TC 58 Z9 60 U1 0 U2 5 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 JUL PY 2000 VL 6 IS 7 BP 2835 EP 2843 PG 9 WC Oncology SC Oncology GA 333TU UT WOS:000088147500035 PM 10914732 ER PT J AU Killoran, CE Abbott, M McKusick, VA Biesecker, LG AF Killoran, CE Abbott, M McKusick, VA Biesecker, LG TI Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis SO CLINICAL GENETICS LA English DT Article DE congenital limb deformities; GLI3 gene; hypothalamic hamartoma; multiple abnormalities; mutation; Pailister-Hall syndrome; VACTERL association ID GLI3 AB The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GLI3, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Johns Hopkins Univ, Ctr Med Genet, Baltimore, MD USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr Room 4C72, Bethesda, MD 20892 USA. NR 9 TC 14 Z9 18 U1 1 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUL PY 2000 VL 58 IS 1 BP 28 EP 30 DI 10.1034/j.1399-0004.2000.580105.x PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 339JA UT WOS:000088472900005 PM 10945658 ER PT J AU Lin, FYC Azimi, PH Weisman, LE Philips, JB Regan, J Clark, P Rhoads, GG Clemens, J Troendle, J Pratt, E Brenner, RA Gill, V AF Lin, FYC Azimi, PH Weisman, LE Philips, JB Regan, J Clark, P Rhoads, GG Clemens, J Troendle, J Pratt, E Brenner, RA Gill, V TI Antibiotic susceptibility profiles for group B streptococci isolated from neonates, 1995-1998 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RESISTANCE; DISEASE; CHEMOPROPHYLAXIS; ERYTHROMYCIN AB Antibiotic susceptibility profiles were analyzed for 119 invasive and 227 colonizing strains of group B streptococci isolated from neonates at 6 US academic centers, All strains were susceptible to penicillin, vancomycin, chloramphenicol, and cefotaxime, The rate of resistance to erythromycin was 20.2% and to clindamycin was 6.9%. Resistance to erythromycin increased in 1997, Type V strains were more resistant to erythromycin than were type Ia (P = .003) and type Tb (P = .004) strains and were more resistant to clindamycin than were type Ia (P < .001), type Tb (P = .01), and type III (P = .001) strains. Resistance rates varied with geographic region: in California, there were high rates of resistance to erythromycin and clindamycin (32% and 12%, respectively), and low rates in Florida (8.5% and 2.1%, respectively). Penicillin continues to be the drug of choice for treatment of group B streptococcus infection. For women who are penicillin intolerant, however, the selection of an alternative antibiotic should be guided by contemporary resistence patterns observed in that region. C1 NICHHD, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Warren G Magnuson Clin Ctr, Microbiol Serv, Bethesda, MD 20892 USA. Westat, Rockville, MD USA. Childrens Hosp, Med Ctr, Oakland, CA 94609 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Alabama, Birmingham, AL USA. Columbia Univ Hlth Sci, New York, NY USA. Univ Florida, Gainesville, FL USA. Univ Med & Dent New Jersey, Piscataway, NJ 08854 USA. RP Lin, FYC (reprint author), 6100 Execut Blvd,Room 7B03,MSC 7510, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-4-3215, N01-HD-4-3214, N01-HD-4-3217] NR 15 TC 72 Z9 73 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 BP 76 EP 79 DI 10.1086/313936 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900015 PM 10913400 ER PT J AU Masur, H Miller, KD Jones, EC Joe, GO Rick, ME Kelly, GG Mican, JM Liu, SY Gerber, LH Blackwelder, WC Lane, HC Davey, RT Polis, MA Walker, RE Falloon, J Kovacs, JA AF Masur, H Miller, KD Jones, EC Joe, GO Rick, ME Kelly, GG Mican, JM Liu, SY Gerber, LH Blackwelder, WC Lane, HC Davey, RT Polis, MA Walker, RE Falloon, J Kovacs, JA TI High prevalence of avascular necrosis (AVN) of the hip in HIV infection: Magnetic resonance imaging of 339 asymptomatic patients SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 15 BP 214 EP 214 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900065 ER PT J AU De Almeida, KNF Graber, CJ Fukuda, CD Gill, VJ Barrett, AJ Bennett, JE AF De Almeida, KNF Graber, CJ Fukuda, CD Gill, VJ Barrett, AJ Bennett, JE TI Viridans streptococcus as the most common cause of neutropenic bacteremia in recipients of allogenic hematopoietic stem cell transplantation at the National Institutes of Health. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 31 BP 218 EP 218 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900081 ER PT J AU Hamill, RJ Pappas, PG Rex, JH Lee, JY Horowitz, H Kauffman, CA Hyslop, N Larsen, RA Stein, DK Graviss, EA Thomas, CJ AF Hamill, RJ Pappas, PG Rex, JH Lee, JY Horowitz, H Kauffman, CA Hyslop, N Larsen, RA Stein, DK Graviss, EA Thomas, CJ CA Mycoses Study Grp TI Multicenter surveillance of non-albicans candidemia SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. Baylor Coll Med, Houston VA Med Ctr, Houston, TX 77030 USA. NIAID, Jacobi Med Ctr, Bethesda, MD 20892 USA. Tulane Univ, New Orleans, LA 70118 USA. Univ Alabama, Birmingham, AL USA. Univ So Calif, Los Angeles, CA USA. Univ Texas, Houston, TX USA. Westchester Cty Hosp, Valhalla, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 36 BP 219 EP 219 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900086 ER PT J AU Ratto-Kim, S Robb, M Sandelli, S Williams, M Sei, S Theofan, G Diveley, J Moss, RB Venzon, D Wood, LV AF Ratto-Kim, S Robb, M Sandelli, S Williams, M Sei, S Theofan, G Diveley, J Moss, RB Venzon, D Wood, LV TI Lymphoproliferative responses induced by HIV-1 immunogen vaccine children with HIV infection. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Immune Response Corp, Carlsbad, CA USA. WRAIR, Rockville, MD USA. RI Venzon, David/B-3078-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 45 BP 220 EP 220 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900095 ER PT J AU Durbin, AP Men, RH Lai, CJ Reynolds, MJ Perreault, J Karron, RA Murphy, BR Whitehead, SS AF Durbin, AP Men, RH Lai, CJ Reynolds, MJ Perreault, J Karron, RA Murphy, BR Whitehead, SS TI A recombinant live attenuated dengue virus type 4 vaccine candidate is highly attenuated and immunogenic in humans SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 56 BP 223 EP 223 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900106 ER PT J AU Gil-Lamaignere, C Roilides, E Maloukou, A Georgopoulou, I Petrikkos, G Walsh, TJ AF Gil-Lamaignere, C Roilides, E Maloukou, A Georgopoulou, I Petrikkos, G Walsh, TJ TI Amphotericin B Lipid complex (ABLC) exhibits an additive effect when combined with human neutrophils against Scedosporium prolificans and Scedosporium apiospermum (Pseduallescheria boydii) SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Aristotelian Univ Salonika, Thessaloniki, Greece. Univ Athens, Athens, Greece. NCI, Bethesda, MD 20892 USA. RI Gil-Lamaignere, Cristina/A-3866-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 112 BP 232 EP 232 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900162 ER PT J AU Graber, CJ de Almeida, KNF Atkinson, JC Javaheri, D Gill, VJ Barrett, AJ Bennett, JE AF Graber, CJ de Almeida, KNF Atkinson, JC Javaheri, D Gill, VJ Barrett, AJ Bennett, JE TI Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 123 BP 234 EP 234 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900173 ER PT J AU Subramanian, AK Willoughby, S Zuzak, KB Theodore, M Tucker, PC Kelen, GD Quinn, TC AF Subramanian, AK Willoughby, S Zuzak, KB Theodore, M Tucker, PC Kelen, GD Quinn, TC TI PCR detection of Chlamydia pneumoniae DNA in patients visiting an inner city hospital's emergency department SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 157 BP 240 EP 240 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900207 ER PT J AU Mitre, ESE Tuazon, C AF Mitre, ESE Tuazon, C TI Tricuspid valve Streptococcus bovis endocarditis - Successful treatment with ceftriaxone SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 George Washington Univ, Med Ctr, Washington, DC 20037 USA. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 206 BP 248 EP 248 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900256 ER PT J AU Savor, C Brust, DG Cuccherini, B Fuss, IJ Sneller, M Gill, VJ Strober, W AF Savor, C Brust, DG Cuccherini, B Fuss, IJ Sneller, M Gill, VJ Strober, W TI Osteomyelitis with bacteremia caused bt a Flexispira-like organism in a patient with X-linked (Bruton's) Agammaglobulinemia SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIAID, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 228 BP 252 EP 252 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900278 ER PT J AU Allende, M Walsh, TJ Kumar, PN AF Allende, M Walsh, TJ Kumar, PN TI Cryptococcal meningitis in an immunocompromised host complicated by increased intracranial pressure and ophthalmologic sequelae despite adequate antifungal treatment. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 241 BP 254 EP 254 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900291 ER PT J AU Larsen, HH Masur, H Kovacs, JA Gill, VJ Silcott, VA Fischer, SH AF Larsen, HH Masur, H Kovacs, JA Gill, VJ Silcott, VA Fischer, SH TI A rapid and quantitative diagnostic real-time PCR assay for Pneumocystis carinii. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 272 BP 259 EP 259 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900322 ER PT J AU Majmudar, MD Madico, G Kelen, GD Gaydos, CA Quinn, TC Rothman, RE AF Majmudar, MD Madico, G Kelen, GD Gaydos, CA Quinn, TC Rothman, RE TI Development of a PCR-based assay for the detection of bacteremia from whole blood using primers from the highly conserved 16S rRNA gene SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIH, Baltimore, MD USA. RI Gaydos, Charlotte/E-9937-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 268 BP 259 EP 259 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900318 ER PT J AU Read, JS Tuomala, R Shapiro, D Samelson, R Ciupak, G McNamara, J Burchett, S Pollack, H AF Read, JS Tuomala, R Shapiro, D Samelson, R Ciupak, G McNamara, J Burchett, S Pollack, H TI Trends in mode of delivery (HIV-infected women, N. America (PACTG 367)) SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Albany Med Ctr, Albany, NY USA. Childrens Hosp, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Frontier Sci, Buffalo, NY USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NYU, Sch Med, New York, NY USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 316 BP 267 EP 267 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900366 ER PT J AU Vestereng, VH Kovacs, JA AF Vestereng, VH Kovacs, JA TI Pneumocystis carinii does not possess a salvage pathway for thymidine utilization SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 369 BP 276 EP 276 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900419 ER PT J AU Henderson, DK Lee, LM Kawana, R Fahey, BJ Wesley, RA Schmitt, JM AF Henderson, DK Lee, LM Kawana, R Fahey, BJ Wesley, RA Schmitt, JM TI Reducing occupational bloodborne pathogen exposures: 12 years' experience and comparison with four Japanese teaching hospitals SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIH, Div Safety, Bethesda, MD 20892 USA. Iwate Med Univ, Morioka, Iwate 020, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 405 BP 282 EP 282 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900455 ER PT J AU O'Bryan, L Pinkston, PK Kumaraswami, VK Vijayan, VK Yenokida, GG Ottesen, EA Crystal, RG Nutman, TB AF O'Bryan, L Pinkston, PK Kumaraswami, VK Vijayan, VK Yenokida, GG Ottesen, EA Crystal, RG Nutman, TB TI Tropical pulmonary eosinophillia: Localized eosinophil degranulation as a major mediator of disease SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. TB Res Ctr, Chennai, India. NR 0 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 465 BP 292 EP 292 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900515 ER PT J AU Keiser, PB Seltman, AK Cathy, S Ottesen, EA Nutman, TB AF Keiser, PB Seltman, AK Cathy, S Ottesen, EA Nutman, TB TI Identification of candidate vaccine antigens for human lymphatic filariasis SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 474 BP 294 EP 294 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900524 ER PT J AU Wood, BJ McKee, KT Gaydos, CA Theodore, M Zuzak, KB Howell, R Quinn, TC Syffus, P Brown, X Gaydos, JC AF Wood, BJ McKee, KT Gaydos, CA Theodore, M Zuzak, KB Howell, R Quinn, TC Syffus, P Brown, X Gaydos, JC TI Usefulness of the urine leukocyte esterase test (LET) to identify which asymptomatic males to screen by urine ligase chain reaction (LCR) for C-trachomatis and N-gonorrhoeae. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIH, Baltimore, MD USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RI Gaydos, Charlotte/E-9937-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 540 BP 306 EP 306 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900590 ER PT J AU Frothingham, R Meeker-O'Connell, WA Cobb, AJ Holland, SM AF Frothingham, R Meeker-O'Connell, WA Cobb, AJ Holland, SM TI Association of Mycobacterium avium sequevars Mav-B and Mav-E with disseminated disease in immunodeficient hosts SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Duke Univ, Med Ctr, Durham, NC USA. Vet Adm Med Ctr, Durham, NC USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 558 BP 309 EP 309 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900608 ER PT J AU Giordano, TP Soini, H Teeter, LD Musser, JM Graviss, EA AF Giordano, TP Soini, H Teeter, LD Musser, JM Graviss, EA TI Tuberculosis cluster size is associated with duration of symptoms SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 556 BP 309 EP 309 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900606 ER PT J AU Soini, H Pan, X Teeter, LD Musser, JM Graviss, EA AF Soini, H Pan, X Teeter, LD Musser, JM Graviss, EA TI Transmission of low-copy number IS6110 Mycobacterium tuberculosis isolates in Houston, Texas SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 557 BP 309 EP 309 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900607 ER PT J AU El-Sahly, HM Reich, RA Dou, SJ Musser, JM Graviss, EA AF El-Sahly, HM Reich, RA Dou, SJ Musser, JM Graviss, EA TI Mannose binding protein polymorphisms and susceptibility to tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 563 BP 310 EP 310 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900613 ER PT J AU Sterling, TR Dorman, SE Chaisson, RE Hackman, J Moore, K Holland, SM AF Sterling, TR Dorman, SE Chaisson, RE Hackman, J Moore, K Holland, SM TI A defect in innate host immunity among HIV-seronegative persons with extrapulmonary tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Eastern Chest Clin, Baltimore City Hlth Dept, Baltimore, MD USA. Johns Hopkins Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 564 BP 310 EP 310 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900614 ER PT J AU Teeter, LD Bui, T Soini, H Musser, JM Graviss, EA AF Teeter, LD Bui, T Soini, H Musser, JM Graviss, EA TI Clinical, demographic and lifestyle correlates of tuberculosis (TB) patients co-infected with human immunodeficiency disease (HIV) SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 561 BP 310 EP 310 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900611 ER PT J AU Edlin, BR Kral, AH Gee, L Seal, KH Lorvick, J O'Brien, TR Tobler, LH Andrews, WW Phelps, BH Busch, MP AF Edlin, BR Kral, AH Gee, L Seal, KH Lorvick, J O'Brien, TR Tobler, LH Andrews, WW Phelps, BH Busch, MP TI Duration of injection drug use affects likelihood of hepatitis C virus infection but not viral persistance SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Ctr Blood, San Francisco, CA USA. Chiron Corp, Emeryville, CA 94608 USA. NCI, Rockville, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 584 BP 314 EP 314 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900634 ER PT J AU Bonville, CA Rosenberg, HF Domachowske, JB AF Bonville, CA Rosenberg, HF Domachowske, JB TI Respiratory syncytial virus-induced expression of cytokeratin-17 participates in cytopathic syncytia formation. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIAID, LHD, NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Syracuse, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 601 BP 316 EP 316 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900651 ER PT J AU Mehta, P Bonville, CA Krilov, L Rosenberg, HF Domachowske, JB AF Mehta, P Bonville, CA Krilov, L Rosenberg, HF Domachowske, JB TI Parainfluenza virus-induced epithelial cell expression of pro-inflammatory chemokines is inhibited by hydrocortisone. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 NIAID, LHD, NIH, Bethesda, MD USA. N Shore Univ Hosp, Manhasset, NY USA. SUNY Syracuse, Upstate Med Univ, Syracuse, NY 13210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 597 BP 316 EP 316 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900647 ER PT J AU Doonquah, LA Frederick, WR Dawkins, F Delapenha, RA Manns, A AF Doonquah, LA Frederick, WR Dawkins, F Delapenha, RA Manns, A TI HHV-8 antibody in HIV-infected patients with Kaposi's sarcoma and lymphoma SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Howard Univ Hosp, Washington, DC USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 603 BP 317 EP 317 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900653 ER PT J AU Liepert, J Hallett, M Samii, A Oddo, D Celnik, P Cohen, LG Wassermann, EM AF Liepert, J Hallett, M Samii, A Oddo, D Celnik, P Cohen, LG Wassermann, EM TI Motor cortex excitability in patients with cerebellar degeneration SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE transcranial magnetic stimulation; corticospinal tract; reaction time; movement disorders; ataxia ID SIMPLE REACTION-TIME; TRANSCRANIAL MAGNETIC STIMULATION; ELECTRICAL-STIMULATION; CORTICAL EXCITABILITY; DENTATE NUCLEUS; ARM MOVEMENTS; VOLUNTARY MOVEMENT; BRAIN-STIMULATION; ATAXIA; FACILITATION AB Objectives: To study motor cortex (M1) excitability and the effect of subthreshold transcranial magnetic stimulation (TMS) in patients with cerebellar degeneration and normals performing a reaction time (RT) task. Methods: Time to wrist flexion after a visual go-signal was measured. TMS was always delivered at 90% of resting motor evoked potential (MEP) threshold. In one experiment, test TMS was delivered at various intervals after the go-signal. In half the trials priming TMS was also given with the go-signal. A second experiment examined the effect on RT of M1 and occipital priming stimulation alone. Results: M1 excitability, measured as the likelihood of producing MEPs in the wrist flexor muscles, increased immediately after the go-signal in the patients and stayed high until movement. In controls, excitability rose gradually. This difference was largely eliminated by priming TMS. RT was longer in the patient group, but improved with priming TMS. Occipital priming produced less effect on RT than M1 stimulation in both controls (P = 0.008) and patients (P = 0.0004). Conclusions: M1 excitability prior to movement in an RT task increases abnormally early in cerebellar patients. This may reflect compensation for deficient thalamocortical drive. Subthreshold TMS can partially normalize the prolonged RT and abnormal excitability rise in cerebellar patients. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. NR 40 TC 16 Z9 16 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2000 VL 111 IS 7 BP 1157 EP 1164 DI 10.1016/S1388-2457(00)00308-4 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 338UN UT WOS:000088441800002 PM 10880788 ER PT J AU Chen, JT Yu, HY Wu, ZA Kao, KP Hallett, M Liao, KK AF Chen, JT Yu, HY Wu, ZA Kao, KP Hallett, M Liao, KK TI Modulation of symptomatic palatal tremor by magnetic stimulation of the motor cortex SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE symptomatic palatal tremor; transcranial magnetic stimulation; resetting ID SUBJECTS MIMICKING TREMOR; PARKINSONS-DISEASE; BRAIN-STIMULATION; SILENT PERIOD; INHIBITION; RESPONSES; MYOCLONUS; MUSCLE; WRIST AB Objectives: Magnetic stimulation of the motor cortex can be used to determine the involvement of the cortex in rhythmic movement disorders. Symptomatic palatal tremor (SPT) is thought to come from a pacemaker that is relatively resistant to internal and external stimulation. In this study, we investigated the effect of magnetic stimulation of motor cortex on SPT. Methods: Five male patients, aged 67-79 years, with SPT after brain stem infarction or hemorrhage, all had a synchronous mouth angle twitch with the palatal movement. Electromyographic activity was recorded with a monopolar needle electrode from orbicularis oris. In experiment 1, transcranial magnetic stimulation (TMS) was delivered at 200% motor threshold (MT) to reset SPT. In experiment 2, the effect of TMS intensities was studied at 80-240% MT in two SPT patients. To determine the influence of the TMS, we used the resetting index (RI). Results: TMS reset the tremor in all 5 SPT patients at 200% MT with RIs of 0.86-0.96. The latency of the tremor reappearance after TMS was longer than the pre-stimulus tremor interval, and the intervals between the subsequent tremor bursts were also prolonged. The degree of tremor resetting was closely correlated with the magnetic stimulus intensity and the latency of the tremor reappearance after TMS. Conclusions: Stimulation of the motor cortex may modulate the generator of SPT. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Vet Gen Hosp, Neurol Inst, Dept Neurol, Taipei 11217, Taiwan. Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. Cathay Gen Hosp, Dept Neurol, Taipei, Taiwan. NINDS, NIH, Bethesda, MD 20892 USA. RP Liao, KK (reprint author), Vet Gen Hosp, Neurol Inst, Dept Neurol, 201 Sect 2,Shih Pai Rd,Pei Tou Dist, Taipei 11217, Taiwan. NR 23 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2000 VL 111 IS 7 BP 1191 EP 1197 DI 10.1016/S1388-2457(00)00301-1 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 338UN UT WOS:000088441800006 PM 10880792 ER PT J AU Goel, V Grafman, J AF Goel, V Grafman, J TI Role of the right prefrontal cortex in ill-structured planning SO COGNITIVE NEUROPSYCHOLOGY LA English DT Article ID PROBLEM SPACES; DESIGN; DAMAGE AB We tested an architect with a lesion to the right prefrontal cortex in a real-world architectural design/planning task that required him to develop a new design for our lab space and compared his performance to an age- and education-matched architect. The patient understood the task and even observed that "this is a very simple problem." His sophisticated architectural knowledge base was still intact and he used it quite skilfully during the problem structuring phase. However, the patient's problem-solving behaviour differed from the control's behaviour in the following ways: (1) he was unable to make the transition from problem structuring to problem solving; (2) as a result preliminary design did not start until two thirds of the way into the session; (3) the preliminary design phase was minimal and erratic, consisting of three independently generated fragments; (4) there was no progression or lateral development of these fragments; (5) there was no carryover of abstract information into the preliminary design or later phases, and (6) the patient did not make it to the detailing phase. This suggests that the key to understanding our patient's deficit is to understand the cognitive processes and mechanisms involved in the preliminary design phase. We appeal to a theory of design problem solving (Goel, 1995) that associates cognitive processes involved in preliminary design with "lateral" state transformations and argues that "ill-structured" representational and computational systems are necessary to support these transformations. We conclude that the neural basis of this system is selectively damaged in our patient. C1 York Univ, Dept Psychol, N York, ON M3J 1P3, Canada. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Goel, V (reprint author), York Univ, Dept Psychol, 4700 Keele St, N York, ON M3J 1P3, Canada. OI Grafman, Jordan H./0000-0001-8645-4457 NR 45 TC 64 Z9 68 U1 3 U2 8 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0264-3294 J9 COGN NEUROPSYCHOL JI Cogn. Neuropsychol. PD JUL PY 2000 VL 17 IS 5 BP 415 EP 436 PG 22 WC Psychology; Psychology, Experimental SC Psychology GA 338JY UT WOS:000088417200002 PM 20945189 ER PT J AU Denicoff, KD Sollinger, AB Frye, MA Ali, SO Smith-Jackson, EE Leverich, GS Post, RM AF Denicoff, KD Sollinger, AB Frye, MA Ali, SO Smith-Jackson, EE Leverich, GS Post, RM TI Neuroleptic exposure in bipolar outpatients in a research setting SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID TARDIVE-DYSKINESIA; DISORDER; LITHIUM; RISK AB The study purpose was to determine the extent of neuroleptic exposure in bipolar outpatients maintained on mood-stabilizing medications and any clinical correlates associated with this exposure. Data on medication and severity of illness were gathered from the records (prospective and retrospective) of 70 bipolar patients involved in outpatient research studies at the National institute of Mental Health (NIMH). The percentage of patients requiring neuroleptic treatment, percentage of time on neuroleptics during the period of observation, total dose of neuroleptics in chlorpromazine (CPZ) equivalency, and number of neuroleptic trials were among the variables calculated. Regression analyses and analyses of variance (ANOVAs) were performed to assess the relationships between neuroleptic exposure and clinical course. Forty-five patients (64.3%) had a neuroleptic trial during the prospective study. Subjects exposed to neuroleptics spent, on average, 15.4% (median, 6.0%) of the time in study on neuroleptic treatment, and were administered, on average, a total of 11,770.5 mg (median, 1,621.9 mg) of neuroleptics (in CPZ equivalency) per year in the prospective study. As expected, bipolar I compared with bipolar II patients had significantly higher neuroleptic exposure by a number of measures. The number of hospitalizations for mania prior to study entry was associated with greater prospective neuroleptic use during the study. Despite maintenance treatment with one or more mood-stabilizing agents, we found a relatively high need for adjunctive neuroleptic medication even in this sample of high-functioning bipolar outpatients. These results highlight the need for the study of alternatives, as well as more effective primary mood-stabilizing agents. This is a US government work. There are no restrictions on its use. C1 NIMH, Sect Psychobiol, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Denicoff, KD (reprint author), NIMH, Sect Psychobiol, Biol Psychiat Branch, Bldg 10,Room 3N212,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Ali, Syed/0000-0003-3131-3299 NR 16 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL-AUG PY 2000 VL 41 IS 4 BP 248 EP 252 DI 10.1053/comp.2000.7430 PG 5 WC Psychiatry SC Psychiatry GA 334FB UT WOS:000088174900004 PM 10929791 ER PT J AU Barr, JT Zadnik, K Wilson, BS Edrington, TB Everett, DF Fink, BA Shovlin, JP Weissman, BA Siegmund, K Gordon, MO AF Barr, JT Zadnik, K Wilson, BS Edrington, TB Everett, DF Fink, BA Shovlin, JP Weissman, BA Siegmund, K Gordon, MO CA CLEK Study Grp TI Factors associated with corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study SO CORNEA LA English DT Article DE keratoconus; cornea; scarring ID INHIBITOR; DISEASE AB Purpose. The multicenter Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study is a prospective, observational study of 1,209 keratoconus patients. We report on the factors associated with corneal scarring at baseline. Methods. We defined corneal scarring as scars that had been detected both by the clinician examining the patient with the slit-lamp biomicroscope and by masked readers of corneal photographs at the CLEK Photography Reading Center. We investigated associations between corneal scarring and patient variables including gender, ethnicity, a family history of keratoconus, a history of ocular trauma, eye rubbing, contact lens wear, rigid contact lens fitting relationships, and corneal findings (such as curvature, Vogt's striae, Fleischer's ring, and central/apical staining). Multiple logistic regression analysis using generalized estimating equations to adjust for the correlation between eyes was used for analysis. Results, The following factors were found to increase the odds of corneal scarring at baseline in the CLEK Study: corneal staining (odds ratios (OR) = 3.40, 95% confidence interval 2.53-4.59), contact lens wear (OR = 3.51, 95% confidence interval 2.27-5.45), Fleischer's ring (OR = 1.63, 95% confidence interval 1.11-2.40), steeper first definite apical clearance lens base curve radius (per diopter, OR = 1.29, 95% confidence interval 1.25-1.33), and age (per decade, OR = 1.54, 95% confidence interval 1.35-1.75). Conclusions. These baseline data suggest that corneal scarring in keratoconus is associated with corneal staining, contact lens wear, Fleischer's ring, a steeper cornea, and increasing age. The factors that imply added risk for corneal scarring that may be affected by practitioner intervention are staining of the cornea, contact lens wear, and the contact lens fitting relationship. C1 Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. Washington Univ, Div Biostat, St Louis, MO USA. So Calif Coll Opt, Fullerton, CA USA. NEI, NIH, Rockville, MD USA. Northeastern Eye Inst, Scranton, PA USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. RP Zadnik, K (reprint author), Ohio State Univ, Coll Optometry, 338 W 10Th Ave, Columbus, OH 43210 USA. FU NEI NIH HHS [EY10419, EY10069, EY10077] NR 22 TC 28 Z9 28 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD JUL PY 2000 VL 19 IS 4 BP 501 EP 507 DI 10.1097/00003226-200007000-00020 PG 7 WC Ophthalmology SC Ophthalmology GA 333TH UT WOS:000088146500019 PM 10928767 ER PT J AU Goldberg, R Goff, D Cooper, L Luepker, R Zapka, J Bittner, V Osganian, S Lessard, D Cornell, C Meshack, A Mann, C Gilliland, J Feldman, H AF Goldberg, R Goff, D Cooper, L Luepker, R Zapka, J Bittner, V Osganian, S Lessard, D Cornell, C Meshack, A Mann, C Gilliland, J Feldman, H TI Age and sex differences in presentation of symptoms among patients with acute coronary disease: the REACT trial SO CORONARY ARTERY DISEASE LA English DT Article DE acute coronary disease; symptoms; sex; age ID ACUTE MYOCARDIAL-INFARCTION; COMMUNITY-WIDE PERSPECTIVE; THROMBOLYTIC THERAPY; GENDER DIFFERENCES; HEART-DISEASE; TEMPORAL TRENDS; CHEST PAIN; WOMEN; MEN; MORTALITY AB Background There are few data on possible age and sex differences in presentation of symptoms for patients with acute coronary disease. Objective To investigate demographic differences in presentation of symptoms at the time of hospital presentation for acute myocardial infarction (AMI) and unstable angina. Methods The medical records of patients who presented with chest pain and who also had diagnoses of AMI (n = 889) or unstable angina (n = 893) on discharge from 43 hospitals were reviewed as part of data collection activities of the Rapid Early Action for Coronary Treatment trial based in 10 pair-matched communities throughout the USA. Results Dyspnea (49%), arm pain (46%), sweating (35%), and nausea (33%) were commonly reported by men and women of all ages in addition to the presenting complaint of chest pain. After we had controlled for various characteristics through regression modeling, older persons with AMI were significantly less likely than were younger persons to complain of arm pain and sweating, and men were significantly less likely to report vomiting than were women. Among persons with unstable angina, arm pain and sweating were reported significantly less often by elderly patients, Nausea and back, neck, and jaw pain were more common complaints of women. Conclusions Results of this study suggest that there are differences between symptoms at presentation of men and women, and those in various age groups, hospitalized with acute coronary disease. Clinicians should be aware of these differences when diagnosing and managing patients suspected to have coronary heart disease. Coron Artery Dis 11:399-407 (C) 2000 Lippincott Williams & Wilkins. C1 Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. NHLBI, Div Epidemiol & Clin Applicat, Rockledge Ctr 2, Bethesda, MD 20892 USA. Univ Alabama, Sch Med, Birmingham, AL USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. New England Res Inst, Watertown, MA 02172 USA. RP Goldberg, R (reprint author), Univ Massachusetts, Sch Med, Dept Med, 55 Lake Ave N, Worcester, MA 01655 USA. NR 22 TC 89 Z9 91 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD JUL PY 2000 VL 11 IS 5 BP 399 EP 407 DI 10.1097/00019501-200007000-00004 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 328LJ UT WOS:000087852100004 PM 10895406 ER PT J AU Domanski, MJ AF Domanski, MJ TI Prevention of sudden cardiac death: management considerations SO CURRENT OPINION IN CARDIOLOGY LA English DT Review ID LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; BYPASS GRAFT-SURGERY; RANDOMIZED TRIAL; HIGH-RISK; HEART-FAILURE; MORTALITY; AMIODARONE; DEFIBRILLATOR; MECHANISMS AB Data, largely from randomized, controlled trials, have clarified the role of the various treatment modalities in preventing sudden cardiac death. The therapeutic usefulness in sudden cardiac death prevention of antirarrhythmic and other drugs, and of the implantable cardioverter-defibrillator, is discussed. The relative effectiveness of the various modalities is also considered and conclusions about an appropriate treatment paradigm and future research directions are discussed. (C) 2000 Lippincott Williams & Wilkins, Inc. C1 NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Grp, Bethesda, MD 20892 USA. RP Domanski, MJ (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Grp, Bethesda, MD 20892 USA. NR 37 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-4705 J9 CURR OPIN CARDIOL JI Curr. Opin. Cardiol. PD JUL PY 2000 VL 15 IS 4 BP 304 EP 308 DI 10.1097/00001573-200007000-00016 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 356AG UT WOS:000089420300016 PM 11139095 ER PT J AU Bezrukov, SM AF Bezrukov, SM TI Functional consequences of lipid packing stress SO CURRENT OPINION IN COLLOID & INTERFACE SCIENCE LA English DT Review DE integral proteins; intra-membrane pressure; non-lamellar lipids ID LATERAL PRESSURE PROFILE; MEMBRANE-FUSION; BILAYER DEFORMATIONS; GRAMICIDIN CHANNELS; PROTEIN; PHASE; MECHANISM; CURVATURE; LAMELLAR; POLYMORPHISM AB When two monolayers of a non-lamellar lipid are brought together to form a planar bilayer membrane, the resulting structure is under elastic stress. This stress changes the membrane's physical properties and manifests itself in at least two biologically relevant functional aspects. First, by modifying the energetics of hydrophobic inclusions, it influences protein-lipid interactions. The immediate consequences are seen in several effects that include changes in conformational equilibrium between different functional forms of integral proteins and peptides, membrane-induced interactions between proteins, and partitioning of proteins between different membranes and between the bulk and the membrane. Secondly, by changing the energetics of spontaneous formation of non-lamellar local structures, lipid packing stress influences membrane stability and fusion. (C) Published by 2000 Elsevier Science Ltd. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Bezrukov, SM (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM bezrukov@helix.nih.gov NR 58 TC 96 Z9 100 U1 1 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1359-0294 J9 CURR OPIN COLLOID IN JI Curr. Opin. Colloid Interface Sci. PD JUL PY 2000 VL 5 IS 3-4 BP 237 EP 243 DI 10.1016/S1359-0294(00)00061-3 PG 7 WC Chemistry, Physical SC Chemistry GA 376MT UT WOS:000165461900011 ER PT J AU Jensen, RT AF Jensen, RT TI Carcinoid and pancreatic endocrine tumors: recent advances in molecular pathogenesis, localization, and treatment SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID ZOLLINGER-ELLISON-SYNDROME; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; NEUROENDOCRINE GASTROENTEROPANCREATIC TUMORS; HEPATIC ARTERIAL CHEMOEMBOLIZATION; STATISTICAL EVALUATION; LIVER-TRANSPLANTATION; GASTROINTESTINAL TUMORS; NEOPLASIA TYPE-1; RADIONUCLIDE THERAPY; PROGNOSTIC FACTORS AB Neuroendocrine tumors include carcinoids and pancreatic endocrine tumors, which share a number of common features in their pathology, ability to cause clinical symptoms due to ectopic hormone and bioamine release, localization methods, and treatment. Although generally slow growing, a proportion demonstrate aggressive tumor growth. Therefore, in many cases treatment must be directed against both the tumor and the hormone-excess state. There have been significant recent advances into their molecular pathogenesis, natural history. and prognostic factors; clinical presentation defined by larger series analysis; localization methods; and the development of new treatments directed against the tumor and to control the hormone-excess state (including depot somatostatin analogues, interferon combinations, embolization, chemoembolization, radiotherapy with novel somatostatin analogues, and liver transplantation). Recent advances in each of these areas are briefly discussed. Curr Opin Oncol 2000, 12:368-377 (C) 2000 Lippincott Williams & Wilkins, Inc. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 12804, Bethesda, MD 20892 USA. NR 111 TC 61 Z9 63 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JUL PY 2000 VL 12 IS 4 BP 368 EP 377 DI 10.1097/00001622-200007000-00015 PG 10 WC Oncology SC Oncology GA 357BU UT WOS:000089479300015 PM 10888424 ER PT J AU Hertle, R AF Hertle, Ralf TI Serratia Type Pore Forming Toxins SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review AB The Serratia marcescens hemolysin represents a new type of hemolysin and has been studied in great molecular detail with regard to structure, activation and secretion. It has nothing in common with the pore forming toxins of E. coli type (RTX toxins), the Staphylococcus aureus alpha-toxin or the thiol activated toxin of group A beta-hemolytic streptococci (Streptolysin O). Studies on erythrocytes, eukaryotic cells and artificial black lipid membranes, have shown that the mechanism of pore formation of ShlA is different form other pore forming toxins. The S. marcescens hemolysin proteins ShlB and ShlA exhibit protein sequence homologues in Proteus mirabilis, Haemophilus ducreyi, Edwardsiella tarda and Erwinia chrysantemi. Furthermore, sequence motifs present in ShlA and Shlb have been shown to be important for activity and secretion of the S. marcescens hemolysin. Thus, the S. marcescens hemolysin forms the prototype of a new class of hemolysins and of a new secretory mechanism. The uniqueness of this new mechanism is underlined by the fact that activation of ShlA by ShlB strictly requires phosphatidylethanolamine as a cofactor. New data implicate a conformational change in ShlA during activation. In addition, ShlA not only forms pores in erythrocytes but also in fibroblasts and epithelial cells. The cytotoxic action of ShlA is mainly determined by lysis of infected cells in vitro. In sublytic doses, as will normally be the situation in vivo, ShlA exerts additionally effects which are currently under investigation. The knowledge of the structure, activation, secretion and mode of action of S. marcescens hemolysin has implications for proteins, related in sequence or in mode of secretion and activation. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hertle, R (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Bldg 37 4B03, Bethesda, MD 20892 USA. EM ralf.hertle@mikrobio.uni-tuebingen.de NR 67 TC 14 Z9 14 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD JUL PY 2000 VL 1 IS 1 BP 75 EP 89 DI 10.2174/1389203003381423 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA V13FY UT WOS:000207653900005 PM 12369921 ER PT J AU Nathan, I Dizdaroglu, M Bernstein, L Junker, U Lee, C Muegge, K Durum, SK AF Nathan, I Dizdaroglu, M Bernstein, L Junker, U Lee, C Muegge, K Durum, SK TI Induction of oxidative DNA damage in U937 cells by TNF or anti-Fas stimulation SO CYTOKINE LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED APOPTOSIS; HUMAN FIBROBLASTS; CYTOCHROME-C; CYTOTOXICITY; MITOCHONDRIA; BCL-2; FRAGMENTATION; GLUTATHIONE; INVOLVEMENT AB TNF and Fas signaling pathways are reported to induce mitochondrial damage associated with production of oxygen radicals. We examined whether such radical production elicited detectable nuclear DNA damage in U937 cells following treatment with TNF or with anti-Fas antibodies, Using GC-mass spectroscopy for analysing base oxidation, several oxidized species increased significantly following TNF treatment, whereas anti-Fas resulted in less detectable oxidative damage using this assay. Cytogenetic analysis showed that, in the presence of aphidicolin, which blocks several types of DNA repair, TNF induced extensive chromosomal damage. Aphidicolin also synergized with TNF and anti-Fas in inducing cell death which was prevented by reducing atmospheric oxygen or addition of n-acetyl cysteine, a scavenger of oxygen radicals. Thus, several lines of evidence point to the TNF and Fas pathways inducing extensive oxidative DNA damage and repair, and suggest potential roles for these pathways in mutagenesis and aging. (C) 2000 Academic Press. C1 NCI, Lab Mol Immunol, Frederick, MD 21702 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. Texas A&M Univ, Hlth Sci Ctr, Dept Pathol & Lab, College Stn, TX 77843 USA. NCI, SAIC, Frederick, MD 21701 USA. RP Durum, SK (reprint author), NCI, Lab Mol Immunol, Frederick, MD 21702 USA. NR 44 TC 14 Z9 14 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 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2000 VL 12 IS 7 BP 881 EP 887 DI 10.1006/cyto.1999.0638 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 335AY UT WOS:000088220900006 PM 10880232 ER PT J AU Kass, E Parker, J Schlom, J Greiner, JW AF Kass, E Parker, J Schlom, J Greiner, JW TI Comparative studies of the effects of recombinant GM-CSF and GM-CSF administered via a poxvirus to enhance the concentration of antigen-presenting cells in regional lymph nodes SO CYTOKINE LA English DT Article DE GM-CSF; recombinant vaccinia-GM-CSF ID COLONY-STIMULATING FACTOR; FACTOR RHGM-CSF; MHC CLASS-II; VACCINIA VIRUS; IMMUNE-RESPONSES; IN-VIVO; CARCINOEMBRYONIC ANTIGEN; ANTITUMOR IMMUNITY; ANTIBODY-RESPONSE; TUMOR-REGRESSION AB Repeated subcutaneous (s.c.) injections of recombinant granulocyte-macrophage colony-stimulating factor (recGM-CSF) for 4-5 days can enrich an immunization site with antigen-presenting cells (APC), which has been correlated with improved immune responses in experimental and clinical studies. A recombinant vaccinia virus encoding the GM-CSF gene (rV-GM-CSF) has been developed and can generate specific antitumour immunity in a whole tumour cell vaccine. In the present study, we examined whether rV-GM-CSF could produce and release GM-CSF locally which, in turn, might enrich a site of immunization for APC as preciously shown for recGM-CSF. S.c. injection of rV-GM-CSF significantly (P < 0.05) enhanced the percentage and overall number of APC, measured by class II expression levels, in the regional lymph nodes that drain the injection site. Dose- and temporal-dependent studies showed class II expression levels in the draining lymph nodes were maximally enhanced 5-7 days after a single injection of 10(7) plaque-forming units (pfu) of rV-GM-CSF. Flow cytometry revealed that the increase in class II expression resulted from (i) a higher class II expression level on CD19(+) B cells and (ii) an increase in the number of CD11c(+)/class II+ professional APC within the draining lymph nodes. Moreover, isolation of lymph nodes from rV-GM-CSF-treated mice revealed their capacity to support higher levels of antigen-specific T cell proliferation and allospecific cytotoxic responses. A comparison between a single injection of rV-GM-CSF and a 4-day course of recGM-CSF revealed comparable changes in class II expression and functional T cell assays. GM-CSF can be delivered in a recombinant poxvirus, and the local production of the cytokine results in cellular and phenotypic changes that are similar to those of recGM-CSF. The ability to utilize rV-GM-CSF as a single inoculum may be more compatible with traditional immunization strategies. (C) 2000 Academic Press. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. NR 37 TC 27 Z9 30 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 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2000 VL 12 IS 7 BP 960 EP 971 DI 10.1006/cyto.2000.0684 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 335AY UT WOS:000088220900015 PM 10880241 ER PT J AU Berger, AC Alexander, HR Wu, PC Tang, GQ Gnant, MFX Mixon, A Turner, ES Libutti, SK AF Berger, AC Alexander, HR Wu, PC Tang, GQ Gnant, MFX Mixon, A Turner, ES Libutti, SK TI Tumour necrosis factor receptor I (p55) is upregulated on endothelial cells by exposure to the tumour-derived cytokine endothelial monocyte-activating polypeptide II (EMAP-II) SO CYTOKINE LA English DT Article DE apoptosis; cytokine receptors; EMAP-II; endothelial cells; tumour necrosis factor ID NF-KAPPA-B; FACTOR-ALPHA; TISSUE FACTOR; TNF-ALPHA; HUMAN-MELANOMA; E-SELECTIN; APOPTOSIS; DEATH; EXPRESSION; PATHWAYS AB Endothelial monocyte activating polypeptide-II (EMAP-II) is an inflammatory cytokine known to have a role in neutrophil and macrophage chemotaxis and in apoptosis, It is a tumour-derived cytokine that sensitizes tumour vasculature to the effects of systemic TNF. In order to gain insight into the mechanism by which EMAP-II sensitizes vessels to TNF, me focused on its effects on TNF receptor expression. In human umbilical vein endothelial cells (HUVEC), TNF-R1 mRNA is increased four-fold following incubation with recombinant EMAP-II. Conditioned media from cell lines known to produce high levels of EMAP-II upregulated TNF-R1 but not TNF-R2 by up to twenty-fold compared to media controls and low expressing cell lines; this effect was blocked by anti-EMP-II antibody, Recombinant EMAP-II upregulated TNF-R1 expression by approximately six-fold. Analysis of HUVEC lysates by ELISA showed increased expression of TNF-R1 within 2 h; TNF-R2 expression was unaffected by recombinant EMAP-II. Finally, immunohistochemistry of human melanomas in vivo showed that TNF-R1 staining is increased on the vessels of rumours known to express high levels of EMAP-II compared to low EMAP-II expressing tumours. These results suggest that EMAP-II upregulates TNF-R1 expression by endothelial cells both in vitro and in vivo, This induction of TNF-R1 expression may be the mechanism by which EMAP-II sensitizes tumour endothelium to the effects of TNF leading to haemorrhagic necrosis. (C) 2000 Academic Press. C1 NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), NCI, Surg Metab Sect, Surg Branch, NIH, Bldg 10,Room 2B17,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Gnant, Michael/0000-0003-1002-2118 NR 37 TC 39 Z9 41 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2000 VL 12 IS 7 BP 992 EP 1000 DI 10.1006/cyto.2000.0687 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 335AY UT WOS:000088220900018 PM 10880244 ER PT J AU Kaufman, JB Wang, G Zhang, W Valle, MA Shiloach, J AF Kaufman, JB Wang, G Zhang, W Valle, MA Shiloach, J TI Continuous production and recovery of recombinant Ca2+ binding receptor from HEK 293 cells using perfusion through a packed bed bioreactor SO CYTOTECHNOLOGY LA English DT Article; Proceedings Paper CT 1998 Joint International Meeting of the Japanese-Association-for-Animal-Cell-Technology/European-Society-for-Ani mal-Cell-Technology (JAACT/ESACT) CY JUL 26-30, 1998 CL KYOTO, JAPAN SP Japanese Assoc Anim Cell Technol, European Soc Anim Cell Technol ID CULTURE; EXPRESSION AB The extracellular domain of human parathyroid Ca2+ receptor was needed in order to study its structure and clinical application. The Ca2+ receptor is a unique member of the G protein-coupled receptor super-family, expressed in parathyroid and kidney cells where it has been shown to play a critical role in extracellular calcium homeostasis. The desired protein was produced by immobilizing the transformed HEK 293 cells in a packed-bed configuration using a 1.6 l (working volume) bioreactor equipped with a vertical mixing impeller assembly and an internal basket. The process included a propagation phase followed by a production phase. In the propagation phase, lasting approximately 160 h, the bed was perfused with a serum-containing medium, allowing the cells to grow at a constant growth rate to approximately 3 x 10(10). At this point the production phase was begun, replacing the medium with serum-free medium and continuing the perfusion process for additional 350 h. During this phase, the medium was pumped through the packed bed at a rate of 4-6 l per day, keeping the residual glucose concentration around 1 g l(-1) and collecting and processing approximately 80 l of spent medium. This continuous perfusion method of the packed-bed bioreactor was compared to a repeated batch method in which existing medium was replenished when the glucose concentration was down to 1 g l(-1). Using this method, serum-free medium was replaced with serum containing medium a few times when a decline in the glucose consumption was observed. Though medium consumption and protein yield are similar in both methods (roughly 10 mg l(-1)), there are differences related to the ease of operation and processing of the produced protein. The continuous perfusion operation was found to be preferable and was chosen as the production strategy. C1 NIDDK, Biotechnol Unit, LCDB, NIH, Bethesda, MD 20892 USA. New Brunswick Sci Co Inc, Edison, NJ 08818 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, LCDB, NIH, Bldg 6,Rm B1-33, Bethesda, MD 20892 USA. NR 13 TC 13 Z9 13 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0920-9069 J9 CYTOTECHNOLOGY JI Cytotechnology PD JUL PY 2000 VL 33 IS 1-3 BP 3 EP 11 DI 10.1023/A:1008143132056 PG 9 WC Biotechnology & Applied Microbiology; Cell Biology SC Biotechnology & Applied Microbiology; Cell Biology GA 359FG UT WOS:000089600400002 PM 19002805 ER PT J AU Takasaki, N McIsaac, R Dean, J AF Takasaki, N McIsaac, R Dean, J TI Gpbox (Psx2), a homeobox gene preferentially expressed in female germ cells at the onset of sexual dimorphism in mice SO DEVELOPMENTAL BIOLOGY LA English DT Article DE homeobox transcription factors; oogenesis; oocyte-specific gene expression; expressed sequence tags ID X-CHROMOSOME INACTIVATION; ZONA-PELLUCIDA GENES; MOUSE EMBRYO; TRANSCRIPTION FACTOR; EXTRAEMBRYONIC TISSUES; COORDINATE EXPRESSION; PLACENTAL DEVELOPMENT; MESSENGER-RNA; MUTANT MICE; STEM-CELLS AB XX gonads differentiate into ovaries, a morphologic event evident by embryonic day 13.5 (E13.5) in mice. To identify early markers of oogenesis, sex-specific urogenital ridge cDNA libraries were constructed from E12-13 embryos. After mass excision and isolation of plasmid DNA, approximately 4800 expressed sequence tags were determined and compared to existing databases. Few cDNAs were specifically expressed in the urogenital ridge, but one, designated GPBOX, encodes a 227-amino-acid homeobox protein that is first expressed at E10.5 in the embryo as well as in the extraembryonic tissues. The Gpbox gene is single copy in the mouse genome and is located on the X chromosome in close proximity to two other homeobox genes, Pem and Psx1. Within the embryo, its expression is limited to the gonad, and transcripts are not detected in adult tissues. Although comparable levels are initially present in both sexes, GPBOX transcripts accumulate faster in female germ cells and peak at E12.5 when they are present in fivefold greater abundance than in males. The persistence of GPBOX transcripts in female germ cells until E15.5 and their virtual disappearance in males by E13.5 suggest that Gpbox may play a role in mammalian oogenesis. (C) 2000 Academic Press. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Takasaki, N (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 62 TC 30 Z9 30 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 1 PY 2000 VL 223 IS 1 BP 181 EP 193 DI 10.1006/dbio.2000.9741 PG 13 WC Developmental Biology SC Developmental Biology GA 332EF UT WOS:000088060400015 PM 10864470 ER PT J AU Weis, J Kaussen, M Calvo, S Buonanno, A AF Weis, J Kaussen, M Calvo, S Buonanno, A TI Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers SO DEVELOPMENTAL DYNAMICS LA English DT Article DE muscle fibers; denervation; MRF4 ID ADULT SKELETAL-MUSCLE; ACETYLCHOLINE-RECEPTOR GENES; ELECTRICAL-ACTIVITY; DEPENDENT EXPRESSION; MYOGENIC FACTORS; MESSENGER-RNA; MYOD FAMILY; M-CADHERIN; DIFFERENTIAL REGULATION; XENOPUS DEVELOPMENT AB Muscle regulatory factor 4 (MRF4) is a member of the family of myogenic transcription factors, including MyoD, myogenin, and myf-5, that are necessary for the commitment and differentiation of mesoderm to skeletal muscle, Although the function of these transcription factors during embryonic development has been demonstrated, their role in adult muscle has remained elusive. Regulation of the MRF4 gene differs from the genes encoding the other myogenic factors in that its transcripts accumulate in neonatal muscle during maturation and continue to be expressed at relatively high levels in the adult, On the basis of its mRNA expression pattern, MRF4 has been suggested to regulate genes encoding adult contractile proteins and acetylcholine receptor subunits, To test this hypothesis, a specific antiserum was developed to study MRF4 protein expression in adult innervated and denervated muscle, because MRF4 mRNA levels increase by approximately threefold 1 day after nerve resection, By using three different immunohistochemical methods that vary widely in sensitivity, we were unable to detect MRF4 immunoreactivity in adult innervated muscles. The same results were obtained with another MRF4 antiserum generated independently, In contrast, any of these three immunologic techniques readily detected MRF4 immunoreactivity in myofiber and satellite cell nuclei of muscles denervated for 24 hours. The highest proportion of immunopositive nuclei (80%) was found 2-3 days after denervation, Immunoreactivity was no longer detectable by 14 days. There was no differential accumulation of MRF4 protein in the nuclei of satellite cells nor in sole plate (synaptic) nuclei at any time after denervation. No differences were found in the temporal accumulation of MRF4 in nuclei of type I and type II: denervated myofibers, consistent with the similar distribution of MRF4 mRNAs in slow- and fast-twitch muscles. Our results are consistent with the lack of phenotype observed in the adult muscles of MRF4-null mutant mice observed by others and suggest that MRF4 may have important roles in the gene programs activated after denervation and during muscle regeneration, Published 2000 Wiley-Liss, Inc. C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Bern, Inst Pathol, Div Neuropathol, Bern, Switzerland. Tech Univ, Rhein Westfal TH Aachen, Inst Neuropathol, Aachen, Germany. RP Buonanno, A (reprint author), NICHHD, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A-38, Bethesda, MD 20892 USA. RI Weis, Joachim/G-1984-2014 OI Weis, Joachim/0000-0003-3280-6773 NR 63 TC 36 Z9 39 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUL PY 2000 VL 218 IS 3 BP 438 EP 451 DI 10.1002/1097-0177(200007)218:3<438::AID-DVDY1001>3.0.CO;2-6 PG 14 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 332KU UT WOS:000088074000004 PM 10878609 ER PT J AU Vannucci, SJ Rutherford, T Wilkie, MB Simpson, IA Lauder, JM AF Vannucci, SJ Rutherford, T Wilkie, MB Simpson, IA Lauder, JM TI Prenatal expression sf the GLUT4 glucose transporter in the mouse SO DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE glucose; development; embryo; cerebellum ID GROWTH-FACTOR-I; ACTIVATED HEXOSE-TRANSPORT; RECEPTOR GENE-EXPRESSION; RAT-BRAIN; SIGNAL-TRANSDUCTION; NEURONAL SURVIVAL; SKELETAL-MUSCLE; DEVELOPMENTAL EXPRESSION; CELLULAR-PATTERN; 5-HT2B RECEPTOR AB The GLUT4 glucose transporter is primarily expressed in skeletal muscle, heart and adipose tissue, where its expression is postnatal, coincident with the acquisition of insulin-regulated glucose transport. In muscle, contraction also regulates GLUT4 activity in the postnatal animal. Here we demonstrate that GLUT4 is expressed in the developing mouse embryo with specific tissue and spatiotemporal patterns. From embryonic day 9 (E9; E1 = day of copulation plug) to postnatal day 70 (P70), mice were analyzed for GLUT4 mRNA and protein expression by in situ hybridization, immunohistochemistry and immunoblot. Specificity was confirmed with sense riboprobe hybridization and peptide competition, respectively. At E9, GLUT4 was detected in the cranial neural folds in the outer (mantle) layer of the neuroepithelium. At E10, expression was present throughout the developing heart and was prominent in the endocardial cushions through E12. At E10-12, GLUT4 was also prominent in craniofacial mesenchyme. GLUT4 expression in cartilage and bone was evident at E12 and was maintained throughout early postnatal life. GLUT4 was apparent throughout embryonic development in the ventricular epithelium, choroid plexus and in the developing cerebellum. At birth, cardiac expression was reduced and GLUT4 was most evident in cartilage, bone and specific brain regions. In the latter, GLUT4 expression was most evident in the cerebellum, specifically in the external granular layer through P7 and in the internal granular layer thereafter. Maximal GLUT4 protein levels in the cerebellum were measured between P14 and P21 and were reduced in the adult brain. These findings suggest that GLUT4-mediated glucose transport may play important roles during development of the brain and nonneuronal tissues in the mouse embryo. Copyright (C) 2000 S. Karger AG, Basel. C1 Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Anat & Neurosci, Hershey, PA 17033 USA. Univ N Carolina, Sch Med, Dept Cell Biol & Anat, Chapel Hill, NC 27599 USA. NIDDK, EDMNS, NIH, Bethesda, MD USA. RP Vannucci, SJ (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat, POB 850, Hershey, PA 17033 USA. EM sjv1@psu.edu NR 53 TC 20 Z9 21 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-5866 J9 DEV NEUROSCI-BASEL JI Dev. Neurosci. PD JUL-AUG PY 2000 VL 22 IS 4 BP 274 EP 282 DI 10.1159/000017451 PG 9 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 348WL UT WOS:000089009400003 PM 10965149 ER PT J AU Caruso, M Miele, C Oliva, A Condorelli, G Oriente, F Riccardi, G Capaldo, B Fiory, F Accili, D Formisano, P Beguinot, F AF Caruso, M Miele, C Oliva, A Condorelli, G Oriente, F Riccardi, G Capaldo, B Fiory, F Accili, D Formisano, P Beguinot, F TI The IR1152 mutant insulin receptor selectively impairs insulin action in skeletal muscle but not in liver SO DIABETES LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; DEPENDENT DIABETES-MELLITUS; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE KINASE; PHOSPHORYLATION; INTERNALIZATION; ENDOCYTOSIS; SUBSTRATE; ASSOCIATION; MUTATION AB In patients harboring the IR1152 mutant insulin receptor, hepatic glucose production was normally suppressed by insulin. Hepatocytes without the insulin receptor gene and expressing IR1152 (Hep(MUT)) also showed normal insulin suppression of glucose production and full insulin response of glycogen synthase. In contrast, expression of the IR1152 mutant in skeletal muscle maximally increased glucose uptake and storage, preventing further insulin stimulation. IRS-1 phosphorylation was normally stimulated by insulin in both intact Hep(MUT) and L6 skeletal muscle cells expressing the IR1152 mutant (L6(MUT)). At variance, IRS-2 phosphorylation exhibited high basal levels with no further insulin-dependent increase in L6(MUT) but almost normal phosphorylation, both basal and insulin-stimulated, in the Hep(MUT) cells. In vitro, IR1152 mutant preparations from both the L6(MUT) and the Hep(MUT) cells exhibited increased basal and no insulin-stimulated phosphorylation of IRS-2 immobilized from either muscle or liver cells. IR1152 internalization in liver and muscle cells closely paralleled the ability of this mutant to phosphorylate IRS-2 in vivo in these cells. Block of receptor internalization (wild-type and mutant) in the liver and muscle cells also inhibited IRS-2, but not IRS-1, phosphorylation. Thus, the mechanisms controlling insulin receptor internalization differ in liver and skeletal muscle cells and may enable IR1152 to control glucose metabolism selectively in liver. In both cell types, receptor internalization seems necessary for IRS-2 but not IRS-1 phosphorylation. C1 Univ Naples Federico II, Sch Med, Dipartimento Biol & Patol Cellulare & Mol, I-80131 Naples, Italy. Univ Naples Federico II, Sch Med, CNR, Ctr Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy. Univ Naples Federico II, Sch Med, Dipartimento Med Clin & Sperimentale, I-80131 Naples, Italy. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Beguinot, F (reprint author), Univ Naples Federico II, Sch Med, Dipartimento Biol & Patol Cellulare & Mol, Via S Pansini 5, I-80131 Naples, Italy. RI riccardi, gabriele/A-9269-2012; OI Capaldo, Brunella/0000-0001-5222-1524; condorelli, gerolama/0000-0003-0177-8829 FU Telethon [E.0896] NR 36 TC 9 Z9 10 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2000 VL 49 IS 7 BP 1194 EP 1202 DI 10.2337/diabetes.49.7.1194 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 329EH UT WOS:000087893400019 PM 10909978 ER PT J AU Harris, MI Eastman, MC AF Harris, MI Eastman, MC TI Early detection of undiagnosed diabetes mellitus: a US perspective SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Review DE diagnostic criteria; fasting blood glucose; epidemiology; clinical care ID NON-HISPANIC WHITES; CORONARY HEART-DISEASE; CARDIOVASCULAR RISK-FACTORS; MEXICAN-AMERICANS; NATIONAL-HEALTH; PREVALENCE; ADULTS; RETINOPATHY; NIDDM; HYPERTENSION AB Undiagnosed Type 2 diabetes has become a common condition in the US, comprising one-third of all cases of the disease. We believe that screening for and detection of undiagnosed Type 2 diabetes is an important endeavor. In this review we provide evidence that diabetes is a condition that is appropriate for population screening and detection. This includes evidence that: 1. Type 2 diabetes is a significant health problem. It affects more than 16 million adults in the US and places these individuals at high risk for serious complications of the eyes, nerves, kidneys, and cardiovascular system. 2. There is a latent phase before diagnosis of Type 2 diabetes. During this period of undiagnosed disease, risk factors for diabetic micro- and macrovascular complications are markedly elevated and diabetic complications are developing. 3. Diagnostic criteria for diabetes have been established and are based on plasma glucose values. These criteria define a group of individuals with significant hyperglycemia who also have a high frequency of risk factors for micro- and macrovascular disease. 4. The natural history of Type 2 diabetes is understood. In most patients, diabetes proceeds inexorably from genetic predisposition, through the stage of insulin resistance and hyperinsulinemia, to beta cell failure and overt clinical disease. 5. There are effective and acceptable therapies available for Type 2 diabetes and its complications. Treating hyperglycemia to prevent complications is more effective than treating these complications after they have developed. Furthermore, guidelines for treatment to prevent cardiovascular disease in people known to have diabetes are more stringent than in those individuals who are not known to have diabetes. 6. There is a suitable test for screening for undiagnosed Type 2 diabetes that has high sensitivity and specificity - measurement of fasting plasma glucose. Guidelines for identifying persons at high risk for diabetes have been established. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 NIDDKD, Natl Diabet Data Grp, NIH, Bethesda, MD 20892 USA. RP Harris, MI (reprint author), NIDDKD, Natl Diabet Data Grp, NIH, 6707 Democracy Blvd,Room 695,MSC-5460, Bethesda, MD 20892 USA. NR 40 TC 117 Z9 122 U1 0 U2 10 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1520-7552 J9 DIABETES METAB RES JI Diabetes-Metab. Res. Rev. PD JUL-AUG PY 2000 VL 16 IS 4 BP 230 EP 236 DI 10.1002/1520-7560(2000)9999:9999<::AID-DMRR122>3.0.CO;2-W PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 343BT UT WOS:000088682400002 PM 10934451 ER PT J AU Fuhrer, MJ AF Fuhrer, MJ TI Subjectifying quality of life as a medical rehabilitation outcome SO DISABILITY AND REHABILITATION LA English DT Article; Proceedings Paper CT Workshop on Clinical Trials in Rehabilitation CY DEC 02, 1998 CL ROCKVILLE, MARYLAND SP Natl Advisory Board Med Rehabilitat Res & Conduct ID SPINAL-CORD INJURY; OF-LIFE; HEALTH-STATUS; SATISFACTION; EVENTS; DISABLEMENT; PERSONALITY; DISABILITY; COMMUNITY; HANDICAP AB In the literature of health-status assessment, it has been argued that quality of life has distinct meaning only if it is conceptualized and assessed according to a subjective perspective. This paper applies that viewpoint to the conceptual components of disablement and to assessing subjective wellbeing (i.e. subjective quality of life) as medical rehabilitation outcomes. The definition and measurement of subjective wellbeing are discussed, and its correlates for people generally are reviewed. Findings for people with disabilities are summarized, and several substantive and methodological issues are highlighted that require additional investigation. C1 NIH, Bethesda, MD 20892 USA. RP Fuhrer, MJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 64 TC 66 Z9 67 U1 4 U2 6 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0963-8288 J9 DISABIL REHABIL JI Disabil. Rehabil. PD JUL PY 2000 VL 22 IS 11 BP 481 EP 489 DI 10.1080/096382800413961 PG 9 WC Rehabilitation SC Rehabilitation GA 342XM UT WOS:000088671500001 PM 10972351 ER PT J AU Jones, HE Johnson, RE Fudala, PJ Henningfield, JE Heishman, SJ AF Jones, HE Johnson, RE Fudala, PJ Henningfield, JE Heishman, SJ TI Nalmefene: blockade of intravenous morphine challenge effects in opioid abusing humans SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE nalmefene; morphine; subjective effects; blockade; pharmacology ID BRAIN MEMBRANES; ORAL NALMEFENE; NALOXONE; DURATION; NALTREXONE; DISPOSITION; ANTAGONIST; DEPENDENCE; SEDATION; BINDING AB No studies have assessed the dose-effect or duration of opioid blockade in opioid abusers produced by oral nalmefene: a mu-opioid antagonist. The present study examined the profile and time course of oral nalmefene blockade of subjective and physiological effects produced by intravenous morphine. To assess these effects, seven opioid abusers received oral nalmefene (0, 50 and 100 mg) followed by intravenous morphine (0, 10 and 20 mg) challenges every 24 h for 96 h using a Latin square randomized cross-over design. The duration of blockade varied by measure and dose. Both 50 and 100 mg nalmefene blocked morphine's effects up to 48 h. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Univ Penn, Sch Med, Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Pinney Associates, Bethesda, MD USA. RP Heishman, SJ (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sheish@intra.nida.nih.gov NR 35 TC 2 Z9 4 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2000 VL 60 IS 1 BP 29 EP 37 DI 10.1016/S0376-8716(99)00138-6 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 320XC UT WOS:000087425300004 ER PT J AU Abernethy, DR Wainer, IW Anacleto, AI AF Abernethy, DR Wainer, IW Anacleto, AI TI Verapamil metabolite exposure in older and younger men during steady-state oral verapamil administration SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID NORVERAPAMIL; AGE; DISPOSITION; ENANTIOMERS; RESPONSES; DYNAMICS; GENDER AB To determine the effect of age on exposure to the circulating major verapamil metabolites norverapamil, N-dealkylverapamil (D-617), and N-dealkylnorverapamil (D-620), plasma concentrations of verapamil and the three metabolites were determined during the last dose interval of a 14-day administration period of 240 mg of sustained release verapamil once daily in 11 older (aged 65-75 years) and 8 younger (20-28 years) healthy male volunteers. Area under the plasma concentration time curve (AUC) was greater for verapamil (mean +/- S.D.) (2815 +/- 733 older versus 1639 +/- 466 ng/ml.h(-1) young; P < .0007) and norverapamil (2927 +/- 655 versus 2143 +/- 471 ng/ml.h(-1); P < .007); however, it was not significantly different for D-617 [2386 +/- 772 versus 1894 +/- 418 ng/ml.h(-1); not significantly different (NS)] and N-dealkylnorverapamil (897 +/- 366 versus 757 +/- 104 ng/ml.h(-1); NS) in older as compared with young subjects. These data indicate that impaired verapamil oral clearance previously described in older men does not result in decreased exposure to the formed major metabolites, rather there is increased exposure to norverapamil and the same or a trend toward greater exposure to D-617 as well. This suggests that in addition to the impaired clearance mechanisms for verapamil, which are thought to be primarily mediated by CYP3A, biotransformation processes distal to the formation of norverapamil and D-617 are impaired as well. C1 Georgetown Univ, Med Ctr, Div Clin Pharmacol, Washington, DC 20007 USA. McGill Univ, Dept Oncol, Pharmacokinet Div, Montreal, PQ, Canada. McGill Univ, Dept Pharmacol, Montreal, PQ H3A 2T5, Canada. RP Abernethy, DR (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIA NIH HHS [AG-08226]; NIGMS NIH HHS [GM-08386] NR 19 TC 11 Z9 11 U1 0 U2 0 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 JUL PY 2000 VL 28 IS 7 BP 760 EP 765 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 326PK UT WOS:000087743800009 PM 10859149 ER PT J AU Dammeler, S Lovric, J Eulitz, M Kolch, W Mushinski, JF Mischak, H AF Dammeler, S Lovric, J Eulitz, M Kolch, W Mushinski, JF Mischak, H TI Identification of the smooth muscle-specific protein, sm22 as a novel protein kinase C substrate using two-dimensional gel electrophoresis and mass spectrometry SO ELECTROPHORESIS LA English DT Article DE protein kinase C; substrate; two-dimensional gel electrophoresis; mass spectrometry ID PHORBOL ESTER; CELLS; DELTA; ISOZYMES; EPSILON; OVEREXPRESSION; DIFFERENTIATION; PHOSPHORYLATION; LOCALIZATION; LYMPHOCYTES AB We report a novel method to identify protein kinase C (PKC) substrates. Tissue lysates were fractionated by ion exchange chromatography and used as substrates in in vitro kinase reactions. The phosphorylated proteins were separated using two-dimensional gel electrophoresis. Spots that contained isolated phosphoproteins were excised and digested with trypsin. The tryptic peptides were analyzed using mass spectrometry. While several of the proteins identified using this technique represent known PKC substrates, we identified a new PKC substrate in the initial screen. This protein, sm22, is expressed in smooth muscle cells and served well as a substrate for PKC in vitro. Sm22 is predominantly associated with the actin cytoskeleton. Upon activation of PKC in vivo, sm22 dissociates from the actin cytoskeleton and is distributed diffusely in the cytoplasm. Our data strongly suggest that phosphorylation by PKC controls the intracellular localization of sm22. This demonstrates that our approach, using a complex mixture of proteins as in vitro kinase substrates and subsequently identifying the newly phosphorylated proteins by mass spectrometry, is a powerful method to identify new kinase substrates. C1 GSF, Inst Klin Mol Biol, Munich, Germany. CRC, Beatson Labs, Glasgow, Lanark, Scotland. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. Med Hsch Hannover, Hannover, Germany. RP Dammeler, S (reprint author), BYK Gulden Pharmaceut, Dept Mol Biol, Byk Gulden Str 2, D-78467 Constance, Germany. RI Mischak, Harald/E-8685-2011; OI Kolch, Walter/0000-0001-5777-5016 NR 24 TC 9 Z9 10 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUL PY 2000 VL 21 IS 12 BP 2443 EP 2453 DI 10.1002/1522-2683(20000701)21:12<2443::AID-ELPS2443>3.0.CO;2-6 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 335UG UT WOS:000088262700022 PM 10939458 ER PT J AU Constantinou, A Tarsounas, M Karow, JK Brosh, RM Bohr, VA Hickson, ID West, SC AF Constantinou, A Tarsounas, M Karow, JK Brosh, RM Bohr, VA Hickson, ID West, SC TI Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest SO EMBO REPORTS LA English DT Article ID ESCHERICHIA-COLI; RUVB PROTEINS; HUMAN-CELLS; DNA; RECOMBINATION; HELICASE; BINDING AB Individuals affected by the autosomal recessive disorder Werner's syndrome (WS) develop many of the symptoms characteristic of premature ageing. Primary fibroblasts cultured from WS patients exhibit karyotypic abnormalities and a reduced replicative life span. The WRN gene encodes a 3'-5' DNA helicase, and is a member of the RecQ family, which also includes the product of the Bloom's syndrome gene (BLM). In this work, we show that WRN promotes the ATP-dependent translocation of Holliday junctions, an activity that is also exhibited by BLM. In cells arrested in S-phase with hydroxyurea, WRN localizes to discrete nuclear foci that coincide with those formed by the single-stranded DNA binding protein replication protein A. These results are consistent with a model in which WRN prevents aberrant recombination events at sites of stalled replication forks by dissociating recombination intermediates. C1 Imperial Canc Res Fund, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. Univ Oxford, John Radcliffe Hosp, Inst Mol Med, ICRF Labs, Oxford OX3 9DS, England. NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP West, SC (reprint author), Imperial Canc Res Fund, Clare Hall Labs, Blanche Lane, S Mimms EN6 3LD, Herts, England. RI Constantinou, Angelos/E-5337-2013 NR 23 TC 293 Z9 298 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUL PY 2000 VL 1 IS 1 BP 80 EP 84 DI 10.1093/emborep.kvd004 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 381MC UT WOS:000165765800019 PM 11256630 ER PT J AU Thurmond, TS Murante, FG Staples, JE Silverstone, AE Korach, KS Gasiewicz, TA AF Thurmond, TS Murante, FG Staples, JE Silverstone, AE Korach, KS Gasiewicz, TA TI Role of estrogen receptor alpha in hematopoietic stem cell development and B lymphocyte maturation in the male mouse SO ENDOCRINOLOGY LA English DT Article ID BONE-MARROW; IN-VIVO; C-KIT; IMMUNOGLOBULIN LEVELS; TISSUE DISTRIBUTION; THYMIC ALTERATIONS; FEMALE MOUSE; RAT BONE; T-CELLS; PRO-B AB Although estrogens and estrogen receptors (ERs) are known to function in the male brain and reproductive tract, few studies have evaluated their involvement in the male hematopoietic and immune systems. This study was undertaken to determine the role of ER alpha in hematopoietic progenitor and B lymphocyte maturation. ERa knockout (ER-/-), wild-type (ER+/+), and radiation chimeric (ER alpha positive Dr negative in either nonhematopoietic or hematopoietic elements, or both) male mice were used to determine target tissues. ER-/- and ER+/+ animals showed similar hematopoietic progenitor profiles, but the ER-/- animals had fewer cells in all bone marrow B lymphocyte subpopulations. Animals receiving a pharmacological dose (5 mg/kg BW) of 17 beta-estradiol (E-2) with both elements, ER+/+, had decreased early hematopoietic progenitors and a shift toward a mature B cell subpopulation, whereas animals with both elements, ER-/-, showed changes only in early hematopoietic progenitors. Hematopoietic element ER+/+ animals exhibited greater E-2-induced hematopoietic progenitor and B lymphocyte alterations than those having only nonhematopoietic ER alpha. These data indicate that 1) ER alpha is not necessary for regulating male mouse normal hematopoietic progenitor cell proportions, but is involved in B cell regulation; and 2) ER alpha in hematopoietic elements is predominantly responsible for mediating E-2-induced hematopoietic and B cell changes. C1 Univ Rochester, Dept Environm Med, Rochester, NY 14642 USA. SUNY Hlth Sci Ctr, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Gasiewicz, TA (reprint author), Univ Rochester, Dept Environm Med, 575 Elmwood Ave,Box EHSC, Rochester, NY 14642 USA. EM Tom_Gasiewicz@urmc.rochester.edu OI Korach, Kenneth/0000-0002-7765-418X NR 44 TC 66 Z9 70 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2000 VL 141 IS 7 BP 2309 EP 2318 DI 10.1210/en.141.7.2309 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WN UT WOS:000088386200005 PM 28201025 ER PT J AU Gao, XG Cao, SG Zhang, KC AF Gao, XG Cao, SG Zhang, KC TI Production, properties and application to nonaqueous enzymatic catalysis of lipase from a newly isolated Pseudomonas strain SO ENZYME AND MICROBIAL TECHNOLOGY LA English DT Article DE lipase; Pseudomonas sp.; nonaqueous medium; monoglyceride; (R,S)2-octanol ID ORGANIC-SOLVENTS; GLYCEROLYSIS; MONOGLYCERIDES; ENZYMES; YIELD; FATS; OILS AB A potent bacterium for lipase production was isolated from soil and identified as Pseudomonas species. It produced lipase constitutively. A mutant of this strain with a lipase productivity 3.25-fold higher was obtained by treatment with ultraviolet (UV) and nitrosoguanidine (NTG). Its fermentation condition was optimized to a lipase yield of 87.5 U/ml. The lipase had maximum activity at pH 9.0 and 45 degrees C. It was stable at pHs from 7.0 to 11.0 and below 60 degrees C. The effects of metal ions, surfactants and bile salts were also studied. The lipase was 1,3-specific. In organic solvents, the thermal stability of the lipase was significantly enhanced. Its optimum temperature was also slightly increased. The optimum water activity was found between 0.5 and 0.6. The lipase was successfully applied in organic phase to catalyze the glycerolysis of palm oil for monoglyceride (MG) production, and the enantioselective esterification of (R,S)-2-octanol. The enantioselectivity of the lipase could be enhanced substantially by treatment with an amphipathic. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Wuxi Univ Light Ind, Sch Biotechnol, Wuxi 214036, Peoples R China. Jilin Univ, Natl Lab Enzyme Engn, Changchun 130023, Peoples R China. RP Gao, XG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,37 Convent Dr,Rm 1B23, Bethesda, MD 20892 USA. NR 25 TC 35 Z9 41 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0141-0229 J9 ENZYME MICROB TECH JI Enzyme Microb. Technol. PD JUL PY 2000 VL 27 IS 1-2 BP 74 EP 82 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 328YX UT WOS:000087880300010 ER PT J AU Lee, GM Neutra, RR Hristova, L Yost, M Hiatt, RA AF Lee, GM Neutra, RR Hristova, L Yost, M Hiatt, RA TI The use of electric bed heaters and the risk of clinically recognized spontaneous abortion SO EPIDEMIOLOGY LA English DT Article DE electric blankets; waterbeds; electric bed heaters; spontaneous abortions; magnetic fields; electromagnetic fields. ID ELECTROMAGNETIC-FIELDS; MAGNETIC-FIELDS; EARLY-PREGNANCY; CHICK-EMBRYOS; BLANKET USE; EXPOSURE; CANCER AB We conducted a prospective cohort study to evaluate the relation of spontaneous abortion and electric bed heater use during the first trimester of pregnancy. Compared with nonusers, rates of spontaneous abortion were lower for women who used electric bed heaters. The adjusted odds ratio and 95% confidence interval (CI) for the two major devices used, electric blankets (N = 524) and waterbeds (N = 796), were, respectively, 0.8 (95% CI = 0.5-1.1) and 0.9 (95% CI = 0.7-1.2). An increase of risk with increasing intensity (setting-duration combination) of use was not observed. Users of electric blankets at low settings for most of the night (N = 171) had lower risks of spontaneous abortion than non-users (adjusted odds ratio = 0.5; 95% CI = 0.3-1.0). Twenty women who used electric blankets at a high setting for 1 hour or less had an adjusted odds ratio of 3.0 (95% CI = 1.1-8.3), but we found no spontaneous abortions among the few women (N = 13) who used a high setting for 2 or more hours. We found that exposure rankings of the magnetic field time-weighted average and a rate of change metric did not correspond monotonically to the pattern of spontaneous abortion risks and that electric blankets contribute less to overnight time-weighted average magnetic fields than has been thought. C1 Dept Hlth Serv, Environm Hlth Invest Branch, Oakland, CA 94612 USA. Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. NIH, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Lee, GM (reprint author), Dept Hlth Serv, Environm Hlth Invest Branch, 1515 Clay St,17th Floor, Oakland, CA 94612 USA. NR 24 TC 14 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2000 VL 11 IS 4 BP 406 EP 415 DI 10.1097/00001648-200007000-00008 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 326CD UT WOS:000087713600008 PM 10874547 ER PT J AU Cantor, KP Lynch, C Hildesheim, M AF Cantor, KP Lynch, C Hildesheim, M TI Chlorinated drinking water and risk of renal cell and pancreas cancers: A case-control study in Iowa, USA SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2000 VL 11 IS 4 MA 134 BP S68 EP S68 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 326CD UT WOS:000087713600079 ER PT J AU Fleming, L Dewailly, E Baden, D AF Fleming, L Dewailly, E Baden, D TI The epidemiology of marine Harmful Algal Blooms SO EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2000 VL 11 IS 4 MA 673 BP S143 EP S143 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 326CD UT WOS:000087713600377 ER PT J AU Rogawski, MA AF Rogawski, MA TI Untitled SO EPILEPSIA LA English DT Letter ID METHYL-D-ASPARTATE; FELBAMATE; RECEPTORS; MECHANISM; INCREASES; CELLS C1 NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 12 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUL PY 2000 VL 41 IS 7 BP 918 EP 918 DI 10.1111/j.1528-1157.2000.tb00265.x PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 330DK UT WOS:000087947400023 PM 10897169 ER PT J AU Magone, MT Chan, CC Beck, L Whitcup, SM Raz, E AF Magone, MT Chan, CC Beck, L Whitcup, SM Raz, E TI Systemic or mucosal administration of immunostimulatory DNA inhibits early and late phases of murine allergic conjunctivitis SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE immunostimulatory DNA; allergic conjunctivitis; Th1; Th2; IL-12; corticosteroids ID BACTERIAL-DNA; CPG OLIGODEOXYNUCLEOTIDES; AIRWAY INFLAMMATION; INTERFERON-GAMMA; DENDRITIC CELLS; OCULAR ALLERGY; IFN-GAMMA; SEQUENCES; ASTHMA; MODEL AB Seasonal allergic conjunctivitis is one of the most common manifestations of allergic disease, affecting 15 % population in the United States annually. Short ragweed (RW) is a major cause of seasonal allergies. Immunostimulatory DNA sequences (ISS or CpG motifs) can inhibit an on-going Th2/allergic response and induce a de novo Th1 response. In this study, we investigated the ability of these ISS to modulate allergic responses in a RW-induced mouse model of seasonal allergic conjunctivitis. Systemic or mucosal administration of ISS oligonucleotide (ISS-ODN) after RW sensitization inhibited both the immediate hypersensitivitiy response and the late-phase cellular infiltration and induced a RW-specific Th1 response. ISS-ODN administration suppressed the rise of RW-specific IgE titers after repeated allergen challenge. Furthermore, ISS administration was more effective than dexamethasone in inhibiting the allergic response. Mechanistically, the ISS-induced immunomodulatory effects were abolished when mice were treated with anti-IL-12 neutralizing antibodies, suggesting a pivotal role for type 1 cytokines in the inhibition of both the immediate hypersensitivity and the late-phase cellular infiltration. Thus, ISS-ODN is a novel antiinflammatory and immunomodulatory agent that significantly inhibits the allergic response and may provide an alternative to the current standard care of ocular allergy. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Chan, CC (reprint author), NEI, NIH, Bldg 10,10N103,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 40682] NR 33 TC 62 Z9 67 U1 2 U2 4 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2000 VL 30 IS 7 BP 1841 EP 1850 DI 10.1002/1521-4141(200007)30:7<1841::AID-IMMU1841>3.0.CO;2-E PG 10 WC Immunology SC Immunology GA 335UC UT WOS:000088262300006 PM 10940873 ER PT J AU Hoshino, T Yagita, H Ortaldo, JR Wiltrout, RH Young, HA AF Hoshino, T Yagita, H Ortaldo, JR Wiltrout, RH Young, HA TI In vivo administration of IL-18 can induce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IL-18; IgE; Th2 cell; CD154; CD4(+) T cell ID INTERFERON-GAMMA PRODUCTION; IMMUNOGLOBULIN AB IL-18 is considered to be a strong cofactor for CD4(+) T helper 1 (Th1) cell induction. We have recently reported that IL-18 can induce IL-13 production in both NK cells and T cells in synergy with IL-2 but not IL-12, suggesting IL-18 can induce Th1 and Th2 cytokines when accompanied by the appropriate first signals for T cells. We have now found that IL-18 can act as a cofactor to induce IL-4, IL-10 and IL-13 as well as IFN-gamma production in T cells in the presence of anti-CDS monoclonal antibodies (mAb). IL-18 can rapidly induce CD40 ligand (CD154) mRNA and surface expression on CD4(+) but not CD8(+) T cells. The administration of IL-18 alone in vivo significantly increased serum IgE levels in C57BL/6 (B6) and B6 IL-4 knockout mice. Furthermore, the administration of IL-18 plus IL-2 induced approximately 70-fold and 10-fold higher serum levels of IgE and IgG1 than seen in control B6 mice, respectively. IgE and IgG1 induction in B6 mice by administration of IL-18 plus IL-2 was eliminated by the pretreatment of mice with anti-CD4 or anti-CD154, but not anti-CD8 or anti-NK1.1 mAb. These results suggest that IL-18 can induce Th2 cytokines and CD154 expression, and can contribute to CD4(+) T cell-dependent, IL-4-independent IgE production. C1 Kurume Univ, Sch Med, Dept Internal Med 1, Kurume, Fukuoka 8300011, Japan. NCI, Frederick Canc Res & Dev Ctr, DBS, Expt Immunol Lab, Frederick, MD USA. Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. RP Hoshino, T (reprint author), Kurume Univ, Sch Med, Dept Internal Med 1, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NCI NIH HHS [N01-CO-56000] NR 21 TC 129 Z9 134 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2000 VL 30 IS 7 BP 1998 EP 2006 DI 10.1002/1521-4141(200007)30:7<1998::AID-IMMU1998>3.0.CO;2-U PG 9 WC Immunology SC Immunology GA 335UC UT WOS:000088262300022 PM 10940889 ER PT J AU Li, ZD Schettino, EW Padlan, EA Ikematsu, H Casali, P AF Li, ZD Schettino, EW Padlan, EA Ikematsu, H Casali, P TI Structure-function analysis of a lupus anti-DNA autoantibody: central role of the heavy chain complementarity-determining region 3 Arg in binding of double- and single-stranded DNA SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE autoantibody; B lymphocyte; complementarity-determining region 3 Arg; DNA; immunoglobulin gene somatic mutation ID HUMAN-IMMUNOGLOBULIN HEAVY; V-H; SOMATIC HYPERMUTATION; CLONAL ANALYSIS; RABIES VIRUS; PREFERENTIAL UTILIZATION; MONOCLONAL IGM; SELF-ANTIGEN; IN-VITRO; ANTIBODIES AB To determine the contribution of the somatic point mutations and that of the complementarity-determining region (CDR)3 Arg to DNA binding, we engineered the germ line V-H and V-kappa gene revertant and site-mutagenized the CDR3 Arg residues of the mutated and "antigen-selected" mAb 412.67. This anti-DNA autoantibody was derived from B-1 cells of a lupus patient and bore two H-CDR3 Arg, Arg105 and Arg107, encoded by N segment additions, and one kappa-CDR3 Arg, Arg97, resulting from a point mutation (Kasaian et al. 1994. J. Immunol 152: 3137-3151; Kasaian et al. 1995. Ann. N.Y. Acad. Sci. 764: 410-423). The germ-line revertant bound double-stranded (ds) DNA and single-stranded (ss) DNA as effectively as its wild-type counterpart (relative avidity: 6.4x10(-7) and 9.9x10(-9) vs. 6.7x10(-7) and 9.1x10(-9) g/mu l), raising the possibility that an antigen other than DNA was responsible for the selection of the mAb 412.67 V-H and V-kappa point mutations. H-CDR3 Arg105 and Arg107 were both required for dsDNA binding, but either Arg105 or Arg107 was sufficient for ssDNA binding, The central role of Arg105 and Arg107 in DNA binding reflected their solvent-exposed orientation at the apex of the H-CDR3 main loop. Consistent with its inward orientation afar from the antigen-binding surface, the kappa-CDR3 Arg97 played no role in either dsDNA or ssDNA binding. C1 Cornell Univ, Weill Med Coll, Dept Pathol, Div Mol Immunol, New York, NY 10021 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Hara Hoi Hosp, Dept Clin Res, Fukuoka, Japan. Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. Cornell Univ, Weill Grad Sch Med Sci, Program Immunol, New York, NY 10021 USA. RP Casali, P (reprint author), Cornell Univ, Weill Med Coll, Dept Pathol, Div Mol Immunol, 1300 York Ave, New York, NY 10021 USA. RI Casali, Paolo/F-6579-2010 FU NIAMS NIH HHS [AR 40908, R01 AR040908] NR 42 TC 41 Z9 42 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2000 VL 30 IS 7 BP 2015 EP 2026 DI 10.1002/1521-4141(200007)30:7<2015::AID-IMMU2015>3.0.CO;2-5 PG 12 WC Immunology SC Immunology GA 335UC UT WOS:000088262300024 PM 10940891 ER PT J AU Pinto, LA Williams, MS Dolan, MJ Henkart, PA Shearer, GM AF Pinto, LA Williams, MS Dolan, MJ Henkart, PA Shearer, GM TI beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE beta-chemokine; activation-induced cell death; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROGRAMMED CELL-DEATH; CD8(+) T-CELLS; INDUCED APOPTOSIS; FAS LIGAND; LYMPH-NODES; EXPRESSION; RANTES; DISEASE; MODULATION AB The present study investigates the role of the HIV-suppressive beta-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and RANTES in activation-induced cell death (AICD). A pool of these beta-chemokines reduced anti-CD3-induced apoptosis of T cell blasts from healthy blood donors in a dose-dependent manner. Although the pooled beta-chemokines were more effective, the inhibitory effect could also be mediated by each of the individual chemokines and was blocked by neutralizing anti-chemokine antibodies. The beta-chemokines also inhibited pokeweed mitogen/staphylococcal enterotoxin B-induced T lymphocyte apoptosis in 33/49 HIV-infected (HIV+) individuals. This anti-apoptotic effect was not correlated with the patients' CD4 T cell counts. beta-chemokines did not lead to altered secretion of IL-2, IL-4, IFN-gamma or IL-10 in response to activation stimuli in either normal T cell blasts or peripheral blood mononuclear cells from HIV+ individuals. Go-incubation with beta-chemokines did not inhibit anti-CD3-induced expression of cell surface Fas ligand, nor did it alter levels of the death receptor Fas or Bcl-2 in T cell blasts, suggesting that the beta-chemokines are blocking AICD downstream of Fas. These observations indicate that beta-chemokines may play a novel role as modulators of AICD, in addition to their known role as chemoattractants and inhibitors of HIV replication. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Dept Immunol, Rockville, MD USA. Wilford Hall USAF Med Ctr, HIV Unit, Lackland AFB, TX 78236 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B 36, Bethesda, MD 20892 USA. NR 34 TC 20 Z9 20 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2000 VL 30 IS 7 BP 2048 EP 2055 DI 10.1002/1521-4141(200007)30:7<2048::AID-IMMU2048>3.0.CO;2-I PG 8 WC Immunology SC Immunology GA 335UC UT WOS:000088262300027 PM 10940894 ER PT J AU Ludviksson, BR Seegers, D Resnick, AS Strober, W AF Ludviksson, BR Seegers, D Resnick, AS Strober, W TI The effect of TGF-beta 1 on immune responses of naive versus memory CD4(+) Th1/Th2 T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE transforming growth factor-beta 1; CD4(+) T cell; Th1; STAT4; Th2 ID GROWTH-FACTOR-BETA; HUMAN LYMPHOCYTES-T; TRANSFORMING GROWTH-FACTOR-BETA-1; IL-12 RESPONSIVENESS; EXPRESSION; ACTIVATION; MACROPHAGES; APOPTOSIS; CYCLE AB The role of TGF-beta 1 in the regulation of T cell responses has been perplexing, possibly because it is dependent on the type of T cell being regulated and its cytokine microenvironment. in the present study, we demonstrate that TGF-beta 1 has a profound inhibitory effect on naive CD4(+) T cell undergoing differentiation under defined neutral, Th1 and Th2 priming conditions, in addition, we show that if CD4(+) T cells are primed in the presence of TGF-beta 1, they exhibit reduced secondary anti-CD3/anti-CD28-induced and antigen-specific immune responses (even when TGF-beta is absent during the secondary response), which is not due to reduced expression of co-stimulatory molecules or to inadequate IL-2 production. Finally, with respect to the effect of TGF-beta on fully differentiated antigen-specific memory CD4(+) T cells, we demonstrate that while antigen-specific activation and cytokine secretion by memory Th1 T cells is inhibited by TGF-beta 1, such inhibition is associated with partial downregulation of IL-12 receptor beta 2 chain expression. In contrast, memory Th2 T cells are not subject to TGF-beta 1-mediated suppression. In summary, these studies reveal that TGF-beta 1 is a powerful negative regulator of the primary immune response of CD4(+) T cells, but only Th1 T cells are subject to such regulation after the memory stage of T cell differentiation has been reached. Thus, these studies define the potential regulatory role of TGF-beta 1 in Th1 and Th2 T-cell-mediated autoimmunity. C1 NIAID, LCI, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, LCI, Mucosal Immun Sect, NIH, Bldg 10,Room 11N238, Bethesda, MD 20892 USA. OI Ludviksson, Bjorn/0000-0002-6445-148X NR 24 TC 110 Z9 118 U1 2 U2 5 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2000 VL 30 IS 7 BP 2101 EP 2111 DI 10.1002/1521-4141(200007)30:7<2101::AID-IMMU2101>3.0.CO;2-P PG 11 WC Immunology SC Immunology GA 335UC UT WOS:000088262300033 PM 10940900 ER PT J AU Fabre, V Beaufour, C Evrard, A Rioux, A Hanoun, N Lesch, KP Murphy, DL Lanfumey, L Hamon, M Martres, MP AF Fabre, V Beaufour, C Evrard, A Rioux, A Hanoun, N Lesch, KP Murphy, DL Lanfumey, L Hamon, M Martres, MP TI Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE 5-HT neurotransmission; adaptive changes; desensitization; down-regulation; G protein coupling ID RAT DORSAL RAPHE; FRONTAL-CORTEX; MESSENGER-RNA; GUINEA-PIG; IN-VITRO; 5-HYDROXYTRYPTAMINE(1B) RECEPTORS; ANTIDEPRESSANT TREATMENTS; CELLULAR-LOCALIZATION; UPTAKE INHIBITOR; BRAIN-SEROTONIN AB By taking up serotonin (5-hydroxytryptamine, 5-HT) released in the extracellular space, the 5-HT transporter (5-HTT) regulates central 5-HT neurotransmission. Possible adaptive changes in 5-HT neurotransmission in knock-out mice that do not express the 5-HT transporter were investigated with special focus on 5-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A receptor protein and mRNA levels were significantly decreased in the dorsal raphe nucleus (DRN), increased in the hippocampus and unchanged in other forebrain areas of 5-HTT-/- vs. 5-HTT+/+ mice. Such regional differences also concerned 5-HT1B receptors because a decrease in their density was found in the substantia nigra (-30%) but not the globus pallidus of mutant mice. Intermediate changes were noted in 5-HTT+/- mice compared with 5-HTT+/+ and 5-HTT-/- animals. Quantification of [S-35]GTP-gamma-S binding evoked by potent 5-HT1 receptor agonists confirmed such changes as a decrease in this parameter was noted in the DRN (-66%) and the substantia nigra (-30%) but not other brain areas in 5-HTT-/- vs. 5-HTT+/+ mice. As expected from actions mediated by functional 5-HT1A and 5-HT1B autoreceptors, a decrease in brain 5-HT turnover rate after i.p. administration of ipsapirone (a 5-HT1A agonist), and an increased 5-HT outflow in the substantia nigra upon local application of GR 127935 (a 5-HT1B/1D antagonist) were observed in 5-HTT+/+ mice. Such effects were not detected in 5-HTT-/- mice, further confirming the occurrence of marked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals. C1 Fac Med Pitie Salpetriere, INSERM, U288, F-75634 Paris 13, France. Univ Wurzburg, Dept Psychiat, D-97080 Wurzburg, Germany. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Fabre, V (reprint author), Fac Med Pitie Salpetriere, INSERM, U288, 91 Blvd Hop, F-75634 Paris 13, France. RI Lanfumey, Laurence/F-7695-2013; hanoun, naima/M-6408-2014; Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 65 TC 193 Z9 198 U1 2 U2 6 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 2000 VL 12 IS 7 BP 2299 EP 2310 DI 10.1046/j.1460-9568.2000.00126.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 336NW UT WOS:000088310300012 PM 10947809 ER PT J AU Clark, NM Gong, M Schork, MA Kaciroti, N Evans, D Roloff, D Hurwitz, M Maiman, LA Mellins, RB AF Clark, NM Gong, M Schork, MA Kaciroti, N Evans, D Roloff, D Hurwitz, M Maiman, LA Mellins, RB TI Long-term effects of asthma education for physicians on patient satisfaction and use of health services SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE asthma; patient outcomes; physician continuing education ID CONTROLLED TRIAL; OUTCOMES; CARE AB This randomized clinical trial evaluated the long-term impact of an interactive seminar for physicians based on principles of self-regulation on clinician behaviour, children's use of health services for asthma, and parent's views of physician performance. Seventy-four general practice paediatricians, and 637 of their asthma patients aged 1-12 yrs, were randomized to treatment or control. Children and parents were blind to physicians' participation. Data were collected at baseline and follow-up through self administered surveys (paediatricians), telephone interviews (parents) and medical records, The seminar focused on development of communication and teaching skills and use of therapeutic medical regimens for asthma as outlined in the National Asthma Education and Prevention Program guidelines. Approximately 2 yrs postintervention, treatment group physicians were more likely than control physicians to: use protocols for delivering asthma education (odds ratio (OR) 4.9, p=0.2), write down for patients how to adjust medicines when symptoms change (OR 5.7, p=0.05), and provide more guidelines for modifying therapy (OR 3.8, p=0.06), Parents scored treatment group physicians higher than control physicians on five specific positive communication behaviours. Children seen by treatment group physicians had fewer hospitalizations (p=0.03) and those with higher levels of emergency department (ED) use at baseline had fewer subsequent ED visits (p=0.03). No differences regarding the number of office visits were noted. There were no significant differences found between treatment and control group physicians in the amount of time spent with patients during office visits (26 versus 29 min) or in the number of patients treated with anti-inflammatory medicine. It is concluded that interactive asthma seminars for paediatricians had significant long-term benefits for their asthma care. C1 Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Paediat & Communicable Dis, Ann Arbor, MI 48109 USA. Columbia Univ, Coll Phys & Surg, Dept Paediat, New York, NY USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Clark, NM (reprint author), Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, 1420 Washington Hts, Ann Arbor, MI 48109 USA. OI Kaciroti, Niko/0000-0001-8843-8231 FU NHLBI NIH HHS [HL-44976] NR 17 TC 113 Z9 118 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD JUL PY 2000 VL 16 IS 1 BP 15 EP 21 DI 10.1034/j.1399-3003.2000.16a04.x PG 7 WC Respiratory System SC Respiratory System GA 335UE UT WOS:000088262500004 PM 10933079 ER PT J AU Murray, EA Bussey, TJ Wise, SP AF Murray, EA Bussey, TJ Wise, SP TI Role of prefrontal cortex in a network for arbitrary visuomotor mapping SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Workshop on Executive Control and the Frontal Lobe CY DEC 01-03, 1998 CL HANSE INST ADV STUDY, DELMENHORST, GERMANY HO HANSE INST ADV STUDY DE conditional motor learning; frontal cortex; premotor cortex; basal ganglia; hippocampus ID CONDITIONAL VISUAL-DISCRIMINATION; INFEROTEMPORAL-FRONTAL DISCONNECTION; SUPPLEMENTARY EYE FIELD; MEDIAL PREMOTOR CORTEX; PERIRHINAL CORTEX; NEURONAL-ACTIVITY; EXCITOTOXIC LESIONS; OCULOMOTOR ASSOCIATIONS; POSTERIOR CINGULATE; CEREBELLAR DISEASE AB In arbitrary visuomotor mapping, an object instructs a particular action or target of action, but does so in a particular way. In other forms of visuomotor control, the object is either the target of action (termed standard mapping) or its location provides the information needed for targeting (termed transformational mapping). By contrast, in arbitrary mapping, the object's location bears no systematic spatial relationship with the action. Neuropsychological and neurophysiological investigation has, in large part, identified the neural network that underlies the rapid acquisition and performance of arbitrary visuomotor mappings. This network consists of parts of the premotor (PM) and prefrontal (PF) cortex, the hippocampal system (HS), and the basal ganglia (BG). Here, we propose specialized contributions of the network's different components to its overall function. To do so, we invoke the concept of distributed information-processing architectures, or modules, which may involve a variety of neural structures. According to this view, recurrent neural networks involving cortex, basal ganglia, and thalamus operate largely in parallel. Each of these interacting networks can be termed a cortical-BG module. A large number of these modules include PM neurons, and they can be termed PM cortical-BG modules. A comparable number include PF neurons. termed PF cortical-BG modules. We propose that PM and PF cortical-BG modules compute specific object-to-action mappings, in which the network learns the action associated with a given input. These mappings serve as specific solutions to arbitrary visuomotor mapping problems. However, they are also exemplars of more abstract rules, such as the knowledge that nonspatial visual information (e.g., color) can guide the choice of action. We propose that PF cortical-BG modules subserve abstract rules of this kind, along with other problem-solving strategies. This view should not be taken to imply that the PF network lacks the capacity to compute specific mappings, but rather that it has higher-order mapping functions in addition to its lower-order ones. Furthermore, it seems likely that PF provides PM with pertinent sensory information. The hippocampal system appears to play a role parallel to that of both neocortical-BG networks discussed here. However, in accord with several models, it operates mainly in the intermediate term, pending the consolidation of the relevant information in those neocortical-BG networks. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM eam@ln.nimh.nih.gov RI Bussey, Timothy/M-2758-2016; OI Bussey, Timothy/0000-0001-7518-4041; Murray, Elisabeth/0000-0003-1450-1642 NR 82 TC 139 Z9 139 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUL PY 2000 VL 133 IS 1 BP 114 EP 129 DI 10.1007/s002210000406 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 335JX UT WOS:000088241300013 PM 10933216 ER PT J AU Mattson, MP AF Mattson, MP TI Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE amyloid; BDNF; calorie; deoxyglucose; Huntington; Parkinson; stem cells; stroke; telomerase reverse transcriptase ID AMYLOID BETA-PEPTIDE; PROTECTS HIPPOCAMPAL-NEURONS; LONG-TERM POTENTIATION; PRECURSOR PROTEIN; LIPID-PEROXIDATION; CALCIUM HOMEOSTASIS; OXIDATIVE STRESS; MUTANT PRESENILIN-1; GLUTAMATE TRANSPORT; TRANSGENIC MICE AB The molecular, biochemical and cellular events that result in synaptic dysfunction and neuronal degeneration in the brain in Alzheimer's disease (AD) are becoming known. Age-related increases in cellular oxidative stress, and impairment of energy metabolism, result in disruption of neuronal calcium homeostasis and increased vulnerability of neurons to excitotoxicity and apoptosis. Inherited forms of AD that result from mutations in the beta-amyloid precursor protein (APP) and presenilins accelerate the neurodegenerative cascade by increasing production and deposition of neurotoxic forms of amyloid beta-peptide and by perturbing calcium homeostasis. Dietary restriction (DR; reduced calorie intake with maintained nutrition) extends life span of rodents and (probably) humans. DR increases resistance of neurons to dysfunction and degeneration, and improves behavioral outcome, in experimental models of AD and other age-related neurodegenerative disorders by a mechanism involving a mild stress response. Telomerase, a specialized reverse transcriptase, has been proposed to possess anti-aging properties. The catalytic subunit of telomerase (TERT) is expressed in neurons throughout the brain during development, but is absent from neurons in the adult brain. TERT exhibits neuroprotective properties in experimental models of neurodegenerative disorders suggesting that manipulations that induce telomerase in neurons may protect against age-related neurodegeneration. Finally, the exciting and exploding field of stem cell research suggests methods for replacing damaged or lost brain cells in an array of neurological disorders. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIA, Lab Neurosci 4F01, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci 4F01, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 99 TC 68 Z9 71 U1 2 U2 16 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 JUL PY 2000 VL 35 IS 4 BP 489 EP 502 DI 10.1016/S0531-5565(00)00115-7 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 356GL UT WOS:000089435500008 PM 10959037 ER PT J AU Carballo, E Lai, WS Blackshear, PJ AF Carballo, E Lai, WS Blackshear, PJ TI Tristetraprolin is a regulator of granulocyte-macrophage colony-stimulating factor mRNA stability SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NIEHS, LST, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 17 BP 36 EP 36 DI 10.1016/S0301-472X(00)00202-2 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200017 ER PT J AU Drutskaya, MS Chertkov, JL Kuprash, DV Nedospasov, SA Drize, NJ AF Drutskaya, MS Chertkov, JL Kuprash, DV Nedospasov, SA Drize, NJ TI Abnormal interaction between stromal and hemapoietic cells in TNF deficient mice SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 All Union Hematol Sci Ctr, VA Engelhardt Mol Biol Inst, Moscow, Russia. NCI, FCRDC, Frederick, MD USA. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 30 BP 40 EP 41 DI 10.1016/S0301-472X(00)00215-0 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200030 ER PT J AU Chute, JP Clark, W Johnson, K Saini, A Wells, M Harlan, DM AF Chute, JP Clark, W Johnson, K Saini, A Wells, M Harlan, DM TI Hematopoietic cytokine production by human brain endothelial cells (HUBEC) is associated with the ex vivo expansion of CD34(+)CD38(-) cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NIDDK, USN, TAB, Bethesda, MD 20889 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 96 BP 61 EP 61 DI 10.1016/S0301-472X(00)00279-4 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200094 ER PT J AU Chinnasamy, D Chinnasamy, N Morgan, RA Candotti, F Bodine, DM AF Chinnasamy, D Chinnasamy, N Morgan, RA Candotti, F Bodine, DM TI Differentiation of T-lymphocytes from human umbilical cord blood stem cells cultured in vitro on murine thymic stroma SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NIH, NHGRI, Gen Clin Therapy Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 106 BP 64 EP 64 DI 10.1016/S0301-472X(00)00288-5 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200103 ER PT J AU Orlic, D Farese, AM Anderson, S MacVittie, T Bodine, DM AF Orlic, D Farese, AM Anderson, S MacVittie, T Bodine, DM TI Expansion of Rhesus monkey hematopoietic stem cells in response to administration of chimeric leridistim or progenipoietin (PRO-GP) SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NIH, NHGRI, Bethesda, MD 20892 USA. Univ Maryland, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 199 BP 93 EP 94 DI 10.1016/S0301-472X(00)00379-9 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200194 ER PT J AU Zhang, S Lee, Y Hangoc, G Cooper, S Leonard, WJ Broxmeyer, HE AF Zhang, S Lee, Y Hangoc, G Cooper, S Leonard, WJ Broxmeyer, HE TI Flt3 ligand induces functional effects through Stat5a activation and bcl-xL expression as evidenced through biochemical analysis and use of Stat 5a-/- mice SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN USA. NHLBI, NIH, Lab Mol Hematol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 214 BP 99 EP 99 DI 10.1016/S0301-472X(00)00394-5 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200209 ER PT J AU Thornton, J Goel, A Tseng-Law, J Szalay, P Malech, H Van Epps, D Freimark, B AF Thornton, J Goel, A Tseng-Law, J Szalay, P Malech, H Van Epps, D Freimark, B TI Centrifugation-enhanced retroviral gene transduction of human CD34(+) cells in RetroNectin (TM)-coated gas permeable X-Fold (TM) containers SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Nexell Therapeut Inc, Irvine, CA USA. NIH, NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 296 BP 125 EP 125 DI 10.1016/S0301-472X(00)00474-4 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200287 ER PT J AU Chang, H Jensen, L Quesenberry, P Bertoncello, I AF Chang, H Jensen, L Quesenberry, P Bertoncello, I TI Standardization of hematopoietic stem cell assays: A summary of a workshop and working group meeting sponsored by the National Heart, Lung, and Blood Institute held at the National Institutes of Health, Bethesda, MD on September 8-9, 1998 and July 30, 1999 SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID COLONY-FORMING CELLS; REGULATORY MOLECULES; CD34(+) CELLS; BONE-MARROW; IN-VIVO; PROGENITORS; MICE C1 NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Ctr Canc, Worcester, MA 01605 USA. Peter MacCallum Canc Inst, Trescowthick Res Labs, Melbourne, Vic 3000, Australia. RP Chang, H (reprint author), NHLBI, Div Blood Dis & Resources, NIH, MSC 7950,6701 Rockledge Dr,Room 10170, Bethesda, MD 20892 USA. RI Bertoncello, Ivan/B-9235-2008 NR 24 TC 15 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 BP 743 EP 752 DI 10.1016/S0301-472X(00)00184-3 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 329DY UT WOS:000087892300003 PM 10907635 ER PT J AU Bankiewicz, KS Eberling, JL Kohutnicka, M Jagust, W Pivirotto, P Bringas, J Cunningham, J Budinger, TF Harvey-White, J AF Bankiewicz, KS Eberling, JL Kohutnicka, M Jagust, W Pivirotto, P Bringas, J Cunningham, J Budinger, TF Harvey-White, J TI Convection-enhanced delivery of AAV vector in parkinsonian monkeys; In vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach SO EXPERIMENTAL NEUROLOGY LA English DT Article; Proceedings Paper CT 7th Intenational Symposium on Neural Transplantation and Repair (INT-7) CY AUG 26-30, 1999 CL ODENSE, DENMARK ID ADENOASSOCIATED VIRUS VECTORS; IN-VIVO; TYROSINE-HYDROXYLASE; BEHAVIORAL RECOVERY; STRIATAL NEURONS; CLINICAL CHANGES; VIRAL VECTOR; DISEASE; MPTP; PRIMATES AB Using an approach that combines gene therapy with aromatic L-amino acid decarboxylase (AADC) gene and a pro-drug (L-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral L-dopa to dopamine and may therefore provide a buffer for unmetabolized L-dopa, This approach to treating Parkinson's disease may reduce the need for L-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum, We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery, Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[F-18]fluoro-L-m-tyrosine, can be used to monitor gene therapy in vine, Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration. (C) 2000 Academic Press. C1 NINDS, Mol Therapeut Sect, LMMN, Bethesda, MD 20892 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Ctr Funct Imaging, Berkeley, CA 94720 USA. Avigen Inc, Alameda, CA USA. Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. Med Acad Warsaw, Dept Expt & Clin Pharmacol, Warsaw, Poland. RP Bankiewicz, KS (reprint author), NINDS, Mol Therapeut Sect, LMMN, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 39 TC 241 Z9 251 U1 4 U2 14 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2000 VL 164 IS 1 BP 2 EP 14 DI 10.1006/exnr.2000.7408 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 336XM UT WOS:000088328300002 PM 10877910 ER PT J AU Fidock, DA Nguyen, TV Ribeiro, JM Valenzuela, JC James, AA AF Fidock, DA Nguyen, TV Ribeiro, JM Valenzuela, JC James, AA TI Plasmodium falciparum: Generation of a cDNA library enriched in sporozoite-specific transcripts by directional tag subtractive hybridization SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; protozoa; parasitic; malaria; human; stage-specific gene expression; subtraction; lambda cDNA libraries ID HUMAN MALARIA PARASITE; MAJOR SURFACE-ANTIGENS; AMINO-ACID-SEQUENCE; PCR SUBTRACTION; MESSENGER-RNAS; GENE; PROTEIN; IDENTIFICATION; MEROZOITES; RESPONSES AB We have adapted the "directional tag subtractive hybridization" technique as a means of investigating stage-specific gene expression in Plasmodium falciparum. This technique utilizes unidirectional cDNA libraries cloned into separate lambda vectors and involves hydroxyapatite chromatographic separation of target antisense cDNA and driver sense strand cRNA followed by PCR amplification of cDNA sequences specific to the target stage. This technique enabled efficient subtraction of asexual blood stage sequences from a P. falciparum sporozoite cDNA library and led to identification of novel sporozoite sequences. This technique can be applied to study gene expression in parasite stages that are difficult to obtain routinely. (C) 2000 Academic Press. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Malaria Genet Sect, NIH, Bethesda, MD 20892 USA. RP Fidock, DA (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. OI Fidock, David/0000-0001-6753-8938; Ribeiro, Jose/0000-0002-9107-0818 NR 25 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUL PY 2000 VL 95 IS 3 BP 220 EP 225 DI 10.1006/expr.2000.4528 PG 6 WC Parasitology SC Parasitology GA 352NC UT WOS:000089223900009 PM 10964651 ER PT J AU Freeman, BD Natanson, C AF Freeman, BD Natanson, C TI Anti-inflammatory therapies in sepsis and septic shock SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Article DE endotoxin; glucocorticoids; inflammatory mediators; sepsis; septic shock ID TUMOR-NECROSIS-FACTOR; PLACEBO-CONTROLLED TRIAL; INTERLEUKIN-1 RECEPTOR ANTAGONIST; HIGH-DOSE METHYLPREDNISOLONE; MULTICENTER CLINICAL-TRIAL; HUMAN MONOCLONAL-ANTIBODY; GRAM-NEGATIVE BACTEREMIA; DOUBLE-BLIND; FACTOR-ALPHA; ESCHERICHIA-COLI AB Despite advances in supportive care, the morbidity and mortality rate resulting from sepsis and septic shock remain high (30 - 50%). A central hypothesis driving sepsis research in recent years is that this syndrome is the result of excessive inflammation. Therapies designed to inhibit the inflammatory response were first shown to be markedly beneficial in animal models of sepsis and then tested in numerous clinical trials involving thousands of patients. Three broad anti-inflammatory strategies have been investigated. First, glucocorticoids in high doses administered at the onset of sepsis were studied. This approach proved unsuccessful. More recently, however, glucocorticoids in lower doses have been found to have a beneficial effect in patients with septic shock. Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative steroid refractoriness occurring during sepsis, remains unknown. The next focus of research were agents active against the endotoxin molecule. However, as with the experience with glucocorticoids, this approach lacked a consistent pattern of efficacy. It is unclear if this lack of efficacy is the result of endotoxin being a poor therapeutic target, or from testing agents which lacked the appropriate biological activity. Most recently, clinical trials in sepsis have focused on inhibiting specific host pro-inflammatory mediators (e.g., TNF, interleukins). While individual trials of inhibitors of these pro-inflammatory mediators failed to show a convincing benefit, pooling the results of these trials suggest that this approach has a marginal effect, supporting a role for excessive inflammation in sepsis. An unanswered question is reconcilling the very favourable effects obtained with anti-inflammatory treatments in animal models with the marginal results in humans. Further clinical and laboratory research is needed and may provide insight into more effective ways to use the anti-inflammatory agents already tested, or to investigate other potentially more effective anti-inflammatory agents in this syndrome. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Freeman, BD (reprint author), Washington Univ, Sch Med, Dept Surg, Box 8109,Suite 6104, St Louis, MO 63110 USA. NR 98 TC 80 Z9 93 U1 1 U2 6 PU ASHLEY PUBL LTD PI LONDON PA 1ST FL, THE LIBRARY, 1 SHEPHERDS HILL HIGHGATE, LONDON N6 5QJ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2000 VL 9 IS 7 BP 1651 EP 1663 DI 10.1517/13543784.9.7.1651 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347PG UT WOS:000088937900017 PM 11060768 ER PT J AU Newman, AH AF Newman, AH TI Novel pharmacotherapies for cocaine abuse 1997-2000 SO EXPERT OPINION ON THERAPEUTIC PATENTS LA English DT Review DE animal models; cocaine; dopamine; substance abuse; transgenic mice; treatment ID CONDITIONED PLACE PREFERENCE; TRANSPORTER KNOCKOUT MICE; SIGMA-RECEPTOR LIGANDS; DRUG-NAIVE RATS; DOPAMINE-TRANSPORTER; MODULATES COCAINE; SEEKING BEHAVIOR; ADDICTIVE DRUGS; REWARD; DEPENDENCE AB The discovery of a pharmacotherapeutic treatment for cocaine at,use and addiction has been a research target that has received much attention in the past three years. Since the patent literature on this topic was last reviewed [1], major advances have been made in the understanding of the neurochemical basis of cocaine addiction. State of the art technologies have aided the characterisation of mechanistic targets of cocaine. For example, the development of transgenic mice and the use of PET imaging to visualise cocaine binding sites in the human brain are exciting new advances that have complemented the more well-established pharmacological paradigms such as radioligand binding assays and animal models of cocaine abuse. In addition, classical and computer-aided drug design has yielded highly potent and selective ligands to target relevant neurochemical substrates and provide valuable information on the role these substrates play in pharmacological actions of cocaine. These advances have opened the door to the discovery of novel agents that selectively interact at various neurotransmitter and receptor systems relevant to cocaine's addictive effects. Animal models of cocaine abuse have then been utilised to predict the efficacy of these agents. Although an efficacious medication for treating cocaine abuse in humans is vet to be identified, numerous candidates are being evaluated in advanced preclinical studies and several agents have reached the clinical trial stage. This article reviews the research advances published in the patent literature from January 1997 through December 1999, supplemented with selected peer-reviewed literature on the design and development of novel agents for the treatment of cocaine abuse. C1 NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 162 TC 31 Z9 31 U1 1 U2 1 PU ASHLEY PUBL LTD PI LONDON PA 1ST FL, THE LIBRARY, 1 SHEPHERDS HILL HIGHGATE, LONDON, ENGLAND N6 5QJ SN 1354-3776 J9 EXPERT OPIN THER PAT JI Expert Opin. Ther. Patents PD JUL PY 2000 VL 10 IS 7 BP 1095 EP 1122 DI 10.1517/13543776.10.7.1095 PG 28 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 332FR UT WOS:000088064000008 ER PT J AU Dell'Angelica, EC Mullins, C Caplan, S Bonifacino, JS AF Dell'Angelica, EC Mullins, C Caplan, S Bonifacino, JS TI Lysosome-related organelles SO FASEB JOURNAL LA English DT Review DE melanosome; lytic granule; MIIC; platelet-dense granule; basophil granule; azurophil granule; pigment granule; Chediak-Higashi syndrome; Griscelli syndrome; Hermansky-Pudlak syndrome; protein trafficking ID HERMANSKY-PUDLAK-SYNDROME; CHEDIAK-HIGASHI-SYNDROME; BASOPHILIC LEUKEMIA-CELLS; CLASS-II COMPARTMENTS; AP-3 ADAPTER COMPLEX; TYROSINASE-RELATED PROTEIN; INTEGRAL MEMBRANE-PROTEIN; STORAGE POOL DEFICIENCY; DENSE GRANULE MEMBRANES; NATURAL-KILLER-CELLS AB Lysosomes are membrane-bound cytoplasmic organelles involved in intracellular protein degradation, They contain an assortment of soluble acid-dependent hydrolases and a set of highly glycosylated integral membrane proteins, Most of the properties of lysosomes are shared with a group of cell type-specific compartments referred to as 'lysosome-related organelles', which include melanosomes, lytic granules, MHC class II compartments, platelet-dense granules, basophil granules, azurophil granules, and Drosophila pigment granules. In addition to lysosomal proteins, these organelles contain cell type-specific components that are responsible for their specialized functions. Abnormalities in both lysosomes and lysosome-related organelles have been observed in human genetic diseases such as the Chediak-Higashi and Hermansky-Pudlak syndromes, further demonstrating the close relationship between these organelles. Identification of genes mutated in these human diseases, as well as in mouse and Drosophila pigmentation mutants, is beginning to shed light on the molecular machinery involved in the biogenesis of lysosomes and lysosome-related organelles. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101,18 Lib Dr,MSC 5430, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 125 TC 313 Z9 318 U1 2 U2 30 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2000 VL 14 IS 10 BP 1265 EP 1278 DI 10.1096/fj.14.10.1265 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 329WV UT WOS:000087932200001 PM 10877819 ER PT J AU Borlongan, CV Yamaoto, M Takei, N Kumazaki, M Ungsuparkorn, C Hida, H Sanberg, PR Nishino, H AF Borlongan, CV Yamaoto, M Takei, N Kumazaki, M Ungsuparkorn, C Hida, H Sanberg, PR Nishino, H TI Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia SO FASEB JOURNAL LA English DT Article DE stroke; gliosis; astrocytes; cell death; free radicals ID MIDBRAIN DOPAMINERGIC-NEURONS; TRANSIENT FOREBRAIN ISCHEMIA; PROTECTS PRIMARY CULTURES; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; 3-NITROPROPIONIC ACID; REGIONAL DIFFERENCES; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; IN-VITRO AB The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 mu mol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 mu g/ml or 100 mu M) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage. C1 NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. Univ S Florida, Coll Med, Dept Neurol Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Program Neurosci, Tampa, FL 33612 USA. Nagoya City Univ, Sch Med, Dept Physiol, Nagoya, Aichi 467, Japan. RP Borlongan, CV (reprint author), NIDA, Cellular Neurobiol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Borlongan, Cesar/0000-0002-2966-9782 NR 67 TC 99 Z9 109 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 JUL PY 2000 VL 14 IS 10 BP 1307 EP 1317 DI 10.1096/fj.14.10.1307 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 329WV UT WOS:000087932200005 PM 10877823 ER PT J AU Matsuo, K Shintani, S Tsuji, T Nagata, E Lerman, M McBride, J Nakahara, Y Ohyama, H Todd, R Wong, DTW AF Matsuo, K Shintani, S Tsuji, T Nagata, E Lerman, M McBride, J Nakahara, Y Ohyama, H Todd, R Wong, DTW TI p12(DOC-1), a growth suppressor, associates with DNA polymerase alpha/primase SO FASEB JOURNAL LA English DT Article DE pol-alpha; primase complex; cell cycle regulator; DNA replication ID SIMIAN VIRUS-40 DNA; REPLICATION IN-VITRO; TUMOR-SUPPRESSOR; CELL-CYCLE; ENZYMOLOGICAL CHARACTERIZATION; MUTATION ANALYSIS; ALPHA-PRIMASE; GENE; PHOSPHORYLATION; DOC-1 AB p12(DOC-1) is a growth suppressor identified and isolated from normal keratinocytes. Ectopic expression of p12(DOC-1) in squamous carcinoma cells led to the reversion of in vitro transformation phenotypes including anchorage independence, doubling time, and morphology. Here we report that p12(DOC-1) associates with DNA polymerase alpha/primase (pol-alpha: primase) in vitro and in cells. The pol-alpha:primase binding domain in p12(DOC-1) is mapped to the amino-terminal six amino acid (MSYKPN). The biological effect of p12(DOC-1) on pol-alpha:primase was examined using in vitro DNA replication assays. Using the SV40 DNA replication assay, p12(DOC-1) suppresses DNA replication, leveling at similar to 50%. Similar results were obtained using the M13 single-stranded DNA synthesis assay. Analysis of the DNA replication products revealed that p12(DOC-1) affects the initiation step, not the elongation phase. The p12(DOC-1) suppression of DNA replication is likely to be mediated either by a direct inhibitory effect on pol-alpha:primase or by its effect on cyclin-dependent kinase 2 (CDK2), a recently identified p12(DOC-1)-associated protein known to stimulate DNA replication by phosphorylating pol-alpha:primase. p12(DOC-1) suppresses CDK2-mediated phosphorylation of pol-alpha:primase. These data support a role of p12(DOC-1) as a regulator of DNA replication by direct inhibition of pol-alpha:primase or by negatively regulating the CDK2-mediated phosphorylation of pol-alpha:primase. C1 Harvard Univ, Sch Dent Med, Div Oral Pathol, Lab Mol Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Lab Oral & Maxillofacial Surg, Boston, MA 02115 USA. NCI, Immunobiol Lab, DBS, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Wong, DTW (reprint author), Harvard Univ, Sch Dent Med, Div Oral Pathol, Lab Mol Pathol, 188 Longwood Ave, Boston, MA 02115 USA. FU NIDCR NIH HHS [R29 DE 11983, R01 DE08680, P01 DE12467] NR 22 TC 41 Z9 49 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 JUL PY 2000 VL 14 IS 10 BP 1318 EP 1324 DI 10.1096/fj.14.10.1318 PG 7 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 329WV UT WOS:000087932200006 PM 10877824 ER PT J AU Parsons, M Young, L Lee, JE Jacobson, KA Liang, BT AF Parsons, M Young, L Lee, JE Jacobson, KA Liang, BT TI Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D SO FASEB JOURNAL LA English DT Article DE ischemia; ventricular myocyte; PKC activity; cardioprotection ID SENSITIVE POTASSIUM CHANNELS; CARDIAC MYOCYTES; A(3) RECEPTORS; RABBIT HEART; ISCHEMIA; STIMULATION; ACTIVATION; PROTECTION; MUSCLE; INJURY AB Adenosine released during cardiac ischemia exerts a marked protective effect in the heart that is mediated by the A(1) and A(3) subtypes of adenosine receptors, The signaling pathways activated by these adenosine receptors have now been characterized in a chick embryo ventricular myocyte culture model of cardioprotection against ischemia. Selective A(1) and A(3) receptor agonists were shown to activate phospholipases C and D, respectively, to achieve their distinct cardioprotective effects. The specificity of the A(3) receptor-phospholipase D interaction was also demonstrated in chick embryo atrial myocytes (which do not express endogenous A(3) receptors) that had been transfected with a vector encoding the human A(3) receptor. Activation of both endogenous A(1) and A(3) receptors in ventricular myocytes resulted in a protective response greater than that induced by stimulation of either receptor alone, Agonists that activate both adenosine A(1) and A(3) receptors may thus prove beneficial for the treatment of myocardial ischemia. C1 Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, 956 BRBII-III,421 Curie Blvd, Philadelphia, PA 19104 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [R01 HL48225] NR 26 TC 76 Z9 77 U1 0 U2 0 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 JUL PY 2000 VL 14 IS 10 BP 1423 EP 1431 DI 10.1096/fj.14.10.1423 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 329WV UT WOS:000087932200017 PM 10877835 ER PT J AU Illera, MJ Juan, LW Stewart, CL Cullinan, E Ruman, J Lessey, BA AF Illera, MJ Juan, LW Stewart, CL Cullinan, E Ruman, J Lessey, BA TI Effect of peritoneal fluid from women with endometriosis on implantation in the mouse model SO FERTILITY AND STERILITY LA English DT Article DE endometriosis; implantation; mouse model; LIF; integrins; endometrium ID LEUKEMIA INHIBITORY FACTOR; COLONY-STIMULATING FACTOR; INFERTILE WOMEN; GROWTH-FACTOR; MILD ENDOMETRIOSIS; MENSTRUAL-CYCLE; IN-VITRO; BLASTOCYST IMPLANTATION; INTEGRIN EXPRESSION; ADHESION MOLECULES AB Objective: To investigate the potential role of peritoneal fluid (PF) from women with or without endometriosis in implantation in mice with use of the delayed implantation model. Design: A murine experimental model with markers of uterine receptivity and prospective comparison of the effects of human PF on implantation. Setting: Academic university and hospital program. Intervention(s): PF collected from women with and without endometriosis was injected intraperitoneally into recently mated mice. Main Outcome Measure(s): Implantation sites were counted in treated and untreated animals, and the alpha v beta 3 integrin was measured in the pregnant mouse uterus by immunohistochemistry with in situ hybridization. Leukemia inhibitory factor and the beta 3 subunit of alpha v beta 3 were measured by Northern blot during early pregnancy and after injections of PF. Result(s): Animals receiving PF from infertile women with endometriosis had a reduction in the number of implantation sites compared with animals that received PF from fertile women or from patients with recently treated endometriosis. In the mouse, expression of alpha v beta 3 and leukemia inhibitory factor peaked at the time of implantation and was reduced by injections of human PF from infertile patients with endometriosis. Conclusion(s): Leukemia inhibitory factor and alpha v beta 3 are coexpressed at the time of implantation in the mouse. PF from women with endometriosis has a detrimental effect on embryo implantation, perhaps by adversely affecting uterine receptivity. (Fertil Steril(R) 2000;74:41-8. (C) 2000 by American Society for Reproductive Medicin). C1 Univ N Carolina, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chapel Hill, NC 27599 USA. Univ Complutense, Sch Vet Med, Dept Physiol, E-28040 Madrid, Spain. NCI, Lab Canc & Dev Biol, Frederick, MD 21701 USA. Lexicon Genet Inc, The Woodlands, TX USA. RP Lessey, BA (reprint author), Univ N Carolina, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, CB 7570,MacNider Bldg, Chapel Hill, NC 27599 USA. FU NICHD NIH HHS [HD 35041, HD 34824] NR 65 TC 45 Z9 50 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2000 VL 74 IS 1 BP 41 EP 48 DI 10.1016/S0015-0282(00)00552-5 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 330RP UT WOS:000087975200008 PM 10899495 ER PT J AU Hearns-Stokes, RM Miller, BT Scott, L Creuss, D Chakraborty, PK Segars, JH AF Hearns-Stokes, RM Miller, BT Scott, L Creuss, D Chakraborty, PK Segars, JH TI Pregnancy rates after embryo transfer depend on the provider at embryo transfer SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 55th Annual Meeting of the American-Society-for-Reproductive-Medicine CY SEP 15-30, 1999 CL TORONTO, CANADA SP Amer Soc Reproductive Med DE embryo transfer; technique; IVF-ET; pregnancy rate; physician ID IN-VITRO FERTILIZATION; INVITRO FERTILIZATION; TRANSFER CATHETER; MULTIPLE ATTEMPTS; LUTEAL-PHASE; IVF; DIFFICULT; PROGRAM; CHOICE AB Objective: To evaluate the effect of individual providers on pregnancy outcome after embryo transfer. Design: Retrospective data analysis. Setting: University-based tertiary-care assisted reproductive technology program with 10 physician-providers. Patient(s): Six hundred and seventeen women who underwent 854 fresh embryo transfers between January 1996 and January 1999. Intervention(s): Pregnancies after embryo transfer were recorded for each provider. Main Outcome Measure(s): Establishment of a clinical pregnancy. Result(s): Three hundred ninety-three clinical pregnancies resulted from 854 embryo transfers, for an overall clinical pregnancy rate of 46.0% per embryo transfer. Three hundred forty-seven (40.6%) pregnancies were ongoing. The clinical pregnancy rate varied Significantly between providers: for example, 17.0% (47 transfers) vs. 54.3% (57 transfers) (P<.05). Similarly, the ratio of high-grade embryos required to produce a gestational sac differed between providers. The number or quality of embryos transferred did not differ significantly. Conclusion(s): Significant differences were observed in pregnancy rates after embryo transfer done by different providers, suggesting that embryo transfer technique may influence pregnancy outcome in assisted reproductive technology. (Fertil Steril(R) 2000;74:80-6. (C) 2000 by American Society for Reproductive Medicine). C1 NICHHD, Pediat & Reprod Endocrine Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Assisted Reprod Technol Program, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Segars, JH (reprint author), NICHHD, Pediat & Reprod Endocrine Branch, NIH, Suite 800,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 30 TC 82 Z9 85 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2000 VL 74 IS 1 BP 80 EP 86 DI 10.1016/S0015-0282(00)00582-3 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 330RP UT WOS:000087975200014 PM 10899501 ER PT J AU Yan, LJ Levine, RL Sohal, RS AF Yan, LJ Levine, RL Sohal, RS TI Effects of aging and hyperoxia on oxidative damage to cytochrome C in the housefly, Musca domestica SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE aging; cytochrome c; housefly; mass spectrum; mitochondria; protein carbonyls; oxidative modification; free radicals ID HYDROGEN-PEROXIDE RELEASE; TRITIATED SODIUM-BOROHYDRIDE; PROTEIN OXIDATION; INDUCED APOPTOSIS; CASPASE ACTIVATION; OXIDASE ACTIVITY; MITOCHONDRIA; DISEASE; STRESS; BCL-2 AB Cytochrome c is a component of the mitochondrial electron transport chain, where it transfers electrons from ubiquinol-cytochrome c reductase to cytochrome c oxidase. Autoxidation of some of the components of the electron transport chain is the main source of intracellular O-2(-.)/H2O2 production in aerobic organisms. Because cytochrome c is located on the outer surface of the inner mitochondrial membrane, it is likely to be constantly exposed to H2O2, secreted by mitochondria into the cytosol. The specific objective of this study was to determine whether cytochrome c in the flight muscle mitochondria of the housefly is oxidatively damaged during aging and/or under severe oxidative stress induced by exposure of flies to 100% oxygen. Results of two independent methods, namely tritiated borohydride labeling for determining carbonylation and mass spectral analysis for the measurement of molecular mass, indicated that neither the carbonyl level nor the molecular mass of cytochrome c was affected by aging or hyperoxia. Thus, either cytochrome c is resistant to oxidative damage in vivo or the oxidized cytochrome c is promptly degraded. These findings also support the concept that protein oxidative damage during aging and under oxidative stress is selective. (C) 2000 Elsevier Science Inc. C1 So Methodist Univ, Dept Biol Sci, Dallas, TX 75275 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Sohal, RS (reprint author), So Methodist Univ, Dept Biol Sci, Dallas, TX 75275 USA. RI Levine, Rodney/D-9885-2011 FU NIA NIH HHS [R01AG7657, R01AG13563] NR 39 TC 19 Z9 21 U1 0 U2 1 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 JUL 1 PY 2000 VL 29 IS 1 BP 90 EP 97 DI 10.1016/S0891-5849(00)00323-3 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 349LL UT WOS:000089046500011 PM 10962209 ER PT J AU McCart, JA Puhlmann, M Lee, J Hu, Y Libutti, SK Alexander, HR Bartlett, DL AF McCart, JA Puhlmann, M Lee, J Hu, Y Libutti, SK Alexander, HR Bartlett, DL TI Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression SO GENE THERAPY LA English DT Article DE replicating vaccinia virus; gene therapy; cytosine deaminase; enzyme/prodrug ID CYTOSINE DEAMINASE GENE; PURINE NUCLEOSIDE PHOSPHORYLASE; VIRUS THYMIDINE KINASE; COLON-CARCINOMA; EXPRESSION VECTORS; ADENOVIRUS VECTOR; THERAPY; 5-FLUOROCYTOSINE; CELLS; MUTANT AB Replicating viruses for cancer gene therapy have beneficial antitumor effects, however, in the setting of an enzyme/prodrug system, the interactions between these viruses and the activated agents are complex. A replicating vaccinia virus expressing the cytosine deaminase gene (VVCD), which converts the prodrug 5-FC into 5-FU, was characterized in vitro and in vivo for its antitumor effects and pathogenicity. Replicating VVCD (+/-5-FC) at various MOls was used to infect MC38 murine colon adenocarcinoma cells. At high MOls (>0.1) virus alone was able to kill the majority (65-90%) of cells by day 5 with no additional benefit from prodrug. At low MOls only the effect of prodrug is seen. Cell lysates demonstrated 300-fold reduced viral recovery from cells treated with both VVCD and 5-FC compared with controls treated with virus alone. Nude mice bearing subcutaneous MC38 tumors were injected with VVCD for control) and treated (with 5FC or control. Mice injected with VVCD (with or without SFC treatment) had smaller tumors than the controls, suggesting that replicating vaccinia alone is cytotoxic to tumors in vivo. The addition of 5-FC improved the antitumor response when a low dose of virus was injected into tumors. Also, compared with mice that received virus alone, those that received VVCD and 5FC had significantly prolonged survival from virus-mediated death. In conclusion, the addition of an enzyme/prodrug system to a replicating virus can improve the antitumor response and decrease viral pathogenicity. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Bartlett, DL (reprint author), NCI, Surg Branch, NIH, Bldg 10,Rm 2B16,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 60 Z9 65 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUL PY 2000 VL 7 IS 14 BP 1217 EP 1223 DI 10.1038/sj.gt.3301237 PG 7 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 336GP UT WOS:000088293800007 PM 10918490 ER PT J AU Kim, RH Wang, D Tsang, M Martin, J Huff, C de Caestecker, MP Parks, WT Meng, XW Lechleider, RJ Wang, TW Roberts, AB AF Kim, RH Wang, D Tsang, M Martin, J Huff, C de Caestecker, MP Parks, WT Meng, XW Lechleider, RJ Wang, TW Roberts, AB TI A novel Smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction SO GENES & DEVELOPMENT LA English DT Article DE TGF-beta; Smad; CBP/p300; signal transduction; transcriptional suppression ID GROWTH-FACTOR-BETA; CREB BINDING-PROTEIN; TRANSCRIPTIONAL COACTIVATORS; RECEPTOR; P300; COOPERATION; SMAD4/DPC4; RESPONSES; CBP/P300; PATHWAYS AB Members of the transforming growth factor-beta superfamily play critical roles in controlling cell growth and differentiation. Effects of TGF-beta family ligands are mediated by Smad proteins. To understand the mechanism of Smad function, we sought to identify novel interactors of Smads by use of a yeast two-hybrid system. A 396-amino acid nuclear protein termed SNIP1 was cloned and shown to harbor a nuclear localization signal (NLS) and a Forkhead-associated (PHA) domain. The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems. However, the amino terminus of SNIP1 harbors binding sites for both Smad4 and the coactivator CBP/p300. Interaction between endogenous levels of SNIP1 and Smad4 or CBP/p300 is detected in NMuMg cells as well as in vitro. Overexpression of full-length SNIP1 or its amino terminus is sufficient to inhibit multiple gene responses to TGF-beta and CBP/p300, as well as the formation of a Smad4/p300 complex. Studies in Xenopus laevis further suggest that SNIP1 plays a role in regulating dorsomedial mesoderm formation by the TGF-beta family member nodal. Thus, SNIP1 is a nuclear inhibitor of CBP/p300 and its level of expression in specific cell types has important physiological consequences by setting a threshold for TGF-beta-induced transcriptional activation involving CBP/p300. C1 NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Dept Genet, Boston, MA 02114 USA. RP Roberts, AB (reprint author), NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. RI TSANG, Michael/E-2758-2013; Tsang, Michael/I-9305-2014 OI TSANG, Michael/0000-0001-6384-2422; Tsang, Michael/0000-0001-7123-0063 NR 43 TC 89 Z9 99 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2000 VL 14 IS 13 BP 1605 EP 1616 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 333TC UT WOS:000088146000006 PM 10887155 ER PT J AU Tissier, A McDonald, JP Frank, EG Woodgate, R AF Tissier, A McDonald, JP Frank, EG Woodgate, R TI Pol iota, a remarkably error-prone human DNA polymerase SO GENES & DEVELOPMENT LA English DT Article DE DNA polymerase eta; Rad30; Rad30B; somatic hypermutation; Xeroderma pigmentosum variant ID XERODERMA-PIGMENTOSUM VARIANT; ESCHERICHIA-COLI DINB; THYMINE-THYMINE DIMER; SOMATIC HYPERMUTATION; TRANSLESION SYNTHESIS; INSERTION FIDELITY; MOUSE HOMOLOGS; GENE ENCODES; B-CELLS; MUTAGENESIS AB The Saccharomyces cerevisiae RAD30 gene encodes DNA polymerase eta. Humans possess two Rad30 homologs. One (RAD30A/POLH) has previously been characterized and shown to be defective in humans with the Xeroderma pigmentosum variant phenotype. Here, we report experiments demonstrating that the second human homolog (RAD30B), also encodes a novel DNA polymerase that we designate pol iota. pol iota, is a distributive enzyme that is highly error-prone when replicating undamaged DNA. At template G or C, the average error frequency was similar to 1 x 10(-2). Our studies revealed, however, a striking asymmetry in misincorporation frequency at template A and T. For example, template A was replicated with the greatest accuracy, with misincorporation of G, A, or C occurring with a frequency of similar to 1 x 10(-4) to 2 x 10(-4). In dramatic contrast, most errors occurred at template T, where the misincorporation of G was, in fact, favored similar to 3:1 over the correct nucleotide, A, and misincorporation of T occurred at a frequency of -6.7 x 10(-1). These findings demonstrate that pol iota is one of the most error-prone eukaryotic polymerases reported to date and exhibits an unusual misincorporation spectrum in vitro. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. NR 61 TC 258 Z9 273 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2000 VL 14 IS 13 BP 1642 EP 1650 PG 9 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 333TC UT WOS:000088146000009 PM 10887158 ER PT J AU McIntyre, LM Martin, ER Simonsen, KL Kaplan, NL AF McIntyre, LM Martin, ER Simonsen, KL Kaplan, NL TI Circumventing multiple testing: A multilocus Monte Carlo approach to testing for association SO GENETIC EPIDEMIOLOGY LA English DT Article DE Monte Carlo method; association; Bonferroni correction ID TRANSMISSION/DISEQUILIBRIUM TEST; LINKAGE DISEQUILIBRIUM; NUCLEAR FAMILIES; RECOMBINATION; MODEL; GENOME; LOCI; TDT AB Advances in marker technology have made a dense marker map a reality. If each marker is considered separately and separate tests for association with a disease gene are performed, then multiple testing becomes an issue. A common solution uses a Bonferroni correction to account for multiple tests performed. However, with dense marker maps, neighboring markers are tightly linked and may have associated alleles; thus tests at nearby marker loci may not be independent. When alleles at different marker loci are associated, the Bonferroni correction may lead to a conservative test, and hence a power loss. As an alternative, for tests of association that use family data, we propose a Monte Carlo procedure that provides a global assessment of significance. We examine the case of tightly linked markers with varying amounts of association between them. Using computer simulations, we study a family-based test for association (the transmission/disequilibrium test), and compare its power when either the Bonferroni or Monte Carlo procedure is used to determine significance. Our results show that when the alleles at different marker loci are not associated, using either procedure results in tests with similar power. However, when alleles at linked markers are associated, the test using the Monte Carlo procedure is more powerful than the test using the Bonferroni procedure. This proposed Monte Carlo procedure can be applied whenever it is suspected that markers examined have high amounts of association, or as a general approach to ensure appropriate significance levels and optimal power. Genet. Epidemiol. 19:18-29, 2000. (C) 2000 Wiley-Liss, Inc. C1 Purdue Univ, Dept Agron, W Lafayette, IN 47907 USA. Vet Affairs Med Ctr, Inst Clin & Epidemiol Res, Durham, NC 27705 USA. Duke Univ, Med Ctr, Div Biometry, Durham, NC USA. Duke Univ, Med Ctr, Dept Human Genet, Durham, NC USA. Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP McIntyre, LM (reprint author), Purdue Univ, Dept Agron, 1150 Lilly Hall Life Sci, W Lafayette, IN 47907 USA. RI Simonsen, Katy/A-4193-2012; McIntyre, Lauren/J-8414-2012 OI McIntyre, Lauren/0000-0002-0077-3359 FU NCI NIH HHS [5PO1CA72099]; NIA NIH HHS [AG16996]; NIGMS NIH HHS [GM45344] NR 17 TC 69 Z9 71 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2000 VL 19 IS 1 BP 18 EP 29 DI 10.1002/1098-2272(200007)19:1<18::AID-GEPI2>3.0.CO;2-Y PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 329XC UT WOS:000087932900002 PM 10861894 ER PT J AU Schaid, DJ Elston, RC Tran, L Wilson, AF AF Schaid, DJ Elston, RC Tran, L Wilson, AF TI Model-free sib-pair linkage analysis: Combining full-sib and half-sib pairs SO GENETIC EPIDEMIOLOGY LA English DT Article DE allele sharing; complex traits; identical by descent; linkage; regression; robust ID ASSESSING GENETIC-LINKAGE; QUANTITATIVE-TRAIT; RELATIVE-PAIRS; PEDIGREES; COMPONENTS AB When sampling full-sibs for linkage studies, half-sibs are often available. Not only are half-sibs convenient to sample, but they can sometimes offer greater power than full-sibs. We propose a method to combine the information from full-sibs and half-sibs into a single test for linkage. This method is based on the Haseman and Elston [1972] method of regressing the squared trait-difference for a pair of sibs (either full- or half-sibs) on the estimated proportion of alleles shared identical by descent. To approximate the distribution of the test statistic, we propose a correction factor that considers the correlation among sibs, and demonstrate by simulations that this approximation works well in many situations, although there are some conditions for which the statistic can have an inflated Type-I error rate. The main appeal of our proposed method is the speed at which it can be computed, offering a rapid way to perform genome-wide linkage screens. Genet. Epidemiol. 19:30-51, 2000. (C) 2000 Wiley-Liss. Inc. C1 Mayo Clin & Mayo Fdn, Biostat Sect, Rochester, MN 55905 USA. Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. McDermott Inc, New Orleans, LA USA. Natl Human Genome Res Inst, NIH, Baltimore, MD USA. RP Schaid, DJ (reprint author), Mayo Clin & Mayo Fdn, Biostat Sect, Harwick 7,200 1st SW, Rochester, MN 55905 USA. RI Wilson, Alexander/C-2320-2009 FU NCRR NIH HHS [RR03655]; NHLBI NIH HHS [HL07567]; NIGMS NIH HHS [GM28356] NR 20 TC 4 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2000 VL 19 IS 1 BP 30 EP 51 DI 10.1002/1098-2272(200007)19:1<30::AID-GEPI3>3.0.CO;2-X PG 22 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 329XC UT WOS:000087932900003 PM 10861895 ER PT J AU Resnick, HE Rodriguez, B Havlik, R Ferrucci, L Foley, D Curb, JD Harris, TB AF Resnick, HE Rodriguez, B Havlik, R Ferrucci, L Foley, D Curb, JD Harris, TB TI Apo E genotype, diabetes, and peripheral arterial disease in older men: The Honolulu Asia-Aging study SO GENETIC EPIDEMIOLOGY LA English DT Article DE apolipoprotein E; peripheral arterial disease; elderly; men; diabetes; smoking ID APOLIPOPROTEIN-E POLYMORPHISM; CORONARY HEART-DISEASE; VASCULAR-DISEASE; E PHENOTYPE; RISK FACTOR; LIPOPROTEIN; MORTALITY; PROFILES; MELLITUS; HAWAII AB The epsilon 4 allele of the gene coding for apolipoprotein (apo) E is associated with an atherogenic lipid profile that has been linked to increased risk of coronary artery disease (CAD). Apo E genotype may also be associated with peripheral arterial disease (PAD). If present, this association may be modified by diabetes, which is also associated with dyslipidemia that predisposes to macrovascular disease. Observable associations between both ApoE genotype and diabetes with PAD may be confounded by smoking, a potent PAD risk factor that is unrelated to lipids. From 1991 to 1993, apo E genotypes (2/3, 3/3, 3/4), PAD (defined as ankle-brachial index [ABI] <0.9), diabetes (prevalent and newly-diagnosed), and smoking history (ever/never) were determined for 3,161 Japanese-American men aged 71-93. Data on hypertension and other potential confounders were also collected. Logistic regression was used to determine odds ratios (OR) between groups cross-categorized by apo E genotype and diabetes with prevalence of PAD, within strata of smoking. In each smoking stratum, non-diabetic apo epsilon 3/3 carriers were considered the reference. Among ever-smokers, there was no association between apo E acid PAD, regardless of diabetes status. Among never-smokers there appeared to be both apo E- and diabetes effects on PAD prevalence. Compared to the non-diabetic epsilon 3/3 group, the ORs of PAD were 2.3 (1.2-4.4) and 2.0 (1.1-3.4) for epsilon 3/3 newly-diagnosed and epsilon 3/3 prevalent diabetic subjects, respectively. Associations were stronger among diabetic individuals in the epsilon 3/4 group: the ORs were 3.0 (1.1-8.8) and 4.1 (1.9-8.7) for epsilon 3/4 newly-diagnosed and epsilon 3/4prevalent diabetic subjects, respectively. Despite associations whose pattern and magnitude suggested interaction between apo E genotype and diabetes on PAD prevalence among never-smokers, formal testing of this interaction did not reach statistical significance. Our finding of an apo E-PAD association among never-smokers may result from the effects of an apo epsilon 4-related atherogenic lipid profile on peripheral arteries. Further studies are needed to clarify the potential mediating role of diabetes on the apo E-PAD association. Genet. Epidemiol. 19:52-63, 2000. (C) 2000 Wiley-Liss, Inc. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Hawaii Manoa, John A Burns Sch Med, Div Clin Epidemiol, Honolulu, HI 96822 USA. Natl Res Inst, INRCA, Dept Geriatr, Florence, Italy. RP Resnick, HE (reprint author), Medstar Res Inst, 108 Irving St NW, Washington, DC 20010 USA. FU NHLBI NIH HHS [1UO1HL56724]; NIA NIH HHS [N01AG42149] NR 21 TC 13 Z9 13 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2000 VL 19 IS 1 BP 52 EP 63 DI 10.1002/1098-2272(200007)19:1<52::AID-GEPI4>3.0.CO;2-M PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 329XC UT WOS:000087932900004 PM 10861896 ER PT J AU Wilk, JB Djousse, L Arnett, DK Rich, SS Province, MA Hunt, SC Crapo, RO Higgins, M Myers, RH AF Wilk, JB Djousse, L Arnett, DK Rich, SS Province, MA Hunt, SC Crapo, RO Higgins, M Myers, RH TI Evidence for major genes influencing pulmonary function in the NHLBI family heart study SO GENETIC EPIDEMIOLOGY LA English DT Article DE segregation analysis; FEV1; FVC; FEV1/FVC ratio ID SEGREGATION ANALYSIS; HUMBOLDT FAMILY; MECHANISMS; SMOKING AB Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0.515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function. Genet. Epidemiol. 19:81-94, 2000. (C) 2000 Wiley-Liss, Inc. C1 Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Univ Utah, Salt Lake City, UT USA. NHLBI, Bethesda, MD 20892 USA. RP Wilk, JB (reprint author), Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, B-604,715 Albany St, Boston, MA 02118 USA. RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU NHLBI NIH HHS [N01-HC25104, N01-HC25105, N01-HC25106] NR 18 TC 56 Z9 58 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2000 VL 19 IS 1 BP 81 EP 94 DI 10.1002/1098-2272(200007)19:1<81::AID-GEPI6>3.0.CO;2-8 PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 329XC UT WOS:000087932900006 PM 10861898 ER PT J AU Davis, ES Shafer, BK Strathern, JN AF Davis, ES Shafer, BK Strathern, JN TI The Saccharomyces cerevisiae RDN1 locus is sequestered from interchromosomal meiotic ectopic recombination in a SIR2-dependent manner SO GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; MATING-TYPE INTERCONVERSION; YEAST CHROMOSOME-III; GENE CONVERSION; RIBOSOMAL DNA; INITIATION SITE; CHROMATIN STRUCTURE; FISSION YEAST; MEIOSIS; SEQUENCES AB Meiotic ectopic recombination occurs at similar frequencies among many sites in the yeast genome, suggesting that all loci are similarly accessible to homology searching. In contrast, we found that his3 sequences integrated in the RDN1 (rDNA) locus were unusually poor participants in meiotic recombination with his3 sequences at other sites. We show that the low rate of meiotic ectopic recombination resulted from the poor ability of RDN1::his3 to act as a donor sequence. SIR2 partially repressed interchromosomal meiotic ectopic recombination at RDN1, consistent with its role in regulating recombination, gene expression, and retrotransposition within RDN1. We propose that RDN1 is physically sequestered from meiotic homology searching mechanisms. C1 NCI, Frederick Canc Res & Dev Ctr, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. RP Davis, ES (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Rm 323,8 Ctr Dr MSC 0840, Bethesda, MD 20892 USA. NR 66 TC 8 Z9 8 U1 0 U2 0 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2000 VL 155 IS 3 BP 1019 EP 1032 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 332CX UT WOS:000088056800004 PM 10880466 ER PT J AU Kargul, GJ Nagaraja, R Shimada, T Grahovac, MJ Lim, MK Nakashima, H Waeltz, P Ma, P Chen, E Schlessinger, D Ko, MSH AF Kargul, GJ Nagaraja, R Shimada, T Grahovac, MJ Lim, MK Nakashima, H Waeltz, P Ma, P Chen, E Schlessinger, D Ko, MSH TI Eleven densely clustered genes, six of them novel, in 176 kb of mouse t-complex DNA SO GENOME RESEARCH LA English DT Article ID PROTEIN; LOCUS; FAMILY; BINDING; CLONING; IDENTIFICATION; CHROMOSOME; HAPLOTYPES; PRODUCT; DR-NM23 AB Targeted sequencing of the mouse t-complex has started with a 176-kb, gene-rich BAC localized with six PCR-based markers in inversion 2/3 of the highly duplicated region. The sequence contains II genes recovered primarily as cDNAs from early embryonic collections, including Igfals (previously placed on chromosome 17], Nubp2 (a fully characterized gene), Jsapl (a JNK-binding protein), Rsp29 (the mouse homologue of the rat gene), Ndk3(a nucleoside diphosphate kinase], and six additional putative genes of unknown function. With 50% GC content, 75% of the DNA transcribed, and one gene/16.0 kb ton average), the region may qualify as one of the most gene-dense segments in the mouse genome and provides candidates for dosage-sensitive phenotypes and mouse embryonic lethals mapped to the vicinity. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. PE Appl Biosyst, Foster City, CA 94404 USA. RP Ko, MSH (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 31 TC 6 Z9 7 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2000 VL 10 IS 7 BP 916 EP 923 DI 10.1101/gr.10.7.916 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 335VE UT WOS:000088264800005 PM 10899141 ER PT J AU Grishin, NV Wolf, YI Koonin, EV AF Grishin, NV Wolf, YI Koonin, EV TI From complete genomes to measures of substitution rate variability within and between proteins SO GENOME RESEARCH LA English DT Article ID DETERMINING DIVERGENCE TIMES; AMINO-ACID SUBSTITUTIONS; PHYLOGENETIC TREES; EVOLUTIONARY DISTANCES; RATE VARIES; SEQUENCES; ORGANISMS; ARCHAEA; ORIGIN; SITES AB Accumulation of complete genome sequences of diverse organisms creates new possibilities for evolutionary inferences from whole-genome comparisons. In the present study, we analyze the distributions of substitution rates among proteins encoded in 19 complete genomes (the interprotein rate distribution). To estimate these rates, it is necessary to employ another fundamental distribution, that of the substitution rates among sites in proteins (the intraprotein distribution]. Using two independent approaches, we show that intraprotein substitution rate variability appears to be significantly greater than generally accepted. This yields more realistic estimates of evolutionary distances from amino-acid sequences, which is critical for evolutionary-tree construction. We demonstrate that the interprotein rate distributions inferred From the genome-to-genome comparisons are similar to each other and can be approximated by a single distribution with a long exponential shoulder. This suggests that a generalized version of the molecular clock hypothesis may be valid on genome scale. We also use the scaling parameter of the obtained interprotein rate distribution to construct a rooted whole-genome phylogeny. The topology of the resulting tree is largely compatible with those of global rRNA-based trees and trees produced by other approaches to genome-wide comparison. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Grishin, NV (reprint author), Univ Texas, SW Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. NR 44 TC 59 Z9 59 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2000 VL 10 IS 7 BP 991 EP 1000 DI 10.1101/gr.10.7.991 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 335VE UT WOS:000088264800012 PM 10899148 ER PT J AU Lash, AE Tolstoshev, CM Wagner, L Schuler, GD Strausberg, RL Riggins, GJ Altschul, SF AF Lash, AE Tolstoshev, CM Wagner, L Schuler, GD Strausberg, RL Riggins, GJ Altschul, SF TI SAGEmap: A public gene expression resource SO GENOME RESEARCH LA English DT Article ID SEQUENCE TAGS; PROFILES; DATABASE; GENOME; CANCER; CELLS AB We have constructed a public gene expression data repository and online data access and analysis, WWW and FTP sites for serial analysis of gene expression (SAGE) data. The WWW and FTP components of this resource, SAGEmap, are located at http://www.ncbi.nlm.nih.gov/sage and ftp://ncbi.nlm.nih.gov/pub/sage, respectively. We herein describe SAGE data submission procedures, the construction and characteristics of SAGE tags to gene assignments, the derivation and use of a novel statistical test designed specifically for differential-type analyses of SAGE data, and the organization and use of this resource. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. NCI, NIH, Bethesda, MD 20894 USA. RP Lash, AE (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. OI Lash, Alex/0000-0003-3787-1590 NR 13 TC 321 Z9 338 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2000 VL 10 IS 7 BP 1051 EP 1060 DI 10.1101/gr.10.7.1051 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 335VE UT WOS:000088264800018 PM 10899154 ER PT J AU Sakao, Y Kawai, T Takeuchi, O Copeland, NG Gilbert, DJ Jenkins, NA Takeda, K Akira, S AF Sakao, Y Kawai, T Takeuchi, O Copeland, NG Gilbert, DJ Jenkins, NA Takeda, K Akira, S TI Mouse proteasomal ATPases Psmc3 and Psmc4: Genomic organization and gene targeting SO GENOMICS LA English DT Article ID PROTEIN-DEGRADATION; BINDING-PROTEIN; LINKAGE MAP; ACTIVATOR; FAMILY; CHROMOSOME-2; EXPRESSION; SUBUNIT; CELL; END AB PSMC3 and PSMC4, components of the 19S complex of the 26S proteasome, show a significant degree of amino acid similarity, especially in the conserved ATPase domain (CAD). In this study, we characterized the mouse Psmc3 and Psmc4 genes. The genomic structures of both genes showed a significant degree of similarity. The Psmc3 gene was composed of 12 coding exons, whereas the Psmc4 gene had 11 exons. Exons encoding the leucine zipper domain and CAD were identical in number between the Psmc3 and Psmc4 genes. The Psmc3 gene mapped to mouse chromosome 2, whereas Psmc4 mapped to chromosome 7. We further addressed the biological roles of Psmc3 and Psmc4 through the generation of gene targeted mice. Both Psmc3- and Psmc4-deficient mice died before implantation, displaying defective blastocyst development. These findings indicate that Psmc3 and Psmc4 have similar and essential roles in early embryogenesis and further that both ATPases have noncompensatory functions in vivo. (C) 2000 Academic Press. C1 Osaka Univ, Dept Host Def, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan. Osaka Univ, Japan Sci & Technol Corp, CREST, Suita, Osaka 5650871, Japan. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. RP Akira, S (reprint author), Osaka Univ, Dept Host Def, Microbial Dis Res Inst, 3-1 Yamadaoka, Suita, Osaka 5650871, Japan. RI Akira, Shizuo/C-3134-2009; Takeda, Kiyoshi/C-9331-2009 NR 26 TC 18 Z9 21 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL 1 PY 2000 VL 67 IS 1 BP 1 EP 7 DI 10.1006/geno.2000.6231 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 334PU UT WOS:000088195500001 PM 10945464 ER PT J AU Britton, RA Chen, SM Wallis, D Koeuth, T Powell, BS Shaffer, LG Largaespada, D Jenkins, NA Copeland, NG Court, DL Lupski, JR AF Britton, RA Chen, SM Wallis, D Koeuth, T Powell, BS Shaffer, LG Largaespada, D Jenkins, NA Copeland, NG Court, DL Lupski, JR TI Isolation and preliminary characterization of the human and mouse homologues of the bacterial cell cycle gene era SO GENOMICS LA English DT Article ID GTP-BINDING PROTEIN; IN-SITU HYBRIDIZATION; 16S RIBOSOMAL-RNA; ESCHERICHIA-COLI; CHROMOSOME 17Q; ALLELIC LOSS; BARRETTS ESOPHAGEAL; BREAST CARCINOMAS; GROWTH-RATE; TUMORS AB Era is an essential GTPase that is required for proper cell cycle progression and cell division in Escherichia coli and is found in nearly all bacteria sequenced to date. To determine whether Era is also present in eukaryotic organisms, we searched the dbEST database and found EST clones coding for proteins that were similar to Era. Full sequencing of these ESTs from human and mouse identified a conserved homologue, ERAL1 (Era-like I). ERAL1 maps to 17q11.2 in human and is located in the syntenic region of mouse chromosome II. ERAL1 may be an attractive candidate for a tumor suppressor gene since ERAL1 is located in a chromosomal region Ts here loss of heterozygosity is often associated with various types of cancer. (C) 2000 Academic Press. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, DBS, Moust Canc Genet Program, Frederick, MD 21702 USA. RP Lupski, JR (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM jlupski@bcm.tmc.edu RI Largaespada, David/C-9832-2014 NR 29 TC 12 Z9 21 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD JUL 1 PY 2000 VL 67 IS 1 BP 78 EP 82 DI 10.1006/geno.2000.6243 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 334PU UT WOS:000088195500009 PM 10945472 ER PT J AU Baas, D Prufer, K Ittel, ME Kuchler-Bopp, S Labourdette, G Sarlieve, LL Brachet, P AF Baas, D Prufer, K Ittel, ME Kuchler-Bopp, S Labourdette, G Sarlieve, LL Brachet, P TI Rat oligodendrocytes express the vitamin D-3 receptor and respond to 1,25-dihydroxyvitamin D-3 SO GLIA LA English DT Article DE vitamin D; differentiation; neurotrophin receptor; myelin; nerve growth factor ID NERVE GROWTH-FACTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NITRIC-OXIDE SYNTHASE; CELLS IN-VITRO; THYROID-HORMONE; RETINOIC ACID; MESSENGER-RNA; GLIAL-CELLS; NUCLEAR RECEPTORS; BRAIN HEMISPHERES AB The present study investigates the presence of vitamin D receptor (VDR) in cells of the rat oligodendrocyte (OL) lineage. VDR transcripts were detected by in situ hybridization in a fraction of rat OL in secondary cultures. The VDR protein was shown to be co-localized in cells that are also recognized by an anti-myelin basic protein (MBP) antibody. Likewise, in vivo, VDR-positive cells were found in the brain white matter, such as the internal capsule of the striatum or the corpus callosum but also in the spinal cord. At least part of these positive cells in vivo correspond to OL, since they were co-stained by an anti-carbonic anhydrase II antiserum. Northern blot analyses of the CG-4 OL cell line demonstrated that the VDR transcripts are already found in the O-2A precursors. There was a two-fold increase in the relative abundance of these transcripts in differentiated OL or in type-2 astrocytes. 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] increased the pool of transcripts encoding its own receptor, the VDR. The hormone also enhanced the abundance of the mRNA of the nerve growth factor (NGF) and of its low-affinity receptor, the p75(NTR) protein. By contrast, the hormone had no effect on the levels of MBP or proteolipid protein (PLP) mRNA. This finding suggests that unlike retinoic acid (RA) or thyroid hormone, 1,25-(OH)(2)D-3 has no regulatory action on the synthesis of myelin proteins. (C) 2000 Wiley-Liss, Inc. C1 Ecole Normale Super Lyon, UMR 5665, F-69364 Lyon 07, France. Fac Med, CNRS, ER 2072, Inst Chim Biol, Strasbourg, France. NIDDK, NIH, LCBB, Bethesda, MD USA. CNRS, Ctr Neurochim, UPR 1352, Strasbourg, France. CHU Hotel Dieu, INSERM, ITERT, U437, Nantes, France. RP Baas, D (reprint author), Ecole Normale Super Lyon, UMR 5665, 46 Allee Italie, F-69364 Lyon 07, France. NR 78 TC 65 Z9 67 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 0894-1491 J9 GLIA JI Glia PD JUL PY 2000 VL 31 IS 1 BP 59 EP 68 DI 10.1002/(SICI)1098-1136(200007)31:1<59::AID-GLIA60>3.0.CO;2-Y PG 10 WC Neurosciences SC Neurosciences & Neurology GA 325AR UT WOS:000087654600006 PM 10816607 ER PT J AU Potterf, SB Furumura, M Dunn, KJ Arnheiter, H Pavan, WJ AF Potterf, SB Furumura, M Dunn, KJ Arnheiter, H Pavan, WJ TI Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3 SO HUMAN GENETICS LA English DT Article ID HIRSCHSPRUNG-DISEASE; MOUSE MODEL; GENE; MUTATION; MICROPHTHALMIA; MELANOCYTES; ACTIVATION; PROMOTER; DEAFNESS AB Waardenburg syndrome (WS) is associated with neural crest-derived melanocyte deficiency caused by mutations in either one of three transcription factors: MITF, PAX3, and SOX10. However, the hierarchical relationship of these transcription factors is largely unknown. We show that SOX10 is capable of transactivating the MITF promoter 100-fold, and that this transactivation is further stimulated by PAX3, Promoter deletion and mutational analyses indicate that SOX10 can activate MITF expression through binding to a region that is evolutionarily conserved between the mouse and human MITF promoters. A SOX10 mutant that models C-terminal truncations in WS can reduce wild-type SOX10 induction of MITF, suggesting these mutations may act in a dominant-negative fashion. Our data support a model in which the hypopigmentation in WS, of which these factors have been implicated, results from a disruption in function of the central melanocyte transcription factor MITF. C1 Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, 49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM bpavan@nhgri.nih.gov NR 28 TC 211 Z9 219 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUL PY 2000 VL 107 IS 1 BP 1 EP 6 DI 10.1007/s004390050001 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 341NU UT WOS:000088597100001 PM 10982026 ER PT J AU Iwata, T Chen, L Li, CI Ovchinnikov, DA Behringer, RR Francomano, CA Deng, CX AF Iwata, T Chen, L Li, CI Ovchinnikov, DA Behringer, RR Francomano, CA Deng, CX TI A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos SO HUMAN MOLECULAR GENETICS LA English DT Article ID HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-FORMATION; FACTOR RECEPTOR 3; DYSPLASIA TYPE-II; THANATOPHORIC DYSPLASIA; PARATHYROID-HORMONE; TARGETED DISRUPTION; INDIAN HEDGEHOG; ACTIVATING MUTATIONS; SKELETAL DYSPLASIA AB We have generated the first mouse model of fibroblast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII), Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of Patched (Pfc) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (Ihh), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. in contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII, This model was successfully crossed with a cartilage-specific Cre transgenic strain, excluding the lung as the primary cause of lethality. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Med Genet Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI Ovchinnikov, Dmitry/J-7963-2014; deng, chuxia/N-6713-2016 OI Ovchinnikov, Dmitry/0000-0001-9603-8385; NR 59 TC 137 Z9 137 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2000 VL 9 IS 11 BP 1603 EP 1613 DI 10.1093/hmg/9.11.1603 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 332RQ UT WOS:000088087600006 PM 10861287 ER PT J AU Bordi, C Aprile, MR Jensen, RT Gibril, F AF Bordi, C Aprile, MR Jensen, RT Gibril, F TI Fundic gland polyps: Do they arise as a by-product of hypergastrinemia in patients with Zollinger-Ellison syndrome? - Reply SO HUMAN PATHOLOGY LA English DT Letter ID GASTRIC ADENOCARCINOMA; ADENOMATOUS POLYPOSIS C1 Univ Parma, Dept Pathol, Parma, Italy. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Bordi, C (reprint author), Univ Parma, Dept Pathol, Parma, Italy. NR 6 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 2000 VL 31 IS 7 BP 890 EP 890 PG 1 WC Pathology SC Pathology GA 336GG UT WOS:000088293100025 ER PT J AU Brugnera, E Bhandoola, A Cibotti, R Yu, Q Guinter, TI Yamashita, Y Sharrow, SO Singer, A AF Brugnera, E Bhandoola, A Cibotti, R Yu, Q Guinter, TI Yamashita, Y Sharrow, SO Singer, A TI Coreceptor reversal in the thymus: Signaled CD4(+)8(+) thymocytes initially terminate CD8 transcription even when differentiating into CD8(+) T cells SO IMMUNITY LA English DT Article ID CD4/CD8 LINEAGE COMMITMENT; INTERLEUKIN-7 RECEPTOR; POSITIVE SELECTION; GENE-EXPRESSION; NUCLEAR-RNA; LYMPHOCYTES; OVEREXPRESSION; SPECIFICITY; PRECURSORS; MATURATION AB A central paradigm of T cell development is that CD4(+)8(+) (DP) thymocytes differentiate into CD4(+) or CD8(+) T cells in response to intrathymic signals that extinguish transcription of the inappropriate coreceptor molecule. Contrary to this prevailing paradigm, we now demonstrate that signaled DP thymocytes initially terminate CD8 transcription even when differentiating into CD8(+) T cells. Remarkably, thymocytes that have selectively terminated CD8 transcription can be signaled by IL-7 to differentiate into CD8(+) T cells by silencing CD4 transcription and reinitiating CD8 transcription, events we refer to as "coreceptor reversal." These observations significantly alter our understanding of CD8(+) T cell differentiation and lead to a new perspective ("kinetic signaling") on CD4/CD8 lineage determination in the thymus. These observations also suggest a novel mechanism by which bipotential cells throughout development can determine their appropriate cell fate. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Oklahoma Med Res Fdn, Immunobiol Program, Oklahoma City, OK 73104 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NR 36 TC 176 Z9 179 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL PY 2000 VL 13 IS 1 BP 59 EP 71 DI 10.1016/S1074-7613(00)00008-X PG 13 WC Immunology SC Immunology GA 339EA UT WOS:000088463600007 PM 10933395 ER PT J AU Stevenson, B Porcella, SF Oie, KL Fitzpatrick, CA Raffel, SJ Lubke, L Schrumpf, ME Schwan, TG AF Stevenson, B Porcella, SF Oie, KL Fitzpatrick, CA Raffel, SJ Lubke, L Schrumpf, ME Schwan, TG TI The relapsing fever spirochete Borrelia hermsii contains multiple, antigen-encoding circular plasmids that are homologous to the cp32 plasmids of Lyme disease spirochetes SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-SURFACE-PROTEIN; IXODES-RICINUS TICKS; LINEAR-PLASMID; IMMUNOLOGICAL CHARACTERIZATION; SUPERCOILED PLASMIDS; NUCLEOTIDE-SEQUENCE; BURGDORFERI B31; GENE FAMILY; IN-VIVO; DNA AB Borrelia hermsii, an agent of tick-borne relapsing fever, was found to contain multiple circular plasmids approximately 30 kb in size. Sequencing of a DNA library constructed from circular plasmid fragments enabled assembly of a composite DNA sequence that is homologous to the cp32 plasmid family of the Lyme disease spirochete, B. burgdorferi. Analysis of another relapsing fever bacterium, B. parkeri, indicated that it contains linear homologs of the B. hermsii and B. burgdorferi cp32 plasmids. The B. hermsii cp32 plasmids encode homologs of the B. burgdorferi Mlp and Bdr antigenic proteins and BlyA/BlyB putative hemolysins, but homologs of B. burgdorferi erp genes were absent. Immunoblot analyses demonstrated that relapsing fever patients produced antibodies to Mlp proteins, indicating that those proteins are synthesized by the spirochetes during human infection. Conservation of cp32-encoded genes in different Borrelia species suggests that their protein products serve functions essential to both relapsing fever and Lyme disease spirochetes. Relapsing fever borreliae replicate to high levels in the blood of infected animals, permitting direct detection and possible functional studies of Mlp, Bdr, BlyA/BlyB, and other cp32-encoded proteins in vivo. C1 Univ Kentucky, Coll Med, Chandler Med Ctr MS 415, Dept Microbiol & Immunol, Lexington, KY 40536 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Microscopy Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Stevenson, B (reprint author), Univ Kentucky, Coll Med, Chandler Med Ctr MS 415, Dept Microbiol & Immunol, Lexington, KY 40536 USA. FU NIAID NIH HHS [R01 AI044254, R01-AI44254] NR 64 TC 38 Z9 38 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 JUL PY 2000 VL 68 IS 7 BP 3900 EP 3908 DI 10.1128/IAI.68.7.3900-3908.2000 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 326AT UT WOS:000087710200016 PM 10858201 ER PT J AU Bhandoola, A Kithiganahalli, B Granger, L Singer, A AF Bhandoola, A Kithiganahalli, B Granger, L Singer, A TI Programming for cytotoxic effector function occurs concomitantly with CD4 extinction during CD8(+) T cell differentiation in the thymus SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE cathepsin C; cathepsin W; cytotoxic lymphocytes; precursor cytotoxic T lymphocyte; thymic selection ID DIPEPTIDYL-PEPTIDASE-I; HUMAN CATHEPSIN-W; POSITIVE SELECTION; LINEAGE COMMITMENT; CHROMOSOMAL LOCALIZATION; GRANZYME-A; EXPRESSION; THYMOCYTES; LYMPHOCYTES; VIVO AB CD4(+) T cells are generally specialized to function as helper cells and CD8(+) T cells are generally specialized to function as cytotoxic effector cells. To explain how such concordance is achieved between co-receptor expression and immune function, we considered two possibilities. In one case, immature CD4(+)CD8(+) thymocyte precursors might first down-regulate expression of one co-receptor molecule, with the remaining co-receptor molecule subsequently activating the appropriate helper or cytotoxic functional program. Alternatively, we considered that the same intrathymic signals that selectively extinguished expression of one or the other co-receptor molecule might simultaneously initiate the appropriate helper or cytotoxic functional program. In the present study, we attempted to distinguish between these alternatives by examining thymocyte precursors of CD8(+) T cells for expression of Cathepsin C and Cathepsin W, molecules important for cytotoxic effector function. We report in developing thymocytes that Cathepsin C and Cathepsin W are expressed coordinately with extinction of CD4 co-receptor expression. We conclude that CD4 extinction and initiation of the cytotoxic functional program occurs simultaneously during differentiation of CD8(+) T cells in the thymus. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 25 TC 6 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUL PY 2000 VL 12 IS 7 BP 1035 EP 1040 DI 10.1093/intimm/12.7.1035 PG 6 WC Immunology SC Immunology GA 340UD UT WOS:000088552600010 PM 10882415 ER PT J AU Keppler-Hafkemeyer, A Kreitman, RJ Pastan, I AF Keppler-Hafkemeyer, A Kreitman, RJ Pastan, I TI Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID DIPHTHERIA-TOXIN; PSEUDOMONAS EXOTOXIN; RECOMBINANT IMMUNOTOXIN; CPP32-LIKE PROTEASES; COMPLETE REGRESSION; MEDIATED APOPTOSIS; LEUKEMIA-CELLS; CANCER-CELLS; ACTIVATION; MICE AB The recombinant immunotoxins anti-Tac(Fv)-PE38 (LMB-2). targeting the interleukin-2 receptor or subunit (IL-2R alpha, Tac or CD25), and RFB4(dsFv)-PE38 (BL22), targeting CD22, are being evaluated in clinical trials as treatment for hematologic malignancies. The toxin moiety Pseudomonas exotoxin A (PE) of these recombinant: molecules leads to the arrest of protein synthesis due to inactivation of elongation factor 2. Here, we provide evidence that cell lines derived from patients with hematologic malignancies react to immunotoxins not only with inhibition of protein synthesis but also with characteristic hallmarks of apoptosis such as caspase activation, cleavage of the "death substrate" poly(ADP)-ribose polymerase and DNA laddering. Anti-Tac(Fv)-PE3B leads to a 10-fold increase in the cleavage of the fluorescent substrate DEVD-AFC, suggesting that a caspase-3-like enzyme is involved. This was verified by cleavage of caspase-3 (CPP32), MTI cells exhibited DNA laddering after treatment with immunotoxin, which was reversed by pre-treatment with the protease inhibitor zVAD-fmk. This caspase inhibitor led to an at least 5-fold improvement in cell viability without altering inhibition of protein synthesis. Interestingly, HUT-102 cells did not undergo programmed cell death after exposure to immunotoxins that kill these cells. We conclude that immunotoxins may be valuable in the treatment of cancers that are resistant toward apoptosis because their targeted killing is often facilitated by, but not completely dependent on, programmed cell death. Int. J. Cancer 87:86-94, 2000. Published 2000 Wiley-Liss. Inc.dagger C1 NCI, Div Basic Sci, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Div Basic Sci, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 26 TC 60 Z9 62 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2000 VL 87 IS 1 BP 86 EP 94 DI 10.1002/1097-0215(20000701)87:1<86::AID-IJC13>3.0.CO;2-I PG 9 WC Oncology SC Oncology GA 320EP UT WOS:000087389100013 PM 10861457 ER PT J AU Thellung, S Florio, T Corsaro, A Arena, S Merlino, M Salmona, M Tagliavini, F Bugiani, O Forloni, G Schettini, G AF Thellung, S Florio, T Corsaro, A Arena, S Merlino, M Salmona, M Tagliavini, F Bugiani, O Forloni, G Schettini, G TI Intracellular mechanisms mediating the neuronal death and astrogliosis induced by the prion protein fragment 106-126 SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article ID CALCIUM CHANNELS; PC12 CELLS; SCRAPIE; PRP; PROLIFERATION; NEUROTOXICITY; AMYLOIDOSIS; INHIBITION; IMPAIRMENT; RESISTANT AB Prion encephalopathies include fatal diseases of the central nervous system of men and animals characterized by nerve cell loss, glial proliferation and deposition of amyloid fibrils into the brain. During these diseases a cellular glycoprotein (the prion protein, PrPC) is converted, through a not yet completely clear mechanism, in an altered isoform (the prion scrapie, PrPSc) that accumulates within the brain tissue by virtue of its resistance to the intracellular catabolism. PrPSc is believed to be responsible for the neuronal loss that is observed in the prion disease, The PrP 106-126, a synthetic peptide that has been obtained from the amyloidogenic portion of the prion protein, represents a suitable model for studying the pathogenic role of the PrPSc, retaining, in vitro, some characteristics of the entire protein, such as the capability to aggregate in fibrils, and the neurotoxicity. In this work we present the results we have recently obtained regarding the action of the PrP 106-126 in different cellular models. We report that the PrP 106-126 induces proliferation of cortical astrocytes, as well as degeneration of primary cultures of cortical neurons or of neuroectodermal stable cell lines (GH(3) cells). In particular, these two opposite effects are mediated by the same attitude of the peptide to interact with the L-type calcium channels: in the astrocytes, the activity of these channels seems to be activated by PrP 106-126, while, in the cortical neurons and in the GH(3) cells, the same treatment causes a blockade of these channels causing a toxic effect. (C) 2000 ISDN. Published by Elsevier Science Ltd. All rights reserved. C1 Univ Genoa, Pharmacol Sect, Dept Oncol,Unit Pharmacol & Neurosci, Adv Biotechnol Ctr,Natl Canc Inst, I-16132 Genoa, Italy. Univ Chieti, Dept Biomed Sci, Pharmacol Sect, Chieti, Italy. Mario Negri Inst Pharmacol Res, I-20157 Milan, Italy. Natl Neurol Inst, I-20123 Milan, Italy. RP Schettini, G (reprint author), Univ Genoa, Pharmacol Sect, Dept Oncol,Unit Pharmacol & Neurosci, Adv Biotechnol Ctr,Natl Canc Inst, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. RI Florio, Tullio/A-2211-2012; OI Florio, Tullio/0000-0002-2394-996X; Thellung, Stefano/0000-0002-2010-331X; salmona, mario/0000-0002-9098-9873; Corsaro, Alessandro/0000-0003-4565-7914 FU Telethon [E.0975] NR 46 TC 43 Z9 45 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD JUL-AUG PY 2000 VL 18 IS 4-5 BP 481 EP 492 DI 10.1016/S0736-5748(00)00005-8 PG 12 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 321MG UT WOS:000087458800016 PM 10817932 ER PT J AU Flegal, KM Troiano, RP AF Flegal, KM Troiano, RP TI Changes in the distribution of body mass index of adults and children in the US population SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE adults; body weight; body mass index; children; health surveys; overweight; obesity; time trends; United States ID SEGREGATION ANALYSES; UNITED-STATES; PIMA-INDIANS; OVERWEIGHT; OBESITY; PREVALENCE; TRENDS; INDIVIDUALS AB BACKGROUND: National survey data show increases in mean body mass index (BMI) and in the prevalence of overweight and obesity for adults and children in the United States, indicating a change in the distribution of BMI. OBJECTIVE: To apply graphical methods to describe changes in the distribution of BMI. DESIGN: BMI values from the third National Health and Nutrition Examination Survey (NHANES III: 1988-94) were compared with data from earlier cross-sectional nationally representative surveys for adults 29-74y of age and for children and adolescents 6-17 y of age. Tukey mean-difference plots were used to investigate the changes in the distributions of BMI within sex-age groups. RESULTS: Mean-difference blots allow qualitative visual comparisons of the distributions of BMI between surveys. For ail sex-age groups, there was increasing skewness with a greater shift in the upper part of the distribution so that, within each group, the heaviest subgroup was heavier in NHANES III than in prior surveys. For the youngest children, the lower part of the distribution showed virtually no change. With increasing age the whole distribution tended to shift upward slightly, suggesting an increase in BMI across the entire population. CONCLUSIONS: These changes in the distribution of BMI suggest the combination of both profound environmental determinants and a population with a high degree of susceptibility. The reasons for the increasing prevalence of obesity should be sought in part by seeking to understand the factors causing increases in the population as a whole. C1 Natl Ctr Hlth Stat, Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Natl Ctr Hlth Stat, Ctr Dis Control & Prevent, 6525 Belcrest Rd,Room 900, Hyattsville, MD 20782 USA. RI Flegal, Katherine/A-4608-2013; OI Troiano, Richard/0000-0002-6807-989X; Flegal, Katherine/0000-0002-0838-469X NR 24 TC 320 Z9 328 U1 4 U2 16 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2000 VL 24 IS 7 BP 807 EP 818 DI 10.1038/sj.ijo.0801232 PG 12 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 331NQ UT WOS:000088025500001 PM 10918526 ER PT J AU Gray, RS Fabsitz, RR Cowan, LD Lee, ET Welty, TK Jablonski, KA Howard, BV AF Gray, RS Fabsitz, RR Cowan, LD Lee, ET Welty, TK Jablonski, KA Howard, BV TI Relation of generalized and central obesity to cardiovascular risk factors and prevalent coronary heart disease in a sample of American Indians: the Strong Heart Study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE Indian; North American; coronary heart disease; obesity ID BODY-FAT DISTRIBUTION; DEPENDENT DIABETES-MELLITUS; MIDDLE-AGED MEN; INSULIN SENSITIVITY; BLOOD-PRESSURE; PIMA-INDIANS; MYOCARDIAL-INFARCTION; ABDOMINAL OBESITY; ADIPOSE-TISSUE; WEIGHT-GAIN AB OBJECTIVE: To examine the hypothesis linking measures of obesity including body mass index (BMI), waist circumference (waist) and percentage body fat to coronary heart disease (CHD) prevalence and its risk factors in American Indians. DESIGN: The Strong Heart Study assesses the prevalence of CHD and its risk factors in American Indians in Arizona, Oklahoma and South/North Dakota. Participants underwent a physical examination and an electrocardiogram; anthropometric and blood pressure measurements were taken, as were measurements of glucose, lipoproteins, fibrinogen, insulin, hemoglobin A(1c) and urinary albumin. PARTICIPANTS: Data were available for 4549 men and women between 45 and 74y of age. MEASUREMENTS: Obesity, measured using body mass index, waist circumference and percentage body fat, was correlated with prevalent CHD and its risk factors. RESULTS: More than 75% of participants were overweight (BMI > 25 kg/m(2)). Measures of obesity were greater in women than in men, in younger than in older participants, and in participants with diabetes than in nondiabetic participants. CHD risk factors were associated with measures of obesity but, except for insulin concentration, changes in metabolic variables with increasing obesity were small. Associations were not stronger with waist than with BMI. The prevalence of CHD in those whose BMI and/or waist measurements lay in the lowest and highest quintiles, by gender and diabetic status, was similar. CONCLUSIONS: Although CHD risk factors are associated with obesity in American Indians, distribution of obesity (ie waist) is no more closely related to risk factors than is generalized obesity (ie BMI), and changes in CHD risk factors with obesity were small. Thus, the relations among obesity, body fat distribution and CHD risk may differ in this population. C1 MedStar Res Inst, Washington, DC 20010 USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Dept Biostat & Epidemiol, Oklahoma City, OK USA. Aberdeen Tribal Chairmens Hlth Board, Rapid City, SD USA. RP Howard, BV (reprint author), MedStar Res Inst, 108 Irving St NW, Washington, DC 20010 USA. FU NHLBI NIH HHS [U01HL41652, UL01HL41654, U01HL41642] NR 70 TC 17 Z9 18 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2000 VL 24 IS 7 BP 849 EP 860 DI 10.1038/sj.ijo.0801243 PG 12 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 331NQ UT WOS:000088025500006 PM 10918531 ER PT J AU Guo, ZK Cella, LK Baum, C Ravussin, E Schoeller, DA AF Guo, ZK Cella, LK Baum, C Ravussin, E Schoeller, DA TI De novo lipogenesis in adipose tissue of lean and obese women: application of deuterated water and isotope ratio mass spectrometry SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE lipogenesis; adipose tissue; obese; deuterated water ID STABLE ISOTOPES; ACID SYNTHESIS; HUMANS; CHOLESTEROL AB OBJECTIVE: To evaluate the feasibility of using deuterated water and isotope ratio mass spectrometry to measure de novo fatty acid synthesis in adipose tissue, and to compare this parameter in obese and lean women. SUBJECTS: Six lean and six obese premenopausal Caucasian women in the main study and three obese Pima Indians in a pilot study. MEASUREMENTS: Deuterated water was administered orally twice daily for 14 days to create stable deuterium enrichment in body water, during which series of brood samples were collected to measure body water deuterium enrichment and deuterium incorporation into plasma total Triacylglycerol (TG) fatty acids and total cholesterol. Subcutaneous fat at different sites were sampled at the beginning and the end of deuterium administration to measure deuterium incorporation into TG fatty acids. RESULTS: Fractional de novo synthesis rate of TG fatty acids in adipose tissue was 0.014+/-0.005 and 0.014+/-0.007% in lean and obese Caucasian women, corresponding to 2+/-0.7 and 5.6+/-3.2g (P=0.3) of fatty acids synthesized daily, respectively. Plasma TG fatty acids and cholesterol synthesis rates were comparable to those reported previously. A pilot study showed that de novo lipid synthesis in adipose tissue of obese Pima Indians was also quantitatively minor. CONCLUSION: Human adipose tissue, like the liver, does not make a major contribution to whole body lipogenesis under eucaloric conditions. A combination of deuterated water and isotope ratio mass spectrometry is a useful research tool for studying accumulation of de novo synthesized lipids in human adipose tissue. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Schoeller, DA (reprint author), Univ Wisconsin, Dept Nutr Sci, 1415 Linden Dr, Madison, WI 53706 USA. NR 17 TC 23 Z9 23 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2000 VL 24 IS 7 BP 932 EP 937 DI 10.1038/sj.ijo.0801256 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 331NQ UT WOS:000088025500018 PM 10918543 ER PT J AU Pietrini, P Alexander, GE Furey, ML Hampel, H Guazzelli, M AF Pietrini, P Alexander, GE Furey, ML Hampel, H Guazzelli, M TI The neurometabolic landscape of cognitive decline: in vivo studies with positron emission tomography in Alzheimer's disease SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE brain metabolism; cognition; dementia; early diagnosis; synaptic dysfunction; human ID CEREBRAL METABOLIC ASYMMETRIES; GLUCOSE-UTILIZATION; ENERGY-METABOLISM; FUNCTIONAL-ACTIVITY; APOLIPOPROTEIN-E; DOWN-SYNDROME; SPINAL-CORD; BLOOD-FLOW; DEMENTIA; STIMULATION AB Alzheimer's disease, the most common form of dementia in the elderly, is characterized by the progressive, global and irreversible deterioration of cognitive abilities. The development of positron emission tomography (PET) methodologies has made it possible to study the in vivo brain metabolic correlates of human cognitive and behavioral functions. Moreover, as PET scan examinations can be repeated, the progression of the neuropathological process and its relation to cognitive dysfunction can be followed over time. In an effort to understand the changes in neural function that precede and accompany onset of dementia and their relation to clinical manifestations, in the last several years, we have conducted clinical, neuropsychological and brain metabolic studies in groups of Alzheimer's disease patients at different stages of dementia severity or with distinct clinical pictures and in populations at risk for developing the disease. Here, we discuss the main findings and implications obtained from these studies. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Pisa, Sch Med, Dept Human & Environm Sci, Inst Med Chem & Biochem, Pisa, Italy. Arizona State Univ, Arizona Alzheimers Dis Res Ctr, Tempe, AZ 85287 USA. Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Munich, Geriat Psychiat Branch, Dept Psychiat, Munich, Germany. Univ Pisa, Sch Med, Dept Psychiat Pharmacol Neurobiol & Biotechnol, I-56100 Pisa, Italy. RP Pietrini, P (reprint author), Univ Pisa, Sch Med, Dept Human & Environm Sci, Inst Med Chem & Biochem, Pisa, Italy. EM pietro.pietrini@bm.med.unipi.it RI Furey, Maura/H-5273-2013 NR 58 TC 46 Z9 46 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUL PY 2000 VL 37 IS 1 BP 87 EP 98 DI 10.1016/S0167-8760(00)00097-0 PG 12 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 326ZG UT WOS:000087766700008 PM 10828377 ER PT J AU Platz, EA Wiencke, JK Kelsey, KT Janower, ML Schottenfeld, D Travis, LB Goldman, MB AF Platz, EA Wiencke, JK Kelsey, KT Janower, ML Schottenfeld, D Travis, LB Goldman, MB TI Chromosomal aberrations and hprt mutant frequencies in long-term American thorotrast survivors SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID CANCER INCIDENCE; EXPOSED PATIENTS; HUMAN-POPULATION; ALPHA-PARTICLES; LYMPHOCYTES AB Purpose: Patients injected with thorotrast, a radiologic contrast medium used from the 1920s to early 1950s, received chronic internal exposure to thorium-232, an alpha-emitter. Epidemiologic studies have observed markedly elevated risks of death from hepatic and hematologic cancers and extensive chromosomal damage among these patients. Few investigations have correlated multiple measures of genetic damage to determine whether these have independent induction kinetics. The distribution of chromosomal aberrations (CA) and mutant frequencies (MF) at the hypoxanthine phosphoribosyltransferase (hprt) locus was evaluated in eight long-term thorotrast survivors (mean exposure time = 47.4 years) and five individuals who received a nonradioactive contrast medium during the same era. Materials and methods: Peripheral blood lymphocytes were harvested from whole blood, CA were scored in 500 complete metaphases and a clonal assay was used to determine hprt MF. Symmetrical aberrations were not evaluated. Differences in frequencies and correlations between endpoints were assessed using nonparametric methods. Results: Thorotrast-exposed individuals differed from the comparison group in total number of multicentrics and centric and acentric rings (per 500 cells [median, mean +/- sd]: 11, 18.3 +/- 23.1 vs 2, 2.4 +/- 1.1, p=0.04). There was no difference between the groups on hprt MF (12.6, 15.9 +/- 13.5 vs 16.6, 14.0 +/- 8.8[ x 10(-6)]; p = 1.0). Among the exposed, hprt MF was moderately correlated with the frequency of asymmetrical chromosomal aberrations, although the association was not statistically significant. Conclusion: Noting the limitations of small samples, long-term thorotrast survivors were observed to be at an increased risk for genetic damage. C1 Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, Lab Mol Epidemiol, San Francisco, CA 94143 USA. Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. St Vincent Hosp, Dept Radiol, Worcester, MA 01604 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. NIH, Div Canc Epidemiol & Genet, NCI, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Platz, EA (reprint author), Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. RI Kelsey, Karl/I-1252-2014 FU NCI NIH HHS [N01-CP-21151] NR 28 TC 7 Z9 8 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD JUL PY 2000 VL 76 IS 7 BP 955 EP 961 PG 7 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 335PG UT WOS:000088251400008 PM 10923619 ER PT J AU Shen, T Zhuang, ZP Gersell, DJ Tavassoli, FA AF Shen, T Zhuang, ZP Gersell, DJ Tavassoli, FA TI Allelic deletion of VHL gene detected in papillary tumors of the broad ligament, epididymis, and retroperitoneum in von Hippel-Lindau disease patients SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE von Hippel-Lindau Disease; papillary tumor; broad ligament; epididymis; peritoneum; genetics; LOH ID RENAL-CELL CARCINOMA; SUPPRESSOR GENE; SHORT ARM; CYSTADENOMA; CHROMOSOME-3; MUTATION; LESIONS; ORIGIN AB Although clinically associated with von Hippel-Lindau (VHL) disease, the pathogenesis of papillary tumors of the broad ligament, epididymis, and peritoneum arising in patients with VHL disease is not clear. The "classic" VBL-associated neoplasms, including hemangioblastoma and renal cell carcinoma, have been found to be associated with the inactivation of both VHL gene copies. It is not known whether a similar inactivation of the VHL gene is also responsible for the development of these uncommon VHL-associated lesions. The authors performed PCR (polymerase chain reaction) and PCR-base SSCP (single-strand conformation polymorphism) analysis on five predominantly papillary tumors in five VHL patients (one papillary cystadenoma of the broad ligament, one endometrioid cystadenoma of the broad ligament, two papillary cystadenomas of the epididymis, one papillary tumor of the retroperitoneum) with four polymorphic markers of VHL gene (D3S1038, D3S1110, D3S2452, 104/105). All five tumors showed allelic loss of VHL gene. The results provide the first genetic evidence for the role of VHL gene in the tumorigenesis of these rare benign neoplasms and confirm these tumors as phenotypic manifestations of VHL disease. C1 Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. RP Shen, T (reprint author), Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, 14th St & Alaska Ave NW, Washington, DC 20306 USA. NR 23 TC 8 Z9 8 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD JUL PY 2000 VL 8 IS 3 BP 207 EP 212 DI 10.1177/106689690000800308 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 357PC UT WOS:000089509200008 PM 11493991 ER PT J AU Grant, MB Spoerri, PE Player, DW Bush, DM Ellis, EA Caballero, S Robison, WG AF Grant, MB Spoerri, PE Player, DW Bush, DM Ellis, EA Caballero, S Robison, WG TI Plasminogen activator inhibitor (PAI)-1 overexpression in retinal microvessels of PAT-1 transgenic mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALDOSE REDUCTASE INHIBITOR; STREPTOZOTOCIN-DIABETIC RATS; HUMAN-ENDOTHELIAL-CELLS; MESSENGER-RNA; HIGH-GLUCOSE; GENE-EXPRESSION; RETINOPATHY; MELLITUS; FIBRONECTIN; CAPILLARIES AB PURPOSE. Previous studies have suggested that disturbances in plasminogen activator inhibitor (PAI)-1 may be relevant to the development of diabetic microvascular complications. To determine whether overexpression of PAI-1 in cells of retinal microvasculature would result in a disease similar to that observed in diabetes, ocular tissue from transgenic mice that overexpress human PAI-1 were examined. METHODS. Transgenic mice were administered ZnSO4 (25 mM) in their water for up to 49 weeks to activate the metallothionein promoter and stimulate human PAI-1. Colloidal gold immunocytochemistry was used to quantify the human PAI-1 antigen at 7, 20, 34, and 49 weeks of ZnSO4 administration. Cross sections of retinal microvessels were examined by electron microscopy for changes in basement membrane (BM) thickness. Retinal digest preparations were examined by light microscopy for possible microangiopathy, including changes in endothelial cell-to-pericyte ratios. RESULTS. Human PAI-1 immunoreactivity was detected throughout the retinal capillaries of transgenic mice receiving zinc and increased significantly (P < 0.001) after 20 to 49 weeks of ZnSO4 administration compared with age-matched transgenic control mice. At 20 and 49 weeks, retinal capillaries of transgenic mice that received zinc showed significantly thickened BMs compared with control animals (P < 0.001). Moreover, wholemounts of the retinal vasculature from PAI-1 transgenic mice demonstrated an increased endothelial cell-to-pericyte ratio. CONCLUSIONS. PAI-1 overexpression in retinal microvasculature leads to retinal disease similar to that observed in diabetic retinopathy. C1 Univ Florida, Div Endocrinol & Metab, Dept Med, Gainesville, FL 32610 USA. Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. NEI, Bethesda, MD 20892 USA. RP Grant, MB (reprint author), Univ Florida, Div Endocrinol & Metab, Dept Med, Box 100226, Gainesville, FL 32610 USA. FU NEI NIH HHS [EY-07739] NR 41 TC 19 Z9 19 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 JUL PY 2000 VL 41 IS 8 BP 2296 EP 2302 PG 7 WC Ophthalmology SC Ophthalmology GA 329WB UT WOS:000087930500042 PM 10892876 ER PT J AU Shafiee, A Penn, JS Krutzsch, HC Inman, JK Roberts, DD Blake, DA AF Shafiee, A Penn, JS Krutzsch, HC Inman, JK Roberts, DD Blake, DA TI Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; PROLIFERATIVE DIABETIC-RETINOPATHY; ENDOTHELIAL-CELL PROLIFERATION; OXYGEN-INDUCED RETINOPATHY; HEPARIN-BINDING; NEONATAL RAT; IN-VIVO; IRIS NEOVASCULARIZATION; REPEAT PEPTIDES; CARBON-DIOXIDE AB PURPOSE. Thrombospondin (TSP)-1 is a tumor suppressor with activity that is associated with its ability to inhibit neovascularization. Previous studies have mapped this antiangiogenic activity to the type 1 repeats and the amino-terminal portion of the molecule within the procollagen-like domain. The present study was performed to investigate the ability of TSP-1 and peptides derived from the type 1 repeats to inhibit retinal angiogenesis. METHODS. TSP-1 and peptides with tryptophan-rich, heparin-binding sequences and transforming growth factor (TGF)-beta 1 activation sequences were evaluated in two models of retinal angiogenesis: a retinal explant assay and a rat model of retinopathy of prematurity (ROP). RESULTS. Platelet-derived TSP-1 inhibited angiogenesis in both experimental models. Peptides from the native TSP-1 sequence, which contained both the tryptophan-rich repeat and the TGF-beta 1 activation sequence, were the most potent inhibitors of endothelial cell outgrowth in the retinal explant assay. In contrast, a peptide containing only the tryptophan-rich, heparin-binding sequence was most active in inhibiting neovascular disease in the rat ROP model. CONCLUSIONS. These results indicate that the type 1 repeats of TSP-1 contain two subdomains that may independently influence the process of neovascularization, and that peptides derived from these type 1 repeats may be promising pharmacologic agents for treatment of retinal angiogenesis. C1 Tulane Univ, Sch Med, Dept Ophthalmol, New Orleans, LA 70112 USA. Vanderbilt Univ, Sch Med, Dept Ophthalmol & Visual Sci, Nashville, TN 37212 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Blake, DA (reprint author), Tulane Univ, Sch Med, Dept Ophthalmol, SL-69,1430 Tulane Ave, New Orleans, LA 70112 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NEI NIH HHS [EY-07533, EY-09092] NR 73 TC 49 Z9 54 U1 0 U2 1 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 JUL PY 2000 VL 41 IS 8 BP 2378 EP 2388 PG 11 WC Ophthalmology SC Ophthalmology GA 329WB UT WOS:000087930500053 PM 10892887 ER PT J AU Anastos, K Gange, SJ Lau, B Weiser, B Detels, R Giorgi, JV Margolick, JB Cohen, M Phair, J Melnick, S Rinaldo, CR Kovacs, A Levine, A Landesman, S Young, M Munoz, A Greenblatt, RM AF Anastos, K Gange, SJ Lau, B Weiser, B Detels, R Giorgi, JV Margolick, JB Cohen, M Phair, J Melnick, S Rinaldo, CR Kovacs, A Levine, A Landesman, S Young, M Munoz, A Greenblatt, RM CA Women's Interagency HIV Study M TI Association of race and gender with HIV-1 RNA levels and immunologic progression SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS DE HIV; race; gender; CD4 cell count; viral load ID VIRUS TYPE-1 RNA; MULTICENTER AIDS COHORT; REVERSE-TRANSCRIPTASE PCR; LYMPHOCYTE-T SUBSETS; VIRAL LOAD; SEX-DIFFERENCES; UNITED-STATES; PLASMA; CD4; INFECTION AB Context: HIV-1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression. Objective: To assess racial and gender differences in HIV-1 RNA levels and CD4(+) lymphocyte decline. Design: A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States. Results: In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral. therapy were included. Women were more Likely to be nonwhite, to have a history of injection drug use, and to have HIV-associated symptoms. After adjustment for differences in measurement method, baseline CD4(+) cell count, age, and clinical symptoms, HIV-1 RNA levels were 32% to 50% lower in women than in men at CD4(+) counts >200 cells/mm(3) (p < .001) but not at CD4(+) cell counts <200 cells/mm(3). HIV-1 RNA levels were also 41% lower in nonwhites than in whites (p < .001) and 21% lower in persons reporting a prior history of injection drug use (p < .001). Women had more rapid declines in CD4(+) cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4(+) cell counts than whites (difference of 39 cells/year). Conclusions: Both race and gender influence the values of HIV-1 RNA and the rate of HIV-1 disease progression as indicated by decline in CD4(+) cell counts over time. These effects could provide clues regarding the factors that influence HIV-disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics. C1 Montefiore Med Ctr, Womens Interagcy HIV Study, Bronx, NY 10467 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. Cook Cty Hosp, Chicago, IL 60612 USA. Northwestern Univ, Sch Med, Chicago, IL USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ So Calif, Los Angeles, CA USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Anastos, K (reprint author), Montefiore Med Ctr, Womens Interagcy HIV Study, 3305 Bainbridge Ave, Bronx, NY 10467 USA. OI Gange, Stephen/0000-0001-7842-512X FU NIAID NIH HHS [U01-AI31834, U01-AI34994, U01-AI35004] NR 52 TC 116 Z9 119 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD JUL 1 PY 2000 VL 24 IS 3 BP 218 EP 226 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 350DX UT WOS:000089086400004 PM 10969345 ER PT J AU Goodpaster, BH Visser, M Scherzinger, A Kelley, DE Stamm, E Carlson, C Harris, T Newman, AB AF Goodpaster, BH Visser, M Scherzinger, A Kelley, DE Stamm, E Carlson, C Harris, T Newman, AB TI The association between leg skeletal muscle composition and muscle strength in the elderly: The Health ABC Study SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JUL PY 2000 VL 8 IS 3 BP 291 EP 292 PG 2 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900110 ER PT J AU Ritter, T Shung, KK Cao, WW Shrout, TR AF Ritter, T Shung, KK Cao, WW Shrout, TR TI Electromechanical properties of thin strip piezoelectric vibrators at high frequency SO JOURNAL OF APPLIED PHYSICS LA English DT Article ID TRANSDUCERS; MHZ AB A method was developed and used to determine the electromechanical properties of high frequency (> 20 MHz) piezoelectric strip vibrators. A nonlinear regression technique was employed to fit the impedance magnitude and phase as predicted by Mason's model to measured values. Results from experimental measurements on 30 MHz array elements supported by an attenuative backing indicated degraded performance when compared to values predicted from the electromechanical properties measured at low frequency. This degradation may be attributed to damage incurred during fabrication and grain size effects, with a fine grain sized material providing superior relative performance. This technique may be used in the evaluation and comparison of different fabrication processes and materials for high frequency medical imaging arrays. (C) 2000 American Institute of Physics. [S0021-8979(00)05913-2]. C1 Penn State Univ, NIH, Resource Ctr Med Ultrason Transducer Technol, University Pk, PA 16802 USA. RP Ritter, T (reprint author), Penn State Univ, NIH, Resource Ctr Med Ultrason Transducer Technol, 205 Hallowell Bldg, University Pk, PA 16802 USA. RI Cao, Wenwu/F-6091-2012 OI Cao, Wenwu/0000-0002-2447-1486 NR 12 TC 9 Z9 9 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0021-8979 J9 J APPL PHYS JI J. Appl. Phys. PD JUL 1 PY 2000 VL 88 IS 1 BP 394 EP 397 DI 10.1063/1.373708 PG 4 WC Physics, Applied SC Physics GA 325YE UT WOS:000087704000061 ER PT J AU Salamone, LM Fuerst, T Visser, M Kern, M Lang, T Dockrell, M Cauley, JA Nevitt, M Tylavsky, F Lohman, TG AF Salamone, LM Fuerst, T Visser, M Kern, M Lang, T Dockrell, M Cauley, JA Nevitt, M Tylavsky, F Lohman, TG TI Measurement of fat mass using DEXA: a validation study in elderly adults SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE body composition; dual-energy X-ray absorptiometry; fan beam; computed tomography ID X-RAY ABSORPTIOMETRY; SOFT-TISSUE MEASUREMENTS; SKELETAL-MUSCLE MASS; TOTAL-BODY WATER; ADIPOSE-TISSUE; LABELED WATER; HYDRATION; HYDRODENSITOMETRY; ACCURACY; DENSITY AB The accuracy of total body fat mass and leg fat mass measurements by fan-beam dual-energy X-ray absorptiometry (DEXA) was assessed in 60 healthy elderly subjects (aged 70-79 yr). Total fat and leg fat mass at four leg regions (total leg, thigh, midthigh, and calf) were measured with the QDR 4500A (Hologic, Waltham, MA). The four-compartment model and multislice computed tomography scans were selected as criterion methods for total fat and leg fat mass, respectively. Total fat mass from DEXA was positively associated with fat mass from the four-compartment model with a standard error of the estimate ranging from 1.4 to 1.6 kg. DEXA fan-beam tended to overestimate fat mass for total leg and total thigh fat mass, whereas only marginal differences in fat mass measurements at the midthigh and calf were demonstrated (less than or equal to 0.08 kg, P < 0.0005). Although there were significant differences between DEXA fan beam and the criterion methods, these differences were of small magnitude, suggesting that DEXA is an accurate method for measurement of fat mass for the elderly. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94105 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94105 USA. San Francisco State Univ, Dept Kinesiol, San Francisco, CA 94132 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38105 USA. Univ Arizona, Coll Med, Dept Physiol, Tucson, AZ 85721 USA. RP Salamone, LM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, A547, Pittsburgh, PA 15261 USA. RI Lang, Thomas/B-2685-2012; Cauley, Jane/N-4836-2015 OI Lang, Thomas/0000-0002-3720-8038; Cauley, Jane/0000-0003-0752-4408 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 34 TC 136 Z9 139 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUL PY 2000 VL 89 IS 1 BP 345 EP 352 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 335EK UT WOS:000088230400043 PM 10904070 ER PT J AU Levine, KE Fernando, RA Essader, MLA Handy, RW Collins, BJ AF Levine, KE Fernando, RA Essader, MLA Handy, RW Collins, BJ TI Development of a method for the determination of ultra-trace level mercury in adipose tissue by cold vapour atomic fluorescence spectrometry SO JOURNAL OF AUTOMATED METHODS & MANAGEMENT IN CHEMISTRY LA English DT Article ID ABSORPTION SPECTROMETRY; DIGESTION; SAMPLES; SOILS AB A method for the determination of total mercury in rat adipose tissue by cold vapour atomic fluorescence spectrometry (CVAFS) has been developed. Adipose samples were initially subjected to a lyophilization procedure in order to facilitate the homogenization and accurate weighing of small tissue aliquots (similar to 50 mg). A closed vessel microwave digestion procedure using a mixture of sulphuric and nitric acids was used to liberate mercury from the adipose matrix. All mercury species were quantitative ly oxidized to Hg (II) by a potassium bromate/bromide oxidation, then reduced to Hg (0) vapour by stannous chloride prior to fluorescence detection. The CVAFS exhibited a linear range of 10 pg Hg/ml to 120 pg Hg/ml. The method detection limit in solution was 2 pg Hg /ml, or 1 ng Hg /g adipose tissue, based on a nominal 50 mg sample and a final volume of 25 ml. A reference material from the National Research Council of Canada (DOLT-2, trace metals in dogfish liver) was prepared in quadruplicate in order to assess the accuracy and precision of the method. Mercury in this material was recovered at 2.22 +/- 0.08 mu g/g, which is 104% of the certified level (2.14 +/- 0.10 mu g/g). C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Levine, KE (reprint author), Res Triangle Inst, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. NR 21 TC 3 Z9 3 U1 0 U2 2 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1463-9246 EI 1464-5068 J9 J AUTOM METHOD MANAG JI J. Autom. Methods Manag. Chem. PD JUL PY 2000 VL 22 IS 4 BP 103 EP 108 DI 10.1155/S1463924600000146 PG 6 WC Chemistry, Analytical; Instruments & Instrumentation SC Chemistry; Instruments & Instrumentation GA 347KR UT WOS:000088928700002 PM 18924864 ER PT J AU Youngren, B Radnedge, L Hu, P Garcia, E Austin, S AF Youngren, B Radnedge, L Hu, P Garcia, E Austin, S TI A plasmid partition system of the P1-P7par family from the pMT1 virulence plasmid of Yersinia pestis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID P1 PLASMID; PARB PROTEIN; CLONING VEHICLES; HOST FACTOR; F-PLASMID; SPECIFICITY; SITE; DNA; SEGREGATION; CENTROMERE AB The complete sequence of the virulence plasmid pMT1 of Yersinia pestis KIM5 revealed a region homologous to the plasmid partition (par) region of the P7 plasmid prophage of Escherichia coli. The essential genes parA and parB and the downstream partition site gene, parS, are highly conserved in sequence and organization. The pMT1parS site and the parA-parB operon were separately inserted into vectors that could be maintained in E. coli. A mini-P1 vector containing pMT1parS was stably maintained when the pMT1 ParA and ParB proteins were supplied in trans, showing that the pMT1par system is fully functional for plasmid partition in E. coli. The pMT1par system exerted a plasmid silencing activity similar to, but weaker than those of P7par and P1par. In spite of the high degree of similarity, especially to P7par, it showed unique specificities with respect to the interactions of key components. Neither the P7 nor P1 Par proteins could support partition via the pMT1parS site, and the pMT1 Par proteins failed to support partition with P1parS or P7parS. Typical of other partition sites. supernumerary copies of pMT1parS exerted incompatibility toward plasmids supported by pMT1par. However, no interspecies incompatibility effect was observed between pMT1par, P7par, and P1par. C1 NCI, Gene Regulat & Chromosome Biol Lab, DBS, NCI FCRDC, Frederick, MD 21702 USA. Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, DBS, NCI FCRDC, Frederick, MD 21702 USA. NR 31 TC 16 Z9 18 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2000 VL 182 IS 14 BP 3924 EP 3928 DI 10.1128/JB.182.14.3924-3928.2000 PG 5 WC Microbiology SC Microbiology GA 329ZN UT WOS:000087938500006 PM 10869068 ER PT J AU Han, CJ Gruschus, JM Greener, T Greene, LE Ferretti, J Eisenberg, E AF Han, CJ Gruschus, JM Greener, T Greene, LE Ferretti, J Eisenberg, E TI H-1, N-15, and C-13 NMR backbone assignments and secondary structure of the C-terminal recombinant fragment of auxilin including the J-domain SO JOURNAL OF BIOMOLECULAR NMR LA English DT Letter DE auxilin; clathrin; 3D NMR; J-domain; secondary structure ID CHAPERONE; REGION C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Eisenberg, E (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 10 TC 4 Z9 5 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUL PY 2000 VL 17 IS 3 BP 281 EP 282 DI 10.1023/A:1008353226591 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 335BW UT WOS:000088223000015 PM 10959640 ER PT J AU Freidlin, B Gastwirth, JL AF Freidlin, B Gastwirth, JL TI Changepoint tests designed for the analysis of hiring data arising in employment discrimination cases SO JOURNAL OF BUSINESS & ECONOMIC STATISTICS LA English DT Article DE binomial data; changepoint; fair hiring practices; hypergeometric data ID CHANGE-POINT; VARIABLES; TREND; CUSUM; POWER AB When a complaint of discrimination is made, an employer may respond by hiring more minorities. From a legal viewpoint, the practices in effect during the time period prior to the complaint are more relevant for determining liability than those of the postcharge period. In Gay v. Waiters, the trial judge observed that the data suggested that a change occurred after the charge was filed. Because the data had not been subject to a formal statistical analysis, the court was reluctant to base its decision on this observation. Gastwirth and Freidlin and Gastwirth proposed cumulative-sumbased procedures for the analysis of hiring data following the binomial model. In this article, the procedures are extended to data following the hypergeometric model and to analysis of stratified data. Several datasets that were submitted to the courts in the United States are analyzed by the proposed methods. Because the data are usually reported by year, the ordinary large-sample theory is not sufficiently accurate. Therefore, we obtain the p values of the statistics by simulation. For binomial data, recent improvements in the Bonferroni inequality are used to derive a new upper hound. C1 NCI, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Freidlin, B (reprint author), NCI, Bethesda, MD 20892 USA. NR 36 TC 4 Z9 4 U1 0 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0735-0015 J9 J BUS ECON STAT JI J. Bus. Econ. Stat. PD JUL PY 2000 VL 18 IS 3 BP 315 EP 322 DI 10.2307/1392264 PG 8 WC Economics; Social Sciences, Mathematical Methods; Statistics & Probability SC Business & Economics; Mathematical Methods In Social Sciences; Mathematics GA 424KW UT WOS:000168232300005 ER PT J AU Grainger, DJ Mosedale, DE Metcalfe, JC Bottinger, EP AF Grainger, DJ Mosedale, DE Metcalfe, JC Bottinger, EP TI Dietary fat and reduced levels of TGF beta 1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions SO JOURNAL OF CELL SCIENCE LA English DT Article DE atherosclerosis; cholesterol; inflammation ID TRANSFORMING GROWTH FACTOR-BETA-1; SMOOTH-MUSCLE CELLS; FACTOR-BETA; DEFICIENT MICE; INBRED STRAINS; TGF-BETA; ATHEROSCLEROSIS; GROWTH-FACTOR-BETA-1; TAMOXIFEN; MOUSE AB Transforming growth factor-beta (TGF beta) has a wide range of activities on vascular cells and inflammatory cells, suggesting it may have different functions during various stages of atherogenesis. We report that mice heterozygous for the deletion of the fgfb1 gene (tgfb1(+/-) mice) have reduced levels of TCF beta 1 in the artery wall until at least 8 weeks of age. On a normal mouse chow diet, the vascular endothelium of tgfbv1(+/-) mice is indistinguishable from wild-type littermates, assessed by morphology and intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, In contrast, levels of the smooth muscle isoforms of actin and myosin in medial smooth muscle cells of tg;tgfb1(+/-) mice are significantly reduced, Following feeding a cholesterol-enriched diet for 12 weeks, high levels of ICAM-1 and VCAM-1 were detected in the vascular endothelial cells of tgfb1(+/-) mice, but not wild-type mice, Furthermore, marked deposition of lipid into the artery wall was only observed in the tafb1(+/-) mice on the cholesterol-enriched diet, These vascular lipid lesions were accompanied by local invasion of macrophages. We conclude that deletion of a single allele of the tgfb1 gene results in a reduced level of TGF beta 1 antigen in the aorta together with reduced smooth muscle cell differentiation, whereas the addition of a high fat dietary challenge is required to activate the vascular endothelium and to promote the formation of fatty streaks resembling early atherosclerosis in humans. C1 Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. Dept Biochem, Cambridge CB2 1QW, England. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Grainger, DJ (reprint author), Addenbrookes Hosp, Dept Med, Hills Rd,Box 157, Cambridge CB2 2QQ, England. NR 41 TC 70 Z9 72 U1 0 U2 1 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 JUL PY 2000 VL 113 IS 13 BP 2355 EP 2361 PG 7 WC Cell Biology SC Cell Biology GA 336TU UT WOS:000088319700003 PM 10852815 ER PT J AU Nawashiro, H Brenner, M Fukui, S Shima, K Hallenbeck, JM AF Nawashiro, H Brenner, M Fukui, S Shima, K Hallenbeck, JM TI High susceptibility to cerebral ischemia in GFAP-null mice SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE astrocytes; glial fibrillary acidic protein; cerebral ischemia; mice ID ENDOTHELIAL-CELLS; INFARCT VOLUME; WHITE-MATTER; BRAIN; ASTROCYTES; GLUTAMATE; PROTEIN; LACKING; EXPRESSION; DEVELOP AB Astrocytes perform a variety of functions in the adult central nervous system (CNS) that contribute to the survival of neurons. Thus, it is likely that the activities of astrocytes affect the extent of brain damage after ischemic stroke. The authors tested this hypothesis by using a mouse ischemia model to compare the infarct volume produced in wild-type mice with that produced in mice lacking glial fibrillary acidic protein (GFAP), an astrocyte specific intermediate filament component. Astrocytes lacking GFAP have been shown to have defects in process formation, induction of the blood-brain barrier, and volume regulation; therefore, they might be compromised in their ability to protect the CNS after injury. The authors reported here that 48 hours after combined permanent middle cerebral artery occlusion (MCAO) and 15 minutes transient carotid artery occlusion (CAO) GFAP-null mice had a significantly (P < 0.001) larger cortical infarct volume (16.7 +/- 2.2 mm(3)) than their wild-type littermates (10.1 +/- 3.9 mm(3)). Laser-Doppler flowmetry revealed that the GFAP-null mice had a more extensive and profound decrease in cortical cerebral blood flow within 2 minutes after MCAO with CAO. These results indicated a high susceptibility to cerebral ischemia in GFAP-null mice and suggested an important role for astrocytes and GFAP in the progress of ischemic with partial reperfusion. C1 Natl Def Med Coll, Dept Neurosurg, Tokorozawa, Saitama 3598513, Japan. Univ Alabama, Dept Neurobiol, Birmingham, AL USA. Univ Alabama, Dept Phys Med & Rehabil, Birmingham, AL USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Nawashiro, H (reprint author), Natl Def Med Coll, Dept Neurosurg, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan. NR 28 TC 91 Z9 103 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2000 VL 20 IS 7 BP 1040 EP 1044 PG 5 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 329NX UT WOS:000087914200003 PM 10908037 ER PT J AU Bertrand, N Siren, AL Tworek, D McCarron, RM Spatz, M AF Bertrand, N Siren, AL Tworek, D McCarron, RM Spatz, M TI Differential expression of HSC73 and HSP72 mRNA and proteins between young and adult gerbils after transient cerebral ischemia: Relation to neuronal vulnerability SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE HSP72; HSC73; mRNA; proteins; ischemia; young; adult; hippocampus; neuronal damage; gerbils ID HEAT-SHOCK-PROTEIN; NEONATAL HYPOXIA-ISCHEMIA; MESSENGER-RNA; RAT-BRAIN; C-FOS; GLUCOSE DEPRIVATION; FOREBRAIN ISCHEMIA; OVER-EXPRESSION; STRESS PROTEINS; HIPPOCAMPUS AB This study presents a quantitative comparison of the time courses and regional distribution of both constitutive HSC73 and inducible HSP72 mRNA expression and their respective encoded proteins between young (3-week-old) and adult (3-month-old) gerbil hippocampus after transient global ischemia. The constitutive expression of HSC73 mRNA and protein in the hippocampus of the young sham-operated gerbils was significantly higher than in the adults. The HSC73 mRNA expression after ischemia in the CA1 layer of young gerbils was greater than in adult gerbils. HSC73 immunoreactivity was not significantly changed after ischemia-reperfusion in adult hippocampus, whereas it decreased in young gerbils. Ischemia-reperfusion led to induction of HSP72 mRNA expression throughout the hippocampus of both young and adult gerbils. HSP72 mRNA induction was more intense and sustained in the CA1 subfield of young gerbils; this was associated with a marked induction of HSP72 proteins and neuronal survival. The transient expression of HSP72 mRNA in the CA1 layer of adult gerbils was not associated with a subsequent synthesis of HSP72 protein but was linked to neuronal loss. Expression of HSP72 mRNA was shifted to an earlier period of reflow in CA3 and dentate gyrus (DG) subfields of young animals. These findings suggest that the induction of both HSP72 mRNA and proteins in the CA1 pyramidal neurons of young gerbils, as well as the higher constitutive expression of HSC73, may partially contribute to higher neuronal resistance of young animals to transient cerebral ischemia. C1 NINDS, NIH, Stroke Branch, Bethesda, MD 20892 USA. Fac Pharm, Lab Pharmacodynamie, Dijon, France. USUHS, Dept Neurol, Bethesda, MD USA. USN, Med Res Ctr, Resuscitat Med Dept, Bethesda, MD 20084 USA. RP Spatz, M (reprint author), NINDS, NIH, Stroke Branch, Bethesda, MD 20892 USA. OI Siren, Anna-Leena/0000-0002-2217-0081 NR 54 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2000 VL 20 IS 7 BP 1056 EP 1065 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 329NX UT WOS:000087914200005 PM 10908039 ER PT J AU Bahler, D Stone, B AF Bahler, D Stone, B TI Symbolic, neural, and Bayesian machine learning models for predicting carcinogenicity of chemical compounds SO JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Mathematical Chemistry CY MAY, 1999 CL DULUTH, MINNESOTA ID NATIONAL-TOXICOLOGY-PROGRAM; RODENT CARCINOGENICITY; CLASSIFICATION; MUTAGENICITY; SYSTEMS AB Experimental programs have been underway for several years to determine the environmental effects of chemical compounds, mixtures, and the like. Among these programs is the National Toxicology Program (NTP) on rodent carcinogenicity. Because these experiments are costly and time-consuming, the rate at which test articles (i.e., chemicals) can be tested is limited. The ability to predict the outcome of the analysis at various points in the process would facilitate informed decisions about the allocation of testing resources. To assist human experts in organizing an empirical testing regime, and to try to shed light on mechanisms of toxicity, we constructed toxicity models using various machine learning and data mining methods, both existing and those of our own devising. These models took the form of decision trees, rule sets, neural networks, rules extracted from trained neural networks, and Bayesian classifiers. As a training set, we used recent results from rodent carcinogenicity bioassays conducted by the NTP on 226 test articles. We performed 10-way cross-validation on each of our models to approximate their expected error rates on unseen data. The data set consists of physical-chemical parameters of test articles, alerting chemical substructures, salmonella mutagenicity assay results, subchronic histopathology data, and information on route, strain, and sex/species for 744 individual experiments. These results contribute to the ongoing process of evaluating and interpreting the data collected from chemical toxicity studies. C1 N Carolina State Univ, Dept Comp Sci, Artificial Intelligence Lab, Raleigh, NC 27695 USA. Shippensburg Univ, Dept Math & Comp Sci, Shippensburg, PA 17257 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Bahler, D (reprint author), N Carolina State Univ, Dept Comp Sci, Artificial Intelligence Lab, Raleigh, NC 27695 USA. NR 40 TC 11 Z9 12 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0095-2338 J9 J CHEM INF COMP SCI JI J. Chem. Inf. Comput. Sci. PD JUL-AUG PY 2000 VL 40 IS 4 BP 906 EP 914 DI 10.1021/ci990116i PG 9 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 338LM UT WOS:000088421300004 PM 10955517 ER PT J AU Eliez, S Rumsey, JM Giedd, JN Schmitt, JE Patwardhan, AJ Reiss, AL AF Eliez, S Rumsey, JM Giedd, JN Schmitt, JE Patwardhan, AJ Reiss, AL TI Morphological alteration of temporal lobe gray matter in dyslexia: An MRI study SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES LA English DT Article DE brain development; brain imaging; cerebral lateralization; dyslexia; reading; temporal lobe ID POSITRON EMISSION TOMOGRAPHY; DEVELOPMENTAL DYSLEXIA; PLANUM TEMPORALE; BRAIN; HANDEDNESS; ASYMMETRY; CHILDREN; CORTEX; PARCELLATION; ACTIVATION AB Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices. To examine the possible contribution of subtle anatomic deviations to these reductions, volumes were measured for the major lobes of the brain, the subcortical nuclei, cerebellum, and lateral ventricles on magnetic resonance imaging (MRI) scans from 16 right-handed dyslexic men, ages 18 to 40, and 14 matched controls, most of whom had previously undergone PET imaging. A specific decrease in tissue volume was localized to the temporal lobes and was particularly prominent on the left (p < .01). An analysis of tissue composition revealed that this reduction was primarily attributable to decreased gray matter within the left temporal lobe (p < .002). Further segmentation of the temporal lobe showed that this reduction was not confined to the superior temporal gyrus, the primary location of primary auditory cortex. Reductions of temporal lobe gray matter may reflect a regional decrease in neuronal number or neuropil, which in turn may result in reading impairment. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. NIMH, Rockville, MD 20857 USA. NIMH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Eliez, S (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, 401 Quarry Rd, Stanford, CA 94305 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 FU NICHD NIH HHS [HD31715]; NIMH NIH HHS [MH01142] NR 39 TC 52 Z9 52 U1 2 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry Allied Discip. PD JUL PY 2000 VL 41 IS 5 BP 637 EP 644 PG 8 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 336TD UT WOS:000088318300010 PM 10946755 ER PT J AU Katz, A Nambi, SS Mather, K Baron, AD Follmann, DA Sullivan, G Quon, MJ AF Katz, A Nambi, SS Mather, K Baron, AD Follmann, DA Sullivan, G Quon, MJ TI Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DEPENDENT DIABETES-MELLITUS; MINIMAL MODEL TECHNIQUES; GLUCOSE-TOLERANCE TEST; HOMEOSTASIS MODEL; BLOOD-PRESSURE; BETA-CELL; CLAMP; RESISTANCE; SECRETION; OBESITY AB Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SIClamp) and minimal model analysis (SIMM) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I-0) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I-0) + log(G(0))]) that has substantially better correlation with SIclamp (r = 0.78) than the correlation we observed between SIMM andSI(clamp). Moreover, we observed a comparable overall correlation between QUICKI and SIClamp in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research. C1 NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Div Endocrinol & Metab, Indianapolis, IN 46202 USA. RP Quon, MJ (reprint author), NHLBI, Hypertens Endocrine Branch, NIH, 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 39 TC 1979 Z9 2063 U1 10 U2 57 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2000 VL 85 IS 7 BP 2402 EP 2410 DI 10.1210/jc.85.7.2402 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337XB UT WOS:000088387500008 PM 10902785 ER PT J AU Weng, NP Hodes, RJ AF Weng, NP Hodes, RJ TI The role of telomerase expression and telomere length maintenance in human and mouse SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article ID T-CELL TURNOVER; HIV-INFECTION; CATALYTIC SUBUNIT; HUMAN FIBROBLASTS; HUMAN-LYMPHOCYTES; REPLICATIVE SENESCENCE; REGULATED EXPRESSION; HEMATOPOIETIC-CELLS; ACTIVATION; CANCER AB The molecular regulation of telomere length has been well elucidated by a series of elegant studies over the past decade. More recently, experimental evidence has accrued that addresses the challenging question of if and how telomere length regulation may contribute to normal human aging or to human disease. Recent studies in mice have provided a mammalian precedent indicating that telomerase deficiency can lead to in vivo dysfunction, most probably as a consequence of progressive telomere shortening. In humans, the evidence that telomere shortening might lead to in vivo dysfunction is far less direct, although the recent description of telomerase deficiency and telomere shortening associated with the DKC syndrome is suggestive of such a link. Methodologies exist and continue to be developed that are increasingly capable of manipulating telomerase activity and telomere length in human cells. It remains to be determined whether scientifically rigorous and (equally important) medically ethical approaches will emerge to directly assess the ability of telomere length modulation to correct functional disorders of human cellular function ex vivo or, more challenging still, in vivo. C1 NIH, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIH, Bldg 31,Room 5C35,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 63 TC 30 Z9 37 U1 1 U2 4 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2000 VL 20 IS 4 BP 257 EP 267 PG 11 WC Immunology SC Immunology GA 338WR UT WOS:000088446700004 PM 10939713 ER PT J AU Eilat, E Zinger, H Nyska, A Mozes, E AF Eilat, E Zinger, H Nyska, A Mozes, E TI Prevention of systemic lupus erythematosus-like disease in (NZBxNZW)F1 mice by treating with CDR1-and CDR3-based peptides of a pathogenic autoantibody SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE SLE-like models; (NZBxNZW)F1 mice; CDR-based peptide; immunomodulation; disease prevention ID MURINE LUPUS; MONOCLONAL-ANTIBODY; AUTOIMMUNE-DISEASE; DNA; INHIBITION; INDUCTION; IDIOTYPE AB Two peptides based on the complementarity-determining regions (CDR) of a pathogenic murine anti-DNA antibody were employed in an attempt to prevent the spontaneous systemic lupus erythematosus (SLE)-like disease of (NZBxNZW)F1 mice. Female mice, at the age of 2 months, were injected with tither the CDR1- or the CDR3-based peptides (pCDR1, pCDR3) subcutaneously or intravenously in aqueous solution for a total of 8-10 treatments. A reduction was observed in the total and pathogenic IpG2a and IgG3 anti-DNA antibody titers in the CDR-treated groups. Treatment reduced the number of mice that developed proteinuria and immune complex deposits in their kidneys. The severity of renal pathology was significantly reduced in the pCDR3 (P < 0.02) and pCDR1 (P less than or equal to 0.05) treated mice. Thus, both CDR-based peptides administered in aqueous solution were capable of preventing the SLE-like disease in (NZBxNZW)F1 mice, although the beneficial effects of pCDR3 appeared to be more pronounced than those of pCDR1 in the treated mice. C1 Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Mozes, E (reprint author), Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. NR 22 TC 42 Z9 44 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2000 VL 20 IS 4 BP 268 EP 278 DI 10.1023/A:1006663519132 PG 11 WC Immunology SC Immunology GA 338WR UT WOS:000088446700005 PM 10939714 ER PT J AU Agarwal, RK Kang, YB Zambidis, E Scott, DW Chan, CC Caspi, RR AF Agarwal, RK Kang, YB Zambidis, E Scott, DW Chan, CC Caspi, RR TI Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID B-CELLS; ORAL TOLERANCE; INDUCTION; EXPRESSION; EPITOPE; UVEORETINITIS; RESISTANCE; RESPONSES; MODEL; MICE AB Immunoglobulins can serve as tolerogenic carriers for antigens, and B cells can function as tolerogenic antigen-presenting cells. We used this principle to design a strategy for gene therapy of experimental autoimmune uveitis, a cell-mediated autoimmune disease model for human uveitis induced with the uveitogenic interphotoreceptor retinoid-binding protein (IRBP). A retroviral vector was constructed containing a major uveitogenic IRBP epitope in frame with mouse IgG1 heavy chain. This construct was used to transduce peripheral B cells, which were infused into syngeneic recipients. A single infusion of transduced cells, 10 days before uveitogenic challenge, protected mice from clinical disease induced with the epitope or with the native IRBP protein. Protected mice had reduced antigen-specific responses, but showed no evidence for a classic Th1/Th2 response shift or for generalized anergy. Protection was not transferable, arguing against a mechanism dependent on regulatory cells. Importantly, the treatment was protective when initiated 7 days after uveitogenic immunization or concurrently with adoptive transfer of primed uveitogenic T cells. We suggest that this form of gene therapy can induce epitope-specific protection not only in naive, but also in already primed recipients, thus providing a protocol for treatment of established autoimmunity. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Dept Immunol, Rockville, MD USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,MSC 1857,10-10N222, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R01 AI035622, R01 AI35622]; NIGMS NIH HHS [T32 GM007356, T32 GM07356] NR 30 TC 87 Z9 90 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2000 VL 106 IS 2 BP 245 EP 252 DI 10.1172/JCI9168 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 335HA UT WOS:000088237000013 PM 10903340 ER PT J AU Bremer, J Nowicki, M Beckner, S Brambilla, D Cronin, M Herman, S Kovacs, A Reichelderfer, P AF Bremer, J Nowicki, M Beckner, S Brambilla, D Cronin, M Herman, S Kovacs, A Reichelderfer, P CA Div AIDS Treatment Res Initiative TI Comparison of two amplification technologies for detection and quantitation of human immunodeficiency virus type 1 RNA in the female genital tract SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HIV-1 RNA; PLASMA; QUANTIFICATION; INFECTION; SEMEN AB Human immunodeficiency virus type 1 (HIV-1) RNA levels in female genital tract and peripheral blood samples were compared using two commercial amplification technologies: the Roche AMPLICOR HIV-1 MONITOR test and either the Organon Teknika nucleic acid sequence-based amplification (NASBA-QT) assay or the NucliSens assay. Estimates of HIV-1 RNA copy number were derived from internal kit standards and analyzed unadjusted and adjusted to a common set of external standards. We found a discordance rate of approximately 18% between the two technologies for the detection of HIV-1 in either the genital tract or peripheral blood samples. Detection discordance was not consistent among specimens or among women. There were no significant differences In adjusted or unadjusted estimates of HIV-1 RNA copy number in the genital tract samples using the AMPLICOR HIV-1 MONITOR test and either the NASBA-QT assay or the NucliSens assay, In addition, the estimated HIV-1 RNA copy number in peripheral blood samples did not differ when tested with the NucliSens assay and the AMPLICOR HIV-1 MONITOR test using kit standards. However, there was a significant difference In estimated RNA copy number between the NASBA-QT assay and the AMPLICOR HIV-1 MONITOR test for internal kit standards, which, as we have previously shown, was eliminated after adjustment with the external standards. Our results suggest that the Roche and Organon Teknika assays are equivalent for quantifying HIV-1 RNA in female genital tract specimens, although variation in detection does exist. C1 Rush Med Coll, Chicago, IL 60612 USA. Univ So Calif, Los Angeles, CA 90033 USA. WESTAT Corp, Rockville, MD 20850 USA. New England Res Inst, Watertown, MA 02472 USA. Organon Tekn Corp, Durham, NC 27712 USA. Roche Mol Syst Inc, Dept Infect Dis, Alameda, CA 94501 USA. NICHHD, Bethesda, MD 20892 USA. RP Bremer, J (reprint author), Rush Med Coll, Chicago, IL 60612 USA. FU NIAID NIH HHS [AI-15123, U01 AI031834, U01 AI034989, U01 AI034993, U01 AI034994, U01 AI035004, U01 AI042590, UO1-AI-31834, UO1-AI-35004]; NICHD NIH HHS [U01 HD032632] NR 14 TC 17 Z9 19 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2000 VL 38 IS 7 BP 2665 EP 2669 PG 5 WC Microbiology SC Microbiology GA 331WR UT WOS:000088042100036 PM 10878061 ER PT J AU Fedorko, DP Williams, EC Nelson, NA Calhoun, LB Yan, SZS AF Fedorko, DP Williams, EC Nelson, NA Calhoun, LB Yan, SZS TI Performance of three enzyme immunoassays and two direct fluorescence assays for detection of Giardia lamblia in stool specimens preserved in ECOFIX SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HUMAN FECAL SPECIMENS; INTESTINAL PROTOZOAN MORPHOLOGY; DIRECT IMMUNOFLUORESCENCE; CRYPTOSPORIDIUM; SULFATE AB ECOFIX is a single-vial stool preservative that is both formalin- and mercury-free, We evaluated the abilities of three commercial Giardia lamblia-specific enzyme immunoassays (EIAs) (ProSpecT Giardia Microplate Assay [Alexon-Trend Inc,], Giardia Test [Techlab], and Premier Giardia lamblia [Meridian Diagnostics, Inc,]) and two commercial direct fluorescent-antibody (FA) assays for G. lamblia (Crypto/Giardia IF Test [Techlab] and Merifluor Cryptosporidium/Giardia [Meridian Diagnostics, Inc.]) to detect G. lamblia in 34 G, lamblia positive and 44 G. lamblia-negative stool specimens (determined by traditional examination for ova and parasites) preserved in ECOFIX compared to their abilities to detect G. lamblia in the same specimens preserved in formalin as the "gold standard" for each assay. Of the 34 formalin fixed positive specimens, the number detected by each assay was as follows:, Alexon EIA, 34; Meridian EIA, 27; Techlab EIA, 29; Meridian PA assay, 31; and Techlab FA. assay, 28, Both FA tests and the Alexon ELA performed well with ECOFIX, but the other two EIAs detected fewer positive specimens (the difference was statistically significant with the Techlab EIA) when ECOFIX was the preservative. Use of G. lamblia cyst antigen from cultured organisms preserved in formalin and ECOFIX demonstrated that the Alexon EIA could detect smaller amounts of antigen in ECOFIX than the other two EIAs could and suggested that cyst antigen is more stable in formalin, We recommend that laboratories use an FA assay or the Alexon EIA if they plan to use ECOFIX as their stool preservative. C1 NIH, Microbiol Serv, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr,CPD, Bethesda, MD 20892 USA. RP Fedorko, DP (reprint author), NIH, Microbiol Serv, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr,CPD, Bldg 10,Room 2C385,10 Ctr Dr MSC 1508, Bethesda, MD 20892 USA. NR 14 TC 4 Z9 6 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2000 VL 38 IS 7 BP 2781 EP 2783 PG 3 WC Microbiology SC Microbiology GA 331WR UT WOS:000088042100063 PM 10878088 ER PT J AU Richardson, MA Sanders, T Palmer, JL Greisinger, A Singletary, SE AF Richardson, MA Sanders, T Palmer, JL Greisinger, A Singletary, SE TI Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ALTERNATIVE MEDICINE; QUESTIONABLE METHODS; TUMOR PATIENTS; UNITED-STATES; THERAPY USE; PREVALENCE; ATTITUDES; CHILDREN; HERBS; CARE AB Purpose: Oncologists are aware that their patients use complementary/alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. Subjects and Methods: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by chi(2) and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. Results: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P <.001) by sex (female), younger age, indigent pay status, and surgery, After excluding spiritual practises and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P <.0001) by sex (female), education, and chemotherapy. Conclusion: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient-provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions. J Clin Oncol 18:2505-2514. (C) 2000 by American Society of Clinical Oncology. C1 Univ Texas, Houston Sch Publ Hlth, Ctr Alternat Med Res, Houston, TX USA. Univ Texas, Houston Sch Publ Hlth, Ctr Hlth Promot Res & Dev, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Richardson, MA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 31 Ctr Dr,Room 5B-58, Bethesda, MD 20892 USA. FU NCI NIH HHS [5U24CA66826-03] NR 63 TC 505 Z9 514 U1 8 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 2000 VL 18 IS 13 BP 2505 EP 2514 PG 10 WC Oncology SC Oncology GA 330AL UT WOS:000087940600002 PM 10893280 ER PT J AU Little, RF Wyvill, KM Pluda, JM Welles, L Marshall, V Figg, WD Newcomb, FM Tosato, G Feigal, E Steinberg, SM Whitby, D Goedert, JJ Yarchoan, R AF Little, RF Wyvill, KM Pluda, JM Welles, L Marshall, V Figg, WD Newcomb, FM Tosato, G Feigal, E Steinberg, SM Whitby, D Goedert, JJ Yarchoan, R TI Activity of thalidomide in AIDS-related Kaposis's sarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ACQUIRED IMMUNODEFICIENCY SYNDROME; NECROSIS-FACTOR-ALPHA; II CLINICAL-TRIALS; PHASE-II; DNA-SEQUENCES; INFLAMMATORY CYTOKINES; PENTOSAN POLYSULFATE; NATURAL-HISTORY; SPINDLE CELLS AB Purpose: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study. Patients and Methods: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. Results: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled, All patients were assessable for toxicity, and 17 for response, Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease, Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response wets 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. Conclusion: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted. C1 NCI, Div Clin Sci, HIV AIDS Malignancy Branch, Med Branch, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol Prod, Bethesda, MD USA. Sci Applicat Int Corp, Frederick, MD USA. RP Yarchoan, R (reprint author), Bldg 10,Room 12N226,MSC 1906,10 Ctr Dr, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012; Figg Sr, William/M-2411-2016 OI Ain, Kenneth/0000-0002-2668-934X; NR 67 TC 194 Z9 202 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 2000 VL 18 IS 13 BP 2593 EP 2602 PG 10 WC Oncology SC Oncology GA 330AL UT WOS:000087940600013 PM 10893291 ER PT J AU Baidas, SM Winer, EP Fleming, GF Harris, L Pluda, JM Crawford, JG Yamauchi, H Isaacs, C Hanfelt, J Tefft, M Flockhart, D Johnson, MD Hawkins, MJ Lippman, ME Hayes, DF AF Baidas, SM Winer, EP Fleming, GF Harris, L Pluda, JM Crawford, JG Yamauchi, H Isaacs, C Hanfelt, J Tefft, M Flockhart, D Johnson, MD Hawkins, MJ Lippman, ME Hayes, DF TI Phase II evaluation of thalidomide in patients with metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR ANGIOGENESIS; APHTHOUS ULCERS; CARCINOMA; PHARMACOKINETICS; DEGRADATION; RECURRENT; INHIBITOR; PLASMA AB Purpose: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. Patients and Methods: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg, Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. Results: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia, Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. Conclusion: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels. (C) 2000 by American Society of Clinical Oncology. C1 Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Breast Canc Program, Washington, DC 20007 USA. Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Dev Therapeut Program, Washington, DC 20007 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Duke Univ, Med Ctr, Durham, NC USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Baidas, SM (reprint author), Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Breast Canc Program, 3800 Reservoir Rd,NW, Washington, DC 20007 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 40 TC 92 Z9 93 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 2000 VL 18 IS 14 BP 2710 EP 2717 PG 8 WC Oncology SC Oncology GA 335UF UT WOS:000088262600009 PM 10894870 ER PT J AU Boccardo, F Rubagotti, A Amoroso, D Mesiti, M Romeo, D Sismondi, P Giai, M Genta, F Pacini, P Distante, V Bolognesi, A Aldrighetii, D Farris, A AF Boccardo, F Rubagotti, A Amoroso, D Mesiti, M Romeo, D Sismondi, P Giai, M Genta, F Pacini, P Distante, V Bolognesi, A Aldrighetii, D Farris, A CA Italian Breast Canc Adjuvant Stu TI Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 14-19, 1998 CL LOS ANGELES, CALIFORNIA SP Amer Soc Clin Oncol ID REQUIRING PROLONGED OBSERVATION; CHEMOENDOCRINE THERAPY; PREMENOPAUSAL PATIENTS; CHEMOTHERAPY; WOMEN; AMENORRHEA; GOSERELIN; DESIGN AB Purpose: To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor-positive patients with early breast cancer. Patients and Methods: Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophasphamide 100 mg/m(2) orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points. Results: Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n=31; and goserelin injections, n = 87). At the rime of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups held emerged with respect to either disease-free or overall survival, Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF, Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable. Conclusion: The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF. (C) 2000 by American Society of Clinical Oncology. C1 Univ Genoa, Professorial Unit Med Oncol, I-16132 Genoa, Italy. Natl Canc Inst, Genoa, Italy. Univ Messina, Inst Oncol, Messina, Italy. Univ Turin, Dept Gynecol Oncol, Turin, Italy. Molinette Mauriziano Hosp, I-10126 Turin, Italy. St Anna Gynecol Hosp, Dept Gynecol & Obstet, Turin, Italy. Univ Florence, Dept Surg, Florence, Italy. Hosp San Raffaele, Dept Oncol Radiotherapy, I-20132 Milan, Italy. Univ Sassari, Dept Clin Oncol, I-07100 Sassari, Italy. RP Boccardo, F (reprint author), Univ Genoa, Professorial Unit Med Oncol, Largo R Benzi 10, I-16132 Genoa, Italy. NR 32 TC 119 Z9 124 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 2000 VL 18 IS 14 BP 2718 EP 2727 PG 10 WC Oncology SC Oncology GA 335UF UT WOS:000088262600010 PM 10894871 ER PT J AU Harris, NL Jaffe, ES Mueller-Hermelink, HK Diebold, J Lister, AK Bloomfield, CA Isaacson, P AF Harris, NL Jaffe, ES Mueller-Hermelink, HK Diebold, J Lister, AK Bloomfield, CA Isaacson, P TI Grading in marginal-zone lymphomas - In reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Wurzburg, Germany. Hosp Hotel Dieu, Paris, France. St Bartholomews Hosp, London, England. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Univ Coll & Middlesex Sch Med, London, England. RP Harris, NL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL PY 2000 VL 18 IS 14 BP 2788 EP 2789 PG 2 WC Oncology SC Oncology GA 335UF UT WOS:000088262600020 ER PT J AU Grafman, J AF Grafman, J TI Conceptualizing functional neuroplasticity SO JOURNAL OF COMMUNICATION DISORDERS LA English DT Article DE neuronal plasticity; recovery of function ID SYNAPTIC PLASTICITY; VISUAL-CORTEX; HUMAN BRAIN; RECOVERY; INJURY; MOTOR; HIPPOCAMPUS; MECHANISMS; CHILDREN; BEHAVIOR AB There are at least four major forms of functional neuroplasticity that can be studied in humans: homologous area adaptation, cross-modal reassignment, map expansion, and compensatory masquerade. Homologous area adaptation is the assumption of a particular cognitive process by a homologous region in the opposite hemisphere. Cross-modal reassignment occurs when structures previously devoted to processing a particular kind of sensory input now accepts input from a new sensory method. Map expansion is the enlargement of a functional brain region on the basis of performance. Compensatory masquerade is a novel allocation of a particular cognitive process to perform a task. By focusing on these four forms of functional neuroplasticity, several fundamental questions about how functional cooperation between brain regions is achieved can be addressed. (C) 2000 by Elsevier Science Inc. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,10 Ctr Dr MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 NR 35 TC 41 Z9 43 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0021-9924 J9 J COMMUN DISORD JI J. Commun. Disord. PD JUL-AUG PY 2000 VL 33 IS 4 BP 345 EP 356 DI 10.1016/S0021-9924(00)00030-7 PG 12 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 354AQ UT WOS:000089308000007 PM 11001161 ER PT J AU Burke, RE AF Burke, RE TI Comparison of alternative designs for reducing complex neurons to equivalent cables SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE electrotonic models; voltage transients; attenuation; voltage propagation delay ID IDENTIFIED ALPHA-MOTONEURONS; CAT SPINAL-CORD; SOMATIC SHUNT; ELECTROTONIC ARCHITECTURE; DENDRITIC STRUCTURE; MEMBRANE-PROPERTIES; TRANSIENT-RESPONSE; GAMMA-MOTONEURONS; ONE BRANCH; MODEL AB Reduction of the morphological complexity of actual neurons into accurate, computationally efficient surrogate models is an important problem in computational neuroscience. The present work explores the use of two morphoelectrotonic transformations, somatofugal voltage attenuation (AT cables) and signal propagation delay (DL cables), as bases for construction of electrotonically equivalent cable models of neurons. In theory, the AT and DL cables should provide more accurate lumping of membrane regions that have the same transmembrane potential than the familiar equivalent cables that are based only on somatofugal electrotonic distance (LM cables). In practice, AT and DL cables indeed provided more accurate simulations of the somatic transient responses produced by fully branched neuron models than LM cables. This was the case in the presence of a somatic shunt as well as when membrane resistivity was uniform. C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20895 USA. RP Burke, RE (reprint author), NINDS, Neural Control Lab, NIH, Bethesda, MD 20895 USA. EM reburke@helix.nih.gov NR 41 TC 10 Z9 10 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD JUL PY 2000 VL 9 IS 1 BP 31 EP 47 DI 10.1023/A:1008934327204 PG 17 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 328UV UT WOS:000087869300002 PM 10946991 ER PT J AU Rautaharju, PM Park, LP Gottdiener, JS Siscovick, D Boineau, R Smith, V Powe, NR AF Rautaharju, PM Park, LP Gottdiener, JS Siscovick, D Boineau, R Smith, V Powe, NR TI Race- and sex-specific ECG models for left ventricular mass in older populations. Factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE left ventricular hypertrophy; left ventricular mass; racial differences; ECG criteria; aging ID ELECTROCARDIOGRAPHIC CRITERIA; CARDIOVASCULAR HEALTH; ETHNIC-DIFFERENCES; MILD HYPERTENSION; BLOOD-PRESSURE; BLACK; WHITE; MEN; AGE; ECHOCARDIOGRAPHY AB The validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to.36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups. C1 Wake Forest Univ, Bowman Gray Sch Med, EPICARE Ctr, Dept Publ Hlth Sci, Winston Salem, NC 27104 USA. Georgetown Univ, Med Ctr, Div Cardiol, Washington, DC 20007 USA. Univ Washington, CHS Coordinating Ctr, Seattle, WA 98195 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Albany Med Coll, Div Cardiol, Albany, NY 12208 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Rautaharju, PM (reprint author), Wake Forest Univ, Bowman Gray Sch Med, EPICARE Ctr, Dept Publ Hlth Sci, Suite 505,Piedmont Plaza 2,2000 W 1st St, Winston Salem, NC 27104 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC-8586, RC-HL 35129] NR 42 TC 34 Z9 36 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JUL PY 2000 VL 33 IS 3 BP 205 EP 218 DI 10.1054/jelc.2000.7667 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339TE UT WOS:000088493300001 PM 10954373 ER PT J AU Morf, CC Weir, C Davidov, M AF Morf, CC Weir, C Davidov, M TI Narcissism and intrinsic motivation: The role of goal congruence SO JOURNAL OF EXPERIMENTAL SOCIAL PSYCHOLOGY LA English DT Article ID COGNITIVE EVALUATION THEORY; PERSONALITY-INVENTORY; MEDIATIONAL ANALYSIS; ACHIEVEMENT ORIENTATION; CONSTRUCT-VALIDITY; SELF-EVALUATIONS; FEEDBACK; INVOLVEMENT; COMPETENCE; ABILITY AB This study investigated the effects of narcissists' chronic preoccupation with satisfying ego concerns on intrinsic motivation. Extending Harackiewicz and Sansone's (1991) "goal-matching" model, we hypothesized that intrinsic motivation depends on the congruence between the goals supported by the environment and the chronic goals the individual brings to the situation. High and low narcissistic students were randomly assigned feedback emphasizing either ego goals (competence is assessed relative to others) or mastery goals (competence is self-referential). Consistent with prediction, male narcissists experienced the most enjoyment, most positive affect, and least apprehension in the ego-goal conditions, whereas low narcissists showed the highest intrinsic motivation with mastery-focused goals. Potential gender differences in narcissism are considered to explain the absence of this pattern for females. The findings extend current understanding of the phenomenology of narcissism, as well as supporting the "goal-matching" model. Discussion revolves around the processing dynamics of male narcissists and possible negative consequences of their continual struggle to demonstrate competence relative to others. (C) 2000 Academic Press. C1 Univ Toronto, Toronto, ON, Canada. Dept Vet Affairs, Salt Lake City, UT USA. RP Morf, CC (reprint author), NIMH, 6001 Execut Blvd,Room 7216,MSC 9651, Bethesda, MD 20892 USA. NR 37 TC 51 Z9 51 U1 4 U2 9 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-1031 J9 J EXP SOC PSYCHOL JI J. Exp. Soc. Psychol. PD JUL PY 2000 VL 36 IS 4 BP 424 EP 438 DI 10.1006/jesp.1999.1421 PG 15 WC Psychology, Social SC Psychology GA 329ZK UT WOS:000087938200005 ER PT J AU Slayman, CL Bertl, A Bihler, H Durell, SR Guy, HR AF Slayman, CL Bertl, A Bihler, H Durell, SR Guy, HR TI Active transport of potassium and the structures of the TRK proteins in the yeast, Saccharomyces cerevisiae SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract C1 Yale Univ, Sch Med, New Haven, CT USA. NCI, Lab Expt & Computat Biol, Bethesda, MD 20892 USA. Univ Karlsruhe, Inst Bot 1, Karlsruhe, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUL PY 2000 VL 116 IS 1 MA 68 BP 24A EP 24A PG 1 WC Physiology SC Physiology GA 332PC UT WOS:000088081800076 ER PT J AU Kim, MG Lee, G Lee, SK Lolkema, M Yim, JB Hong, SH Schwartz, RH AF Kim, MG Lee, G Lee, SK Lolkema, M Yim, JB Hong, SH Schwartz, RH TI Epithelial cell-specific laminin 5 is required for survival of early thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMIC STROMAL CELLS; CHAIN GENE LAMC2; BASEMENT-MEMBRANES; EPIDERMOLYSIS-BULLOSA; EXTRACELLULAR-MATRIX; TISSUE DISTRIBUTION; T-LYMPHOCYTES; EXPRESSION; INTEGRINS; ALPHA-3-BETA-1 AB The gene LamC2 encoding the gamma(2) chain of laminin 5, an epithelial cell-specific extracellular matrix protein, was identified in a PCR-based subtracted cDNA library from mouse thymic stromal cells. The mRNA existed in two alternative forms (5.1 and 2.4 kb). The full-length message was highly expressed in SCID thymus and in a nurse cell line, but not in other thymic epithelial cell lines, while the short form was more widely expressed. In situ hybridization and immunohistochemical staining revealed laminin 5 expression mostly in the subcapsular region of the adult thymus. Addition to fetal thymic organ cultures of a cell adhesion-blocking mAb to the alpha(3) chain of laminin 5 interrupted T cell development. There was a 40% reduction in the total yield of thymocytes, and the most profound decrease (75-90%) was seen in the CD25(+)CD44(+) and CD25(+)CD44(-)subsets of the CD4(-)CD8(-) double negative fraction. Most of the surviving double negative thymocytes expressed Sea-1, and there were significant increases in the number of cells with CD69 expression and in the fraction of annexin V-stained cells. None of these changes were observed with a nonblocking anti-laminin alpha(3) chain mAb. These results suggest that the interaction between double negative thymocytes and laminin 5 made by subcapsular epithelial cells is required for the survival and differentiation of mouse thymocytes. C1 Seoul Natl Univ, Inst Mol Biol & Genet, Natl Creat Res Initiat Ctr Genet Reprograming, Seoul, South Korea. NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Dept Mol Biol, Seoul, South Korea. Kangneung Natl Univ, Coll Dent, Dept Oral Pathol, Kangneung, South Korea. RP Kim, MG (reprint author), Seoul Natl Univ, Inst Mol Biol & Genet, Natl Creat Res Initiat Ctr Genet Reprograming, Bldg 105 Room 319, Seoul, South Korea. NR 49 TC 39 Z9 39 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2000 VL 165 IS 1 BP 192 EP 201 PG 10 WC Immunology SC Immunology GA 327WH UT WOS:000087816800027 PM 10861052 ER PT J AU Wang, IM Contursi, C Masumi, A Ma, XJ Trinchieri, G Ozato, K AF Wang, IM Contursi, C Masumi, A Ma, XJ Trinchieri, G Ozato, K TI An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON REGULATORY FACTORS; MURINE PERITONEAL-MACROPHAGES; HISTONE ACETYLASE PCAF; NF-KAPPA-B; IMMUNE-RESPONSES; FACTOR FAMILY; IN-VIVO; INTERLEUKIN-12 EXPRESSION; INTRACELLULAR INFECTION; CELLS AB IL-12 is a cytokine that links innate and adaptive immunity, Its subunit p40 is induced in macrophages following IFN-gamma/LPS stimulation. Here we studied the role for IFN consensus sequence binding protein (ICSBP), an IFN-gamma/LPS-inducible transcription factor of the IFN regulatory factor (IRF) family in IL-12 p40 transcription. Macrophage-like cells established from ICSBP-/- mice did not induce IL-12 p40 transcripts, nor stimulated IL-12 p40 promoter activity after IFN-gamma/LPS stimulation, although induction of other inducible genes was normal in these cells. Transfection of ICSBP led to a marked induction of both human and mouse IL-12 p40 promoter activities in ICSBP+/+ and ICSBP-/- cells, even in the absence of IFN-gamma/LPS stimulation. Whereas IRF-1 alone was without effect, synergistic enhancement of promoter activity was observed following cotransfection of ICSBP and IRF-1, Deletion analysis of the human promoter indicated that the Ets site, known to be important for activation by IFN-gamma/LPS, also plays a role in the ICSBP activation of IL-12 p40. A DNA affinity binding assay revealed that endogenous ICSBP is recruited to the Ets site through protein-protein interaction. Last, transfection of ISCBP alone led to induction of the endogenous IL-12 p40 mRNA in the absence of IFN-gamma and LPS, Taken together, our results show that ICSBP induced by IFN-gamma/LPS, acts as a principal activator of IL-12p40 transcription in macrophages. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Room 2A01, Bethesda, MD 20892 USA. NR 54 TC 129 Z9 129 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2000 VL 165 IS 1 BP 271 EP 279 PG 9 WC Immunology SC Immunology GA 327WH UT WOS:000087816800036 PM 10861061 ER PT J AU Sgadari, C Toschi, E Palladino, C Barillari, G Carlei, D Cereseto, A Ciccolella, C Yarchoan, R Monini, P Sturzl, M Ensoli, B AF Sgadari, C Toschi, E Palladino, C Barillari, G Carlei, D Cereseto, A Ciccolella, C Yarchoan, R Monini, P Sturzl, M Ensoli, B TI Mechanism of paclitaxel activity in Kaposi's sarcoma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; IMMUNODEFICIENCY-VIRUS TYPE-1; TAXOL-INDUCED APOPTOSIS; PROSTATE-CANCER CELLS; LONG-TERM CULTURE; TAT PROTEIN; SPINDLE CELLS; INFLAMMATORY CYTOKINES; ENDOTHELIAL-CELLS; NUDE-MICE AB Kaposi's sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-shaped cells predominantly of endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. At least in early stage, KS behaves as a reactive lesion sustained by the action of inflammatory cytokines and growth factors, has a polyclonal nature, and can regress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increased expression of antiapoptotic oncogenes, We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spindle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatment of certain neoplasms, has recently been found to be active also in patients with advanced HIV-associated KS. Zn this report we investigated the mechanism(s) of paclitaxel activity in KS, By using a model of experimental KS induced by the inoculation of KS-derived spindle cells in nude mice and primary cultures of KS spindle cells, we found that paclitaxel promotes regression of RS lesions in vivo and that it blocks the growth, migration, and invasion of KS cells in vitro. Furthermore, paclitaxel treatment promoted apoptosis and down-regulated Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. Our results suggest that paclitaxel interferes with KS by down-regulating Bcl-2 antiapoptotic effect. C1 Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. GSF, Natl Res Ctr Environm & Hlth GmbH, Inst Mol Virol, Neuherberg, Germany. RP Ensoli, B (reprint author), Ist Super Sanita, Virol Lab, Viale Regina Elena 299, I-00161 Rome, Italy. RI Sturzl, Michael/B-3019-2015; Sgadari, Cecilia/H-4302-2016; Ensoli, Barbara/J-9169-2016; Monini, Paolo/K-1429-2016; Palladino, Clelia/K-7555-2016 OI Sturzl, Michael/0000-0002-9276-2824; Sgadari, Cecilia/0000-0003-0364-4912; Ensoli, Barbara/0000-0002-0545-8737; Monini, Paolo/0000-0002-4941-6854; Palladino, Clelia/0000-0003-0740-5863 NR 76 TC 57 Z9 59 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2000 VL 165 IS 1 BP 509 EP 517 PG 9 WC Immunology SC Immunology GA 327WH UT WOS:000087816800065 PM 10861090 ER PT J AU Wang, X Chen, M Wandinger, KP Williams, G Dhib-Jalbut, S AF Wang, X Chen, M Wandinger, KP Williams, G Dhib-Jalbut, S TI IFN-beta-1b inhibits IL-12 production in peripheral blood mononuclear cells in an IL-10-dependent mechanism: Relevance to IFN-beta-1b therapeutic effects in multiple sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEQUENCE-BINDING PROTEIN; GROWTH-FACTOR-BETA; INTERFERON-GAMMA; T-CELLS; INTERLEUKIN-12 PRODUCTION; INTRACELLULAR INFECTION; IMMUNE-RESPONSES; DISEASE-ACTIVITY; VIRAL-INFECTION; DENDRITIC CELLS AB IL-12 is a proinflammatory cytokine secreted by dendritic cells in response to microbial Ags and mitogens, IL-12 is thought to contribute to the pathogenesis of autoimmune diseases such as multiple sclerosis (MS), This is based on studies in experimental allergic encephalomyelitis and the demonstration that PBMC IL-12 production correlates with disease progression in MS. IFN-beta-1b is an effective treatment for MS, which is thought to involve in part inhibition of proinflammatory cytokines. In this study we examined the effect of in vitro treatment with IFN-beta-1b, on mitogen-induced IL-12 production in human PBMC and myelin basic protein-specific T cell lines obtained from healthy donors and MS patients. We demonstrate that IFN-beta-1b significantly inhibits inducible IL-12 p40 up to 80% and biologically active IL-12 p70 up to 70% beginning at a dose of 10 IU/ml. This inhibition is IL-10 dependent, as it could be blocked by anti-IL-10 but not anti-IL-4 or control Abs, Thus, endogenously produced IL-10 is a required cofactor for the IFN-beta-1b inhibitory effect on IL-12 to occur, We conclude that IFN-beta-1b has a profound inhibitory effect on PBMC IL-12 production in vitro, and that this effect is IL-10 dependent. These findings are potentially relevant to the therapeutic mechanism of IFN-beta-1b in MS. C1 Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Berlex Labs Inc, Richmond, CA 94806 USA. RP Dhib-Jalbut, S (reprint author), Univ Maryland Hosp, Dept Neurol, 22 S Greene St,N4w46, Baltimore, MD 21201 USA. FU NINDS NIH HHS [K24NS02082-01] NR 47 TC 74 Z9 77 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2000 VL 165 IS 1 BP 548 EP 557 PG 10 WC Immunology SC Immunology GA 327WH UT WOS:000087816800070 PM 10861095 ER PT J AU Stewart, JH Rosenberg, SA AF Stewart, JH Rosenberg, SA TI Long-term survival of anti-tumor lymphocytes generated by vaccination of patients with melanoma with a peptide vaccine SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE melanoma; g209-2M ID LOCAL RADIATION-THERAPY; BREAST-CANCER; T-CELLS; MEMORY; POPULATION AB Immunization with the modified gp100 melanoma peptide gp100:109-217 (210M) in Incomplete Freund's Adjuvant (IFA) results in the generation of antipeptide and antitumor lymphocytes in the patients' circulation. In this study, the authors have evaluated the persistence of these immune cells. Reactivity against the native peptide persisted for 138 to 403 days after immunization. Reactivity also persisted in three of five patients that received external beam radiotherapy and in both patients who received systemic chemotherapy after the completion of peptide immunization. Thus, immune lymphocytes with anti gp100:209-217 peptide activity appear to persist for prolonged periods after vaccination with modified peptide in IFA. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. FU NCI NIH HHS [K08 CA131482] NR 13 TC 6 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2000 VL 23 IS 4 BP 401 EP 404 DI 10.1097/00002371-200007000-00002 PG 4 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 332NB UT WOS:000088079400002 PM 10916748 ER PT J AU Nielsen, MB Kirkin, AF Loftus, D Nissen, MH Rivoltini, L Zeuthen, J Geisler, C Odum, N AF Nielsen, MB Kirkin, AF Loftus, D Nissen, MH Rivoltini, L Zeuthen, J Geisler, C Odum, N TI Amino acid substitutions in the melanoma antigen recognized by T cell 1 peptide modulate cytokine responses in melanoma-specific T cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE heteroclitic peptides; cytotoxic T lymphocytes; MART-1; interleukin-10; immunotherapy ID IN-VITRO; TUMOR; CLONES; INTERLEUKIN-10; REACTIVITY; GENERATION; VACCINE; PROFILE; TYPE-1; CTL AB Single amino acid substitutions in melanoma-associated peptides dramatically enhance T-cell cytotoxicity against target cells presenting the modified peptides (often referred to as heteroclitic peptides). The authors tried to determine whether peptide modifications influence other aspects of T-cell immunity toward malignant melanoma. A heteroclitic peptide, E26F, with an E to F substitution in melanoma antigen recognized by T cell 1 (MART-1)(26-35) triggers an enhanced tyrosine phosphorylation response when compared with the native- and other-modified MART-1 peptides. Similarly, the E26F peptide enhances the production of mRNA for interleukin (IL)-5, IL-10, IL-13, IL-15, and interferon-gamma and significantly enhances release of IL-13 and IL-10 from anti-MART-1 cytotoxic T cells. Another heteroclitic peptide, 1L, with an A to L substitution in MART-1(27-35) also enhances the tyrosine phosphorylation response in anti-MART-1 cytotoxic CD8(+) T cells. Yet, 1L does not enhance the production of T helper cell type 2-like cytokines (IL-10 and IL-13). Together these data show that minor amino acid modifications of immunodominant melanoma peptides profoundly influence the cytokine response in melanoma-specific T cells. C1 Univ Copenhagen, Inst Med Microbiol & Immunol, DK-2200 Copenhagen N, Denmark. Danish Canc Soc, Dept Tumor Cell Biol, Copenhagen, Denmark. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Inst Nazl Tumori, Div Expt Oncol D, Milan, Italy. RP Odum, N (reprint author), Univ Copenhagen, Inst Med Microbiol & Immunol, Panum 22534,Tagensvej 3C, DK-2200 Copenhagen N, Denmark. RI Nissen, Mogens/B-4825-2008; Geisler, Carsten/A-7056-2012; OI Rivoltini, Licia/0000-0002-2409-6225 NR 23 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2000 VL 23 IS 4 BP 405 EP 411 DI 10.1097/00002371-200007000-00003 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 332NB UT WOS:000088079400003 PM 10916749 ER PT J AU McKee, MD Clay, TM Diamond, RA Rosenberg, SA Nishimura, MI AF McKee, MD Clay, TM Diamond, RA Rosenberg, SA Nishimura, MI TI Quantitation of T-cell receptor frequencies by competitive polymerase chain reaction: Dynamics of T-cell clonotype frequencies in an expanding tumor-infiltrating lymphocyte culture SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE T-cell receptor; TIL; melanoma; competitive PCR ID MELANOMA ANTIGEN GP100; BETA GENE USAGE; CLASS-I; LINES; RECOGNITION; REPERTOIRE; DIVERSITY; IDENTIFICATION; MOLECULE; PEPTIDES AB The use of T-cell receptor (TCR) genes as markers for antigen-reactive T cells is dependent on the ability of the TCR genes to rapidly identify antigen-reactive T-cell clonotypes in patient samples. We recently reported a competitive reverse-transcriptase polymerase chain reaction (cRT-PCR) method that can measure the frequency of individual TCRBV subfamilies and clonotypes in mixed lymphocyte populations more accurately than other semiquantitative PCR assays. However, it is impractical to measure changes in the absolute frequency of each TCRBV subfamily to identify those T cells with increasing frequency after antigen stimulation in vivo or in vitro. Therefore, we have modified our cRT-PCR method to more rapidly identify expanding T-cell populations by combining all of the TCRBV subfamily-specific competitors into a single sample to determine the relative abundance of each TCRBV subfamily. Using an expanding TIL 620 culture, we identified four TCRBV (BV2, BV12. BV17 and BV23) subfamilies that expanded over a 23-day period. These subfamilies accounted for 23% of the T cells in the day 35 culture and increased to 57%, 92%, and 80% of the days 44, 51, and 58 cultures respectively. Analysis of DNA sequences demonstrated that the observed expansion was caused primarily by a single clonotype within each subfamily. T cells expressing BV17 and BV23 recognized gp100 and MART-1 respectively. Therefore, this cRT-PCR method can detect expanding T-cell populations based solely on their TCRBV subfamily expression. Furthermore,T-cell expansion in a mixed TV. population was a good predictor of antigen reactivity. C1 Univ Chicago, Med Ctr, Dept Surg, Chicago, IL 60637 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. RP Nishimura, MI (reprint author), Univ Chicago, Med Ctr, Dept Surg, 5841 S Maryland Ave,MC 5093, Chicago, IL 60637 USA. NR 47 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2000 VL 23 IS 4 BP 419 EP 429 DI 10.1097/00002371-200007000-00005 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 332NB UT WOS:000088079400005 PM 10916751 ER PT J AU Hassan, R Viner, JL Wang, QC Margulies, I Kreitman, RJ Pastan, I AF Hassan, R Viner, JL Wang, QC Margulies, I Kreitman, RJ Pastan, I TI Anti-tumor activity of K1-LysPE38QQR, an immunotoxin targeting mesothelin, a cell-surface antigen overexpressed in ovarian cancer and malignant mesothelioma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE monoclonal antibody; immunotoxin; ovarian cancer; mesothelioma; mesothelin ID MONOCLONAL-ANTIBODY; PSEUDOMONAS EXOTOXIN; K1; LYMPHOMA; TOXIN; MICE AB Mesothelin, a differentiation antigen, is a 40-kD glycosylphosphatidylinositol-linked cell-surface glycoprotein, that is present on the surface of normal mesothelium and is overexpressed in many patients with epithelial ovarian cancer and malignant mesotheliomas. Monoclonal antibody K1 is a murine immunoglobulin G1 that recognizes mesothelin. LysPE38QQR is a truncated form of Pseudomonas exotoxin that lacks the cell-binding domain, but retains the translocation and adenosine diphosphate-ribosylation domains. It has a single lysine residue near the amino terminus that is available for conjugation to antibodies. To prevent chemical conjugation of the antibody to lysine residues at the C-terminus of Pseudomonas exotoxin, the two lysine residues at positions 590 and 606 were mutated to glutamine, and the lysine residue at position 613 was mutated to arginine. Monoclonal antibody K1 was chemically conjugated with LysPE38QQR, by modifying the antibody with sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate and coupling it with SPDP N-succinimidyl 3-(2-pyridyldithio)propionate-modified LysPE38QQR. The resulting immunotoxin K1-LysPE38QQR was highly toxic to A431-K5 cells (a human epidermoid carcinoma cell line transfected with a mesothelin expression plasmid) with a half-maximal inhibitory concentration of 3-6 ng/mL. The immunotoxin had negligible activity against A431 cells, which do not express mesothelin (median inhibitory concentration > 100 ng/mL). This immunotoxin also caused complete regression of turners in nude mice that received xenografts of mesothelin-positive human carcinomas. These results show that immunotoxins directed against mesothelin are a therapeutic option that merits further investigation for the treatment of ovarian cancer and malignant mesotheliomas. C1 NCI, Mol Biol Lab, Div Canc Biol, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Canc Biol, NIH, 37-4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 23 TC 48 Z9 48 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2000 VL 23 IS 4 BP 473 EP 479 DI 10.1097/00002371-200007000-00011 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 332NB UT WOS:000088079400011 PM 10916757 ER PT J AU Panelli, MC Wunderlich, J Jeffries, J Wang, E Mixon, A Rosenberg, SA Marincola, FM AF Panelli, MC Wunderlich, J Jeffries, J Wang, E Mixon, A Rosenberg, SA Marincola, FM TI Phase 1 study in patients with metastatic melanoma of immunization with dendritic cells presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100 SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE melanoma antigen vaccination; anti-tumor response; intravenous administration; patient monitoring ID TUMOR-INFILTRATING LYMPHOCYTES; IN-VITRO; T-LYMPHOCYTES; ANTITUMOR IMMUNITY; SYNTHETIC PEPTIDES; MULTIPLE EPITOPES; PERIPHERAL-BLOOD; REACTIVE CTL; IDENTIFICATION; RECOGNITION AB Dendritic cells (DCs) have been shown to enhance anti-tumor immune responses in several preclinical models. Furthermore, DC-like function can be elicited from peripheral blood monocytes cultured in vitro with interleukin-4 and granulocyte-macrophage colony-stimulating factor. For this reason, a phase 1 study was initiated at the Surgery Branch of the National Cancer Institute to test the toxicity and biological activity of the intravenous administration of peripheral blood monocyte-derived DCs. The DCs were generated by 5- to 7-day incubation in interleukin-4 (1,000 U/mL) and granulocyte-macrophage colony-stimulating factor (1,000 U/mL) of peripheral blood monocytes obtained by leukapheresis. Before administration, the DCs were pulsed separately with the HLA-A*0201-associated melanoma epitopes MART-1(27-35) and gp-100-209-2M. The DCs were administered four times at 3-week intervals. A first cohort of patients (n = 3) was treated with 6 x 10(7) DCs and a second cohort (n = 5) with 2 x 10(8) DCs (in either case, one half of the DCs were pulsed with MART-1(27-35) and the other half was pulsed with gp-100-209-2M). In a final cohort under accrual (n = 2)2 x 10(8) DCS were administered in combination with interleukin-2 (720,000 IU/kg every 8 hours). The recovery of DCs after in vitro culture ranged from 3% to 35% (mean, 15%) of the original peripheral blood monocytes. Administration of DCs caused no symptoms at any of the doses, and the concomitant administration of interleukin-2 did not cause toxicity other than that expected for interleukin-2 alone. Monitoring of patients' cytotoxic T lymphocyte reactivity before and after treatment revealed enhancement of cytotoxic T lymphocyte reactivity only in one of five patients tested. Of seven patients evaluated for response, one had a transient partial response with regression of pulmonary and cutaneous metastases. A relatively large number of DCs can be safely administered intravenously. The poor clinical outcome of this study perhaps could be explained by the type of protocol used for DC maturation: the route of administration, or both. For this reason, this clinical protocol was interrupted prematurely, whereas other strategies for DC preparation and route of administration are being investigated at the authors' institution. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B56,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. NR 39 TC 123 Z9 126 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2000 VL 23 IS 4 BP 487 EP 498 DI 10.1097/00002371-200007000-00013 PG 12 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 332NB UT WOS:000088079400013 PM 10916759 ER PT J AU Groll, AH Giri, N Petraitis, V Petraitiene, R Candelario, M Bacher, JS Piscitelli, SC Walsh, TJ AF Groll, AH Giri, N Petraitis, V Petraitiene, R Candelario, M Bacher, JS Piscitelli, SC Walsh, TJ TI Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID COLLOIDAL DISPERSION; CRYPTOCOCCAL MENINGITIS; FUNGAL-INFECTIONS; PULMONARY ASPERGILLOSIS; MURINE CRYPTOCOCCOSIS; LIPOSOMAL FORMULATION; TISSUE DISTRIBUTION; AMBISOME; THERAPY; RABBITS AB The central nervous system (CNS) distribution and antifungal efficacy of all 4 approved formulations of amphotericin B (AmB) were investigated in a rabbit model of hematogenous Candida albicans meningoencephalitis. Treatment with AmB deoxycholate (1 mg/kg/day) or Liposomal AmB (5 mg/kg/day) yielded the highest peak plasma concentration (C-max), area under concentration versus time curve from zero to 24 h (AUC(0-24)), and time during dosing level tau (T-tau) > minimum inhibitory complex (MIC) values and led to complete eradication of C. albicans from brain tissue (P < .05 vs, untreated controls). By comparison, AmB colloidal dispersion and AmB lipid complex (5 mg/kg/day each) were only partially effective (not significant vs. untreated controls). There was a strong correlation of C-max, AUC(0-24), C-max/MIC, AUC(0-24)/MIC, and T-tau > MIC with clearance of C. albicans from brain tissue (P less than or equal to .0002), Although pharmacodynamic parameters derived from the MIC of free AmB were highly predictive of antifungal efficacy, parameters derived from MICs of individual formulations were not predictive. AmB deoxycholate and liposomal AmB had the greatest antifungal efficacy. This activity was concentration and time dependent. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Pharmacokinet Res Lab, Dept Pharm, Bethesda, MD 20892 USA. NIH, Natl Ctr Res Resources, Surg Serv, Vet Resources Program, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 59 TC 191 Z9 195 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL PY 2000 VL 182 IS 1 BP 274 EP 282 DI 10.1086/315643 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 340FK UT WOS:000088522300034 PM 10882607 ER PT J AU Havlir, DV Tierney, C Friedland, GH Pollard, RB Smeaton, L Sommadossi, JP Fox, L Kessler, H Fife, KH Richman, DD AF Havlir, DV Tierney, C Friedland, GH Pollard, RB Smeaton, L Sommadossi, JP Fox, L Kessler, H Fife, KH Richman, DD TI In vivo antagonism with zidovudine plus stavudine combination therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS ID HUMAN-IMMUNODEFICIENCY-VIRUS; PHOSPHORYLATION IN-VITRO; HIV; 2',3'-DIDEOXY-2',3'-DIDEHYDROTHYMIDINE; REPLICATION; RIBAVIRIN AB Human immunodeficiency virus (HIV)-infected subjects receiving zidovudine were randomized either to add stavudine (d4T) or didanosine (ddI) to their current regimen or to switch to ddI or d4T monotherapy, After 16 weeks of therapy, the mean reduction in HIV RNA from baseline was 0.14 log(10) copies/mL in patients receiving d4T or zidovudine plus d4T. In subjects receiving ddI or ddI plus zidovudine, reductions were 0.39 and 0.56 log(10), respectively. CD4 cell counts remained stable or showed modest increases in all arms except the zidovudine plus d4T arm. Patients receiving zidovudine plus d4T showed progressive declines in CD4 cell counts with a median of 22 cells/mm(3) below baseline by 16 weeks. Examination of intracellular levels of d4T-triphosphate in 6 subjects was consistent with previous in vitro studies demonstrating pharmacologic antagonism between zidovudine and d4T. Analysis of these data suggests that zidovudine and d4T should not be prescribed in combination and that ddI provides greater antiviral activity than d4T in zidovudine-treated patients. C1 Univ Calif San Diego, San Diego, CA 92103 USA. San Diego VA Med Ctr, San Diego, CA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Yale Univ, Sch Med, New Haven, CT 06510 USA. Univ Texas, Galveston, TX 77555 USA. Univ Alabama, Birmingham, AL 35294 USA. NIH, Div AIDS, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Indiana Univ, Med Ctr, Indianapolis, IN 46204 USA. RP Havlir, DV (reprint author), 150 W Washington St,Ste 100, San Diego, CA 92103 USA. NR 14 TC 65 Z9 67 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL PY 2000 VL 182 IS 1 BP 321 EP 325 DI 10.1086/315683 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 340FK UT WOS:000088522300043 PM 10882616 ER PT J AU Yang, D Chen, Q Chertov, O Oppenheim, JJ AF Yang, D Chen, Q Chertov, O Oppenheim, JJ TI Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE alpha-defensins; chemotaxis; T lymphocytes ID ANTIMICROBIAL PEPTIDES; CHEMOKINE RECEPTORS; HOST-DEFENSE; CUTTING EDGE; IN-VIVO; ACTIVATION; IMMUNITY; MEMORY; COMPONENTS; MATURATION AB Defensins, a family of cationic, structurally related, antimicrobial peptides, contribute to host defense by disrupting the cytoplasmic membrane of microbes, Here we show that human neutrophil defensins selectively induce the migration of human CD4(+)/CD45RA(+) naive and CD8(+), but not CD4(+)/CD45RO(+) memory, T cells. Moreover, hunan neutrophil defensins are chemotactic for immature human dendritic cells derived from either CD34(+) progenitors or peripheral blood monocytes. Upon maturation induced by treatment with tumor necrosis factor alpha (TNF-alpha), dendritic cells lose their responsiveness to human neutrophil defensins. The chemotactic effect of human neutrophil defensins on both T and dendritic cells is pertussis toxin-sensitive suggesting that a G(i alpha) protein-coupled receptor is responsible. Human neutrophil defensins are also chemotactic for immature murine dendritic cells, These data suggest that, in addition to their antimicrobial role, human neutrophil defensins also contribute to adaptive immunity by mobilizing T cells and dendritic cells. C1 NCI, Frederick Canc Res & Dev Ctr, DBS, LMI,SAIC, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, DBS, LMI,SAIC, Bldg 560,Room 21-89, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 42 TC 328 Z9 349 U1 2 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2000 VL 68 IS 1 BP 9 EP 14 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332NP UT WOS:000088080600002 PM 10914484 ER PT J AU Sayers, TJ Brooks, AD Seki, N Smyth, MJ Yagita, H Blazar, BR Malyguine, AM AF Sayers, TJ Brooks, AD Seki, N Smyth, MJ Yagita, H Blazar, BR Malyguine, AM TI T cell lysis of murine renal cancer: multiple signaling pathways for cell death via Fas SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Fas ligand; cell-rnediated cytotoxicity; Renca cells; kidney cancer ID FLICE-INHIBITORY PROTEIN; TUMOR-NECROSIS-FACTOR; MEDIATED CYTOTOXICITY; IN-VIVO; APOPTOSIS; RECEPTOR; ACTIVATION; DOMAIN; INVOLVEMENT; SENSITIVITY AB Activated T cells lyse the murine renal cancer Renca. We have examined the mechanism of tumor cell lysis with the use of T tells derived from C57BL/6, BALB/c, B6.gld, and B6.Pfp(-/-) mice, C57BL/6 and BALB/c T cells can lyse Renca cells through the use of both granule- and Fas Ligand (FasL)-mediated pathways. However, B6.gld T cells predominantly use granule-mediated killing, whereas B6.Pfp(-/-) T cells use Fast. The lysis of Renca by Pfp(-/-) T cells is only partially inhibited by the caspase inhibitor ZVAD-FMK, suggesting that caspase-independent signaling is also important for Renca cell lysis, When the reactive oxygen scavenger butylated hydroxyanisole was used alone or hi combination with ZVAD-FMK a substantial reduction of Renca lysis was observed. Therefore, the caspase-independent generation of reactive oxygen intermediates in Renca after Fas triggering contributes to the lysis of these cells. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Ckin Serv Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Expt Immunol, DBS, Frederick, MD 21702 USA. Austin Res Inst, Cellular Cytotox Lab, Heidelberg, Vic, Australia. Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. Univ Minnesota, Dept Pediat, Div Bone Marrow Transplantat, Minneapolis, MN 55455 USA. RP Sayers, TJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Ckin Serv Program, Bldg 560,Room 31-30, Frederick, MD 21702 USA. RI Sayers, Thomas/G-4859-2015; Smyth, Mark/H-8709-2014 OI Smyth, Mark/0000-0001-7098-7240 FU PHS HHS [N01-C0-56000] NR 28 TC 27 Z9 27 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2000 VL 68 IS 1 BP 81 EP 86 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332NP UT WOS:000088080600011 PM 10914493 ER PT J AU Shakhov, AN Lyakhov, IG Tumanov, AV Rubtsov, AV Drutskaya, LN Marino, MW Nedospasov, SA AF Shakhov, AN Lyakhov, IG Tumanov, AV Rubtsov, AV Drutskaya, LN Marino, MW Nedospasov, SA TI Gene profiling approach in the analysis of lymphotoxin and TNF deficiencies SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article; Proceedings Paper CT 8th Conference of the International-Cytokine-Society CY DEC 05-10, 1999 CL HILTON HEAD ISL, SOUTH CAROLINA SP Int Cytokine Soc DE gene arrays; subtractive cloning; knockout mice; spleen ID TUMOR-NECROSIS-FACTOR; LYMPHOID ORGAN DEVELOPMENT; B-CELL; ALPHA; MICE; EXPRESSION; RESPONSES; CLONING; TISSUES; IMMUNE AB Mice with combined lymphotoxin-alpha (LT alpha) and tumor necrosis factor (TNF) deficiencies show defects hi the structure of peripheral lymphoid organs such as spleen, lymph nodes, and gut-associated lymphoid tissues. To identify genes associated with this defective phenotype in spleen. we applied a gene profiling approach, including subtractive cloning and gene array hybridizations, to mice with combined TNF/LT deficiency. The differentially expressed genes identified by these techniques was then evaluated by Northern blot analysis for splenic expression ill knockout mice with single LT alpha or single TNF deficiency. Most of the genes detected in this analysis are directly or indirectly associated with disrupted LT and not TNF signaling. C1 NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Mol Immunoregulat, Frederick, MD 21702 USA. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Mol Immunol, Moscow, Russia. Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia. Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York Branch, New York, NY 10021 USA. RP Shakhov, AN (reprint author), NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC Frederick, Bldg 560,Rm 31-33, Frederick, MD 21702 USA. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 FU NCI NIH HHS [N01-CO-56000] NR 24 TC 18 Z9 19 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2000 VL 68 IS 1 BP 151 EP 157 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332NP UT WOS:000088080600021 PM 10914503 ER PT J AU Levin, I Leapman, RD Kaiser, DL AF Levin, I Leapman, RD Kaiser, DL TI Microstructure and chemistry of nonstoichiometric (Ba,Sr)TiO3 thin films deposited by metalorganic chemical vapor deposition SO JOURNAL OF MATERIALS RESEARCH LA English DT Article ID DIELECTRIC-PROPERTIES; ELECTRICAL-PROPERTIES; BARIUM-TITANATE; (BA; ACCOMMODATION; MOCVD AB The microstructure and chemistry of (Ba,Sr)TiO3 thin films deposited on Pt/SiO2/Si substrates by metalorganic chemical Vapor deposition were studied using high-resolution transmission electron microscopy and quantitative spectrum imaging in electron energy loss spectroscopy. The grain boundaries in all films with overall Ti content ranging from 50.7% to 53.4% exhibit a significant increase in Ti/Ba ratio as compared to the grain interiors. The results suggest that the deviations of Ti/(Ba + Sr) ratio from the stoichiometric value of unity are accommodated by the creation of Ba/Sr vacancies, which segregate to the grain boundary regions. The films with Ti contents equal to or greater than 52% additionally contained an amorphous Ti-rich phase at some grain boundaries and multiple grain junctions; the amount of this phase increases with increasing overall Ti content. The analysis indicates that the amorphous phase can only partially account for the significant drop in dielectric permittivity accompanying increases in the Ti/(Ba + Sr) ratio. C1 NIST, Div Ceram, Gaithersburg, MD 20899 USA. NIH, Off Res Serv, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. RP Levin, I (reprint author), NIST, Div Ceram, Gaithersburg, MD 20899 USA. RI Levin, Igor/F-8588-2010 NR 20 TC 12 Z9 12 U1 0 U2 0 PU MATERIALS RESEARCH SOCIETY PI WARRENDALE PA 506 KEYSTONE DR, WARRENDALE, PA 15086 USA SN 0884-2914 J9 J MATER RES JI J. Mater. Res. PD JUL PY 2000 VL 15 IS 7 BP 1433 EP 1436 DI 10.1557/JMR.2000.0207 PG 4 WC Materials Science, Multidisciplinary SC Materials Science GA 330NK UT WOS:000087968000002 ER PT J AU Killeen, GF Foy, BD Shahabuddin, M Roake, W Williams, A Vaughan, TJ Beier, JC AF Killeen, GF Foy, BD Shahabuddin, M Roake, W Williams, A Vaughan, TJ Beier, JC TI Tagging bloodmeals with phagemids allows feeding of multiple-sample arrays to single cages of mosquitoes (Diptera : Culicidae) and the recovery of single recombinant antibody fragment genes from individual insects SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE monoclonal antibody; phage display; scFv; Anopheles gambiae; screening; transmission blocking ID ANOPHELES-GAMBIAE; DISPLAY; TRANSFORMATION; SURVIVAL; BACTERIA; DISEASE; VECTORS; TOXIN AB A recombinant single-chain variable-region human antibody fragment (scFv) was expressed in Escherichia coli, extracted in hypertonic sucrose, mixed directly with blood and fed to Anopheles gambiae Giles mosquitoes. When E. coli containing the phagemids that encode these scFv were included in bloodmeals, phagemids could be recovered fr om the mosquito midgut for up to 3 d after feeding. Furthermore, large an arrays of such gene-tagged scFv-containing bloodmeals could be fed to cages of mosquitoes using microtiter plates. Arrays of phagemids with and without an antibody insert were fed to single cages of mosquitoes to test whether individual mosquitoes fed from single wells of such arrays, Phagemids were recovered from 95% of blood-fed females and >80% of these phagemids were monoclonal. Therefore, it is possible to feed multiple sample arrays of recombinant proteins to single cages of mosquitoes and to recover the genetic material that encodes for only one of the array elements from individual mosquitoes. This demonstration indicates that multiple-sample feeding and recovery strategies are feasible and may represent a viable strategy for future rapid screening of biologically active genes, gene products or microorganisms in live arthropods. C1 Tulane Univ, Med Ctr, Sch Publ Hlth & Trop Med, Dept Trop Med,Ctr Infect Dis, New Orleans, LA 70112 USA. Tulane Univ, Med Ctr, Program Mol & Cellular Biol, New Orleans, LA 70112 USA. NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Cambridge Antibody Technol Ltd, Melbourne SG8 6JJ, Cambs, England. RP Killeen, GF (reprint author), Tulane Univ, Med Ctr, Sch Publ Hlth & Trop Med, Dept Trop Med,Ctr Infect Dis, 1501 Canal St, New Orleans, LA 70112 USA. RI Foy, Brian/E-6230-2017 OI Foy, Brian/0000-0002-9117-203X FU NIAID NIH HHS [R01-(AI)29000] NR 22 TC 5 Z9 5 U1 0 U2 0 PU ENTOMOL SOC AMER PI LANHAM PA 9301 ANNAPOLIS RD, LANHAM, MD 20706 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD JUL PY 2000 VL 37 IS 4 BP 528 EP 533 DI 10.1603/0022-2585-37.4.528 PG 6 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 359RF UT WOS:000089625300005 PM 10916292 ER PT J AU Mukhopadhyay, J Ghosh, K AF Mukhopadhyay, J Ghosh, K TI Morphology of larval antennae and mouthparts of four Indian sand flies (Diptera : Psychodidae) by scanning electron microscopy SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Phlebotomus; Sergentomyia; Indian sand flies; larvae; mouthparts; antenna AB The mouthparts and antennae of the fourth-instar larvae of four sand fly species were studied using scanning electron microscopy. The morphology of the clypeus, labrum, mandible, maxilla, mentum, and antennae were compared for Phlebotomus argentipes Annandale & Brunetti, P. papatasin (Scopoli), Sergentomyia babu babu (Annandale), and S. bailyi (Sinton). Most of structures exhibited species-specific features, particularly the characteristics of the antennae. P. papatasin larvae had heart-shaped antennae, a long mandible, stout maxilla, and a heavy mentum with large teeth. In contrast, P. argentipes larvae had dumbbell-shaped antennae and a singular club-shaped labrum. The antennae of S. b. babu were ovoid, whereas those of S. bailyi were elliptical. The labrum of S. b. babu was lanceolate, whereas that of S, bailyi was rounded and exhibited a small, thick projection with several folds. The teeth of the mentum of both Sergentomyia species were shelter than those of the Phlebotomus species. Species-specific differences in the morphology of larval mouthparts and antennae indicate that it may not always be necessary to rely on adult morphology to identify sympatric phlebotomines. C1 Univ Calcutta, Dept Zool, Calcutta 700019, W Bengal, India. Bose Inst, Reg Sophisticated Instrumentat Ctr, Scanning Electron Microscop Unit, SEM Facil, Calcutta 700009, W Bengal, India. NCI, Immunobiol Lab, NIH, Frederick, MD 21702 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. RP Mukhopadhyay, J (reprint author), Univ Calcutta, Dept Zool, 35 Ballygunge Circular Rd, Calcutta 700019, W Bengal, India. RI pasuvalingam, visha/B-5717-2012 NR 24 TC 4 Z9 4 U1 0 U2 5 PU ENTOMOL SOC AMER PI LANHAM PA 9301 ANNAPOLIS RD, LANHAM, MD 20706 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD JUL PY 2000 VL 37 IS 4 BP 575 EP 580 DI 10.1603/0022-2585-37.4.575 PG 6 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 359RF UT WOS:000089625300012 PM 10916299 ER PT J AU Kovbasnjuk, ON Spring, KR AF Kovbasnjuk, ON Spring, KR TI The apical membrane glycocalyx of MDCK cells SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE pH; sialic acid; neuraminidase; lectin; microenvironment ID LATERAL INTERCELLULAR SPACES; SURFACE PH; GUINEA-PIG; SIALIC ACIDS; RAT; GLYCOPROTEINS; MICROCLIMATE; DEPENDENCE; EPITHELIUM; DIFFUSION AB The microenvironment near the apical membrane of MDCK cells was studied by quantitation of the fluorescence of wheat germ agglutin attached to fluorescein (WGA). WGA was shown to bind to sialic acid residues attached to galactose at the alpha-2,3 position in the glycocalyx on the apical membrane. Young MDCK cells (5-8 days after splitting) showed a patchy distribution of WGA at stable sites that returned to the same locations after removal of sialic acid residues by neuraminidase treatment. Other lectins also showed stable binding to patches on the apical membrane of young cells. The ratio of WGA fluorescence emission at two excitation wavelengths was used to measure near-membrane pH. The near-membrane pH was markedly acidic to the pH 7.4 bathing solution in both young and older cells (13-21 days after splitting). Patches on the apical membrane of young cells exhibited a range of near-membrane pH values with a mean +/- SEM of 6.86 +/- 0.04 (n = 121) while the near-membrane pH of older cells was 6.61 +/- 0.04 (n = 120) with a uniform WGA distribution. We conclude that the distribution of lectin binding sites in young cells reflects the underlying nonrandom location of membrane proteins in the apical membrane and that nonuniformities in the pH of patches may indicate regional differences in membrane acid-base transport as well as in the location of charged sugars in the glycocalyx. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Spring, KR (reprint author), Johns Hopkins Univ, Dept Med, Div Gastroenterol, Baltimore, MD 21218 USA. NR 28 TC 30 Z9 30 U1 0 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 JUL 1 PY 2000 VL 176 IS 1 BP 19 EP 29 DI 10.1007/s002320001072 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 332PB UT WOS:000088081700002 PM 10882425 ER PT J AU Rashid, MA Gustafson, KR Boswell, JL Boyd, MR AF Rashid, MA Gustafson, KR Boswell, JL Boyd, MR TI Haligramides A and B, two new cytotoxic hexapeptides from the marine sponge Haliclona nigra SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ALKALOIDS; TULEARENSIS AB Bioassay-guided fractionation of a cytotoxic aqueous extract of the sponge Haliclona nigra provided two new cyclic hexapeptides, haligramides A (1) and B (2), in addition to the known peptide, waiakeamide (3). The structures of peptides 1 and 2 were elucidated by extensive NMR analyses and by comparison of their spectral data with those of waiakeamide (3). The identity of haligramide A (1) was confirmed by its oxidative conversion to waiakeamide (3). Further structural confirmation was provided by oxidation of peptides 1, 2, and 3 to the common bis-sulfone derivative 4. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Bldg 1052,Room 121, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 21 TC 35 Z9 37 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 2000 VL 63 IS 7 BP 956 EP 959 DI 10.1021/np000051+ PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 340XN UT WOS:000088562000014 PM 10924173 ER PT J AU Pettit, GR Lippert, JW Herald, DL Hamel, E Pettit, RK AF Pettit, GR Lippert, JW Herald, DL Hamel, E Pettit, RK TI Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1,2-dihydroxy-1-(2 ',3 '-dihydroxy-4 '-methoxyphenyl)-2-(3 '',4 '',5 ''-trimethoxyphenyl)-ethane SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ANTIMITOTIC AGENTS; COMBRETUM-CAFFRUM; TUBULIN POLYMERIZATION; NATURAL-PRODUCTS; COLCHICINE SITE; CELL-GROWTH; CURACIN-A; ANALOGS; POTENT; DIHYDROXYLATION AB The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S,)-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell Line with ED(50) values of 3.9 and 2.9 mu g/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S,S)7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 mu g/mL). C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Pettit, GR (reprint author), Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. FU NCI NIH HHS [CA44344-6-11] NR 49 TC 38 Z9 39 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 2000 VL 63 IS 7 BP 969 EP 974 DI 10.1021/np0000623 PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 340XN UT WOS:000088562000017 PM 10924176 ER PT J AU Wei, HF Leeds, P Chen, RW Wei, WL Leng, Y Bredesen, DE Chuang, DM AF Wei, HF Leeds, P Chen, RW Wei, WL Leng, Y Bredesen, DE Chuang, DM TI Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: Characterization and protection by dantrolene and Bcl-2 overexpression SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 3-hydroxykynurenine; apoptosis; hydrogen peroxide; dantrolene; Bcl-2; neuroprotection ID RAT ALVEOLAR MACROPHAGES; RETICULUM CALCIUM-PUMP; NITRIC-OXIDE SYNTHASE; METHYL-D-ASPARTATE; INTRACELLULAR CALCIUM; CELL-DEATH; HUNTINGTONS-DISEASE; TRYPTOPHAN-METABOLITES; ENDOGENOUS NEUROTOXIN; CYTOCHROME-C AB We have studied neurotoxicity induced by pharmacological concentrations of 3-hydroxykynure-nine (3-HK), an endogenous toxin implicated in certain neurodegenerative diseases, in cerebellar granule cells, PC12 pheochromocytoma cells, and GT1-7 hypothalamic neurosecretory cells. In all three cell types, the toxicity was induced in a dose-dependent manner by 3-HK at high micromolar concentrations and had features characteristic of apoptosis, including chromatin condensation and internucleosomal DNA cleavage. In cerebellar granule cells, the 3-HK neurotoxicity was unaffected by xanthine oxidase inhibitors but markedly potentiated by superoxide dismutase and its heme-like mimetic, MnTBAP [manganese(III) tetrakis(benzoic acid)porphyrin chloride]. Catalase blocked 3-HK neurotoxicity in the absence and presence of superoxide dismutase or MnTBAP. The formation of H2O2 was demonstrated in PC12 and GT1-7 cells treated with 3-HK, by measuring the increase in the fluorescent product, 2',7'-dichlorofluorescein. In both PC12 and cerebellar granule cells, inhibitors of the neutral amino acid transporter that mediates the uptake of 3-HK failed to block 3-HK toxicity. However, their toxicity was slightly potentiated by the iron chelator, deferoxamine. Taken together, our results suggest that neurotoxicity induced by pharmacological concentrations of 3-HK in these cell types is mediated primarily by H2O2, which is formed most likely by auto-oxidation of 3-HK in extracellular compartments. 3-HK-induced death of PC12 and GT1-7 cells was protected by dantrolene, an inhibitor of calcium release from the endoplasmic reticulum. The protection by dantrolene was associated with a marked increase in the protein level of Bcl-2, a prominent antiapoptotic gene product. Moreover, overexpression of Bet-ii in GT1-7 cells elicited by gene transfection suppressed 3-HK toxicity. Thus, dantrolene may elicit its neuroprotective effects by mechanisms involving up-regulation of the level and function of Bcl-2 protein. C1 NIMH, Mol Neurobiol Sect, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Biol Psychiat Branch, NIH, Bldg 10,Room 3N212,10 Ctr Dr MSC 1272, Bethesda, MD 20892 USA. NR 63 TC 63 Z9 63 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2000 VL 75 IS 1 BP 81 EP 90 DI 10.1046/j.1471-4159.2000.0750081.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 325CP UT WOS:000087659000011 PM 10854250 ER PT J AU Shippenberg, TS Hen, R He, M AF Shippenberg, TS Hen, R He, M TI Region-specific enhancement of basal extracellular and cocaine-evoked dopamine levels following constitutive deletion of the serotonin(1B) receptor SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE serotonin(1B) receptor knockout mice; serotonin/dopamine interactions; microdialysis; nucleus accumbens; striatum ID LACKING 5-HT1B RECEPTORS; IN-VIVO MICRODIALYSIS; FREELY MOVING RATS; MICE LACKING; NUCLEUS-ACCUMBENS; KNOCKOUT MICE; QUANTITATIVE MICRODIALYSIS; UPTAKE BLOCKERS; RELEASE; STRIATUM AB The behavioral effects of cocaine are enhanced following constitutive deletion of the serotonin(1B) receptor. The neural substrates mediating the enhanced response to cocaine are unknown. The present studies determined whether basal dopamine dynamics or cocaine-evoked dopamine levels are altered in projection areas of mesostriatal or mesoaccumbens dopamine neurons following serotonin(1B) receptor deletion. Male wildtype and serotonin(1B) knockout mice were implanted with microdialysis guide cannulas aimed at the dorsal striatum or nucleus accumbens. The zero net flux method of quantitative microdialysis was used to quantify basal extracellular dopamine concentrations (DA(ext)) and the extraction fraction of dopamine (E-d), which provides an index of dopamine uptake. Conventional microdialysis techniques were used to quantify cocaine (0, 5.0, and 20.0 mg/kg)-evoked dopamine overflow. Basal DA(ext) and E-d did not differ in striatum of wild-type and knockout mice. Similarly, cocaine-stimulated dopamine overflow did not differ between genotype. The basal E-d did not differ in the nucleus accumbens of wild-type and knockout mice. However, DA(ext) was significantly elevated in the nucleus accumbens of knockout mice. Cocaine-evoked dopamine overflow (nM) was also enhanced in the nucleus accumbens of knockout mice. However, the cocaine-induced increase in dopamine levels, relative to basal values, did not differ between genotype. These data demonstrate that deletion of the serotonin(1B) receptor is associated with increases in basal DA(ext) in the nucleus accumbens. This increase is not associated with an alteration in E-d, suggesting increased basal dopamine release in these animals. It is hypothesized that these alterations in presynaptic neuronal activity are a compensatory response to constitutive deletion of the serotonin(1B) receptor and may contribute to the enhanced behavioral effects of psychostimulants observed in knockout mice. C1 NIDA, IRP, Integrat Neurosci Unit, Behav Neurosci Lab,NIH, Baltimore, MD 21224 USA. Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. RP Shippenberg, TS (reprint author), NIDA, IRP, Integrat Neurosci Unit, Behav Neurosci Lab,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 43 TC 42 Z9 42 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2000 VL 75 IS 1 BP 258 EP 265 DI 10.1046/j.1471-4159.2000.0750258.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 325CP UT WOS:000087659000030 PM 10854269 ER PT J AU Guo, ZH Ersoz, A Butterfield, DA Mattson, MP AF Guo, ZH Ersoz, A Butterfield, DA Mattson, MP TI Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: Preservation of glucose and glutamate transport and mitochondrial function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic acid SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; apoptosis; cerebral cortex; glucose-regulated protein; glutamate; heat-shock protein; Huntington's disease; ion; mitochondria; synaptosomes ID PROTECTS HIPPOCAMPAL-NEURONS; MANGANESE SUPEROXIDE-DISMUTASE; HEAT-SHOCK-PROTEIN; OXIDATIVE STRESS; LIPID-PEROXIDATION; CALORIC RESTRICTION; FOOD RESTRICTION; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; PEROXYNITRITE PRODUCTION AB Recent studies have shown that rats and mice maintained on a dietary restriction (DR) regimen exhibit increased resistance of neurons to excitotoxic, oxidative, and metabolic insults in experimental models of Alzheimer's, Parkinson's, and Huntington's diseases and stroke. Because synaptic terminals are sites where the neurodegenerative process may begin in such neurodegenerative disorders, we determined the effects of DR on synaptic homeostasis and vulnerability to oxidative and metabolic insults. Basal levels of glucose uptake were similar in cerebral cortical synaptosomes from rats maintained on DR for 3 months compared with synaptosomes from rats fed ad libitum. Exposure of synaptosomes to oxidative insults (amyloid beta-peptide and Fe2+) and a metabolic insult (the mitochondrial toxin 3-nitropropionic acid) resulted in decreased levels of glucose uptake. Impairment of glucose uptake following oxidative and metabolic insults was significantly attenuated in synaptosomes from rats maintained on DR. DR was also effective in protecting synaptosomes against oxidative and metabolic impairment of glutamate uptake. Loss of mitochondrial function caused by oxidative and metabolic insults, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated in synaptosomes from rats maintained on DR. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from DR rats, consistent with previous data suggesting that the neuroprotective mechanism of DR involves a "preconditioning" effect. Collectively, our data provide the first evidence that DR can alter synaptic homeostasis in a manner that enhances the ability of synapses to withstand adversity. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Chem, Lexington, KY 40536 USA. Univ Kentucky, Ctr Membrane Sci, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr,GRC 4F01, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 59 TC 74 Z9 78 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2000 VL 75 IS 1 BP 314 EP 320 DI 10.1046/j.1471-4159.2000.0750314.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 325CP UT WOS:000087659000037 PM 10854276 ER PT J AU Zhang, JH Lai, ZN Simonds, WF AF Zhang, JH Lai, ZN Simonds, WF TI Differential expression of the G protein beta(5) gene: Analysis of mouse brain, peripheral tissues, and cultured cell lines SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE signal transduction; regulator of G protein signaling proteins; effectors ID ADULT-RAT BRAIN; RGS PROTEINS; GAMMA-SUBUNIT; REGULATORS; COMPLEX; LOCALIZATION; ACTIVATION; RECEPTORS; G-BETA-5; PATHWAYS AB A neurally expressed heterotrimeric G protein beta subunit, G beta(5), has been found to exhibit functional specialization with respect to its interactions with effector targets and G alpha subunits. A splice Variant of G beta(5) that contains an N-terminal 42-residue extension, G beta(5)-long, has been described in the retina. To define better the potential range of its specialized interactions, analysis of G beta(5) gene transcript and protein expression in mouse brain and other tissues and cell lines was performed, Quantification by ribonuclease protection assay of G beta(5) transcript expression in the developing brain demonstrates a fivefold increase that occurs postnatally. Analysis of transcript expression by in situ hybridization and ribonuclease protection assay indicates that the G beta(5) gene is differentially expressed among multiple adult mouse brain regions, including the motor and occipital cortex, the olfactory bulb and associated rhinencephalic structures, hypothalamus, pontine cochlear nuclei, and Purkinje cells in the cerebellum, G beta(5) is also expressed in several cultured cell lines of neuroendocrine origin, including murine alpha T3-1 pituitary gonadotrophs and GT1-7 hypothalamic cells, and rat PC12 pheochromocytoma cells. Immunoblotting of tissue homogenates with antibodies to two peptides common to G beta(5) and G beta(5)-long confirmed expression of G beta(5) in multiple brain regions and in spinal cord and expression of G beta(5)-long in retina. Taken together, these results suggest that the specialized molecular properties of G beta(5) have been adapted to diverse neural functions in the adult brain. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Genet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. NR 33 TC 22 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2000 VL 75 IS 1 BP 393 EP 403 DI 10.1046/j.1471-4159.2000.0750393.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 325CP UT WOS:000087659000046 PM 10854285 ER PT J AU Montuenga, LM Burrell, MA Garayoa, M Llopiz, D Vos, M Moody, T Garcia-Ros, D Martinez, A Villaro, AC Elsasser, T Cuttitta, F AF Montuenga, LM Burrell, MA Garayoa, M Llopiz, D Vos, M Moody, T Garcia-Ros, D Martinez, A Villaro, AC Elsasser, T Cuttitta, F TI Expression of proadrenomedullin derived peptides in the mammalian pituitary: Co-localization of follicle stimulating hormone and proadrenomedullin N-20 terminal peptide-like peptide in the same secretory granules of the gonadotropes SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE adrenomedullin; proadrenomedullin; N-terminal 20 peptide; gonadotropes; pituitary ID STEROIDOGENIC FACTOR-I; ORPHAN NUCLEAR RECEPTOR; ADRENOMEDULLIN GENE; IMMUNOREACTIVE ADRENOMEDULLIN; N-TERMINAL-20 PEPTIDE; HYPOTENSIVE PEPTIDE; PORCINE TISSUE; MESSENGER-RNA; RAT; TRANSCRIPTION AB Expression of proadrenomedullin-derived peptides in the rat, cow and human pituitary was studied by a variety of techniques. Immunocytochemical detection showed a widespread expression of adrenomedullin peptide in the adenohypophysis and the neural lobe, with low expression in the intermediate pituitary. Proadrenomedullin N-20 terminal peptide (PAMP)-immunoreactivity was also present in the anterior pituitary but showed a more marked heterogeneous distribution, with cells going from very strong to negative immunostaining. Lower levels of PAMP were found in the neural lobe. Interestingly, the distribution of adrenomedullin and PAMP immunoreactivity in the anterior pituitary did not completely overlap. In the present study, we concentrated our efforts to determine which cell type of the adenohypophysis expresses PAMP. Paraffin and semithin serial sections immunostained for PAMP and the classical pituitary hormones revealed that a subpopulation of the gonadotropes expresses high levels of PAMP-immunoreactive material. Ultrastructural analysis clearly showed PAMP-immunoreactivity in the follicle stimulating hormone (FSH)-containing large secretory granules of the gonadotropes, suggesting simultaneous secretion of PAMP and FSH by this cell type. Three mouse adenohypophysis-derived cell lines (AtT20, GH3, and alpha T3-1 derived from corticotropes, lacto/somatotropes and gonadotropes, respectively) were also analysed and showed expression of both proadrenomedullin-derived peptides and their mRNA. Functional studies in these three cell lines showed that neither adrenomedullin nor PAMP was able to stimulate cAMP production in our experimental conditions. Taken together, our results support that proadrenomedullin derived peptides are expressed in the pituitary in cell-specific and not overlapping patterns, that could be explained by differences in postranslational processing. Our data showing costorage of PAMP and FSH in the same secretory granules open a way by which PAMP could be involved in the control of reproductive physiology in a coordinated manner with FSH. C1 Univ Navarra, Sch Med, Dept Histol & Pathol, E-31080 Pamplona, Spain. NCI, Dept Cell & Canc Biol, DCS, NIH, Bethesda, MD 20892 USA. USDA ARS, Beltsville, MD 20705 USA. RP Montuenga, LM (reprint author), Univ Navarra, Sch Med, Dept Histol & Pathol, C-Irunlarres 1, E-31080 Pamplona, Spain. RI Martinez, Alfredo/A-3077-2013; Burrell, Maria/J-2570-2012 OI Martinez, Alfredo/0000-0003-4882-4044; Burrell, Maria/0000-0002-8018-764X NR 45 TC 24 Z9 24 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD JUL PY 2000 VL 12 IS 7 BP 607 EP 617 PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 321XU UT WOS:000087481300003 PM 10849205 ER PT J AU Li, M Dalakas, MC AF Li, M Dalakas, MC TI Expression of human IAP-like protein in skeletal muscle: a possible explanation for the rare incidence of muscle fiber apoptosis in T-cell mediated inflammatory myopathies SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE hILP; apoptosis; myopathies ID INCLUSION-BODY MYOSITIS; MUSCULAR-DYSTROPHY; CYTOCHROME-C; DEATH; DERMATOMYOSITIS; POLYMYOSITIS; FAMILY; CPP32; FAS AB In Polymyositis (PM) and sporadic Inclusion Body Myositis (s-IBM), the CD8(+) cytotoxic T cells invade the muscle membrane and release perforin and granzyme B to induce cell death. Although granzyme B is a direct activator of executioner caspases, there is no convincing evidence of apoptosis in the muscle fibers of these patients. To search for an explanation, we examined the muscle expression of the human IAP-Like Protein (hILP), an evolutionarily conserved cell death suppressor, that exerts major anti-apoptotic effects by inhibiting the executioner caspases. Muscle biopsy specimens from patients with inflammatory myopathies and controls were studied with: (a) immunocytochemistry using antibodies against hILP and caspase-3 in single and double-labeled confocal laser microscopy; (b) immunoblotting of muscle extracts immunoreacted with anti-hILP antibodies; and (c) subcellular fractionation of muscle lysates immunoreacted with antibodies against hILP. We found that hILP is expressed on the sarcolemmal region and co-localizes with dystrophin. Caspase-3 is undetectable. Subcellular fractionation of the muscle specimens confirmed that hILP is a membrane-associated protein. By immunoblotting, the 57 kD hILP was abundantly expressed in the normal as well as the diseased muscles. We conclude that in s-IBM and PM the expression of hILP, a major cell death suppressor, on the muscle membrane may prevent the induction of apoptosis by the autoinvasive cytotoxic T cells on the cell surface, by inhibiting the caspase activation. (C) 2000 Published by Elsevier Science BN. All rights reserved. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 23 TC 35 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL 1 PY 2000 VL 106 IS 1-2 BP 1 EP 5 DI 10.1016/S0165-5728(99)00162-9 PG 5 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 318AB UT WOS:000087260200001 PM 10814776 ER PT J AU Stern, EL Quan, N Proescholdt, MG Herkenham, M AF Stern, EL Quan, N Proescholdt, MG Herkenham, M TI Spatiotemporal induction patterns of cytokine and related immune signal molecule mRNAs in response to intrastriatal injection of lipopolysaccharide SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE cytokine; endotoxin; intracerebral injection; brain inflammation; interleukin-1 ID TUMOR-NECROSIS-FACTOR; NITRIC-OXIDE SYNTHASE; MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; INTERLEUKIN-1 RECEPTOR ANTAGONIST; MICROVESSEL ENDOTHELIAL-CELLS; FACTOR-ALPHA EXPRESSION; FACTOR KAPPA-B; GENE-EXPRESSION; RAT-BRAIN AB The brain's response to a direct immune challenge was examined by in situ hybridization histochemistry. Lipopolysaccharide (bacterial endotoxin) injected acutely into rat striatum induced mRNA expression for inhibitory factor kappa B alpha, interleukin (IL)-1 beta, tumor necrosis facror-alpha, IL-6, IL-12 p35, inducible nitric oxide synthase, IL-1 receptor antagonist, and the type 1 IL-1 receptor. Expression patterns were evaluated at select time points ranging from 15 min to 3 days post-injection. Rats injected with vehicle alone were used to control for mechanical effects. Following lipopolysaccharide administration, a wave of mRNA induction within brain parenchyma radiated outward from the injection site, generally peaking in intensity at the 16-h time point. The individual profiles of cytokine mRNA induction patterns reveal that the brain's immune response to local inflammatory stimulation is quite elaborate and in many ways resembles the progression of cytokine induction customary of localized inflammation in peripheral tissues. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 89 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUL 1 PY 2000 VL 106 IS 1-2 BP 114 EP 129 DI 10.1016/S0165-5728(00)00194-6 PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 318AB UT WOS:000087260200014 PM 10814789 ER PT J AU Powell, KD Goldberg, ME AF Powell, KD Goldberg, ME TI Response of neurons in the lateral intraparietal area to a distractor flashed during the delay period of a memory-guided saccade SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSTERIOR PARIETAL CORTEX; FRONTAL EYE FIELDS; MOTOR INTENTION ACTIVITY; SUPERIOR COLLICULUS; SELECTIVE ATTENTION; MACAQUE MONKEY; SINGLE NEURONS; REPRESENTATION; MOVEMENTS; DISSOCIATION AB Recent experiments raised the possibility that the lateral intraparietal area (LIP) might be specialized for saccade planning. If this was true, one would expect a decreased sensitivity to irrelevant visual stimuli appearing late in the delay period of a memory-guided delayed-saccade task to a target outside the neurons' receptive fields. We trained two monkeys to perform a standard memory-guided delayed-saccade task and a distractor task in which a stimulus flashed for 200 ms at a predictable time 300-100 ms before the end of the delay period. We used two locations, one in the most active part of the receptive field and another well outside the receptive field. We used six kinds of trials randomly intermixed: simple delayed-saccade trials into or away from the receptive field and distractor trials with saccade target and distractor both in the receptive field, both out of the receptive field, or one at each location. This enabled us to study the response to the distractor as a function of the monkey's preparation of a memory-guided delayed-saccade task. We had assumed that the preparation of a saccade away from the receptive field would result in an attenuation of the response to the distractor, i.e., a distractor at the location of the saccade goal would evoke a greater response than when it appeared at a location far from the saccade goal. Instead we found that neurons exhibited either a normal or an enhanced visual response to the distractor during the memory period when the target flashed outside the receptive field. When the distractor flashed at the location of the saccade target, the response to the distractor was either unchanged or diminished. The response to a distractor away from the target location of a memory-guided saccade was even greater than the response to the same target when it was the target for the memory-guided saccade task. Immediate presaccadic activity did not distinguish between a saccade to the receptive field when there was no distractor and a distractor in the receptive field when the monkey made a saccade elsewhere. Nonetheless the distractor had no significant effect on the saccade latency, accuracy, or velocity despite the brisk response it evoked immediately before the saccade. We suggest that these results are inconsistent with a role for LIP in the specific generation of saccades, but they are consistent with a role for LIP in the generation of visual attention. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Powell, KD (reprint author), NEI, Sensorimotor Res Lab, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 44 TC 89 Z9 89 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2000 VL 84 IS 1 BP 301 EP 310 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 334YU UT WOS:000088215000028 PM 10899205 ER PT J AU Port, NL Sommer, MA Wurtz, RH AF Port, NL Sommer, MA Wurtz, RH TI Multielectrode evidence for spreading activity across the superior colliculus movement map SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SACCADE-RELATED ACTIVITY; GAZE SHIFTS; REVERSIBLE INACTIVATION; EYE-MOVEMENTS; MONKEY; SYSTEM; CORTEX; WAVES; CELLS; MODEL AB The monkey superior colliculus (SC) has maps for both visual input and movement output in the superficial and intermediate layers, respectively, and activity on these maps is generally related to visual stimuli only in one part of the visual field and/or to a restricted range of saccadic eye movements to those stimuli. For some neurons within these maps, however, activity has been reported to spread from the caudal SC to the rostral SC during the course of a saccade. This spread of activity was inferred from averages of recordings at different sites on the SC movement map during saccades of different amplitudes and even in different monkeys. In the present experiments, SC activity was recorded simultaneously in pairs of neurons to observe the spread of activity during individual saccades. Two electrodes were positioned along the rostral-caudal axis of the SC with one being more caudal than the other, and 60 neuron pairs whose movement fields were large enough to see a spread of activity were studied. During individual saccades, the relative time of discharge of the two neurons was compared using 1) the time difference between peak discharge of the two neurons, 2) the difference between the "median activation time" of the two neurons, and 3) the shift required to align the two discharge patterns using cross-correlation. All three analysis methods gave comparable results. Many pairs of neurons were activated in sequence during saccade generation, and the order of activation was most frequently caudal to rostral. Such a sequence of activation was not observed in every neuron pair, but over the sample of neuron pairs studied, the spread was statistically significant. When we compared the time of neuronal activity to the time of saccade onset, we found that the caudal neuronal activity was more likely to be before the saccade, whereas the rostral neuronal activity was more likely to be during the saccade. These results demonstrate that when individual pairs of neurons are examined during single saccades there is evidence of a caudal to rostral spread of activity within the monkey SC, and they confirm the previous inferences of a spread of activity drawn from observations on averaged neuronal activity during multiple saccades. The functional contribution of this spread of activity remains to be determined. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Port, NL (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20982 USA. NR 27 TC 24 Z9 24 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2000 VL 84 IS 1 BP 344 EP 357 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 334YU UT WOS:000088215000032 PM 10899209 ER PT J AU Oppenheim, RW Houenou, LJ Parsadanian, AS Prevette, D Snider, WD Shen, LY AF Oppenheim, RW Houenou, LJ Parsadanian, AS Prevette, D Snider, WD Shen, LY TI Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: Regulation of programmed cell death among motoneuron subtypes SO JOURNAL OF NEUROSCIENCE LA English DT Article DE motoneurons; cell death; GDNF; spinal cord; embryo; mouse GDNF receptors; knock-out; transgenic ID C-RET PROTOONCOGENE; MICE LACKING GDNF; NERVOUS-SYSTEM; MESSENGER-RNA; MOTOR-NEURONS; IN-VIVO; NEURTURIN RECEPTOR; TYROSINE KINASE; SKELETAL-MUSCLE; SURVIVAL FACTOR AB Because of discrepancies in previous reports regarding the role of glial cell line-derived neurotrophic factor (GDNF) in motoneuron (MN) development and survival, we have reexamined MNs in GDNF-deficient mice and in mice exposed to increased GDNF after in utero treatment or in transgenic animals overexpressing GDNF under the control of the muscle-specific promoter myogenin (myo-GDNF). With the exception of oculomotor and abducens MNs, the survival of all other populations of spinal and cranial MNs were reduced in GDNF-deficient embryos and increased in myo-GDNF and in utero treated animals. By contrast, the survival of spinal sensory neurons in the dorsal root ganglion and spinal interneurons were not affected by any of the perturbations of GDNF availability. In wild-type control embryos, all brachial and lumbar MNs appear to express the GDNF receptors c-ret and GFR alpha 1 and the MN markers ChAT, islet-1, and islet-2, whereas only a small subset express GFR alpha 2. GDNF-dependent MNs that are lost in GDNF-deficient animals express ret/GFR alpha 1/islet-1, whereas many surviving GDNF-independent MNs express ret/GFR alpha 1/GFR alpha 2 and islet-1/islet-2. This indicates that many GDNF-independent MNs are characterized by the presence of GFR alpha 2/islet-2. It seems likely that the GDNF-independent population represent MNs that require other GDNF family members (neurturin, persephin, artemin) for their survival. GDNF-dependent and -independent MNs may reflect subtypes with distinct synaptic targets and afferent inputs. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Neurosci Program, Winston Salem, NC 27157 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Univ N Carolina, Ctr Neurosci, Chapel Hill, NC 27599 USA. RP Shen, LY (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bldg 37,Room 2B15,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS31380, NS20402, NS37273] NR 54 TC 114 Z9 118 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 1 PY 2000 VL 20 IS 13 BP 5001 EP 5011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 327WC UT WOS:000087816300027 PM 10864958 ER PT J AU Mason, RB Pluta, RM Walbridge, S Wink, DA Oldfield, EH Boock, RJ AF Mason, RB Pluta, RM Walbridge, S Wink, DA Oldfield, EH Boock, RJ TI Production of reactive oxygen species after reperfusion in vitro and in vivo: protective effect of nitric oxide SO JOURNAL OF NEUROSURGERY LA English DT Article DE stroke; oxygen free radical; nitric oxide; anoxia; reperfusion injury; nitric oxide donor ID FOCAL CEREBRAL-ISCHEMIA; HYDROXYL RADICAL GENERATION; INFARCT VOLUME; THROMBOLYTIC THERAPY; SYNTHASE INHIBITION; RELAXING FACTOR; NOS INHIBITOR; RAT MODEL; INJURY; BRAIN AB Object. Thrombolytic treatments for ischemic stroke can restore circulation, but reperfusion injury, mediated by oxygen free radicals, can limit their utility. The authors hypothesized that, during reperfusion, nitric oxide (NO) provides cytoprotection against oxygen free radical species. Methods. Levels of NO and oxygen free radicals were determined in both reoxygenation in vitro and reperfusion in vivo models using an NO electrochemical probe and high-performance liquid chromatography with the 2,3- and 2,5-dihydroxybenzoic acid trapping method, before and after addition of the NO donor diethanolamine nitric oxide (DEA/NO). Reoxygenation after anoxia produced a twofold increase in NO release by human fetal astrocytes and cerebral endothelial cells (p < 0.005). In both cell lines, there was also a two- to threefold increase in oxygen free radical production (p ( 0.005). In human fetal astrocytes and cerebral endothelial cells given a single dose of DEA/NO, free radical production dropped fivefold compared with peak ischemic levels (p ( 0.001). In a study in which a rat global cerebral ischemia model was used, NO production in a vehicle-treated group increased 48 +/- 16% above baseline levels after reperfusion. After intravenous DEA/NO infusion, NO reached 1.6 times the concentration of the postischemic peak in vehicle-treated animals. In vehicle-treated animals during reperfusion, free radical production increased 4.5-fold over basal levels (p < 0.01). After intravenous DEA/NO infusion, free radical production dropped nearly 10-fold compared with peak levels in vehicle-treated animals (p < 0.006). The infarct volume in the vehicle-treated animals was 111 +/- 16.9 mm(3); after DEA/NO infusion it was 64.8 +/- 23.4 mm(3) (p < 0.01). Conclusions. The beneficial effect of early restoration of cerebral circulation after cerebral ischemia is limited by reperfusion injury. These results indicate that NO release and oxygen free radical production increase during reperfusion, and suggest a possible early treatment of reperfusion injury using NO donors. C1 NINDS, Surg Neurol Branch, Dept Neurosurg, Natl Naval Med Ctr, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD USA. RP Oldfield, EH (reprint author), NINDS, Surg Neurol Branch, Dept Neurosurg, Natl Naval Med Ctr, Bldg 10,Room 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. NR 59 TC 77 Z9 79 U1 0 U2 7 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2000 VL 93 IS 1 BP 99 EP 107 DI 10.3171/jns.2000.93.1.0099 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 327UW UT WOS:000087813100014 PM 10883911 ER PT J AU Wacker, P Ozsahin, H Groll, AH Gervaix, A Reinhard, L Humbert, J AF Wacker, P Ozsahin, H Groll, AH Gervaix, A Reinhard, L Humbert, J TI Trimethoprim-sulfamethoxazole salvage for refractory listeriosis during maintenance chemotherapy for acute lymphoblastic leukemia SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE listeriosis; cancer; children; leukemia ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTOGENES; INFECTION; MENINGITIS; DISEASE; CANCER AB A 5-year-old boy with acute lymphoblastic leukemia (ALL) and intolerance to oral trimethoprim-sulfamethoxazole (TMP/SMX) had Listeria monocytogenes bacteremia and meningitis develop during maintenance chemotherapy. Despite prompt administration of IV amoxicillin/gentamicin and microbiologic clearance of the bloodstream, the patient had no response to therapy after a course of 7 days. Intravenous TMP/SMX (10 mg/kg per day of TMP) was added to the antibiotic regimen after desensitization. Fever and meningeal signs rapidly resolved? and the patient was ultimately cured. Amoxicillin and gentamicin, although highly active and synergistic in vitro against L. monocytogenes, have limited intracellular penetration and activity. In contrast, TMP/SMX has bactericidal extracellular and intracellular activity against Listeria and excellent central nervous system penetration, and thus may be effective for the treatment of refractory listeriosis. C1 Hop Univ Geneve, Hop Enfants, Hematol Oncol Unit, CH-1211 Geneva 14, Switzerland. Hop Univ Geneve, Dept Pediat, Emergency Room Unit, CH-1211 Geneva, Switzerland. NCI, Immunocompromised Hosp Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Wacker, P (reprint author), Hop Univ Geneve, Hop Enfants, Hematol Oncol Unit, CH-1211 Geneva 14, Switzerland. NR 19 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JUL-AUG PY 2000 VL 22 IS 4 BP 340 EP 343 DI 10.1097/00043426-200007000-00011 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 344BG UT WOS:000088737300011 PM 10959905 ER PT J AU Hertle, RW Raab, EL Ing, M Helveston, E AF Hertle, RW Raab, EL Ing, M Helveston, E TI Infantile esotropia SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Editorial Material C1 NEI, Bethesda, MD 20892 USA. RP Hertle, RW (reprint author), NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD JUL-AUG PY 2000 VL 37 IS 4 BP 228 EP 231 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 342AF UT WOS:000088622600008 PM 10955546 ER PT J AU Gafni, RI Papanicolaou, DA Nieman, LK AF Gafni, RI Papanicolaou, DA Nieman, LK TI Nighttime salivary cortisol measurement as a simple, noninvasive, outpatient screening test for Cushing's syndrome in children and adolescents SO JOURNAL OF PEDIATRICS LA English DT Article ID CIRCADIAN-RHYTHM; SERUM CORTISOL; DIAGNOSIS; VALUES; BOYS; AGE AB Objective: There is currently no optimal test to screen for endogenous Cushing's syndrome (CS) in children. Traditional 24-hour urine or midnight serum cortisol values may be difficult to obtain or elevated by venipuncture stress. We hypothesized that salivary cortisol measurement is a reliable way to screen for CS in children. Study design: Sixty-seven children (5-17 years) were studied: 24 obese volunteers, 29 non-obese volunteers, and 14 children with CS. Saliva was obtained at 7:30 AM, bedtime, and midnight for measurement of free cortisol by radioimmunoassay. Results: Salivary cortisol was detectable in all morning and evening samples from patients with CS but was frequently undetectable in healthy children at bedtime (66% and at midnight (90%). With cut points that excluded healthy children, a midnight salivary cortisol value of 7.5 nmol/L (0.27 mu g/dL) identified 13 of 14 patients with CS, whereas a bedtime value >27.6 nmol/L (1 mu g/dL) detected CS in 5 of 6 patients. The diagnostic accuracies of midnight salivary cortisol and urinary free cortisol per square meter were the same (93%). Conclusion: Salivary cortisol measurement at bedtime or midnight rules out CS in nearly all cases. Nighttime salivary cortisol sampling is thus a simple, accurate way to screen for hypercortisolism in children. C1 Nichhd, Dev Endocrinol Branch, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Nichhd, Dev Endocrinol Branch, Warren Grant Magnuson Clin Ctr, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. NR 25 TC 54 Z9 55 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2000 VL 137 IS 1 BP 30 EP 35 DI 10.1067/mpd.2000.106226 PG 6 WC Pediatrics SC Pediatrics GA 334UL UT WOS:000088204000009 PM 10891818 ER PT J AU Rudek, MA March, CL Bauer, KS Pluda, JM Figg, WD AF Rudek, MA March, CL Bauer, KS Pluda, JM Figg, WD TI High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE COL-3; mass spectrometry; chromatography; tetracycline ID CHLORTETRACYCLINE; OXYTETRACYCLINE; INVASION AB COL-3, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, is a matrix metalloproteinase inhibitor. A specific and sensitive analytical method was necessary to quantitate the analyte in human plasma. High-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry detection was utilized to quantitate COL-3 from 30 to 10000 ng/ml in two calibration curves: 30-1500 and 400-10000 ng/ml. The sample preparation consisted of acetonitrile precipitation for all plasma samples. COL-3 is separated on a Waters Symmetry(R) C-18 (2.1 x 150 mm) column with oxalic acid (0.01 M, pH 2.2)-acetonitrile mobile phase. The total run time was 23 min. Identification of COL-3 and the internal standard was through positive chemical ionization and selective ion monitoring. A quantifying and qualifying ion for COL-3 is used to verify the presence of COL-3 in patient samples Inter- and intra-run mean percent errors for all of the quality controls were less than 18.3% and relative standard deviations were all less than 14.9%. Recovery of COL-3 and the internal standard was approximately 55 and 72%, respectively. Freeze-thaw stability of COL-3 was variable. This method is suitable for quantifying COL-3 in patient samples and to further characterize the clinical pharmacology of this compound. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 8 TC 16 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JUL PY 2000 VL 22 IS 6 BP 1003 EP 1014 DI 10.1016/S0731-7085(00)00257-0 PG 12 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 318XU UT WOS:000087310600013 PM 10857569 ER PT J AU Shinar, Y Livneh, A Langevitz, P Zaks, N Aksentijevich, I Koziol, DE Kastner, DL Pras, M Pras, E AF Shinar, Y Livneh, A Langevitz, P Zaks, N Aksentijevich, I Koziol, DE Kastner, DL Pras, M Pras, E TI Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE familial Mediterranean fever; genotype; phenotype ID AMYLOIDOSIS; MUTATIONS; GENE; FMF; INHERITANCE; COLCHICINE; FREQUENCY; ARMENIANS AB Objective. To study genotype-phenotype correlation for the 4 most common genotypes found among patients with familial Mediterranean fever (FMF). Methods. Thirty patients with the M694V/M694V genotype, 32 with M694V/V726A genotype, 25 with M694V/E148Q genotype, and 21 with V726A/V726A genotype were assessed for various clinical manifestations of FMF, and overall disease severity. Results. Patients with the M694V/M694V genotype were found to have an earlier age of onset, higher frequency of joint involvement, higher frequency of erysipelas-like erythema, and required higher doses of colchicine to control the disease compared to the other 3 genotypes. Conclusion. The M694V/M694V genotype is associated with more severe disease compared to other common genotypes in patients with FMF. C1 Chaim Sheba Med Ctr, Inst Human Genet, Dept Med C, IL-52621 Tel Hashomer, Israel. NIAMSD, Genet Sect, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, Heller Inst Med Sci, IL-52621 Tel Hashomer, Israel. RP Pras, E (reprint author), Chaim Sheba Med Ctr, Inst Human Genet, Dept Med C, IL-52621 Tel Hashomer, Israel. NR 25 TC 94 Z9 96 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2000 VL 27 IS 7 BP 1703 EP 1707 PG 5 WC Rheumatology SC Rheumatology GA 331FL UT WOS:000088007600023 PM 10914855 ER PT J AU Lins, U Farina, M Kurc, M Riordan, G Thalmann, R Thalmann, I Kachar, B AF Lins, U Farina, M Kurc, M Riordan, G Thalmann, R Thalmann, I Kachar, B TI The otoconia of the guinea pig utricle: Internal structure, surface exposure, and interactions with the filament matrix SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE otoconia; otoconial membrane; otoliths; otolithic membrane; utricle; mechanosensory transduction; vestibular system; biomineralization ID VESTIBULAR SENSORY APPARATUS; ELECTRON-MICROSCOPY; MECHANICAL TRANSDUCTION; OTOLITHIC MEMBRANE; INNER-EAR; CALCITE; PROTEIN; MACROMOLECULES; ARAGONITE; NEWT AB A unique feature of the vertebrate gravity receptor organs, the saccule and utricle, is the mass of biomineral structures, the otoconia, overlying a gelatinous matrix also called "otoconial membrane" on the surface of the sensory epithelium. In mammals, otoconia are deposits of calcium carbonate in the form of composite calcite crystals. We used quick-freezing, deep etching to examine the otoconial mass of the guinea pig utricle. The deep-etching step exposed large expenses of intact and fractured otoconia, showing the fine structure and relationship between their internal crystal structure, their surface components, and the filament matrix in which they are embedded, Each otoconium has a compact central core meshwork of filaments and a composite outer shell of ordered crystallites and macromolecular aggregates, A distinct network of 20-nm beaded filaments covers the surface of the otoconia, The otoconia are interconnected and secured to the gelatinous matrix by surface adhesion and by confinement within a loose interotoconial filament matrix. The gelatinous matrix is a dense network made of yet another type of filament, 22 nm in diameter, which are cross-linked by shorter filaments, characteristically 11 nm in diameter. Our freeze-etching data provide a structural framework for considering the molecular nature of the components of the otoconial complex, their mechanical properties, and the degree of biological versus chemical control of otoconia biosynthesis, (C) 2000 Academic Press. C1 NIDCD, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Dept Microbiol Geral, BR-21941590 Rio De Janeiro, Brazil. Univ Fed Rio de Janeiro, Dept Anat, BR-21941590 Rio De Janeiro, Brazil. Washington Univ, Sch Med, Dept Otolaryngol, St Louis, MO 63110 USA. RP Kachar, B (reprint author), NIDCD, Sect Struct Cell Biol, NIH, Bldg 36,Rm 5D-15, Bethesda, MD 20892 USA. RI Farina, Marcos/I-3744-2014; Lins, Ulysses/N-7282-2015 OI Lins, Ulysses/0000-0002-1786-1144 NR 30 TC 50 Z9 52 U1 0 U2 13 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JUL PY 2000 VL 131 IS 1 BP 67 EP 78 DI 10.1006/jsbi.2000.4260 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 351UT UT WOS:000089177100008 PM 10945971 ER PT J AU Swedo, SE Leibenluft, E AF Swedo, SE Leibenluft, E TI Recurrent depression: Infectious-autoimmune etiology? Comment by Drs. Swedo and Leibenluft, at the invitation of the Editor SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter ID DIAGNOSIS C1 NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Swedo, SE (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 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 JUL PY 2000 VL 39 IS 7 BP 812 EP 812 DI 10.1097/00004583-200007000-00008 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 327WL UT WOS:000087817100008 ER PT J AU Flisher, AJ Kramer, RA Hoven, CW King, RA Bird, HR Davies, M Gould, MS Greenwald, S Lahey, BB Regier, DA Schwab-Stone, M Shaffer, D AF Flisher, AJ Kramer, RA Hoven, CW King, RA Bird, HR Davies, M Gould, MS Greenwald, S Lahey, BB Regier, DA Schwab-Stone, M Shaffer, D TI Risk behavior in a community sample of children and adolescents SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE risk behavior; suicidality ID HIGH-SCHOOL-STUDENTS; DRUG-USE; SUICIDAL BEHAVIORS; TAKING BEHAVIOR; ALCOHOL; DROPOUTS; EPIDEMIOLOGY; RELIABILITY; INFORMATION; COMPETENCE AB Objectives: First, to investigate whether there is covariation between risk behaviors, including suicidality, in a community probability sample of children and adolescents; and second, to investigate whether risk behavior is associated with selected potential correlates. Method: A sample of 9- to 17-year-old youths (N = 1,285) and their caretakers were interviewed in the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. The risk behaviors were marijuana smoking, alcohol use, intercourse, fighting, cigarette smoking, and suicidal ideation/attempts. Relationships between the risk behaviors were described using odds ratios. Linear regression analyses of an index of risk behavior on the selected potential correlates of risk behavior were conducted. Results: There were significant relationships between all pairs of risk behaviors. The score on the index of risk behavior was associated with stressors, lack of resources, family psychiatric disorder, psychopathology, and functional impairment. Conclusions: Clinicians should be alerted to the possibility of risk behaviors, especially in children and adolescents engaging in other risk behaviors and those with inadequate resources, stressors, functional impairment, or psychopathology. C1 Columbia Univ, New York, NY 10027 USA. Yale Univ, New Haven, CT 06520 USA. Univ Cape Town, ZA-7700 Rondebosch, South Africa. Univ Chicago, Chicago, IL 60637 USA. NIMH, Bethesda, MD 20892 USA. RP Flisher, AJ (reprint author), Groote Schuur Hosp, Dept Psychiat, ZA-7925 Cape Town, South Africa. FU NIMH NIH HHS [MH38198-05A2, MH46091, T32 MH16434] NR 47 TC 67 Z9 68 U1 6 U2 11 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 JUL PY 2000 VL 39 IS 7 BP 881 EP 887 DI 10.1097/00004583-200007000-00017 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 327WL UT WOS:000087817100017 PM 10892230 ER PT J AU Liu, XC Guo, CQ Okawa, M Zhai, J Li, Y Uchiyama, M Neiderhiser, JM Kurita, H AF Liu, XC Guo, CQ Okawa, M Zhai, J Li, Y Uchiyama, M Neiderhiser, JM Kurita, H TI Behavioral and emotional problems in Chinese children of divorced parents SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE Child Behavior Checklist; parental divorce; behavioral problems ID SINGLE-PARENT; FAMILY TYPE; AMERICAN-CHILDREN; TEACHER REPORTS; MARITAL-STATUS; AGE CHILDREN; ADJUSTMENT; RISK; PREVALENCE; RATINGS AB Objective: This study examined the behavioral problems in Chinese children of divorced parents. Method: A total of 58 children of divorce and 116 gender-, age-, and school class-matched controls were ascertained from a general population sample of children aged 6 through 15 years. Parents completed the Child Behavior Checklist (CBCL), and teachers completed the Teacher's Report Form (TRF) and Conners Hyperkinesis index. Results: Parent-reported problem scores on the CBCL total scale and each subscale, and prevalence of all CBCL syndromes except for Somatic Complaints, were significantly higher in children of divorce than in controls. Teacher-reported problem scores on the TRF total scale and Social and Attention Problems and prevalence of Attention Problems were significantly different for the 2 groups of children. Social competence was rated significantly lower in children of divorce than in controls. Discriminant function analysis showed that behavioral problems in children of divorce were characterized by aggressive behavior, withdrawal, and social problems. Conclusions: The findings emanating from China provide the first evidence of the link between parental divorce and children's psychopathology and clarify the psychopathological dimensions in Chinese children of divorced parents. C1 Shandonng Med Univ, Dept Psychiat, Jinan, Shandong, Peoples R China. Shandong Mental Hlth Ctr, Jinan, Shandong, Peoples R China. NIMH, NCNP, Ichikawa, Japan. George Washington Univ, Washington, DC USA. Univ Tokyo, Grad Sch Med, Tokyo, Japan. RP Liu, XC (reprint author), NIEHS, Epidemiol Branch, POB 12233,111 TW Alexander Dr,Room A363E, Res Triangle Pk, NC 27709 USA. NR 37 TC 14 Z9 15 U1 5 U2 17 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 JUL PY 2000 VL 39 IS 7 BP 896 EP 903 DI 10.1097/00004583-200007000-00019 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 327WL UT WOS:000087817100019 PM 10892232 ER PT J AU Slavkin, HC AF Slavkin, HC TI A personal change and a changing panorama: Looking toward the next decade SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Craniofacial Res, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUL PY 2000 VL 131 IS 7 BP 1071 EP 1075 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 335LF UT WOS:000088244400028 PM 10916338 ER PT J AU Iwao, S Iwao, N Muller, DC Elahi, D Shimokata, H Andres, R AF Iwao, S Iwao, N Muller, DC Elahi, D Shimokata, H Andres, R TI Effect of aging on the relationship between multiple risk factors and waist circumference SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE waist circumference; age; risk factors; coronary disease ID DENSITY-LIPOPROTEIN CHOLESTEROL; CARDIOVASCULAR RISK; FAT DISTRIBUTION; BODY-FAT; AGE; PLASMA; CLASSIFICATION; GLUCOSE; WOMEN AB OBJECTIVE: To examine the relationship between various coronary risk factors and the different levels of fat distribution in younger (<65 years) and older (greater than or equal to 65 years) men and women, using the classifications proposed by the National Heart, Lung and Blood Institute (NHLBI) and the World Health Organization (WHO). DESIGN: Cross-sectional study of subjects enrolled in the Baltimore Longitudinal Study of Aging. MEASUREMENTS: Systolic blood pressure, diastolic blood pressure, fasting glucose, 2-hour glucose, fasting insulin, homeostasis model assessment insulin resistance (HOMA(IR)), triglyceride, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)cholesterol were measured as risk factors. The proportion of subjects with abnormal risk factor levels by waist circumference classifications was determined in the age and gender subgroups. RESULTS: There were significant adverse effects of age per se on all risk factors with the exception of fasting insulin and HOMA(IR) in both men and women, total cholesterol in men, and diastolic blood pressure in women. HDL-cholesterol was higher in older subjects. There were significant correlations between waist circumference and all of the risk factors in the younger group. Waist circumference did not have a significant correlation with total cholesterol in older men, or with total cholesterol and LDL-cholesterol in older women. The proportion of subjects with an abnormal risk factor level increased with increasing waist circumference for most risk factors in both younger and older subjects, but proportions of subjects in each individual waist group were higher in older than in younger groups for systolic blood pressure, diastolic blood pressure, fasting glucose, and 2-hour glucose in men, and for systolic blood pressure, fasting glucose, 2-hour glucose, total and LDL-cholesterol, and triglyceride in women. CONCLUSIONS: Our data indicate that the waist circumference cutpoints proposed by NHLBI and WHO standards are useful for the prediction of cardiovascular disease risk factors in older as well as in younger men and women. C1 NIA, NIH, Baltimore, MD 21224 USA. Massachusetts Gen Hosp, Geriatr Res Lab, Boston, MA 02114 USA. Natl Inst Longev Sci, Longitudinal Study Aging, Nagoya, Aichi, Japan. RP Andres, R (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 21 TC 25 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2000 VL 48 IS 7 BP 788 EP 794 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 333HK UT WOS:000088124700011 PM 10894318 ER PT J AU Hodes, RJ AF Hodes, RJ TI Encouraging older patients to exercise SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter C1 NIA, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIA, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2000 VL 48 IS 7 BP 854 EP 854 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 333HK UT WOS:000088124700025 PM 10894332 ER PT J AU Walker, CL Burroughs, KD Davis, B Sowell, K Everitt, JI Fuchs-Young, R AF Walker, CL Burroughs, KD Davis, B Sowell, K Everitt, JI Fuchs-Young, R TI Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Article DE tamoxifen; raloxifene; uterus; leiomyoma ID REPRODUCTIVE-TRACT LEIOMYOMATA; BREAST-CANCER; POSTMENOPAUSAL WOMEN; OVARIECTOMIZED RATS; ENDOMETRIAL CANCER; RODENT MODEL; DOUBLE-BLIND; TAMOXIFEN; RALOXIFENE; GROWTH AB OBJECTIVE: Uterine leiomyoma are the most common gynecologic neoplasm and a primary cause of hysterectomy in premenopausal women. Preclinical studies were conducted in the Eker rat model to investigate the potential efficacy of selective estrogen receptor modulators (SERMs) as therapeutic agents for this tumor. METHODS: Twelve-month-old Eker rats were randomized into five treatment arms including tamoxifen, placebo, LY 326315, vehicle, and no treatment. Additional animals received ovariectomy or sham surgery at 4 months of age to determine the effect of ovarian ablation on tumor development. The study was terminated after 2 to 4 months of treatment, and tumor incidence, size, proliferative and apoptotic indices were determined. Size and incidence data were subjected to chi-square analysis. One-way analysis of variance and Fisher's least significant difference tests were used to compare proliferative and apoptotic indices. RESULTS: Ovariectomy virtually ablated leiomyoma development, indicating that these tumors were dependent on ovarian hormones for growth and development. Treatment with tamoxifen or raloxifene analog LY 326315 reduced leiomyoma incidence by 40-60% and reduced the size of remaining tumors. The effect of SERMs on leiomyomas was mediated by a decrease in cell proliferation without a decrease in apoptotic index. CONCLUSION: SERMs have been shown to be therapeutically efficacious against breast cancer and to reduce tumor incidence in women at increased risk for this disease. The present data indicate that therapeutic efficacy may also be extended to uterine leiomyoma and demonstrate the utility of this animal model for preclinical studies to identify new therapeutic modalities. (J Soc Gynecol Investig 2000;7:249-56) Copyright (C) 2000 by the Society for Gynecologic Investigation. C1 Univ Texas, MD Anderson Canc Ctr, Div Res, Dept Carcinogenesis, Smithville, TX 78957 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. RP Walker, CL (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Res, Dept Carcinogenesis, Sci Pk,POB 389, Smithville, TX 78957 USA. FU NCI NIH HHS [CA 16672, CA 72253, CA 77863] NR 37 TC 49 Z9 53 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD JUL-AUG PY 2000 VL 7 IS 4 BP 249 EP 256 DI 10.1016/S1071-5576(00)00056-3 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 347QZ UT WOS:000088941800011 PM 10964025 ER PT J AU Walther, MM Herring, J Choyke, PL Linehan, WM AF Walther, MM Herring, J Choyke, PL Linehan, WM TI Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma SO JOURNAL OF UROLOGY LA English DT Article DE adrenal glands; laparoscopy; adrenalectomy; pheochromocytoma; Hippel-Lindau disease ID ENDOCRINE NEOPLASIA TYPE-2; BILATERAL ADRENALECTOMY; LINDAU-DISEASE; MANAGEMENT AB Purpose: Patients with von Hippel-Lindau disease are predisposed to multiple bilateral adrenal pheochromocytoma. In these patients partial adrenalectomy may preserve adrenocortical function and avoid the morbidity associated with medical adrenal replacement. We report our experience with such cases. Materials and Methods: Laparoscopic partial adrenalectomy was performed in patients with von Hippel-Lindau disease and pheochromocytoma when there was evidence of normal adrenocortical tissue on preoperative imaging or intraoperative examination. Suture ligature or a harmonic scalpel was used to excise the tumors, leaving a 2 to 3 mm. margin of normal tissue. Results: Two patients underwent laparoscopic partial adrenalectomy and 1 laparoscopic bilateral partial adrenalectomy with preservation of normal adrenocortical tissue. Seven pheochromocytomas were removed. Laparoscopic ultrasound was essential for localizing 2 pheochromocytomas that were not visualized by the camera. Median operative time was 324 minutes, blood loss 100 cc and parenteral narcotic requirement 22 mg. morphine equivalents. No patient required hydrocortisone replacement. There has been no pheochromocytoma recurrence during short-term followup. Conclusions: Laparoscopic partial adrenalectomy is technically feasible in patients with a hereditary form of pheochromocytoma, and may preserve adrenocortical function. Laparoscopic ultrasound was necessary to identify 2 of the 7 pheochromocytomas removed. C1 NCI, Urol Oncol Branch, Dept Radiol, NIH, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, Dept Radiol, NIH, Bethesda, MD 20892 USA. NR 16 TC 69 Z9 74 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2000 VL 164 IS 1 BP 14 EP 17 DI 10.1016/S0022-5347(05)67438-1 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 323GK UT WOS:000087557600005 PM 10840414 ER PT J AU Zheng, ZM Quintero, J Reid, ES Gocke, C Baker, CC AF Zheng, ZM Quintero, J Reid, ES Gocke, C Baker, CC TI Optimization of a weak 3 ' splice site counteracts the function of a bovine papillomavirus type 1 exonic splicing suppressor in vitro and in vivo SO JOURNAL OF VIROLOGY LA English DT Article ID PRE-MESSENGER-RNA; IMMUNODEFICIENCY-VIRUS TYPE-1; SR PROTEINS; IN-VIVO; POLYPYRIMIDINE TRACT; MAMMALIAN INTRONS; CATALYTIC STEP; HNRNP A1; ENHANCER; SEQUENCES AB Alternative splicing is a critical component of the early to late switch in papillomavirus gene expression. In bovine papillomavirus type 1 (BPV-1), a switch in 3' splice site utilization from an early 3' splice site at nucleotide (nt) 3225 to a late-specific 3' splice site at nt 3605 is essential for expression of the major capsid (L1) mRNA. Three viral splicing elements have recently been identified between the two alternative 3' splice sites and have been shown to play an important role in this regulation. A bipartite element lies approximately 30 nt downstream of the nt 3225 3' splice site and consists of an exonic splicing enhancer (ESE), SE1, followed immediately by a pyrimidine-rich exonic splicing suppressor (ESS). A second ESE (SE2) is located approximately 125 nt downstream of the ESS, We have previously demonstrated that the ESS inhibits use of the suboptimal nt 3225 3' splice site in vitro through binding of cellular splicing factors, However, these in vitro studies did not address the role of the ESS in the regulation of alternative splicing. In the present study, we have analyzed the role of the ESS in the alternative splicing of a BPV-1 late pre-mRNA in vivo. Mutation or deletion of just the ESS did not significantly change the normal splicing pattern where the nt 3225 3' splice site is already used predominantly. However, a pre-mRNA containing mutations in SE2 is spliced predominantly using the nt 3605 3' splice site. In this context, mutation of the ESS restored preferential use of the nt 3225 3' splice site, indicating that the ESS also functions as a splicing suppressor in vivo. Moreover, optimization of the suboptimal nt 3225 3' splice site counteracted the in vivo function of the ESS and led to preferential selection of the nt 3225 3' splice site even in pre-mRNAs with SE2 mutations, In vitro splicing assays also showed that the ESS is unable to suppress splicing of a pre-mRNA with an optimized nt 3225 3' splice site. These data confirm that the function of the ESS requires a suboptimal upstream 3' splice site, A surprising finding of our study is the observation that SE1 can stimulate both the first and the second steps of splicing. C1 NCI, Div Basic Sci, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Rm 13N240,9000 Rockville Pke, Bethesda, MD 20892 USA. NR 55 TC 18 Z9 18 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2000 VL 74 IS 13 BP 5902 EP 5910 DI 10.1128/JVI.74.13.5902-5910.2000 PG 9 WC Virology SC Virology GA 322GH UT WOS:000087501500020 PM 10846071 ER PT J AU Qiu, JT Liu, BD Tian, CJ Pavlakis, GN Yu, XF AF Qiu, JT Liu, BD Tian, CJ Pavlakis, GN Yu, XF TI Enhancement of primary and secondary cellular immune responses against human immunodeficiency virus type 1 Gag by using DNA expression vectors that target Gag antigen to the secretory pathway SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; IN-VIVO TRANSFECTION; PROTECTIVE EFFICACY; DENDRITIC CELLS; MAMMALIAN-CELLS; MATRIX PROTEIN; VIRAL PROTEIN; INFECTION; HIV; INDUCTION AB In this study, we have investigated the influence of antigen targeting after DNA vaccination upon the induction of cellular immune responses against human immunodeficiency virus type 1 (HIV-1) Gag. In addition to the standard version of HIV-1 Gag, we constructed Gag expression vectors that encode a secreted (Sc-Gag) and a cytoplasmic (Cy-Gag) Gag molecule. Although all three HIV-1 Gag expression vectors induced detectable humoral and cellular immune responses, after intramuscular injection the DNA vector encoding the Sc-Gag generated the highest primary cytotoxic T-lymphocyte (CTL) and T-helper responses. Mice immunized with one of the HIV-1 Gag DNA vectors (but not with the control vector pcDNA3.1) developed a protective immune response against infection with recombinant vaccinia virus expressing HIV-1 Gag, and this response persisted for 125 days. The magnitude of the protection correlated with the levels of Gag-specific ex vivo CTL activity and the number of CD8(+) T cells producing gamma interferon. The DNA vector encoding the Sc-Gag induced higher levels of protection and greater secondary CTL responses than did the DNA vector encoding Cy-Gag. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Yu, XF (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NIAID NIH HHS [AI-42624, AI-33862] NR 42 TC 54 Z9 55 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 JUL PY 2000 VL 74 IS 13 BP 5997 EP 6005 DI 10.1128/JVI.74.13.5997-6005.2000 PG 9 WC Virology SC Virology GA 322GH UT WOS:000087501500030 PM 10846081 ER PT J AU Fearns, R Collins, PL Peeples, ME AF Fearns, R Collins, PL Peeples, ME TI Functional analysis of the genomic and antigenomic promoters of human respiratory syncytial virus SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; RNA REPLICATION; MESSENGER-RNA; SENDAI VIRUS; TERMINAL COMPLEMENTARITY; NUCLEOTIDE-SEQUENCES; RABIES VIRUS; GENE-START; N-PROTEIN; TRANSCRIPTION AB The promoters involved in transcription and RNA replication by respiratory syncytial virus (RSV) were examined by using a plasmid-based minireplicon system. The 3' ends of the genome and antigenome, which, respectively, contain the 44-nucleotide (nt) leader (Le) and 155-nt trailer-complement (TrC) regions, should each contain a promoter for RNA replication. The 3' genome end also should have the promoter for transcription. Substitution for the Le with various lengths of TrC demonstrated that the 3'-terminal 36 nt of TrC are sufficient for extensive (but not maximal) replication and that when juxtaposed with a transcription gene-start (GS) signal, this sequence was also able to direct transcription. It was also shown that the region of Le immediately preceding the GS signal of the first gene could be deleted with either no effect or with a slight decrease in transcription initiation. Thus, the TrC is competent to direct transcription even though it does not do so in nature, and the partial sequence identity it shares with the 3' end of the genome likely represents the important elements of a conserved promoter active in both replication and transcription. Increasing the length of the introduced TrC sequence incrementally to 147 nt resulted in a fourfold increase in replication and a nearly complete inhibition of transcription. These two effects were unrelated, implying that transcription and replication are not interconvertible processes mediated by a common polymerase, but rather are independent processes. The increase in replication was specific to the TrC sequence, implying the presence of a nonessential, replication-enhancing cis-acting element. In contrast, the inhibitory effect on transcription was due solely to the altered spacing between the 3' end of the genome and GS signal, which implies that the transcriptase recognizes the first GS signal as a promoter element. Neither the enhancement of replication nor the inhibition of transcription was due to increased base-pairing potential between the 3' and 5' ends, The relative strengths of the Le and TrC promoters for directing RNA synthesis were compared and found to be very similar. Thus, these findings highlighted a high degree of functional similarity between the RSV antigenomic and genomic promoters, but provided a further distinction between promoter requirements for transcription and replication. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. RP Collins, PL (reprint author), 7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. NR 42 TC 34 Z9 35 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2000 VL 74 IS 13 BP 6006 EP 6014 DI 10.1128/JVI.74.13.6006-6014.2000 PG 9 WC Virology SC Virology GA 322GH UT WOS:000087501500031 PM 10846082 ER PT J AU Penrose, KJ McBride, AA AF Penrose, KJ McBride, AA TI Proteasome-mediated degradation of the papillomavirus E2-TA protein is regulated by phosphorylation and can modulate viral genome copy number SO JOURNAL OF VIROLOGY LA English DT Article ID KAPPA-B-ALPHA; SIGNAL-INDUCED DEGRADATION; BPV-1 DNA-REPLICATION; BOVINE PAPILLOMAVIRUS; EPISOMAL MAINTENANCE; RAPID DEGRADATION; E2 TRANSACTIVATOR; PEST HYPOTHESIS; TRANSCRIPTION; TYPE-1 AB The bovine papillomavirus E2 proteins regulate viral transcription, replication, and episomal genome maintenance. We have previously mapped the major phosphorylation sites of the E2 proteins to serine residues 298 and 301 and shown that mutation of serine residue 301 to alanine leads to a dramatic (10- to 20-fold) increase in viral DNA copy number. In this study we analyzed how phosphorylation regulates E2 protein function, S301 is located in a PEST sequence; these sequences are often found in proteins with a short half-life and can be regulated by phosphorylation, We show here that the E2 protein is ubiquitinated and degraded by the proteasome. Mutation of serine 301 to alanine increases the half-life of E2 from approximately 50 min to 160 min. Furthermore, the A301 E2 protein shows greatly reduced ubiquitination and degradation by the proteasome, These results suggest that the E2 protein level is regulated by phosphorylation, which in turn determines viral episomal copy number. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr,MSC 0455, Bethesda, MD 20892 USA. OI McBride, Alison/0000-0001-5607-5157 NR 35 TC 59 Z9 60 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 JUL PY 2000 VL 74 IS 13 BP 6031 EP 6038 DI 10.1128/JVI.74.13.6031-6038.2000 PG 8 WC Virology SC Virology GA 322GH UT WOS:000087501500034 PM 10846085 ER PT J AU Hug, P Lin, HMJ Korte, T Xiao, XD Dimitrov, DS Wang, JM Puri, A Blumenthal, R AF Hug, P Lin, HMJ Korte, T Xiao, XD Dimitrov, DS Wang, JM Puri, A Blumenthal, R TI Glycosphingolipids promote entry of a broad range of human immunodeficiency virus type 1 isolates into cell lines expressing CD4, CXCR4, and/or CCR5 SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 ENVELOPE GLYCOPROTEINS; MEDIATE CD4-DEPENDENT FUSION; MEMBRANE-FUSION; GLUCOSYLCERAMIDE SYNTHASE; CONFORMATIONAL-CHANGES; SURFACE ASSOCIATION; RESISTANT FACTORS; CO-RECEPTORS; CORECEPTORS; MODULATION AB Treatment of human osteosarcoma cells, expressing CD4 and various chemokine receptors, with the glucosylceramide synthase inhibitor 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), blocked target membrane glycosphingolipid (GSL) biosynthesis and reduced the susceptibility of cells to infection and fusion mediated by envelope glycoproteins from a variety of human immunodeficiency virus type 1 (HIV-1) isolates that utilize CXCR4 and/or CCR5. PPMP treatment of the cell lines did not significantly change the cell surface expression of CD4, CXCR4, and/or CCR5, nor did it alter the chemokine receptor association with CD4. PPMP-treated cells exhibited no changes in chemokine-induced Ca2+ mobilization and chemotaxis. However, massive envelope glycoprotein conformational changes triggered by CD4 and the appropriate chemokine receptor on the target membrane were inhibited when the target cells were treated,vith PPMP. Addition of various purified GSLs to PPMP-treated target cells showed that for all isolates tested, globotriaosylceramide (Gb3) was the most potent GSL in restoring the fusion susceptibility of target cells with cells expressing HIV-1 envelope glycoproteins; addition of the monosialoganglioside GM3 yielded a slight enhancement of fusion susceptibility. Our data are consistent with the notion that a limited number of specific GSL species serve as crucial elements in organizing gp120-gp41, CD4, and an appropriate chemokine receptor into a membrane fusion complex. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Div Basic Sci, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bld 469,Rm 213, Frederick, MD 21702 USA. NR 47 TC 120 Z9 123 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 JUL PY 2000 VL 74 IS 14 BP 6377 EP 6385 DI 10.1128/JVI.74.14.6377-6385.2000 PG 9 WC Virology SC Virology GA 327WU UT WOS:000087817900017 PM 10864648 ER PT J AU Arthos, J Rubbert, A Rabin, RL Cicala, C Machado, E Wildt, K Hanbach, M Steenbeke, TD Swofford, R Farber, JM Fauci, AS AF Arthos, J Rubbert, A Rabin, RL Cicala, C Machado, E Wildt, K Hanbach, M Steenbeke, TD Swofford, R Farber, JM Fauci, AS TI CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes SO JOURNAL OF VIROLOGY LA English DT Article ID CHEMOKINE RECEPTOR; CELL TROPISM; HIV-1 ENTRY; T-CELLS; PRIMARY LYMPHOCYTES; AMINO-ACIDS; V3 LOOP; TYPE-1; INFECTION; PROTEIN AB The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1 beta. Distinct differences in the capacity of envelopes to mediate calcium mobilization were observed. Envelopes derived from viruses capable of replicating in macrophages mobilized relatively high levels of calcium, while envelopes derived from viruses incapable of replicating in macrophages mobilized relatively low levels of calcium. The failure to efficiently mobilize calcium was not restricted to envelopes derived from CXCR4-utilizing isolates but also included envelopes derived from CCR5-utilizing isolates that fail to replicate in macrophages. We characterized one CCR5-utilizing isolate, 92MW959, which entered macrophages but failed to replicate. A recombinant envelope derived from this virus mobilized low levels of calcium. When macrophages were inoculated with 92MW959 in the presence of MIP-1 alpha, viral replication was observed, indicating that a CC chemokine mediated signal provided the necessary stimulus td allow the virus to complete its replication cycle. Although the role that envelope-CCR5 signal transduction plays in viral replication is not yet understood, it has been suggested that envelope-mediated signals facilitate early postfusion events in viral replication. The data presented here are consistent with this hypothesis and suggest that the differential capacity of viral envelopes to signal through CCR5 may influence their ability to replicate in macrophages. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Arthos, J (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A-08,10 Ctr Dr, Bethesda, MD 20892 USA. NR 51 TC 77 Z9 80 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 JUL PY 2000 VL 74 IS 14 BP 6418 EP 6424 DI 10.1128/JVI.74.14.6418-6424.2000 PG 7 WC Virology SC Virology GA 327WU UT WOS:000087817900022 PM 10864653 ER PT J AU Tao, T Skiadopoulos, MH Davoodi, F Riggs, JM Collins, PL Murphy, BR AF Tao, T Skiadopoulos, MH Davoodi, F Riggs, JM Collins, PL Murphy, BR TI Replacement of the ectodomains of the hemagglutinin-neuraminidase and fusion glycoproteins of recombinant parainfluenza virus type 3 (PIV3) with their counterparts from PIV2 yields attenuated PIV2 vaccine candidates SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; SENDAI VIRUS; PARA-INFLUENZA; CELL-FUSION; CYTOPLASMIC DOMAIN; MEASLES VIRUSES; F-PROTEIN; LIVE; MUTATIONS; CHILDREN AB We sought to develop a live attenuated parainfluenza virus type 2 (PIV2) vaccine strain for use in infants and young children, using reverse genetic techniques that previously were used to rapidly produce a live attenuated PIV1 vaccine candidate. The PIV1 vaccine candidate, designated rPIV3-1cp45, was generated by substituting the full-length HN and F proteins of PIV1 for those of PIV3 in the attenuated cp45 PIV3 vaccine candidate (T. Tao et al., J. Virol. 72:2955-2961, 1998; M. H. Skiadopoulos et al., Vaccine 18:503-510, 1999). However, using the same strategy, we failed to recover recombinant chimeric PIV3-PIV2 isolate carrying the full-length PIV2 glycoproteins in a wild-type PIV3 backbone. Viable PIV3-PIV2 chimeras were recovered when chimeric HN and F open reading frames (ORFs) rather than complete PIV;I F and HN ORFs were used to construct the full-length cDNA, The recovered viruses, designated rPIV3-2CT, in which the PIV2 ectodomain and transmembrane domain were fused to the PIV3 cytoplasmic domain, and rPIV3-2TM, in which the PIV2 ectodomain was fused to the PIV3 transmembrane and cytoplasmic tail domain, possessed similar in vitro and in vivo phenotypes. Thus, it appeared that only the cytoplasmic tail of the HN or F glycoprotein of PIV3 was required for successful recovery of PIV3-PIV2 chimeras. Although rPIV3-2CT and rPIV3-2TM replicated efficiently in vitro, they were moderately to highly attenuated for replication in the respiratory tracts of hamsters, African green monkeys (AGMs), and chimpanzees. This unexpected finding indicated that chimerization of the HN and F proteins of PIV2 and PIV3 itself specified an attenuation phenotype in vivo, Despite this attenuation, these viruses were highly immunogenic and protective against challenge with wild-type PIV2 in hamsters and AGMs, and they represent promising candidates for clinical evaluation as a vaccine against PIV2. These chimeric viruses were further attenuated by the addition of 12 mutations of PIV3cp45 which lie outside of the HN and F genes. The attenuating effects of these mutations were additive with that of the chimerization, and thus inclusion of all or some of the cp45 mutations provides a means to further attenuate the PIV3-PIV2 chimeric vaccine candidates if necessary. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Tao, T (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 7,Rm 134,7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-000087] NR 53 TC 29 Z9 29 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 JUL PY 2000 VL 74 IS 14 BP 6448 EP 6458 DI 10.1128/JVI.74.14.6448-6458.2000 PG 11 WC Virology SC Virology GA 327WU UT WOS:000087817900026 PM 10864657 ER PT J AU Boyer, PL Hughes, SH AF Boyer, PL Hughes, SH TI Effects of amino acid substitutions at position 115 on the fidelity of human immunodeficiency virus type 1 reverse transcriptase SO JOURNAL OF VIROLOGY LA English DT Article ID TEMPLATE-PRIMER; DNA-SYNTHESIS; HIV-1; RESISTANCE; MECHANISM; MISALIGNMENT; MUTATIONS; RNA; POLYMERIZATION; PROCESSIVITY AB We compared the fidelity of wild-type human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) and two RT mutants, Y115F and Y115V. Although neither mutation had a large effect on the overall fidelity of the enzyme, both mutations altered the spectrum of mutations and the precise nature of the mutational hot spots. The effects of Y115V were greater than those of Y115F. When we compared the behavior of the wild-type enzyme with published data, we found that, in contrast to what has been published, misalignment/slippage could account for only a small fraction of the mutations we observed. We also found that a preponderance of the mutations (both transitions and transversions) resulted in the insertion of an A. Because we were measuring DNA-dependent DNA synthesis (plus-strand synthesis), this bias could contribute to the A-rich nature of the HIV-1 genome. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. NR 26 TC 22 Z9 22 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 JUL PY 2000 VL 74 IS 14 BP 6494 EP 6500 DI 10.1128/JVI.74.14.6494-6500.2000 PG 7 WC Virology SC Virology GA 327WU UT WOS:000087817900031 PM 10864662 ER PT J AU Egger, D Teterina, N Ehrenfeld, E Bienz, K AF Egger, D Teterina, N Ehrenfeld, E Bienz, K TI Formation of the poliovirus replication complex requires coupled viral translation, vesicle production, and viral RNA synthesis SO JOURNAL OF VIROLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; ENDOPLASMIC-RETICULUM; 2C PROTEIN; MEMBRANE-BINDING; BREFELDIN-A; INFECTED CELLS; VIRUS PROTEIN; PRECURSOR; 2BC; REGION AB Poliovirus (PV) infection induces the rearrangement of intracellular membranes into characteristic vesicles which assemble into an RNA replication complex. To investigate this transformation, endoplasmic reticulum (ER) membranes in HeLa cells were modified by the expression of different cellular or viral membrane binding proteins. The membrane-binding proteins induced two types of membrane alterations, i.e., extended membrane sheets and vesicles similar to those found during a PV infection. Cells expressing membrane-binding proteins were superinfected with PV and then analyzed for virus replication, location of membranes, viral protein, and RNA by immunofluorescence and fluorescent in situ hybridization. Cultures expressing cellular or viral membrane-binding proteins, but not those expressing soluble proteins, showed a markedly reduced ability to support PV replication as a consequence of the modification of ER membranes. The altered membranes, regardless of their morphology, were not used for the formation of viral replication complexes during a subsequent PV infection. Specifically, membrane sheets were not substrates for PV-induced vesicle formation, and, surprisingly, vesicles induced by and carrying one or all of the PV replication proteins did not contribute to replication complexes formed by the superinfecting PV. The formation of replication complexes required active viral RNA replication. The extensive alterations induced by membrane-binding proteins in the ER resulted in reduced viral protein synthesis, thus affecting the number of cells supporting PV multiplication. Our data suggest that a functional replication complex is formed in cis, in a coupled process involving viral translation, membrane modification and vesicle budding, and viral RNA synthesis. C1 Univ Basel, Inst Med Microbiol, CH-4003 Basel, Switzerland. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bienz, K (reprint author), Univ Basel, Inst Med Microbiol, Peterspl 10, CH-4003 Basel, Switzerland. NR 69 TC 118 Z9 121 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2000 VL 74 IS 14 BP 6570 EP 6580 DI 10.1128/JVI.74.14.6570-6580.2000 PG 11 WC Virology SC Virology GA 327WU UT WOS:000087817900040 PM 10864671 ER PT J AU Halvas, EK Svarovskaia, ES Freed, EO Pathak, VK AF Halvas, EK Svarovskaia, ES Freed, EO Pathak, VK TI Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2 ',3 '-dideoxy-3 '-thiacytidine SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH-LEVEL RESISTANCE; AIDS-RELATED COMPLEX; COMBINATION THERAPY; ANGSTROM RESOLUTION; CONFERS RESISTANCE; DRUG-RESISTANCE; DNA-SYNTHESIS; PHASE-I; LAMIVUDINE AB The antiretroviral nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC) is a potent inhibitor of wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), A methionine-to-valine or methionine-to-isoleucine substitution at residue 184 in the HIV-1 YMDD motif, which is located at the RT active site, leads to a high level of resistance to 3TC. We sought to determine whether 3TC can inhibit the replication of wild-type murine leukemia virus (MLV), which contains V223 at the YVDD active site motif of the MLV RT, and of the V223M, V223I, V223A, and V223S mutant RTs. Surprisingly, the wild type and all four of the V223 mutants of MLV RT were highly resistant to 3TC. These results indicate that determinants outside the YVDD motif of MLV RT confer a high level of resistance to 3TC. Therefore, structural differences among similar RTs might result in widely divergent sensitivities to antiretroviral nucleoside analogs. C1 NCI, HIV Drug Resistance Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Frederick Canc Res & Dev Ctr, Bldg 535,Rm 334, Frederick, MD 21702 USA. FU NCI NIH HHS [CA58875] NR 55 TC 15 Z9 16 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 JUL PY 2000 VL 74 IS 14 BP 6669 EP 6674 DI 10.1128/JVI.74.14.6669-6674.2000 PG 6 WC Virology SC Virology GA 327WU UT WOS:000087817900052 PM 10864683 ER PT J AU Lekstrom-Himes, JA LeBlanc, RA Pesnicak, L Godleski, M Straus, SE AF Lekstrom-Himes, JA LeBlanc, RA Pesnicak, L Godleski, M Straus, SE TI Gamma interferon impedes the establishment of herpes simplex virus type 1 latent infection but has no impact on its maintenance or reactivation in mice SO JOURNAL OF VIROLOGY LA English DT Article ID TRIGEMINAL GANGLION; NEURONAL DEATH; EXPRESSION; RESISTANCE; RADIATION; RECEPTOR; PROTECTS; IMMUNITY AB Murine models of gamma interferon (IFN-gamma) deficiency demonstrate the role of this cytokine in attenuating acute herpes simplex virus (HSV) disease; however, the effect of IFN-gamma on the establishment and maintenance of neuronal latency and viral reactivation is not known. Using the IFN-gamma knockout (GKO) model of IFN-gamma deficiency and sensitive quantitative PCR methods, we show that IFN-gamma significantly reduces the ganglion content of latent HSV-1 in BALB/c mice, which in turn delays viral time to reactivation following UV irradiation. Similar effects were not seen in the C57BL/6 strain. These results indicate that IFN-gamma significantly attenuates latent HSV infection in the mouse model of ocular infection but has no impact on the maintenance of latency or virus reactivation. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), 10 Ctr Dr,11N228, Bethesda, MD 20892 USA. NR 27 TC 27 Z9 27 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 JUL PY 2000 VL 74 IS 14 BP 6680 EP 6683 DI 10.1128/JVI.74.14.6680-6683.2000 PG 4 WC Virology SC Virology GA 327WU UT WOS:000087817900054 PM 10864685 ER PT J AU Barrett-Connor, E Espeland, MA Greendale, GA Trabal, J Johnson, S Legault, C Kritz-Silverstein, D Einhorn, P AF Barrett-Connor, E Espeland, MA Greendale, GA Trabal, J Johnson, S Legault, C Kritz-Silverstein, D Einhorn, P TI Postmenopausal hormone use following a 3-year randomized clinical trial SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID REPLACEMENT THERAPY; UNITED-STATES; ESTROGEN/PROGESTIN INTERVENTIONS; WOMEN; COHORT; MENOPAUSE; ESTROGENS; ATTITUDES; TERM AB Postmenopausal women often discontinue estrogen therapy within the first year. No studies have examined reasons why women continue or discontinue hormone replacement therapy (HRT) after several years of use, when hormone side effects have subsided. We wanted to identify determinants of estrogen use after participation in a 3-year randomized placebo-controlled trial. The Postmenopausal Estrogen/Progestin Intervention (PEPI) study compared the effects of estrogen alone or in combination with one of three progestogens with placebo. Post-PEPI use of hormone therapy was ascertained 1-4 years after the trial in 775 (90%) of the originally enrolled women. Potential correlates of treatment decisions were identified from sociodemographic characteristics, medical histories, and clinical measures ascertained at baseline and during and after the trial. Among women who had been assigned to placebo during PEPI, post-PEPI hormone use was significantly less common in women who were adherent to placebo during PEPI, older, or of non-Caucasian ethnicity. Hormone use was positively associated with hysterectomy. Among women assigned to an active regimen during PEPI, post-PEPI hormone use was significantly more common in women who used hormones before PEPI and in women who were adherent to hormones during PEPI. Older age, less education, and being non-Caucasian predicted less hormone use. Post-PEPI hormone use was highest in San Diego and lowest in Iowa City. Women on placebo who lost more bone mineral density (BMD) were more likely to begin hormones than women with less bone loss. Lipids, blood pressure, and other cardiovascular risk factors had relatively little influence on hormone use. The main predictors of post-PEPI hormone use were those associated with use in the general population (education, ethnicity, geographical region, hysterectomy, and prior use/adherence). C1 Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. Wake Forest Univ, Bowman Gray Sch Med, Biostat Sect, Winston Salem, NC USA. London Sch Hyg & Trop Med, Med Stat Unit, London WC1, England. Univ Calif Los Angeles, Med Ctr, Div Geriatr, Los Angeles, CA 90024 USA. Univ Texas, Hlth Sci Ctr, Dept Obstet & Gynecol, San Antonio, TX 78284 USA. Univ Iowa Hosp & Clin, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Barrett-Connor, E (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, 9500 Gilman Dr,0607, La Jolla, CA 92093 USA. FU NHLBI NIH HHS [U01-HL40195, U01-HL40154, U01-HL40185] NR 29 TC 16 Z9 16 U1 0 U2 0 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 JUL-AUG PY 2000 VL 9 IS 6 BP 633 EP 643 DI 10.1089/15246090050118161 PG 11 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 347HG UT WOS:000088922000007 PM 10957752 ER PT J AU Babar, SI Enright, PL Boyle, P Foley, D Sharp, DS Petrovitch, H Quan, SF AF Babar, SI Enright, PL Boyle, P Foley, D Sharp, DS Petrovitch, H Quan, SF TI Sleep disturbances and their correlates in elderly Japanese American men residing in Hawaii SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-of-Professional-Sleep-Societies CY MAY 28-JUN 02, 1996 CL WASHINGTON, D.C. SP Assoc Profess Sleep Soc ID OLDER ADULTS; RESPIRATORY SYMPTOMS; DAYTIME SLEEPINESS; GENERAL-POPULATION; RISK-FACTORS; INSOMNIA; COMPLAINTS; DISEASE; APNEA; HEALTH AB Background. Elderly people frequently report the presence of chronically disturbed sleep. However, most data are derived from predominantly Caucasian populations. The current study is an investigation of the prevalence and correlates of sleep disturbances in a cohort of elderly Japanese American men residing in Hawaii. The importance of this population lies in its representation of an ethnic group living in a culture different from their ancestry. Methods. This study is a cross-sectional cohort analysis of data pertaining to sleep disturbances and their potential correlates from 3,845 elderly Japanese American men residing in Hawaii (mean age. 78 years; range, 71-93 years) who participated in the fourth survey of the Honolulu Heart Program (1991-1994), which is the baseline exam for the Honolulu-Asia Aging Study. information collected included an extensive survey of medication use, medical history, and assessments of physical and mental function, quality of life, and sleep. Results. The prevalence of insomnia (DIMS) was 32.6%, a rate similar to that reported in predominantly Caucasian populations. Depression, benzodiazepine use, and several chronic health problems were the most important factors associated with DIMS. In contrast, excessive daytime sleepiness (EDS) had a prevalence of 8.9%, a rate lower than that found in elderly Caucasian populations but close to that reported among native Japanese. Important factors related to EDS were symptoms of nocturnal respiratory disturbance, depression, perception of adverse quality of life. Parkinson's disease, and digitalis use. Conclusions. Elderly Japanese men are less likely than elderly Caucasian men to report excessive daytime sleepiness. However, their insomnia rates are similar. C1 Univ Arizona, Coll Med, Resp Sci Ctr, Tucson, AZ 85724 USA. Univ Arizona, Coll Med, Sleep Disorders Ctr, Tucson, AZ 85724 USA. NIA, Bethesda, MD 20892 USA. Honolulu Heart Program, Honolulu, HI USA. RP Quan, SF (reprint author), Univ Arizona, Coll Med, Resp Sci Ctr, 1501 N Campbell Ave, Tucson, AZ 85724 USA. NR 38 TC 10 Z9 11 U1 2 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2000 VL 55 IS 7 BP M406 EP M411 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XW UT WOS:000088044800014 ER PT J AU Fernandez-Llama, P Jimenez, W Bosch-Marce, M Arroyo, V Nielsen, S Knepper, MA AF Fernandez-Llama, P Jimenez, W Bosch-Marce, M Arroyo, V Nielsen, S Knepper, MA TI Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis SO KIDNEY INTERNATIONAL LA English DT Article DE sodium-chloride cotransporter; thiazide; urinary dilution; water channels; hepatic cirrhosis ID WATER CHANNEL; COLLECTING DUCT; ASCITES FORMATION; PLASMA-MEMBRANE; RAT; VASOPRESSIN; RETENTION; EXPRESSION; PROTEIN; MICROPUNCTURE AB Background. Severe hepatic cirrhosis is associated with abnormal renal water retention. Methods. Semiquantitative immunoblotting was employed to investigate the abundance of the major renal aquaporins (water channels) and sodium-dependent cotransporters in kidneys from control rats and rats with cirrhosis secondary to chronic CCl4 inhalation. Results. The cirrhotic rats had ascites and manifested a water excretion defect detected by a standard water-loading test. The abundance of aquaporin-1 (the major aquaporin in the proximal tubule) was increased, an effect markedly accentuated in high-density membrane fractions prepared by differential centrifugation. Differential centrifugation studies demonstrated a redistribution of aquaporin-2 from high-density to low-density membranes, compatible with increased trafficking of aquaporin-2 to the plasma membrane. The abundance of aquaporin-3, but not aquaporin-2, was increased in collecting ducts of rats with CCl4-induced cirrhosis. The Na-K-2Cl cotransporter of the thick ascending limb showed no change in abundance. However, the abundance of the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule was markedly suppressed in cirrhotic rats, possibly contributing to a defect in urinary dilution. Conclusions. In this model of cirrhosis, the development of a defect in urinary dilution may be multifactorial, with contributions from at least four abnormalities in transporter regulation: (1) an increase in the renal abundance of aquaporin-1, (2) a cellular redistribution of aquaporin-2 in the collecting duct compatible with trafficking to the plasma membrane without an increase in total cellular aquaporin-2, (3) an increase in the renal abundance of aquaporin-3, and (4) a decrease in the abundance of the thiazide-sensitive cotransporter of the distal convoluted tubule. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Barcelona, Hosp Clin Univ, Inst Malalties Digest, Hormonal Lab, Barcelona, Spain. Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. Inst Reina Sofia Invest Nefrol, Madrid, Spain. Univ Aarhus, Inst Anat, Dept Cell Biol, Aarhus, Denmark. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. RI Arroyo, Vicente/F-9189-2015 OI Arroyo, Vicente/0000-0002-2728-1848 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 45 TC 54 Z9 54 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2000 VL 58 IS 1 BP 216 EP 228 DI 10.1046/j.1523-1755.2000.00156.x PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 328VE UT WOS:000087870100023 PM 10886566 ER PT J AU Cheung, AK Sarnak, MJ Yan, GF Dwyer, JT Heyka, RJ Rocco, MV Teehan, BP Levey, AS AF Cheung, AK Sarnak, MJ Yan, GF Dwyer, JT Heyka, RJ Rocco, MV Teehan, BP Levey, AS CA Hemodialysis HEMO Study TI Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients SO KIDNEY INTERNATIONAL LA English DT Article DE coronary risk factors; uremia; blood pressure; dialysis; serum total cholesterol; vascular disease ID CORONARY HEART-DISEASE; BLOOD-PRESSURE; MAINTENANCE HEMODIALYSIS; MORTALITY; UREMIA AB Background. Cardiovascular diseases are the most common causes of death among chronic hemodialysis patients, yet the risk factors for these events have not been well established. Methods. In this cross-sectional study, we examined the relationship between several traditional cardiovascular disease risk factors and the presence or history of cardiovascular events in 936 hemodialysis patients enrolled in the baseline phase of the Hemodialysis Study sponsored by the U.S. National Institutes of Health. The adjusted odds ratios for each of the selected risk factors were estimated using a multivariable: logistic regression model, controlling for the remaining risk factors, clinical center, and years on dialysis. Results. Forty percent of the patients had coronary heart disease. Nineteen percent had cerebrovascular disease, and 23% had peripheral vascular disease. As expected, diabetes and smoking were strongly associated with cardiovascular diseases. Increasing age was also an important contributor, especially in the group less than 55 years and in nondiabetic patients. Black race was associated with a lower risk of cardiovascular diseases than non-blacks. Interestingly, neither serum total cholesterol nor predialysis systolic blood pressure was associated with coronary heart disease, cerebrovascular disease, or peripheral vascular disease. Further estimation of the coronary risks in our cohort using the Framingham corollary point score suggests that traditional risk factors ale inadequate predictors of coronary heart disease in hemodialysis patients. Conclusions. Some of the traditional coronary risk factors in the general population appear to be also applicable to the hemodialysis population, while other factors did nut correlate with atherosclerotic cardiovascular diseases in this cross-sectional study. Nontraditional risk factors, including the uremic milieu and perhaps the hemodialysis procedure itself, are likely to be contributory. Further studies are necessary to define the cardiovascular risk factors in order to devise preventive and interventional strategies For the chronic hemodialysis population. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Cheung, AK (reprint author), Univ Utah, Div Nephrol & Hypertens, 85 N Med Dr Front, Salt Lake City, UT 84112 USA. OI Dwyer, Johanna/0000-0002-0783-1769 NR 28 TC 482 Z9 509 U1 2 U2 3 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2000 VL 58 IS 1 BP 353 EP 362 DI 10.1046/j.1523-1755.2000.00173.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 328VE UT WOS:000087870100039 PM 10886582 ER PT J AU Nevalainen, MT Ahonen, TJ Yamashita, H Chandrashekar, V Bartke, A Grimley, PM Robinson, GW Hennighausen, L Rui, H AF Nevalainen, MT Ahonen, TJ Yamashita, H Chandrashekar, V Bartke, A Grimley, PM Robinson, GW Hennighausen, L Rui, H TI Epithelial defect in prostates of Stat5a-null mice SO LABORATORY INVESTIGATION LA English DT Article ID GROWTH-HORMONE GH; RAT PROSTATE; ORGAN-CULTURE; TYROSINE PHOSPHORYLATION; PROLACTIN RECEPTOR; LATERAL PROSTATE; ADHESION KINASE; GENE-EXPRESSION; DIFFERENT LOBES; STAT5B AB The transcription factor Stat5a critically mediates prolactin (PRL)-induced mammary gland development and lactogenesis. PRL also stimulates growth and differentiation of prostate tissue. Specifically, hyperprolactinemia gives rise to prostate hyperplasia, and prostate size is reduced in PRL-deficient mice. We therefore investigated the importance of Stat5a for prostate development acid function by examining Stat5a-null mice. The absence of Stat5a in mice was associated with a distinct prostate morphology characterized by an increased prevalence of local disorganization within acinar epithelium of ventral prostates. Affected acini were typically filled with desquamated, granular epithelial cells that had become embedded in dense, coagulated secretory material. These features were reminiscent of acinar cyst formation and degeneration frequently observed in human benign prostate hyperplasia, however, cystic changes in prostate acini of Stat5a-deficient mice were not associated with increased prostate size or morphologic hallmarks of epithelial hyperplasia. Instead, immunohistochemistry of the prostate-specific secretory marker, probasin, suggested that hypersecretory function of the epithelium could underlie local congestion and cyst formation in prostates of Stat5a-null mice. Serum testosterone and PRL levels were normal in Stat5a knockout mice, but prostate PRL receptor expression was reduced as determined by immunohistochemistry. Expression levels or activation states of other PRL signal transduction proteins, including Stat5b, Stat3, Stat1, ERK1, and ERK2 were not altered. The present study offers the first evidence for a direct role of Stat5a in the maintenance of normal tissue architecture and function of the mouse prostate. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Pathol, Bethesda, MD 20814 USA. NIDKD, Lab Genet & Physiol, NIH, Bethesda, MD USA. So Illinois Univ, Dept Physiol, Carbondale, IL 62901 USA. Univ Turku, Inst Biomed, Dept Anat, FIN-20520 Turku, Finland. RP Rui, H (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Pathol, Bethesda, MD 20814 USA. EM hrui@usuhs.mil RI Robinson, Gertraud/I-2136-2012; Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X FU NIDDK NIH HHS [R01 DK52013] NR 47 TC 31 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUL PY 2000 VL 80 IS 7 BP 993 EP 1006 DI 10.1038/labinvest.3780105 PG 14 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 335UN UT WOS:000088263300001 PM 10908145 ER PT J AU Bennett, JM Catovsky, D Daniel, MT Flandrin, G Galton, DAG Gralnick, HR Willman, CL AF Bennett, JM Catovsky, D Daniel, MT Flandrin, G Galton, DAG Gralnick, HR Willman, CL TI Hypergranular promyelocytic leukemia: correlation between morphology and chromosomal translocations including t(15;17) and t(11;17) SO LEUKEMIA LA English DT Article DE t(15;17); promyelocytic leukemia; t(11;17) ID TRANS-RETINOIC ACID; ZINC FINGER GENE; RECEPTOR-ALPHA; RAR-ALPHA; MOLECULAR CHARACTERIZATION; 15-17 TRANSLOCATION; FUSION; DIFFERENTIATION; CLASSIFICATION; IDENTIFICATION AB The FAB group has reviewed 32 cases of promyelocytic leukemia and variant forms. By utilizing published criteria the ability to make a correct diagnosis by morphology with molecular genetic confirmation and to eliminate cases that did not have the PML/RAR alpha rearrangement was excellent. C1 Univ Rochester, Ctr Canc, Rochester, NY 14642 USA. Royal Marsden Hosp, Acad Dept Haematol & Cytogenet, London SW3 6JJ, England. Hop St Louis, Inst Rech Leucemies & Malad Sang, Paris, France. Grp Hosp Necker Enfants Malad, Serv Cent Hematol, Paris, France. Royal Postgrad Med Sch, MRC, Leukemia Unit, London, England. NIH, Hematol Serv, Bethesda, MD 20892 USA. Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. RP Bennett, JM (reprint author), Univ Rochester, Ctr Canc, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. FU NCI NIH HHS [CA32102, CA11083] NR 26 TC 15 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2000 VL 14 IS 7 BP 1197 EP 1200 DI 10.1038/sj.leu.2401795 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 332FM UT WOS:000088063600005 PM 10914542 ER PT J AU An, WG Hwang, SG Trepel, JB Blagosklonny, MV AF An, WG Hwang, SG Trepel, JB Blagosklonny, MV TI Protease inhibitor-induced apoptosis: accumulation of wt p53, p21(WAF1/CIP1) and induction of apoptosis are independent markers of proteasome inhibition SO LEUKEMIA LA English DT Article DE leukemia; cancer; apoptosis; proteasome; p53; p21 ID MYELOID-LEUKEMIA CELLS; WILD-TYPE P53; DNA FRAGMENTATION; IN-VIVO; CASPASE ACTIVATION; HUMAN FIBROBLASTS; DEATH PROGRAM; CANCER-CELLS; CATHEPSIN-D; DEGRADATION AB Inhibitors of proteases are currently emerging as a potential anti-cancer modality. Nonselective protease inhibitors are cytotoxic to leukemia and cancer cell lines and we found that this cytotoxicity is correlated with their potency as inhibitors of the proteasome but not as inhibitors of calpain and cathepsin. Highly selective inhibitors of the proteasome were more cytotoxic and fast-acting than less selective inhibitors (PS341>>ALLN>>ALLM). Induction of wt p53 correlated with inhibition of the proteasome and antiproliferative effect in MCF-7, a breast cancer cell line, which was resistant to apoptosis caused by proteasome inhibitors. In contrast, inhibitors of the proteasome induced apoptosis in four leukemia cell lines lacking wt p53. The order of sensitivity of leukemia cells was: Jurket>HL60 greater than or equal to U937>>K562. The highly selective proteasome inhibitor PS-341 induced cell death with an IC50 as low as 5 nM in apoptosis-prone leukemia cells. Cell death was preceded by p21(WAF1/CIP1) accumulation, an alternative marker of proteasome inhibition, and by cleavage of PARP and Rb proteins and nuclear fragmentation. Inhibition of caspases abrogated PARP cleavage and nuclear fragmentation and delayed, but did not completely prevent cell death caused by PS-341. Reintroduction of wt p53 into p53-null PC3 prostate carcinoma cells did not increase their sensitivity to proteasome inhibitors. Likewise, comparison of parental and p21-deficient cells demonstrated that p21(WAF1/CIP1) was dispensable for proteasome inhibitor-induced cytotoxicity. We conclude that accumulation of wt p53 and induction of apoptosis are independent markers of proteasome inhibition. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. NR 62 TC 174 Z9 182 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2000 VL 14 IS 7 BP 1276 EP 1283 DI 10.1038/sj.leu.2401812 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 332FM UT WOS:000088063600016 PM 10914553 ER PT J AU Fowler, DH Gress, RE AF Fowler, DH Gress, RE TI Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: Considerations for the allogeneic transplantation therapy of leukemia and lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE GVHD; GVL; therapy of leukemia & lymphoma; Th1 cells; Th2 cells; Tc1 and Tc2 cells; allotransplantation; stem cell transplant ID VERSUS-HOST-DISEASE; BONE-MARROW TRANSPLANTATION; TUMOR-NECROSIS-FACTOR; CHRONIC MYELOID-LEUKEMIA; CD8(+) T-CELLS; PERIPHERAL-BLOOD LYMPHOCYTES; CHRONIC MYELOGENOUS LEUKEMIA; GROWTH-FACTOR-BETA; FAS-LIGAND; EFFECTOR POPULATIONS AB Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4(+), Th1/Th2 and CD8(+), Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential for improving treatment outcome. C1 NCI, Dept Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. RP Fowler, DH (reprint author), NCI, Dept Expt Transplantat & Immunol, NIH, 9000 Rockville Pike,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. NR 84 TC 85 Z9 102 U1 0 U2 0 PU HARWOOD ACAD PUBL GMBH PI READING PA C/O STBS LTD, PO BOX 90, READING, BERKS, ENGLAND RG1 8JL SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUL PY 2000 VL 38 IS 3-4 BP 221 EP 234 DI 10.3109/10428190009087014 PG 14 WC Oncology; Hematology SC Oncology; Hematology GA 314NE UT WOS:000087061500002 PM 10830730 ER PT J AU Sazawal, S Bhatia, K Gurbuxani, S Arya, LS Raina, V Khattar, A Vats, T Magrath, I Bhargava, M AF Sazawal, S Bhatia, K Gurbuxani, S Arya, LS Raina, V Khattar, A Vats, T Magrath, I Bhargava, M TI Pattern of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements in childhood acute lymphoblastic leukemia in India SO LEUKEMIA RESEARCH LA English DT Article DE ALL in India; biology of ALL; childhood ALL; Ig gene rearrangements; immunophenotype; TCR gene rearrangements ID HEAVY-CHAIN GENE; ORIGIN; VH AB In 120 cases of acute lymphoblastic leukemia (median age 8 years), IgH chain gene was rearranged in 99% B-Cell Precursor (BCP) ALLs and 13% T-ALLs. One or the other TCR locus was rearranged not only in all T-ALLs, but also in 87% of BCP-ALLs. TCR-beta rearrangement in BCP-ALL was associated with a higher mean age at presentation (8.7 vs. 6.2 years, P = 0.008), lower mean platelet counts (61.2 x 109/l vs. 103.7 x 109/1, P = 0.003) and a poorer DFS (% cummulative survival 0 vs. 88.9 +/- 10.5, P = 0.004). TCR-gamma rearrangement in T-ALL was associated with a higher mean WBC count (186.3 x 10(9)/l vs. 63.4 x 109/l, P = 0.002). Also, the pattern of rearrangement of these genes appeared to be different from the West; viz. TCR-beta rearrangement in a higher proportion of BCP-ALLs (58%, 95% confidence intervals 45-69%), invariable deletion of C gamma 1 and only monoallelic rearrangement for TCR-delta locus. This repertoire of gene rearrangement may have a bearing on the poor treatment outcome reported previously from our geographic region. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 All India Inst Med Sci, Dept Haematol, AIIMS, New Delhi 110029, India. NCI, Lymphoma Biol Sect, Paediat Branch, NIH, Bethesda, MA USA. All India Inst Med Sci, Dept Med Oncol, New Delhi, India. Texas Tech Univ, Hlth Sci Ctr, Dept Paediat, Amarillo, TX USA. RP Bhargava, M (reprint author), All India Inst Med Sci, Dept Haematol, AIIMS, IRCH Bldg,1st Floor, New Delhi 110029, India. OI Bhargava, Manorama/0000-0003-2135-7298 NR 25 TC 13 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2000 VL 24 IS 7 BP 575 EP 582 DI 10.1016/S0145-2126(00)00025-4 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 333RX UT WOS:000088145500004 PM 10867131 ER PT J AU Barrett, J AF Barrett, J TI Myelodysplastic syndrome and aplastic anemia - diagnostic and conceptual uncertainties SO LEUKEMIA RESEARCH LA English DT Article ID BONE-MARROW; ANTITHYMOCYTE GLOBULIN C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, J (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2000 VL 24 IS 7 BP 595 EP 596 DI 10.1016/S0145-2126(00)00026-6 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 333RX UT WOS:000088145500007 PM 10867134 ER PT J AU Murphy, EJ Prows, DR Stiles, T Schroeder, F AF Murphy, EJ Prows, DR Stiles, T Schroeder, F TI Liver and intestinal fatty acid-binding protein expression increases phospholipid content and alters phospholipid fatty acid composition in L-cell fibroblasts SO LIPIDS LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; DIHYDROXYACETONE PHOSPHATE ACYLTRANSFERASE; ACYL-COENZYME-A; RAT-LIVER; CHOLINE PLASMALOGENS; METABOLISM; LIPIDS; BIOSYNTHESIS; PEROXISOMES; CULTURES AB Although fatty acid-binding proteins (FABP) differentially affect fatty acid uptake, nothing is known regarding their role(s) in determining cellular phospholipid levels and phospholipid fatty acid composition. The effects of liver (L)- and intestinal (I)-FABP expression on these parameters were determined using stably transfected L-cells. Expression of L- and I-FABP increased cellular total phospholipid mass (nmol/mg protein) 1.7- and 1.3-fold relative to controls, respectively. L-FABP expression increased the masses of choline glycerophospholipids (ChoGpl) 1.5-fold, phosphatidylserine (PtdSer) 5.6-fold, ethanolamine glycerophospholipids 1.4-fold, sphingomyelin 1.7-fold, and phosphatidylinositol 2.6-fold. In contrast, I-FABP expression only increased the masses of ChoGpl and PtdSer, 1.2- and 3.1-fold, respectively. Surprisingly, both L- and I-FABP expression increased ethanolamine plasmalogen mass 1.6- and 1.1-fold, respectively, while choline plasmalogen mass was increased 2.3- and 1.7-fold, respectively. The increase in phospholipid levels resulted in dramatic 48 and 33% decreases in the cholesterol-to-phospholipid ratio in L- and I-FABP expressing cells, respectively. L-FABP expression generally increased polyunsaturated fatty acids, primarily by increasing 20:4n-6 and 22:6n-3, while decreasing 18:1n-9 and 16:1n-7. I-FABP expression generally increased only 20:4n-6 proportions. Hence, expression of both I- and L-FABP differentially affected phospholipid mass, class composition, and acyl chain composition. Although both proteins enhanced phospholipid synthesis, the effect of L-FABP was much greater, consistent with previous work suggesting that these two FABP differentially affect lipid metabolism. C1 Texas A&M Univ, Dept Physiol & Pharmacol, TVMC, College Stn, TX 77843 USA. Univ Cincinnati, Coll Pharm, Div Pharmacol & Med Chem, Cincinnati, OH 45267 USA. RP Murphy, EJ (reprint author), NIA, Sect Brain Physiol & Metab, Bldg 10,Room 6C103, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK 41402] NR 62 TC 26 Z9 26 U1 1 U2 3 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 JUL PY 2000 VL 35 IS 7 BP 729 EP 738 DI 10.1007/s11745-000-0579-x PG 10 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 339WG UT WOS:000088500400004 PM 10941873 ER PT J AU Corn, M AF Corn, M TI The granting game: Part II, How to love NIH form 398 and set that grant SO M D COMPUTING LA English DT Editorial Material C1 Natl Lib Med, Bethesda, MD USA. RP Corn, M (reprint author), Natl Lib Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0724-6811 J9 M D COMPUT JI M D Comput. PD JUL-AUG PY 2000 VL 17 IS 4 BP 23 EP 26 PG 4 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 356AD UT WOS:000089420000012 PM 11014073 ER PT J AU Vathyam, S Byrd, RA Miller, AF AF Vathyam, S Byrd, RA Miller, AF TI Mapping the effects of metal ion reduction and substrate analog binding to Fe-superoxide dismutase by NMR spectroscopy SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Article DE NMR; non-heme iron; paramagnetic; superoxide dismutase; redox-linked changes; substrate binding ID REDOX-LINKED CHANGES; ESCHERICHIA-COLI-B; IRON ACTIVE-SITES; CHEMICAL-SHIFTS; RELAXATION MEASUREMENTS; 2-DIMENSIONAL H-1-NMR; CATALYTIC MECHANISM; BACKBONE ASSIGNMENT; STRUCTURAL-CHANGES; CRYSTAL-STRUCTURE AB Fe-containing superoxide dismutase (FeSOD) is an excellent model for studies of the role of the protein in shaping redox catalytic activity in metalloenzymes. In order to use NMR spectroscopy to monitor the protons in FeSOD, we have assigned all the observable backbone resonances in the HN heteronuclear single quantum correlation spectrum (HN-HSQC), in both of the reduced and oxidized states. This task required H-2, C-13 and N-15 triple labeling and quadruple resonance techniques due to FeSOD's molecular weight of 42 kDa and paramagnetic high-spin active site Fe. The unobserved and unassigned residues of FeSOD are accounted for by paramagnetic relaxation and slow back-exchange of solvent protons into backbone H-N positions. Of FeSOD's 192 residues, we have previously assigned resonances for 118 in the oxidized state and now 141 in the reduced state. For residues > 14 Angstrom from Fe, resonances are observable in both oxidation states. Relatively small chemical shift changes were found to accompany Fe2+ oxidation, but these extend throughout the protein. Specific binding of the substrate analog F- to Fe2+ SOD was found to involve residues near Tyr34, consistent with participation of this residue in substrate binding. This represents the first location of substrate binding to Fe2+SOD. Additional residues at the dimer interface are sensitive to a variety of anions in both of FeSOD's oxidation states and also Fe oxidation, consistent with either interaction with substrate or domain movement associated with substrate binding and metal ion oxidation. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Miller, AF (reprint author), Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 NR 59 TC 13 Z9 13 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD JUL PY 2000 VL 38 IS 7 BP 536 EP 542 DI 10.1002/1097-458X(200007)38:7<536::AID-MRC719>3.0.CO;2-8 PG 13 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 330UW UT WOS:000087980400010 ER PT J AU Gakh, YG Gakh, AA Gronenborn, AM AF Gakh, YG Gakh, AA Gronenborn, AM TI Fluorine as an NMR probe for structural studies of chemical and biological systems SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Article DE NMR; fluorine NMR; probe; chemical structure; biological systems ID SPIN-COUPLING-CONSTANTS; F-19 NMR; ESCHERICHIA-COLI; CONFORMATIONAL HETEROGENEITY; DIHYDROFOLATE-REDUCTASE; CARBON-FLUORINE; CUBYL CATION; C-13; H-1; PROTEINS AB Applications of fluorine NMR to probe long-range interactions in rigid organic molecules, namely cubanes, and to study structures and dynamics of proteins and other biological systems, are presented. F-19 NMR parameters, especially long-range coupling constants are shown to reveal intrinsic features of the molecules. Correlations between long-range (more than three-bond) couplings involving fluorine and other chemical and physicochemical properties of the compounds are demonstrated, and examples of unusual couplings which cannot be explained by existing theories of 'through-bond' and 'through-space' mechanisms are discussed. Recent applications of fluorine labeling of aromatic and aliphatic amino acids in investigating protein structures and dynamics are highlighted. The potential of using F-19 NMR parameters, such as large spin-spin coupling constants observed for organic compounds, for structural analysis of biological macromolecules is outlined. Copyright (C) 2000 John Wiley & Sons. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 70 TC 78 Z9 78 U1 2 U2 17 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD JUL PY 2000 VL 38 IS 7 BP 551 EP 558 DI 10.1002/1097-458X(200007)38:7<551::AID-MRC686>3.0.CO;2-Q PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 330UW UT WOS:000087980400012 ER PT J AU Basser, PJ Pajevic, S AF Basser, PJ Pajevic, S TI Statistical artifacts in diffusion tensor MRI (DT-MRI) caused by background noise SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; diffusion; DTI; DT-MRI; tensor; dyadic; bias; noise; eigenvalue; eigenvector; artifact ID WATER DIFFUSION; HUMAN BRAIN; TISSUES; ANISOTROPY; FEATURES; IMAGES AB This work helps elucidate how background noise introduces statistical artifacts in the distribution of the sorted eigenvalues and eigenvectors in diffusion tensor MRI (DT-MRI) data, Although it was known that sorting eigenvalues (principal diffusivities) by magnitude introduces a bias in their sample mean within a homogeneous region of interest (ROI), here it is shown that magnitude sorting also introduces a significant bias in the variance of the sample mean eigenvalues. New methods are presented to calculate the mean and variance of the eigenvectors of the diffusion tensor, based on a dyadic tensor representation of eigenvalue-eigenvector pairs. Based on their use it is shown that sorting eigenvalues by magnitude also introduces a bias in the mean and the variance of the sample eigenvectors (principal directions), This required the development of new methods to calculate the mean and variance of the eigenvectors of the diffusion tensor, based on a dyadic tensor representation of eigenvalue-eigenvector pairs. Moreover, a new approach is proposed to order these pairs within an ROI, To do this, a correspondence between each principal axis of the diffusion ellipsoid, an eigenvalue-eigenvector pair, and a dyadic tensor constructed from it is exploited, A measure of overlap between principal axes of diffusion ellipsoids in different voxels is defined that employs projections between these dyadic tensors, The optimal eigenvalue assignment within an ROI maximizes this overlap. Bias in the estimate of the mean and of the variance of the eigenvalues and of their corresponding eigenvectors is reduced in DT-MRI experiments and in Monte Carlo simulations of such experiments. Improvement is most significant in isotropic regions, but some is also observed in anisotropic regions. This statistical framework should enhance our ability to characterize microstructure and architecture of healthy tissue, and help to assess its changes in development, disease, and degeneration. Mitigating these artifacts should also improve the characterization of diffusion anisotropy and the elucidation of fiber-tract trajectories in the brain and in other fibrous tissues. Published 2000 Wiley-Liss, Inc.(dagger). C1 NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bld 13,Rm 3W16,13 South Dr, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 26 TC 218 Z9 224 U1 0 U2 7 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2000 VL 44 IS 1 BP 41 EP 50 DI 10.1002/1522-2594(200007)44:1<41::AID-MRM8>3.0.CO;2-O PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329PW UT WOS:000087917000008 PM 10893520 ER PT J AU Ye, FQ Frank, JA Weinberger, DR McLaughlin, AC AF Ye, FQ Frank, JA Weinberger, DR McLaughlin, AC TI Noise reduction in 3D perfusion imaging by attenuating the static signal in arterial spin tagging (ASSIST) SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE arterial spin tagging; cerebral blood flow; human; brain; background suppression ID FUNCTIONAL MRI; ARTIFACTS; FMRI AB Phase-encoded multishot SPIRAL approaches were used to acquire true 3D cerebral blood flow images of the human head using arterial spin tagging approaches. Multiple-inversion background suppression techniques, which suppress phase noise due to interacquisition fluctuations in the static magnetic field, reduced the temporal standard deviation of true 3D Delta M images acquired using arterial spin tagging approaches by similar to 50%, Background suppressed arterial spin tagging (ASSIST) approaches were used to obtain high-resolution isotropic true 3D cerebral blood flow images, and to obtain true 3D activation images during cognitive (working memory) tasks. Published 2000 Wiley-Liss, Inc.(dagger). C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, CC, Bethesda, MD 20892 USA. RP McLaughlin, AC (reprint author), NIH, Bldg 10,Room B1D-61,10 Ctr Dr,MSC 1063, Bethesda, MD 20892 USA. NR 29 TC 172 Z9 173 U1 2 U2 7 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2000 VL 44 IS 1 BP 92 EP 100 DI 10.1002/1522-2594(200007)44:1<92::AID-MRM14>3.0.CO;2-M PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329PW UT WOS:000087917000014 PM 10893526 ER PT J AU Dasmahapatra, AK Wimpee, BAB Budsberg, KJ Dorschner, MO Phillips, RB Hutz, RJ AF Dasmahapatra, AK Wimpee, BAB Budsberg, KJ Dorschner, MO Phillips, RB Hutz, RJ TI Lack of effect of beta-naphthoflavone on induction of Nramp genes in adult rainbow trout Oncorhynchus mykiss SO MARINE ENVIRONMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 10th international Symposium on Pollutant Responses in Marine Organisms (PRIMO 10) CY APR 25-29, 1999 CL COLL WILLIAM & MARY, WILLIAMSBURG, VIRGINIA HO COLL WILLIAM & MARY DE Nramp; CYP1A1; ovary; rainbow trout; BNF; RT-PCR ID NATURAL-RESISTANCE; MACROPHAGE; TRANSFERRIN; INFECTIONS; EXPRESSION; SYSTEM; CDNA AB Natural resistance-associated macrophage protein (Nramp) genes in rainbow trout, Oncorhynchus mykiss, were identified and characterized. The greatest mRNA level encoding these genes was in the developing ovary of rainbow trout. We evaluated the response of these genes to a certain aromatic hydrocarbon receptor (AHR) agonist. Adult rainbow trout were treated with beta -naphthoflavone (BNF) (50 and 100 mg/kg) for 48 h. Using reverse-transcriptase polymerase chain reaction with ovary and head kidney RNA and specific alpha and beta Nramp primers, a 400 bp Nramp-alpha- and a 400 bp Nramp-beta -specific cDNA were obtained. There were no changes in the alpha and beta Nramp mRNA levels in the ovary following BNF administration. CYP1A1 mRNA was increased in the ovary and kidney, suggesting the presence of AHR in rainbow trout ovary, while the AHR agonist produced no effect on Nramp mRNAs. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Wisconsin, NIEHS, Marine & Freshwater Biomed Sci Ctr, Milwaukee, WI 53204 USA. RP Hutz, RJ (reprint author), Univ Wisconsin, NIEHS, Marine & Freshwater Biomed Sci Ctr, Milwaukee, WI 53204 USA. NR 12 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 0141-1136 J9 MAR ENVIRON RES JI Mar. Environ. Res. PD JUL-DEC PY 2000 VL 50 IS 1-5 BP 147 EP 151 DI 10.1016/S0141-1136(00)00113-6 PG 5 WC Environmental Sciences; Marine & Freshwater Biology; Toxicology SC Environmental Sciences & Ecology; Marine & Freshwater Biology; Toxicology GA 376ZG UT WOS:000165486700025 PM 11460681 ER PT J AU Klein, HG AF Klein, HG TI Transfusion safety - Reply SO MAYO CLINIC PROCEEDINGS LA English DT Letter ID AUTOLOGOUS BLOOD DONATION; DONORS C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2000 VL 75 IS 7 BP 769 EP 770 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 332AM UT WOS:000088050900019 ER PT J AU Kondaiah, P Taira, M Vempati, UD Dawid, IB AF Kondaiah, P Taira, M Vempati, UD Dawid, IB TI Transforming growth factor-beta 5 expression during early development of Xenopus laevis SO MECHANISMS OF DEVELOPMENT LA English DT Article DE TGF-beta; Xenopus laevis; in situ whole-mount hybridization; mRNA; gene expression; somites; cement gland; branchial arches; notochord; olfactory placode ID TGF-BETA; MESODERM INDUCTION; MESSENGER-RNA; ACTIVIN-A; EMBRYOS; IDENTIFICATION; INHIBITORS; PROTEIN; BMP-4 AB Members of the transforming growth factor-beta (TGF-beta) superfamily play various roles during development in both vertebrates and invertebrates. Two isoforms, TGF-beta 2 and -beta 5, have been isolated from Xenopus laevis. We describe here the localization of TGF-beta 5 mRNA in early embryos of X. laevis, assessed by whole-mount in situ hybridization. The first detectable expression of TGF-beta 5 was seen in the stage 14 embryo at the posterior tip of notochord, which continued to later stages, accompanied by the expression in bilateral regions of posterior wall in the tail region next to the notochord. At later stages, transient expression was seen in the cement gland (around stage 21) and in the somites (stages 24-27). In addition, expression was present in the branchial arches (stage 29-36) and olfactory placodes (stage 36). (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India. NICHD, Genet Mol Lab, NIH, Bethesda, MD USA. RP Kondaiah, P (reprint author), Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India. NR 25 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUL PY 2000 VL 95 IS 1-2 BP 207 EP 209 DI 10.1016/S0925-4773(00)00326-9 PG 3 WC Developmental Biology SC Developmental Biology GA 341UC UT WOS:000088607200018 PM 10906463 ER PT J AU Du, XL Freeman, JL Warren, JL Nattinger, AB Zhang, D Goodwin, JS AF Du, XL Freeman, JL Warren, JL Nattinger, AB Zhang, D Goodwin, JS TI Accuracy and completeness of medicare claims data for surgical treatment of breast cancer SO MEDICAL CARE LA English DT Article; Proceedings Paper CT 17th Annual Meeting of the Association-for-Health-Services-Research CY JUN 25-27, 2000 CL LOS ANGELES, CALIFORNIA SP Assoc Hlth Serv Res DE breast cancer; mastectomy; breast conserving surgery; SEER; Medicare ID GEOGRAPHIC-VARIATION; ELDERLY AMERICANS; LINKED MEDICARE; DATA-BASE; SURGERY; STAGE; WOMEN; SURVEILLANCE; ADVANTAGES; MASTECTOMY AB BACKGROUND. Although a number of studies have used Medicare claims data to study trends and variations in breast cancer treatment, the accuracy and completeness of information on surgical treatment for breast cancer in the Medicare data have not been validated. OBJECTIVES. This study assessed the accuracy and completeness of Medicare claims data for breast cancer surgery to determine whether Medicare claims can serve as a source of data to augment information collected by cancer registries. METHODS. We used the Surveillance, Epidemiology and End Results (SEER) Cancer Registry-Medicare data and compared Medicare claims on surgery with the surgery recorded by the SEER registries for 23,709 women diagnosed with breast cancer at greater than or equal to 65 years of age from 1991 through 1993. RESULTS. More than 95% of women having mastectomies according to the Medicare data were confirmed by SEER. For breast-conserving surgery, 91% of cases were confirmed by SEER. The Medicare physician services claims and inpatient claims were approximately equal in accuracy on type of surgery. The Medicare outpatient claims were less accurate for breast-conserving surgery. In terms of completeness, when the 3 claims sources were combined, 94% of patients receiving breast cancer surgery according to SEER were identified by Medicare. CONCLUSIONS. The combined Medicare claims database, which includes the inpatient, outpatient, and physician service claims, provides valid information on surgical treatment among women known to have breast cancer. The claims are a rich source of data to augment the information collected by tumor registries and provide information that can be used to follow long-term outcomes of Medicare beneficiaries. C1 Univ Texas, Med Branch, Dept Internal Med, Galveston, TX 77555 USA. Univ Texas, Med Branch, Sealy Ctr Aging, Galveston, TX 77555 USA. NCI, Appl Res Branch, Bethesda, MD 20892 USA. Med Coll Wisconsin, Div Gen Internal Med, Milwaukee, WI 53226 USA. Univ Texas, Med Branch, Off Biostat, Galveston, TX 77555 USA. RP Du, XL (reprint author), Univ Texas, Med Branch, Dept Internal Med, 301 Univ Blvd, Galveston, TX 77555 USA. FU NCI NIH HHS [CA72076] NR 32 TC 83 Z9 84 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2000 VL 38 IS 7 BP 719 EP 727 DI 10.1097/00005650-200007000-00004 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 330DG UT WOS:000087947100004 PM 10901355 ER PT J AU Yamada, T Richiert, D Tumminia, SJ Russell, P AF Yamada, T Richiert, D Tumminia, SJ Russell, P TI The tensegrity model applied to the lens: a hypothesis for the presence of the fiber cell ball and sockets SO MEDICAL HYPOTHESES LA English DT Article ID CYTOSKELETON; DIFFERENTIATION; MATURATION; MEMBRANES; NETWORK AB The concept of tensegrity refers to the tensional integrity of a system. Such a system mechanically stabilizes itself by balancing the opposing forces of tension and compression. One category of this model involves a 'pre-stressed' condition in which the structural elements are in a state of tensional compression. The other category includes rigid struts that can sustain the opposing forces. The lens of the eye contains epithelial cells that differentiate at the lens equator to fiber cells. With time, these fiber cells are packed into the center of the lens or the lens nucleus. Part of the process of differentiation is the loss of the cellular nucleus and organelles, During maturation of the lens fiber cells, much of the cytoskeleton is lost as a result of proteolysis. As the lens cells mature, ball and socket joints and interlocking ridges appear on the cellular surface. Applying the tensegrity model to the lens, it appears that the lens cells go from prestressed state of tensional compression to the other state that is defined by rigid connections between cells. (C) 2000 Harcourt Publishers Ltd. C1 NEI, Lab Mechanisms Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Russell, P (reprint author), 6 Ctr Dr MSC 2735,Bldg 6 Rm 228, Bethesda, MD 20892 USA. NR 20 TC 8 Z9 8 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 0306-9877 J9 MED HYPOTHESES JI Med. Hypotheses PD JUL PY 2000 VL 55 IS 1 BP 36 EP 39 DI 10.1054/mehy.1999.0994 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 343ZY UT WOS:000088734200007 PM 11021323 ER PT J AU Talvani, A Ribeiro, CS Aliberti, JCS Michailowsky, V Santos, PVA Murta, SMF Romanha, AJ Almeida, IC Farber, J Lannes-Vieira, J Silva, JS Gazzinelli, RT AF Talvani, A Ribeiro, CS Aliberti, JCS Michailowsky, V Santos, PVA Murta, SMF Romanha, AJ Almeida, IC Farber, J Lannes-Vieira, J Silva, JS Gazzinelli, RT TI Kinetics of cytokine gene expression in experimental chagasic cardiomyopathy: tissue parasitism and endogenous IFN-gamma as important determinants of chemokine mRNA expression during infection with Trypanosoma cruzi SO MICROBES AND INFECTION LA English DT Article DE Trypanosoma cruzi; chemokines; macrophages; inflammation ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; IN-VIVO; INTERFERON-GAMMA; TNF-ALPHA; MICROBICIDAL ACTIVITY; MEDIATES RESISTANCE; ENDOTHELIAL-CELLS; IL-2 PRODUCTION; MICE AB We investigated the kinetics of parasite replication, leukocyte migration, and cytokine/chemokine mRNA expression in the heart tissue from animals infected with the Colombiana strain of Trypanosoma cruzi. Cardiac tissue parasitism was noticeable at 15 days, peaked around 30 days and was dramatically reduced at 120 days postinfection (p.i.), Kinetic studies showed that the inflammatory infiltrate was dominated by the presence of alpha beta T CD3(+) CD4(+) CD8(-), alpha beta T CD3(+) CD4(-)CD8(+) lymphocytes and macrophages. The mRNA expression of the monokines IL-1 beta and IL-12(p40) was elevated at 15 days p,i. and controlled at later time points. In contrast, TNF-alpha mRNA was expressed throughout the infection. Interestingly, we found that at 15 and 30 days p.i. cytokine expression was dominated by the presence of IFN-gamma mRNA, whereas at 60 days or later time points the balance of type 1 and type 2 cytokines was switched in favor of IL-4 and IL-10 mRNAs, The chemokine mRNAs encoding JE, MIP-l alpha, MIP-1 beta, KC, and MIP-2 were all mainly expressed at 15 and/or 30 days p,i. and diminished thereafter. In contrast, the expression of RANTES, MIG and IP-10 mRNAs was augmented at 15 days p.i. and persisted at high levels up to 120 days p,i. Taken together, our results indicate that regulation of IFN-gamma and chemokine expression, associated with decreased tissue parasitism, may be largely responsible for the control of inflammation and immunopathology observed in the cardiac tissue of animals infected with ir: cruzi. (C) 2000 Editions scientifiques et medicales Elsevier SAS. C1 UFMG, Dept Biochem & Immunol, ICB, BR-31270910 Belo Horizonte, MG, Brazil. FIOCRUZ, CPqRR, Immunopathol Lab, BR-30190002 Belo Horizonte, MG, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Microbiol Immunol & Parasitol, BR-14049900 Ribeirao Preto, Brazil. FIOCRUZ, Inst Oswaldo Cruz, Dept Immunol, BR-21045900 Rio De Janeiro, Brazil. Univ Sao Paulo, Dept Parasitol, ICB, BR-05508900 Sao Paulo, Brazil. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Gazzinelli, RT (reprint author), UFMG, Dept Biochem & Immunol, ICB, Av Antonio Carlos 6627, BR-31270910 Belo Horizonte, MG, Brazil. RI Silva, Joao/A-4484-2008; Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 60 TC 119 Z9 121 U1 0 U2 2 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2000 VL 2 IS 8 BP 851 EP 866 DI 10.1016/S1286-4579(00)00388-9 PG 16 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 345ZX UT WOS:000088846600001 PM 10962268 ER PT J AU Ryschkewitsch, CF Friedlaender, JS Mgone, CS Jobes, DV Agostini, HT Chima, SC Alpers, MP Koki, G Yanagihara, R Stoner, GL AF Ryschkewitsch, CF Friedlaender, JS Mgone, CS Jobes, DV Agostini, HT Chima, SC Alpers, MP Koki, G Yanagihara, R Stoner, GL TI Human polyomavirus JC variants in Papua New Guinea and Guam reflect ancient population settlement and viral evolution SO MICROBES AND INFECTION LA English DT Article DE Polyomavirus bominis 2; Pacific Islands; melanesia; Papua New Guinea; micronesia; Guam; urine ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; COMPLETE GENOMES; VIRUS-DNA; GENOTYPES; REARRANGEMENTS; BRAIN; TRANSMISSION; INDIVIDUALS; MIGRATIONS; AMERICANS AB The peopling of the Pacific was a complex sequence of events that is best reconstructed by reconciling insights from various disciplines. Here we analyze the human polyomavirus JC (JCV) in Highlanders of Papua New Guinea (PNG), in Austronesian-speaking Tolai people on the island of New Britain, and in nearby non-Austronesian-speaking Baining people. We also characterize JCV from the Chamorro of Guam, a Micronesian population. All JCV strains from PNG and Guam fall within the broad Asian group previously defined in the VP1 gene as Type 2 or Type 7, but the PNG strains were distinct from both genotypes. Among the Chamorro JCV samples, 8 strains (Guam-1) were like the Type 7 strains found in Southeast Asia, while nine strains (Guam-2) were distinct from both the mainland strains and most PNG strains. We identified three JCV variants within Papua New Guinea (PNG-1, PNG-2 and PNG-3), but none of the Southeast Asian (Type 7) strains. PNG-1 strains were present in all three populations (Highlanders and the Baining and Tolai of New Britain), but PNG-2 strains were restricted to the Highlanders. Their relative lack of DNA sequence variation suggests that they arose comparatively recently. The single PNG-3 strain, identified in an Austronesian-speaking Tolai individual, was closely related to the Chamorro variants (Guam-2), consistent with a common Austronesian ancestor. In PNG-2 variants a complex regulatory region mutation inserts a duplication into a nearby deletion, a change reminiscent of those seen in the brains of progressive multifocal leukoencephalopathy patients. This is the first instance of a complex JCV rearrangement circulating in a human population. (C) 2000 Editions scientifiques et medicales Elsevier SAS. C1 NINDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. Inst Med Res, Goroka, Papua N Guinea. Univ Freiburg, Dept Ophthalmol, D-79106 Freiburg, Germany. Univ Hawaii Manoa, Pacific Biomed Res Ctr, Retrovirol Res Lab, Honolulu, HI 96822 USA. Appl Biosyst Inc, Foster City, CA 94404 USA. RP Stoner, GL (reprint author), NINDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. RI Chima, Sylvester Chidi/N-5564-2013 NR 51 TC 28 Z9 28 U1 0 U2 3 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2000 VL 2 IS 9 BP 987 EP 996 DI 10.1016/S1286-4579(00)01252-1 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 353PG UT WOS:000089284200001 PM 10967279 ER PT J AU Gerard, HC Schumacher, HR El-Gabalawy, H Goldbach-Mansky, R Hudson, AP AF Gerard, HC Schumacher, HR El-Gabalawy, H Goldbach-Mansky, R Hudson, AP TI Chlamydia pneumoniae present in the human synovium are viable and metabolically active SO MICROBIAL PATHOGENESIS LA English DT Article DE C. pneumoniae; reactive arthritis; bacterial pathogenesis; synovium ID REACTIVE ARTHRITIS; STRAIN TWAR; TRACHOMATIS DNA; GENE; IDENTIFICATION; INFECTION; TISSUE; FLUID AB We demonstrated that chromosomal DNA from Chlamydia pneumoniae is present in synovial tissue in at least some patients with reactive arthritis/Reiter's syndrome and other arthritides. Here, we provide initial molecular evidence that the bacterium is viable and metabolically active when present in the synovium. We used reverse transcription-polymerase chain reaction (RT-PCR) assays targeting primary transcripts from the chlamydial rRNA operons, and mRNA from several C, pneumoniae genes (hsp60, ompA, KDO transferase, Mr=76000 protein), to analyse RNA preparations from synovial tissue of 10 patients with various forms of arthritis; each patient was known to be PCR-positive for C. pneumoniae DNA in synovium prior to RT-PCR assays. Two PCR-negative patients served as controls for RT-PCR assays. in the in patients PCR-positive for C. pneumoniae DNA, RT-PCR assays targeting primary transcripts from the rRNA operons of the organism showed that these molecules were present in each sample, as were transcripts from the bacterial hsp60 gene. Assays targeting mRNAs from the Mr=76000 protein and the KDO transferase genes of C. pneumoniae gave positive results for 6/10 preparations. We were unable to identify mRNA from the chlamydial major outer membrane protein gene (ompA) in any preparation. RNA preparations from the two control patients were negative in all RT-PCR assays targeting C. pneumoniae transcripts. These results indicate that in patients infected with the organism, synovial C. pneumoniae are viable and metabolically active, as are C. trachomatis cells in the same context. Such viability is consistent with a role in long-term contribution to pathogenesis in joint disease. (C) 2000 Academic Press. C1 Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. Univ Penn, Sch Med, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Med Res Serv, Philadelphia, PA 19104 USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. RP Hudson, AP (reprint author), Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Gordon H Scott Hall,540 E Canfield Ave, Detroit, MI 48201 USA. FU NIAMS NIH HHS [AR42541] NR 24 TC 48 Z9 49 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD JUL PY 2000 VL 29 IS 1 BP 17 EP 24 DI 10.1006/mpat.2000.0360 PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 333LX UT WOS:000088132500003 PM 10873487 ER PT J AU Berger, AC Alexander, HR Tang, GQ Wu, PS Hewitt, SM Turner, E Kruger, E Figg, WD Grove, A Kohn, E Stern, D Libutti, SK AF Berger, AC Alexander, HR Tang, GQ Wu, PS Hewitt, SM Turner, E Kruger, E Figg, WD Grove, A Kohn, E Stern, D Libutti, SK TI Endothelial monocyte activating polypeptide II induces endothelial cell apoptosis and may inhibit tumor angiogenesis SO MICROVASCULAR RESEARCH LA English DT Article DE apoptosis; angiogenesis; EMAP-II; necrosis; tumor ID BCL-2 FAMILY PROTEINS; NECROSIS-FACTOR; CYTOKINE; MECHANISMS; INDUCTION; DIFFERENTIATION; INVITRO; FORMS AB Endothelial monocyte activating polypeptide II (EMAP-II) is a tumor-derived cytokine with potent effects on endothelial cells in vitro and in vivo including upregulation of tissue factor and the sensitization of human melanoma to systemic TNF treatment via its effects on the tumor vasculature. We investigated the effects of EMAP-II on tumor growth, angiogenesis, vasculogenesis, and apoptosis. EMAP-II inhibited endothelial cell proliferation, vasculogenesis, and neovessel formation. In vivo growth of human melanoma lines expressing high amounts of EMAP-II demonstrated slower growth, smaller tumors, and increased amounts of tumor necrosis than those expressing lower amounts of EMAP-II. EMAP-II induced endothelial-cell-specific apoptosis via a pathway that includes upregulation of the Fas-associated death domain and downregulation of Bcl-2. EMAP-II appears to have important effects on angiogenesis and may play a role in regulating tumor vascular growth. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016; OI Hewitt, Stephen/0000-0001-8283-1788 NR 25 TC 74 Z9 77 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0026-2862 J9 MICROVASC RES JI Microvasc. Res. PD JUL PY 2000 VL 60 IS 1 BP 70 EP 80 DI 10.1006/mvre.2000.2249 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 333UT UT WOS:000088149700008 PM 10873516 ER PT J AU Kleer, CG Giordano, TJ Merino, MJ AF Kleer, CG Giordano, TJ Merino, MJ TI Squamous cell carcinoma of the thyroid: An aggressive tumor associated with tall cell variant of papillary thyroid carcinoma SO MODERN PATHOLOGY LA English DT Article DE squamous cell carcinoma; tall cell variant; thyroid neoplasms ID P53 GENE-MUTATIONS; PROGNOSTIC FACTORS; BREAST CARCINOMAS; SUPPRESSOR GENE; CANCER; GLAND; OVEREXPRESSION; ANTIBODIES; EXPRESSION; DELETIONS AB Squamous cell carcinoma of the thyroid (SCT) is an unusual neoplasm thought to arise as a primary tumor or as a component of an undifferentiated carcinoma. The role of p53 and Ki-67 as prognostic indicators in this type of tumor is not known. We studied eight cases of primary SCT. Three cases were analyzed for Ki-67 by immunohistochemistry and for p53 by immunohistochemistry and loss of heterozygosity. Seven patients were women, and one was a man (age range, 31 to 90 years). SCT were firm, were tan with areas of necrosis, and ranged in size from 2 to 8 cm. Histologically, they had islands of squamous cells with spindle cell areas (two of eight). In four of eight cases, SCT was associated with the tall cell variant of papillary carcinoma (TCV). Positive staining for p53 was seen in two of three cases, and in one of three the TCV was also positive for p53. Mean MIB1 labeling index was 30% and 17% in SCT and TCV, respectively. At the time of presentation, six of eight patients had cervical lymph node metastases. In one case, the primary tumor had SCT and TCV; however, only the SCT component metastasized. After mean follow-up of 48 months, one patient had died of disease, five were alive with recurrent or metastatic tumor, and two were lost to follow-up. Primary SCT is an aggressive neoplasm that may be found in association with TCV. p53 expression and high MIB1 labeling index occur in these tumors and may be useful prognosticators. C1 Univ Michigan, Med Ctr, Dept Pathol, Ann Arbor, MI 48109 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Kleer, CG (reprint author), Univ Michigan Hosp, Dept Pathol 2G332, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. OI Giordano, Thomas/0000-0003-0641-8873 NR 27 TC 34 Z9 37 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2000 VL 13 IS 7 BP 742 EP 746 DI 10.1038/modpathol.3880129 PG 5 WC Pathology SC Pathology GA 335QN UT WOS:000088255900005 PM 10912933 ER PT J AU Wang, L Menting, JGT Stowers, A Charoenvit, Y Sacci, JB Coppel, RL AF Wang, L Menting, JGT Stowers, A Charoenvit, Y Sacci, JB Coppel, RL TI Antigens cross reactive with Plasmodium falciparum merozoite surface protein 4 are found in pre-erythrocytic and sexual stages SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; MSP4; SALSA; stage-specific expression; shared epitope ID LIVER STAGES; GENE; CHROMOSOME-2; SPOROZOITE; EPITOPES; CLONING; YOELII C1 Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. USN, Malaria Program, Med Res Ctr, Rockville, MD 20852 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Coppel, RL (reprint author), Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. RI Coppel, Ross/A-6626-2008 OI Coppel, Ross/0000-0002-4476-9124 NR 14 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUL PY 2000 VL 109 IS 2 BP 189 EP 194 DI 10.1016/S0166-6851(00)00248-6 PG 6 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 340QE UT WOS:000088545300012 PM 10960179 ER PT J AU Reeves, R Leonard, WJ Nissen, MS AF Reeves, R Leonard, WJ Nissen, MS TI Binding of HMG-I(Y) imparts architectural specificity to a positioned nucleosome on the promoter of the human interleukin-2 receptor alpha gene SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROUP PROTEIN I/Y; DNA-BINDING; TRANSCRIPTIONAL ACTIVATORS; CHROMOSOMAL-PROTEINS; HISTONE OCTAMER; LINKER HISTONES; CHAIN PROMOTER; CHROMATIN; MOBILITY; ENHANCER AB Transcriptional induction of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene is a key event regulating T-cell-mediated immunity in mammals. In vivo, the T-cell-restricted protein Elf-1 and the general architectural transcription factor HMG-I(Y) cooperate in transcriptional regulation of the human IL-2R alpha gene by binding to a specific positive regulatory region (PRRII) in its proximal promoter. Employing chromatin reconstitution analyses, we demonstrate that the binding sites for both HMG-I(Y) and Elf-1 in the PRRII element are incorporated into a strongly positioned nucleosome in vitro. A variety of analytical techniques was used to determine that a stable core particle is positioned over most of the PRRII element and that this nucleosome exhibits only a limited amount of lateral translational mobility. Regardless of its translational setting, the in vitro position of the nucleosome is such that DNA recognition sequences for both HMG-I(Y) and Elf-1 are located on the surface of the core particle. Restriction nuclease accessibility analyses indicate that a similarly positioned nucleosome also exists on the PRRII element in unstimulated lymphocytes when the IL-2R alpha gene is silent and suggest that this core particle is remodeled following transcriptional activation of the gene In vivo. In vitro experiments employing the chemical cleavage reagent 1,10-phenanthroline copper (II) covalently attached to its C-terminal end demonstrate that HMG-I(Y) protein binds to the positioned PRRII nucleosome in a direction-specific manner, thus imparting a distinct architectural configuration to the core particle. Together, these findings suggest a role for the HMG-I(Y) protein in assisting the remodeling of a critically positioned nucleosome on the PRRII promoter element during IL-2R alpha transcriptional activation in lymphocytes in vivo. C1 Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Reeves, R (reprint author), Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. FU NIGMS NIH HHS [R01-GM46352] NR 65 TC 47 Z9 48 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 13 BP 4666 EP 4679 DI 10.1128/MCB.20.13.4666-4679.2000 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 323QL UT WOS:000087576400019 PM 10848593 ER PT J AU Zhou, MS Halanski, MA Radonovich, MF Kashanchi, F Peng, JM Price, DH Brady, JN AF Zhou, MS Halanski, MA Radonovich, MF Kashanchi, F Peng, JM Price, DH Brady, JN TI Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FACTOR P-TEFB; PROTEINS SPECIFICALLY ASSOCIATE; ACTIVATING KINASE CAK; HIV-1 TAT; SACCHAROMYCES-CEREVISIAE; IN-VITRO; LARGE SUBUNIT; CYCLIN T1; SUBSTRATE-SPECIFICITY; TRANS-ACTIVATION AB Tat stimulates human immunodeficiency virus type 1 (HIV-1) transcriptional elongation by recruitment of carboxyl-terminal domain (CTD) kinases to the HIV-1 promoter. Using an immobilized DNA template assay, we have analyzed the effect of Tat on kinase activity during the initiation and elongation phases of HIV-1 transcription. Our results demonstrate that cyclin-dependent kinase 7 (CDK7) (TFIIH) and CDK9 (P-TEFb) both associate with the HIV-1 preinitiation complex. Hyperphosphorylation of the RNA polymerase II (RNAP II) CTD in the HIV-1 preinitiation complex, in the absence of Tat, takes place at CTD serine 2 and serine 5. Analysis of preinitiation complexes formed in immunodepleted extracts suggests that CDK9 phosphorylates serine 2, while CDK7 phosphorylates serine 5. Remarkably, in the presence of Tat, the substrate specificity of CDK9 is altered, such that the kinase phosphorylates both serine 2 and serine 5. Tat-induced CTD phosphorylation by CDK9 is strongly inhibited by low concentrations of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, an inhibitor of transcription elongation by RNAP II. Analysis of stalled transcription elongation complexes demonstrates that CDK7 is released from the transcription complex between positions +14 and +36, prior to the synthesis of transactivation response (TAR) RNA. In contrast, CDK9 stays associated with the complex through +79. Analysis of CTD phosphorylation indicates a biphasic modification pattern, one in the preinitiation complex and the other between +36 and +79. The second phase of CTD phosphorylation is Tat-dependent and TAR-dependent. These studies suggest that the ability of Tat to increase transcriptional elongation may be due to its ability to modify the substrate specificity of the CDK9 complex. C1 NCI, Virus Tumor Biol Sect, LRBGE, Div Basic Sci, Bethesda, MD 20892 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, LRBGE, Div Basic Sci, Bethesda, MD 20892 USA. RI Price, David/F-6173-2010 NR 85 TC 192 Z9 195 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 5077 EP 5086 DI 10.1128/MCB.20.14.5077-5086.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000012 PM 10866664 ER PT J AU Hemavathy, K Guru, SC Harris, J Chen, JD Ip, YT AF Hemavathy, K Guru, SC Harris, J Chen, JD Ip, YT TI Human slug is a repressor that localizes to sites of active transcription SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ZINC-FINGER PROTEIN; PROMYELOCYTIC LEUKEMIA PROTEIN; DROSOPHILA EMBRYO; NEURAL CREST; SNAIL FAMILY; DNA-BINDING; MUTANT EMBRYOS; GENE SNAIL; WILD-TYPE; EXPRESSION AB Snail/Slug family proteins have been identified in diverse species of both vertebrates and invertebrates. The proteins contain four to six zinc fingers and function as DNA-binding transcriptional regulators. Various members of the family have been demonstrated to regulate cell movement, neural cell fate, left-right asymmetry, cell cycle, and apoptosis. However, the molecular mechanisms of how these regulators function and the target genes involved are largely unknown. In this report, we demonstrate that human Slug (hSlug) is a repressor and modulates both activator-dependent and basal transcription. The repression depends on the C-terminal DNA-binding zinc fingers and on a separable repression domain located in the N terminus. This domain may recruit histone deacetylases to modify the chromatin and effect repression. Protein localization study demonstrates that hSlug is present in discrete foci in the nucleus. This subnuclear pattern does not colocalize with the PML foci or the coiled bodies. Instead, the hSlug foci overlap extensively with areas of the SC-35 staining, some of which have been suggested to be sites of active splicing or transcription. These results lead us to postulate that hSlug localizes to target promoters, where activation occurs, to repress basal and activator-mediated transcription. C1 Univ Massachusetts, Sch Med, Dept Cell Biol, Program Mol Med, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Biol, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Toxicol, Worcester, MA 01605 USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Ip, YT (reprint author), Univ Massachusetts, Sch Med, Dept Cell Biol, Program Mol Med, 373 Plantat St, Worcester, MA 01605 USA. FU NIDDK NIH HHS [R01 DK052542, R01DK52542] NR 66 TC 68 Z9 71 U1 0 U2 7 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 JUL PY 2000 VL 20 IS 14 BP 5087 EP 5095 DI 10.1128/MCB.20.14.5087-5095.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000013 PM 10866665 ER PT J AU Peters, JM Lee, SST Li, W Ward, JM Gavrilova, O Everett, C Reitman, ML Hudson, LD Gonzalez, FJ AF Peters, JM Lee, SST Li, W Ward, JM Gavrilova, O Everett, C Reitman, ML Hudson, LD Gonzalez, FJ TI Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta) SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PPAR-GAMMA; DIFFERENTIAL EXPRESSION; LIPOPROTEIN METABOLISM; HORMONE RECEPTOR; MESSENGER-RNA; FATTY-ACIDS; ALPHA; RAT; GENES; BETA AB To determine the physiological roles of peroxisome proliferator-activated receptor beta (PPAR beta), null mice were constructed by targeted disruption of the ligand binding domain of the murine PPAR beta gene. Homozygous PPAR beta-null term fetuses were smaller than controls, and this phenotype persisted postnatally. Gonadal adipose stores were smaller, and constitutive mRNA levels of CD36 were higher, in PPAR beta-null mice than in controls. In the brain, myelination of the corpus callosum was altered in PPAR beta-null mice. PPAR beta was not required for induction of mRNAs involved in epidermal differentiation induced by O-tetradecanoylphorbol-13-acetate (TPA). The hyperplastic response observed in the epidermis after TPA application was significantly greater in the PPAR beta-null mice than in controls. Inflammation induced by TPA in the skin was lower in wild-type mice fed sulindac than in similarly treated PPAR beta-null mice. These results are the first to provide in vivo evidence of significant roles for PPAR beta in development, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Resources, Frederick, MD 21702 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol, Fenske Lab 226, University Pk, PA 16802 USA. RI Peters, Jeffrey/D-8847-2011; Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Grueter, Carrie/0000-0002-1913-2527 NR 51 TC 492 Z9 501 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 5119 EP 5128 DI 10.1128/MCB.20.14.5119-5128.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000016 PM 10866668 ER PT J AU Niklinski, J Claassen, G Meyers, C Gregory, MA Allegra, CJ Kaye, FJ Hann, SR Zajac-Kaye, M AF Niklinski, J Claassen, G Meyers, C Gregory, MA Allegra, CJ Kaye, FJ Hann, SR Zajac-Kaye, M TI Disruption of Myc-tubulin interaction by hyperphosphorylation of c-Myc during mitosis or by constitutive hyperphosphorylation of mutant c-Myc in Burkitt's lymphoma SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID N-TERMINAL DOMAIN; IN-VIVO; DIFFERENTIAL EXPRESSION; TRANSACTIVATION DOMAIN; TRANSFORMING ACTIVITY; PROTEIN-DEGRADATION; POINT MUTATIONS; GENE-REGULATION; CELL-CYCLE; PHOSPHORYLATION AB Somatic mutations at Thr-58 of c-Myc have been detected in Burkitt's lymphoma (BL) tumors and have been shown to affect the transforming potential of the Myc oncoprotein. In addition, the N-terminal domain of c-Myc has been shown to interact with microtubules in vivo, and the binding of c-Myc to alpha-tubulin was localized to amino acids 48 to 135 within the c-Myc protein. We demonstrate that c-Myc proteins harboring a naturally occurring mutation at Thr-58 from BL cell lines have increased stability and are constitutively hyperphosphorylated, which disrupts the in vivo interaction of c-Myc with alpha-tubulin. In addition, we show that wild-type c-Myc-alpha-tubulin interactions are also disrupted during a transient mitosis-specific hyperphosphorylation of c-Myc, which resembles the constitutive hyperphosphorylation pattern of Thr-58 in BL cells. C1 NCI, Dept Dev Therapeut, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. NCI, Dept Genet, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA. RP Zajac-Kaye, M (reprint author), NCI, Navy Oncol Branch, Bldg 8,R 5101, Bethesda, MD 20889 USA. RI kaye, frederic/E-2437-2011 NR 45 TC 34 Z9 35 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 JUL PY 2000 VL 20 IS 14 BP 5276 EP 5284 DI 10.1128/MCB.20.14.5276-5284.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000032 PM 10866684 ER PT J AU Mullins, C Hartnell, LM Bonifacino, JS AF Mullins, C Hartnell, LM Bonifacino, JS TI Distinct requirements for the AP-3 adaptor complex in pigment granule and synaptic vesicle biogenesis in Drosophila melanogaster SO MOLECULAR AND GENERAL GENETICS LA English DT Article DE AP-3; biogenesis; pigment granule; synaptic vesicle; Drosophila ID TEMPERATURE-SENSITIVE MUTANT; PROTEIN COMPLEX; ALPHA-ADAPTIN; LYSOSOMAL DELIVERY; SORTING SIGNALS; DEEP ORANGE; IN-VITRO; GENE; SHIBIRE; ENDOCYTOSIS AB The AP-3 adaptor protein complex has been implicated in the biogenesis of lysosome-related organelles, such as pigment granules/melanosomes, and synaptic vesicles. Here we compare the relative importance of AP-3 in the biogenesis of these organelles in Drosophila melanogaster. We report that the Drosophila pigmentation mutants orange and ruby carry genetic lesions in the sigma 3 and beta 3-adaptin subunits of the AP-3 complex, respectively. Electron microscopy reveals dramatic reductions in the numbers of electron-dense pigment granules in the eyes of these AP-3 mutants. Mutant flies also display greatly reduced levels of pigments housed in these granules. In contrast, electron microscopy of retinula cells reveals numerous synaptic vesicles in both AP-3 mutant and wild-type flies, while behavioral assays show apparently normal locomotor ability of AP-3 mutant larvae. Together, these results demonstrate that Drosophila AP-3 is critical for the biogenesis of pigment granules, but is apparently not essential for formation of a major population of synaptic vesicles in vivo. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 69 TC 38 Z9 39 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0026-8925 J9 MOL GEN GENET JI Mol. Gen. Genet. PD JUL PY 2000 VL 263 IS 6 BP 1003 EP 1014 DI 10.1007/PL00008688 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 343WN UT WOS:000088725600014 PM 10954086 ER PT J AU Leikina, E Chernomordik, LV AF Leikina, E Chernomordik, LV TI Reversible merger of membranes at the early stage of influenza hemagglutinin-mediated fusion SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INDUCED CONFORMATIONAL-CHANGES; LOW-PH; VIRUS HEMAGGLUTININ; CELL-FUSION; PLANAR MEMBRANES; MECHANISM; LIPIDS; HEMIFUSION; ECTODOMAIN; KINETICS AB Fusion mediated by influenza hemagglutinin (HA), a prototype fusion protein, is commonly detected as lipid and content mixing between fusing cells. Decreasing the surface density of fusion-competent HA inhibited these advanced fusion phenotypes and allowed us to identify an early stage of fusion at physiological temperature. Although lipid flow between membranes was restricted, the contacting membrane monolayers were apparently transiently connected, as detected by the transformation of this fusion intermediate into complete fusion after treatments known to destabilize hemifusion diaphragms. These reversible connections disappeared within 10-20 min after application of low pH, indicating that after the energy released by HA refolding dissipated, the final low pH conformation of HA did not support membrane merger. Although the dynamic character and the lack of lipid. mixing at 37 degrees C distinguish the newly identified fusion intermediate from the intermediate arrested at 4 degrees C described previously, both intermediates apparently belong to the same family of restricted hemifusion (RH) structures. Because the formation of transient RH structures at physiological temperatures was as fast as fusion pore opening and required less HA, we hypothesize that fusion starts with the formation of multiple RH sites, only a few of which then evolve to become expanding fusion pores. C1 NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chernomordik, LV (reprint author), NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 41 TC 61 Z9 62 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2000 VL 11 IS 7 BP 2359 EP 2371 PG 13 WC Cell Biology SC Cell Biology GA 334KC UT WOS:000088184800015 PM 10888674 ER PT J AU Ramakrishna, GT Bialkowska, A Perella, C Birely, L Fornwald, LW Diwan, BA Shiao, YH Anderson, LM AF Ramakrishna, GT Bialkowska, A Perella, C Birely, L Fornwald, LW Diwan, BA Shiao, YH Anderson, LM TI Ki-ras and the characteristics of mouse lung tumors SO MOLECULAR CARCINOGENESIS LA English DT Article DE carcinoma; Ki-ras-GTP; raf-1; proliferating cell nuclear antigen; extracellularly regulated kinase ID INCREASING COMPLEXITY; SIGNALING PATHWAY; CANCER CELLS; ACTIVATION; MUTATIONS; APOPTOSIS; GROWTH; MICE; ADENOCARCINOMA; PROLIFERATION AB Codon 12 mutations are frequent in the Ki-ras oncogene in human lung adenocarcinomas, but the effects of these alterations have not been well characterized in lung epithelial cells. Murine primary lung tumors derived from peripheral epithelial cells also may present Ki-ras mutations and are useful models for study of early phases of tumor development. One hypothesis is that Ki-ras mutation and/or a Ki-ras p21 increase could enhance Ki-ras p21-GTP and cell-cycle stimulation through raf-1 and extracellularly regulated protein kinases (Erks). We examined lung tumors 1-7 mm in largest dimension initiated in male Swiss mice by N-nitrosoldimethylamine for pathologic type, Ki-ras mutations and levels of total Ki-ras p21, Ki-ras p21 bound to GTP, raf-1, Erk1 and Erk2 and their phosphorylated (activated) forms; and proliferating cell nuclear antigen. Total Ki-ras p21 and activated ras-GTP were not significantly greater in tumors than in normal lung or in tumors with versus those without Ki-ras mutations. Carcinomas with Ki-ras mutations were significantly smaller than those without mutations. Carcinomas were significantly larger than adenomas only for tumors without mutations. High levels of Erk1 and correlation of Erk2 amount with ras-GTP were specific characteristics of tumors with Ki-ras mutations. Size of all tumors correlated with ras-GTP but not with proliferating cell nuclear antigen. Raf-1 was expressed mainly in alveolar macrophages in normal lung but was focally upregulated in papillary areas of some tumors. The results indicate that Ki-ras influences the characteristics of lung tumors, but a linear ras-raf-Erk-cell-cycle control sequence does not adequately characterize tumorigenic events in this model. Published 2000 Wiley-Liss, Inc.(dagger). C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAIC Frederick Inc, Intramural Res Support Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Lab Anim Sci Program, Frederick, MD 21702 USA. RP Anderson, LM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Box B,Bldg 538, Frederick, MD 21702 USA. RI Bialkowska, Aneta/G-9280-2014 FU NCI NIH HHS [N01-CO-56000] NR 47 TC 13 Z9 15 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUL PY 2000 VL 28 IS 3 BP 156 EP 167 DI 10.1002/1098-2744(200007)28:3<156::AID-MC4>3.0.CO;2-M PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 342LH UT WOS:000088645700004 PM 10942532 ER PT J AU Sanders, S Thorgeirsson, SS AF Sanders, S Thorgeirsson, SS TI Promotion of hepatocarcinogenesis by phenobarbital in c-myc/TGF-alpha transgenic mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE apoptosis; bcl-2; liver ID GROWTH-FACTOR-ALPHA; HEPATIC TUMORIGENESIS; TUMOR PROMOTERS; RAT HEPATOCYTES; MAMMARY-GLAND; DNA-SYNTHESIS; B6C3F1 MICE; APOPTOSIS; LIVER; MYC AB Previous work has shown that phenobarbital (PB) can promote cell survival in double transgenic c-myc/transforming growth factor (TGF)-alpha mice. This was achieved through a suppression of cell death brought about, at least in part, by a general increase in the level of bcl-2 protein and a decrease in TGF-beta 1 in treated versus untreated animals. No changes were found in TGF-beta type II receptor or in bcl-X-L protein levels. In the present work, we followed these animals for up to 31 wk of age (28 wk of treatment), by which time numerous tumors could be observed. A PB-dependent decrease in tumor latency and a significant increase in multiplicity were seen. No statistically significant changes in the phenotype of foci, nodules, or neoplasms were observed after PB administration, and no effect on median tumor size was detected. Levels of the anti-apoptotic protein bcl-2 did not correlate with tumor formation in PR-treated animals. However, in untreated mice, bcl-2 was higher in tumors than in surrounding tissue in all tumors examined. We believe that the PB-dependent modification of tumorigenesis in the livers of c-myc/TGF-alpha mice was predominantly a result of the ability of this drug to block cell death during the early stages of tumor development. The effect of PB was exerted apparently by a pathway similar to, but separate from, that of TGF-alpha. However, these pathways appear to converge downstream, having common effectors in the form of bcl-2 family proteins. Published 2000 Wiley-Liss. Inc.(dagger). C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, NIH, 37-3C28,37 Convent Dr,MSC4255, Bethesda, MD 20892 USA. NR 24 TC 11 Z9 11 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUL PY 2000 VL 28 IS 3 BP 168 EP 173 DI 10.1002/1098-2744(200007)28:3<168::AID-MC5>3.0.CO;2-E PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 342LH UT WOS:000088645700005 PM 10942533 ER PT J AU Bennett, LM McAllister, KA Blackshear, PE Malphurs, J Goulding, G Collins, NK Ward, T Bunch, DO Eddy, EM Davis, BJ Wiseman, RW AF Bennett, LM McAllister, KA Blackshear, PE Malphurs, J Goulding, G Collins, NK Ward, T Bunch, DO Eddy, EM Davis, BJ Wiseman, RW TI Brca2-null embryonic survival is prolonged on the BALB/c genetic background SO MOLECULAR CARCINOGENESIS LA English DT Article DE Brca2; BALB/c; gene targeting; embryonic lethality ID BREAST-CANCER SUSCEPTIBILITY; TUMOR-SUPPRESSOR GENE; DNA-DAMAGE RESPONSE; MEIOTIC CELLS; MICE LACKING; CELLULAR PROLIFERATION; GERMLINE MUTATIONS; EGF RECEPTOR; BRCA1; MOUSE AB Women who inherit mutations in the BRCA2 cancer susceptibility gene have an 85% chance of developing breast cancer. The function of the BRCA2 gene remains elusive, but there is evidence to support its role in transcriptional transactivation, tumor suppression, and the maintenance of genomic integrity. Individuals with identical BRCA2 mutations display a different distribution of cancers, suggesting that there are low-penetrance genes that can modify disease outcome. We hypothesized that genetic background could influence embryonic survival of a Brca2 mutation in mice. Brca2-null embryos with a 129/SvEv genetic background (129(B2-/-)) died before embryonic day 8.5. Transfer of this Brca2 mutation onto the BALB/cJ genetic background (BALB/c(B2-/-)) extended survival to embryonic day 10.5. These results indicate that the BALB/c background harbors genetic modifiers that can prolong Brca2-null embryonic survival. The extended survival of BALB/cB2-/- embryos enabled us to ask whether transcriptional regulation of the Brca1 and Brca2 genes is interdependent. The interdependence of Brca1 and Brca2 was evaluated by studying Brca2 gene expression in BALB/c(B1-/-) embryos and Brca1 gene expression in BALB/c(B2-/-) embryos. Nonisotopic in situ hybridization demonstrated that Brca2 transcript levels were comparable in BALB/c(B1-/-) embryos and wild-type littermates. Likewise, reverse transcriptase-polymerase chain reactions confirmed Brca1 mRNA expression in embryonic day 8.5 BALB/c(B2-/-) embryos that was comparable to Brca2-heterozygous littermates. Thus, the Brca1 and Brca2 transcripts are expressed independently of one another in Brca1- and Brca2-null embryos. (C) 2000 Wiley-Liss. Inc. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Bennett, LM (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 39 TC 17 Z9 17 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUL PY 2000 VL 28 IS 3 BP 174 EP 183 DI 10.1002/1098-2744(200007)28:3<174::AID-MC6>3.0.CO;2-C PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 342LH UT WOS:000088645700006 PM 10942534 ER PT J AU Feng, X Jiang, Y Meltzer, P Yen, PM AF Feng, X Jiang, Y Meltzer, P Yen, PM TI Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-KINASE-B; NF-KAPPA-B; IN-VIVO; HEPATOCYTE PROLIFERATION; EXPRESSION PATTERNS; GLYCOGEN-SYNTHASE; CDNA MICROARRAYS; SPOT-14 PROTEIN; RAT-LIVER; INSULIN AB The liver is an important target organ of thyroid hormone. However, only a limited number of hepatic target genes have been identified, and little is known about the pattern of their regulation by thyroid hormone. We used a quantitative fluorescent cDNA microarray to identify novel hepatic genes regulated by thyroid hormone. Fluorescent-labeled cDNA prepared from hepatic RNA of T-3-treated and hypothyroid mice was hybridized to a cDNA microarray, representing 2225 different mouse genes, followed by computer analysis to compare relative changes in gene expression. Fifty five genes, 45 not previously known to be thyroid hormone-responsive genes, were found to be regulated by thyroid hormone. Among them, 14 were positively regulated by thyroid hormone, and unexpectedly, 41 were negatively regulated. The expression of 8 of these genes was confirmed by Northern blot analyses. Thyroid hormone affected gene expression for a diverse range of cellular pathways and functions, including gluconeogenesis, lipogenesis, insulin signaling, adenylate cyclase signaling, cell proliferation, and apoptosis. This is the first application of the microarray technique to study hormonal regulation of gene expression In vivo and should prove to be a powerful tool for future studies of hormone and drug action. C1 NIDDK, Mol regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Yen, PM (reprint author), NIDDK, Mol regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 69 TC 230 Z9 234 U1 0 U2 3 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 JUL PY 2000 VL 14 IS 7 BP 947 EP 955 DI 10.1210/me.14.7.947 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330AE UT WOS:000087940000002 PM 10894146 ER PT J AU Smith, CL Wolford, RG O'Neill, TB Hager, GL AF Smith, CL Wolford, RG O'Neill, TB Hager, GL TI Characterization of transiently and constitutively expressed progesterone receptors: Evidence for two functional states SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID LONG TERMINAL REPEAT; LIGAND-INDEPENDENT ACTIVATION; DNASEI HYPERSENSITIVE SITES; STEROID-HORMONE RECEPTORS; EPIDERMAL GROWTH-FACTOR; YEAST SWI/SNF COMPLEX; TUMOR VIRUS TEMPLATES; GLUCOCORTICOID RECEPTOR; ESTROGEN-RECEPTOR; IN-VIVO AB Activated steroid receptors induce chromatin remodeling events in the promoters of some target genes. We previously reported that transiently expressed progesterone receptor (PR) cannot activate mouse mammary tumor virus (MMTV) promoter when it adopts the form of ordered chromatin. However, when expressed continuously, the PR acquires this ability. In this study we explored whether this gain of function occurs through alterations in nucleoprotein structure at the MMTV promoter or through changes in receptor status. We observed no major structural differences at the MMTV promoter in the presence of constitutively expressed PR and found its mechanism of activation to be very similar to that of the glucocorticoid receptor (GR). However, a systematic comparison of the functional behavior of the transiently and constitutively expressed PR elucidated significant differences. The transiently expressed PR is activated in the absence of ligand by cAMP and by components in FBS and has significantly increased sensitivity to progestins. In contrast, the constitutively expressed PR is refractory to activation by cAMP and serum and has normal sensitivity to its ligand. In addition, while the PR is localized to the nucleus in both cases, a significant fraction of the transiently expressed PR is tightly bound to the nucleus even in the absence of ligand, while the majority of constitutively expressed PR is not. These results strongly suggest that the PR undergoes processing in the cell subsequent to its initial expression and that this processing is important for various aspects of its function, including its ability to productively interact with target genes that require chromatin remodeling for activation. C1 NCI, NIH, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Smith, CL (reprint author), NCI, NIH, Lab Receptor Biol & Gene Express, Bldg 41,Room B600,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 74 TC 23 Z9 23 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2000 VL 14 IS 7 BP 956 EP 971 DI 10.1210/me.14.7.956 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330AE UT WOS:000087940000003 PM 10894147 ER PT J AU Kaul, S Blackford, JA Chen, J Ogryzko, VV Simons, SS AF Kaul, S Blackford, JA Chen, J Ogryzko, VV Simons, SS TI Properties of the glucocorticoid modulatory element binding proteins GMEB-1 and-2: Potential new modifiers of glucocorticoid receptor transactivation and members of the family of KDWK proteins SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID TYROSINE AMINOTRANSFERASE GENE; ESTROGEN-REGULATED RNAS; RETINOIC ACID RECEPTOR; TISSUE-CULTURE CELLS; NUCLEAR-RECEPTOR; RESPONSE ELEMENT; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; HISTONE ACETYLTRANSFERASE; HORMONE RECEPTORS AB An important component of glucocorticoid steroid induction of tyrosine aminotransferase (TAT) gene expression is the glucocorticoid modulatory element (GME), which is located at -3.6 kb of the rat TAT gene. The GME both mediates a greater sensitivity to hormone, due to a left shift in the dose-response curve of agonists, and increases the partial agonist activity of antiglucocorticoids. These properties of the GME are intimately related to the binding of a heteromeric complex of two proteins (GMEB-1 and -2). We previously cloned the rat GMEB-2 as a 67-kDa protein. We now report the cloning of the other member of the GME binding complex, the 88-kDa human GMEB-1, and various properties of both proteins. GMEB-1 and -2 each possess an intrinsic transactivation activity in mammalian one-hybrid assays, consistent with our proposed model in which they modify glucocorticoid receptor (GR)-regulated gene induction. This hypothesis is supported by interactions between GR and both GMEB-1 and -2 in mammalian two-hybrid and in pull-down assays. Furthermore, overexpression of GMEB-1 and -2, either alone or in combination, results in a reversible right shift in the dose-response curve, and decreased agonist activity of antisteroids, as expected from the squelching of other limiting factors. Additional mechanistic details that are compatible with the model of GME action are suggested by the interactions in a two-hybrid assay of both GMEBs with CREB-binding protein (CBP) and the absence of histone acetyl transferase (HAT) activity in both proteins. GMEB-1 and -2 share a sequence of 90 amino acids that is 80% identical. This region also displays homology to several other proteins containing a core sequence of KDWK. Thus, the GMEBs may be members of a new family of factors with interesting transcriptional properties. C1 NIDDK, LMCB, NIH, Steroid Hormones Sect, Bethesda, MD 20892 USA. NICHHD, Eukaryot Transcript Regulat Sect, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LMCB, NIH, Steroid Hormones Sect, Bldg 8,Room B2A-07, Bethesda, MD 20892 USA. RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 NR 87 TC 37 Z9 38 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2000 VL 14 IS 7 BP 1010 EP 1027 DI 10.1210/me.14.7.1010 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330AE UT WOS:000087940000007 PM 10894151 ER PT J AU Rucker, EB Dierisseau, P Wagner, KU Garrett, L Wynshaw-Boris, A Flaws, JA Hennighausen, L AF Rucker, EB Dierisseau, P Wagner, KU Garrett, L Wynshaw-Boris, A Flaws, JA Hennighausen, L TI Bcl-x and bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID DEFICIENT MICE; IN-VIVO; DEATH; GENE; EXPRESSION; GROWTH; MIGRATION; SPERMATOGENESIS; RECOMBINATION; MITOCHONDRIA AB Restricted germ cell loss through apoptosis is initiated in the fetal gonad around embryonic day 13.5 (E13.5) as part of normal germ cell development. The mechanism of this germ cell attrition is unknown. We show that Bcl-x plays a crucial role in maintaining the survival of mouse germ cells during gonadogenesis. A bcl-x hypomorphic mouse was generated through the introduction of a neomycin (neo) gene into the promoter of the bcl-x gene by homologous recombination. Mice that contained two copies of the hypomorphic allele had severe reproductive defects attributed to compromised germ cell development, Males with two mutant alleles lacked spermatogonia and were sterile; females showed a severely reduced population of primordial and primary follicles and exhibited greatly impaired fertility. Primordial germ cells (PGCs) in bcl-x hypomorph mice migrated to the genital ridge by E12.5 but were depleted by E15.5, a time when Bcl-x and Bax were present. Two additional bcl-x transcripts were identified in fetal germ cells more than 300 bp upstream of previously reported start sites. Insertion of a neo cassette led to a down-regulation of the bcl-x gene at E12.5 in the hypomorph. Bax was detected by immunohistochemistry in germ cells from bcl-x hypomorph and control testes at E12.5 and E13.5. Bcl-x function was restored, and animals of both genders were fertile after removal of the neo selection cassette using Ore-mediated recombination. Alternatively, the loss of Bcl-x function in the hypomorph was corrected by the deletion of both copies of the bax gene, resulting in a restoration of germ cell survival. These findings demonstrate that the balance of Bcl-x and Bax control PGC survival and apoptosis. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Wagner, Kay-Uwe/B-6044-2009 NR 46 TC 163 Z9 164 U1 0 U2 6 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 JUL PY 2000 VL 14 IS 7 BP 1038 EP 1052 DI 10.1210/me.14.7.1038 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330AE UT WOS:000087940000009 PM 10894153 ER PT J AU Johnston, MI AF Johnston, MI TI The role of nonhuman primate models in AIDS vaccine development SO MOLECULAR MEDICINE TODAY LA English DT Editorial Material ID SIMIAN IMMUNODEFICIENCY VIRUS; COMBINATION IMMUNIZATION REGIMEN; SIVMNE GP160 VACCINES; RHESUS MACAQUES; IMMUNE-RESPONSES; INFECTION; RECOMBINANT; PROTECTION; HIV-1; ENVELOPE AB Although animal models have been useful in guiding vaccine development, HIV/AIDS models have not yielded a clear correlate of immunity nor given consistent results on the potential efficacy of various vaccine approaches. Further development and improved uniformity in the use of animal models would maximize their potential to meet the urgent worldwide need for a safe and effective HIV vaccine. C1 NIAID, Div AIDS, Bethesda, MD 20892 USA. RP Johnston, MI (reprint author), NIAID, Div AIDS, 6700-B Rockledge Dr,Room 4101, Bethesda, MD 20892 USA. NR 28 TC 17 Z9 17 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1357-4310 J9 MOL MED TODAY JI Mol. Med. Today PD JUL PY 2000 VL 6 IS 7 BP 267 EP 270 DI 10.1016/S1357-4310(00)01724-X PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 330DR UT WOS:000087948000009 PM 10859562 ER PT J AU Heymann, JAW Subramaniam, S AF Heymann, JAW Subramaniam, S TI Integration of deletion mutants of bovine rhodopsin into the membrane of the endoplasmic reticulum SO MOLECULAR MEMBRANE BIOLOGY LA English DT Article DE glycosylation; G protein-coupled receptor; membrane protein biogenesis; topology; truncation mutant ID ONE SIGNAL SEQUENCE; TRANSMEMBRANE ORIENTATION; MONOCLONAL-ANTIBODIES; PROTEIN-TRANSPORT; SEC61P COMPLEX; TRANSLOCATION; INSERTION; SEGMENTS; TOPOGENESIS; DEGRADATION AB Newly synthesized eukaryotic membrane proteins must be integrated into the membrane of the endoplasmic reticulum with the correct topology to enable the subsequent acquisition of the correctly folded, functional conformation. Here, an analysis is presented of N-terminal glycosylation and steady-state membrane orientation of a series of truncation mutants of the seven-helix protein rhodopsin expressed in COS-1 cells. Mutants containing one, three, or five N-terminal transmembrane segments of rhodopsin, as well as mutants containing only the first transmembrane segment, but with hydrophilic extensions at the C-terminus were studied. The findings demonstrate that the C-terminal transmembrane segments play a crucial role in determining the final orientation of rhodopsin, and that the commitment to the correct orientation occurs only after the synthesis of at least three transmembrane segments. The experiments also suggest that the molecular machinery involved in the integration of a newly synthesized seven-helix membrane protein into the endoplasmic reticulum membrane is sensitive to the overall hydrophobicity of the sequence that follows the first transmembrane segment. C1 NCI, NIH, Biochem Lab, Bethesda, MD 20892 USA. RP Heymann, JAW (reprint author), NCI, NIH, Biochem Lab, Bethesda, MD 20892 USA. FU NCI NIH HHS [N02-BC-81038] NR 38 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0968-7688 J9 MOL MEMBR BIOL JI Mol. Membr. Biol. PD JUL-SEP PY 2000 VL 17 IS 3 BP 165 EP 174 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 376ZE UT WOS:000165486500005 PM 11128975 ER PT J AU Grigorova, M Balajee, AS Natarajan, AT AF Grigorova, M Balajee, AS Natarajan, AT TI Spontaneous and X-ray-induced chromosomal aberrations in Werner syndrome cells detected by FISH using chromosome-specific painting probes SO MUTAGENESIS LA English DT Article ID VARIEGATED TRANSLOCATION MOSAICISM; FIBROBLAST-CULTURES; HYBRIDIZATION; INSTABILITY; LYMPHOCYTES AB Werner syndrome (WS) is a rare autosomal disorder characterized by premature aging exhibiting chromosome instability and predisposition to cancer. Cells derived from WS patients show a variety of constitutionally stable chromosomal aberrations as detected by conventional chromosome banding techniques. We have employed the fluorescence in situ hybridization (FISH) technique using painting probes for 12 different chromosomes to detect stable chromosome exchanges in three WS cell lines and three control cell lines. WS cell lines showed increased frequencies of both stable and unstable chromosome aberrations detected by FISH and Giemsa staining, respectively. One WS lymphoblastoid cell line (KO375) had a 5/12 translocation in all the cells and similar to 60% of the cells had an additional translocated chromosome 12. A high frequency of aneuploid cells was found in all the WS cell lines studied. Though WS cells are known to be chromosomally unstable, unlike other chromosome instability syndromes they are not sensitive to mutagenic agents. We studied the frequencies of X-ray-induced chromosomal aberrations in two WS cell lines and found an similar to 60% increase in the frequencies of fragments and no consistent increase in the frequencies of exchanges. C1 Leiden Univ, Med Ctr, Dept Radiat Genet & Chem Mutagenesis, NL-2333 AL Leiden, Netherlands. NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Natarajan, AT (reprint author), Leiden Univ, Med Ctr, Dept Radiat Genet & Chem Mutagenesis, Wassenaarseweg 72, NL-2333 AL Leiden, Netherlands. NR 19 TC 24 Z9 24 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD JUL PY 2000 VL 15 IS 4 BP 303 EP 310 DI 10.1093/mutage/15.4.303 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 340GC UT WOS:000088523900002 PM 10887208 ER PT J AU Katagiri, Y Takeda, K Yu, ZX Ferrans, VJ Ozato, K Guroff, G AF Katagiri, Y Takeda, K Yu, ZX Ferrans, VJ Ozato, K Guroff, G TI Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B SO NATURE CELL BIOLOGY LA English DT Article ID NERVE GROWTH-FACTOR; HORMONE RECEPTOR SUPERFAMILY; ORPHAN RECEPTORS; MEMBRANE DEPOLARIZATION; GENE-EXPRESSION; DNA-BINDING; PC12 CELLS; PROTEIN; IDENTIFICATION; STRESS AB The retinoid-X receptor (RXR) regulates multiple hormonal pathways through heterodimerization with nuclear receptors such as the all-trans retinoic acid receptor (RAR). The orphan nuclear receptor NGFI-B (also called Nur77) can heterodimerize with RXR. Here we show that nerve growth factor (NGF) induces the phosphorylation of Ser 105 of NGFI-B in PC12 phaeochromocytoma cells, resulting in translocation of the NGFI-B-RXR heterodimer complex out of the nucleus using nuclear export signals within NGFI-B. As a consequence of the redistribution of RXR, the transcriptional activity of RXR-RAR is reduced. NGFI-B-mediated nuclear export of receptors may serve as a mechanism for crosstalk between NGF and retinoid pathways. C1 NICHD, Growth Factors Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Katagiri, Y (reprint author), Amer Red Cross, Holland Lab, Dept Biochem, 15601 Crabbs Branch Way, Rockville, MD 20892 USA. NR 34 TC 138 Z9 146 U1 1 U2 6 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2000 VL 2 IS 7 BP 435 EP 440 DI 10.1038/35017072 PG 6 WC Cell Biology SC Cell Biology GA 333MK UT WOS:000088133700020 PM 10878809 ER PT J AU Moreau, V Frischknecht, F Reckmann, I Vincentelli, R Rabut, G Stewart, D Way, M AF Moreau, V Frischknecht, F Reckmann, I Vincentelli, R Rabut, G Stewart, D Way, M TI A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization SO NATURE CELL BIOLOGY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; SYNDROME PROTEIN WASP; ARP2/3 COMPLEX; LISTERIA-MONOCYTOGENES; SHIGELLA-FLEXNERI; DEPOLYMERIZING PROTEIN; INTERACTING PROTEIN; TYROSINE KINASES; VACCINIA VIRUS; MOTILITY AB Wiskott-Aldrich syndrome protein (WASP) and N-WASP have emerged as key proteins connecting signalling cascades to actin polymerization. Here we show that the amino-terminal WH1 domain, and not the polyproline-rich region, of N-WASP is responsible for its recruitment to sites of actin polymerization during Cdc42-independent, actin-based motility of vaccinia virus. Recruitment of M-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex. We propose that the N-WASP-WIP complex has a pivotal function in integrating signalling cascades that lead to actin polymerization. C1 European Mol Biol Lab, D-69117 Heidelberg, Germany. NCI, NIH, Bethesda, MD 20892 USA. RP Way, M (reprint author), European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany. RI Rabut, Gwenael/E-7257-2011 OI Rabut, Gwenael/0000-0003-2658-2769 NR 50 TC 238 Z9 244 U1 0 U2 10 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2000 VL 2 IS 7 BP 441 EP 448 PG 8 WC Cell Biology SC Cell Biology GA 333MK UT WOS:000088133700021 PM 10878810 ER PT J AU Robertson, KD Ait-Si-Ali, S Yokochi, T Wade, PA Jones, PL Wolffe, AP AF Robertson, KD Ait-Si-Ali, S Yokochi, T Wade, PA Jones, PL Wolffe, AP TI DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters SO NATURE GENETICS LA English DT Article ID DNA METHYLTRANSFERASE GENE; RETINOBLASTOMA PROTEIN; HISTONE DEACETYLASE; IMMUNODEFICIENCY SYNDROME; CYTOSINE METHYLATION; REPLICATION; MUTATIONS; MECP2 AB Methylation of CpG islands is associated with transcriptional silencing and the formation of nuclease-resistant chromatin structures enriched in hypoacetylated histones(1-3). Methyl-CpG-binding proteins, such as MeCP2, provide a link between methylated DNA and hypoacetylated histones by recruiting histone deacetylase(4,5), but the mechanisms establishing the methylation patterns themselves are unknown. Whether DNA methylation is always causal for the assembly of repressive chromatin or whether features of transcriptionally silent chromatin might target methyltransferase remains unresolved. Mammalian DNA methyltransferases show little sequence specificity in vitro, yet methylation can be targeted in vivo within chromosomes to repetitive elements(6,7), centromeress(8-10) and imprinted loci(11). This targeting is frequently disrupted in tumour cells, resulting in the improper silencing of tumour-suppressor genes associated with CpG islands(1,2). Here we show that the predominant mammalian DNA methyltransferase, DNMT1, co-purifies with the retinoblastoma (Rb) tumour suppressor gene product, E2F1. and HDAC1 and that DNMT1 cooperates with Rb to repress transcription from promoters containing E2F-binding sites. These results establish a link between DNA methylation, histone deacetylase and sequence-specific DNA binding activity, as well as a growth-regulatory pathway that is disrupted in nearly all cancer cells. C1 NICHD, Mol Embryol Lab, NIH, Bethesda, MD USA. RP Wolffe, AP (reprint author), Sangamo Biosci Inc, Point Richmond Tech Ctr, Richmond, CA USA. NR 28 TC 638 Z9 656 U1 4 U2 22 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2000 VL 25 IS 3 BP 338 EP 342 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 329RD UT WOS:000087920900026 PM 10888886 ER PT J AU O'Shea, JJ Visconti, R AF O'Shea, JJ Visconti, R TI Type IIFNs and regulation of THI responses: enigmas both resolved and emerge SO NATURE IMMUNOLOGY LA English DT News Item ID IFN-ALPHA; STAT4; PHOSPHORYLATION; LYMPHOCYTES; INTERFERONS; ACTIVATION; TYROSINE AB STATs are critical in immune responses to type I IFNs. The human and mouse pathways differ, partly due to differences in STAT2, but unpredicted responses after viral infections raise new questions. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N252,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. RI Visconti, Roberta/C-5299-2009 NR 14 TC 45 Z9 47 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2000 VL 1 IS 1 BP 17 EP 19 DI 10.1038/76872 PG 3 WC Immunology SC Immunology GA 363BV UT WOS:000089814800008 PM 10881168 ER PT J AU Lantz, O Grandjean, I Matzinger, P Di Santo, JP AF Lantz, O Grandjean, I Matzinger, P Di Santo, JP TI gamma chain required for naive CD4(+) T cell survival but not for antigen proliferation SO NATURE IMMUNOLOGY LA English DT Article ID CYTOKINE RECEPTORS; POSITIVE SELECTION; MICE DEFICIENT; IN-VIVO; MEMORY; BCL-2; DIFFERENTIATION; LYMPHOCYTES; VIRGIN; MODEL AB Lymphoid homeostasis is required to ensure immune responsiveness and to prevent immunodeficiency, As such, the immune system must maintain distinct populations of naive T cells that are able to respond to new antigens as well as memory T cells specific to those antigens it has already encountered,Though both naive and memory T cells reside in and traffic through secondary lymphoid organs, there is growing evidence that the two populations may be regulated differently,We show here that naive T cell survival and memory T cell survival have different requirements for cytokines (including the interleukins IL-2, IL-4, IL-7, IL-9 and IL-15) that use the common cytokine receptor gamma chain (gamma(c)). Using monoclonal populations of antigen-specific CD4(+) T cells, we found that naive T cells cannot survive without gamma(c), whereas memory T cells show no such requirement. In contrast, neither naive nor gamma(c)-deficient memory T cells were impaired in their ability to proliferate and produce cytokines in response to in vivo antigenic stimulation,These data call into question the physiological role of gamma(c)-dependent cytokines as T cell growth factors and show that naive and memory CD4(+)T cell survival is maintained by distinct mechanisms. C1 Inst Pasteur, Unite Cytokines & Dev Lymphoide, Paris, France. NIAID, Ghost Lab, LCMI, NIH, Bethesda, MD 20892 USA. Univ Paris 11, Le Kremlin Bicetre, France. Hop Necker Enfants Malad, INSERM, U25, Paris, France. RP Di Santo, JP (reprint author), Inst Pasteur, Unite Cytokines & Dev Lymphoide, Paris, France. RI Lantz, Olivier/J-4960-2012; Di Santo, James/M-4298-2014 OI Lantz, Olivier/0000-0003-3161-7719; Di Santo, James/0000-0002-7146-1862 NR 33 TC 237 Z9 243 U1 1 U2 5 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2000 VL 1 IS 1 BP 54 EP 58 PG 5 WC Immunology SC Immunology GA 363BV UT WOS:000089814800014 PM 10881175 ER PT J AU Pandey, A Ozaki, K Baumann, H Levin, SD Puel, A Farr, AG Ziegler, SF Leonard, WJ Lodish, HF AF Pandey, A Ozaki, K Baumann, H Levin, SD Puel, A Farr, AG Ziegler, SF Leonard, WJ Lodish, HF TI Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin SO NATURE IMMUNOLOGY LA English DT Article ID COMMON GAMMA-CHAIN; JAK-3 JANUS KINASE; IGM(+) B-CELLS; IL-2 RECEPTOR; BETA-CHAIN; INTERLEUKIN-7 RECEPTOR; FUNCTIONAL COMPONENT; LYMPHOID DEVELOPMENT; CYTOPLASMIC DOMAINS; CYTOKINE RECEPTORS AB Signaling by type 1 cytokines involves the formation of receptor homodimers, heterodimers or higher order receptor oligomers. Here we report the cloning of a type I cytokine receptor subunit that is most closely related to the common cytokine receptor gamma chain (gamma(c)). Binding and crosslinking experiments demonstrate that this protein is the receptor for a recently described interleukin 7 (IL-7)-like factor, thymic stromal lymphopoietin (TSLP). Binding of TSLP to the thymic stromal lymphopoietin receptor (TSLPR) is increased markedly in the presence of the IL-7 receptor alpha chain (IL-7R alpha). IL-7R alpha-expressing but not parental 32D cells proliferate in the presence of exogenous TSLP, Moreover, a combination of IL-7R alpha and TSLPR is required for TSLP-dependent activation of a STAT5-dependent reporter construct. Thus it is shown that IL-7R alpha is a component of both the IL-7 and TSLP receptors, which helps to explain why deletion of the gene that encodes IL-7R alpha affects the lymphoid system more severely than deletion of the gene encoding IL-7 does. Cloning of TSLPR should facilitate an understanding of TSLP function and its signaling mechanism. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. Virginia Mason Res Ctr, Seattle, WA 98101 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Pandey, Akhilesh/B-4127-2009 OI Pandey, Akhilesh/0000-0001-9943-6127 FU NCI NIH HHS [CA 26122]; NHLBI NIH HHS [HL 32262]; NIAID NIH HHS [AI 44160, AI 44259] NR 49 TC 247 Z9 256 U1 1 U2 9 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2000 VL 1 IS 1 BP 59 EP 64 PG 6 WC Immunology SC Immunology GA 363BV UT WOS:000089814800015 PM 10881176 ER PT J AU Aliberti, J Sousa, CRE Schito, M Hieny, S Wells, T Huffnagle, GB Sher, A AF Aliberti, J Sousa, CRE Schito, M Hieny, S Wells, T Huffnagle, GB Sher, A TI CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha(+) dendritic cells SO NATURE IMMUNOLOGY LA English DT Article ID TOXOPLASMA-GONDII; CHEMOKINE RECEPTOR-5; MACROPHAGE FUNCTION; ACUTE INFECTION; TROPIC HIV-1; IFN-GAMMA; IMMUNITY; INTERLEUKIN-12; MICE; RESPONSIVENESS AB The activation of dendritic cells (DC) to produce interleukin 12 (IL-12) is thought to be a key step in the initiation of cell-mediated immunity to intracellular pathogens. Here we show that ligation of the C-C chemokine receptor (CCR) 5 can provide a major signal for the induction of IL-12 synthesis by the CD8 alpha(+) subset of DC and that this pathway is important in establishing interferon gamma-dependent resistance to the protozoan parasite Toxoplasma gondii. These findings support the concept that the early induction of chemokines by invading pathogens is a critical step not only for the recruitment of DC but also for the determination of their subsequent immunologic function. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Ares Serono Pharmaceut Res Inst SA, Geneva, Switzerland. Imperial Canc Res Fund, Immunobiol Lab, London WC2A 3PX, England. Univ Michigan, Med Ctr, Dept Pulm Med, Ann Arbor, MI USA. Univ Michigan, Med Ctr, Dept Immunol Microbiol, Ann Arbor, MI USA. RP Aliberti, J (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 26 TC 249 Z9 258 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2000 VL 1 IS 1 BP 83 EP 87 DI 10.1038/76957 PG 5 WC Immunology SC Immunology GA 363BV UT WOS:000089814800019 PM 10881180 ER PT J AU Mattson, MP AF Mattson, MP TI Activin to the rescue for overexcited neurons SO NATURE MEDICINE LA English DT Editorial Material ID BRAIN INJURY; RESPONSES; ROLES AB Overactivation of receptors for the excitatory neurotransmitter glutamate may be involved in disorders ranging from epilepsy to Alzheimer disease. This destructive pathway may be held in check by basic fibroblast growth factor acting through an intermediary cytokine called activin A (pages 812-815). C1 Natl Inst Aging Gerontol, Neurosci Lab, Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), Natl Inst Aging Gerontol, Neurosci Lab, Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 10 TC 6 Z9 6 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 739 EP 741 DI 10.1038/77453 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100023 PM 10888914 ER PT J AU McKay, R AF McKay, R TI Mammalian deconstruction for stem cell reconstruction SO NATURE MEDICINE LA English DT Editorial Material ID MUSCLE AB A collection of recent studies have suggested that adult stem cells taken from brain, muscle and blood can be converted into multiple mammalian tissue types. Can we build entire animals from stem cells found in the adult body? C1 NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. RP McKay, R (reprint author), NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. NR 11 TC 8 Z9 9 U1 1 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 747 EP 748 DI 10.1038/77468 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100028 PM 10888919 ER PT J AU Caughey, B AF Caughey, B TI Transmissible spongiform encephalopathies, amyloidoses and yeast prions: Common threads? SO NATURE MEDICINE LA English DT Review ID PROTEASE-RESISTANT FORMS; CELL-FREE CONVERSION; SACCHAROMYCES-CEREVISIAE; IN-VITRO; SUP35 PROTEIN; SCRAPIE; PROPAGATION; DISEASE; URE2P; SUSCEPTIBILITY AB Mammalian transmissible spongiform encephalopathy (prion) and amyloid diseases seem to involve the self-propagation of abnormal fibrillar or sub-fibrillar protein aggregates. Similar processes explain protein-mediated inheritance by yeast prions. Indeed, yeast prions are more surely mediated solely by aberrant protein aggregates than are their mammalian namesakes. Tantalizing parallels make yeast prions attractive models of mammalian protein-folding diseases. C1 NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. NR 47 TC 59 Z9 59 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 751 EP 754 DI 10.1038/77476 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100030 PM 10888922 ER PT J AU Chun, TW Davey, RT Ostrowski, M Justement, JS Engel, D Mullins, JI Fauci, AS AF Chun, TW Davey, RT Ostrowski, M Justement, JS Engel, D Mullins, JI Fauci, AS TI Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy SO NATURE MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; POTENT ANTIRETROVIRAL THERAPY; HETERODUPLEX MOBILITY ASSAY; COMBINATION THERAPY; HIV-1 INFECTION; REPLICATION; ERADICATION; EVOLUTION; AIDS AB We examined the pathogenic significance of the latent viral reservoir in the resting CD4(+) T cell compartment of HIV-1-infected individuals as well as its involvement in the rebound of plasma viremia after discontinuation of highly active anti-retroviral therapy (HAART). Using heteroduplex mobility and tracking assays, we show that the detectable pool of latently infected, resting CD4(+) T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. In the majority of patients examined, the rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and the replication-competent virus within the detectable pool of latently infected, resting CD4(+) T cells. These results indicate the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia after cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Microbiol, Seattle, WA 98104 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 42 TC 304 Z9 306 U1 2 U2 6 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 757 EP 761 DI 10.1038/77481 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100031 PM 10888923 ER PT J AU Wu, SJL Grouard-Vogel, G Sun, W Mascola, JR Brachtel, E Putvatana, R Louder, MK Filgueira, L Marovich, MA Wong, HK Blauvelt, A Murphy, GS Robb, ML Innes, BL Birx, DL Hayes, CG Frankel, SS AF Wu, SJL Grouard-Vogel, G Sun, W Mascola, JR Brachtel, E Putvatana, R Louder, MK Filgueira, L Marovich, MA Wong, HK Blauvelt, A Murphy, GS Robb, ML Innes, BL Birx, DL Hayes, CG Frankel, SS TI Human skin Langerhans cells are targets of dengue virus infection SO NATURE MEDICINE LA English DT Article ID ANTIBODY-DEPENDENT ENHANCEMENT; MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; TRANSMISSION; DETERMINANTS; MATURATION; SURFACE; RNA AB Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine(1,2). Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukoctye antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin. C1 Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. Naval Med Res Ctr, Viral & Rickettsial Dis Dept, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20889 USA. Dept Prevent Med, Bethesda, MD 20889 USA. Dept Biometr, Bethesda, MD 20889 USA. Dept Med, Bethesda, MD 20889 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. Walter Reed Army Inst Res, Div Viral Dis, Bethesda, MD 20889 USA. Armed Forces Inst Pathol, Dept Infect & Parasit Dis Pathol, Washington, DC 20306 USA. Univ Zurich Irchel, Inst Anat, CH-8057 Zurich, Switzerland. NCI, Dermatol Branch, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Dermatol, Bethesda, MD 20889 USA. RP Frankel, SS (reprint author), Walter Reed Army Inst Res, Div Retrovirol, 13 Taft Court,Suite 200, Rockville, MD 20850 USA. RI Filgueira, Luis/B-6492-2008 NR 21 TC 366 Z9 383 U1 1 U2 18 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 816 EP 820 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100041 PM 10888933 ER PT J AU Lawinger, P Venugopal, R Guo, ZS Immaneni, A Sengupta, D Lu, WY Rastelli, L Carneiro, AMD Levin, V Fuller, GN Echelard, Y Majumder, S AF Lawinger, P Venugopal, R Guo, ZS Immaneni, A Sengupta, D Lu, WY Rastelli, L Carneiro, AMD Levin, V Fuller, GN Echelard, Y Majumder, S TI The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells SO NATURE MEDICINE LA English DT Article ID RESTRICTIVE SILENCER FACTOR; GENE-EXPRESSION; P53 MUTATIONS; TARGET GENES; REST AB Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown(1-6). Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16. C1 Univ Texas, MD Anderson Canc Ctr, Brain Tumor Ctr, Houston, TX 77005 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Genzyme Transgen Corp, Framingham, MA 01710 USA. RP Majumder, S (reprint author), Univ Texas, MD Anderson Canc Ctr, Brain Tumor Ctr, 1515 Holcombe Blvd,Box 316, Houston, TX 77005 USA. OI Fuller, Gregory/0000-0001-9447-2647 FU NCI NIH HHS [CA51255]; NIGMS NIH HHS [GM53454] NR 24 TC 107 Z9 108 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 826 EP + PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100043 PM 10888935 ER PT J AU Li, J Derewenda, U Dauter, Z Smith, S Derewenda, ZS AF Li, J Derewenda, U Dauter, Z Smith, S Derewenda, ZS TI Crystal structure of the Escherichia coli thioesterase II, a homolog of the human Nef binding enzyme SO NATURE STRUCTURAL BIOLOGY LA English DT Letter ID CATALYTIC TRIADS; ACYL; IDENTIFICATION; PURIFICATION; MECHANISM; CLONING; SYSTEM; HIV-1; GENE AB Here we report the solution and refinement at 1.9 Angstrom resolution of the crystal structure of the Escherichia coli medium chain length acyl-CoA thioesterase II. This enzyme is a close homolog of the human protein that interacts with the product of the HIV-1 Nef gene, sharing 45% amino acid sequence identity with it. The structure of the a coli thioesterase II reveals a new tertiary fold, a 'double hot dog: showing an internal repeat with a basic unit that is structurally similar to the recently described beta-hydroxydecanoyl thiol ester dehydrase, The catalytic site, inferred from the crystal structure and verified by site directed mutagenesis, involves novel chemistry and includes Asp 204, Gin 278 and Thr 228, which synergistically activate a nucleophilic water molecule. C1 Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. NCI, Frederick, MD 21701 USA. Brookhaven Natl Lab, Upton, NY 11973 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. RP Derewenda, ZS (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, POB 800736, Charlottesville, VA 22908 USA. NR 34 TC 105 Z9 108 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD JUL PY 2000 VL 7 IS 7 BP 555 EP 559 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 330MR UT WOS:000087966300011 PM 10876240 ER PT J AU Levine, BK Beason-Held, LL Purpura, KP Aronchick, DM Optican, LM Alexander, GE Horwitz, B Rapoport, SI Schapiro, MB AF Levine, BK Beason-Held, LL Purpura, KP Aronchick, DM Optican, LM Alexander, GE Horwitz, B Rapoport, SI Schapiro, MB TI Age-related differences in visual perception: a PET study SO NEUROBIOLOGY OF AGING LA English DT Article DE positron emission tomography; aging; vision; form; imaging; brain; human ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; HUMAN EXTRASTRIATE CORTEX; WORD IDENTIFICATION; FORM PERCEPTION; SPATIAL VISION; MEMORY; ACTIVATION; BRAIN; DISSOCIATION AB To assess age-related differences in cortical activation during form perception, two classes of visual textures were shown to young and older subjects undergoing positron emission tomography (PET). Subjects viewed even textures that were rich in rectangular blocks and extended contours and random textures that lacked these organized form elements. Within-group significant increases in regional cerebral blood flow (rCBF) during even stimulation relative to random stimulation in young subjects were seen in occipital, inferior and medial temporal regions, and cerebellum, and in older subjects, in posterior occipital and frontal regions. Group by texture type interactions revealed significantly smaller rCBF increases in older subjects relative to young in occipital and medlar temporal regions. These results indicate that young subjects activate the occipitotemporal pathway during form perception, whereas older subjects activate occipital and frontal regions. The between-group differences suggest that age-related reorganization of cortical activation occur during early Visual processes in humans. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIA, Neurosci Lab, Nihon Univ, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY USA. NEI, Sect Neural Modeling, NIH, Bethesda, MD 20892 USA. RP Beason-Held, LL (reprint author), NIA, Neurosci Lab, Nihon Univ, Bldg 10, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS36699] NR 50 TC 24 Z9 26 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL-AUG PY 2000 VL 21 IS 4 BP 577 EP 584 DI 10.1016/S0197-4580(00)00144-5 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 342VR UT WOS:000088666300014 PM 10924775 ER PT J AU Matochik, JA Chefer, SI Lane, MA Woolf, RI Morris, ED Ingram, DK Roth, GS London, ED AF Matochik, JA Chefer, SI Lane, MA Woolf, RI Morris, ED Ingram, DK Roth, GS London, ED TI Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging SO NEUROBIOLOGY OF AGING LA English DT Article DE magnetic resonance imaging; aging monkey; striatum; caudate nucleus; putamen; volumetric; partial volume effect ID D-2 RECEPTOR-BINDING; LIVING HUMAN-BRAIN; C-11 RACLOPRIDE; DOPAMINE-RECEPTORS; RHESUS-MONKEYS; PUTAMEN NUCLEI; IRON CONTENT; RESTRICTION; TOMOGRAPHY; DECREASE AB Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whale brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young,group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (it = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIDA, Brain Imaging Ctr, Neuroimaging Branch, NIH, Baltimore, MD 21224 USA. NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Matochik, JA (reprint author), NIDA, Brain Imaging Ctr, Neuroimaging Branch, NIH, POB 5180, Baltimore, MD 21224 USA. NR 28 TC 38 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL-AUG PY 2000 VL 21 IS 4 BP 591 EP 598 DI 10.1016/S0197-4580(00)00134-2 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 342VR UT WOS:000088666300016 PM 10924777 ER PT J AU Tomsic, D Alkon, DL AF Tomsic, D Alkon, DL TI Background illumination effects upon in vitro conditioning in Hermissenda SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE associative learning; stimulus salience; background illumination; Hermissenda ID B-PHOTORECEPTORS; SHORT-TERM; CUMULATIVE DEPOLARIZATION; ACTIVATION; CURRENTS; CALCIUM; FACILITATION; ENHANCEMENT; CONNECTIONS; INDUCTION AB In the marine snail Hemissenda, associative learning can be accomplished by paired presentations of light and vestibular stimulation. It is generally assumed that associative learning depends upon the intensity or salience of the conditioned or unconditioned stimulus (CS and US, respectively), Accordingly, during Hermissenda conditioning a stronger dark adaptation is expected to render the CS (the light) more salient and hence facilitate association. We studied the influence of background illumination level using an in vitro pairing procedure in Hermissenda. This procedure allows one to assess the effect of conditioning upon a single. cell, the B photoreceptor, which is implicated in this learning process. After 15 min of adaptation to a dim background light, B photoreceptors maintained a basal rate of firing, while after adaptation to complete darkness, they stopped firing. Paired and unpaired groups received 10 training trials in either a completely dark or a dim light environment. Although a trial to trial cumulative increase in excitability was found in the paired group trained in darkness, only the paired group trained under dim background light showed a higher input resistance and cell excitability 10 min after training. These results suggest that the background dim illumination was not needed for the induction but played a role in the maintenance of the pairing effect. Possible mechanisms for such a modulatory effect are discussed. (C) 2000 Academic Press. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Tomsic, D (reprint author), Dept Biol, Lab Neurobiol Memoria, Pabellon 2,Ciudad Univ, RA-1428 Buenos Aires, DF, Argentina. NR 26 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD JUL PY 2000 VL 74 IS 1 BP 56 EP 64 DI 10.1006/nlme.1999.3938 PG 9 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 331KU UT WOS:000088018900004 PM 10873520 ER PT J AU Gaildrat, P Falcon, J AF Gaildrat, P Falcon, J TI Melatonin receptors in the pituitary of a teleost fish: mRNA expression, 2-[I-125]iodomelatonin binding and cyclic AMP response SO NEUROENDOCRINOLOGY LA English DT Article DE fishes; anteroventral pituitary; melatonin; melatonin receptors; cyclic AMP ID SUPRACHIASMATIC CIRCADIAN CLOCK; PARS-TUBERALIS; CHICK BRAIN; SITES; LOCALIZATION; SECRETION; CLONING; RETINA; NUCLEI; REPRODUCTION AB Melatonin has for a long time been involved in the photoperiodic control of fish physiology (growth, reproduction) and behavior (locomotor activity); but its mechanisms of action are not understood. We show here that 2-[I-125]iodomelatonin binds specifically to membrane preparations from Pike (Esox lucius, L.) pituitaries (K-D: 556 pMmax: 2.8 fmol/mg proteins). Radioautography indicated that the binding was restricted to a part of the pituitary only. Using polymerase chain reaction from pike genomic DNA, we subcloned two partial cDNAs encoding the P1.4 (Mel(1a)) and the P2.6 (Mel(1b)) melatonin receptor subtypes, The two corresponding transcripts were expressed in the pituitary as revealed by RT-PCR assay and Southern blot hybridization. In culture, melatonin inhibited in a time- and dose-dependent manner cyclic AMP levels in pituitaries cultured in the presence of forskolin, an adenylyl cyclase activator. This is the first evidence for the expression of melatonin receptors and binding sites, and for the modulation of a second messenger by melatonin in the pituitary of a nonmammalian species. We suggest that in fish, the melatonin-mediated photoperiodic control of neuroendocrine functions involves, at least, a direct effect on the pituitary. Copyright (C) 2000 S. Karger AG, Basel. C1 Univ Poitiers, Dept Neurosci, Lab Neurobiol Cellulaire, CNRS UMR 6558, Poitiers, France. RP Falcon, J (reprint author), NICHHD, Dev Neurobiol Lab, NIH49 6A83, 49 Convent Dr, Bethesda, MD 20892 USA. EM FalconJ@mail.nih.gov RI FALCON, Jack/I-5302-2013 OI FALCON, Jack/0000-0002-7572-6581 NR 49 TC 35 Z9 39 U1 2 U2 6 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD JUL PY 2000 VL 72 IS 1 BP 57 EP 66 DI 10.1159/000054571 PG 10 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 342NT UT WOS:000088652300007 PM 10940739 ER PT J AU Torrey, EF Miller, J Rawlings, R Yolken, RH AF Torrey, EF Miller, J Rawlings, R Yolken, RH TI Seasonal birth patterns of neurological disorders SO NEUROEPIDEMIOLOGY LA English DT Review DE seasonality; epilepsy; multiple; sclerosis; amyotrophic lateral sclerosis; Parkinson's disease ID ALZHEIMERS-DISEASE; MULTIPLE-SCLEROSIS; DOWN-SYNDROME; RISK-FACTORS; POPULATION; INFLUENZA; PREVALENCE; DEMENTIA; EPILEPSY AB Existing seasonal birth studies were reviewed for multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, cerebral palsy, congenital malformations of the central nervous system and mental retardation. Epilepsy appears to have the most consistent pattern, with an excess of births in winter and a deficit in September. MS, ALS and possibly Parkinson's disease appear to have an excess of spring births. Studies of cerebral palsy are not conclusive, although there are suggestions that there may be an excess of summer births. The findings for Alzheimer's disease, congenital malformations of the central nervous system, and mental retardation are contradictory and insufficient to draw any conclusions. Copyright (C) 2000 S. Karger AG, Basel. C1 NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIAAA, Stanley Fdn, Res Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Med Ctr, Stanley Div Dev Neurovirol, Baltimore, MD 21218 USA. RP Torrey, EF (reprint author), 5430 Grosvenor Lane,Suite 200, Bethesda, MD 20814 USA. NR 66 TC 81 Z9 82 U1 2 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-5350 J9 NEUROEPIDEMIOLOGY JI Neuroepidemiology PD JUL-AUG PY 2000 VL 19 IS 4 BP 177 EP 185 DI 10.1159/000026253 PG 9 WC Public, Environmental & Occupational Health; Clinical Neurology SC Public, Environmental & Occupational Health; Neurosciences & Neurology GA 328TD UT WOS:000087865400001 PM 10859496 ER PT J AU Longnecker, MP Kamel, F Umbach, DM Munsat, TL Shefner, JM Lansdell, LW Sandler, DP AF Longnecker, MP Kamel, F Umbach, DM Munsat, TL Shefner, JM Lansdell, LW Sandler, DP TI Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis SO NEUROEPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; diet; case-control studies; calcium; magnesium; antioxidants ID ANTECEDENT EVENTS; DISEASE; QUESTIONNAIRE; CAROTENOIDS; LYCOPENE; BIOLOGY AB Dietary factors have long been suspected of being risk factors for amyotrophic lateral sclerosis (ALS), but few human studies have been reported. To address several of the dietary hypotheses, a case-control study of risk factors for ALS conducted in New England in 1993-1996 included an abbreviated food frequency questionnaire. We examined the dietary intake of calcium, magnesium and antioxidants among 107 ALS cases and 262 community controls. Overall, these dietary factors were not related to risk of ALS, though modestly protective associations were suggested for magnesium and lycopene. Copyright (C) 2000 S. Karger AG, Basel. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. CODA Res Inc, Res Triangle Pk, NC USA. New England Med Ctr, Dept Neurol, Boston, MA 02111 USA. SUNY Hlth Sci Ctr, Dept Neurol, Syracuse, NY 13210 USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. OI Kamel, Freya/0000-0001-5052-6615; Longnecker, Matthew/0000-0001-6073-5322; Sandler, Dale/0000-0002-6776-0018 NR 21 TC 28 Z9 29 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-5350 J9 NEUROEPIDEMIOLOGY JI Neuroepidemiology PD JUL-AUG PY 2000 VL 19 IS 4 BP 210 EP 216 DI 10.1159/000026258 PG 7 WC Public, Environmental & Occupational Health; Clinical Neurology SC Public, Environmental & Occupational Health; Neurosciences & Neurology GA 328TD UT WOS:000087865400006 PM 10859501 ER PT J AU Knutson, B Westdorp, A Kaiser, E Hommer, D AF Knutson, B Westdorp, A Kaiser, E Hommer, D TI FMRI visualization of brain activity during a monetary incentive delay task SO NEUROIMAGE LA English DT Article DE incentives; reward; punishment; monetary; caudate; putamen; thalamus; anterior cingulate; mesial prefrontal cortex; FMRI; human ID PREFRONTAL CORTICAL PROJECTIONS; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; MACAQUE MONKEYS; CEREBRAL-CORTEX; ACTIVATION; REWARD; ANTICIPATION; STIMULATION; PREDICTION AB Comparative studies have implicated striatal and mesial forebrain circuitry in the generation of autonomic, endocrine, and behavioral responses for incentives. Using blood oxygen level-dependent functional magnetic resonance imaging, we sought to visualize functional activation of these regions in 12 normal volunteers as they anticipated and responded for monetary incentives. Both individual and group analyses of time-series data revealed significant activation of striatal and mesial forebrain structures (including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving both monetary rewards and punishments. In addition to these areas, during trials involving punishment, group analysis revealed activation foci in the anterior cingulate and thalamus. These results corroborate comparative studies which implicate striatal and mesial forebrain circuitry in the elaboration of incentive-driven behavior. This report also introduces a new paradigm for probing the functional integrity of this circuitry in humans. C1 NIAAA, Sect Brain Electrophysiol & Imaging, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Knutson, B (reprint author), NIAAA, Sect Brain Electrophysiol & Imaging, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. OI Knutson, Brian/0000-0002-7669-426X NR 36 TC 501 Z9 506 U1 4 U2 57 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL PY 2000 VL 12 IS 1 BP 20 EP 27 DI 10.1006/nimg.2000.0593 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 336RX UT WOS:000088317700003 PM 10875899 ER PT J AU Feldman, DE AF Feldman, DE TI Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; EXPERIENCE-DEPENDENT PLASTICITY; INTRINSIC FIRING PATTERNS; VISUAL-CORTEX; SYNAPTIC PLASTICITY; SOMATOSENSORY CORTEX; THALAMOCORTICAL SYNAPSES; HIPPOCAMPAL-NEURONS; CORTICAL PLASTICITY; CRITICAL PERIOD AB Experience-dependent plasticity in somatosensory (S1) and visual (V1) cortex involves rapid depression of responses to a deprived sensory input (a closed eye or a trimmed whisker). Such depression occurs first in layer II/III and may reflect plasticity at vertical inputs from layer IV to layer II/III pyramids. Here, I describe a timing-based, associative form of long-term potentiation and depression (LTP/LTD) at this synapse in S1. LTP occurred when excitatory postsynaptic potentials (EPSPs) led single postsynaptic action potentials (APs) within a narrow temporal window, and LTD occurred when APs led EPSPs within a significantly broader window. This long LTD window is unusual among timing-based learning rules and causes EPSPs that are uncorrelated with postsynaptic APs to become depressed. This behavior suggests a simple model for depression of deprived sensory responses in S1 and V1. C1 NINDS, Neural Dev Sect, NIH, Bethesda, MD 20892 USA. RP Feldman, DE (reprint author), NINDS, Neural Dev Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RI yu, yan/C-2322-2012 NR 65 TC 400 Z9 407 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL PY 2000 VL 27 IS 1 BP 45 EP 56 DI 10.1016/S0896-6273(00)00008-8 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 339XU UT WOS:000088503800009 PM 10939330 ER PT J AU Brebion, G Amador, X Smith, S Malaspina, D Sharif, Z Gorman, JM AF Brebion, G Amador, X Smith, S Malaspina, D Sharif, Z Gorman, JM TI Depression, psychomotor retardation, negative symptoms, and memory in schizophrenia SO NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY LA English DT Article ID COGNITIVE DISORDERS; PROCESSING SPEED; IMPAIRMENT; PERFORMANCE; DIMENSIONS; SYMPTOMATOLOGY; METAANALYSIS; DEFICITS; RECALL; AGE AB Objective: The purpose of this study was to examine the relations between depression, psychomotor retardation, and negative symptoms in schizophrenia as well as the specific contribution of each of these factors to memory impairment. Background: It has been suggested that depression overlaps with negative symptomatology in schizophrenia. The relation between psychomotor retardation and negative symptomatology has been unclear. Method: The Hamilton Depression Rating Scale, The Positive and Negative Symptom Scale for Schizophrenia, and Scale for the Assessment of Negative Symptoms were used to assess depressive and negative symptomatology in a sample of patients with schizophrenia. Verbal memory performance was assessed by a free recall test. Two indices of processing speed were measured. Correlations among variables were computed. Results: Depression score was correlated with the avolition item from the Scale for the Assessment of Negative Symptoms and with both measures of processing speed. Negative symptomatology was unrelated to processing speed. Memory performance was correlated with depression score, slowing of processing speed, and avolition. Its correlation with depression score and processing speed remained significant when the other factors were partialled out. Conclusions: Memory performance in schizophrenia may be affected by lack of motivation, psychomotor retardation, and depression. It is suggested that negative symptoms could be split between a volitional component linked to depression and cognitive efficiency and an emotional component unrelated to them. C1 Inst Psychiat, Dept Psychol Med, London SE5 8AZ, England. New York State Psychiat Inst, Schizophrenia Res Unit, New York, NY 10032 USA. NIMH, Clin Studies Lab, Bethesda, MD 20892 USA. Creedmoor Psychiat Ctr, Schizophrenia Res Unit, New York, NY USA. RP Brebion, G (reprint author), Inst Psychiat, Dept Psychol Med, 103 Denmark Hill, London SE5 8AZ, England. FU NIMH NIH HHS [5P20MH50727] NR 46 TC 33 Z9 34 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-878X J9 NEUROPSY NEUROPSY BE JI Neuropsychiatr. Neuropsychol. Behav. Neurol. PD JUL PY 2000 VL 13 IS 3 BP 177 EP 183 PG 7 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 332PH UT WOS:000088082300005 PM 10910088 ER PT J AU Maki, PM Bylsma, FW Brandt, J AF Maki, PM Bylsma, FW Brandt, J TI Conceptual and perceptual implicit memory in Huntington's disease SO NEUROPSYCHOLOGY LA English DT Article ID FRONTAL-LOBE FUNCTIONS; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; EXPLICIT MEMORY; PRIMING DEFICITS; AGE-DIFFERENCES; SYSTEMS; DISSOCIATION; DISORDERS; ATTENTION AB The aims of this study were to examine and compare perceptual and conceptual implicit memory (CIM) in Huntington's disease (HD) and to characterize the relationship between tests of frontal lobe functioning and CIM. Sixteen HD patients and 16 normal controls completed structurally parallel tests of perceptual implicit memory and CIM (i.e., rhyme and category exemplar generation), tests of explicit memory, and verbal fluency. HD patients showed intact implicit memory for both rhyme and category exemplars, despite evidence of frontal dysfunction on other tests. An unexpected finding was that patients showed a deficit in cued rhyme generation that correlated with severity of neurological impairment. The authors replicated findings in controls of a correlation between letter fluency and CIM but found no relationship in patients. Frontal dysfunction in HD may lessen the influence of generative strategies on tests of CIM without compromising performance. C1 NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21218 USA. RP Maki, PM (reprint author), NIA, Lab Personal & Cognit, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Brandt, Jason/0000-0001-7381-6244 FU NINDS NIH HHS [NS16375] NR 50 TC 6 Z9 6 U1 1 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD JUL PY 2000 VL 14 IS 3 BP 331 EP 340 DI 10.1037//0894-4105.14.3.331 PG 10 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 335PV UT WOS:000088253400001 PM 10928736 ER PT J AU Gourovitch, ML Kirkby, BS Goldberg, TE Weinberger, DR Gold, JM Esposito, G Van Horn, JD Berman, KF AF Gourovitch, ML Kirkby, BS Goldberg, TE Weinberger, DR Gold, JM Esposito, G Van Horn, JD Berman, KF TI A comparison of rCBF patterns during letter and semantic fluency SO NEUROPSYCHOLOGY LA English DT Article ID WORD PRODUCTION; FRONTAL-CORTEX; HUMAN BRAIN; ACTIVATION; MEMORY; SCHIZOPHRENIA; RETRIEVAL; TASKS; PET AB To evaluate the functional neuroanatomies underlying letter and category fluency, 18 normal controls were studied with oxygen-15 water regional cerebral blood how positron emission tomography. Three counterbalanced conditions each consisted of 6 trials (45 s each): letter fluency (generating words when cued with a particular letter), semantic fluency (generating words when cued with a particular category), and a control condition (generating days of the week and months of the year). Relative to the control, participants activated similar brain regions during both fluency tasks, including the anterior cingulate, left prefrontal regions, thalamus, and cerebellum; reductions were found in parietal and temporal regions. In a direct comparison of the 2 fluency tasks, inferior frontal cortex and temporoparietal cortex (hypothesized to participate in a phonologic loop for accessing word pronunciation) were activated more during letter than semantic fluency, whereas left temporal cortex (associated with access to semantic storage) was activated more during semantic than letter fluency. This study identifies subtle differences in the neural networks underlying letter and semantic fluency that may underlie the dissociation of these abilities in patients. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIMH, Unit Integrat Neuroimaging, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bldg 10,Room 4C-101, Bethesda, MD 20892 USA. NR 41 TC 164 Z9 167 U1 2 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD JUL PY 2000 VL 14 IS 3 BP 353 EP 360 DI 10.1037//0894-4105.14.3.353 PG 8 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 335PV UT WOS:000088253400003 PM 10928738 ER PT J AU Raedler, TJ Knable, MB Jones, DW Lafargue, T Urbina, RA Egan, MF Pickar, D Weinberger, DR AF Raedler, TJ Knable, MB Jones, DW Lafargue, T Urbina, RA Egan, MF Pickar, D Weinberger, DR TI In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE muscarinic receptor; olanzapine; IQNB; SPECT; schizophrenia; antipsychotic ID IN-VIVO; CHOLINERGIC RECEPTORS; DOUBLE-BLIND; RAT-BRAIN; CAUDATE-PUTAMEN; DOPAMINE; HALOPERIDOL; ANTAGONISM; BINDING; D-2 AB Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K-i = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M-2 subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects. [Neuropsychopharmacology 23:56-68, 2000] Published by Elsevier Science Inc. on behalf of the American College of Neuropsychopharmacology. C1 NIMH, Clin Brain Disorders Branch, NIH, DIRP, Bethesda, MD 20892 USA. Stanley Res Fdn, Bethesda, MD 20814 USA. NIMH, Expt Therapeut Branch, DIRP, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, NIH, DIRP, 10 Ctr Dr,4S-235 MSC 1379, Bethesda, MD 20892 USA. NR 59 TC 56 Z9 57 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2000 VL 23 IS 1 BP 56 EP 68 DI 10.1016/S0893-133X(99)00162-1 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 327BH UT WOS:000087772700006 PM 10869886 ER PT J AU Ferguson, SA Flynn, KM Delclos, KB Newbold, RR AF Ferguson, SA Flynn, KM Delclos, KB Newbold, RR TI Maternal and offspring toxicity but few sexually dimorphic behavioral alterations result from nonylphenol exposure SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE nonylphenol; endocrine disrupter; sodium intake; activity ID OPEN-FIELD BEHAVIOR; ENDOCRINE DISRUPTORS; SEX-DIFFERENCES; MALE-RATS; RESEARCH NEEDS; P-NONYLPHENOL; FEMALE RATS; ESTROGEN; ANDROGENS; TESTOSTERONE AB Nonylphenol ethoxylates are used in the production of surfactants and are found in numerous manufactured substances, para-Nonylphenol (NP) is a suspected endocrine disrupter, exhibiting estrogen-like activity and might cause alterations with developmental exposure. To evaluate such effects, pregnant Sprague-Dawley rats consumed diets containing 0 (n = 11), 25 (n = 10), 500 (n = 10), or 2,000 (n = 9) ppm NP beginning on gestational day (GD) 7. At postnatal day (PND) 21, offspring continued on the same maternal diets until PND 77 and were evaluated for behavioral alterations (open-field activity at PNDs 22-24, 43-45, 64-66, play behavior at PND 35, running wheel activity at PND 63-77, flavored solution intake at PND 69-75). During pregnancy and lactation, darns in the 25-, 500-, and 2,000-ppm groups consumed 9 to 25% less food, which was associated with a 17% less weight gain during GDs 1 to 21 in dams of the 2,000-ppm group, although this effect was not statistically significant. Gestation duration, birth weight, sex ratio of live pups, and number of live or dead pups per litter did not differ between treatment groups. Offspring body weight and food consumption were decreased in the ?,000ppm group beginning at PNP 28; however, an effect of feed aversion could not be eliminated. Behavioral assessments of offspring indicated no consistent NP-related effects in open-field activity at PNDs 22-24, 43-45, and 65-67 nor in running wheel activity at PNDs 63-75. Play behavior at PND 35 and intake of a 0.3% saccharin-flavored solution at PNDs 69-71 did not differ with respect to treatment groups. However, intake of a 3% sodium-flavored solution at PNDs 73-75 was significantly increased in offspring of the 2,000-ppm group and intake of regular water during this same time was also significantly increased. These results indicate that developmental NP treatment results in maternal and offspring toxicity as evidenced by decreased food intake and weight gain. However, behavioral alterations were evident only in increased intake of a sodium solution. (C) 2000 Elsevier Science Inc. All rights reserved. C1 US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NIEHS, Environm Toxicol Program, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Ferguson, SA (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. FU PHS HHS [224-93-0001] NR 45 TC 40 Z9 40 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-AUG PY 2000 VL 22 IS 4 BP 583 EP 591 DI 10.1016/S0892-0362(00)00071-4 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 350RX UT WOS:000089115900011 PM 10974597 ER PT J AU Lang, LX Jagoda, E Schmal, B Sassaman, M Ma, Y Eckelman, WC AF Lang, LX Jagoda, E Schmal, B Sassaman, M Ma, Y Eckelman, WC TI Fluoro analogs of WAY-100635 with varying pharmacokinetics properties SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT Conference on the Imaging of Brain 5-HT(1A) Receptors In-Vivo - Radioligands, Clincial Applications, and Drug Development CY OCT 29-30, 1999 CL KAROLINSKA INST, STOCKHOLM, SWEDEN HO KAROLINSKA INST DE serotonin receptor; 5-HT1A subtype; fluorine-18; FCWAY; MeFBWAY ID 5-HT1A RECEPTORS; HUMAN-BRAIN; H-3 WAY-100635; RAT-BRAIN; SEROTONIN RECEPTORS; BINDING; PET; WAY-100635; LOCALIZATION; RADIOLIGAND AB Radiolabeled derivatives of WAY-100635 have been shown to be important for imaging in vivo because of their antagonist properties and their specificity for the 5-hydroxytryptamine(1A) (5-HT1A) receptor. Our goal is to prepare a series of radiofluorinated derivatives of WAY-100635 that, in the rat, range in pharmacokinetic properties from nearly irreversible to reversible in their behavior. It appears that derivatives containing a cyclohexanecarboxylic acid (e.g., FCWAY) with its high affinity and high target to nontarget contrast, has properties suited to measure receptor concentration. Derivatives based on phenylcarboxamide (e.g., FBWAY and MeFBAWAY) have properties more suited to the measurement of changes in endogenous serotonin. The compound containing the pyrimidine moiety in place of the pyridine moeity in FBWAY (FBWAY 1,3N) appears to have intermediate properties. NUCL MED BIOL 27;5:457-462, 2000. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bld 10 Rm 1C495,10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. NR 27 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2000 VL 27 IS 5 BP 457 EP 462 DI 10.1016/S0969-8051(00)00111-6 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 352KK UT WOS:000089214300006 PM 10962250 ER PT J AU Carson, RE Lan, LX Watabe, H Der, MG Adams, HR Jagoda, E Herscovitch, P Eckelman, WC AF Carson, RE Lan, LX Watabe, H Der, MG Adams, HR Jagoda, E Herscovitch, P Eckelman, WC TI PET evaluation of [F-18]FCWAY, an analog of the 5-HT1A receptor antagonist, WAY-100635 SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT Conference on the Imaging of Brain 5-HT(1A) Receptors In-Vivo - Radioligands, Clincial Applications, and Drug Development CY OCT 29-30, 1999 CL KAROLINSKA INST, STOCKHOLM, SWEDEN HO KAROLINSKA INST DE FCWAY; 5-HT1A receptors; modeling; volume of distribution ID HUMAN BRAIN; RADIOACTIVE METABOLITES; HUMAN PLASMA; WAY-100635; RADIOLIGAND; DELINEATION; BINDING; MONKEY AB We synthesized [F-18]FCWAY, an analog of [carbonyl-C-11]WAY-100635 ([C-11]N-(2-(1-(4(2-methoxyphenyl)-piperazinyl)ethyl))-N-(2-(pyridinyl))cyclohexanecarboxamide}, by replacing the cyclohexanecarbonyl group acid with a trans-4-fluorocyclohexanecarbonyl group (FC). Control and preblocking studies were performed in anesthetized monkeys. Plasma radioactive metabolite analysis showed the presence of [F-18]FC and [F-18]fluoride. Tissue time-radioactivity curves were corrected for metabolite contamination based on separate positron-emission tomography studies of these two labeled metabolites. Analysis using a two-tissue compartment model gave distribution volume (V) estimates (mL/mL) ranging from 33 in frontal cortex to 4 in cerebellum. Preblocking data showed uniform V of 2-3 mL/mL. These studies demonstrate that [F-18]FCWAY has very similar kinetic characteristics to [C-11]WAY-100635. NUCL MED BIOL 27;5:493-497, 2000. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Carson, RE (reprint author), NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bldg 10,Room 1C-401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 13 TC 58 Z9 59 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2000 VL 27 IS 5 BP 493 EP 497 DI 10.1016/S0969-8051(00)00118-9 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 352KK UT WOS:000089214300013 PM 10962257 ER PT J AU Jefferson, WN Newbold, RR AF Jefferson, WN Newbold, RR TI Potential endocrine-modulating effects of various phytoestrogens in the diet SO NUTRITION LA English DT Article ID ESTROGEN-RECEPTOR-BETA; EXPOSURE; DIETHYLSTILBESTROL; YEAST; ISOFLAVONES; GENISTEIN; CHEMICALS; HORMONE C1 NIEHS, Dev Endocrinol Sect, Environm Toxicol Program, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Jefferson, WN (reprint author), NIEHS, Dev Endocrinol Sect, Environm Toxicol Program, Toxicol Lab, Mail Drop E4-02, Res Triangle Pk, NC 27709 USA. NR 30 TC 43 Z9 45 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD JUL-AUG PY 2000 VL 16 IS 7-8 BP 658 EP 662 DI 10.1016/S0899-9007(00)00306-3 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 337RF UT WOS:000088374900065 PM 10906588 ER PT J AU Trimble, E Valmonte, CM Cheson, BD AF Trimble, E Valmonte, CM Cheson, BD TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Trimble, E (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUL PY 2000 VL 14 IS 7 BP 1045 EP 1045 PG 1 WC Oncology SC Oncology GA 368QR UT WOS:000090129500018 PM 10929590 ER PT J AU Chernomordik, V Hattery, D Gandjbakhche, AH Pifferi, A Taroni, P Torricelli, A Valentini, G Cubeddu, R AF Chernomordik, V Hattery, D Gandjbakhche, AH Pifferi, A Taroni, P Torricelli, A Valentini, G Cubeddu, R TI Quantification by random walk of the optical parameters of nonlocalized abnormalities embedded within tissuelike phantoms SO OPTICS LETTERS LA English DT Article ID TIME-DOMAIN; SCATTERING; ABSORPTION; MEDICINE AB We have extended a random-walk theory that uses time-dependent contrast functions to quantify the cross section and the corrected scattering and absorption coefficients of abnormal nonlocalized targets from time-of-flight (TOF) data obtained in time-resolved transillumination experiments. Experimental TOF's are used to show that this newly developed random-walk method is able to quantify the size and the optical properties of embedded nonlocalized targets in with an error rate of less than or equal to 25%. (C) 2000 Optical Society of America. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Politecn Milan, Ist Nazl Fis Mat, Dept Phys, I-20133 Milan, Italy. RP Chernomordik, V (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RI Taroni, Paola/C-4709-2012; Torricelli, Alessandro/F-2591-2012; Pifferi, Antonio/C-4688-2012; OI Taroni, Paola/0000-0001-7486-0001; Torricelli, Alessandro/0000-0002-6878-8936; Pifferi, Antonio/0000-0002-2261-2089; Valentini, Gianluca/0000-0002-6340-3021 NR 8 TC 25 Z9 25 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD JUL 1 PY 2000 VL 25 IS 13 BP 951 EP 953 DI 10.1364/OL.25.000951 PG 3 WC Optics SC Optics GA 330CC UT WOS:000087944400005 PM 18064237 ER PT J AU Brennan, MT Fox, PC AF Brennan, MT Fox, PC TI Cytokine mRNA expression in the labial salivary glands of healthy volunteers SO ORAL DISEASES LA English DT Article DE cytokine; salivary glands; mRNA ID MESSENGER-RNA EXPRESSION; PRIMARY SJOGRENS-SYNDROME AB OBJECTIVE: To examine the cytokine profile in minor salivary glands of healthy volunteers and examine differential cytokine production from acinar and ductal tissues. STUDY DESIGN: Acinar and ductal elements were isolated by a cell-specific micro-dissection technique from frozen 8 mu m sections of minor salivary glands from healthy volunteers. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization using P-32-labeled cytokine gene-specific probes were utilized to detect cytokine mRNA, mRNA transcripts for the Th1 cytokines (IL-2, TNF-alpha, and IFN-gamma), Th2 cytokines (IL-4, IL-6, and IL-10), TGF-beta, actin, and CD3 delta were analyzed in acini, ducts and total tissue sections of minor salivary glands of six healthy controls. RESULTS: Actin, TGF beta and TNF alpha was present in 6/6 acinar, 6/6 ductal, and 6/6 total section samples. IFN gamma was present in 2/6 acinar, 3/6 ductal, and 6/6 total samples. IL-2 was found in 3/6 acinar, 3/6 ductal and 5/6 total sections. IL-6 was found in 1/6 acinar, 0/6 ductal, and 5/6 total sections, IL-10 was found in 3/6 acinar, 3/6 ductal, and 5/6 total sections. IL-4 was present in 0/6 acinar, 0/6 ductal and 1/6 total samples. CD3 delta was present in 6/6 acinar, 5/6 ductal and 6/6 total sections. CONCLUSIONS: These results demonstrate abundant expression of cytokines in healthy minor salivary glands. The production of these cytokines in healthy tissues demonstrates a likely role of supporting normal cellular function. C1 NIDCR, CRC, NIH, Bethesda, MD 20892 USA. Amarillo Biosci Inc, Amarillo, TX USA. RP Brennan, MT (reprint author), NIDCR, CRC, NIH, Bldg 10,Room 1N113,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 10 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1354-523X J9 ORAL DIS JI Oral Dis. PD JUL PY 2000 VL 6 IS 4 BP 222 EP 226 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 337RH UT WOS:000088375100004 PM 10918559 ER PT J AU Kamhawi, S Modi, GB Pimenta, PFP Rowton, E Sacks, DL AF Kamhawi, S Modi, GB Pimenta, PFP Rowton, E Sacks, DL TI The vectorial competence of Phlebotomus sergenti is specific for Leishmania tropica and is controlled by species-specific, lipophosphoglycan-mediated midgut attachment SO PARASITOLOGY LA English DT Article DE Phlebotomus sergenti; Leishmania tropica; lipophosphoglycan; vector specificity ID SANDFLY VECTOR; DONOVANI LIPOPHOSPHOGLYCAN; SURFACE LIPOPHOSPHOGLYCAN; CUTANEOUS LEISHMANIASIS; PAPATASI; PROMASTIGOTES; IDENTIFICATION; POLYMORPHISMS; PURIFICATION; PSYCHODIDAE AB The vectorial competence of Phlebotomus sergenti for 3 Old World species of Leishmania, L. tropica, L. major and L. donovani, was investigated in vivo and by in vitro midgut binding assays using living promastigotes and purified lipophosphoglycan (LPG). P. sergenti consistently showed a high specificity for L. tropica strains, which were able to develop mature, potentially transmissible infections. The loss of infection with L. major and L. donovani correlated with the excretion of the digested bloodmeal. These strains were able to produce sustained infections in the midguts of their appropriate vectors, P. papatasi and P. argentipes, respectively. In in vitro binding assays, a significantly higher number of L. tropica procyclic promastigotes attached to the midgut lining of P. sergenti, compared to those of L. major and L. donovani (P < 0.05). The prediction that the species specificity of midgut attachment is controlled by polymorphic structures on the parasite LPG was supported by the finding that P. sergenti midguts were intensely stained following incubation with purified phosphoglycan (PG) from L. tropica compared with PGs from L. major or L. donovani. The results provide further evidence that LPG structural polymorphisms are driven by the species diversity of molecules present on the sandfly midgut that function as parasite attachment sites. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Fiocruz MS, Ctr Pesquisas Rene Rachou, Lab Entomol Med, BR-30190002 Belo Horizonte, MG, Brazil. Walter Reed Army Med Ctr, Dept Entomol, Washington, DC 20307 USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126, Bethesda, MD 20892 USA. RI Rowton, Edgar/A-4474-2012; Rowton, Edgar/A-1975-2011 OI Rowton, Edgar/0000-0002-1979-1485 NR 37 TC 58 Z9 63 U1 1 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD JUL PY 2000 VL 121 BP 25 EP 33 DI 10.1017/S0031182099006125 PN 1 PG 9 WC Parasitology SC Parasitology GA 345YQ UT WOS:000088843200004 PM 11085222 ER PT J AU Davis-Hayman, SR Shah, PH Finley, RW Lushbaugh, WB Meade, JC AF Davis-Hayman, SR Shah, PH Finley, RW Lushbaugh, WB Meade, JC TI Trichomonas vaginalis: analysis of a heat-inducible member of the cytosolic heat-shock-protein 70 multigene family SO PARASITOLOGY RESEARCH LA English DT Article ID HSP70; METRONIDAZOLE; INVITRO AB A 2253-nucleotide (nt) transcript for a Trichomonas vaginalis heat-shock protein 70, TVCHSP70, has been isolated that encodes for a protein of 659 amino acids with a predicted molecular weight of 71.3 kDa. TVCHSP70 has a short (10-nt) 5' untranslated region (UTR), and the 263-nt 3' UTR is the longest reported for a Trichomonas peptide. Amino-acid sequence anal; sis and phylogenetic comparison identifies TVCHSP70 as a member of the heat-inducible cytoplasmic HSP70 gene family. Southern-blot data indicate that T. vaginalis contains at least four members of the cytoplasmic HSP70 gene Family. Members of the TVCHSP70 family are expressed as 2.3-kb transcripts at low levels during 37 degrees C culture, and their expression is significantly up-regulated at 43 degrees C. Slot-blot analysis of seven T. vaginalis clinical isolates demonstrated a 3- to 44-fold up-regulation of TVCHSP70 under conditions of heat shock (43 degrees C) or oxidative stress (500 mu m H2O2) as compared with controls (37 degrees C). C1 Univ Mississippi, Med Ctr, Dept Microbiol, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Med, Div Infect Dis, Jackson, MS 39216 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Meade, JC (reprint author), Univ Mississippi, Med Ctr, Dept Microbiol, 2500 N State St, Jackson, MS 39216 USA. NR 13 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0044-3255 J9 PARASITOL RES JI Parasitol. Res. PD JUL PY 2000 VL 86 IS 7 BP 608 EP 612 DI 10.1007/PL00008538 PG 5 WC Parasitology SC Parasitology GA 335JJ UT WOS:000088240100014 PM 10935914 ER PT J AU Bundy, D Sher, A Michael, E AF Bundy, D Sher, A Michael, E TI Good worms or bad worms: Do worm infections affect the epidemiological patterns of other diseases? SO PARASITOLOGY TODAY LA English DT Editorial Material ID IMMUNE-RESPONSES; T-CELL; AIDS C1 World Bank, Washington, DC 20433 USA. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Oxford, Wellcome Trust Ctr Epidemiol Infect Dis, Oxford OX1 2FY, England. RP Bundy, D (reprint author), World Bank, 1818 H St NW, Washington, DC 20433 USA. RI Michael, Edwin/D-3388-2014 NR 14 TC 52 Z9 55 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0169-4758 J9 PARASITOL TODAY JI Parasitol. Today PD JUL PY 2000 VL 16 IS 7 BP 273 EP 274 DI 10.1016/S0169-4758(00)01689-6 PG 2 WC Parasitology SC Parasitology GA 331BQ UT WOS:000087997800005 PM 10858643 ER PT J AU Ferdig, MT Su, XZ AF Ferdig, MT Su, XZ TI Microsatellite markers and genetic mapping in Plasmodium falciparum SO PARASITOLOGY TODAY LA English DT Article ID HUMAN MALARIA PARASITE; CHLOROQUINE RESISTANCE; LINKAGE DISEQUILIBRIUM; RECOMBINATION; SEQUENCE; GENOME; MAP; PROTEIN; AFRICA; LOCUS AB Whole-genome methods are changing the scope of biological questions that can be addressed in malaria research. In the rich context provided by Plasmodium falciparum genome sequencing, genetic mapping is a powerful tool for identifying genes involved in parasite development, invasion, transmission and drug resistance. The recent development of a high-resolution P. falciparum linkage map consisting of hundreds of microsatellite markers will facilitate an integrated genomic approach to understanding the relationship between genetic variations and biological phenotypes. Here, Michael Ferdig and Xin-zhuan Su provide an overview for applying microsatellite markers and genetic maps to gene mapping, parasite typing and studies of parasite population changes. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Ferdig, MT (reprint author), NIH, Parasit Dis Lab, 4 Ctr Dr 0425, Bethesda, MD 20892 USA. RI Ferdig, Michael/C-6627-2016; OI Su, Xinzhuan/0000-0003-3246-3248 NR 29 TC 34 Z9 35 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0169-4758 J9 PARASITOL TODAY JI Parasitol. Today PD JUL PY 2000 VL 16 IS 7 BP 307 EP 312 DI 10.1016/S0169-4758(00)01676-8 PG 8 WC Parasitology SC Parasitology GA 331BQ UT WOS:000087997800012 PM 10858651 ER PT J AU Moriuchi, H Rodriguez, W AF Moriuchi, H Rodriguez, W TI Role of varicella-zoster virus in stroke syndromes SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE varicella-zoster virus; herpes zoster ophthalmicus; vasculitis; strokes ID CENTRAL-NERVOUS-SYSTEM; HERPES-ZOSTER; CONTRALATERAL HEMIPARESIS; CEREBRAL VASCULOPATHY; VASCULITIS; OPHTHALMICUS; CHICKENPOX; INFECTION; HEMIPLEGIA; CHILDHOOD C1 Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. NIAID, Bethesda, MD 20892 USA. RP Moriuchi, H (reprint author), Nagasaki Univ, Sch Med, Dept Pediat, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. NR 26 TC 33 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2000 VL 19 IS 7 BP 648 EP 653 DI 10.1097/00006454-200007000-00014 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 334HE UT WOS:000088180400012 PM 10917224 ER PT J AU Yakar, S Liu, JL Le Roith, D AF Yakar, S Liu, JL Le Roith, D TI The growth hormone/insulin-like growth factor-I system: implications for organ growth and development SO PEDIATRIC NEPHROLOGY LA English DT Article; Proceedings Paper CT 6th Symposium on Growth and Development in Children with Chronic Renal Failure CY MAR 11-13, 1999 CL NEW YORK, NEW YORK DE growth hormone; insulin-like growth factor-I; growth; development; knock-out mice ID SOMATOMEDIN-C; CRE RECOMBINASE; RAT; HORMONE; RECEPTOR; GENE; MICE; MANIPULATION; TISSUES; SERUM AB Growth hormone (GH) and insulin-like growth factors (IGFs) are essential for normal growth and development during embryonic stages as well as postnatally. While GH has little effect on these processes prenatally, the IGFs are important during these stages. On the other hand the GH-IGF-I axis is important for pubertal growth. To determine whether postnatal growth and development are dependent on circulating or locally produced IGF-I, we deleted the ICF-I gene in the liver using the cre/LoxP system used for tissue-specific gene deletion. These animals demonstrated approximately 75%-80% reduction in circulating IGF-I and an approximate fourfold increase in circulating GH. Despite the marked reductions in circulating IGF-I, growth and development was apparently normal. Thus the original somatomedin hypothesis needs to be re-evaluated in the light of these new findings. C1 NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NIDDKD, Sect Mol & Cellular Physiol, Clin Endocrinol Branch, Bethesda, MD 20892 USA. RP Le Roith, D (reprint author), NIH, Clin Endocrinol Branch, Room 8D12,Bldg 10,MSC 1758, Bethesda, MD 20892 USA. NR 31 TC 24 Z9 25 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2000 VL 14 IS 7 BP 544 EP 549 PG 6 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 342WQ UT WOS:000088668800004 PM 10912516 ER PT J AU Rother, KI Accili, D AF Rother, KI Accili, D TI Role of insulin receptors and IGF receptors in growth and development SO PEDIATRIC NEPHROLOGY LA English DT Article; Proceedings Paper CT 6th Symposium on Growth and Development in Children with Chronic Renal Failure CY MAR 11-13, 1999 CL NEW YORK, NEW YORK DE growth; IGF-1; IGF-2; insulin-like growth factor receptor; insulin receptor; mutant mouse models; leprechaunism ID HOMOZYGOUS NONSENSE MUTATION; FACTOR-I; GLUCOSE-TOLERANCE; POSTNATAL-GROWTH; ADIPOSE-TISSUE; GENE; LEPRECHAUNISM; MICE; RESISTANCE; LETHALITY AB Observations in targeted mouse mutants and patients with genetic abnormalities grant insight into the various and distinct roles of insulin-like growth factor receptors (IGF-Rs) and insulin receptors (IRs) during early development. While IGF-1Rs (mediating both IGF-1 and IGF-2 actions) are important for embryonic and fetal growth, IRs (mediating IGF-2 rather than insulin action) play a minor role. However, it is an oversimplification to conclude that IGF-1Rs mediate growth and IRs mediate metabolic responses. Mice lacking both IRs and IGF-1Rs are more severely growth retarded than mice lacking either receptor alone. The phenotype of combined deficiency of IRs and IGF-1Rs is similar to the phenotype caused by the absence of IGF-1 and IGF-2. This provides genetic proof that these two receptors account for the entirety of the growth promoting effects of IGF-1 and IGF-2. There is little evidence that hybrid insulin/IGF-1 receptors promote embryonic growth to a significant degree. The clinical presentation regarding severity of growth retardation and metabolic disturbances observed in animal models versus in humans may differ greatly and the reasons will be reviewed in detail. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10D18, Bethesda, MD 20892 USA. NR 30 TC 54 Z9 58 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2000 VL 14 IS 7 BP 558 EP 561 PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 342WQ UT WOS:000088668800006 PM 10912518 ER PT J AU Gafni, RI Baron, J AF Gafni, RI Baron, J TI Catch-up growth: possible mechanisms SO PEDIATRIC NEPHROLOGY LA English DT Article; Proceedings Paper CT 6th Symposium on Growth and Development in Children with Chronic Renal Failure CY MAR 11-13, 1999 CL NEW YORK, NEW YORK DE catch-up growth; growth plate; glucocorticoids; chondrocyte ID RENAL-TRANSPLANTATION; HEIGHT; HYPOTHYROIDISM; CHILDHOOD; CHILDREN; THERAPY; STATURE AB Many systemic diseases impair linear growth. If remission occurs, growth will often accelerate beyond the normal rate for age, a phenomenon termed "catch-up growth." As a result, final height is improved, although this recovery of adult stature is frequently incomplete. Two principal models have been proposed to explain catch-up growth. The first model postulates a central nervous system mechanism that compares actual body size with an age-appropriate set-point and then adjusts growth rate accordingly. However, there is recent evidence that growth inhibition in a single growth plate is followed by local catch-up growth, a finding not readily explained by the neuroendocrine model. Thus, a new model has been proposed that places the mechanism within the growth plate itself. According to this model, growth-inhibiting conditions decrease proliferation of growth plate stem cells, thus conserving their proliferative potential. Additional research is needed to determine whether the mechanisms governing catch-up growth are local, systemic, or both. C1 NICHHD, Dev Endocrinol Branch, Unit Growth & Dev, NIH, Bethesda, MD 20892 USA. RP Gafni, RI (reprint author), NICHHD, Dev Endocrinol Branch, Unit Growth & Dev, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. NR 24 TC 36 Z9 36 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2000 VL 14 IS 7 BP 616 EP 619 PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 342WQ UT WOS:000088668800017 PM 10912529 ER PT J AU Furey, ML Pietrini, P Alexander, GE Mentis, MJ Szczepanik, J Shetty, U Greig, NH Holloway, HW Schapiro, MB Freo, U AF Furey, ML Pietrini, P Alexander, GE Mentis, MJ Szczepanik, J Shetty, U Greig, NH Holloway, HW Schapiro, MB Freo, U TI Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE physostigmine; pharmacodynamics; pharmacokinetics; rCBF; PET; cognition; working memory; brain; humans ID CEREBRAL BLOOD-FLOW; ALZHEIMERS-DISEASE; WORKING-MEMORY; CHOLINERGIC STIMULATION; PERFORMANCE; DEMENTIA; RCBF AB In imaging studies of brain functions using pharmacological probes, identification of the time point at which central effects of intravenously infused drugs become stable is crucial to separate the effects of experimental variables from the concomitant changes in drug effects over time. We evaluated the time courses of the pharmacokinetics and pharmacodynamics, including butyrylcholinesterase inhibition and central neural responses. of physostigmine in healthy young subjects. Ten positron emission tomography (PET) scans that alternated between a rest condition (eyes open, ears unplugged) and a working memory for faces (WM) task were acquired in healthy subjects. Subjects in the drug group received a saline infusion for the first two scans, providing a baseline measure, then received an infusion of physostigmine for all subsequent scans. Subjects in the control group received a placebo infusion of saline for all scans. Physostigmine plasma levels and percent butyrylcoholinesterase inhibition increased over time (p < 0.0001). and both became stable by 40 min. Physostigmine decreased reaction time (RT) (p = 0.0005), and this effect was detected after 20 min of infusion and stable thereafter. Physostigmine also decreased regional cerebral blood flow (rCBF) in right prefrontal cortex during task (p = 0.0002), and this effect was detected after 40 min of infusion and stable thereafter. No change in RT or rCBF was observed in the control group. These results indicate that a 40-min infusion of physostigmine was necessary to obtain stable central effects. More generally, we have demonstrated that experimental effects can vary with time. especially during the initial phases of a drug infusion, Indicating that it is critical that these changes are controlled. (C) 2000 Elsevier Science Inc. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Univ Pisa, Dept Human & Environm Sci, Pisa, Italy. NIA, Lab Cellular & Mol Biol Drug Design & Dev, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Furey, ML (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Rm 4C104,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Furey, Maura/H-5273-2013 NR 24 TC 27 Z9 27 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUL PY 2000 VL 66 IS 3 BP 475 EP 481 DI 10.1016/S0091-3057(00)00186-6 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 337HN UT WOS:000088351500002 PM 10899358 ER PT J AU Lomnitski, L Foley, JF Grossman, S Ben Shaul, V Maronpot, RR Moomaw, CR Carbonatto, M Nyska, A AF Lomnitski, L Foley, JF Grossman, S Ben Shaul, V Maronpot, RR Moomaw, CR Carbonatto, M Nyska, A TI Effects of apocynin and natural antioxidant from spinach on inducible nitric oxide synthase and cyclooxygenase-2 induction in lipopolysaccharide-induced hepatic injury in rat SO PHARMACOLOGY & TOXICOLOGY LA English DT Article ID IN-VIVO; LIPID-PEROXIDATION; MESSENGER-RNA; GUINEA-PIGS; EXPRESSION; ENDOTOXIN; MICE; LIPOXYGENASE; MACROPHAGES; ACTIVATION AB The immunoreactivity of inducible nitric oxide synthase, and cyclooxygenase-2 was compared among groups of male Wistar rats comprising those injected with lipopolysaccharide following pretreatment with either natural antioxidant from spinach or the antioxidant apocynin, with lipopolysaccharide without pretreatment with antioxidants, with each of the two antioxidants alone, and untreated controls. The grade of staining of both inducible nitric oxide synthase and cyclooxygenase-2 increased with the severity of the inflammatory reaction in the lipopolysaccharide-treated animals, compared to the antioxidant-treated groups. Interpretation of the results of the immunostained tissues indicated that pretreatment with either antioxidant significantly (P<0.05) attenuated the lipopolysaccharide-stimulated inducible nitric oxide synthase induction. Analysis of the cycloxygenase-2-stained liver samples indicated that the pretreatment with the natural antioxidant NAO significantly (P<0.05) attenuated lipopolysaccharide-stimulated cycloxygenase-2 induction; whereas, in animals pretreated with apocynin, there was a trend of reduction in the cyclooxygenase-2 expression, but not statistically significant (P>0.05). The negative nitrotyrosine immunoreactivity of the lipopolysaccharide-related hepatic lesions may indicate that there was relatively low interaction between superoxide anions and nitric oxide to form peroxynitrite or that the expression levels of the nitrotyrosine were below the limit of detection. In all treatment groups a positive correlation (P<0.05, r=0.86) found between the inducible nitric oxide synthase and cyclooxygenase-2 scores suggests a strong relationship between these two parameters. The results indicate the possible therapeutic efficacy of NAO and apocynin in the prevention of liver damage related to clinical endotoxemia known to be associated with oxidative stress. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Bar Ilan Univ, IL-52900 Ramat Gan, Israel. Antoine Marxer SpA, Inst Biomed Res, LCG RBM, I-10015 Turin, Italy. RP Nyska, A (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 50 TC 21 Z9 23 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI FREDERIKSBERG C PA 1 ROSENORNS ALLE, DK-1970 FREDERIKSBERG C, DENMARK SN 0901-9928 J9 PHARMACOL TOXICOL JI Pharmacol. Toxicol. PD JUL PY 2000 VL 87 IS 1 BP 18 EP 25 DI 10.1111/j.0901-9928.2000.870104.x PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 345ZC UT WOS:000088844500004 PM 10987211 ER PT J AU Calis, KA Anderson, DW Auth, DA Mays, DA Turcasso, NM Meyer, CC Young, LR AF Calis, KA Anderson, DW Auth, DA Mays, DA Turcasso, NM Meyer, CC Young, LR TI Quality of pharmacotherapy consultations provided by drug information centers in the United States SO PHARMACOTHERAPY LA English DT Article AB We evaluated the performance of 116 U.S. drug information centers in responding to specific questions about drugs. The primary measures were correctness of responses and extent of probing for patient data. Questions addressed the effect of ranitidine on blood alcohol concentrations, the potential interaction between didanosine and dapsone, prevention of nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcers, and use of erythromycin for diabetic gastroparesis. The percentages of centers providing correct overall responses were 70% for the ranitidine question, 90% for the didanosine-dapsone question, 8% for the NSAID question, and 20% for the erythromycin question. For the three patient-specific questions, the percentages of centers eliciting vital patient data were 27% for the didanosine-dapsone question, 86% for the NSAID question, and 5% for the erythromycin question. In providing pharmacotherapy consultations, drug information centers generally failed to obtain pertinent patient data, thereby risking incorrect responses and inappropriate recommendations. C1 NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Drug Informat Serv, Bethesda, MD 20892 USA. NINDS, Biostat Branch, Populat Studies Unit, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Pharm, Drug Informat Ctr, Baltimore, MD USA. Med Univ S Carolina, Coll Pharm, Drug Informat Ctr, Charleston, SC 29425 USA. Univ Missouri, Sch Pharm, Drug Informat Ctr, Kansas City, MO 64110 USA. Univ Tennessee, Coll Pharm, Drug Informat Ctr, Memphis, TN USA. RP Calis, KA (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Drug Informat Serv, Bldg 10,Room 1S-259,10 Ctr Dr MSC 1196, Bethesda, MD 20892 USA. NR 9 TC 4 Z9 4 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER BOX 806 171 HARRISON AVE, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2000 VL 20 IS 7 BP 830 EP 836 DI 10.1592/phco.20.9.830.35193 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 331ZD UT WOS:000088047800011 PM 10907973 ER PT J AU Hilioti, Z Richards, C Brown, KM AF Hilioti, Z Richards, C Brown, KM TI Regulation of pollination-induced ethylene and its role in petal abscission of Pelargonium x hortorum SO PHYSIOLOGIA PLANTARUM LA English DT Review ID 1-AMINOCYCLOPROPANE-1-CARBOXYLATE SYNTHASE GENES; CARNATION FLOWER PETALS; 1-(MALONYLAMINO)CYCLOPROPANE-1-CARBOXYLIC ACID; COROLLA ABSCISSION; BIOSYNTHETIC GENES; MAJOR CONJUGATE; PETUNIA FLOWERS; ORCHID FLOWERS; TOMATO FRUIT; SENESCENCE AB Pollination in geranium (Pelargonium x hortorum) results in rapid non-autocatalytic ethylene production followed by abscission of turgid petals. In the present work, the regulation of post-pollination ethylene was investigated in various floral organs. Ethylene production and petal abscission increased as the number of stigmatic lobes pollinated increased. Direct application of 1-aminocyclopropane-1-carboxylic acid (ACC) to the stigma induced ethylene production and petal abscission only at high concentrations, which are not naturally present in the pollen. Application of aminoethoxyvinylglycine (AVG), an inhibitor of ACC synthase activity, to the stigma effectively prevented pollination-induced ethylene production and petal abscission, Pollination increased the levels of ACC 46-fold in stigma plus style tissue and 6-fold in the basal portion of petals. Enhanced accumulation of N-malonyl-ACC (MACC), a conjugated form of ACC, was also observed in stigma and style tissues after pollination. Pollination increased the activity of ACC synthase 2.5-fold in stigma and style tissues and 3-fold in the basal portion of petals. At 2 h after pollination, a 4-fold increase in the expression of the ACC synthase gene GAG-1 was detected specifically in the stigma and style. In vivo activity of ACC oxidase was 1.5-fold higher in pollinated than in unpollinated or wounded stigma and style. In the lower part of the pistil, the activity of ACC oxidase was lower than in the upper pistil, regardless of treatment. The activity of ACC oxidase was significantly higher in the basal portion of petals than the upper portion of petals. Pollination had no effect on the activity of ACC oxidase in petals. Treatment of florets with cycloheximide effectively prevented pollination-induced petal abscission, but ethylene production was completely unaffected, providing evidence for the post-transcriptional regulation of ethylene production. Stigma and style tissues accounted for 57% of the total ethylene production in the flower following pollination. When the stigma and style were removed and the top of the sterile ovary pollinated, there was no pollination-induced ethylene production or petal abscission. We propose that rapid petal abscission in response to pollination results from increased ethylene production, which occurs via activation of ACC synthase primarily in the stigma and style. This contrasts with post-pollination ethylene production in some wilting-type flowers in timing, lack of autocatalytic ethylene and predominantly post-transcriptional regulation. C1 Penn State Univ, Dept Hort, University Pk, PA 16802 USA. NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brown, KM (reprint author), Penn State Univ, Dept Hort, University Pk, PA 16802 USA. NR 54 TC 16 Z9 16 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0031-9317 J9 PHYSIOL PLANTARUM JI Physiol. Plant. PD JUL PY 2000 VL 109 IS 3 BP 322 EP 332 DI 10.1034/j.1399-3054.2000.100314.x PG 11 WC Plant Sciences SC Plant Sciences GA 334MR UT WOS:000088190700014 ER PT J AU Ross, SA McCaffery, PJ Drager, UC De Luca, LM AF Ross, SA McCaffery, PJ Drager, UC De Luca, LM TI Retinoids in embryonal development SO PHYSIOLOGICAL REVIEWS LA English DT Review ID ACID RESPONSE ELEMENT; PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; FETAL ALCOHOL SYNDROME; CRANIAL NEURAL CREST; VITAMIN-A INTAKE; NORMAL CARDIOVASCULAR DEVELOPMENT; TERATOCARCINOMA STEM-CELLS; HOMEOBOX-CONTAINING GENES; BINDING-PROTEIN CRABP; EARLY MOUSE EMBRYO AB The key role of vitamin A in embryonal development is reviewed. Special emphasis is given to the physiological action of retinoids, as evident from the retinoid ligand knockout models. Retinoid metabolism in embryonic tissues and teratogenic consequences of retinoid administration at high doses are presented. Physiological and pharmacological actions of retinoids are outlined and explained on the basis of their interactions as ligands of the nuclear retinoid receptors. Immediate target genes and the retinoid response elements of their promoters are summarized. The fundamental role of homeobox genes in embryonal development and the actions of retinoids on their expression are discussed. The similarity of the effects of retinoid ligand knockouts to effects of compound retinoid receptor knockouts on embryogenesis is presented. Although much remains to be clarified, the emerging landscape offers exciting views for future research. C1 US FDA, Ctr Food Safety & Appl Nutr, Off Nutr Prod Labeling & Dietary Supplements, Washington, DC 20204 USA. Eunice Kennedy Shriver Ctr Mental Retardat Inc, Waltham, MA 02154 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Ross, SA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Nutr Prod Labeling & Dietary Supplements, Washington, DC 20204 USA. OI Drager, Ursula C/0000-0003-1815-190X NR 321 TC 533 Z9 572 U1 3 U2 35 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2000 VL 80 IS 3 BP 1021 EP 1054 PG 34 WC Physiology SC Physiology GA 332TE UT WOS:000088088900006 PM 10893430 ER PT J AU Pandeya, SN Mishra, V Ponnilavarasan, I Stables, JP AF Pandeya, SN Mishra, V Ponnilavarasan, I Stables, JP TI Anticonvulsant activity of p-chlorophenyl substituted arylsemicarbazones - The role of primary terminal amino group SO POLISH JOURNAL OF PHARMACOLOGY LA English DT Article DE anticonvulsant; p-chlorophenylsemicarbazone; synthesis ID THIOSEMICARBAZONES; SEMICARBAZONES; KETONES; AGENTS AB A series of p-chlorophenyl substituted arylsemicarbazones were synthesized and evaluated for anticonvulsant activity. Most of the compounds provided significant protection against maximal electroshock-induced seizures (MES) at 100 mg/kg after 0.5 h and at 300 mg/kg after 4 h in both MES and pentetrazole-induced (PTZ) seizures. In the strychnine-induced seizures (scSTY), the majority of the compounds showed protection at 30 mg/kg. The compound 2 was active in both MES and PTZ tests. The study has shown that the terminal primary amino group is not necessary for anticonvulsant activity. C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NIH, Antiepilept Drug Dev Programme, Epilepsy Branch, Rockville, MD USA. NR 11 TC 23 Z9 25 U1 0 U2 1 PU POLISH ACAD SCIENCES INST PHARMACOLOGY PI KRAKOW PA SMETNA 12, 31-343 KRAKOW, POLAND SN 1230-6002 J9 POL J PHARMACOL JI Pol. J. Pharmacol. PD JUL-AUG PY 2000 VL 52 IS 4 BP 283 EP 290 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 370KA UT WOS:000165121300005 PM 11345484 ER PT J AU Lerman, C Hughes, C Croyle, RT Main, D Durham, C Sndyer, C Bonney, A Lynch, JF Narod, SA Lynch, HT AF Lerman, C Hughes, C Croyle, RT Main, D Durham, C Sndyer, C Bonney, A Lynch, JF Narod, SA Lynch, HT TI Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing SO PREVENTIVE MEDICINE LA English DT Article DE genetic testing; breast cancer; risk; screening ID OVARIAN-CANCER SUSCEPTIBILITY; BREAST-CANCER; FAMILY HISTORY; PSYCHOLOGICAL DISTRESS; WOMEN; RISK; GENE; MASTECTOMY; ATTITUDES; CARRIERS AB Background Although genetic testing for breast cancer risk is clinically available, its impact on health-related behaviors is unknown. This study examined prophylactic surgery and surveillance behavior during the year following BRCA1/2 gene testing, Methods, Participants were female members (n = 216) of hereditary breast-ovarian cancer families (84 mutation carriers, 83 noncarriers and 49 test decliners). In this prospective observational study, utilization of prophylactic surgery and surveillance behavior were assessed 1-year following BRCA1/2 testing. Results. Only 3% of the unaffected carriers obtained prophylactic mastectomy during the 1-year follow-up period. Among the remaining females, carriers had significantly higher rates of mammography (68%) than noncarriers (44%); (OR = 7.1; C.I = 1.36-37.1; P = 0.02), However, the adherence rate in carriers was unchanged from baseline, suggesting that this difference is attributable to a reduction in screening among noncarriers. Women ages 25-39 years were significantly less likely to obtain mammograms than those aged 40 years and older. Cancer-related distress had a positive but nonsignificant (P < 0.07) association with adherence in bivariate but not multivariate analysis. With regard to ovarian risk, only 13% of carriers obtained prophylactic oophorectomy; of the remaining female carriers, only 21% reported a CA125 and 15% reported a transvaginal ultrasound. Conclusion. The vast majority of BRCA1/2 carriers may not opt for prophylactic surgery, and many do not adhere to surveillance recommendations. Greater attention to risk communication and medical decisionmaking is warranted, (C) 2000 American Health Foundation and Academic Press. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Creighton Univ, Med Ctr, Dept Prevent Med & Publ Hlth, Omaha, NE USA. Womens Coll Hosp, Dept Med, Toronto, ON M5S 1B2, Canada. RP Lerman, C (reprint author), Georgetown Univ, Med Ctr, Lombardi Canc Ctr, 2233 Wisconsin Ave NW,Suite 317, Washington, DC 20007 USA. NR 30 TC 169 Z9 170 U1 2 U2 12 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUL PY 2000 VL 31 IS 1 BP 75 EP 80 DI 10.1006/pmed.2000.0684 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 334HF UT WOS:000088180500010 PM 10896846 ER PT J AU Miyazawa, S Jernigan, RL AF Miyazawa, S Jernigan, RL TI Identifying sequence-structure pairs undetected by sequence alignments SO PROTEIN ENGINEERING LA English DT Article DE empirical potentials; inverse protein folding; protein fold recognition; sequence-structure alignment; threading and inverse threading with gaps and insertions ID PROTEIN FOLD RECOGNITION; AMINO-ACID-SEQUENCES; STATISTICAL SIGNIFICANCE; 3-DIMENSIONAL STRUCTURES; SECONDARY STRUCTURE; GLOBULAR-PROTEINS; CONTACT ENERGIES; NATIVE FOLDS; MEAN FORCE; POTENTIALS AB We examine how effectively simple potential functions previously developed can identify compatibilities between sequences and structures of proteins for database searches. The potential function consists of pairwise contact energies, repulsive packing potentials of residues for overly dense arrangement and short-range potentials for secondary structures, all of which were estimated from statistical preferences observed in known protein structures. Each potential energy term was modified to represent compatibilities between sequences and structures for globular proteins. Pairwise contact interactions in a sequence-structure alignment are evaluated in a mean field approximation on the basis of probabilities of site pairs to be aligned. Gap penalties are assumed to be proportional to the number of contacts at each residue position, and as a result gaps will be more frequently placed on protein surfaces than in cores. In addition to minimum energy alignments, we use probability alignments made by successively aligning site pairs in order by pairwise alignment probabilities. The results show that the present energy function and alignment method can detect well both folds compatible with a given sequence and, inversely, sequences compatible with a given fold, and yield mostly similar alignments for these two types of sequence and structure pairs, Probability alignments consisting of most reliable site pairs only can yield extremely small root mean square deviations, and including less reliable pairs increases the deviations. Also, it is observed that secondary structure potentials are usefully complementary to yield improved alignments with this method. Remarkably, by this method some individual sequence-structure pairs are detected having only 5-20% sequence identity. C1 Gunma Univ, Fac Technol, Kiryu, Gumma 376, Japan. NCI, Lab Expt & Computat Biol, DBS, NIH, Bethesda, MD 20892 USA. RP Miyazawa, S (reprint author), Gunma Univ, Fac Technol, Kiryu, Gumma 376, Japan. RI Jernigan, Robert/A-5421-2012 NR 51 TC 17 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD JUL PY 2000 VL 13 IS 7 BP 459 EP 475 DI 10.1093/protein/13.7.459 PG 17 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 344DV UT WOS:000088743100002 PM 10906342 ER PT J AU Liu, YY Gordienko, I Mathias, A Ma, SL Thompson, J Woo, JH Neville, DM AF Liu, YY Gordienko, I Mathias, A Ma, SL Thompson, J Woo, JH Neville, DM TI Expression of an anti-CD3 single-chain immunotoxin with a truncated diphtheria toxin in a mutant CHO cell line SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID HIGH-LEVEL EXPRESSION; ESCHERICHIA-COLI; ELONGATION FACTOR-2; ADP-RIBOSYLATION; FUSION PROTEINS; TRANSLOCATION; DIPHTHAMIDE; FRAGMENT; RECEPTOR; REVERSAL AB ADP-ribosylating immunotoxins are generally expressed in Escherichia coli and then refolded in vitro, Because the efficiency of the in vitro refolding process decreases with the number of protein domains and internal disulfide bonds, these immunotoxins have been generally limited to single-chain monovalent structures. We now show that using the hamster cell line CHO K1 RE1.22c (J, M. Moehring and T. J. Moehring, 1979, Somat. Cell Genet. 5, 453-468) that has been mutated to ADP-ribosylation insensitivity, a level of 4 mu g/ml of a truncated anti-T cell immunotoxin, DT390-scFvUCHT1, can be secreted into the medium. This immunotoxin is glycosylated at the two potential N-linked glycosylation sites in the toxin moiety: positions 16-18 in the A chain and residues 235-237 in the B chain. The glycosylated immunotoxin is relatively nontoxic (IC50 4.8 x 10(-10) M). Removal of the N-linked oligosaccharides by N-glycosidase F treatment or mutations at the two N-linked glycosylation sites results in a highly active immunotoxin with an IC50 of 4 x 10(-12) M toward CD3(+) Jurkat cells. This is a 12-fold increase in toxicity over the same immunotoxin harvested from E. coli periplasm without refolding. A single Asn(235) Ala mutation that removed the B chain glycosylation was nearly as toxic as the double mutant. This suggests that B chain glycosylation is the major cause for the loss of toxicity. (C) 2000 Academic Press. C1 NIMH, Sect Biophys Chem, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Alabama Birmingham, Div Transplantat Immunol, Birmingham, AL 35294 USA. Fenske Lab, University Pk, PA 16802 USA. RP Liu, YY (reprint author), NIMH, Sect Biophys Chem, Mol Biol Lab, Bethesda, MD 20892 USA. NR 38 TC 23 Z9 27 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUL PY 2000 VL 19 IS 2 BP 304 EP 311 DI 10.1006/prep.2000.1255 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 330JK UT WOS:000087958800013 PM 10873546 ER PT J AU Kapust, RB Waugh, DS AF Kapust, RB Waugh, DS TI Controlled intracellular processing of fusion proteins by TEV protease SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID MALTOSE-BINDING-PROTEIN; HIGH-LEVEL EXPRESSION; CLONED GENE-PRODUCTS; ESCHERICHIA-COLI; PROTEOLYTIC DEGRADATION; RECOMBINANT PROTEINS; TIGHT REGULATION; PROMOTER; AFFINITY; PURIFICATION AB Here we describe a method for controlled intracellular processing (CIP) of fusion proteins by tobacco etch virus (TEV) protease, A fusion protein containing a TEV protease recognition site is expressed in Escherichia coli cells that also contain a TEV protease expression vector. The fusion protein vector is an IPTG-inducible ColE1-type plasmid, such as a T7 or tac promoter vector. In contrast, the TEV protease is produced by a compatible p15A-type vector that is induced by tetracyclines, Not only is the TEV protease regulated independently of the fusion protein, but its expression is highly repressed in the absence of inducer, Certain fusion partners have been shown to enhance the yield and solubility of their passenger proteins. When CIP is used as a purification step, it is possible to take advantage of these characteristics while both eliminating the need for large amounts of pure protease at a later stage and possibly simplifying the purification process. Additionally, we have observed that in some cases the timing of intracellular proteolysis can affect the solubility of the cleaved passenger protein, allowing it to be directed to either the soluble or the insoluble fraction of the crude cell lysate. This method also makes it possible to quickly gauge the efficiency of proteolysis in vivo, before protein purification has begun and in vitro processing is attempted. (C) 2000 Academic Press. C1 NCI, Program Struct Biol, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Program Struct Biol, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. EM waughd@ncifcrf.gov NR 35 TC 126 Z9 130 U1 1 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUL PY 2000 VL 19 IS 2 BP 312 EP 318 DI 10.1006/prep.2000.1251 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 330JK UT WOS:000087958800014 PM 10873547 ER PT J AU Wolff, J Zambito, AM Britto, PJ Knipling, L AF Wolff, J Zambito, AM Britto, PJ Knipling, L TI Autopalmitoylation of tubulin SO PROTEIN SCIENCE LA English DT Article DE denaturation; electrostatics; mobility shift; palmitoyl CoA; polymerization ID FATTY ACYLATION; TRANSFERRIN RECEPTOR; PROTEOLIPID PROTEIN; COLCHICINE-BINDING; PALMITIC ACID; COENZYME-A; IN-VIVO; PALMITOYLATION; POLYMERIZATION; MYELIN AB Purr rat brain tubulin is readily palmitoylated in vitro using [H-3]palmitoyl CoA but no added enzymes. A maximum of approximately six palmitic acids are added per dimer in 2-3 h at 36-37 degrees C under native conditions. Both alpha and beta tubulin are labeled, and 63-73% of the label was hydroxylamine-labile, presumed thioesters. Labeling increases with increasing pH and temperature, and with low concentrations of guanidine HCl or KCl (but not with urea) to a maximum of similar to 13 palmitates/dimer. High SDS and guanidine HCl concentrations are inhibitory. At no time could all 20 cysteine residues of the dimer be palmitoylated. Polymerization to microtubules, or use of tubulin S, markedly decreases the accessibility of the palmitoylation sites, Palmitoylation increases the electrophoretic mobility of a portion of cr tubulin toward the beta band. Palmitoylated tubulin binds a colchicine analogue normally, but during three warm/cold polymerization/depolymerization cycles there is a progressive loss of palmitoylated tubulin, indicating decreased polymerization competence. We postulate that local electrostatic factors are major regulators of reactivity of tubulin cysteine residues toward palmitoyl CoA, and that the negative charges surrounding a number of the cysteines are sensitive to negative charges on palmitoyl CoA. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wolff, J (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 2A23, Bethesda, MD 20892 USA. NR 46 TC 15 Z9 16 U1 6 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2000 VL 9 IS 7 BP 1357 EP 1364 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337RU UT WOS:000088376100011 PM 10933501 ER PT J AU Zhang, H Huang, K Li, Z Banerjei, L Fisher, KE Grishin, NV Eisenstein, E Herzberg, O AF Zhang, H Huang, K Li, Z Banerjei, L Fisher, KE Grishin, NV Eisenstein, E Herzberg, O TI Crystal structure of YbaK protein from Haemophilus influenzae (HI1434) at 1.8 angstrom resolution: Functional implications SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE structural genomics; hypothetical proteins; X-ray crystallography; C-lectin fold; circular permutation ID TRANSFER-RNA SYNTHETASES; ESCHERICHIA-COLI; MACROMOLECULAR STRUCTURES; SALMONELLA-TYPHIMURIUM; ANOMALOUS DIFFRACTION; BINDING PROTEIN; SEQUENCE; ENDOSTATIN; REFINEMENT; REVEALS AB Structural genomics of proteins of unknown function most straightforwardly assists with assignment of biochemical activity when the new structure resembles that of proteins whose functions are known. When a new fold is revealed, the universe of known folds is enriched, and once the function is determined by other means, novel structure-function relationships are established. The previously unannotated protein HI1434 from LT. influenzae provides a hybrid example of these two paradigms. It is a member of a microbial protein family, labeled in SwissProt as YbaK and ebsC. The crystal structure at 1.8 Angstrom resolution reported here reveals a fold that is only remotely related to the C-lectin fold, in particular to endostatin, and thus is not sufficiently similar to imply that YbaK proteins are saccharide binding proteins. However, a crevice that may accommodate a small ligand is evident, The putative binding site contains only one invariant residue, Lys46, which carries a functional group that could play a role in catalysis, indicating that YbaK is probably not an enzyme. Detailed sequence analysis, including a number of newly sequenced microbial organisms, highlights sequence homology to an insertion domain in prolyl-tRNA synthetases (proRS) from prokaryote, a domain whose function is unknown. A HI1434-based model of the insertion domain shows that it should also contain the putative binding site. Being part of a tRNA synthetases, the insertion domain is likely to be involved in oligonucleotide binding, with possible roles in recognition/discrimination or editing of prolyl-tRNA. By analogy, YbaK may also play a role in nucleotide or oligonucleotide binding, the nature of which is yet to be determined. (C) 2000 Wiley-Liss, Inc. C1 Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Inst Genomic Res, Rockville, MD USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. NIST, Gaithersburg, MD 20899 USA. RP Herzberg, O (reprint author), Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. FU NIGMS NIH HHS [P01 GM57890] NR 58 TC 40 Z9 42 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUL 1 PY 2000 VL 40 IS 1 BP 86 EP 97 DI 10.1002/(SICI)1097-0134(20000701)40:1<86::AID-PROT100>3.0.CO;2-Y PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 320QN UT WOS:000087412000010 PM 10813833 ER PT J AU Post, RM Denicoff, KD Leverich, GS Huggins, T Post, SW Luckenbaugh, D AF Post, RM Denicoff, KD Leverich, GS Huggins, T Post, SW Luckenbaugh, D TI Neuropsychological deficits of primary affective illness: Implications for therapy SO PSYCHIATRIC ANNALS LA English DT Article ID LONG-TERM POTENTIATION; FACIAL EMOTION DISCRIMINATION; BIPOLAR DISORDER; DEPRESSED-PATIENTS; COGNITIVE IMPAIRMENT; BEHAVIORAL FINDINGS; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; RAT-BRAIN; MEMORY C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, Bldg 10,Room 3N212,10 Ctr Dr MSC 1272, Bethesda, MD 20892 USA. NR 80 TC 5 Z9 5 U1 2 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUL PY 2000 VL 30 IS 7 BP 485 EP 494 PG 10 WC Psychiatry SC Psychiatry GA 335QY UT WOS:000088257100006 ER PT J AU Elvevag, B Duncan, J McKenna, PJ AF Elvevag, B Duncan, J McKenna, PJ TI The use of cognitive context in schizophrenia: an investigation SO PSYCHOLOGICAL MEDICINE LA English DT Article ID CONTINUOUS PERFORMANCE-TEST; IDENTICAL PAIRS VERSION; ATTENTION; INFORMATION; MEMORY; CORTEX AB Background. Cognitive deficits in schizophrenia have recently been ascribed to impaired representation and use of cognitive context. Context is defined as relevant information held temporarily in mind to mediate appropriate but often non-habitual responses. Methods. Parallel studies in a variety of cognitive domains were designed in order to explore the generality of any schizophrenic deficit in context use. In all of the tasks (a Stroop task, a Continuous Performance Task and a cued spatial location task), we examined how performance was affected by the time for which contextual information must be held in mind, and by whether context or task demands were consistent or varying between trials. It was predicted that manipulation of these variables would produce tests especially sensitive to schizophrenic attentional problems. Results. Predictions were partially confirmed. Although increasing contextual demands failed in most cases to produce disproportionate slowing of performance in patients, error data were largely in line with predictions. At the same time, the data did not suggest a simple unitary context deficit. Instead, different aspects of context - the time over which contextual information must be held in mind and the consistency of context - were differentially important in different tasks. Conclusions. The cognitive impairments of schizophrenic patients cannot be simply characterized as a generalized context deficit. A more differentiated, if not task specific, picture of schizophrenic deficits is suggested. C1 MRC, Cognit & Brain Sci Unit, Cambridge, England. Fulbourn Hosp, Cambridge, England. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Room 4C215,Bldg 10,MSC 1373, Bethesda, MD 20892 USA. NR 31 TC 18 Z9 18 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2000 VL 30 IS 4 BP 885 EP 897 DI 10.1017/S003329179900255X PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 348CA UT WOS:000088965900016 PM 11037097 ER PT J AU Schenk, S Partridge, B Shippenberg, TS AF Schenk, S Partridge, B Shippenberg, TS TI Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593 SO PSYCHOPHARMACOLOGY LA English DT Article DE U69593; cocaine; WIN 35,428; RTI-55; relapse; kappa-opioid ID COCAINE-SEEKING BEHAVIOR; DOPAMINE UPTAKE INHIBITOR; TEMPORAL CHARACTERISTICS; NUCLEUS-ACCUMBENS; RHESUS-MONKEYS; SENSITIZATION; BINDING; ACTIVATION; MODULATION; MORPHINE AB Rationale: Results of a previous study indicated that prior administration of the kappa-opioid receptor agonist, U69593, blocked the ability of cocaine to reinstate extinguished cocaine-taking behavior. Objectives: In order to determine whether the effect of U69593 was specific to cocaine or was common to cocaine seeking produced by other dopamine uptake inhibitors, the effects of U69593 on cocaine seeking produced by experimenter-administered injections of cocaine, the dopamine uptake inhibitor, GBR 12909, or the cocaine analogs, WIN 35,428 and RTI-55, were compared. Methods: Reinstatement of extinguished cocaine-taking behavior was measured fur rats that received injections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 15 min prior to injections of cocaine- (0.0-20.0 mg/kg, IP), GBR 12909- (0.0-30.0 mg/kg, IP), WIN 35,428- (0.0-3.0 mg/kg, IP) or RTI-55 (0.0-0.50 mg/kg, IP). Results: All of the drugs produced a dose-dependent reinstatement of extinguished cocaine-taking behavior. However, only the effects of cocaine and RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC). The U69593-produced attenuation of cocaine-produced cocaine seeking was reversed by prior administration of the kappa-opioid antagonist, norbinaltorphimine (30.0 mu g, ICV), indicating that the effect was mediated by central kappa-opioid receptors. Conclusions: The failure of U69593 to attenuate GBR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55-produced cocaine seeking raises the possibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter. C1 Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. Natl Inst Drug Abuse, Integrat Neurosci Unit, Behav Neurosci Lab, Baltimore, MD 21224 USA. RP Schenk, S (reprint author), Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. FU NIDA NIH HHS [DA 10084] NR 52 TC 49 Z9 50 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2000 VL 151 IS 1 BP 85 EP 90 DI 10.1007/s002130000476 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 342EW UT WOS:000088633100013 PM 10958121 ER PT J AU Christenfeld, N Glynn, LM Gerin, W AF Christenfeld, N Glynn, LM Gerin, W TI On the reliable assessment of cardiovascular recovery: An application of curve-fitting techniques SO PSYCHOPHYSIOLOGY LA English DT Article DE cardiovascular recovery; reactivity; logistic equation; curve fitting; cardiovascular disease ID BLOOD-PRESSURE; STRESS REACTIVITY; HYPERTENSION; FINGER; MANAGEMENT; HARASSMENT; GENDER; ANGER; STYLE AB The underuse of cardiovascular recovery as an adjunct to reactivity may stem from a lack of research on how to assess the process reliably. We explore the test-retest reliability of three simple, intuitive approaches to measuring recovery, and of a more sophisticated curve-fitting technique. Eighteen young normotensive subjects experienced three stressors twice each, with 10-min baseline, 3-min task, and 20-min recovery periods and continuous monitoring of heart rate and blood pressure. Reactivity showed moderate reliability, but the three simple approaches to measuring recovery revealed essentially none. However, the curve-fitting approach, using a three-parameter (amount, speed, and level of recovery) logistic function was reliable. This approach, capturing the inherently dynamic process of cardiovascular recovery, may allow researchers to usefully add the assessment of recovery to paradigms exploring reactivity as a risk factor for cardiovascular disease. C1 Univ Calif San Diego, Dept Psychol, La Jolla, CA 92093 USA. Univ Calif Irvine, Dept Psychol, Irvine, CA USA. Cornell Univ, Med Ctr, Dept Psychol, New York, NY 10021 USA. NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Christenfeld, N (reprint author), Univ Calif San Diego, Dept Psychol, 9500 Gilman Dr, La Jolla, CA 92093 USA. NR 30 TC 39 Z9 39 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD JUL PY 2000 VL 37 IS 4 BP 543 EP 550 DI 10.1017/S0048577200982246 PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 339AN UT WOS:000088455600016 PM 10934913 ER PT J AU Sher, L AF Sher, L TI Psychological factors, immunity, and heart disease SO PSYCHOSOMATICS LA English DT Letter ID INFECTION; SYSTEM C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Sect Biol Rhythms, Bldg 10,Room 3S-231,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2000 VL 41 IS 4 BP 372 EP 373 DI 10.1176/appi.psy.41.4.372 PG 2 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 329QK UT WOS:000087918600021 PM 10906367 ER PT J AU Avila, NA Kelly, JA Chu, SC Dwyer, AJ Moss, J AF Avila, NA Kelly, JA Chu, SC Dwyer, AJ Moss, J TI Lymphangioleiomyomatosis: Abdominopelvic CT and US findings SO RADIOLOGY LA English DT Article DE angiomyolipoma; kidney neoplasms, CT; kidney neoplasms, US; liver neoplasms; lung, CT; lung, diseases; lymphangiomyomatosis; lymphatic system, CT; lymphatic system, US ID PULMONARY LYMPHANGIOMYOMATOSIS; RENAL ANGIOMYOLIPOMA; TUBEROUS SCLEROSIS AB PURPOSE: To describe the abdominal computed tomographic (CT) and ultrasonographic (US) findings in patients with thoracic lymphangioleiomyomatosis (LAM) and to relate the prevalence of the findings to the severity of pulmonary disease. MATERIALS AND METHODS: Eighty patients with LAM underwent chest and abdominopelvic CT and abdominopelvic US. The images were reviewed prospectively by one radiologist, and the abdominal findings were recorded and correlated with the severity of pulmonary disease at thin-section CT. RESULTS: Sixty-one (76%) of 80 patients had positive abdominal findings. The most common abdominal findings included renal angiomyolipoma (AML) in 43 patients (54%), enlarged abdominal lymph nodes in 31 (39%), and lymphangiomyoma in 13 (16%). Less common findings included ascites in eight (10%), dilatation of the thoracic duct in seven (9%), and hepatic AML in three (4%). a significant correlation (P = .02) was observed between enlarged abdominal lymph nodes and increased severity of lung disease. CONCLUSION: There are characteristic abdominal findings in patients with LAM that, in conjunction with the classic thin-section CT finding of pulmonary cysts, are useful in establishing this diagnosis. C1 NHLBI, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Avila, NA (reprint author), NHLBI, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bldg 10,Rm 1C-660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 31 TC 94 Z9 113 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2000 VL 216 IS 1 BP 147 EP 153 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 328BT UT WOS:000087829500020 PM 10887241 ER PT J AU Summers, RM Beaulieu, CF Pusanik, LM Malley, JD Jeffrey, RB Glazer, DI Napel, S AF Summers, RM Beaulieu, CF Pusanik, LM Malley, JD Jeffrey, RB Glazer, DI Napel, S TI Automated polyp detector for CT colonography: Feasibility study SO RADIOLOGY LA English DT Article DE colon, CT; colon, neoplasms; computed tomography (CT), image display and recording; computed tomography (CT), three-dimensional; computers, simulation; phantoms ID VIRTUAL BRONCHOSCOPY; COLORECTAL NEOPLASMS; COLONIC POLYPS; DISPLAY MODES; COLONOSCOPY; COLOGRAPHY; SENSITIVITY; LESIONS AB An abdominal computed tomographic scan was modified by inserting 10 simulated colonic polyps with use of methods that closely mimic the attenuation, noise, and polyp-colon wall interface of naturally occurring polyps. A shape-based polyp detector successfully located six of the 10 polyps. When settings that enhanced the edge profile of polyps were chosen, eight of 10 polyps were detected. There were no false-positive detections. Shape analysis is technically feasible and is a promising approach to automated polyp detection. C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Stanford Univ, Med Ctr, Dept Radiol, Stanford, CA 94305 USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU NCI NIH HHS [1R01 CA72023]; NLM NIH HHS [LM 07033] NR 26 TC 174 Z9 178 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2000 VL 216 IS 1 BP 284 EP 290 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 328BT UT WOS:000087829500042 PM 10887263 ER PT J AU Moorman, WJ Ahlers, HW Chapin, RE Daston, GP Foster, PMD Kavlock, RJ Morawetz, JS Schnorr, TM Schrader, SM AF Moorman, WJ Ahlers, HW Chapin, RE Daston, GP Foster, PMD Kavlock, RJ Morawetz, JS Schnorr, TM Schrader, SM TI Prioritization of NTP reproductive toxicants for field studies SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE prioritization; reproductive toxicants; NTP; RACE; NOES; HSDB AB Population studies that evaluate human reproductive impairment are time consuming, expensive, logistically difficult, and with limited resources must be prioritized to effectively prevent the adverse health effects in humans. Interactions among health scientists, unions, and industry can serve to identify populations exposed to potential hazards and develop strategies to evaluate and apply appropriate controls. This report describes a systematic method for prioritizing chemicals that may need human reproductive health field studies. Rodent reproductive toxicants identified from the National Toxicology Program (NTP) Reproductive Assessment by Continuous Breeding (RACB) protocol were prioritized on the basis of potency of toxic effect and population at risk. This model for prioritization links NTP findings with data fi om the National Occupational Exposure Survey (NOES) and the Hazardous Substance Data Base (HSDB) or the High Production Volume Chemical Database (HPVC) to prioritize chemicals for their potential impact on worker populations. The chemicals with the highest priority for field study were: dibutyl phthalate, boric acid, tricresyl phosphate, and N,N-dimethylformamide. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIOSH, Cincinnati, OH 45226 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Procter & Gamble Co, Miami Valley Labs, Cincinnati, OH USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27711 USA. ICWU, Res Triangle Pk, NC USA. RP Moorman, WJ (reprint author), NIOSH, 4676 Columbia Pkwy, Cincinnati, OH 45226 USA. RI Schrader, Steven/E-8120-2011; OI Chapin, Robert/0000-0002-5997-1261 NR 15 TC 37 Z9 41 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL-AUG PY 2000 VL 14 IS 4 BP 293 EP 301 DI 10.1016/S0890-6238(00)00089-7 PG 9 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 340TH UT WOS:000088550700002 PM 10908832 ER PT J AU Kimmel, PL Greer, JW Milam, RA Thamer, M AF Kimmel, PL Greer, JW Milam, RA Thamer, M TI Trends in erythropoietin therapy in the US dialysis population: 1995 to 1998 SO SEMINARS IN NEPHROLOGY LA English DT Review ID RECOMBINANT ERYTHROPOIETIN; HEMODIALYSIS-PATIENTS; ANEMIA; ACCESS C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. US Hlth Care Financing Adm, Off Strateg Planning, Baltimore, MD 21207 USA. Johns Hopkins Sch Med, Sch Publ Hlth, Baltimore, MD USA. RP Kimmel, PL (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Room 607,2 Democracy Pl,6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 18 TC 11 Z9 11 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2000 VL 20 IS 4 BP 335 EP 344 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 333QT UT WOS:000088141300004 PM 10928335 ER PT J AU Rao, PN Acosta, CK Bahr, ML Burdett, JE Cessac, JW Morrison, PA Kim, HK AF Rao, PN Acosta, CK Bahr, ML Burdett, JE Cessac, JW Morrison, PA Kim, HK TI A practical large-scale synthesis of 17 alpha-acetoxy-11 beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) SO STEROIDS LA English DT Article DE steroids; synthesis; antiprogestins AB A new practical synthesis of 17 alpha-acetoxy-11 beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) is described. The synthesis gives easily isolable solids at all steps and is amenable to large-scale process. (C) 2000 Elsevier Science Inc. All rights reserved. C1 SW Fdn Biomed Res, Dept Organ Chem, San Antonio, TX 78245 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Rao, PN (reprint author), SW Fdn Biomed Res, Dept Organ Chem, POB 760549, San Antonio, TX 78245 USA. NR 12 TC 10 Z9 13 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-128X J9 STEROIDS JI Steroids PD JUL PY 2000 VL 65 IS 7 BP 395 EP 400 DI 10.1016/S0039-128X(00)00100-8 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 335YC UT WOS:000088273500005 PM 10899539 ER PT J AU Bond, V Vaccaro, P Caprarola, M Millis, RM Blakely, R Wood, R Roltsch, M Fairfax, J Hatfield, B Franks, BD Williams, D Davis, GC Adams, RG AF Bond, V Vaccaro, P Caprarola, M Millis, RM Blakely, R Wood, R Roltsch, M Fairfax, J Hatfield, B Franks, BD Williams, D Davis, GC Adams, RG TI Blood pressure reactivity to mental stress and aerobic fitness in normotensive young adult African-American males with parental history of hypertension SO STRESS MEDICINE LA English DT Article DE blood pressure; stress; aerobic fitness; African-Americans; parental hypertension ID CARDIOVASCULAR REACTIVITY; EXERCISE; PREDICTION AB Hypertension (HT) is the leading health problem in the adult African-American (AA) community and is associated with risk factors of stress, physical inactivity, and family history. We examined the influences of aerobic fitness and parental history of HT on blood pressure (BP) reactivity to mental stress in 60 normotensive young adult AA males. A S-min mental arithmetic test was used as a provocative stress. Measurements of peak oxygen uptake (VO2peak) were used to classify physically active and inactive subjects into groups of high and low aerobic fitness. A questionnaire was used to evaluate parental BP histories. Reactivity of BP rc,as indexed by differences in values (delta) measured during baseline and stress testing periods. Subjects with a parental history of HT (PH+) had significantly higher baseline systolic BP and mean arterial BP (SBP, MABP) values than subjects with no parental history of HT (PH-). Among the group of PH+ subjects, BP reactivity to mental stress was its follows: the high aerobic fitness subgroup (VO2peak = 54.6 +/- 1.2 ml/kg/min) (n = 15) exhibited a 7.3 +/- 2.0 mmHg rise in SEP and a 3.2 +/- 2.0 mmHg rise in MABP, and the low aerobic fitness subgroup (VO2peak = 37.1 +/- 0.7 ml/kg/min) (n = 15) had a 15.8 +/- 2.0 mmHg rise in SEP and an 11.8 +/- 2.0 mmHg rise in MABP (p < 0.05). Among the group of PH- subjects with high and low aerobic fitness (n = 30, 15/group), no differences in BP reactivity to mental stress were found. These results suggest that a lifestyle of physical activity associated with a high level of aerobic fitness may attenuate BP reactivity to mental stress and reduce the risk of HT in AA men. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Howard Univ, Div Exercise Physiol, Dept Educ Phys, Washington, DC 20059 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. Univ Montevallo, Dept Kinesiol, Montevallo, AL USA. Howard Univ, Coll Med, Washington, DC USA. Univ Maryland, Dept Phys Therapy, Princess Anne, MD USA. Louisiana State Univ, Dept Kinesiol, Baton Rouge, LA 70803 USA. NIH, Bethesda, MD 20892 USA. RP Bond, V (reprint author), Howard Univ, Div Exercise Physiol, Dept Educ Phys, 6th & Girard St NW, Washington, DC 20059 USA. NR 29 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0748-8386 J9 STRESS MEDICINE JI Stress Med. PD JUL PY 2000 VL 16 IS 4 BP 219 EP 227 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 339HF UT WOS:000088471000004 ER PT J AU Vautrin, J Maric, D Sukhareva, M Schaffner, AE Barker, JL AF Vautrin, J Maric, D Sukhareva, M Schaffner, AE Barker, JL TI Surface-accessible GABA supports tonic and quantal synaptic transmission SO SYNAPSE LA English DT Article DE exocytosis; ganglioside; surface matrix; synaptogenesis; adsorption; membrane noise ID GAMMA-AMINOBUTYRIC-ACID; RAT HIPPOCAMPAL-NEURONS; FLOW CYTOMETRIC ANALYSIS; END-PLATE POTENTIALS; SPINAL-CORD NEURONS; PROTEIN-KINASE-C; TRANSMITTER RELEASE; INTRAMEMBRANE PARTICLES; CALCIUM TRANSIENTS; NONNEURONAL CELLS AB Exocytosis is commonly viewed as the only secretory process able to account for quantal forms of fast synaptic transmission. However, the demonstrated variability and composite properties of miniature postsynaptic signals are not easily explained by all-or-none exocytotic discharge of transmitter in solution from inside vesicles. Recent, studies of endocrine secretion have shown that hormone release does not coincide with exocytosis due to its trapping in the core matrix of the granule. Thus, we tested whether the synaptic transmitter GABA could also be held in a matrix before being released. Using confocal microscopy and flow cytometry of embryonic rat hippocampal neurons, we found a GABA immunoreaction at the surface of live cell bodies and growth cones that coincided spatially and quantitatively with the binding of tetanus toxin fragment, C (TTFC). TTFC binds predominantly at membrane sites containing the trisialoglycosphingolipid GT1b. Using flow cytometry, GT1b-containing Liposomes preincubated in 100 nM GABA exhibited the same relationship between GABA and TTFC surface binding as found on neurons and growth cones. Embryonic neurons differentiated in culture expressed initially a tonic, and after 3-5 days, transient, postsynaptic signals mediated by GABA acting at GABA(A)receptor/Cl- channels. A stream of saline applied to the neuronal surface rapidly and reversibly suppressed both tonic and transient signals. A brief application of the GABAmimetic isoguvacine immediately transformed both tonic and transient GABAergic signals into tonic and transient isoguvacinergic signals. These results and those in the literature are consistent with an immediately releasable compartment of transmitter accessible from the presynaptic surface. (C) 2000 Wiley-Liss, Inc. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Vautrin, J (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C02,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 95 TC 21 Z9 22 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 JUL PY 2000 VL 37 IS 1 BP 38 EP 55 DI 10.1002/(SICI)1098-2396(200007)37:1<38::AID-SYN5>3.0.CO;2-C PG 18 WC Neurosciences SC Neurosciences & Neurology GA 318DY UT WOS:000087269700005 PM 10842350 ER PT J AU Hohmann, AG Herkenham, M AF Hohmann, AG Herkenham, M TI Localization of cannabinoid CB1 receptor mRNA in neuronal subpopulations of rat striatum: A double-label in situ hybridization study SO SYNAPSE LA English DT Article DE anandamide; double-label; digoxigenin; substance P; enkephalin; dynorphin; somatostatin; GABA ID GLUTAMIC-ACID DECARBOXYLASE; PARVALBUMIN-IMMUNOREACTIVE NEURONS; CENTRAL-NERVOUS-SYSTEM; INHIBIT N-TYPE; MESSENGER-RNAS; BASAL GANGLIA; INSITU HYBRIDIZATION; ROTATIONAL BEHAVIOR; DOPAMINERGIC SYSTEM; GABAERGIC INTERNEURONS AB Double-label in situ hybridization was used to identify the phenotypes of striatal neurons that express mRNA for cannabinoid CB, receptors. Simultaneous detection of multiple mRNAs was performed by combining a S-35-labeled ribonucleotide probe for CB, mRNA with digoxigenin-labeled riboprobes for striatal projection neurons (preprotachykinin A, prodynorphin, and preproenkephalin mRNAs) and interneurons (vesicular acetylcholine transporter (VAChT), choline acetyltransferase (ChAT), somatostatin, and glutamic acid decarboxylase (Mr 67,000; GAD67) mRNAs). To ascertain whether CB1 mRNA was a marker for striatal efferents, digoxigenin-labeled probes for mRNA markers of both striatonigral (prodynorphin or preprotachykinin A mRNAs), and striatopallidal (proenkephalin mRNAs) projection neurons were combined with the 35S-labeled probe for CB1. A mediolateral gradient in CB1 mRNA expression was observed at rostral and mid-striatal levels; in the same coronal sections the number of silver grains per cell ranged from below the threshold of detectability at the medial and ventral poles to saturation at the dorsolateral boundary bordered by the corpus callosum. At the caudal level examined, CB1 mRNA was denser in the ventral sector relative to the dorsal sector. Virtually all neurons expressing mRNA markers for striatal projection neurons colocalized CB1 mRNA. Combining a S-35-labeled riboprobe for CB1 with digoxigenin-labeled riboprobes for both preproenkephalin and prodynorphin confirmed localization of CB1 mRNA to striatonigral and striatopallidal neurons expressing prodynorphin and preproenkephalin mRNAs, respectively. However, CB1 mRNA-positive cells that failed to coexpress the other markers were also apparent. CB1 mRNA was localized to putative GABAergic interneurons that express high levels of GAD67 mRNA. These interneurons enable functional interactions between the direct and indirect striatal output pathways. By contrast, aspiny interneurons that express preprosomatostatin mRNA and cholinergic interneurons that coexpress ChAT and VAChT mRNAs were CB1 mRNA-negative, The present data provide direct evidence that cannabinoid receptors are synthesized in striatonigral neurons that contain dynorphin and substance P and striatopallidal neurons that contain enkephalin. By contrast, local circuit neurons in striatum that contain somatostatin or acetylcholine do not synthesize cannabinoid receptors. Published 2000 Wiley-Liss, Inc(dagger). C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 61 TC 132 Z9 137 U1 1 U2 4 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 JUL PY 2000 VL 37 IS 1 BP 71 EP 80 DI 10.1002/(SICI)1098-2396(200007)37:1<71::AID-SYN8>3.0.CO;2-K PG 10 WC Neurosciences SC Neurosciences & Neurology GA 318DY UT WOS:000087269700008 PM 10842353 ER PT J AU Mitsiades, N Poulaki, V Tseleni-Balafouta, S Chrousos, GP Koutras, DA AF Mitsiades, N Poulaki, V Tseleni-Balafouta, S Chrousos, GP Koutras, DA TI Fas ligand expression in thyroid follicular cells from patients with thionamide-treated Graves' disease SO THYROID LA English DT Article ID HASHIMOTOS-THYROIDITIS; MOLECULAR-CLONING; ANTITHYROID DRUGS; INDUCED APOPTOSIS; PATHOGENESIS; MECHANISM; RECEPTOR; FAMILY; MEMBER AB Thionamides are used in the treatment of Graves' disease (GD) and act mainly by inhibiting the organification of iodide, but also lower We levels of thyroid autoantibodies, sometimes leading to long-term remission. Fas ligand (FasL) induces apoptosis of susceptible cells by cross-linking its own receptor, Fas. While Fas is present in a wide variety of normal tissues, Fast expression is limited mainly to cells of the immune system, where it acts as an effector molecule of cell-mediated cytotoxicity, and to the placenta, brain, eye, and testis where it presumably contributes to their immune-privileged status by eliminating infiltrating lymphocytes. We examined immunohistochemically the presence of Fast in thyroid tissue from 15 glands of thionamide-treated GD patients and in 8 normal thyroid control specimens. We also investigated We presence of Fast in thionamide-treated thyrocytes in vitro and their ability to induce Fas-mediated apoptosis in lymphocytes. We found that Fast expression was very weak to undetectable in normal thyroid tissue and cultured thyrocytes, whereas it was strong in thionamide-treated GD glands and cultured thyrocytes. Methimazole-treated thyrocytes induced Fast-dependent apoptosis in cocultured lymphocytes, whereas methimazole treatment of lymphocytes grown in the absence of thyrocytes had no such effect. We conclude that Fast is highly expressed in follicular cells of thyroid glands obtained from thionamide-treated Graves' patients and may contribute to the immunomodulatory effect of thionamides in this disease. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Evgenidion Hosp, Endocrine Unit, Athens, Greece. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M557,44 Binney St, Boston, MA 02115 USA. NR 24 TC 31 Z9 37 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2000 VL 10 IS 7 BP 527 EP 532 DI 10.1089/thy.2000.10.527 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 342LX UT WOS:000088647000002 PM 10958304 ER PT J AU Kim, WB Chung, HK Park, YJ Park, DJ Tahara, K Kohn, LD Cho, BY AF Kim, WB Chung, HK Park, YJ Park, DJ Tahara, K Kohn, LD Cho, BY TI The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves' disease SO THYROID LA English DT Article ID THYROID-STIMULATING ANTIBODIES; TSH RECEPTOR; ENDOCRINE OPHTHALMOPATHY; AUTOANTIBODIES; IMMUNOGLOBULINS; RADIOIODINE; LYMPHOCYTES; EPITOPES; THERAPY; SERA AB The goal of this study was to evaluate the clinical significance of the blocking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ovary (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mcl+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in FRTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patients who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Graves' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wild-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean stimulating TSHRAb activities measured by FRTL-5, Mcl+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not different between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T-4) levels, or goiter size. However, the prevalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the patients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disease when measured with chimeric receptor expressing cells, Blocking TSHRAb in Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of stimulating TSHRAb activities measured by CHO-hTSHR. The association of blocking TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves' patients is different in those who do and who do not have ophthalmopathy. C1 Seoul Natl Univ Hosp, Dept Internal Med, Ctr Hormone Res, Clin Res Inst, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. Chiba Univ, Sch Med, Dept Internal Med 2, Chiba 280, Japan. NIDDKD, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Cho, BY (reprint author), Seoul Natl Univ Hosp, Dept Internal Med, Ctr Hormone Res, Clin Res Inst, 28 Yungun Dong, Seoul 110744, South Korea. RI Park, Do-Joon/J-2736-2012; Park, Young Joo/J-4161-2012; OI Park, Young Joo/0000-0002-3671-6364; Kim, Won Bae/0000-0003-4544-1750 NR 35 TC 22 Z9 24 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2000 VL 10 IS 7 BP 579 EP 586 DI 10.1089/thy.2000.10.579 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 342LX UT WOS:000088647000008 PM 10958310 ER PT J AU Morabito, A Pera, C Longo, A Delfino, L Ferrara, GB AF Morabito, A Pera, C Longo, A Delfino, L Ferrara, GB TI Identification of a new DRB3*02 allelic variant (DRB3*0209) by high-resolution sequence-based typing SO TISSUE ANTIGENS LA English DT Article DE HLA-DRB3/B4/B5; PCR-SBT; PCR-SSP; new allele ID CELLS AB The HLA-DRB3/B4/B5 sequence-based typing method developed in this study in combination with PCR-SSP, enabled us to identify a new DRB3*02 allele, that was named as DRB3*0209 (GenBank accession number AF148518). This name has been officially assigned by the WHO Nomenclature Committee in May 1999. The new allele differs from DRB3*0207 by one substitution in codon 51 from AGG to ACG and another in codon 60 from TAC to TCC resulting in aminoacid changes from Arg-->Thr (codon 51) and from Tyr-->Ser (codon 60). The DRB3*0209 allele was discovered in two related North Italian families The fact that it was present in an hemizygous situation in three members of the paternal family and in one member of the secondary related family enabled us to isolate and sequence the new DRB3 allele without cloning, to identify its association with the DRB1 locus, and to generate an Epstein-Barr virus (EBV)-transformed cell line, now present in our ECBR (European Collection for Biomedical Research) Cell Line Bank. C1 Adv Biotechnol Ctr, Immunogenet Lab, IST, Natl Canc Inst, I-16132 Genoa, Italy. RP Ferrara, GB (reprint author), Adv Biotechnol Ctr, Immunogenet Lab, IST, Natl Canc Inst, Lgo R Benzi 10, I-16132 Genoa, Italy. NR 9 TC 4 Z9 5 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2000 VL 56 IS 1 BP 90 EP 94 DI 10.1034/j.1399-0039.2000.560113.x PG 5 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 339JK UT WOS:000088473800012 PM 10958362 ER PT J AU Hong, HHL Devereux, TR Melnick, RL Moomaw, CR Boorman, GA Sills, RC AF Hong, HHL Devereux, TR Melnick, RL Moomaw, CR Boorman, GA Sills, RC TI Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years SO TOXICOLOGIC PATHOLOGY LA English DT Article DE cardiac hemangiosarcoma; 1,3-butadiene; p53; ras ID MULTIPLE ORGAN CARCINOGENICITY; VINYL-CHLORIDE EXPOSURE; INDUCED LUNG-TUMORS; INHALATION EXPOSURE; K-RAS; CHLOROPRENE 2-CHLORO-1,3-BUTADIENE; METHYLENE-CHLORIDE; BUTADIENE MONOXIDE; DNA-ADDUCTS; ACTIVATION AB 1,3-Butadiene is a multisite carcinogen in rodents. Incidences of cardiac hemangiosarcomas were significantly increased in male and female B6C3F1 mice that inhaled 1,3-butadiene (BD) for 2 years. Eleven ED-induced cardiac hemangiosarcomas were examined for genetic alterations in ras protooncogenes and in the p53 tumor suppressor gene. Nine of 11 (82%) ED-induced hemangiosarcomas had K-ras mutations and 5 of 11 (46%) had H-ras mutations. All of the K-ras mutations were G --> C transversions (GGC --> CGC) at codon 13; this pattern is consistent with reported results in ED-induced lung neoplasms and lymphomas. Both K-ras codon 13 CGC mutations and H-ras codon 61 CGA mutations were detected in 5 of 9 (56%) hemangiosarcomas. The 11 hemangiosarcomas stained positive for p53 protein by immunohistochemistry and were analyzed for p53 mutations using cycle sequencing of polymerase chain reaction (PCR) amplified DNA isolated from paraffin-embedded sections. Mutations in exons 5 to 8 of the p53 gene were identified in 5 of 11 (46%) hemangiosarcomas, and all of these were from the 200- or 625-ppm exposure groups that also had K-ras codon 13 CGC mutations. Our data indicate that K-ras, H-ras and p53 mutations in these hemangiosarcomas most likely occurred as a result of the genotoxic effects of ED and that these mutations may play a role in the pathogenesis of ED-induced cardiac hemangiosarcomas in the B6C3F1 mouse. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Hong, HHL (reprint author), NIEHS, Environm Toxicol Program, MD E1-07,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hong@niehs.nih.gov NR 56 TC 35 Z9 37 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2000 VL 28 IS 4 BP 529 EP 534 DI 10.1177/019262330002800404 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 338QW UT WOS:000088431600004 PM 10930038 ER PT J AU Diwan, BA Ramakrishna, G Anderson, LM Ramljak, D AF Diwan, BA Ramakrishna, G Anderson, LM Ramljak, D TI Overexpression of Grb2 in inflammatory lesions and preneoplastic foci and tumors induced by N-nitrosodimethylamine in helicobacter hepaticus-infected and -noninfected A/J mice SO TOXICOLOGIC PATHOLOGY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the American-Association-for-Cancer-Research CY APR 10-14, 1999 CL PHILADELPHIA, PENNSYLVANIA SP Amer Assoc Canc Res DE mice; Grb2; Helicobacter hepaticus; liver tumors; hepatitis; promotion; Ras p21 ID EPIDERMAL GROWTH-FACTOR; CHRONIC ACTIVE HEPATITIS; TRANSGENIC MOUSE MODEL; HUMAN BREAST-CANCER; FACTOR-ALPHA; C-MYC; FACTOR RECEPTORS; PROTEIN; HEPATOCARCINOGENESIS; EXPRESSION AB Growth factors bind to membrane receptor tyrosine kinases, resulting in autophosphorylation and subsequent binding to proteins with SH2 domains, including growth factor receptor-bound protein 2 (Grb2). Grb2 bridges receptors to tyrosine kinase substrates such as SHC and SOS, which in turn facilitate the activation of downstream signaling pathways, including Pas and mitogen-activated protein kinase (MAPK). Overexpression of Grb2 has been demonstrated in several types of neoplasia but has not been investigated in liver tumorigenesis. Here we investigated Grb2 expression in liver lesions in N-nitrosodimethylamine (NDMA)-treated Helicobacter hepaticus-infected and -noninfected A/J mice at 1 year of age. Previously, we reported (6) that infection promotes the development of these NDMA-initiated tumors. In controls, Grb2 immunostaining was absent from normal hepatic tissues, whereas the inflammatory lesions in infected livers were positive for cytoplasmic Grb2 in both hepatocytes and infiltrating leukocytes. All preneoplastic foci (7 of 7), 15 of 27 adenomas, and 3 of 7 carcinomas were positive for Grb2 by immunostaining in both infected and noninfected NDMA-initiated livers. Involvement of Grb2 was confirmed by immunoblotting of similarly infected mice at 9 to 18 months of age, showing a 2.5- to 3.3-fold increase in Grb2 protein in infected livers (p < 0.05 compared with uninfected controls) as well as in preneoplastic foci, adenomas, and carcinomas. These livers also showed a 2.5- to 2.8-fold increase in total Ras protein. The results suggest that upregulation of Grb2 is an early event in liver carcinogenesis, whether caused by the bacterial infection or by NDMA. Concomitant upregulation of Ras p21 would ensure transmission of amplified signal from growth factors via Grb2. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Diwan, BA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Bldg 538,Room 205E, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 26 TC 8 Z9 8 U1 0 U2 2 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2000 VL 28 IS 4 BP 548 EP 554 DI 10.1177/019262330002800407 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 338QW UT WOS:000088431600007 PM 10930041 ER PT J AU Lomnitski, L Nyska, B Ben-Shaul, V Maronpot, RR Haseman, JK Harrus, TL Bergman, M Grossman, S AF Lomnitski, L Nyska, B Ben-Shaul, V Maronpot, RR Haseman, JK Harrus, TL Bergman, M Grossman, S TI Effects of antioxidants apocynin and the natural water-soluble antioxidant from spinach on cellular damage induced by lipopolysaccaride in the rat SO TOXICOLOGIC PATHOLOGY LA English DT Article DE oxidative stress; necrosis; liver; adrenal; spleen; thymus ID LIPID-PEROXIDATION; PLASMA-CATECHOLAMINES; CECAL LIGATION; SEPTIC SHOCK; ENDOTOXIN; LIVER; INHIBITION; APOPTOSIS; LUNG; NEUTROPHILS AB Oxidative damage plays a key role in septic shock induced by the endotoxin lipopolysaccaride (LPS) by enhancing the formation of reactive oxygen species such as superoxide anion radicals, peroxides, and their secondary product, malondialdehyde, especially in the liver. In this study, histopathologic changes in several organs were compared among groups of male Wistar rats that had been injected with LPS following prophylactic pretreatment with either of 2 antioxidants, a group that had been injected with LPS without pretreatment with antioxidants, an untreated control group, and groups that had been injected with either of the 2 antioxidants only. The antioxidants used were a water-soluble natural antioxidant from spinach (NAO) and the NADPH oxidase inhibitor apocynin. Hematoxylin-and-eosin-stained slides were prepared, and lesions were semiquantitatively scored. Exposure to LPS alone was associated with multifocal hepatocellular necrosis and acute inflammation, thymic and splenic lymphoid necrosis, ocular retinal hemorrhage and acute endophthalmitis, adrenal medullary vacuolation and necrosis and acute inflammation, and decreased adrenal cortical cytoplasmic vacuolation (consistent with depletion of steroidal hormone contents). Results indicated that pretreatment with both antioxidants for 8 days reduced, in some organs, the necrotic and inflammatory changes associated with the LPS challenge. These findings suggest a potential therapeutic application for these antioxidants in clinical sepsis. C1 Bar Ilan Univ, IL-52900 Ramat Gan, Israel. RP Nyska, B (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov NR 50 TC 23 Z9 24 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2000 VL 28 IS 4 BP 580 EP 587 DI 10.1177/019262330002800412 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 338QW UT WOS:000088431600012 PM 10930046 ER PT J AU Lomnitski, L Carbonatto, M Ben-Shaul, V Peano, S Conz, A Corradin, L Maronpot, RR Grossman, S Nyska, A AF Lomnitski, L Carbonatto, M Ben-Shaul, V Peano, S Conz, A Corradin, L Maronpot, RR Grossman, S Nyska, A TI The prophylactic effects of natural water-soluble antioxidant from spinach and apocynin in a rabbit model of lipopolysaccharide-induced endotoxemia SO TOXICOLOGIC PATHOLOGY LA English DT Article DE oxidative stress; inflammation; liver; adrenal; spleen; thymus; eye ID TUMOR-NECROSIS-FACTOR; NITRIC-OXIDE; LIPID-PEROXIDATION; SEPTIC SHOCK; BACTERIAL LIPOPOLYSACCHARIDE; ESCHERICHIA-COLI; LIVER; MACROPHAGES; INHIBITION; APOPTOSIS AB Radical-scavenging antioxidants, as part of the cellular defense system, function to inhibit the formation and propagation of free radicals and active oxygen species formation. In previous studies we demonstrated that endotoxin lipopolysaccharide (LPS) promotes oxidative stress and associated pathological changes in a rat model and that use of selected antioxidants was effective in reducing LPS-related lipid peroxidation product formation in the liver, as well as LPS-related pathological changes in different organs. In this study, several toxicological parameters (ie, clinical signs, blood chemistry, and histopathological changes) were compared among groups of male New Zealand rabbits injected with LPS following prophylactic pretreatment with either of 2 antioxidants, a group injected with LPS without pretreatment with antioxidants, groups injected with either of the 2 antioxidants only, and an untreated control group. The antioxidants used were a water-soluble natural antioxidant (NAO) from spinach and the NADPH oxidase inhibitor, apocynin. Exposure to LPS alone was associated clinically with depression, tachypnea, outer ear vasodilation, and iris congestion; biochemically with a significant increase in blood total bilirubin, transaminase activity, and glucose, total cholesterol, and triglyceride levels; macroscopically with multiple whitish areas in the liver; and histologically with hepatocellular focal necrosis and acute inflammation, thymic and splenic lymphoid necrosis and depletion, acute uveitis and hemorrhages in the ciliary processes, and decreased adrenal cortical cytoplasmic vacuolation considered consistent with depletion of steroidal hormone contents. The NAO had more effective prophylactic capacities than the apocynin. The protective effects were obvious in all investigated parameters. The results indicate the possible therapeutic efficacy of NAO in the treatment of clinical endotoxemia associated with gram-negative bacterial sepsis that is known to be associated with oxidative stress. C1 Bar Ilan Univ, IL-52900 Ramat Gan, Israel. RP Nyska, A (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov NR 60 TC 17 Z9 17 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2000 VL 28 IS 4 BP 588 EP 600 DI 10.1177/019262330002800413 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA 338QW UT WOS:000088431600013 PM 10930047 ER PT J AU Bordelon, NR Donnelly, KC King, LC Wolf, DC Reeves, WR George, SE AF Bordelon, NR Donnelly, KC King, LC Wolf, DC Reeves, WR George, SE TI Bioavailability of the genotoxic components in coal tar contaminated soils in Fischer 344 rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE bioavailability; P-32-postlabeling; coal tar; DNA adducts; genotoxicity; polycyclic aromatic hydrocarbons; soil ingestion; coal tar; contaminated soil ID POLYCYCLIC AROMATIC-HYDROCARBONS; GAS PLANT RESIDUE; DNA-ADDUCTS; MOUSE LUNG; IN-VITRO; BENZOPYRENE; SENSITIVITY; SEPARATION; SEDIMENTS; INGESTION AB The effect of chemical aging on the bioavailability and subsequent genotoxicity of coal tar (CT)-contaminated soils was evaluated in a 17-day feeding study using Fischer 344 male rats. Rats consumed a control diet or diets amended with soil, 0.35% CT, or soil freshly prepared or aged for 9 months with 0.35% CT. Mild treatment-related microscopic lesions in liver tissue and elevated enzyme levels in serum were detected in all CT treatment groups. The P-32-postlabeling assay was employed to determine DNA adduct formation in treated animals. All CT treatment groups induced DNA adducts in both the liver and lung. Adduct levels were 3-fold higher in lung DNA compared to hepatic DNA. After correcting adduct levels for total ingested polycyclic aromatic hydrocarbons (PAHs), a significant decrease (p < 0.05) in adduct levels was observed in both CT/soil treatment groups compared to CT control in liver and lung DNA. Adduct profiles of P-32-postlabeled hepatic and lung DNA displayed several nonpolar DNA adducts that comigrated with PAH-adducted calf thymus DNA standards as determined through both thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC), These results suggest that soil, but not aging of contaminants in soil, decreases the bioavailability of genotoxic components in CT, as evidenced by DNA adduct analysis. C1 Texas A&M Univ, Dept Vet Anat & Publ Hlth, College Stn, TX USA. US EPA, Natl Hlth & Enivronm Effects Res Lab, Div Environm Carcinogenesis, Res Triangle Pk, NC 27711 USA. RP Bordelon, NR (reprint author), NIEHS, Mail Drop B3-07,POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27711 USA. FU NIEHS NIH HHS [P42ES04917-10] NR 32 TC 20 Z9 20 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2000 VL 56 IS 1 BP 37 EP 48 DI 10.1093/toxsci/56.1.37 PG 12 WC Toxicology SC Toxicology GA 330BL UT WOS:000087942900008 PM 10869452 ER PT J AU Wang, W Chapin, RE AF Wang, W Chapin, RE TI Differential gene expression detected by suppression subtractive hybridization in the ethylene glycol monomethyl ether-induced testicular lesion SO TOXICOLOGICAL SCIENCES LA English DT Article DE gene expression; suppression subtractive hybridization; ethylene glycol monomethyl ether; apoptosis; testis; mouse ID DYNEIN LIGHT-CHAIN; CALCIUM-CHANNEL BLOCKERS; MOUSE T-COMPLEX; CYTOPLASMIC DYNEIN; SPERMATOCYTE TOXICITY; METHOXYACETIC-ACID; MEIOTIC DRIVE; MESSENGER-RNA; CELL-DEATH; F344 RATS AB The solvent ethylene glycol monomethyl ether (EGME) produces the same testicular lesions in rodents and human testis cultures, whose onset is characterized by apoptosis of pachytene spermatocytes. To identify gene changes early in the lesion and determine the possible involvement of cells other than the spermatocytes, we employed a suppression subtractive hybridization technique using whole testes from mice treated 8 h previously with 500 mg/kg EGME to generate two subtracted mouse testis cDNA libraries enriched for gene populations either up-regulated or down-regulated by EGME. A total of 70 clones were screened, and 6 of them were shown by Northern blotting to be differentially expressed in the EGME lesion. The three clones with increased expression after EGME treatment were identical to t-complex testis expressed gene 1 (tctex1), a gene encoding ribosomal protein S25, and a heretofore uncharacterized mouse testis expressed sequence tag. Three other genes suppressed by EGME were tctex2, alpha-2,6-sialyltransferase gene, and another uncharacterized mouse testis expressed sequence tag. Predicted peptide sequences of these clones contain multiple motifs for phosphorylation, glycosylation, and myristoylation. In situ hybridization with the antisense RNA probes further supported the expression changes of these six clones and localized the changes in multiple germ cell stages as well as other cell types (Sertoli, interstitial and peritubular cells). These data at the gene expression level are the first to demonstrate the early involvement in this lesion of cell types other than the dying spermatocytes. C1 NIEHS, Toxicol Lab, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Chapin, RE (reprint author), NIEHS, Toxicol Lab, Natl Toxicol Program, POB 12233,Mail Drop B3-05, Res Triangle Pk, NC 27709 USA. OI Chapin, Robert/0000-0002-5997-1261 NR 37 TC 11 Z9 13 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 JUL PY 2000 VL 56 IS 1 BP 165 EP 174 DI 10.1093/toxsci/56.1.165 PG 10 WC Toxicology SC Toxicology GA 330BL UT WOS:000087942900021 PM 10869465 ER PT J AU Waalkes, MP Keefer, LK Diwan, BA AF Waalkes, MP Keefer, LK Diwan, BA TI Induction of proliferative lesions of the uterus, testes, and liver in Swiss mice given repeated injections of sodium arsenate: Possible estrogenic mode of action SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; uterus; testes; liver; proliferative lesions; mice ID NITRIC-OXIDE SYNTHASE; HUMAN BREAST-CANCER; ENVIRONMENTAL ESTROGENS; DIMETHYLARSINIC ACID; ENDOMETRIAL CANCER; TUMOR PROGRESSION; CARCINOGENESIS; EXPRESSION; DIETHYLSTILBESTROL; RECEPTOR AB inorganic arsenic (As) is a human carcinogen but has not been unequivocally proven carcinogenic in rodents. For instance, one older study indicates that repeated iv injections of sodium arsenate might induce lymphomas in Swiss mice (58% incidence) (Osswald and Goerttler, Verh. Dtsch. Ges. Pathol. 55, 289-293, 1971), but it was considered inadequate for critical evaluation of carcinogenic potential largely because of issues in experimental design. Therefore, we studied repeated iv sodium arsenate injection and neoplastic response in male and female Swiss mice. Groups (n = 25) of mice received sodium arsenate (0.5 mg/kg, iv) or saline (control) once/week for 20 weeks and were observed for a total of 96 weeks when the study ended. Differences in survival and body weights were unremarkable. In females, arsenate induced marked increases in the incidence and severity of cystic hyperplasia of the uterus compared against controls. Arsenate also was associated with a rare adenocarcinoma of the uterus. Hyperplastic uterine epithelium from arsenate-exposed animals showed strong positive immunostaining for the proliferating cell nuclear antigen (PCNA). There was also an upregulation of estrogen receptor (ER) immunoreactive protein in the early lesions of uterine luminal and glandular hyperplasia, although a progressive decrease in its expression was seen in the severe hyperplastic or neoplastic epithelium. In common with the preneoplastic and neoplastic gynecological lesions in humans, the levels of immunoreactive inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine-containing proteins were greater in the uterine hyperplastic epidermis and their intensity was positively correlated with the severity of the lesions. Arsenate-induced uterine hyperplastic lesions also showed a strong upregulation of cyclin D1, an estrogen-associated gene product essential for progression through the G1 phase of the cell cycle. In other tissues, arsenate increased testicular interstitial cell hyperplasia incidence and severity over control but without affecting the incidence of tubular degeneration. Arsenate also induced increases in hepatic proliferative lesions (HPL; foci of alteration + neoplasia), but only in females. Significant skin changes (incidence of hyperkeratotic lesions) and renal lesions (severity of nephropathy) also occurred in arsenate-treated females. Thus, repeated arsenate exposure, though not outright tumorigenic in the present study, was associated with proliferative, preneoplastic lesions of the uterus, testes, and liver. Estrogen treatment has been associated with proliferative lesions and tumors of the uterus, female liver, and testes in other studies, supporting a hypothesis that arsenate might somehow act through an estrogenic mode of action. C1 NIEHS, NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 57 TC 69 Z9 79 U1 0 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 1 PY 2000 VL 166 IS 1 BP 24 EP 35 DI 10.1006/taap.2000.8963 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 334RP UT WOS:000088199700003 PM 10873715 ER PT J AU Moses, LA Stroncek, DF Cipolone, KM Marincola, FM AF Moses, LA Stroncek, DF Cipolone, KM Marincola, FM TI Detection of HLA antibodies by using flow cytometry and latex beads coated with HLA antigens SO TRANSFUSION LA English DT Article AB BACKGROUND: Detection of HLA class I antibodies in sera is needed in various clinical situations. The standard method for detecting HLA class I antibodies is the complement-dependent lymphocytotoxicity (CDC) assay, but solid-phase assays are now available. STUDY DESIGN AND METHODS: This study assessed the ability of a flow cytometric assay using latex beads coated with HLA class I antigens to detect HLA class I-specific antibodies. The CDC assay was compared with the pooled-bead assay for the detection of HLA class I antibodies. Thirty-one randomly selected serum samples previously tested by CDC assay were tested with pooled beads and analyzed by flow cytometry. Twenty-seven additional serum samples, chosen by clinical criteria and CDC assay results, were tested against the pooled beads. Next, samples from six patients from whom three or more serum samples were drawn on consecutive days were tested with both methods. Finally, serum samples that were proved positive by both methods were tested with selected beads coated with antigens from a single person. RESULTS: Among the randomly selected serum samples, there was 90-percent agreement between the two assays. There was 96-percent agreement between the two assays of the 27 samples that were selected by clinical criteria and CDC assay results. Testing the sera with individual beads suggested that the HLA class I antibodies react with beads expressing the corresponding HLA antigen and beads expressing antigens in the same cross-reactive group. CONCLUSION: The pooled-bead assay can be used as an alternative method for detecting HLA class I antibodies. However, if the specificity of the HLA class I antibody is required, another assay must be used. C1 NCI, Dept Transfus Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), Bldg 10,Room 1C711,10 Ctr Dr,MSC1184, Bethesda, MD 20892 USA. NR 6 TC 15 Z9 17 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 JUL PY 2000 VL 40 IS 7 BP 861 EP 866 DI 10.1046/j.1537-2995.2000.40070861.x PG 6 WC Hematology SC Hematology GA 341DC UT WOS:000088574900017 PM 10924616 ER PT J AU Balla, T Bondeva, T Varnai, P AF Balla, T Bondeva, T Varnai, P TI How accurately can we image inositol lipids in living cells? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAIN; PLASMA-MEMBRANE; PH DOMAIN; TRANSLOCATION; BINDING; PHOSPHOINOSITIDES; LOCALIZATION; CYTOHESIN-1; ASSOCIATION; PROTEIN C1 NICHD, Unit Mol Signal Transduct, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), NICHD, Unit Mol Signal Transduct, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A35,49 Convent Dr, Bethesda, MD 20892 USA. OI Balla, Tamas/0000-0002-9077-3335 NR 20 TC 99 Z9 100 U1 1 U2 9 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 JUL PY 2000 VL 21 IS 7 BP 238 EP 241 DI 10.1016/S0165-6147(00)01500-5 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 333MW UT WOS:000088134700003 PM 10871889 ER PT J AU Gallo, V Ghiani, CA AF Gallo, V Ghiani, CA TI Glutamate receptors in glia: new cells, new inputs and new functions SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; ASTROCYTES IN-SITU; PROGENITOR CELLS; NMDA RECEPTOR; OLIGODENDROCYTE PROGENITORS; HIPPOCAMPAL ASTROCYTES; PRECURSOR CELLS; AMPA RECEPTORS; MEMBRANE DEPOLARIZATION; INTRACELLULAR CALCIUM AB Functional glutamate receptors are expressed on the majority of glial cell types in the developing and mature brain. Although glutamate receptors an glia are activated by glutamate released from neurons, their physiological role remains largely unknown. Potential roles for these receptors in glia include regulation of proliferation and differentiation, and modulation of synaptic efficacy. Recent anatomical and functional evidence indicates that glutamate receptors on immature glia are activated through direct synaptic inputs. Therefore, glutamate and its receptors appear to be involved in a continuous crosstalk between neurons and glia during development and also in the mature brain. C1 NICHHD, Sect Mol & Cellular Neurobiol, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Brain Res Inst, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Gallo, V (reprint author), NICHHD, Sect Mol & Cellular Neurobiol, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Room 5A-78,49 Convent Dr, Bethesda, MD 20892 USA. OI Ghiani, Cristina/0000-0002-9867-6185 NR 69 TC 162 Z9 170 U1 2 U2 6 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 JUL PY 2000 VL 21 IS 7 BP 252 EP 258 DI 10.1016/S0165-6147(00)01494-2 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 333MW UT WOS:000088134700008 PM 10871893 ER PT J AU Villa, G Gipponi, M Buffoni, F Vecchio, C Bianchi, P Agnese, G Di Somma, C Catturich, A Rosato, F Tomei, D Nicolo, G Badellino, F Mariani, G Canavese, G AF Villa, G Gipponi, M Buffoni, F Vecchio, C Bianchi, P Agnese, G Di Somma, C Catturich, A Rosato, F Tomei, D Nicolo, G Badellino, F Mariani, G Canavese, G TI Localization of the sentinel lymph node in breast cancer by combined lymphoscintigraphy, blue dye and intraoperative gamma probe SO TUMORI LA English DT Article; Proceedings Paper CT 2nd Italian Congress of the Italian-Group-of-the-Radioguided-Surgery-and-Immunoscintigraphy CY JAN 27-28, 2000 CL IST NAZL STUDIO CURA TUMORI, MILAN, ITALY SP Italian Grp Radioguided Surg & Immunoscintig HO IST NAZL STUDIO CURA TUMORI DE axillary lymph node dissection; breast cancer; lymphoscintigraphy; sentinel lymph node ID AXILLARY DISSECTION; BIOPSY AB Axillary lymph node status represents the most important prognostic factor in patients with operable breast cancer. A severe limitation of this technique is the relatively high rate of false negative sentinel lymph nodes (>5%), We studied 284 patients suffering from breast cancer; 264 had T-1 tumors (16 T-1a, 37 T-1b and 211 T-1c), while 20 had T-2 tumors. All patients underwent lymphoscintigraphy 18-h before surgery. At surgery, 0.5 mL of patent blue violet was infected subdermally, and the sentinel lymph node (SN) was searched by gamma probe and by the dye method. The surgically isolated SN was processed for intraoperative and delayed examinations. The SN was successfully identified by the combined radioisotopic procedure and patent blue dye technique in 278/284 cases (97.9%). Analysis of the predictive value of the SN in relation to the status of the axillary lymph nodes was limited to 191 patients undergoing standard axillary dissection irrespective of the SN status. Overall, 63/191 (33%) identified SNs were metastatic, the SN alone being involved in 37/63 (58.7%) patients; a positive axillary status with negative SN was found in 10/73 (13.7%) patients with metastatic involvement. In T-1a-T-1b patients the SN turned out to be metastatic in 9/53 patients (17.0%). In 7/9 patients the SN was the only site of metastasis, while in 2/9 patients other axillary lymph nodes were found to be metastatic in addition to the SN. None of the 44 patients in whom the SN proved to be non-metastatic showed any metastatic involvement of other axillary lymph nodes. Our results demonstrate a good predictive value of SN biopsy in patients with breast cancer; the predictive Value was excellent in those subjects with nodules smaller than 1 cm. C1 Univ Genoa, Sch Med, DIMI, Nucl Med Serv, I-16132 Genoa, Italy. Natl Canc Inst, Div Surg Oncol, Genoa, Italy. Natl Canc Inst, Div Pathol, Genoa, Italy. RP Villa, G (reprint author), Univ Genoa, Sch Med, DIMI, Nucl Med Serv, Viale Benedetto XV, I-16132 Genoa, Italy. NR 13 TC 8 Z9 8 U1 0 U2 1 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA BRADANO 3/C, 00199 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD JUL-AUG PY 2000 VL 86 IS 4 BP 297 EP 299 PG 3 WC Oncology SC Oncology GA 354RF UT WOS:000089342900008 PM 11016707 ER PT J AU Miyoshi, N Igarashi, T Riesz, P AF Miyoshi, N Igarashi, T Riesz, P TI Evidence against singlet oxygen formation by sonolysis of aqueous oxygen-saturated solutions of Hematoporphyrin and Rose Bengal - The mechanism of sonodynamic therapy SO ULTRASONICS SONOCHEMISTRY LA English DT Article DE electron paramagnetic resonance; singlet oxygen; sonodynamic therapy ID PORPHYRIN ANALOG ATX-70; ULTRASOUND; SARCOMA-180; HYDROGEN; CELLS AB The possible role of singlet oxygen in the mechanism of sonodynamic therapy, the synergistic effect of ultrasound and certain sonosensitizers, was investigated. We used 4,4'-bis(1-p-carboxyphenyl-3-methyl-5-hydroxyl)-pyrazole (DRD 156), a sensitive new reagent which reacts specifically with singlet oxygen (O-1(2)) but not with OH radicals, superoxide anion radicals or H2O2, to produce an EPR detectable signal. Sonolysis (48 kHz) of 90% D2O oxygen-saturated PBS solutions of Hematoporphyrin or Rose Bengal did not lead to the formation of detectable EPR signals of the semiquinone radical of DRD156. In contrast, the EPR signal of the semiquinone radical of DRD156 was observed during photoirradiation of Hematoporphyrin at 505 nm or of Rose Bengal at 544 nm, These results are inconsistent with a major role for singlet oxygen formation in the sonolysis of aqueous solutions of these compounds. An alternative mechanism for sonodynamic therapy involving peroxyl and alkoxyl radicals is discussed. (C) 2000 Published by Elsevier Science B.V. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Fukui Med Univ, Dept Pathol, Matsuoka, Fukui 9101193, Japan. Daiichi Radioisotope Labs, Res Ctr, Chiba 2891592, Japan. RP Riesz, P (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NR 18 TC 56 Z9 69 U1 6 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD JUL PY 2000 VL 7 IS 3 BP 121 EP 124 DI 10.1016/S1350-4177(99)00042-5 PG 4 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 334AT UT WOS:000088163500005 PM 10909730 ER PT J AU LaBuda, CJ Sora, I Uhl, GR Fuchs, PN AF LaBuda, CJ Sora, I Uhl, GR Fuchs, PN TI Stress-induced analgesia in mu-apioid receptor knockout mice reveals normal function of the delta-opioid receptor system SO BRAIN RESEARCH LA English DT Article DE antinociception; morphine; opioid receptor; naltrindole; transgenic mouse; stress-induced analgesia ID CROSS-TOLERANCE; SWIM-STRESS; INDUCED ANTINOCICEPTION; MEDIATING ANALGESIA; STRAIN COMPARISONS; OPIATE RECEPTORS; SPINAL-CORD; MORPHINE; MOUSE; AGONISTS AB Stress-induced analgesia (SIA) was examined in wildtype and mu-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20 degrees C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective delta-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact delta-receptor-mediated function of a physiologically-released endogenous agonist in the mu-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice. (C) 2000 Elsevier Science BN. All rights reserved. C1 Univ Texas, Dept Psychol, Arlington, TX 76019 USA. Johns Hopkins Univ, Sch Med, Dept Neurol & Neurosci, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD 21224 USA. RP LaBuda, CJ (reprint author), Univ Texas, Dept Psychol, Box 19528, Arlington, TX 76019 USA. NR 36 TC 29 Z9 31 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 30 PY 2000 VL 869 IS 1-2 BP 1 EP 5 DI 10.1016/S0006-8993(00)02196-X PG 5 WC Neurosciences SC Neurosciences & Neurology GA 330YY UT WOS:000087990300001 PM 10865052 ER PT J AU Santella, RM Gammon, MD Zhang, YJ Motykiewicz, G Young, TL Hayes, SC Terry, MB Schoenberg, JB Brinton, LA Bose, S Teitelbaum, SL Hibshoosh, H AF Santella, RM Gammon, MD Zhang, YJ Motykiewicz, G Young, TL Hayes, SC Terry, MB Schoenberg, JB Brinton, LA Bose, S Teitelbaum, SL Hibshoosh, H TI Immunohistochemical analysis of polycyclic aromatic hydrocarbon-DNA adducts in breast tumor tissue SO CANCER LETTERS LA English DT Article DE breast cancer; immunohistochemistry; polycyclic aromatic hydrocarbon-DNA adducts; cigarette smoking ID CIGARETTE-SMOKING; CANCER RISK; LUNG-CANCER; UNITED-STATES; WOMEN; CELLS; ETIOLOGY; 4-AMINOBIPHENYL; NONSMOKERS; SMOKERS AB Environmental carcinogens may play a role in the etiology of breast cancer, but the extent of their contribution is not yet defined. The aims of this study were to determine whether polycyclic aromatic hydrocarbon (PAH)-DNA adducts could be detected in stored paraffin blocks of boast tumor tissue (n = 147) with an immunoperoxidase technique and whether they correlated with smoking, history and/or mutant p53 protein expression. There was no significant difference in mean relative nuclear staining intensity in non-smokers (444 +/- 90, n = 75), ever smokers (435 +/- 91, n = 72), and current smokers (456 +/- 98, n = 35), In either current or ever smokers, PAH-DNA adducts were non-significantly elevated in those with greater compared with lower exposure in relation to age at started smoking, years of smoking, cigarettes per day, and pack years. DNA damage levels were not elevated in tissues with compared with those without mutant p53 protein expression. These data demonstrate that immunohistochemical methods can he used to monitor DNA damage levels in archived boast tissues. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Environm Hlth Sci, New York, NY 10032 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10032 USA. New Jersey Dept Hlth & Senior Serv, Appl Canc Epidemiol Program, Hamilton, NJ 08690 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Pathol, Los Angeles, CA 90024 USA. RP Santella, RM (reprint author), Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Environm Hlth Sci, 701 W 168th St, New York, NY 10032 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NCI NIH HHS [CA70633] NR 42 TC 23 Z9 25 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUN 30 PY 2000 VL 154 IS 2 BP 143 EP 149 DI 10.1016/S0304-3835(00)00367-0 PG 7 WC Oncology SC Oncology GA 396WY UT WOS:000166661900005 PM 10806302 ER PT J AU Ginis, I Faller, DV AF Ginis, I Faller, DV TI Hypoxia affects tumor cell invasiveness in vitro: the role of hypoxia-activated ligand HAL1/13 (Ku86 autoantigen) SO CANCER LETTERS LA English DT Article DE hypoxia; tumor cells; invasion; metastasis; adhesion molecules ID HUMAN ENDOTHELIAL-CELLS; GLUCOSE STARVATION; GENE-EXPRESSION; DNA-BINDING; SOMATOSTATIN; ADHESION; PROTEIN; PROGRESSION; METASTASIS; ACIDOSIS AB We have recently identified and characterized a new adhesion ligand, HAL1/13 (hypoxia-activated ligand), which mediates the increase in leukocyte adhesion to endothelium under hypoxic conditions (J. Immunol. 155 (1995) 802-810). The HAL1/13 antigen was cloned and found to be identical to p86 subunit of Ku autoantigen. In this study we demonstrate that exposure of neuroblastoma and breast carcinoma. cells to hypoxia results in upregulation of HAL1/13 surface expression, coincident with an increased ability of these tumor cells to invade endothelial monolayers, which could be partially attenuated by the anti-HAL1/ 13 antibody. Hypoxia also potentiated neuroblastoma acid breast carcinoma cell transmigration through Matrigel filters. Anti-HAL1/13 antibody inhibited haptotactic locomotion of hypoxic tumor cells on laminin. (C) 2000 Published by Elsevier Science ireland Ltd. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Ctr Canc Res, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. RP Ginis, I (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Room 4A03, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [P60AR20613] NR 41 TC 19 Z9 19 U1 0 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUN 30 PY 2000 VL 154 IS 2 BP 163 EP 174 DI 10.1016/S0304-3835(00)00388-8 PG 12 WC Oncology SC Oncology GA 396WY UT WOS:000166661900007 PM 10806304 ER PT J AU Finkel, T AF Finkel, T TI Redox-dependent signal transduction SO FEBS LETTERS LA English DT Review DE signal transduction; redox; peroxide; rac1; NADPH oxidase ID TYROSINE-PHOSPHATASE 1B; EPIDERMAL GROWTH-FACTOR; SMOOTH-MUSCLE CELLS; NADH/NADPH OXIDASE; HYDROGEN-PEROXIDE; OXYGEN RADICALS; NADPH OXIDASE; RAC1; GENERATION; ACTIVATION AB Reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide appear to be transiently produced in response to growth factor and cytokine stimulation. A variety of evidence suggests that this ligand-stimulated change in the cellular redox state participates in downstream signal transduction. This review will focus on the effects of ROS on signal transduction pathways, the molecules that regulate intracellular ROS production and the potential protein targets of oxidants. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Mol Biol Lab, NIH, Bldg 10-6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA61774]; NIGMS NIH HHS [GM43880] NR 24 TC 402 Z9 428 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 30 PY 2000 VL 476 IS 1-2 BP 52 EP 54 DI 10.1016/S0014-5793(00)01669-0 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 332DR UT WOS:000088058900012 PM 10878249 ER PT J AU Spiegel, S Milstein, S AF Spiegel, S Milstein, S TI Sphingosine-1-phosphate: signaling inside and out SO FEBS LETTERS LA English DT Review DE sphingosine-1-phosphate; EDG-1; sphingosine kinase; cell growth; apoptosis ID PROTEIN-COUPLED RECEPTOR; SPHINGOSINE 1-PHOSPHATE; MOLECULAR-CLONING; KINASE; EXPRESSION; GROWTH; PROLIFERATION; ANGIOGENESIS; ACTIVATION; APOPTOSIS AB Ample evidence indicates that sphingosine-1-phosphate (SPP) can serve as an intracellular second messenger regulating calcium mobilization, and cell growth and survival. Moreover, the dynamic balance between levels of the sphingolipid metabolites, ceramide and SPP, and consequent regulation of opposing signaling pathways, is an important factor that determines whether a cell survives or dies. SPP has recently also been shown to be the ligand for the EDG-1 family of G-protein-coupled receptors, which now includes EDG-1, -3, -5, -6 and -8, SPP is thus a lipid mediator that has novel dual actions signaling inside and outside of the cell. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NCI NIH HHS [CA61774]; NIGMS NIH HHS [GM43880] NR 33 TC 204 Z9 207 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 30 PY 2000 VL 476 IS 1-2 BP 55 EP 57 DI 10.1016/S0014-5793(00)01670-7 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 332DR UT WOS:000088058900013 PM 10878250 ER PT J AU Liu, H Sugiura, M Nava, VE Edsall, LC Kono, K Poulton, S Milstien, S Kohama, T Spiegel, S AF Liu, H Sugiura, M Nava, VE Edsall, LC Kono, K Poulton, S Milstien, S Kohama, T Spiegel, S TI Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; PROGRAMMED CELL-DEATH; CALCIUM MOBILIZATION; RECEPTOR EDG-1; GROWTH-FACTORS; SMOOTH-MUSCLE; 2ND MESSENGER; 1-PHOSPHATE; SPHINGOSINE-1-PHOSPHATE; ACTIVATION AB Sphingosine-1-phosphate (SPP) has diverse biological functions acting inside cells as a second messenger to regulate proliferation and survival, and extracellularly, as a ligand for G protein-coupled receptors of the endothelial differentiation gene-1 subfamily. Based on sequence homology to murine and human sphingosine kinase-1 (SPHK1), which we recently cloned (Kohama, T., Oliver, A., Edsall, L., Nagiec, M. M., Dickson, R., and Spiegel, S. (1998) J. Biol. Chem. 273, 23722-23728), we have now cloned a second type of mouse and human sphingosine kinase (mSPNK2 and hSPHK2). mSPHK2 and hSPHK2 encode proteins of 617 and 618 amino acids, respectively, both much larger than SPHK1, and though diverging considerably, both contain the conserved domains found in all SPHK1s. Northern blot analysis revealed that SPHK2 mRNA expression had a strikingly different tissue distribution from that of SPHK1 and appeared later in embryonic development. Expression of SPHK2 in HEK 293 cells resulted in elevated SPP levels. D-erythro-dihydrosphingosine was a better substrate than D-erythro-sphingosine for SPHK2. Surprisingly, D, L-threo-dihydrosphingosine was also phosphorylated by SPHK2. In contrast to the inhibitory effects on SPHK1, high salt concentrations markedly stimulated SPHK2. Triton X-100 inhibited SPHK2 and stimulated SPHK1, whereas phosphatidylserine stimulated both type 1 and type 2 SPHK. Thus, SPHK2 is another member of a growing class of sphingolipid kinases that may have novel functions. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Sankyo Co Ltd, Pharmacol Res Labs, Tokyo 1408710, Japan. Sankyo Co Ltd, Mol Biol Res Labs, Tokyo 1408710, Japan. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NIGMS NIH HHS [GM43880] NR 44 TC 423 Z9 439 U1 1 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19513 EP 19520 DI 10.1074/jbc.M002759200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300013 PM 10751414 ER PT J AU Gomez-Angelats, M Bortner, CD Cidlowski, JA AF Gomez-Angelats, M Bortner, CD Cidlowski, JA TI Protein kinase C (PKC) inhibits Fas receptor-induced apoptosis through modulation of the loss of K+ and cell shrinkage - A role for PKC upstream of caspases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; CEREBELLAR GRANULE CELLS; JURKAT T-CELLS; MEDIATED APOPTOSIS; DNA FRAGMENTATION; PROTEOLYTIC ACTIVATION; INTRACELLULAR SIGNALS; SELECTIVE-INHIBITION; IMMUNE-SYSTEM; ICE-LIKE AB Cell shrinkage and loss of intracellular K+ are early requisite features for the activation of effector caspases and apoptotic nucleases in Fas receptor-mediated apoptosis of Jurkat cells, although the mechanisms responsible for both process remain unclear (Bortner, C. D., Hughes, F. M., Jr., and Cidlowski, J. A. (1997) J. Biol Chem, 272, 32436-32442), We have now investigated the role of protein kinase C (PKC)-dependent signaling in the regulation of Fas-induced cell shrinkage and loss of KC during apoptosis, Anti-Fas induced cell shrinkage was blocked during PKC stimulation by the phorbol ester 12-O-tetradecanoylphorbol-3-acetate (PMA) and by bryostatin-1. Conversely, inhibition of PKC with Go6976, enhanced the anti-Fas-mediated loss of cell volume. Analyses of mitochondrial membrane potential and DNA fragmentation revealed that the PKC-mediated effect observed in cell volume is propagated to these late features of apoptosis, Flow cytometric analyses and Rb-86 efflux experiments revealed that a primary effect of PKC appears to be on the modulation of Fas-induced K+ efflux, since both PMA and bryostatin-1 inhibited extrusion of K+ that occurs during Fas-mediated cell death, and Go6976 exacerbated the effect of anti-Fas. Interestingly, high extracellular K+ significantly blocked the effect of anti-Fas alone or anti-Fas combined with Go6976, suggesting an underlying effect of PKC on K+ loss. Western blot analyses showed the caspase-dependent proteolysis of PKC isotypes delta, epsilon, and theta in whole cell extracts from anti-Fas treated Jurkat T cells. However, stimulation of PKC by PMA or bryostatin-1 prevented this isotypic-specific PKC cleavage during apoptosis, providing further evidence that PKC itself exerts an upstream signal in apoptosis and controls the caspase-dependent proteolytic degradation of PKC isotypes, Finally, we show that PMA or bryostatin-1 prevents the activation of caspase-3 and caspase-8, Thus, this study shows that the protective effect that PRC stimulation exerts in the Fas-mediated apoptotic pathway occurs at a site upstream of caspases-3 and -8. C1 NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 91 TC 104 Z9 107 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19609 EP 19619 DI 10.1074/jbc.M909563199 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300025 PM 10867019 ER PT J AU Caffrey, M Braddock, DT Louis, JM Abu-Asab, MA Kingma, D Liotta, L Tsokos, M Tresser, N Pannell, LK Watts, N Steven, AC Simon, MN Stahl, SJ Wingfield, PT Clore, GM AF Caffrey, M Braddock, DT Louis, JM Abu-Asab, MA Kingma, D Liotta, L Tsokos, M Tresser, N Pannell, LK Watts, N Steven, AC Simon, MN Stahl, SJ Wingfield, PT Clore, GM TI Biophysical characterization of gp41 aggregates suggests a model for the molecular mechanism of HIV-associated neurological damage and dementia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-DEFICIENCY SYNDROME; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; AIDS DEMENTIA; NERVOUS-SYSTEM; SIV GP41; SPONGIFORM ENCEPHALOPATHY; CLINICAL-FEATURES; CRYSTAL-STRUCTURE AB In human immunodeficiency virus (HIV)-infected individuals, the level of the HIV envelope protein gp41 in brain tissue is correlated with neurological damage and dementia, In this paper we show by biochemical methods and electron microscopy that the extracellular ectodomain of purified HIV and simian immunodeficiency virus gp41 (e-gp41) forms a mixture of soluble high molecular weight aggregate and native trimer at physiological pH. The e-gp41 aggregate is shown to be largely alpha-helical and relatively stable to denaturants, The high molecular weight form of e-gp41 is variable in size ranging from 7 to 70 trimers, which associate by interactions at the interior of the aggregate involving the loop that connects the N- and C-terminal helices of the e-gp41 core. The trimers are predominantly arranged with their long axes oriented radially, and the width of the high molecular weight aggregate corresponds to the length of two e-gp41 trimers (similar to 200 Angstrom). Using both light and electron microscopy combined with immunohistochemistry we show that HIV gp41 accumulates as an extracellular aggregate in the brains of HIV-infected patients diagnosed with dementia, We postulate that the high molecular weight aggregates of e-gp41 are responsible for HIV-associated neurological damage and dementia, consistent with known mechanisms of encephalopathy. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NIAMS, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm B1-301, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Abu-Asab, Mones/0000-0002-4047-1232 NR 52 TC 24 Z9 24 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19877 EP 19882 DI 10.1074/jbc.M001036200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300061 PM 10747981 ER PT J AU Kinyamu, HK Fryer, CJ Horwitz, KB Archer, TK AF Kinyamu, HK Fryer, CJ Horwitz, KB Archer, TK TI The mouse mammary tumor virus promoter adopts distinct chromatin structures in human breast cancer cells with and without glucocorticoid receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; IN-VIVO; HORMONE RECEPTOR; MMTV PROMOTER; HYPERSENSITIVE SITES; GENE-EXPRESSION; ACTIVATION; SEQUENCE; NUCLEOSOME; ELEMENT AB Steroid receptors represent a class of transcription regulators that act in part by overcoming the often repressive nature of chromatin to modulate gene activity. The mouse mammary tumor virus (MMTV) promoter is a useful model for studying transcriptional regulation by steroid hormone receptors in the context of chromatin. The chromatin architecture of the promoter prevents the assembly of basal transcription machinery and binding of ubiquitous transcription factors. However, in human breast carcinoma T47D cells lacking the glucocorticoid receptor (GR), but expressing the progesterone receptor (PR), nucleosome B (nuc B) assumes a constitutively hypersensitive chromatin structure. This correlation led us to test the hypothesis that the chromatin structure of nuc B was dependent on GR expression in T47D cells. To examine this possibility, we stably cotransfected the MMTV promoter and the GR into T47D cells that lacked both the GR and the PR. We found that in T47D cells that lack both the GR and the PR or express only the GR, nuc B assumes a constitutively "open" chromatin structure, which allows hormone independent access by restriction endonucleases and transcription factors. These results suggest that in GR(+)/pr(-) T47D cells, the MMTV chromatin structure permits GR transcriptional activation, independent of chromatin remodeling. C1 NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Western Ontario, Dept Obstet & Gynaecol, London, ON N6A 4L6, Canada. Univ Western Ontario, Dept Biochem, London, ON N6A 4L6, Canada. Univ Colorado, Hlth Sci Ctr, Div Endocrinol Diabet & Metab, Denver, CO 80262 USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr,POB 12233,MD E4-06, Res Triangle Pk, NC 27709 USA. NR 50 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 20061 EP 20068 DI 10.1074/jbc.M001142200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300085 PM 10751396 ER PT J AU Harper, JL Daly, JW AF Harper, JL Daly, JW TI Store-operated calcium channels in HL-60 cells - Effects of temperature, differentiation and loperamide SO LIFE SCIENCES LA English DT Article DE loperamide; store-operated calcium channels; ATP; thapsigargin; miconazole; HL-60 cells ID INTRACELLULAR CA2+ STORES; PLASMA-MEMBRANE; ENDOTHELIAL-CELLS; INFLUX; ENTRY; THAPSIGARGIN; MICROFILAMENTS; LYMPHOCYTES; MECHANISMS; INHIBITION AB The effect of temperature on calcium release and influx has been compared in differentiated and un differentiated HL-60 cells. Receptor-mediated release of intracellular calcium by ATP was little affected by temperature in HL-60 cells. In differentiated HL-60 cells the store-operated calcium (SOC) channel-dependent sustained elevation of calcium levels after ATP was maximal at 25-29 degrees C; at higher temperatures calcium levels returned relatively rapidly rewards basal levels. In undifferentiated cells, a SOC channel-dependent sustained elevation of calcium levels was not observed with levels returning to basal levels much more rapidly than in differentiated cells. The initial thapsigargin-initiated elevation of calcium did not become maximal until about 25 degrees C in both differentiated and undifferentiated HL-50 cells. In differentiated cells, the SOC channel-dependent sustained elevation of calcium after thapsigargin was maximal at 30-37 degrees C, while in undifferentiated cells, the sustained elevation was maximal at 25-30 degrees C. Loperamide, which augments the SOC channel-dependent sustained elevation of calcium, showed a temperature-dependent response that was maximal at about 22 degrees C after either ATP or thapsigargin and was minimal at 37 degrees C, In contrast, inhibition of SOC channel-dependent elevation of calcium by miconazole or trifluoperazine was not greatly affected by temperature. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIH, Bioorgan Chem Lab, Bldg 8,Rm 1A17, Bethesda, MD 20892 USA. RI Harper, Jacquie/A-8920-2014 NR 30 TC 5 Z9 5 U1 0 U2 5 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 JUN 30 PY 2000 VL 67 IS 6 BP 651 EP 662 DI 10.1016/S0024-3205(00)00659-7 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 332LZ UT WOS:000088076900006 PM 12659171 ER PT J AU Resnick, MA Cox, BS AF Resnick, MA Cox, BS TI Editorial to Special Issue on Yeast DNA Repair and Human Implications: Past, Present and Future Perspectives on DNA Repair in Yeast - Yeast as an honorary mammal SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; SENSITIVE MUTANTS; GENE C1 NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Kent, Sch Biol Sci, Canterbury CT6 8EJ, Kent, England. RP Resnick, MA (reprint author), NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 28 TC 47 Z9 50 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 30 PY 2000 VL 451 IS 1-2 SI SI BP 1 EP 11 DI 10.1016/S0027-5107(00)00036-1 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 343FR UT WOS:000088691500001 PM 10915861 ER PT J AU Lewis, LK Resnick, MA AF Lewis, LK Resnick, MA TI Tying up loose ends: nonhomologous end-joining in Saccharomyces cerevisiae SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review ID DOUBLE-STRAND BREAKS; DNA DOUBLE-STRAND; DEPENDENT PROTEIN-KINASE; ARRESTED YEAST-CELLS; LIGASE-IV; HOMOLOGOUS RECOMBINATION; INTRACHROMOSOMAL RECOMBINATION; V(D)J RECOMBINATION; ESCHERICHIA-COLI; DAMAGE RESPONSE AB The ends of chromosomal DNA double-strand breaks (DSBs) can be accurately rejoined by at least two discrete pathways, homologous recombination and nonhomologous end-joining (NHEJ). The NHEJ pathway is essential for repair of specific classes of DSB termini in cells of the budding yeast Saccharomyces cerevisiae. Endonuclease-induced DSBs retaining complementary single-stranded DNA overhangs are repaired efficiently by end-joining. In contrast, damaged DSB ends (e.g., termini produced by ionizing radiation) are poor substrates for this pathway. NHEJ repair involves the functions of at least 10 genes, including YKU70, YKU80, DNL4, LIF1, SIR2, SIR3, SIR4, RAD50, MRE11, and XRS2. Most or all of these genes are required for efficient recombination-independent recircularization of linearized plasmids and for rejoining of EcoRI endonuclease-induced chromosomal DSBs in vivo. Several NHEJ mutants also display aberrant processing and rejoining of DSBs that are generated by HO endonuclease or formed spontaneously in dicentric plasmids. In addition, all NHEJ genes except DNL4 and LIF1 are required for stabilization of telomeric repeat sequences. Each of the proteins involved in NHEJ appears to bind, directly or through protein associations, with the ends of linear DNA. Enzymatic and/or structural roles in the rejoining of DSB termini have been postulated for several proteins within the group. Most yeast NHEJ genes have homologues in human cells and many biochemical activities and protein:protein interactions have been conserved in higher eucaryotes. Similarities and differences between NHEJ repair in yeast and mammalian cells are discussed. Published by Elsevier Science B.V. C1 NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 145 TC 128 Z9 132 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 30 PY 2000 VL 451 IS 1-2 SI SI BP 71 EP 89 DI 10.1016/S0027-5107(00)00041-5 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 343FR UT WOS:000088691500006 PM 10915866 ER PT J AU Aultman, KS Walker, ED Gifford, F Severson, DW Ben Beard, C Scott, TW AF Aultman, KS Walker, ED Gifford, F Severson, DW Ben Beard, C Scott, TW TI Research ethics - Managing risks of arthropod vector research SO SCIENCE LA English DT Article ID TRANSMISSION; DISEASE C1 NIAID, Parasitol & Int Programs Branch, Bethesda, MD 20892 USA. Michigan State Univ, Dept Entomol, E Lansing, MI 48824 USA. Michigan State Univ, Dept Philosophy, E Lansing, MI 48824 USA. Univ Notre Dame, Dept Biol, Notre Dame, IN 46556 USA. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. RP Aultman, KS (reprint author), NIAID, Parasitol & Int Programs Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 7 TC 16 Z9 16 U1 0 U2 2 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 JUN 30 PY 2000 VL 288 IS 5475 BP 2321 EP 2322 DI 10.1126/science.288.5475.2321 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329NP UT WOS:000087913400021 PM 10917830 ER PT J AU Chan, FKM Chun, HJ Zheng, LX Siegel, RM Bui, KL Lenardo, MJ AF Chan, FKM Chun, HJ Zheng, LX Siegel, RM Bui, KL Lenardo, MJ TI A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling SO SCIENCE LA English DT Article ID TUMOR-NECROSIS-FACTOR; RESONANCE ENERGY-TRANSFER; CRYSTALLOGRAPHIC EVIDENCE; ERYTHROPOIETIN RECEPTOR; DEATH DOMAIN; KAPPA-B; ACTIVATION; BINDING; APOPTOSIS; COMPLEX AB A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific Ligand-independent assembly of receptor trimers. This pre-ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts with ligand, but is necessary and sufficient for the assembly of TNFR complexes that bind TNF-alpha and mediate signaling. Other members of the TNFR superfamily, including TRAIL receptor 1 and CD40, show similar homotypic association. Thus, TNFRs and related receptors appear to function as preformed complexes rather than as individual receptor subunits that oligomerize after ligand binding. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009; Chun, Hyung/K-1859-2013; Chan, Francis/E-9647-2014; Chan, Francis K. L./F-4851-2010 OI Siegel, Richard/0000-0001-5953-9893; Chan, Francis/0000-0002-4803-8353; Chan, Francis K. L./0000-0001-7388-2436 NR 47 TC 492 Z9 511 U1 2 U2 11 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 JUN 30 PY 2000 VL 288 IS 5475 BP 2351 EP 2354 DI 10.1126/science.288.5475.2351 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329NP UT WOS:000087913400035 PM 10875917 ER PT J AU Siegel, RM Frederiksen, JK Zacharias, DA Chan, FKM Johnson, M Lynch, D Tsien, RY Lenardo, MJ AF Siegel, RM Frederiksen, JK Zacharias, DA Chan, FKM Johnson, M Lynch, D Tsien, RY Lenardo, MJ TI Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations SO SCIENCE LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; FAS GENE-MUTATIONS; LYMPHOCYTE APOPTOSIS; TNF-RECEPTOR; DEATH DOMAIN; MECHANISM; DISORDER; CASPASES; PROTEIN; BINDING AB Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced Lymphocyte apoptosis in human autoimmune Lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand-independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Sch Med, Howard Hughes Med Inst, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009; Frederiksen, John/C-4946-2012; Chan, Francis/E-9647-2014; Chan, Francis K. L./F-4851-2010 OI Siegel, Richard/0000-0001-5953-9893; Chan, Francis/0000-0002-4803-8353; Chan, Francis K. L./0000-0001-7388-2436 FU NINDS NIH HHS [NS27177] NR 30 TC 432 Z9 442 U1 2 U2 9 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 JUN 30 PY 2000 VL 288 IS 5475 BP 2354 EP 2357 DI 10.1126/science.288.5475.2354 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329NP UT WOS:000087913400036 PM 10875918 ER PT J AU Schneider, D Shahabuddin, M AF Schneider, D Shahabuddin, M TI Malaria parasite development in a Drosophila model SO SCIENCE LA English DT Article ID PLASMODIUM-FALCIPARUM; MOSQUITO MIDGUT; SPOROZOITES; TRANSMISSION; HOST AB Malaria is a devastating public health menace, killing over one million people every year and infecting about half a billion. Here it is shown that the protozoan Plasmodium gallinaceum, a close relative of the human malaria parasite Plasmodium falciparum, can develop in the fruit fly Drosophila melanogaster. Plasmodium gallinaceum ookinetes injected into the fly developed into sporozoites infectious to the vertebrate host with similar kinetics as seen in the mosquito host Aedes aegypti. In the fly, a component of the insect's innate immune system, the macrophage, can destroy Plasmodia. These experiments suggest that Drosophila can be used as a surrogate mosquito for defining the genetic pathways involved in both vector competence and part of the parasite sexual cycle. C1 Whitehead Inst, Cambridge, MA 02142 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Schneider, D (reprint author), Whitehead Inst, 9 Cambridge Ctr, Cambridge, MA 02142 USA. NR 16 TC 81 Z9 82 U1 2 U2 9 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 JUN 30 PY 2000 VL 288 IS 5475 BP 2376 EP 2379 DI 10.1126/science.288.5475.2376 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329NP UT WOS:000087913400043 PM 10875925 ER PT J AU Burshtyn, DN Shin, J Stebbins, C Long, EO AF Burshtyn, DN Shin, J Stebbins, C Long, EO TI Adhesion to target cells is disrupted by the killer cell inhibitory receptor SO CURRENT BIOLOGY LA English DT Article ID TYROSINE-PHOSPHATASE SHP-1; NK CELLS; CLASS-I; MACROPHAGES; ACTIVATION; MOLECULES; KINASE; PHOSPHORYLATION; CYTOTOXICITY; PROTEINS AB Killer cell immunoglobulin-like receptors (KIR) inhibit the cytotoxic activity of natural killer (NK) cells by recruitment of the tyrosine phosphatase SHP-1 to immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in the KIR cytoplasmic tail [1]. The precise steps in the NK activation pathway that are inhibited by KIR are yet to be defined. Here, we have studied whether the initial step of adhesion molecule LFA-1-dependent adhesion to target cells was altered by the inhibitory signal. Using stable expression of an HLA-C-specific KIR in the NK cell line YTS [2] and a two-color flow cytometry assay for conjugate formation, we show that adhesion to a target cell expressing cognate HLA-C was disrupted by KIR engagement. Conjugate formation was abruptly interrupted by KIR within less than 5 minutes. Inhibition of adhesion to target cells was mediated by a chimeric KIR molecule carrying catalytically active SHP-1 in place of its cytoplasmic tail. These results suggest that other ITIM bearing receptors, many of which have no known function, may regulate adhesion in a wide variety of cell types. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 18 TC 81 Z9 82 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 29 PY 2000 VL 10 IS 13 BP 777 EP 780 DI 10.1016/S0960-9822(00)00568-6 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 348HG UT WOS:000088979000018 PM 10898979 ER PT J AU Daly, JW Gupta, TH Padgett, WL Pei, XF AF Daly, JW Gupta, TH Padgett, WL Pei, XF TI 6 beta-acyloxy(nor)tropanes: Affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AGONISTS; BRAIN; CELLS; SELECTIVITY; DERIVATIVES; SUBTYPES; POTENT; DRUGS; RATIO; INDEX AB A series of esters of 6 beta-hydroxynortropane and the N-methyl analogue 6 beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites on human m(1)-, m(2)-, m(3)-, and m(4)-muscarinic receptors in transfected cell membranes and on native M-1-muscarinic receptors in rat brain membranes and native M-2-muscarinic receptors in rat heart membranes. Most 6 beta-acyloxy(nor)tropanes had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at transfected m(1)- and native M-1-receptors, indicative of agonist activity. 6 beta-Acetoxynortropane had K-i values versus oxotremorine-M binding at m(1)-, m(2)-, and m(4)-receptors ranging from 4 to 7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The affinity of 6 beta-benzoyloxynortropane and other analogues with larger acyl moieties was little affected by N-methylation or in some cases was increased. 6 beta-Acyloxy(nor)tropanes and classical muscarinic agonists, such as muscarine and oxotremorine, had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at native M-2-muscarinic receptors of heart, but not at transfected m(2)-muscarinic receptors. Antagonist/agonist binding ratios were not obtained for transfected m(3)-receptors, since significant oxotremorine-M binding could not be detected. 6 beta-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic agonists had higher affinity versus agonist binding compared to antagonist binding for transfected m(4)-receptors. The antagonist/agonist binding ratio method is clearly not always reliable for predicting agonist activity at muscarinic receptors. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8,Rm 1A17, Bethesda, MD 20892 USA. NR 28 TC 7 Z9 9 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 29 PY 2000 VL 43 IS 13 BP 2514 EP 2522 DI 10.1021/jm9904001 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 329TT UT WOS:000087924900004 PM 10891110 ER PT J AU Steinbach, G Lynch, PM Phillips, RKS Wallace, MH Hawk, E Gordon, GB Wakabayashi, N Saunders, B Shen, Y Fujimura, T Su, LK Levin, B Godio, L Patterson, S Rodriguez-Bigas, MA Jester, SL King, KL Schumacher, M Abbruzzese, J DuBois, RN Hittelman, WN Zimmerman, S Sherman, JW Kelloff, G AF Steinbach, G Lynch, PM Phillips, RKS Wallace, MH Hawk, E Gordon, GB Wakabayashi, N Saunders, B Shen, Y Fujimura, T Su, LK Levin, B Godio, L Patterson, S Rodriguez-Bigas, MA Jester, SL King, KL Schumacher, M Abbruzzese, J DuBois, RN Hittelman, WN Zimmerman, S Sherman, JW Kelloff, G TI The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INDUCED COLON CARCINOGENESIS; RHEUMATOID-ARTHRITIS; COLORECTAL-CANCER; SULINDAC THERAPY; RECTAL ADENOMAS; ASPIRIN USE; EXPRESSION; RISK; RATS AB Background: Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. Methods: We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. Results: At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P = 0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P = 0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P = 0.33 for the comparison with placebo) and 14.6 percent (P = 0.09), respectively. The incidence of adverse events was similar among the groups. Conclusions: In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps. (N Engl J Med 2000;342:1946-52.) (C)2000, Massachusetts Medical Society. C1 Univ Texas, MD Anderson Canc Ctr, Div Canc Prevent, Houston, TX 77030 USA. St Marks Hosp, Imperial Canc Res Fund, London EC1V 2PS, England. NCI, Bethesda, MD 20892 USA. GD Searle & Co, Skokie, IL 60077 USA. RP Steinbach, G (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Canc Prevent, Box 203,1515 Holcombe Blvd, Houston, TX 77030 USA. OI Shen, Yu/0000-0002-3899-7868 FU NCI NIH HHS [CA-16672, N01 CN-65118] NR 39 TC 1655 Z9 1726 U1 4 U2 43 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 29 PY 2000 VL 342 IS 26 BP 1946 EP 1952 DI 10.1056/NEJM200006293422603 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 328TZ UT WOS:000087867400003 PM 10874062 ER PT J AU Leethanakul, C Patel, V Gillespie, J Pallente, M Ensley, JF Koontongkaew, S Liotta, LA Emmert-Buck, M Gutkind, JS AF Leethanakul, C Patel, V Gillespie, J Pallente, M Ensley, JF Koontongkaew, S Liotta, LA Emmert-Buck, M Gutkind, JS TI Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays SO ONCOGENE LA English DT Article DE oral cancel; tumor progression; oncogenes; tumor suppressor genes; biomarkers ID APOPTOSIS; DISEASE; CANCER AB Although risk factors for squamous cell carcinomas of the head and neck (HNSCC) are well recognized, very little is known about the molecular mechanisms responsible for this malignancy. Furthermore, the ability to investigate gene expression profiles at different stages of tumor progression is usually limited by the remarkable heterogeneity of these neoplastic lesions. Here, we show the successful use of laser capture microdissection (LCM) to procure specific cell populations. The 5000 cells from representative sets of HNSCC and their matching normal tissues are sufficient to extract RNA of high integrity for the synthesis of labeled amplified cDNA probes which can then be hybridized to these membranes arrayed with known human cancer-related cDNAs. Furthermore, when compared to normal tissues, we demonstrate a consistent decrease in expression of differentiation markers such as cytokeratins, and an increase in the expression of a number of signal transducing and cell cycle regulatory molecules, as well as growth and angiogenic factors and tissue degrading proteases. Unexpectedly, we also found that most HNSCC overexpress members of the wnt and notch growth and differentiation regulatory system, thus suggesting that the,wnt and notch pathways mag contribute in squamous cell carcinogenesis. This experimental approach may facilitate the identification candidate markers for the early detection of preneoplastic lesions, as well as novel targets for pharmacological intervention in this disease. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Div Hematol Oncol, Detroit, MI USA. Prince Songkla Univ, Fac Dent, Dept Oral Biol & Occlus, Hat Yai, Thailand. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 15 TC 205 Z9 215 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 29 PY 2000 VL 19 IS 28 BP 3220 EP 3224 DI 10.1038/sj.onc.1203703 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 331KX UT WOS:000088019200012 PM 10918578 ER PT J AU Fiore, MC Bailey, WC Cohen, SJ Dorfman, SF Fox, BJ Goldstein, MG Gritz, E Hasselblad, V Heyman, RB Jaen, CR Jorenby, D Kottke, TE Lando, HA Mecklenburg, RE Mullen, PD Nett, L Piper, M Robinson, L Stitzer, M Tommasello, A Welsch, S Villejo, L Wewers, ME Baker, TB AF Fiore, MC Bailey, WC Cohen, SJ Dorfman, SF Fox, BJ Goldstein, MG Gritz, E Hasselblad, V Heyman, RB Jaen, CR Jorenby, D Kottke, TE Lando, HA Mecklenburg, RE Mullen, PD Nett, L Piper, M Robinson, L Stitzer, M Tommasello, A Welsch, S Villejo, L Wewers, ME Baker, TB CA Tobacco Use Dependence Clin Prac TI A clinical practice guideline for treating tobacco use and dependence - A US Public Health Service report SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SMOKING-CESSATION; COST-EFFECTIVENESS; NICOTINE GUM; MAINTENANCE ORGANIZATION; QUIT; ADVICE; PROGRAMS; PATTERNS; BENEFITS; SMOKERS AB Objective To summarize the recently published US Public Health Service report Treating Tobacco Use and Dependence. A Clinical Practice Guideline, which provides recommendations for brief clinical interventions, intensive clinical interventions, and system changes to promote the treatment of tobacco dependence. Participants An independent panel of 18 scientists, clinicians, consumers, and methodologists selected by the US Agency for Healthcare Research and Quality. A consortium of 7 governmental and nonprofit organizations sponsored the update. Evidence Approximately 6000 English-language, peer-reviewed articles and abstracts, published between 1975 and 1999, were reviewed for data that addressed assessment and treatment of tobacco dependence. This literature served as the basis for more than 50 meta-analyses. Consensus Process One panel meeting and numerous conference calls and staff meetings were held to evaluate meta-analytic and other results, to synthesize the results, and to develop recommendations. The updated guideline was then externally reviewed by more than 70 experts and revised. Conclusions This evidence-based, updated guideline provides specific recommendations regarding brief and intensive tobacco cessation interventions as well as system-level changes designed to promote the assessment and treatment of tobacco use. Brief clinical approaches for patients willing and unwilling to quit are described. Major conclusions and recommendations include: (1) Tobacco dependence is a chronic condition that warrants repeated treatment until long-term or permanent abstinence is achieved. (2) Effective treatments for tobacco dependence exist and all tobacco users should be offered those treatments. (3) Clinicians and health care delivery systems must institutionalize the consistent identification, documentation, and treatment of every tobacco user at every visit. (4) Brief tobacco dependence treatment is effective, and every tobacco user should be offered at least brief treatment. (5) There is a strong dose-response relationship between the intensity of tobacco dependence counseling and its effectiveness. (6) Three types of counseling were found to be especially effective-practical counseling, social support as part of treatment, and social support arranged outside of treatment. (7) Five first-line pharmacotherapies for tobacco dependence-sustained-release bupropion hydrochloride, nicotine gum, nicotine inhaler, nicotine nasal spray, and nicotine patch-are effective, and at least 1 of these medications should be prescribed in the absence of contraindications. (8) Tobacco dependence treatments are cost-effective relative to other medical and disease prevention interventions; as such, all health insurance plans should include as a reimbursed benefit the counseling and pharmacotherapeutic treatments identified as effective in the updated guideline. C1 Univ Wisconsin, Sch Med, Ctr Tobacco Res & Intervent, Madison, WI 53711 USA. Univ Alabama, Birmingham, AL USA. Univ Arizona, Prevent Ctr, Tucson, AZ 85721 USA. Bayer Inst Hlth Care Commun, Portland, OR USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Duke Clin Res Inst, Durham, NC USA. Amer Acad Pediat, Elk Grove Village, IL USA. SUNY Buffalo, Buffalo, NY 14260 USA. Mayo Clin, Rochester, MN USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. NCI, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Natl Lung Hlth Educ Program, Denver, CO USA. Philadelphia Dept Hlth, Philadelphia, PA USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. Univ Maryland, Sch Pharm, College Pk, MD 20742 USA. Ohio State Univ, Columbus, OH 43210 USA. NHLBI, NIH, Bethesda, MD USA. Agcy Hlth Care Res & Qual, Rockville, MD USA. NIDA, Bethesda, MD USA. Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. RP Fiore, MC (reprint author), Univ Wisconsin, Sch Med, Ctr Tobacco Res & Intervent, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. NR 43 TC 474 Z9 491 U1 9 U2 80 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 28 PY 2000 VL 283 IS 24 BP 3244 EP 3254 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 326TY UT WOS:000087753900039 ER PT J AU Bewley, CA Clore, GM AF Bewley, CA Clore, GM TI Determination of the relative orientation of the two halves of the domain-swapped dimer of cyanovirin-N in solution using dipolar couplings and rigid body minimization SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HIV-INACTIVATING PROTEIN; NMR STRUCTURES AB The HIV-inactivating protein cyanovirin-N (CVN) exists in two forms that are pH- and solvent-dependent: a monomer which predominates at neutral pH (greater than or equal to 90%) and a symmetric domain-swapped dimer. We have investigated the orientation of the two halves of the domain-swapped dimer of CVN at neutral pH in solution using dipolar couplings measured in a neutral liquid crystalline bicelle medium. D-1(NH) dipolar couplings for the dimer were readily measured for 18 out of 101 residues, and are shown to be inconsistent with the orientation of the two halves of the dimer observed in the X-ray structure obtained from crystals grown at low pH in the presence of organic solvent. The orientation of the two halves of the domain-swapped dimer was determined by rigid body minimization, subject to the requirements of C-2 symmetry. The starting coordinates for the calculations consisted of the X-ray coordinates for the two halves (with the linker residues deleted), separated by similar to 45 Angstrom and placed in three different relative orientations. One-half of the dimer is held fixed, the other half is free to rotate and translate (6 degrees of freedom), and the alignment tensor for the dipolar couplings is free to rotate (3 degrees of freedom). The target function comprised only four terms: dipolar coupling restraints (18 x 2), distance restraints (12) to link the two halves and to prevent steric clash, a radius of gyration restraint to achieve appropriate compaction, and a quartic van der Waals repulsion term. Structures were calculated for different target values of the radius of gyration, and back-calculation of the alignment tensor and dipolar couplings on the basis of molecular shape was used to filter the resulting structures, Prediction of dipolar couplings in this manner is predicated on the assumption that orientational order is dictated by steric interactions between the liquid crystalline medium and the protein. The validity of this assumption in this particular case is evidenced by the excellent agreement between predicted and observed dipolar couplings for the monomer. We show that the data is only consistent with a very small range of orientations of the two halves of the dimer in which the angle between the long axes of the two halves is similar to 110 degrees. The relative orientation of the two halves of the dimer at neutral pH in solution is quite different from that observed in the crystals obtained at low pH in organic solvent. The factors stabilizing the relative orientation of the two halves of the dimer under different conditions are discussed. The methodology presented in this paper should find a wide range of applicability to numerous other structural problems involving multimeric proteins and protein-protein complexes. C1 NIDDKD, Labs Bioorgan Chem & Chem Phys, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Labs Bioorgan Chem & Chem Phys, NIH, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 18 TC 71 Z9 71 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 28 PY 2000 VL 122 IS 25 BP 6009 EP 6016 DI 10.1021/ja000858o PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 332CB UT WOS:000088054900011 ER PT J AU Henry, AJ McDonnell, JM Ghirlando, R Sutton, BJ Gould, HJ AF Henry, AJ McDonnell, JM Ghirlando, R Sutton, BJ Gould, HJ TI Conformation of the isolated C epsilon 3 domain of IgE and its complex with the high-affinity receptor, Fc epsilon RI SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNOGLOBULIN-E; INTRACHAIN DISULFIDE BOND; BINDING-SITE; ESCHERICHIA-COLI; CHAIN FRAGMENT; CIRCULAR-DICHROISM; EFFECTOR FUNCTIONS; CONSTANT FRAGMENT; STRUCTURAL BASIS; TERMINAL REGION AB Immunoglobulin E (IgE) exhibits a uniquely high affinity for its receptor, Fc epsilon RI, on the surface of mast cells and basophils. Previous work has implicated the third domain of the constant region of the epsilon-heavy chain (C epsilon 3) in binding to FceRI, but the smallest fragment of IgE that is known to bind with full affinity is a covalent dimer of the C epsilon 3 and C epsilon 4 domains. We have expressed the isolated C epsilon 3 in Escherichia coli, measured its affinity for Fc epsilon RI, and examined its conformation alone and in the complex with Fc epsilon RI. Sedimentation equilibrium in the analytical centrifuge reveals that this product is a monomer. The kinetics of binding to an immobilized fragment of the Fc epsilon RI alpha-chain, measured by surface plasmon resonance, yields an affinity constant K-a = 5 x 10(6) M-1, as compared with 4 x 10(9) M-1 for IgE. The circular dichroism spectrum and measurements of fluorescence as a function of the concentration of a denaturant do not reveal any recognizable secondary structure or hydrophobic core. On binding to the Fc epsilon RI alpha-chain fragment, there is no change in the circular dichroism spectrum, indicating that the conformation of C epsilon 3 is unchanged in the complex. Thus the isolated C epsilon 3 domain is sufficient for binding to Fc epsilon RI, but with lower affinity than IgE. This may be due to the loss of its native immunoglobulin domain structure or to the requirement for two C epsilon 3 domains to constitute the complete binding site for Fc epsilon RI or to a combination of these factors. C1 Kings Coll London, Randall Ctr Mol Mechanisms Cell Funct, London SE1 1UL, England. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gould, HJ (reprint author), Kings Coll London, Randall Ctr Mol Mechanisms Cell Funct, New Hunts House,Guys Campus,London Bridge, London SE1 1UL, England. RI Ghirlando, Rodolfo/A-8880-2009; OI Gould, Hannah/0000-0003-0411-688X NR 59 TC 23 Z9 26 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 27 PY 2000 VL 39 IS 25 BP 7406 EP 7413 DI 10.1021/bi9928391 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 329QF UT WOS:000087918200010 PM 10858288 ER PT J AU Van Boven, RW Hamilton, RH Kauffman, T Keenan, JP Pascual-Leone, A AF Van Boven, RW Hamilton, RH Kauffman, T Keenan, JP Pascual-Leone, A TI Tactile spatial resolution in blind Braille readers SO NEUROLOGY LA English DT Article DE touch; blindness; discrimination learning; form perception ID FREQUENCY-DISCRIMINATION TASK; ADULT OWL MONKEYS; CORTICAL AREA 3B; SOMATOSENSORY CORTEX; VISUAL-CORTEX; MECHANORECEPTIVE AFFERENTS; 2-POINT DISCRIMINATION; PROBE ARRAY; REPRESENTATION; PLASTICITY AB Objective: To determine if blind people have heightened tactile spatial acuity. Bachground: Recently, studies using magnetic source imaging and somatosensory evoked potentials have shown that the cortical representation of the reading fingers of blind Braille readers is expanded compared to that of fingers of sighted subjects. Furthermore, the visual cortex is activated during certain tactile tasks in blind subjects but not sighted subjects. The authors hypothesized that the expanded cortical representation of fingers used in Braille reading may reflect an enhanced fidelity in the neural transmission of spatial details of a stimulus. If so, the quantitative limit of spatial acuity would be superior in blind people. Methods: The authors employed a grating orientation discrimination task in which threshold performance is accounted for by the spatial resolution limits of the neural image evoked by a stimulus. The authors quantified the psychophysical limits of spatial acuity at the middle and index fingers of 15 blind Braille readers and 15 sighted control subjects. Results: The mean grating orientation threshold was significantly (p = 0.003) lower in the blind group (1.04 mm) compared to the sighted group (1.46 mm). The self-reported dominant reading finger in blind subjects had a mean grating orientation threshold of 0.80 mm, which was significantly better than other fingers tested. Thresholds at non-Braille reading fingers in blind subjects averaged 1.12 mm, which were also superior to sighted subjects' performances. Conclusion: Superior tactile spatial acuity in blind Braille readers may represent an adaptive, behavioral correlate of cortical plasticity. C1 Beth Israel Deaconess Med Ctr, Dept Neurol, Behav Neurol Unit, Lab Magnet Brain Stimulat, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Northwestern Univ, Sch Med, Dept Neurol, Chicago, IL 60611 USA. RP Van Boven, RW (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA. RI Pascual-Leone, Alvaro/G-6566-2011 FU NCRR NIH HHS [RR 01032]; NEI NIH HHS [R01 EY12091] NR 48 TC 192 Z9 195 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 27 PY 2000 VL 54 IS 12 BP 2230 EP 2236 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 327QQ UT WOS:000087804600009 PM 10881245 ER PT J AU Bolla, KI Funderburk, FR Cadet, JL AF Bolla, KI Funderburk, FR Cadet, JL TI Differential effects of cocaine and cocaine plus alcohol on neurocognitive performance SO NEUROLOGY LA English DT Article DE neurobehavior; cocaine; alcohol; cognitive ID ABUSERS; COCAETHYLENE; SOLVENTS AB Objective: To investigate the dose-related effects of cocaine with or without alcohol use on the CNS by measuring performance on neurobehavioral tests. Background: Chronic use of cocaine is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Specific neurobehavioral deficits in areas such as executive function and impulsivity would make it difficult for the cocaine abuser to discontinue using drugs. Because alcohol is often used in conjunction with cocaine, the CNS effects of alcohol when taken with cocaine deserve further investigation. Method: The authors evaluated the dose-related effects of cocaine and alcohol use on performance in a variety of neuropsychological tests after 1 to 3 days of abstinence and again after 4 weeks of abstinence. Fifty-six chronic cocaine abusers who had used cocaine during the past 24 to 48 hours volunteered to perform a battery of neuropsychological tests on two separate occasions during a period of enforced abstinence. in addition to using cocaine, most of the volunteers consumed alcohol. Approximately half of the participants consumed more than 10 alcohol-containing drinks per week. Results: After controlling for the effects of age, sex, and intelligence on performance, the authors found dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1 to 3 days of abstinence, with these effects persisting after 4 weeks of abstinence. Conclusion: The concomitant use of cocaine and alcohol may have additive negative effects on the brain as compared to the use of only one of these two substances. C1 Johns Hopkins Med Inst, Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. NIH, NIDA, IRP, Bethesda, MD USA. In Compass Syst, Baltimore, MD USA. RP Bolla, KI (reprint author), Johns Hopkins Med Inst, Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 34 TC 120 Z9 121 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 27 PY 2000 VL 54 IS 12 BP 2285 EP 2292 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 327QQ UT WOS:000087804600016 PM 10881254 ER PT J AU Thomas, JM Eckhoff, DE Contreras, JL Lobashevsky, AL Hubbard, WJ Moore, JK Cook, WJ Thomas, FT Neville, DM AF Thomas, JM Eckhoff, DE Contreras, JL Lobashevsky, AL Hubbard, WJ Moore, JK Cook, WJ Thomas, FT Neville, DM TI Durable donor-specific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin - Absence of chronic allograft nephropathy (Retracted Article. See vol 82, pg 577, 2006) SO TRANSPLANTATION LA English DT Article; Retracted Publication ID TRANSPLANT RECIPIENTS; CHRONIC REJECTION; BONE-MARROW; KIDNEY-TRANSPLANTS; NONHUMAN-PRIMATES; RENAL-ALLOGRAFTS; GRAFT-REJECTION; INDUCTION; MONKEYS; ANTIGEN AB Tolerance induction can prevent acute kidney allograft rejection without chronic immunosuppression. It is uncertain whether specific tolerance can prevent chronic allograft nephropathy (CAN), which involves both nonimmune and immune injury. This report provides evidence that immunologically tolerant macaques, induced with immunotoxin and deoxyspergualin, developed neither acute rejection nor CAN. Long survivors, bearing MHC-mismatched grafts without chronic immunosuppression for 0.8 to 3.4 years, exhibited general immune competence with donor-specific T and B cell tolerance and no functional or histological evidence of CAN. Stringent criteria for tolerance were satisfied by specific prolongation of donor skin grafts with rapid rejection of third-party skin, followed by indefinite acceptance of a second donor kidney graft and establishment of microchimerism. Primate tolerance with documented absence of CAN may give impetus to the clinical application of tolerance. C1 Univ Alabama, Transplant Ctr, Dept Surg & Pathol, Birmingham, AL 35294 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Thomas, JM (reprint author), Univ Alabama, Transplant Ctr, Dept Surg & Pathol, Birmingham, AL 35294 USA. EM jthomas@uab.edu FU NIAID NIH HHS [AI 22293]; NIDDK NIH HHS [1U19 DK57958] NR 47 TC 72 Z9 73 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2000 VL 69 IS 12 BP 2497 EP 2503 DI 10.1097/00007890-200006270-00007 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 335HU UT WOS:000088238700007 PM 10910269 ER PT J AU Giugliano, RP Lloyd-Jones, DM Camargo, CA Makary, MA O'Donnell, CJ AF Giugliano, RP Lloyd-Jones, DM Camargo, CA Makary, MA O'Donnell, CJ TI Association of unstable angina guideline care with improved survival SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; PECTORIS; MANAGEMENT AB Background: An unstable angina guideline was published in 1994 by the Agency for Health Care Policy and Research, Bethesda, Md. However, the relationship between guideline-concordant care and patient outcomes is unknown. Objective: To determine whether guideline-concordant care is associated with improved outcomes. Methods: The study sample consisted of 275 consecutive nonreferral patients hospitalized with primary unstable angina. One-year survival and survival free of myocardial infarction were compared between patients who received care concordant with 8 selected guideline recommendations and patients who received discordant care. Results: Care concordant with the 8 key guideline recommendations was associated with improved 1-year survival (95% vs 81%; log-rank P<.001) and survival free of myocardial infarction (91% vs 74%; P<.001), compared with guideline-discordant care. Patients in high risk subgroups had the largest survival benefit associated with guideline-concordant care (aged greater than or equal to 65 years, 91% vs 74% [P=.005]; heart failure at presentation, 91% vs 68% [P=.10]). Aspirin therapy was the single recommendation most strongly associated with improved 1-year survival (94% vs 78%; P=.002). Conclusions: Care as outlined in the unstable angina clinical practice guideline is associated with improved 1-year outcomes. Subgroups of patients at highest risk and recommendations firmly based on randomized clinical trial data were mast strongly associated with better outcomes. These findings support the use of an evidence-based approach to guideline development and assessment of quality of care in patients with primary unstable angina. C1 Brigham & Womens Hosp, TIMI Study Off, Div Cardiovasc, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. Georgetown Univ, Med Ctr, Dept Surg, Washington, DC 20007 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Giugliano, RP (reprint author), Brigham & Womens Hosp, TIMI Study Off, Div Cardiovasc, 333 Longwood Ave,Suite 402, Boston, MA 02115 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 17 TC 27 Z9 27 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 26 PY 2000 VL 160 IS 12 BP 1775 EP 1780 DI 10.1001/archinte.160.12.1775 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 327TQ UT WOS:000087809900007 PM 10871970 ER PT J AU Blanchette-Mackie, EJ AF Blanchette-Mackie, EJ TI Intracellular cholesterol trafficking: role of the NPC1 protein SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE cholesterol trafficking; Golgi; late endosome; NPC1 protein; Niemann-Pick type C disease ID ACYL-COENZYME-A; MANNOSE 6-PHOSPHATE RECEPTOR; CLEAVAGE-ACTIVATING PROTEIN; NIEMANN-PICK DISEASE; DENSITY LIPOPROTEIN CHOLESTEROL; BINDING CASSETTE TRANSPORTER-1; GPI-ANCHORED PROTEINS; HAMSTER OVARY CELLS; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM C1 NIDDKD, Lab Cell Biochem & Biol, Lipid Cell Biol Sect, Bethesda, MD 20892 USA. RP Blanchette-Mackie, EJ (reprint author), NIDDKD, Lab Cell Biochem & Biol, Lipid Cell Biol Sect, Bldg 8,Room 427,8 Ctr Dr, Bethesda, MD 20892 USA. NR 76 TC 85 Z9 88 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI BBA-Mol. Cell. Biol. Lipids PD JUN 26 PY 2000 VL 1486 IS 1 BP 171 EP 183 DI 10.1016/S1388-1981(00)00055-X PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 328NR UT WOS:000087857400013 PM 10856720 ER PT J AU Mofenson, LM McIntyre, JA AF Mofenson, LM McIntyre, JA TI Advances and research directions in the prevention of mother-to-child HIV-1 transmission SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED TRIAL; COTE-DIVOIRE; VERTICAL TRANSMISSION; SOUTH-AFRICA; PERINATAL TRANSMISSION; HIV-1-INFECTED WOMEN; PREGNANCY OUTCOMES; CESAREAN-SECTION; ORAL ZIDOVUDINE AB Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and less-developed countries. C1 NICHHD, Pediat Adolescent & Mat AIDS Branch, Ctr Res Mothers & Children, NIH, Rockville, MD 20852 USA. Chris Hani Baragwanath Hosp, Johannesburg, South Africa. RP Mofenson, LM (reprint author), NICHHD, Pediat Adolescent & Mat AIDS Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 52 TC 129 Z9 136 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 24 PY 2000 VL 355 IS 9222 BP 2237 EP 2244 DI 10.1016/S0140-6736(00)02415-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 327DX UT WOS:000087779000041 PM 10881908 ER PT J AU Andjus, RK Konjevic, D Damjanovic, I Gacic, Z AF Andjus, RK Konjevic, D Damjanovic, I Gacic, Z TI Effects of xanthine derivatives on electroretinographic responsiveness SO BRAIN RESEARCH LA English DT Article DE electroretinography (ERG); propentofylline; theophylline; vision; xanthines ID INDUCED HIPPOCAMPAL DAMAGE; ANGUILLA-ANGUILLA L; PROPENTOFYLLINE HWA-285; ADAPTIVE PROPERTIES; ROD PHOTORECEPTORS; SEXUAL-MATURATION; BUFO-MARINUS; ISCHEMIA; PHOTOTRANSDUCTION; INHIBITORS AB In view of the use of synthetic propentofylline (PPF) as a protective agent in brain ischemia, its possible side effects on vision capacities have been explored by electroretinography in comparative experiments with theophylline. We used eyecup preparations of small-spotted dogfish sharks and of European eels, particularly ly suitable for long-lasting experiments. The drug exerted profound but reversible modifications of ERG records: (1) a dose-dependent increase of the amplitude and duration of the chemically isolated late receptor potential (LRP), (2) a partial unmasking of LRP, (3) a strong potentiation of the LRP-unmasking effect of low temperature, (3) a potentiation of light adaptation effects, and (5) a strong potentiation of the post-illumination hyperexcitability. The effects were explicable as due to a strong phosphodiesterase (PDE) inhibiting, cyclic guanosine monophosphate (cGMP) promoting, action of the drug. The effects were considerably stronger, or even of opposite sign, in comparison to those of the chemically related theophylline. PPF did not seriously affect the ERG c-wave originating in the pigment epithelium. The results suggested that the effects of PPF on vision may not seriously hamper the therapeutic use of the drug. They indicated, on the other hand, that PPF was a retinoactive drug of potential usefulness in the exploration of the complex biochemical events underlying visual transduction. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Belgrade, Ctr Multidisciplinary Studies, YU-11000 Belgrade, Yugoslavia. Inst Marine Biol, YU-85331 Kotor, Montenegro, Yugoslavia. Russian Acad Sci, Inst Informat Transmiss Problems, Lab 8, Moscow, Russia. RP Andjus, RK (reprint author), Care of Dragoslava, NICHD, ERRB, NIH, Bldg 49,Room 6B,2349 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. NR 39 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 23 PY 2000 VL 868 IS 2 BP 176 EP 190 DI 10.1016/S0006-8993(00)02328-3 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 327HW UT WOS:000087789300002 PM 10854570 ER PT J AU Lamensdorf, I Eisenhofer, G Harvey-White, J Nechustan, A Kirk, K Kopin, IJ AF Lamensdorf, I Eisenhofer, G Harvey-White, J Nechustan, A Kirk, K Kopin, IJ TI 3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells SO BRAIN RESEARCH LA English DT Article DE dihydroxyphenylacetaldehyde; dihydroxyphenylethanol; dihydroxyphenylacetic acid; dopamine; complex I; MPP; rotenone; Parkinson's disease ID PARKINSONS-DISEASE; INHIBITION; DOPAMINE; NEUROTOXICITY; DEATH; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; 1-METHYL-4-PHENYLPYRIDINIUM; MECHANISMS; SEROTONIN; MPTP AB 3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells. Here, we examined the potential role of DOPAL in the toxicity induced by complex I inhibition in PC12 cells and compared the effects of rotenone on concentrations of DOPAL and DOPET to those of MPP+. DOPAL and DOPET levels were increased by rotenone but decreased by MPP+. Inhibition of ALDH by daidzein reduced the formation of DOPAC and increased the accumulation of DOPAL. Inhibition of ARs (with AL1576) diminished DOPET formation and elevated DOPAL concentrations. Combined inhibition of ALDH and ARs markedly elevated DOPAL concentrations while diminishing DOPET and DOPAC levels. The elevation of DOPAL levels induced by combined inhibition of ALDH and ARs had no effect on cell viability. However, combined inhibition of ALDH and ARs potentiated rotenone-induced toxicity. Both the potentiation of toxicity and, the increase in DOPAL levels were blocked by inhibition of monoamine oxidase with clorgyline indicating that accumulation of DOPAL was responsible for the potentiated rotenone-induced toxicity following combined inhibition of ALDH and ARs. Since complex I dysfunction is reported to be involved in the pathogenesis of Parkinson's disease, DOPAL potentiation of the deleterious effects of complex I inhibition may contribute to the specific vulnerability of dopaminergic neurons to injury. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Chem Lab, NIH, Bethesda, MD 20892 USA. RP Lamensdorf, I (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. NR 30 TC 65 Z9 66 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 23 PY 2000 VL 868 IS 2 BP 191 EP 201 DI 10.1016/S0006-8993(00)02309-X PG 11 WC Neurosciences SC Neurosciences & Neurology GA 327HW UT WOS:000087789300003 PM 10854571 ER PT J AU Donaldson, JG Lippincott-Schwartz, J AF Donaldson, JG Lippincott-Schwartz, J TI Sorting and signaling at the Golgi complex SO CELL LA English DT Review ID BINDING-PROTEIN; GTP HYDROLYSIS; TRANSPORT; MEMBRANE; COATOMER; VESICLES; CDC42; CELLS; COPI C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 18T,Room 101,18 Lib Dr, Bethesda, MD 20892 USA. NR 20 TC 70 Z9 74 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 23 PY 2000 VL 101 IS 7 BP 693 EP 696 DI 10.1016/S0092-8674(00)80881-8 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327YE UT WOS:000087821400003 PM 10892740 ER PT J AU Dimitrov, DS AF Dimitrov, DS TI Cell biology of virus entry SO CELL LA English DT Article ID MEMBRANE-FUSION; CD4; HIV C1 NCI, Lab Expt & Computat Biol, FCRDC, NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Lab Expt & Computat Biol, FCRDC, NIH, Bldg 469,Room 104,POB B,Miller Dr, Frederick, MD 21702 USA. NR 27 TC 70 Z9 83 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 23 PY 2000 VL 101 IS 7 BP 697 EP 702 DI 10.1016/S0092-8674(00)80882-X PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327YE UT WOS:000087821400004 PM 10892741 ER PT J AU Valenzuela, JG Charlab, R Mather, TN Ribeiro, JMC AF Valenzuela, JG Charlab, R Mather, TN Ribeiro, JMC TI Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-H; COMPLEMENT; DAMMINI; PARASITES; EVASION AB The alternative pathway of complement is an important defense against pathogens and in tick rejection reactions. The tick Ixodes scapularis is able to feed repeatedly on its natural host and has a salivary anticomplement activity that presumably facilitates feeding. In this study, we purified and then obtained the aminoterminal sequence of the I. scapularis salivary anticomplement (Isac), We found a full-length clone coding for Isac by random screening of a salivary gland cDNA library. Expressing Isac cDNA in COS cells reproduced the activity found in tick saliva, namely, inhibition of rabbit erythrocyte lysis by human serum in the presence of Mg2+ and EGTA, inhibition of C3b binding to agarose in the presence of Mg2+ and EGTA, and acceleration of factor Bb uncoupling from the C3 convertase generated by the alternative pathway. Recombinant Isac had no effect on the recalcification time of human platelet-poor plasma or in the classical complement pathway, indicating that it is a specific inhibitor similar to the regulators of complement activation of the alternative pathway such as factor H. Isac, however, has no similarity to any protein in the GenBank(TM) data base, indicating that it is a novel and relatively small (18.5 kDa) anticomplement molecule. C1 NIAID, NIH, Parasit Dis Lab, Sect Med Entomol, Bethesda, MD 20892 USA. Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. RP Ribeiro, JMC (reprint author), NIAID, NIH, Parasit Dis Lab, Sect Med Entomol, Bldg 4,Rm 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI 37230] NR 25 TC 147 Z9 150 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 18717 EP 18723 DI 10.1074/jbc.M001486200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900016 PM 10749868 ER PT J AU Lee, C Kim, SR Chung, JK Frohman, MA Kilimann, MW Rhee, SG AF Lee, C Kim, SR Chung, JK Frohman, MA Kilimann, MW Rhee, SG TI Inhibition of phospholipase D by amphiphysins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATION-FACTOR; PHOSPHATIDYLINOSITOL TRANSFER PROTEIN; CLATHRIN-MEDIATED ENDOCYTOSIS; SECRETORY VESICLE FORMATION; PHOSPHATIDIC-ACID; INOSITIDE PHOSPHORYLATION; LYSOPHOSPHATIDIC ACID; NERVE-TERMINALS; PLASMA-MEMBRANE; BINDING-SITE AB Two distinct proteins inhibiting phospholipase D (PLD) activity in rat brain cytosol were previously purified and identified as synaptojanin and AP180, which are specific to nerve terminals and associate with the clathrin coat. Two additional PLD-inhibitory proteins have now been purified and identified as the amphiphysins I and II, which forms a heterodimer that also associates with the clathrin coat. Bacterially expressed recombinant amphiphysins inhibited both PLD1 and PLDS isozymes in vitro with a potency similar to that of brain amphiphysin (median inhibitory concentration of similar to 15 nM). Expressions of either amphiphysin in COS-7 cells reduced activity of endogenous PLD as well as exogenously expressed PLD1 and PLD2, Coprecipitation experiments suggested that the inhibitory effect of amphiphysins results from their direct interaction with PLDs. The NH2 terminus of amphiphysin I was critical for both inhibition of and binding to PLD. Phosphatidic acid formed by signal-induced PLD is thought to be required for the assembly of clathrin-coated vesicles during endocytosis, Thus, the inhibition of PLD by amphiphysins, synaptojanin, and AP180 might play an important role in synaptic vesicle trafficking. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. Ruhr Univ Bochum, Inst Physiol Chem, D-44780 Bochum, Germany. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 3,Rm 120,3 Ctr Dr,MSC 0320, Bethesda, MD 20892 USA. NR 55 TC 51 Z9 52 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 18751 EP 18758 DI 10.1074/jbc.M001695200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900021 PM 10764771 ER PT J AU Boyer, LA Logie, C Bonte, E Becker, PB Wade, PA Wolffe, AP Wu, C Imbalzano, AN Peterson, CL AF Boyer, LA Logie, C Bonte, E Becker, PB Wade, PA Wolffe, AP Wu, C Imbalzano, AN Peterson, CL TI Functional delineation of three groups of the ATP-dependent family of chromatin remodeling enzymes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID YEAST SWI/SNF COMPLEX; SWI-SNF COMPLEX; HISTONE DEACETYLASE; CORE PARTICLE; IN-VITRO; DNA; DROSOPHILA; PROTEIN; ISWI; BINDING AB ATP-dependent chromatin remodeling enzymes antagonize the inhibitory effects of chromatin. We com pare six different remodeling complexes: ySWI/SNF, yRSC, hSWI/SNF, xMi-2, dCHRAC, and dNURF. We find that each complex uses similar amounts of ATP to remodel nucleosomal arrays at nearly identical rates. We also perform assays with arrays reconstituted with hyperacetylated or trypsinized histones and isolated histone (H3/H4)(2) tetramers. The results define three groups of the ATP-dependent family of remodeling enzymes. In addition we investigate the ability of an acidic activator to recruit remodeling complexes to nucleosomal arrays. We propose that ATP-dependent chromatin remodeling enzymes share a common reaction mechanism and that a key distinction between complexes is in their mode of regulation or recruitment. C1 Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Biol, Worcester, MA 01605 USA. NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Adolf Butenandt Inst, D-80336 Munich, Germany. Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Peterson, CL (reprint author), Univ Massachusetts, Sch Med, Program Mol Med, 373 Plantat St,Biotech 2,Suite 301, Worcester, MA 01605 USA. RI Logie, Colin/A-1528-2010 OI Logie, Colin/0000-0002-8534-6582 FU NIGMS NIH HHS [GM49650, GM56244, R01 GM049650, R37 GM049650] NR 59 TC 94 Z9 94 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 18864 EP 18870 DI 10.1074/jbc.M002810200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900035 PM 10779516 ER PT J AU Liang, M Mallari, C Rosser, M Ng, HP May, K Monahan, S Bauman, JG Islam, I Ghannam, A Buckman, B Shaw, K Wei, GP Xu, W Zhao, Z Ho, E Shen, J Oanh, H Subramanyam, B Vergona, R Taub, D Dunning, L Harvey, S Snider, RM Hesselgesser, J Morrissey, MM Perez, HD Horuk, R AF Liang, M Mallari, C Rosser, M Ng, HP May, K Monahan, S Bauman, JG Islam, I Ghannam, A Buckman, B Shaw, K Wei, GP Xu, W Zhao, Z Ho, E Shen, J Oanh, H Subramanyam, B Vergona, R Taub, D Dunning, L Harvey, S Snider, RM Hesselgesser, J Morrissey, MM Perez, HD Horuk, R TI Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; TRANSPLANT REJECTION; MULTIPLE-SCLEROSIS; INDUCED ARTHRITIS; RANTES CHEMOKINE; T-CELLS; EXPRESSION; INTEGRIN AB The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471), Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1 alpha (MIP-1 alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K-i ranged from 1 nM to 5.5 nM), BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca2+ mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration, BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors, Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis, This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases. C1 Berlex Biosci, Dept Discovery Res, Richmond, CA 94804 USA. Berlex Biosci, Dept Biol Res, Richmond, CA 94804 USA. Berlex Biosci, Dept Pharmacol, Richmond, CA 94804 USA. Berlex Biosci, Dept Immunol, Richmond, CA 94804 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Liang, M (reprint author), Berlex Biosci, Dept Mol Pharmacol, 15049 San Pablo Ave, Richmond, CA 94804 USA. NR 39 TC 140 Z9 144 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 19000 EP 19008 DI 10.1074/jbc.M001222200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900052 PM 10748002 ER PT J AU Yang, FQ Zhang, TY Liu, QH Xu, GQ Zhang, YB Zhang, S Ito, Y AF Yang, FQ Zhang, TY Liu, QH Xu, GQ Zhang, YB Zhang, S Ito, Y TI Preparative isolation and purification of notopterol and isoimperatorin from Notopterygium forbessi boiss (Chinese traditional medicinal herb) by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; Notopterygium forbessi; pharmaceutical analysis; notopterol; isoimperatorin; coumarins ID CRUDE DRUG; HUO AB Preparative high-speed counter-current chromatography was successfully used for isolation and purification of coumarins from Chinese traditional medicinal herb Notopterygium forbessi Boiss (Qianghuo in Chinese) using stepwise elution with a pair of two-phase solvent systems composed of light petroleum-ethyl acetate-methanol-water at volume ratios of 5:5:4.8:5 and 5:5:5:4. Four major components including notopterol and isoimperatorin were isolated, each at over 98% purity. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Yang, FQ (reprint author), Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. NR 6 TC 47 Z9 49 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 23 PY 2000 VL 883 IS 1-2 BP 67 EP 73 DI 10.1016/S0021-9673(00)00359-9 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 330GN UT WOS:000087954600006 PM 10910201 ER PT J AU Gillette, WK Martin, RG Rosner, JL AF Gillette, WK Martin, RG Rosner, JL TI Probing the Escherichia coli transcriptional activator MarA using alanine-scanning mutagenesis: Residues important for DNA binding and activation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE marbox; backbone contacts; RNA polymerase; hydrophobic core; AraC ID MULTIPLE ANTIBIOTIC-RESISTANCE; ARAC FAMILY; PROTEIN; PROMOTERS; ORIENTATION; REPRESSOR; REGULATOR; REGULON; CORE; SOXS AB The MarA transcriptional activator binds to a 20 bp asymmetric degenerate sequence (marbox) located at different positions and orientations within the promoters of the genes of the Escherichia coli mar regulon. Solution of the MarA-marbox X-ray crystallographic structure suggested the presence of base-specific and non-specific interactions between the marbox and two helix-turn-helix (HTH) motifs on the monomeric MarA. Here, we use alanine-scanning mutagenesis and DNA retardation analysis to: (i) evaluate the contacts between MarA and the marboxes of five differently configured mau regulon promoters; (ii) assess the role of conserved hydrophobic amino acid residues for MarA activity; and (iii) identify residues required for RNA polymerase activation. These analyses revealed that the phosphate-backbone contacts and hydrogen bonds with the bases of the marbox are more significant for DNA binding than are the van der Waals interactions. While both N and C-terminal HTH motifs make essential contributions to binding site affinity, MarA is more sensitive to alterations in the N-terminal HTH. In a similar way, the activity of MarA is more sensitive to alterations in the hydrophobic core of this HTH. Solvent-exposed amino acid residues located at many positions on the MarA surface are important for activity. Some of these residues affect activity on all promoters and thus, are implicated in maintaining MarA structure whereas several solvent-exposed amino acids not involved in DNA binding were important for MarA activity on specific promoters. The pattern of activation defects defined a class II promoter-specific activating region. However, a localized class I activating region was not apparent. These results suggest that MarA activates transcription by at least two distinct mechanisms. Furthermore, the important role of phosphate contacts in marbox affinity suggests that indirect readout contributes to binding site recognition by MarA. (C) 2000 Academic Press. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gillette, WK (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room 230, Bethesda, MD 20892 USA. NR 19 TC 28 Z9 28 U1 0 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 23 PY 2000 VL 299 IS 5 BP 1245 EP 1255 DI 10.1006/jmbi.2000.3827 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 328HJ UT WOS:000087844400008 PM 10873449 ER PT J AU Jeohn, GH Chang, RCC Kim, WG Wilson, B Mohney, RP Wetsel, WC Hong, JS AF Jeohn, GH Chang, RCC Kim, WG Wilson, B Mohney, RP Wetsel, WC Hong, JS TI Post-transcriptional inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by Go6976 in murine microglia SO MOLECULAR BRAIN RESEARCH LA English DT Article DE go6976; iNOS; PKC; microglia; post-transcription; glia; lipopolysaccharide ID PROTEIN-KINASE-C; TYROSINE KINASE; GLIAL-CELLS; INTERFERON-GAMMA; TNF-ALPHA; INDUCTION; MACROPHAGES; CULTURES; INVOLVEMENT; ASTROCYTES AB Glia in the brain respond to various toxins with an increased expression of inducible nitric oxide synthase (iNOS) and an increased production of nitric oxide (NO). Hen, we report that lipopolysaccharide (LPS)-induced expression of iNOS was down-regulated post-transcriptionally through the destabilization of iNOS mRNA by the indolocarbazole compound, Go6976, in murine microglia. This Go6976 effect is specific for iNOS since tumor necrosis factor alpha was unaffected by the compound. Interestingly, the post-transcriptional effects ascribed to Go6976 were not observed with other inhibitors of protein kinase A, C (PKC), G, or protein tyrosine kinases. Instead, these kinases appear to affect the iNOS/NO system at the transcriptional level. In the past, Go6976 has been reported to be a rather specific inhibitor of PKC in vitro. Results from our experiments, through prolonged treatment with phorbol esters and with the various PKC inhibitors including phorbol ester-insensitive PKC isotype inhibitor, suggest that the Go6976-mediated post-transcriptional regulation of iNOS gene expression and NO production in microglia is not mediated through its reputed effects on PKC activity. Since the effects of various neurotoxins and certain neurodegenerative diseases may be manifested through alterations in the iNOS/NO system, post-transcriptional control of this system may represent a novel strategy for therapeutic intervention. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, Neuropharmacol Sect, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med Endocrinol, Durham, NC 27710 USA. RP Jeohn, GH (reprint author), NIEHS, Neuropharmacol Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Chang, Raymond Chuen-Chung/C-1107-2009 OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993 NR 44 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 23 PY 2000 VL 79 IS 1-2 BP 18 EP 31 DI 10.1016/S0169-328X(00)00081-4 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000002 ER PT J AU Jeohn, GH Wilson, B Wetsel, WC Hong, JS AF Jeohn, GH Wilson, B Wetsel, WC Hong, JS TI The indolocarbazole Go6976 protects neurons from lipopolysaccharide/intesferon-gamma-induced cytotoxicity in murine neuron/glia co-cultures SO MOLECULAR BRAIN RESEARCH LA English DT Article DE neurotoxicity; glia; lipopolysaccharide; endotoxin; neuroprotection; protein kinase C ID NITRIC-OXIDE SYNTHASE; TYROSINE KINASE INHIBITORS; GLIAL-CELLS; SELECTIVE INHIBITORS; EXPRESSION; INDUCTION; POTENT; ASTROCYTES; INJURY; NEUROTOXICITY AB The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) after exposure to endotoxins has been implicated in immune-mediated neurotoxicity. The indolocarbazole compound Go6976, which has been described as a selective protein kinase C (PKC) inhibitor in vitro, rescued neurons from lipopolysaccharide/interferon-gamma (LPS/IFN gamma)- or interleukin-1 alpha/tumor necrosis alpha/IFN gamma (IL-1 alpha/TNF alpha/IFN gamma)-induced cytotoxicity in murine primary neuron-glia co-cultures. Other compounds known to inhibit PE;C, Ro31-8220, GF109203X, Go7874, H7, staurosporine and H89, failed to rescue neurons from the LPS/IFN gamma-induced cytotoxicity. These results suggest that the neuroprotection by Go6976 from the LPS/IFN gamma-induced neuronal cell death is not mediated through its reputed effects on PKC activity. The neuroprotection paralleled the inhibition of iNOS gene expression and NO production. However, further analyses correlating NO production with the extent of neurotoxicity suggested that additional mechanism(s) besides the inhibition of the iNOS/NO system may be responsible for the neuroprotective effects of Go6976. An understanding of the mechanism underlying the neuroprotective effect of Go6976 may provide key insights into potential interventions for immune-mediated neurodegenerative diseases. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, Lab Pharmacol & Chem, Neuropharmacol Sect, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med Endocrinol, Durham, NC 27710 USA. RP Jeohn, GH (reprint author), NIEHS, Lab Pharmacol & Chem, Neuropharmacol Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 33 TC 17 Z9 17 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 23 PY 2000 VL 79 IS 1-2 BP 32 EP 44 DI 10.1016/S0169-328X(00)00082-6 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000003 ER PT J AU Zollner, C Johnson, PS Wang, DB Roy, AJ Layton, KM Wu, JM Surratt, CK AF Zollner, C Johnson, PS Wang, DB Roy, AJ Layton, KM Wu, JM Surratt, CK TI Control of mu opioid receptor expression by modification of cDNA 5 '- and 3 '-noncoding regions SO MOLECULAR BRAIN RESEARCH LA English DT Article DE opioid; morphine; G protein; untranslated region; regulation; expression ID 3' UNTRANSLATED REGION; MESSENGER-RNA DEGRADATION; DEPENDENT PROTEIN-KINASE; AU-RICH ELEMENT; TRANSCRIPTION TERMINATION; TRANSLATIONAL REGULATION; ESCHERICHIA-COLI; OPIATE RECEPTOR; POLY(A) TAIL; DESENSITIZATION AB Removal of a 712 base pair (bp) sequence following the coding region of a human mu opioid receptor (h mu OR) cDNA unexpectedly increased expression of the receptor protein. A series of 3'-noncoding region deletion mutants revealed that at least three discrete regions following the stop codon influenced receptor expression levels. Deletion of the 205-bp 5'-noncoding region immediately preceding the Kozak sequence doubled receptor expression relative to wild type, and simultaneous deletion of 5'- and 3'-noncoding regions increased expression several fold. The h mu OR noncoding regions may participate in a regulatory mechanism that controls the number of cell surface receptors. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Psychiat, Bronx, NY 10461 USA. RP Surratt, CK (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, 1410 Pelham Pkwy S, Bronx, NY 10461 USA. NR 35 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 23 PY 2000 VL 79 IS 1-2 BP 159 EP 162 DI 10.1016/S0169-328X(00)00100-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000016 ER PT J AU Mima, T Matsuoka, T Hallett, M AF Mima, T Matsuoka, T Hallett, M TI Functional coupling of human right and left cortical motor areas demonstrated with partial coherence analysis SO NEUROSCIENCE LETTERS LA English DT Article DE partial coherence; electroencephalography; interhemispheric coherence; Mu rhythm ID VOLUME CONDUCTION; EEG; SYNCHRONIZATION; MECHANISM; CORTEX AB Although a linear correlation between oscillatory activities in the right and left motor cortices during movements has been shown in monkeys, there has been a debate whether scalp-recorded EEG coherence in human reflects a similar association. By applying partial coherence analysis, we demonstrated that interhemispheric coherence during movements cannot be explained by contamination from the occipital alpha rhythm or common reference signal. A significant increase of net interhemispheric communication in the beta1 band was shown during movements. We propose that the partial coherence method can be a useful tool to measure cortico-cortical functional coupling reliably. (C) Published by Elsevier Science Ireland Ltd. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC1428, Bethesda, MD 20892 USA. OI Mima, Tatsuya/0000-0001-7787-4855 NR 20 TC 95 Z9 96 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 23 PY 2000 VL 287 IS 2 BP 93 EP 96 DI 10.1016/S0304-3940(00)01165-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 327QT UT WOS:000087804800004 PM 10854720 ER PT J AU Stover, CK Warrener, P VanDevanter, DR Sherman, DR Arain, TM Langhorne, MH Anderson, SW Towell, JA Yuan, Y McMurray, DN Kreiswirth, BN Barry, CE Baker, WR AF Stover, CK Warrener, P VanDevanter, DR Sherman, DR Arain, TM Langhorne, MH Anderson, SW Towell, JA Yuan, Y McMurray, DN Kreiswirth, BN Barry, CE Baker, WR TI A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis SO NATURE LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; F-420-DEPENDENT GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; MYCOLIC ACIDS; METRONIDAZOLE; BIOSYNTHESIS; MECHANISM; SMEGMATIS; BACILLI AB Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually(1). Estimates indicate that one-third of the world population is infected with latent M. tuberculosis(2). The synergy between tuberculosis and the AIDS epidemic(3-5), and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrug-resistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis. C1 PathoGenesis Corp, Seattle, WA 98119 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Pathobiol, Seattle, WA 98195 USA. Texas A&M Univ, Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. Publ Hlth Res Inst City New York Inc, TB Ctr, New York, NY 10016 USA. NIAID, TB Res Sect, Host Def Lab, NIH, Rockville, MD 20852 USA. RP Stover, CK (reprint author), PathoGenesis Corp, 201 Elliott Ave W, Seattle, WA 98119 USA. RI Barry, III, Clifton/H-3839-2012; OI Stover, Charles/0000-0002-7406-1696; VanDevanter, Donald/0000-0002-5727-8164 FU Intramural NIH HHS [Z01 AI000693-15] NR 24 TC 556 Z9 585 U1 3 U2 30 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 22 PY 2000 VL 405 IS 6789 BP 962 EP 966 DI 10.1038/35016103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 326JT UT WOS:000087732700054 PM 10879539 ER PT J AU Raman, V Martensen, SA Reisman, D Evron, E Odenwald, WF Jaffee, E Marks, J Sukumar, S AF Raman, V Martensen, SA Reisman, D Evron, E Odenwald, WF Jaffee, E Marks, J Sukumar, S TI Compromised HOXA5 function can limit p53 expression in human breast tumours SO NATURE LA English DT Article ID REGULATORY REGIONS; GENE-EXPRESSION; CANCER; MUTATIONS; APOPTOSIS; ASSAY AB Expression of the p53 gene protects cells against malignant transformation(1,2). Whereas control of p53 degradation has been a subject of intense scrutiny, little is known about the factors that regulate p53 synthesis(1,2). Here we show that p53 messenger RNA levels are low in a large proportion of breast tumours. Seeking potential regulators of p53 transcription, we found consensus HOX binding sites(3,4) in the p53 promoter(5). Transient transfection of Hox/HOXA5 activated the p53 promoter. Expression of HOXA5 in epithelial cancer cells expressing wild-type p53, but not in isogenic variants lacking the p53 gene(6), led to apoptotic cell death. Moreover, breast cancer cell lines and patient tumours display a coordinate loss of p53 and HOXA5 mRNA and protein expression. The HOXA5 promoter region was methylated in 16 out of 20 p53-negative breast tumour specimens. We conclude that loss of expression of p53 in human breast cancer may be primarily due to lack of expression of HOXA5. C1 Johns Hopkins Oncol Ctr, Breast Canc Program, Baltimore, MD 21231 USA. Univ S Carolina, Columbia, SC 29208 USA. NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Sukumar, S (reprint author), Johns Hopkins Oncol Ctr, Breast Canc Program, Baltimore, MD 21231 USA. NR 28 TC 305 Z9 331 U1 3 U2 18 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 22 PY 2000 VL 405 IS 6789 BP 974 EP 978 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 326JT UT WOS:000087732700057 PM 10879542 ER PT J AU Giannakakou, P Poy, G Zhan, ZR Knutsen, T Blagosklonny, MV Fojo, T AF Giannakakou, P Poy, G Zhan, ZR Knutsen, T Blagosklonny, MV Fojo, T TI Paclitaxel selects for mutant or pseudo-null p53 in drug resistance associated with tubulin mutations in human cancer SO ONCOGENE LA English DT Article DE paclitaxel; p53; tubulin; drug resistance; human cancer ID ANTICANCER-DRUG; P53-EXPRESSING ADENOVIRUS; GENOMIC INSTABILITY; HUMAN-CELLS; GENE; TAXOL; SENSITIVITY; CHECKPOINT; EXPRESSION; APOPTOSIS AB The efficacy of anticancer therapy is limited by the development of drug resistance. While the role of p53 in the intrinsic sensitivity of human cancer cells to paclitaxel (PTX) remains controversial, its role in acquired paclitaxel resistance has never been addressed. In this study me examined the p53 status of three paclitaxel selected human ovarian carcinoma sublines, resistant to paclitaxel due to acquired P-tubulin mutations which impair paclitaxel's interaction with tubulin, In contrast to parental cells which have wt p53, in all PTX-resistant sublines p53 was functionally inactive. Two of the resistant sublines expressed high levels of transcriptionally inactive p53 protein, each with a distinct point mutation in codons 236 and 239 of the DNA binding domain. The third subline presented a novel p53 pseudo-null phenotype as a result of markedly decreased wt p53 mRNA expression, Introduction of ectopic wt p53 had no effect on PTX sensitivity in both parental and resistant cells, while it induced p21(WAF1/CIP1), demonstrating an intact p53 pathway, While PTX resistance is primarily conferred by the tubulin mutations, the loss of functional p53 observed in all clones, suggests that this loss may facilitate the development of resistance potentially by providing a clonal advantage which promotes the isolation of paclitaxel resistant cells. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Giannakakou, P (reprint author), NCI, Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. OI Giannakakou, Paraskevi/0000-0001-7378-262X NR 33 TC 51 Z9 53 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 22 PY 2000 VL 19 IS 27 BP 3078 EP 3085 DI 10.1038/sj.onc.1203642 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 329JM UT WOS:000087903900005 PM 10871860 ER PT J AU Hooper, JD Bowen, N Marshall, H Cullen, LM Sood, R Daniels, R Stuttgen, MA Normyle, JF Higgs, DR Kastner, DL Ogbourne, SM Pera, MF Jazwinska, EC Antalis, TM AF Hooper, JD Bowen, N Marshall, H Cullen, LM Sood, R Daniels, R Stuttgen, MA Normyle, JF Higgs, DR Kastner, DL Ogbourne, SM Pera, MF Jazwinska, EC Antalis, TM TI Localization, expression and genomic structure of the gene encoding the human serine protease testisin SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE serine protease; testis; premeiotic spermatocyte; PRSS21; testisin; tumor suppressor ID CHROMOSOMAL LOCALIZATION; MESSENGER-RNA; CPG ISLAND; MAST-CELLS; TRANSCRIPTION; LOCUS; METHYLATION; SEQUENCE; PROTEINS; DISEASE AB Testisin is a recently identified human serine protease expressed by premeiotic testicular germ cells and is a candidate tumor suppressor for testicular cancer. Here, we report the characterization of the gene encoding testisin, designated PRSS21, and its localization on the short arm of human chromosome 16 (16p13.3) between the microsatellite marker D16S246 and the radiation hybrid breakpoint CY23HA. We have further refined the localization to cosmid 406D6 in this interval and have established that the gene is approximately 4.5 kb in length, and contains six exons and five intervening introns. The structure of PRSS21 is very similar to the human prostasin gene (PRSS8) which maps nearby on 16p11.2, suggesting that these genes may have evolved through gene duplication. Sequence analysis showed that the two known isoforms of testisin are generated by alternative pre-mRNA splicing. A major transcription initiation site was identified 97 nucleotides upstream of the testisin translation start and conforms to a consensus initiator element. The region surrounding the transcription initiation site lacks a TATA consensus sequence, but contains a CCAAT sequence and includes a CpG island. The 5'-flanking region contains several consensus response elements including Sp1, AP1 and several testis-specific elements. Analysis of testisin gene expression in tumor cell lines shows that testisin is not expressed in testicular tumor cells but is aberrantly expressed in some tumor cell lines of non-testis origin. These data provide the basis for identifying potential genetic alterations of PRSS21 that may underlie both testicular abnormalities and tumorigenesis. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Queensland Inst Med Res, Cellular Oncol Lab, Brisbane, Qld 4029, Australia. Univ Queensland, Brisbane, Qld 4029, Australia. Queensland Inst Med Res, Clin Sci Unit, Brisbane, Qld 4029, Australia. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Inst Mol Med, Mol Haematol Unit, Oxford OX3 9DS, England. Monash Univ, Monash Med Ctr, Inst Reprod & Dev, Clayton, Vic 3168, Australia. RP Antalis, TM (reprint author), Queensland Inst Med Res, Cellular Oncol Lab, PO Royal Brisbane Hosp, Brisbane, Qld 4029, Australia. RI Hooper, John/B-4153-2011; PERA, MARTIN/A-9812-2012; Hooper, John/C-1481-2016 OI PERA, MARTIN/0000-0001-6239-0428; Hooper, John/0000-0003-1054-8486 NR 45 TC 30 Z9 31 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JUN 21 PY 2000 VL 1492 IS 1 BP 63 EP 71 DI 10.1016/S0167-4781(00)00071-3 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 329TJ UT WOS:000087924000007 PM 11004480 ER PT J AU Kwon, SY Carlson, BA Park, JM Lee, BJ AF Kwon, SY Carlson, BA Park, JM Lee, BJ TI Structural organization and expression of the gaegurin 4 gene of Rana rugosa SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE gaegurin 4; antimicrobial peptide; promoter; innate immunity; nuclear factor kappa B/dl ID KAPPA-B; ANTIMICROBIAL PEPTIDES; INNATE IMMUNITY; DROSOPHILA IMMUNITY; MOLECULAR-CLONING; INSECT IMMUNITY; PROMOTER; DEFENSE; SKIN; MICROORGANISMS AB Gaegurin 4 (GGN4) is a member of the antimicrobial peptide subfamily isolated from the skin of Rana rugosa. We cloned gDNA encoding GGN4 to study its gene organization and regulation of expression. The GGN4 gene occurs in single copy in the R. rugosa genome and contains a single intron of about 3.4 kb. The transcription start site is located 68 bases upstream of the translation initiation codon. The GGN4 gene was expressed both in Xenopus kidney epithelial cells (A6) and in Xenopus oocytes using the chloramphenicol acetyltransferase reporter gene system. The 5' flanking region of the GGN4 gene contains a dl binding site that is known to regulate acute phase immune response related gene expression in mammals and insects. The dl protein bound specifically to the GGN4 gene promoter region. Mutants that serially delete the 5' flanking region show that removal of the dl binding site inhibited GGN4 gene expression in both A6 cells and Xenopus oocytes. From these results, we propose that expression of the GGN4 gene may be regulated by the region containing the dl element which plays a key role in the regulation of antimicrobial peptide genes in Drosophila and mammals. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Seoul Natl Univ, Inst Mol Biol & Genet, Mol Genet Lab, Seoul 151742, South Korea. NCI, Sect Mol Biol Selenium, Lab Basic Res, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Inst Mol Biol & Genet, Mol Genet Lab, Seoul 151742, South Korea. RI Kwon, So Yeon/M-5625-2014 OI Kwon, So Yeon/0000-0002-8490-9101 NR 24 TC 10 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JUN 21 PY 2000 VL 1492 IS 1 BP 185 EP 190 DI 10.1016/S0167-4781(00)00082-8 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 329TJ UT WOS:000087924000021 PM 11004488 ER PT J AU Alberts, MJ Hademenos, G Latchaw, RE Jagoda, A Marler, JR Mayberg, MR Starke, RD Todd, HW Viste, KM Girgus, M Shephard, T Emr, M Shwayder, P Walker, MD AF Alberts, MJ Hademenos, G Latchaw, RE Jagoda, A Marler, JR Mayberg, MR Starke, RD Todd, HW Viste, KM Girgus, M Shephard, T Emr, M Shwayder, P Walker, MD CA Brain Attack Coalition TI Recommendations for the establishment of primary stroke centers SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE ISCHEMIC STROKE; TISSUE-PLASMINOGEN ACTIVATOR; AMERICAN-HEART-ASSOCIATION; HEALTH-CARE-PROFESSIONALS; SPECIAL-WRITING-GROUP; UNITED-STATES; TRAUMA CENTER; COST-EFFECTIVENESS; FIRST-EVER; MANAGEMENT AB Objective To develop recommendations for the establishment and operation of primary stroke centers as an approach to improve the medical care of patients with stroke. Participants Members of the Brain Attack Coalition (BAC), a multidisciplinary group of representatives from major professional organizations involved with delivering stroke care. Supplemental input was obtained from other experts involved in acute stroke care. Evidence A review of literature published from 1966 to March 2000 was performed using MEDLINE. More than 600 English-language articles that had evidence from randomized clinical trials, meta-analyses, care guidelines, or other appropriate methods supporting specific care recommendations for patients with acute stroke that could be incorporated into a stroke center model were selected. Consensus Process Articles were reviewed initially by 1 author (M.J.A.). Members of the BAC reviewed each recommendation in the context of current practice parameters, with special attention to improving the delivery of care to patients with acute stroke, cost-effectiveness, and logistical issues related to the establishment of primary stroke centers. Consensus was reached among all BAC participants before an element was added to the list of recommendations. Conclusions Randomized clinical trials and observational studies suggest that several elements of a stroke center would improve patient care and outcomes. Key elements of primary stroke centers include acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. Important support services include availability and interpretation of computed tomography scans 24 hours everyday and rapid laboratory testing. Administrative support, strong leadership, and continuing education are also important elements for stroke centers. Adoption of these recommendations may increase the use of appropriate diagnostic and therapeutic modalities and reduce peristroke complications. The establishment of primary stroke centers has the potential to improve the care of patients with stroke. C1 Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. Amer Heart Assoc, Dallas, TX USA. Univ Miami, Sch Med, Dept Radiol, Miami, FL USA. Mt Sinai Med Ctr, Dept Emergency Med, New York, NY 10029 USA. NINDS, NIH, Rockville, MD USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. Natl Stroke Assoc, Englewood, CO USA. Lakeside Neurocare, Oshkosh, WI USA. Virginia Commonwealth Univ, Ctr Neurosci, Richmond, VA USA. Med Coll Virginia Hosp, Richmond, VA USA. RP Alberts, MJ (reprint author), Duke Univ, Med Ctr, Div Neurol, POB 3392,Bryan Res Bldg,Room 227E, Durham, NC 27710 USA. OI Mayberg, Marc/0000-0002-6718-7143 NR 68 TC 407 Z9 417 U1 4 U2 35 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 21 PY 2000 VL 283 IS 23 BP 3102 EP 3109 DI 10.1001/jama.283.23.3102 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 323PV UT WOS:000087574900035 PM 10865305 ER PT J AU Taktakishvili, M Neamati, N Pommier, Y Pal, S Nair, V AF Taktakishvili, M Neamati, N Pommier, Y Pal, S Nair, V TI Recognition and inhibition of HIV integrase by novel dinucleotides SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL-DNA; ISOMERIC DIDEOXYNUCLEOSIDES; PHOSPHOTRIESTER APPROACH; ANTIVIRAL AGENTS; CHEMOTHERAPY; DOMAIN; SITE AB HIV integrase is involved in the integration of viral DNA into chromosomal DNA, a biological process that occurs by a sequence involving HIV DNA splicing and subsequent integration steps. in the quest for small nucleotide systems with nuclease stability of the internucleotide phosphate bond and critical structural features for recognition and inhibition of HIV-1 integrase, we have discovered novel, nuclease-resistant dinucleotides with defined base sequences that are inhibitors of this key viral enzyme. Synthetic methodologies utilized for the syntheses of the novel dinucleotides include an excellent new phosphorylating agent. C1 Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. NCI, Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Nair, V (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. NR 34 TC 42 Z9 43 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 21 PY 2000 VL 122 IS 24 BP 5671 EP 5677 DI 10.1021/ja992528d PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 328HX UT WOS:000087845700001 ER PT J AU Orr, MS O'Connor, PM Kohn, KW AF Orr, MS O'Connor, PM Kohn, KW TI Effects of c-erbB2 overexpression on the drug sensitivities of normal human mammary epithelial cells SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NEGATIVE BREAST-CANCER; ADJUVANT THERAPY; ERBB-2; DOXORUBICIN; EXPRESSION; CARCINOMA; HER-2/NEU; RECEPTOR; KINASE; LINES AB Background: Overexpression of the gene c-erbB2, which encodes a receptor tyrosine kinase, in breast tumors has been linked with either increased or decreased response of breast cancer patients to various therapies. In breast cancer cell lines, overexpression of exogenous c-erbB2 sometimes alters drug sensitivities but sometimes has no effect. To avoid the genetic complexities associated with established cancer cell lines, normal human mammary epithelial cells (HMECs) were studied to determine whether c-erbB2 overexpression by itself would alter chemosensitivity. Methods: HMECs were designed to overexpress c-erbB2, and these cells were then evaluated for alterations in chemosensitivity. Results: HMECs overexpressing c-erbB2 failed to show any alterations in chemosensitivity to a panel of chemotherapeutic agents, as indicated by 95% confidence intervals on growth curves of cells treated with or without the agent of interest, With the use of fluorescence-activated cell sorting to enrich for HMECs overexpressing c-erbB2 on their surface, an 85% pure population of cells was isolated and their chemosensitivity was evaluated. Again, the cells failed to display any alterations in chemosensitivity. Conclusions: These results suggest that overexpression of c-erbB2 is not sufficient by itself to induce changes in chemosensitivity. Cellular studies using normal human cells in which the complexity of the system can be carefully controlled by the addition of one, two, or even more genes associated with cancer development may provide valuable information about how the products of the genes interact with each other and which combinations are critical in regulating chemosensitivity. C1 Gene Log Inc, Gaithersburg, MD 20878 USA. Agouron Pharmaceut Inc, San Diego, CA USA. NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Orr, MS (reprint author), Gene Log Inc, 708 Quince Orchard Rd, Gaithersburg, MD 20878 USA. NR 31 TC 27 Z9 28 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 21 PY 2000 VL 92 IS 12 BP 987 EP 994 DI 10.1093/jnci/92.12.987 PG 8 WC Oncology SC Oncology GA 326KX UT WOS:000087735600011 PM 10861310 ER PT J AU Goldstein, AM Struewing, JP Chidambaram, A Fraser, MC Tucker, MA AF Goldstein, AM Struewing, JP Chidambaram, A Fraser, MC Tucker, MA TI Genotype-phenotype relationships in US melanoma-prone families with CDKN2A and CDK4 mutations SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GERMLINE MUTATIONS; PANCREATIC-CANCER; P16; RISK; KINDREDS AB Background: Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer. Methods: We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families, We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi, The three recurrent mutations were haplotyped, All P values were two-sided. Results: The median age at CMM diagnosis (P = .70) and the median numbers of CMMs (P = .73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P =. 80) or in tumor number (P = .24), There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P = .004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi, Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3), Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes, Conclusions: The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD USA. RP Goldstein, AM (reprint author), NIH, Execut Plaza S,Rm 7004,6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 21 TC 114 Z9 115 U1 1 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 21 PY 2000 VL 92 IS 12 BP 1006 EP 1010 DI 10.1093/jnci/92.12.1006 PG 5 WC Oncology SC Oncology GA 326KX UT WOS:000087735600014 PM 10861313 ER PT J AU Cox, JT Koutsky, L Schiffman, M Solomon, D AF Cox, JT Koutsky, L Schiffman, M Solomon, D TI Re: Emerging technologies and cervical cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Univ Calif Santa Barbara, Colposcopy Qual Control Grp, Santa Barbara, CA 93106 USA. Univ Washington, HPV Res Grp, Seattle, WA 98195 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Solomon, D (reprint author), NIH, Execut Plaza N,Rm 233, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 21 PY 2000 VL 92 IS 12 BP 1014 EP 1014 DI 10.1093/jnci/92.12.1014 PG 1 WC Oncology SC Oncology GA 326KX UT WOS:000087735600016 PM 10861315 ER PT J AU Yeo, AET Matsumoto, A Hisada, M Shih, JW Alter, HJ Goedert, JJ AF Yeo, AET Matsumoto, A Hisada, M Shih, JW Alter, HJ Goedert, JJ CA Multictr Hemophilia Cohort Study TI Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; C VIRUS; CYTOMEGALOVIRUS-INFECTION; DISEASE PROGRESSION; AIDS; COINFECTION; RISK; RNA AB Background: Infection with hepatitis G virus (HGV), also known as GB virus C, is prevalent but is not known to be associated with any chronic disease. Infection with HGV may affect the risk for AIDS in HIV-infected persons. Objective: To compare AIDS-free survival in patients with and those without HGV infection during 16 years of followup after HIV seroconversion. Design: Subanalysis of a prospective cohort study. Setting: Comprehensive hemophilia treatment centers in the United States and Europe. Patients: 131 patients with hemophilia who became HIV-positive between 1978 and 1985. Measurements: Age, CCR5 genotype, HIV and HCV viral loads, CD4(+) and CD8(+) lymphocyte counts, and 12-year AIDS-free survival by HGV positivity (viremia [RNA] or anti-E2 antibodies). Results: Compared with HGV-negative patients, the 60 HGV-positive patients (46%), including 22 who were positive for HGV RNA, had higher CD4(+) lymphocyte counts (difference, 211 cells/mm(3) [95% CI, 88 to 333 cells/mm(3)]) and 12-year AIDS-free survival rates (68% compared with 40%; rate difference, 1.9 per 100 person-years [Cl, -0.3 to 4.2 per 100 person-years]), despite similar ages and HIV viral loads. In multivariate proportional hazards models, risk for AIDS was 40% lower for HCV-positive patients independent of age, HIV and HCV viral loads, CD4(+) and CD8(+) lymphocyte counts, and CCR5 genotype. Conclusions: Patients with past or current HGV infection have higher CD4(+) lymphocyte counts and better AIDS-free survival rates. The mechanism of this association is unknown. C1 NIH, Bethesda, MD 20892 USA. RP Goedert, JJ (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Blvd,Room 8012 MSC 7248, Rockville, MD 20852 USA. FU NCI NIH HHS [N01-CP-33002] NR 20 TC 83 Z9 86 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 20 PY 2000 VL 132 IS 12 BP 959 EP 963 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 325HU UT WOS:000087670800005 PM 10858179 ER PT J AU Ballestar, E Yusufzai, TM Wolffe, AP AF Ballestar, E Yusufzai, TM Wolffe, AP TI Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA SO BIOCHEMISTRY LA English DT Article ID HISTONE DEACETYLASE; CHROMATIN STRUCTURE; CHROMOSOMAL PROTEIN; GENE; COMPLEX AB We have investigated the properties of mutant forms of the methyl-CpG binding transcriptional repressor MeCP2 associated with Rett syndrome, a childhood neurodevelopmental disorder. We find that four Rett syndrome mutations at known sites within the methyl-CpG binding domain (MBD) impair binding to methylated DNA, but have little effect on nonspecific interactions with unmethylated DNA. Three of these mutations (R106W, R133C, and F155S) have their binding affinities for methylated DNA reduced more than 100-fold; this is consistent with the hypothesis that impaired selectivity for methylated DNA of mutant MeCP2 contributes to Rett syndrome. However, a fourth mutant, T158M, has its binding affinity for methylated DNA reduced only 2-fold, indicative either of additional distinct regulatory functions associated with the MBD or of an exquisite sensitivity of developing neurons to the selective association of MeCP2 with methylated DNA. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Genet, Washington, DC 20052 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. OI Ballestar, Esteban/0000-0002-1400-2440 NR 23 TC 85 Z9 87 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 20 PY 2000 VL 39 IS 24 BP 7100 EP 7106 DI 10.1021/bi0001271 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327DQ UT WOS:000087778300008 PM 10852707 ER PT J AU Garant, MJ Maksimova, E Montrose-Rafizadeh, C Lee-Kwon, W Kole, S Bernier, M AF Garant, MJ Maksimova, E Montrose-Rafizadeh, C Lee-Kwon, W Kole, S Bernier, M TI Cysteine 981 of the human insulin receptor is required for covalent cross-linking between beta-subunit and a thiol-reactive membrane-associated protein SO BIOCHEMISTRY LA English DT Article ID TYROSINE KINASE; 3T3-L1 ADIPOCYTES; HYDROGEN-PEROXIDE; PERMEABILIZED CELLS; CRYSTAL-STRUCTURE; BINDING PROTEIN; PHOSPHORYLATION; AUTOPHOSPHORYLATION; PATHWAYS; DOMAINS AB The cytoplasmic domain of the insulin receptor (IR) beta-subunit contains cysteine (Cys) residues whose reactivity and function remain uncertain. In this study, we examined the ability of the bifunctional cross-linking reagent 1,6-bismaleimidohexane (BMH) to covalently link IR with interacting proteins that possess reactive thiols, Transfected Chinese hamster ovary cells expressing either the wild-type human IR, C-terminally truncated receptors, or mutant receptors with Cys --> Ala substitutions and mouse 3T3-L1 adipocytes were used to compare the BMH effect. The results showed the formation of a large complex between the wild-type human receptor beta-subunit and molecule X, a thiol-reactive membrane-associated protein, in both intact and semipermeabilized cells in response to BMH. Prior cell stimulation with insulin had only a modest effect in this process. Western blot analysis revealed that the receptor alpha-subunit was not present in the beta-X complex. The BMH cross-linking did not inhibit in vitro tyrosine phosphorylation of the receptor complexed with molecule X. Both the human IR Cys981Ala mutant and murine IR, that lacks the equivalent of human Cys(981), failed to react, with BMH. Finally, Ilo covalent association between IR beta-subunit and IRS-1, the protein tyrosine phosphatase LAR or SHP-2 was observed in BMH-treated cells expressing the wild-type human IR. These results demonstrate a striking difference in reactivity among the cytoplasmic IR beta-subunit thiols and clearly show that Cys(981) of human IR beta-subunit is in close proximity to a thiol-reactive membrane-associated protein under basal and insulin-stimulated conditions. C1 NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, Clin Invest Lab, NIH, 5600 Nathan Shock Dr,Box 23, Baltimore, MD 21224 USA. OI Bernier, Michel/0000-0002-5948-368X NR 54 TC 4 Z9 4 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 20 PY 2000 VL 39 IS 24 BP 7178 EP 7187 DI 10.1021/bi992947n PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327DQ UT WOS:000087778300017 PM 10852716 ER PT J AU Huang, KP Huang, FL Li, JF Schuck, P McPhie, P AF Huang, KP Huang, FL Li, JF Schuck, P McPhie, P TI Calcium-sensitive interaction between calmodulin and modified forms of rat brain neurogranin/RC3 SO BIOCHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; NITRIC-OXIDE MODIFICATION; S-THIOLATION; BINDING-PROTEIN; CREATINE-KINASE; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; CIRCULAR-DICHROISM; RC3 PROTEIN; NEUROMODULIN; SUBSTRATE AB Neurogranin (NC) binding of calmodulin (CaM) at its IQ domain is sensitive to Ca2+ concentration and to modifications by protein kinase C (PKC) and oxidants. The PKC phosphorylation site of NG is within the IQ domain whereas the four oxidant-sensitive Cys residues are outside this region. These Cys residues were oxidized forming two pairs of intramolecular disulfides, and could also be glutathiolated by S-nitrosoglutathione resulting in the incorporation of four glutathiones per NG. Circular dichroism (CD) showed that modification of NG by phosphorylation, oxidation forming intramolecular disulfides, or glutathiolation did not affect the alpha-helical content of this protein. Mutation of the four Cys residues [Cys(-)-NG] to Gly and Ser did not affect the alpha-helical content either. Interaction of CaM with the reduced (red)-, glutathiolated (GS)-, or Cys(-)-NG in the Ca2+-free solution resulted in an increase in the cx-helicity determined by their CD spectra, but relatively little change was seen with the oxidized NG (ox-NG) or phosphorylated NG (PO4-NG). The binding affinities between the various modified forms of NG and CaM were determined by CD spectrometry and sedimentation equilibrium: their affinities were Cys(-)-NG > red-NG, CS-NG > ox-NC > PO4-NG. Unlike Cys(-)-, red-, and GS-NG, neither ox- nor PO4-NG bound to a CaM-affinity column. Thus, both oxidation of NG to form intramolecular disulfides and phosphorylation of NG by PKC are effective in modulating the intracellular level of CaM. These results indicate that modification of NG to form intramolecular disulfides outside the IQ domain provides an alternative mechanism fur regulation of its binding affinity to CaM. C1 NICHHD, Metab Regulat Sect,Endocrinol & Reprod Branch, Mol Interact Resource Bioengn & Phys Sci Program, ORS,NIH, Bethesda, MD 20892 USA. NIDDKD, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP NICHHD, Metab Regulat Sect,Endocrinol & Reprod Branch, Mol Interact Resource Bioengn & Phys Sci Program, ORS,NIH, Bldg 49,Room 6A36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM kphuang@helix.nih.gov RI Li, Junfa/H-8707-2013; OI Li, Junfa/0000-0002-1930-9724; Schuck, Peter/0000-0002-8859-6966 NR 44 TC 36 Z9 39 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 20 PY 2000 VL 39 IS 24 BP 7291 EP 7299 DI 10.1021/bi0003361 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327DQ UT WOS:000087778300030 PM 10852729 ER PT J AU Feit, F Brooks, MM Sopko, G Keller, NM Rosen, A Krone, R Berger, PB Shemin, R Attubato, MJ Williams, DO Frye, R Detre, KM AF Feit, F Brooks, MM Sopko, G Keller, NM Rosen, A Krone, R Berger, PB Shemin, R Attubato, MJ Williams, DO Frye, R Detre, KM CA BARI Investigators TI Long-term clinical outcome in the bypass angioplasty revascularization investigation registry comparison with the randomized trial SO CIRCULATION LA English DT Article DE atherosclerosis; coronary disease; angioplasty; bypass; revascularization ID CORONARY-ARTERY DISEASE; INVESTIGATION BARI; SURGERY AB Background-The Bypass Angioplasty Revascularization Investigation (BARI) included 4039 patients with multivessel coronary artery disease; 1829 consented to randomization, and 2010 did not but were followed up in a registry. Thus, we can evaluate the outcome of physician-guided versus random assignment of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG). Methods and Results-We compared the baseline features and outcomes for PTCA and CABG in the overall registry and its predesignated subgroups. We assessed the impact of treatment by choice versus random assignment by comparing the results in the registry with those of the randomized trial. Statistical adjustments for differences in baseline characteristics were made. Within the registry, nearly twice as many patients were selected for PTCA (1184) as CABG (625); mortality at 7 years was similar for PTCA (13.9%) and CABG (14.2%) (P=0.66) before and after adjustment for baseline differences between patients selected for PTCA versus CABG(adjusted RR, 1.02; P=0.86). In contrast to the randomized trial, the 7-year mortality rate of treated diabetics in the registry was equally high (26%) with PTCA or CABG. Seven-year mortality was higher for patients undergoing PTCA in the randomized trial than in the registry (19.1% versus 13.9%, P<0.01) but not for those undergoing CABG (15.6% versus 14.2%, P=0.57). The adjusted relative mortality risk for PTCA in the randomized versus registry population was 1.17 (P=0.16), Conclusions-BARI physicians were able to select PTCA rather than CABG for 65% of registry patients who underwent revascularization without compromising long-term survival either in the overall population or in treated diabetics. C1 NYU, Med Ctr, New York, NY 10016 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NHLBI, Bethesda, MD 20892 USA. Jewish Hosp St Louis, St Louis, MO 63110 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Boston Univ, Boston, MA 02215 USA. Rhode Isl Hosp, Providence, RI USA. RP Feit, F (reprint author), NYU, Med Ctr, 550 1St Ave,Room H576, New York, NY 10016 USA. OI Brooks, Maria/0000-0002-2030-7873 FU NHLBI NIH HHS [HL-38493, HL-38504, HL-38509] NR 18 TC 135 Z9 145 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 20 PY 2000 VL 101 IS 24 BP 2795 EP 2802 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 326JE UT WOS:000087731100005 PM 10859284 ER PT J AU Dasmahapatra, AK Wimpee, BAB Trewin, AL Wimpee, CF Ghorai, JK Hutz, RJ AF Dasmahapatra, AK Wimpee, BAB Trewin, AL Wimpee, CF Ghorai, JK Hutz, RJ TI Demonstration of 2,3,7,8-tetrachlorodibenzo-p-dioxin attenuation of P450 steroidogenic enzyme mRNAs in rat granulosa cell in vitro by competitive reverse transcriptase-polymerase chain reaction assay SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 81st Annual Meeting of the Endocrine-Society CY JUN 12-16, 1999 CL SAN DIEGO, CALIFORNIA SP Endocrine Soc DE TCDD; granulosa cells; steroidogenesis; competitive RT-PCR; estrogen ID MESSENGER-RIBONUCLEIC-ACID; IMPAIRS PROSTATE DEVELOPMENT; ARYL-HYDROCARBON RECEPTOR; HEPA 1C1C7 CELLS; ESTROGEN-RECEPTOR; LACTATIONAL EXPOSURE; IN-UTERO; ENVIRONMENTAL CONTAMINANTS; CYTOCHROME-P450 AROMATASE; CONSTITUTIVE EXPRESSION AB We investigated the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in prepubertal (PP) and adult (A) rat granulosa cells (GC) in vitro by examining the changes in estrogen secretion, aromatase enzyme activity and mRNAs for steroidogenic enzymes P450scc, 3 beta-HSDI, P450arom; and for components of the AHR signaling pathway-CYP1Al, aromatic hydrocarbon receptor (AHR), and the AHR nuclear translocator protein (ARNT). In PP and A rat GC, TCDD (3.1 nM) reduced estrogen secretion at 48 h without altering aromatase enzyme activity. Addition of FSH (50 ng/ml) increased aromatase activity in CC with or without TCDD. FSH-induced aromatase activity was significantly reduced by TCDD (3.1 nM) at 48 h. Semi-quantitative RT-PCR showed a significant increase in CYP1Al mRNA both at 24 and 48 h with TCAP, while a significant reduction in P450scc and P450arom mRNA was observed with competitive RT-PCR. All steroidogenic enzyme mRNAs were significantly lower in adults than in PP GC. We conclude that in rat GC, TCDD modulates the level of cytochrome P450 enzymes involved in the steroid biosynthetic cascade. This effect may be attributable to AHR interaction with dioxin-responsive elements present in the genes encoding these enzymes. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Wisconsin, NIEHS Marine & Freshwater Biomed Sci Ctr, Milwaukee, WI 53204 USA. Univ Wisconsin, Dept Math Sci, Milwaukee, WI 53204 USA. Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. RP Hutz, RJ (reprint author), Univ Wisconsin, NIEHS Marine & Freshwater Biomed Sci Ctr, Milwaukee, WI 53204 USA. FU NIEHS NIH HHS [ES08342, ES04184] NR 51 TC 59 Z9 63 U1 0 U2 3 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 JUN 20 PY 2000 VL 164 IS 1-2 BP 5 EP 18 DI 10.1016/S0303-7207(00)00245-8 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 346AR UT WOS:000088848400002 PM 11026553 ER PT J AU Qin, SF Stadtman, ER Chock, PB AF Qin, SF Stadtman, ER Chock, PB TI Regulation of oxidative stress-induced calcium release by phosphatidylinositol 3-kinase and Bruton's tyrosine kinase in B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PHOSPHOLIPASE C-GAMMA; RECEPTOR-MEDIATED ACTIVATION; EPIDERMAL GROWTH-FACTOR; SRC HOMOLOGY DOMAINS; SIGNAL-TRANSDUCTION; HYDROGEN-PEROXIDE; ANTIGEN RECEPTOR; PHOSPHOINOSITIDE 3-KINASE; C-GAMMA-2 ACTIVATION; PHOSPHATASE 1B AB Hydrogen peroxide stimulates a tyrosine kinase-dependent calcium release from intracellular stores, which is assumed to be achieved through the activation of phospholipase C gamma 2 (PLC gamma 2) via a tyrosine phosphorylation mechanism in B cells. Here we show that H2O2 induces both tyrosine phosphorylation on PLC gamma 2 and the activation of phosphatidylinositol 3-kinase (PI3K) in B cells, and that the phosphatidylinositol 3-kinase inhibitor, Wortmannin, partially inhibited the H2O2-induced calcium release without affecting tyrosine phosphorylation on PLC gamma 2. Overexpression of human Bruton's tyrosine kinase (Btk), which was activated by H2O2, almost completely overcame the inhibition of calcium release by Wortmannin, The reversal of Wortmannin's inhibition by enhancing Btk concentration seemed unique to the H2O2-mediated effect, because Btk failed to overcome the inhibition of Wortmannin on B cell receptor-triggered calcium mobilization. Immunoblot analysis revealed that Btk formed stable complexes with several tyrosine-phosphorylated proteins, including PLC gamma 2, only in Btk-overexpressed cells on H2O2 stimulation. Together, our data are consistent with the notion that PIP3 and/or a high concentration of Btk target the activated PLC gamma 2 to its substrate site for maximal catalytic efficiency. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Chock, PB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 204,3 Ctr Dr,MSC-0342, Bethesda, MD 20892 USA. NR 49 TC 47 Z9 47 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7118 EP 7123 DI 10.1073/pnas.130198197 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600037 PM 10840066 ER PT J AU Mukhopadhyay, S Chattoraj, DK AF Mukhopadhyay, S Chattoraj, DK TI Replication-induced transcription of an autorepressed gene: The replication initiator gene of plasmid P1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESCHERICHIA-COLI; DNA-REPLICATION; COPY NUMBER; NEGATIVE CONTROL; CHROMOSOME-REPLICATION; PROTEINS; BINDING; SEQUESTRATION; ORIGIN; SEQUENCES AB The replication origin of plasmid P1 contains an array of five repeats (iterons) that bind the plasmid-encoded initiator RepA, Within the array lies the repA promoter, which becomes largely repressed on RepA binding (autorepression). One might expect that extra iterons produced on plasmid replication would titrate RepA and release the repression. The promoter, however, is induced poorly by extra iterons, The pi copy number is reduced by extra iterons in the presence of the autorepressed repA gene but not when additional RepA is provided from constitutive sources. It has been proposed that the iteron-bound RepA couples with the promoter-bound RepA and thereby maintains repression. Although not the product of replication, we find that the act of replication itself can renew RepA synthesis. Replication apparently cleans the promoter of bound RepA and provides a window of opportunity for repA transcription, We propose that replication-induced transcription is required to ensure initiator availability in a system that is induced poorly when challenged with additional initiator binding sites. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Chattoraj, DK (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 31 TC 16 Z9 16 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7142 EP 7147 DI 10.1073/pnas.130189497 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600041 PM 10840063 ER PT J AU Li, SD Aufiero, B Schiltz, RL Walsh, MJ AF Li, SD Aufiero, B Schiltz, RL Walsh, MJ TI Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEAR RECEPTOR COACTIVATOR; DNA-BINDING; CUT REPEATS; TRANSCRIPTION FACTORS; GENE PROMOTER; ACETYLATION; DROSOPHILA; EXPRESSION; ACTIVATION; REPRESSION AB The CCAAT displacement protein/cut homologue (CDP/cut) is a divergent homeodomain protein that is highly conserved through evolution and has properties of a potent transcriptional repressor. CDP/cut contains three conserved cut-repeat domains and a conserved homeobox, each involved in directing binding specificity to unique nucleotide sequence elements. Furthermore, CDP/cut may play a role as a structural component of chromatin through its direct interaction with nucleosomal DNA and association with nuclear matrix attachment regions. CDP/cut is cell-cycle regulated through interactions with Rb, p107, specific kinases and phosphatases directing the transcriptional activity of CDP/cut on such genes encoding p21(WAF1,CIP1), c-myc, thymidine kinase, and histones. Our previous studies indicate that CDP/cut is associated with histone deacetylase activity and is associated with a corepressor complex through interactions with histone deacetylases, Here, we report the interaction of CDP/cut with CBP and p300/ CREB-binding protein-associated factor (PCAF) along with the modification of CDP/cut by the histone acetyltransferase PCAF, Acetylation of CDP/cut by PCAF is directed at conserved lysine residues near the homeodomain region and regulates CDP/cut function. These observations are consistent with the ability of CDP/cut to regulate genes as a transcriptional repressor, suggesting acetylation as a mechanism that regulates CDP/cut function. C1 NYU, Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. NICHHD, Lab Mol Growth Regulation, Sect Eukaryot Transcript Regulat, NIH, Bethesda, MD 20892 USA. RP Walsh, MJ (reprint author), NYU, Mt Sinai Sch Med, Dept Pediat, 1 Gustave L Levy Pl, New York, NY 10029 USA. NR 41 TC 48 Z9 48 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7166 EP 7171 DI 10.1073/pnas.130028697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600045 PM 10852958 ER PT J AU Kotani, T Banno, K Ikura, M Hinnebusch, AG Nakatani, Y Kawaichi, M Kokubo, T AF Kotani, T Banno, K Ikura, M Hinnebusch, AG Nakatani, Y Kawaichi, M Kokubo, T TI A role of transcriptional activators as antirepressors for the autoinhibitory activity of TATA box binding of transcription factor IID SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; HERPES-SIMPLEX VIRUS; ARTIFICIAL RECRUITMENT; PREINITIATION COMPLEX; DNA-BINDING; IN-VITRO; PROTEIN; DOMAIN; YEAST; TBP AB The TATA box-binding activity of transcription factor IID (TFIID) is autoinhibited by the N-terminal domain of the Drosophila TATA box-binding protein- (TBP) associated factor 230/yeast TBP-associated factor 145 subunit, which binds to the TATA box-binding domain of TBP by mimicking the TATA box structure. Here, we propose a mechanism of transcriptional activation that involves antirepression of this autoinhibitory activity by transcriptional activators. Like the autoinhibitory domain of TFIID, various acidic activators interact with the TATA box-binding domain of TBP. Moreover, the autoinhibitory domain of TFIID, which is known to interact with only the TATA box-binding domain of Tap, acts as an activation domain when fused to the GAL4 DNA-binding domain, indicating that interaction with the TATA-binding domain of TBP is crucial for activation of transcription. In a reciprocal fashion, the acidic activation domains can function as the autoinhibitory domain when the latter is replaced by the former within TFIID. These results indicate that activation domains and the autoinhibitory domain of TFIID are interchangeable. supporting a role for transcriptional activators as antirepressors of the autoinhibitory activity of the TATA box binding of TFIID. C1 Nara Inst Sci & Technol, Div Gene Funct Anim, Nara 6300101, Japan. Univ Toronto, Ontario Canc Inst, Div Mol & Struct Biol, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Kokubo, T (reprint author), Nara Inst Sci & Technol, Div Gene Funct Anim, 8916-5 Takayama, Nara 6300101, Japan. NR 39 TC 37 Z9 38 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7178 EP 7183 DI 10.1073/pnas.120074297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600047 PM 10852950 ER PT J AU Self, WT Stadtman, TC AF Self, WT Stadtman, TC TI Selenium-dependent metabolism of purines: A selenium-dependent purine hydroxylase and xanthine dehydrogenase were purified from Clostridium purinolyticum and characterized SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NICOTINIC-ACID HYDROXYLASE; ASPERGILLUS-NIDULANS; CYANOLYZABLE SULFUR; CRYSTAL-STRUCTURE; MOLYBDENUM; INACTIVATION; PURIFICATION; MECHANISM; BARKERI; OXIDASE AB During purification of the selenium-dependent xanthine dehydrogenase (XDH) from Clostridium purinolyticum, another hydroxylase was uncovered that also contained selenium and exhibited similar spectral properties. This enzyme was purified to homogeneity, It uses purine, 2OH-purine, and hypoxanthine as substrates, and based on its substrate specificity, this selenoenzyme is termed purine hydroxylase (PH), The product of hydroxylation of purine by PH is xanthine, A concomitant release of selenium from the enzyme and loss of catalytic activity on treatment with cyanide indicates that selenium is essential for PH activity. Selenium-dependent XDH, also purified from C, purinolyticum, was found to be insensitive to oxygen during purification and to use both potassium ferricyanide and 2,6-dichloroindophenol as electron accepters. Selenium is required for the xanthine-dependent reduction of 2,6-dichloroindophenol by XDH, Kinetic analyses of both enzymes revealed that xanthine is the preferred substrate for XDH and purine and hypoxanthine are preferred by PH. This characterization of these selenium-requiring hydroxylases involved in the interconversion of purines describes an extension of the pathway for purine fermentation in the purinolytic clostridia. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Self, William/A-6704-2008 NR 25 TC 24 Z9 25 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7208 EP 7213 DI 10.1073/pnas.97.13.7208 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600052 PM 10860985 ER PT J AU Lapidus, LJ Eaton, WA Hofrichter, J AF Lapidus, LJ Eaton, WA Hofrichter, J TI Measuring the rate of intramolecular contact formation in polypeptides SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRIPLET-STATE; ROOM-TEMPERATURE; ENERGY-TRANSFER; CYTOCHROME-C; TIME SCALES; TRYPTOPHAN; PHOSPHORESCENCE; DIFFUSION; PROTEINS; PARVALBUMIN AB Formation of a specific contact between two residues of a polypeptide chain is an important elementary process in protein folding. Here we describe a method for studying contact formation between tryptophan and cysteine based on measurements of the lifetime of the tryptophan triplet state. With tryptophan at one end of a flexible peptide and cysteine at the other, the triplet decay rate is identical to the rate of quenching by cysteine. We show that this rate is also close to the diffusion-limited rate of contact formation. The length dependence of this end-to-end contact rate was studied in a series of Cys-(Ala-Gly-Gln)(kappa)-Trp peptides, with k varying from 1 to 6. The rate decreases from similar to 1/(40 ns) for k = 1 to similar to 1/(140 ns) for k = 6. approaching the length dependence expected for a random coil (n(-3/2)) for the longest peptides. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. NR 42 TC 319 Z9 321 U1 1 U2 24 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 JUN 20 PY 2000 VL 97 IS 13 BP 7220 EP 7225 DI 10.1073/pnas.97.13.7220 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600054 PM 10860987 ER PT J AU Fossett, N Zhang, Q Gajewski, K Choi, CY Kim, Y Schulz, RA AF Fossett, N Zhang, Q Gajewski, K Choi, CY Kim, Y Schulz, RA TI The multitype zinc-finger protein U-shaped functions in heart cell specification in the Drosophila embryo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; GENE-EXPRESSION; VENTRAL MORPHOGENESIS; TUBE FORMATION; FGF-RECEPTOR; MESODERM; COFACTOR; ENCODES; PANNIER; TINMAN AB Multitype zinc-finger proteins of the Friend of GATA/U-shaped (Ush) class function as transcriptional regulators of gene expression through their modulation of GATA factor activity. To better understand intrinsic properties of these proteins, we investigated the expression and function of the ush gene during Drosophila embryogenesis. ush is dynamically expressed in the embryo, including several cell types present within the mesoderm, The gene is active in the cardiogenic mesoderm. and a loss of function results in an overproduction of both cardial and pericardial cells, indicating a requirement for the gene in the formation of these distinct cardiac cell types. Conversely, ectopic expression of lah results in a decrease in the number of cardioblasts in the heart and the inhibition of a cardial cell enhancer normally regulated by the synergistic activity of the Pannier and Tinman cardiogenic factors. These findings suggest that, similar to its known function in thoracic bristle patterning, Ush functions in the control of heart cell specification through its modulation of Pannier transcriptional activity. ush is also required for mesodermal cell migration early in embryogenesis. where it shows a genetic interaction with the Heartless fibroblast growth factor receptor gene. Taken together, these results demonstrate a critical role for the Ush transcriptional regulator in several diverse processes of mesoderm differentiation and heart formation. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Schulz, RA (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, 1515 Holcombe Blvd, Houston, TX 77030 USA. FU NHLBI NIH HHS [R01 HL059151, HL59151]; NICHD NIH HHS [T32 HD007324, T32-HD07324] NR 36 TC 37 Z9 39 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7348 EP 7353 DI 10.1073/pnas.97.13.7348 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600076 PM 10861002 ER PT J AU Kawakami, Y Kitaura, J Hartman, SE Lowell, CA Siraganian, RP Kawakami, T AF Kawakami, Y Kitaura, J Hartman, SE Lowell, CA Siraganian, RP Kawakami, T TI Regulation of protein kinase C beta I by two protein-tyrosine kinases, Btk and Syk SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID B-CELL DEVELOPMENT; FC-EPSILON-RI; X-LINKED AGAMMAGLOBULINEMIA; AFFINITY IGE RECEPTOR; NECROSIS-FACTOR-ALPHA; MAST-CELLS; DEFICIENT MICE; SRC FAMILY; PHOSPHOLIPASE C-GAMMA-2; MEDIATED ACTIVATION AB Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (Fc epsilon RI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on Fc epsilon RI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKC beta I among the conventional PKC isoforms (alpha, beta I, and beta II) expressed in mast cells. Syk/Btk-mediated PKC beta I regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor or genes through the JNK pathway induced by FceRI stimulation. Accordingly, Fc epsilon RI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKC beta. Specific regulation of PKC beta I by Btk is consistent with the selective association of Btk with PKC beta I. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases. C1 La Jolla Inst Allergy & Immunol, Div Allergy, San Diego, CA 92121 USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Kawakami, T (reprint author), La Jolla Inst Allergy & Immunol, Div Allergy, 10355 Sci Ctr Dr, San Diego, CA 92121 USA. RI Kawakami, Toshiaki/O-1616-2015 FU NIAID NIH HHS [U19 AI42244, AI33617, AI38348, R01 AI038348] NR 58 TC 74 Z9 76 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7423 EP 7428 DI 10.1073/pnas.120175097 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600089 PM 10852954 ER PT J AU Takenaka, T Murray, GJ Qin, GJ Quirk, JM Ohshima, T Qasba, P Clark, K Kulkarni, AB Brady, RO Medin, JA AF Takenaka, T Murray, GJ Qin, GJ Quirk, JM Ohshima, T Qasba, P Clark, K Kulkarni, AB Brady, RO Medin, JA TI Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ALPHA-GALACTOSIDASE-A; GENE-TRANSFER; HEMATOPOIETIC-CELLS; RETROVIRAL VECTOR; STROMAL CELLS; DISEASE; EXPRESSION; SECRETION; THERAPY; VIVO AB Fabry disease is a compelling target for gene therapy as a treatment strategy. A deficiency in the lysosomal hydrolase alpha-galactosidase A (alpha-gal A; PC 3.2.1.22) leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop vascular occlusions that cause cardiovascular, cerebrovascular, and renal disease. Unlike for some lysosomal storage disorders, there is limited primary nervous system involvement in Fabry disease. The enzyme defect can be corrected by gene transfer. Overexpression of alpha-gal A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells presumably by receptor-mediated endocytosis, Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. In this paper we report studies on long-term genetic: correction in an alpha-gal A-deficient mouse model of Fabry disease. alpha-gal A-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-gal A and transplanted into sublethally and lethally irradiated or-gal A-deficient mice. alpha-gal A activity and Gb3 levels were analyzed in plasma, peripheral blood mononuclear cells, BMMCs, liver, spleen, heart, lung, kidney, and brain. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased alpha-gal A activity and decreased Gb3 storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may have utility for phenotypic correction of patients with this disorder. C1 Univ Illinois, Hematol Oncol Sect, Dept Med, Chicago, IL 60607 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Biochem & Mol Biol, Chicago, IL 60612 USA. RP Medin, JA (reprint author), Univ Illinois, Hematol Oncol Sect, Dept Med, MBRB Rm 3150,M-C 734,900 S Ashland Ave, Chicago, IL 60607 USA. NR 20 TC 68 Z9 71 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7515 EP 7520 DI 10.1073/pnas.120177997 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600105 PM 10840053 ER EF