FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kriska, AM Saremi, A Hanson, RL Bennett, PH Kobes, S Williams, DE Knowler, WC AF Kriska, AM Saremi, A Hanson, RL Bennett, PH Kobes, S Williams, DE Knowler, WC TI Physical activity, obesity, and the incidence of type 2 diabetes in a high-risk population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diabetes mellitus; exercise; incidence; motor activity; obesity ID IMPAIRED GLUCOSE-TOLERANCE; PIMA-INDIANS; LIFE-STYLE; MELLITUS; EXERCISE; ASSOCIATION; WOMEN AB This study, examining the longitudinal relation among physical activity, body mass index, and development of type 2 diabetes in a high-risk population, is unique because diabetes was determined by oral glucose tolerance testing rather than by self-report. A physical activity questionnaire assessing past year leisure and occupational activity was administered to 1,728 nondiabetic Pima individuals aged 15-59 years as part of a series of clinic examinations in the Gila River Indian Community from 1987 to 2000. During an average follow-up period of 6 years, 346 subjects developed diabetes. Using time-dependent Cox proportional hazards modeling adjusting for age, the authors found that total activity was related to diabetes incidence in women and men (p < 0.05 in women only). After additional adjustment for body mass index, the relation between activity and diabetes incidence was weakened in both men and women. When the age-adjusted diabetes incidence rates were examined by levels of activity stratified by tertile of body mass index, the diabetes incidence rate remained lower in more active than in less active men and women from all body mass index groups, with the exception of the middle body mass index tertile in men (p < 0.05 in women only). These results suggest that the adoption and maintenance of a physically active lifestyle can play a significant role in preventing type 2 diabetes. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. NIDDKD, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Kriska, AM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Room 505B,Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Kriska, Andrea/0000-0002-3522-0869 FU NIDDK NIH HHS [R01 DK43394-06A1] NR 20 TC 123 Z9 130 U1 0 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2003 VL 158 IS 7 BP 669 EP 675 DI 10.1093/aje/kwg191 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 728EJ UT WOS:000185702200009 PM 14507603 ER PT J AU Eknoyan, G Hostetter, T Bakris, GL Hebert, L Levey, AS Parving, HH Steffes, MW Toto, R AF Eknoyan, G Hostetter, T Bakris, GL Hebert, L Levey, AS Parving, HH Steffes, MW Toto, R TI Proteinuria and other markers of chronic kidney disease: A position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material DE proteinuria; glomerular filtration rate (GFR); chronic kidney disease (CKD) ID ELIMINATION PARADE; RISK; ALBUMINURIA C1 Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Prevent Med, Hypertens Training Program, Chicago, IL 60612 USA. Ohio State Univ, Dept Internal Med, Div Nephrol, Columbus, OH 43210 USA. Tufts Univ, Sch Med, Div Nephrol, New England Med Ctr, Boston, MA 02111 USA. Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Steno Diabet Ctr, DK-2820 Gentofte, Denmark. Univ Texas, SW Med Ctr, Dallas, TX USA. RP Eknoyan, G (reprint author), Natl Kidney Fdn, 30 E 33rd St, New York, NY 10016 USA. RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 NR 4 TC 209 Z9 216 U1 0 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD OCT PY 2003 VL 42 IS 4 BP 617 EP 622 DI 10.1053/S0272-6386(03)00826-6 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 728XK UT WOS:000185741500001 PM 14520612 ER PT J AU Meyers, CM Seeff, LB Stehman-Breen, CO Hoofnagle, JH AF Meyers, CM Seeff, LB Stehman-Breen, CO Hoofnagle, JH TI Hepatitis C and renal disease: An update SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE hepatitis C virus (HCV); cirrhosis; cryoglobulinemia; glomerulonephritis; dialysis; renal transplantation; interferon alfa; ribavirin; peginterferon; randomized controlled trials ID INTERFERON-ALPHA THERAPY; LIVER-TRANSPLANT RECIPIENTS; RECOMBINANT LEUKOCYTE INTERFERON; FIBROSING CHOLESTATIC HEPATITIS; CHRONIC-HEMODIALYSIS PATIENTS; DIALYSIS-ASSOCIATED DISEASES; II MIXED CRYOGLOBULINEMIA; CHRONIC VIRAL-HEPATITIS; TERM-FOLLOW-UP; VIRUS-INFECTION AB Hepatitis C is both a cause and a complication of chronic renal disease. Chronic infection with hepatitis C virus (HCV) can lead to the immune complex syndromes of cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN). The pathogenetic mechanisms for these conditions have not been defined, although they are clearly caused by the chronic viral infection. Management of HCV-related cryoglobulinemia and MPGN is difficult; antiviral therapy is effective in clearing HCV infection in a proportion of patients, but these conditions can be severe and resistant to antiviral therapy. Hepatitis C also is a complicating factor among patients with end-stage renal disease and renal transplants. The source of HCV infection in these patients can be nosocomial. Screening and careful attention to infection control precautions are mandatory for dialysis units to prevent the spread of hepatitis C. Prevention of spread is particularly important in these patients because HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation. Furthermore, therapy for hepatitis C is problematic, only partially effective, and associated with significant side effects in this population. There are significant needs in both basic and clinical research in the pathogenesis, natural history, prevention, and therapy for hepatitis C in patients with renal disease. C1 NIDDKD, Div Kidney, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Urol, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Hematol Dis, NIH, Bethesda, MD 20892 USA. NIDDKD, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Dept Vet Affairs, Puget Sound Healthcare Syst, Seattle, WA USA. RP Hoofnagle, JH (reprint author), NIDDK, NIH, Bldg 31,Rm 9A27A,31 Ctr Dr, Bethesda, MD 20892 USA. NR 183 TC 201 Z9 212 U1 1 U2 5 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 OCT PY 2003 VL 42 IS 4 BP 631 EP 657 DI 10.1053/S0272-6386(03)00828-X PG 27 WC Urology & Nephrology SC Urology & Nephrology GA 728XK UT WOS:000185741500004 PM 14520615 ER PT J AU Marcy, TW Thabault, P Olson, J Tooze, JA Liberty, B Nolan, S AF Marcy, TW Thabault, P Olson, J Tooze, JA Liberty, B Nolan, S TI Smoking status identification: Two managed care organizations' experiences with a pilot project to implement identification systems in independent practice associations SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID INTERVENTIONS; PHYSICIANS; REVIEWS AB Objective: To determine whether managed care organizations (MCOs) can effectively promote the sustained use of smoking status identification systems among independent practice associations. Study Design: Quasi-experimental design measuring smoking status documentation before and after an intervention. Methods: A chart review of the MCOs' patients at 4 participating primary care clinics determined the baseline for smoking status documentation before intervention. Baseline data were unavailable from a fifth participating clinic. Two quality improvement personnel were sent by the MCOs to help the clinics chose and implement a system for identifying smoking status. All of the clinics chose a sticker system. The change in smoking status documentation was assessed by chart reviews of patients enrolled in the MCOs who were seen during the period between 3 and 16 months after implementation of the system. Results: Following the intervention, a significant increase in smoking status documentation was noted among participating clinics. The proportion of patients whose smoking status was identified and documented by any method increased from 50% to 87% (P < .01) at the 4 clinics with baseline data. By clinic, the increase varied from 6% to 60%. The sticker system was the method by which most patients' smoking status was documented (77%). There were no controls, so the influence of outside factors, including a regional smoking cessation campaign that coincided with this study, cannot be quantified. Conclusions: Managed care organizations may be an effective change agent for implementing the guidelines for tobacco use and dependence treatment. C1 Univ Vermont, Coll Med, Off Hlth Promot Res, Burlington, VT 05401 USA. Off Prevent Oncol, Div Canc Prevent, NCI, Rockville, MD USA. Univ Vermont, Vermont Canc Ctr, Burlington, VT 05405 USA. Vermont Hlth Plan, Williston, VT USA. Blue Cross & Blue Shield Vermont, Montpellier, France. RP Marcy, TW (reprint author), Univ Vermont, Coll Med, Off Hlth Promot Res, 4th Floor Arnold Bldg,1 S Prospect St, Burlington, VT 05401 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU AMER MED PUBLISHING, M W C COMPANY PI JAMESBURG PA 241 FORSGATE DR, STE 102, JAMESBURG, NJ 08831 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD OCT PY 2003 VL 9 IS 10 BP 672 EP 676 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 731PP UT WOS:000185895900004 PM 14572177 ER PT J AU England, LJ Levine, RJ Mills, JL Klebanoff, MA Yu, KF Cnattingius, S AF England, LJ Levine, RJ Mills, JL Klebanoff, MA Yu, KF Cnattingius, S TI Adverse pregnancy outcomes in snuff users SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2003 CL SAN FRANCISCO, CALIFORNIA SP Soc Maternal Fetal Med DE smoking; snuff; fetal growth; preterm delivery; preeclampsia ID SMOKELESS TOBACCO USE; SMOKING; PREECLAMPSIA; RISK AB OBJECTIVE: The purpose of the study was to evaluate the effects of smokeless tobacco use during pregnancy. STUDY DESIGN: We examined birth weight, preterm delivery, and preeclampsia in women who were delivered of singleton, live-born infants in Sweden from 1999 through 2000. For each snuff user, 10 cigarette smokers and 10 tobacco nonusers were selected randomly. RESULTS: After exclusions, 789 snuff users, 11,240 smokers, and 11,495 nonusers remained. Compared with nonusers, adjusted mean birth weight was reduced in snuff users by 39 g (95% Cl, 6-72 g) and in smokers by 190 g (95% Cl, 178-202 g). Preterm delivery was increased in snuff users and smokers (adjusted odds ratios, 1.98 [95% Cl, 1.46-2.68] and 1.57 [95% Cl, 1.38-1.80], respectively). Preeclampsia was reduced in smokers (adjusted odds ratio, 0.63; 95% Cl, 0.53-0.75) but increased in snuff users (adjusted odds ratio, 1.58; 95% Cl, 1.09-2.27). CONCLUSION: Snuff use was associated with increased risk of preterm delivery and preeclampsia. Snuff does not appear to be a safe alternative to cigarettes during pregnancy. C1 NICHHD, Div Epidemiol Stat & Prevent REs, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. RP England, LJ (reprint author), NICHHD, Div Epidemiol Stat & Prevent REs, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. NR 22 TC 93 Z9 94 U1 1 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2003 VL 189 IS 4 BP 939 EP 943 DI 10.1067/S0002-9378(03)00661-6 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 740BN UT WOS:000186381100009 PM 14586330 ER PT J AU Kim, YM Bujold, E Chaiworapongsa, T Gomez, R Yoon, BH Thaler, HT Rotmensch, S Romero, R AF Kim, YM Bujold, E Chaiworapongsa, T Gomez, R Yoon, BH Thaler, HT Rotmensch, S Romero, R TI Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2003 CL SAN FRANCISCO, CALIFORNIA SP Soc Maternal Fetal Med DE placental bed; placenta; physiologic transformation; placentation; preterm labor; preeclampsia; spiral artery ID PLACENTAL BED; HUMAN CYTOTROPHOBLASTS; ENDOVASCULAR INVASION; TROPHOBLAST INVASION; NORMAL-PREGNANCY; PREECLAMPSIA; PHENOTYPE; VESSELS AB OBJECTIVE: The purpose of this study was to determine whether abnormal placentation (defined as the failure of physiologic transformation of spiral arteries) is present in patients with preterm labor and intact membranes who delivered a preterm neonate. STUDY DESIGN: A cross-sectional study was conducted to examine the histopathologic findings in the placental bed and placenta of patients with preterm labor and intact membranes (n = 27), preeclampsia (n = 43), and healthy pregnant women at term (n = 103). Immunohistochemistry studies with cytokeratin 7 and periodic acid-Schiff were used to detect trophoblast and fibrinoid, respectively, and diagnose the failure of physiologic transformation of the spiral arteries. RESULTS: The mean percentage of spiral arteries with failure of physiologic transformation in the myometrium was significantly higher in patients with preterm labor and preeclampsia than in normal pregnant women at term (P = .0004 and P < .0001, respectively). Similar findings were observed in the decidual segment of spiral arteries within the placental bed (P = .001 and P < .0001). In contrast, the mean percentage of the spiral arteries with failure of physiologic transformation in the clecidua of the basal plate was not significantly different between patients with preterm labor and normal pregnant women (P = .17). CONCLUSION: Failure of physiologic transformation of the spiral arteries in the myometrial and decidual segments of the placental bed is frequent in patients with preterm labor and intact membranes. C1 Wayne State Univ, Hutzel Hosp, NICHHD,DHHS, Dept Obstet & Gynecol,Perinatol Res Branch,NIH, Detroit, MI 48201 USA. Sotero del Rio Hosp, Ctr Perinatal Diag & Res, Puente Alto, Chile. Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Edith Wolfson Med Ctr, Dept Obstet & Gynecol, Holon, Israel. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, NICHHD,DHHS, Dept Obstet & Gynecol,Perinatol Res Branch,NIH, 4707 St Antoine, Detroit, MI 48201 USA. RI Yoon, Bo Hyun/H-6344-2011 NR 19 TC 180 Z9 185 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2003 VL 189 IS 4 BP 1063 EP 1069 DI 10.1067/S0002-9378(03)00838-X PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 740BN UT WOS:000186381100035 PM 14586356 ER PT J AU Zhang, J Schisterman, EF AF Zhang, J Schisterman, EF TI Maternal plasma cellular fibronectin for early prediction of preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2003 VL 189 IS 4 BP 1212 EP 1212 DI 10.1067/S0002-9378(03)00704-X PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 740BN UT WOS:000186381100062 PM 14619833 ER PT J AU Hertle, RW Beck, RW Birch, EE Chandler, DL Duckman, RH Holmes, JM Kivlin, JD Kraker, RT Olson, RJ Repka, MX Rutstein, RP Saunders, RA AF Hertle, RW Beck, RW Birch, EE Chandler, DL Duckman, RH Holmes, JM Kivlin, JD Kraker, RT Olson, RJ Repka, MX Rutstein, RP Saunders, RA CA Pediat Eye Dis Investigator Grp TI The course of moderate amblyopia treated with patching in children: Experience of the amblyopia treatment study SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ACUITY TESTING PROTOCOL/; STRABISMIC AMBLYOPIA; OCCLUSION THERAPY; FOLLOW-UP AB PURPOSE: To assess the course of the response to patching treatment of moderate amblyopia and to assess factors predictive of the response in children 3 years old to younger than 7 years old. DESIGN: Multicenter, randomized clinical trial comparing patching and atropine (one of the amblyopia treatment studies). METHODS: A total of 209 children 3 years old to younger than 7 years of age with amblyopia in the range of 20/40 to 20/100 from the patching treatment arm of this trial were treated with patching of the sound eye from 6 hours per day up to all waking hours. Follow,up examinations were performed at 5 weeks, 16 weeks, and 6 months. The primary outcome measure was visual acuity in the amblyopic eye at 6 months. RESULTS: After 5 weeks of treatment, mean amblyopic ye acuity improved from baseline by 2.2 lines. For patients with baseline acuity of 20/80 or 20/100, a greater number of hours of prescribed patching was associated with greater improvement in the first 5 weeks (P = .05). However, this relationship was not present when baseline acuity was 20/40 to 20/60 (P = .57). At 6 months, visual acuity was improved from baseline by a mean of 3.1 lines, with the amount of improvement no longer related to the number of hours patching prescribed at baseline (P = .93). Among the 15 7 patients improving at least 3 lines from baseline, 15% achieved their maxi, mum improvement by 5 weeks and 52% by 16 weeks. None of the demographic or clinical factors assessed was predictive of the response to treatment. CONCLUSIONS: In the treatment of moderate amblyopia, a beneficial effect of patching is present throughout the age range of 3 years old to younger than 7 years old and the acuity range of 20/40 to 20/100. At 6 months, the amount of improvement appears to be similar when 6 hours of daily patching are initially prescribed vs a greater number of hours. However, when the baseline acuity is 20/80 to 20/100, a greater number of hours of prescribed patching may improve acuity faster. (C) 2003 by Elsevier Inc. All rights reserved. C1 Pediat Ophthalmol Erie, Erie, PA USA. Ctr Adult Strabismus, Dallas, TX USA. Pediat Ophthalmol & Strabismus Associates, Providence, RI USA. Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. NEI, Bethesda, MD 20892 USA. Ophthalm Associates, Anchorage, AK USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. So Calif Coll Optometry, Fullerton, CA USA. Texas Childrens Hosp, Houston, TX 77030 USA. Vanderbilt Eye Ctr, Nashville, TN USA. Casey Eye Inst, Portland, OR USA. Permanente Med Grp Inc, Sacramento, CA USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. Wilmer Inst, Baltimore, MD 21205 USA. Indiana Univ, Med Ctr, Indianapolis, IN USA. NOVA SE Univ, Ft Lauderdale, FL USA. Greater Baltimore Med Ctr, Baltimore, MD 21204 USA. Emory Eye Ctr, Atlanta, GA USA. Cardinal Glennon Childrens Hosp, St Louis, MO USA. Ophthalm Surg Associates, Waterbury, CT USA. Pediat Ophthalmol PC, Grand Rapids, MI USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Green Vision Grp, Wichita, KS USA. Mayo Clin, Rochester, MN USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. Childrens Hosp, Buffalo, NY 14222 USA. Family Eye Grp, Eye Specialists Lancaster, Lancaster, PA USA. Speciality Eye Care, Palm Harbor, FL USA. Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. Univ Arizona, Tucson, AZ USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Univ Minnesota, Minneapolis, MN USA. Alabama Ophthalmol Associates, Birmingham, AL USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. Scott & White Ophthalmol, Temple, TX USA. Univ Utah, Moran Eye Ctr, Salt Lake City, UT USA. Asheville Eye Associates, Asheville, NC USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Eye Ctr Ohio, Canton, OH USA. Med Univ S Carolina, Storm Eye Inst, Charleston, SC 29425 USA. New England Coll Optometry, Boston, MA USA. SUNY Coll Optometry, New York, NY 10010 USA. Data Coordinating Ctr, Tampa, FL USA. RP Hertle, RW (reprint author), PEDIG Coordinating Ctr, Jaeb Ctr Hlth Res, 3010 E 138th Ave,Suite 9, Tampa, FL 33613 USA. NR 24 TC 20 Z9 20 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2003 VL 136 IS 4 BP 620 EP 629 DI 10.1016/S0002-9394(03)00392-1 PG 10 WC Ophthalmology SC Ophthalmology GA 725HQ UT WOS:000185538500004 ER PT J AU Cotter, S Astle, WF Beck, RW Birch, EE Chandler, DL Davitt, BV Holmes, JM Kraker, RT Miller, MM Repka, MX Saunders, RA Wallace, DK AF Cotter, S Astle, WF Beck, RW Birch, EE Chandler, DL Davitt, BV Holmes, JM Kraker, RT Miller, MM Repka, MX Saunders, RA Wallace, DK CA Pediat Eye Dis Investigator Grp TI The course of moderate amblyopia treated with atropine in children: Experience of the amblyopia treatment study SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ACUITY TESTING PROTOCOL/; PENALIZATION TREATMENT; STRABISMIC AMBLYOPIA; TROPICAMIDE; OCCLUSION; MYOPIA AB PURPOSE: To assess the course of the response to tropine treatment of moderate amblyopia and to assess factors predictive of the treatment response in children 3 years old to younger than 7 years old. DESIGN: Multicenter, randomized clinical trial comparing atropine and patching (one of the amblyopia treatment studies). METHODS. A total of 195 children 3 years old to younger than 7 years of age with amblyopia in the range of 20/40 to 20/100 from the atropine treatment arm of this trial were enrolled and included in this analysis. At baseline, daily topical atropine was prescribed for the sound eye. During follow-up, a plano spectacle lens was prescribed for the sound eye for patients whose amblyopia had not been successfully treated with atropine alone. Follow-up examinations were performed at 5 weeks, 16 weeks, and 6 months. The primary outcome measure was visual acuity in the amblyopic eye at 6 months. RESULTS: Mean visual acuity improved from baseline by 1.3 lines after 5 weeks of treatment, by 2.4 lines after 16 weeks, and by 2.8 lines at 6 months. Visual acuity of 20/30 or better and/or 3 or more lines of improvement from baseline was achieved by 75% of the patients. Improvement occurred over the entire range of baseline acuities (20/40 to 20/100) and was not related to patient age (P = .36). Among the 134 patients improving 3 or more lines from baseline, 7% achieved their maximum improvement by 5 weeks and 46% by 16 weeks. Among the 55 patients who did not respond adequately to atropine alone and were prescribed a plano lens for the sound eye, the mean improvement before the use of the plano lens was 1.0 lines, compared with 1.6 lines after prescribing the plano lens (P = .11). None of the demographic or clinical factors assessed was predictive of the response to treatment. A shift in fixation preference at/near from the atropinized sound eye to the amblyopic eye was not required for the amblyopic eye to improve; amblyopic eye acuity improved 3 or more lines in 29 (60%) of the 48 patients who were found to be using the atropinized sound eye on fixation preference testing. A 2 or more line decrease in sound eye visual acuity occurred more frequently when a plano lens was prescribed in addition to atropine (7 of 43, 16%) compared with treatment with atropine alone (4 of 123, 3%; P = .01). CONCLUSIONS: A beneficial effect of atropine is present throughout the age range of 3 years old to younger than 7 years old, and with an acuity range of 20/40 to 20/100. A shift in near fixation to the amblyopic eye is not essential for atropine to be effective in all cases. Sound eye acuity should be monitored when a plano spectacle lens is prescribed for the sound eye to augment the treatment effect of atropine. (C) 2003 by Elsevier Inc. All rights reserved. C1 Pediat Ophthalmol Erie, Erie, PA USA. Ctr Adult Strabismus, Dallas, TX USA. Pediat Ophthalmol & Strabismus Associates, Providence, RI USA. Childrens Hosp, Calgary, AB, Canada. NEI, Bethesda, MD 20892 USA. Ophthalmol Associates, Anchorage, AK USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. So Calif Coll Optometry, Fullerton, CA USA. Texas Childrens Hosp, Houston, TX 77030 USA. Vanderbilt Eye Ctr, Nashville, TN USA. Casey Eye Inst, Portland, OR USA. Permanente Med Grp Inc, Sacramento, CA USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. Wilmer Eye Inst, Baltimore, MD 21287 USA. Indiana Univ, Med Ctr, Indianapolis, IN USA. NOVA Southeastern Univ, Ft Lauderdale, FL USA. Greater Baltimore Med Ctr, Baltimore, MD 21204 USA. Emory Eye Ctr, Atlanta, GA USA. Cardinal Glennon Childrens Hosp, St Louis, MO USA. Ophthalmol Surg Associates, Waterbury, CT USA. Michigan Pediat Ophthalmol, Grand Rapids, MI USA. UT Southwestern Med Ctr, Dallas, TX USA. Grene Vis Grp, Wichita, KS USA. Mayo Clin, Rochester, MN USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. Childrens Hosp, Buffalo, NY 14222 USA. Family Eye Grp, Eye Specialist Lancaster, Lancaster, PA USA. Special Eye Care, Palm Harbour, FL USA. Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. Univ Arizona, Tucson, AZ USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Univ Minnesota, Minneapolis, MN USA. Alabama Ophthalmol Associates PC, Birmingham, AL USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. Scott & White Ophthalmol, Temple, TX USA. Univ Utah, Moran Eye Ctr, Salt Lake City, UT USA. Ashville Eye Associates, Asheville, NC USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Eye Ctr Ohio, Canton, OH USA. Med Univ S Carolina, Storm Eye Inst, Charleston, SC 29425 USA. New England Coll Optometry, Boston, MA USA. SUNY Coll Optometry, New York, NY 10010 USA. Data Coordinating Ctr, Tampa, FL USA. RP Beck, RW (reprint author), PEDIG Coordinating Ctr, Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. NR 21 TC 23 Z9 23 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2003 VL 136 IS 4 BP 630 EP 639 DI 10.1016/S0002-9394(03)00458-6 PG 10 WC Ophthalmology SC Ophthalmology GA 725HQ UT WOS:000185538500005 ER PT J AU Heselmeyer-Haddad, K Janz, V Castle, PE Chaudhri, N White, N Wilber, K Morrison, LE Auer, G Burroughs, FH Sherman, ME Ried, T AF Heselmeyer-Haddad, K Janz, V Castle, PE Chaudhri, N White, N Wilber, K Morrison, LE Auer, G Burroughs, FH Sherman, ME Ried, T TI Detection of genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; IN-SITU HYBRIDIZATION; INTERPHASE CYTOGENETICS; CHROMOSOMAL-ABERRATIONS; RECURRENT PATTERN; UTERINE CERVIX; COPY NUMBER; CANCER; CARCINOMA; LESIONS AB Invasive cervical carcinomas frequently reveal additional copies of the long arm of chromosome 3. The detection of this genetic aberration in diagnostic samples could therefore complement the morphological interpretation. We have developed a triple-color DNA probe set for the visualization of chromosomal copy number changes directly in thin-layer cervical cytology slides by fluorescence in situ hybridization. The probe set consists of a BAC contig that contains sequences for the RNA component of the human telomerase gene (TERC) on chromosome band 3q26, and repeat sequences specific for the centromeres of chromosomes 3 and 7 as controls. in a blinded study, we analyzed 57 thin-layer slides that had been rigorously screened and classified as normal (n = 13), atypical squamous cells (ASC, n = 5), low-grade squamous intraepithelial lesions (LSIL, n = 14), and high-grade squamous intraepithelial lesions (HSM) grade 2 (CIN2, n = 8), and grade 3 (CIN3, n = 17). The percentage of tetraploid cells (P-Trend < 0.0005) and cells with multiple 3q signals increased with the severity of the cytologic interpretation (P-Trend < 0.0005). While only few normal samples, ASC and LSIL lesions, revealed copy number increases of 3q, 63% of the HSIL (CIN2) lesions and 76% of the HSIL (CIN3) lesions showed extra copies of 3q. We conclude that the visualization of chromosome 3q copy numbers in routinely prepared cytological material using BAC clones specific for TERC serves as an independent screening test for HSIL and may help to determine the progressive potential of individual lesions. C1 NCI, CCR, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Vysis Inc, Abbott Labs, Downers Grove, IL USA. Karolinska Inst, Canc Ctr Karolinska, Stockholm, Sweden. Johns Hopkins Univ Hosp, John K Frost Lab Cytopathol, Dept Pathol, Baltimore, MD 21205 USA. RP Ried, T (reprint author), NCI, CCR, Genet Branch, NIH, Bldg 50,Room 1306,50 South Dr, Bethesda, MD 20892 USA. NR 40 TC 87 Z9 109 U1 0 U2 5 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2003 VL 163 IS 4 BP 1405 EP 1416 DI 10.1016/S0002-9440(10)63498-0 PG 12 WC Pathology SC Pathology GA 724ZE UT WOS:000185517500018 PM 14507648 ER PT J AU van de Loo, FAJ Bennink, MB Arntz, OJ Smeets, RL Lubberts, E Joosten, LAB van Lent, PLEM Coenen-de Roo, CJJ Cuzzocrea, S Segal, BH Holland, SM van den Berg, WB AF van de Loo, FAJ Bennink, MB Arntz, OJ Smeets, RL Lubberts, E Joosten, LAB van Lent, PLEM Coenen-de Roo, CJJ Cuzzocrea, S Segal, BH Holland, SM van den Berg, WB TI Deficiency of NADPH oxidase components p47phox and gp91 phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RESISTANT ACID-PHOSPHATASE; NECROSIS-FACTOR-ALPHA; SUPEROXIDE-DISMUTASE; RHEUMATOID-ARTHRITIS; ARTICULAR-CARTILAGE; NITRIC-OXIDE; POLYMORPHONUCLEAR LEUKOCYTES; RESPIRATORY BURST; HUMAN-NEUTROPHILS; INFLAMMATORY ARTHRITIS AB Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement Q were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage. C1 Univ Nijmegen, Med Ctr, Rheumatol Res Lab, Dept Rheumatol, Nijmegen, Netherlands. NV Organon, Oss, Netherlands. Univ Messina, Inst Pharmacol, Sch Med, Messina, Italy. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP van de Loo, FAJ (reprint author), Univ Nijmegen, Med Ctr, Rheumatol Res Lab, Dept Rheumatol, Geert Grootepl 26-28,POB 9101, Nijmegen, Netherlands. RI van Lent, Peter/A-4269-2014; van de Loo, Fons/A-3425-2014; van Lent, Peter/A-4047-2014; Berg, W.B./H-8010-2014; Smeets, Ruben/M-9478-2015 OI van de Loo, Fons/0000-0002-5851-099X; Smeets, Ruben/0000-0002-2862-1058 NR 59 TC 69 Z9 69 U1 3 U2 6 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2003 VL 163 IS 4 BP 1525 EP 1537 DI 10.1016/S0002-9440(10)63509-2 PG 13 WC Pathology SC Pathology GA 724ZE UT WOS:000185517500029 PM 14507659 ER PT J AU Garruto, RM Chin, CT Weitz, CA Liu, JC Liu, RL He, X AF Garruto, RM Chin, CT Weitz, CA Liu, JC Liu, RL He, X TI Hematological differences during growth among Tibetans and Han Chinese born and raised at high altitude in Qinghai, China SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE hemoglobin; hematocrit; altitude hypoxia; children; adolescents ID HEMOGLOBIN CONCENTRATION; LUNG-FUNCTION; CIGARETTE-SMOKING; IRON-DEFICIENCY; WESTERN CHINA; SEA-LEVEL; RESIDENTS; SHERPAS; NATIVES; VALUES AB This study describes the hemoglobin concentration ([Hb]) and hematocrit (HCT) of over 1,000 Tibetan and Han children, adolescents, and young adults who were born and raised at 3,200 m, 3,800 m, or 4,300 m in Qinghai Province, western China. At 3,200 m, no altitude effect is evident in the hematological characteristics of either group. At 3,800 m and 4,300 m, both groups show [Hb] and HCT values that are above low-altitude norms. At both altitudes, Tibetan and Han children show no differences in the pattern of hematological response up to age 13. Among adolescents and young adults, however, the [Hb] and HCT of Han males and females are elevated compared to Tibetans. This indicates that the adolescent period may involve a divergence in the responses to hypoxia made by some individuals in these two groups. Also, many other adolescents and young adults in both groups show similar hematological characteristics, indicating that many Tibetans and Han share similar hematological responses to hypoxia. (C) 2003 Wiley-Liss, Inc. C1 SUNY Binghamton, Dept Anthropol, Binghamton, NY 13902 USA. NIH, Bethesda, MD 20892 USA. Beijing Med Univ, Clin Coll 1, Womens & Childrens Hosp, Dept Pediat, Beijing 100034, Peoples R China. Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. Qinghai Bur Publ Hlth, Dept Maternal & Child Hlth, Xining 810000, Peoples R China. RP Garruto, RM (reprint author), SUNY Binghamton, Dept Anthropol, Sci 1,Room 113,POB 6000, Binghamton, NY 13902 USA. NR 54 TC 25 Z9 28 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD OCT PY 2003 VL 122 IS 2 BP 171 EP 183 DI 10.1002/ajpa.10283 PG 13 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 722VZ UT WOS:000185399900008 PM 12949837 ER PT J AU Fuhrer, MJ AF Fuhrer, MJ TI Overview of clinical trials in medical rehabilitation - Impetuses, challenges, and needed future directions SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article; Proceedings Paper CT Clinical Trials in Medical Rehabilitation Conference CY NOV 01-02, 2002 CL PARSIPPANY, NEW JERSEY DE randomized clinical trials; outcomes research; medical rehabilitation ID STROKE CARE; GUIDELINES AB The goal of clinical trials is to provide the strongest possible basis for inferring that the observed results of a health-oriented intervention are attributable to that intervention and not to other factors. Particularly strong causal inferences can be drawn from the randomized clinical trial in which participants are assigned on a random basis to either the intervention of interest or to a comparison condition. This article explains the reasons for that contention and explores its implications for medical rehabilitation research. Among the topics discussed are: the role of evidence-based practice in fostering interest in randomized clinical trials; a contextual view of randomized clinical trials that emphasizes strategies of investigation and the goals of particular studies; two key distinctions, efficacy-oriented vs. effectiveness-oriented clinical trials and pragmatic vs. explanatory clinical trials; the sequencing of different study designs, including randomized clinical trials; and needed advances in treatment theory, treatment fidelity, and adherence. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Fuhrer, MJ (reprint author), 13 Kings Valley Court, Damascus, MD 20872 USA. NR 28 TC 32 Z9 32 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD OCT PY 2003 VL 82 IS 10 SU S BP S8 EP S15 DI 10.1097/01.PHM.0000086995.80644.D7 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 724YP UT WOS:000185516100003 PM 14502033 ER PT J AU Ai, H Ralston, E Lauritzen, HPMM Galbo, H Ploug, T AF Ai, H Ralston, E Lauritzen, HPMM Galbo, H Ploug, T TI Disruption of microtubules in rat skeletal muscle does not inhibit insulin- or contraction-stimulated glucose transport SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE cytoskeleton; metabolism; signaling; glucose transporter 4; exercise; colchicine; nocodazole ID 3T3-L1 ADIPOCYTES; GOLGI-COMPLEX; TRANSFERRIN RECEPTOR; GLUT4 DISTRIBUTION; CYTOSKELETON; TRANSLOCATION; TRAFFICKING; MYOGENESIS; VESICLES; FIBERS AB Insulin and muscle contractions stimulate glucose transport in skeletal muscle through a translocation of intracellular GLUT4 glucose transporters to the cell surface. Judged by immunofluorescence microscopy, part of the GLUT4 storage sites is associated with the extensive microtubule cytoskeleton found in all muscle fibers. Here, we test whether microtubules are required mediators of the effect of insulin and contractions. In three different incubated rat muscles with distinct fiber type composition, depolymerization of microtubules with colchicine for less than or equal to 8 h did not inhibit insulin- or contraction-stimulated 2-deoxyglucose transport or force production. On the contrary, colchicine at least partially prevented the similar to30% decrease in insulin- stimulated transport that specifically developed during 8 h of incubation in soleus muscle but not in flexor digitorum brevis or epitrochlearis muscles. In contrast, nocodazole, another microtubule-disrupting drug, rapidly and dose dependently blocked insulin- and contraction-stimulated glucose transport. A similar discrepancy between colchicine and nocodazole was also found in their ability to block glucose transport in muscle giant "ghost" vesicles. This suggests that the ability of insulin and contractions to stimulate glucose transport in muscle does not require an intact microtubule network and that nocodazole inhibits glucose transport independently of its microtubule-disrupting effect. C1 Univ Copenhagen, Panum Inst, Dept Med Physiol, Copenhagen Muscle Res Ctr, DK-2200 Copenhagen, Denmark. Bispebjerg Hosp, Dept Rheumatol, DK-2400 Copenhagen, Denmark. Peking Univ, Hosp 3, Inst Sports Med, Beijing 100083, Peoples R China. NIAMSD, Light Imaging Sect, NIH, Bethesda, MD 20892 USA. RP Ploug, T (reprint author), Univ Copenhagen, Panum Inst, Dept Med Physiol, Copenhagen Muscle Res Ctr, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. NR 30 TC 19 Z9 24 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD OCT 1 PY 2003 VL 285 IS 4 BP E836 EP E844 DI 10.1152/ajpendo.00238.2002 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 718ZU UT WOS:000185178200019 PM 12746214 ER PT J AU Kim, WH Hong, F Radaeva, S Jaruga, B Fan, SJ Gao, B AF Kim, WH Hong, F Radaeva, S Jaruga, B Fan, SJ Gao, B TI STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE liver injury; interferon-gamma; hepatitis; Hep3B; TNF-alpha ID CHRONIC ACTIVE HEPATITIS; NITRIC-OXIDE SYNTHASE; C VIRUS-INFECTION; INTERFERON-GAMMA; IFN-GAMMA; CARBON-TETRACHLORIDE; MICE; DISEASE; CYTOKINES; TRANSCRIPTION AB Interferon-gamma (IFN-gamma) has been implicated in liver damage in animal models and chronic hepatitis C infection; however, the underlying mechanism is not clear. Here we examined the role of STAT1, a key signaling molecule for IFN-gamma, in a model of murine hepatitis induced by the injection of LPS/D-galactosamine and in human hepatoma Hep3B cells. STAT1 is rapidly activated and highly induced after injection of LPS/D-galactosamine. Both overexpression of STAT1 and hepatocellular damage are located in the same pericentral region. Disruption of the STAT1 gene abolishes LPS/D-galactosamine- induced liver injury. Studies from IFN-gamma deficient mice indicate that IFN-gamma is the major cytokine responsible for activation and hyperexpression of STAT1 in LPS/D-galactosamine- induced hepatitis. Hep3B cells overexpressing dominant negative STAT1 are resistant to IFN-gamma and IFN-gamma + TNF-alpha-induced cell death, whereas Hep3B cells overexpressing wild-type STAT1 are more susceptible to cell death. Taken together, these findings suggest that STAT1 plays an essential role in LPS/D-galactosamine- induced liver apoptosis and injury. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Mol Oncol Lab, Washington, DC 20007 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg Rm 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. NR 29 TC 38 Z9 41 U1 1 U2 3 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 OCT PY 2003 VL 285 IS 4 BP G761 EP G768 DI 10.1152/ajpgi.00224.2003 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 720MZ UT WOS:000185265700012 PM 12816762 ER PT J AU Aslamkhan, A Han, YH Walden, R Sweet, DH Pritchard, JB AF Aslamkhan, A Han, YH Walden, R Sweet, DH Pritchard, JB TI Stoichiometry of organic anion/dicarboxylate exchange in membrane vesicles from rat renal cortex and hOAT1-expressing cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE p-aminohippurate; hOAT1; organic anion transport; anion exchange; Madin-Darby canine kidney cells ID BASOLATERAL MEMBRANE; ANION TRANSPORTER; P-AMINOHIPPURATE; KIDNEY; CLONING; SLC22A8; CATIONS; OAT3; NA+ AB Although membrane vesicle studies have established the driving forces that mediate renal organic anion secretion and the organic anion transporter Oat1 has now been cloned in several species, its stoichiometry has remained uncertain. In this study, we used electrophysiology, kinetic measurements, and static head experiments to determine the coupling ratio for Oat1-mediated organic anion/dicarboxylate exchange. Initial experiments demonstrated that uptake of PAH by voltage-clamped Xenopus laevis oocytes expressing rOat1 led to net entry of positive charge, suggesting that coupling was one-to-one. This conclusion was confirmed by kinetic analysis of PAH and glutarate fluxes in native basolateral membrane vesicles from the rat renal cortex, which showed a Hill coefficient of 1. Similarly, static head experiments on the rat vesicles also showed a 1:1 coupling ratio. To confirm these conclusions in a system expressing a single cloned transporter, Madin-Darby canine kidney cells were stably transfected with the human exchanger hOAT1. The hOAT1-expressing cell line showed extensive PAH transport, which was very similar in all respects to transport expressed by hOAT1 in Xenopus oocytes. Its K(m) for PAH was 8 muM and glutarate effectively trans-stimulated PAH transport. When stoichiometry was assessed using plasma membranes isolated from the hOAT1-expressing cells, both kinetic and static head data indicated that hOAT1 also demonstrated a 1: 1 coupling between organic anion and dicarboxylate. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM pritcha3@niehs.nih.gov RI Sweet, Douglas/H-7914-2013 OI Sweet, Douglas/0000-0002-8911-9184 NR 31 TC 28 Z9 28 U1 0 U2 0 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 OCT 1 PY 2003 VL 285 IS 4 BP F775 EP F783 DI 10.1152/ajprenal.00140.2003 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 717RL UT WOS:000185103800020 PM 12837685 ER PT J AU Hansen, PB Schnermann, J AF Hansen, PB Schnermann, J TI Vasoconstrictor and vasodilator effects of adenosine in the kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE adenosine receptors; vascular resistance; renal blood flow; endothelium ID A(1) RECEPTOR ANTAGONIST; MEDIATES TUBULOGLOMERULAR FEEDBACK; INDUCED RENAL VASOCONSTRICTION; GLOMERULAR-FILTRATION RATE; NITRIC-OXIDE PRODUCTION; RAT-KIDNEY; A(2A) RECEPTORS; ANGIOTENSIN-II; ENDOTHELIAL-CELLS; BLOOD-FLOW AB Adenosine is an ATP breakdown product that in most vessels causes vasodilatation and that contributes to the metabolic control of organ perfusion, i.e., to the match between oxygen demand and oxygen delivery. In the renal vasculature, in contrast, adenosine can produce vasoconstriction, a response that has been suggested to be an organ-specific version of metabolic control designed to restrict organ perfusion when transport work increases. However, the vasoconstriction elicited by an intravenous infusion of adenosine is only short lasting, being replaced within 1-2 min by vasodilatation. It appears that the steady-state response to the increase of plasma adenosine levels above normal resulting from the infusion is global renal vasorelaxation that is the result of A(2)AR activation in most parts of the renal vasculature, including larger renal arteries, juxtamedullary afferent arterioles, efferent arterioles, and medullary vessels. A(2)AR-mediated vasorelaxation is probably facilitated by endothelial receptors that cause the release of nitric oxide and other endothelial relaxing factors. In contrast, isolated perfused afferent arterioles of superficial and midcortical nephrons of rabbit and mouse, especially in their most distal segment at the entrance to the glomerulus, respond to adenosine with persistent vasoconstriction, indicating predominant or exclusive expression of A(1)AR. A(1)AR in afferent arterioles are selectively activated from the interstitial aspect of the vessel. This property can dissociate A1AR activation from changes in vascular adenosine concentration, a characteristic that is ideally suited for the role of renal adenosine as a paracrine factor in the control of glomerular function. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Rm 4 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov NR 92 TC 64 Z9 67 U1 0 U2 2 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 OCT 1 PY 2003 VL 285 IS 4 BP F590 EP F599 DI 10.1152/ajprenal.00051.2003 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 717RL UT WOS:000185103800002 PM 12954591 ER PT J AU Zhang, Z Ferraris, JD Brooks, HL Brisc I Burg, MB AF Zhang, Z Ferraris, JD Brooks, HL Brisc, I Burg, MB TI Expression of osmotic stress-related genes in tissues of normal and hyposmotic rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aldose reductase; transcription factor; TonEBP ID ENHANCER-BINDING PROTEIN; STIMULATES TRANSCRIPTION; TONEBP/NFAT5; HSP70; HYPERTONICITY; ANTIDIURESIS; ACTIVATION; TONICITY; CELLS; NFAT5 AB TonEBP is a transcription factor that, when activated by hypertonicity, increases transcription of genes, including those involved in organic osmolyte accumulation. Surprisingly, it is expressed in virtually all tissues, including many never normally exposed to hypertonicity. We measured TonEBP mRNA (real-time PCR) and protein (Western blot analysis) in tissues of control (plasma osmolality 294 +/- 1 mosmol/kgH(2)O) and hyposmotic (dDAVP infusion plus water loading for 3 days, 241 +/- 2 mosmol/kgH(2)O) rats to test whether the ubiquitous expression of TonEBP mRNA is osmotically regulated around the normal plasma osmolality. TonEBP protein is reduced by hyposmolality in thymus and liver, but not in brain, and is not detected in heart and skeletal muscle. TonEBP mRNA decreases in brain and liver but is unchanged in other tissues. There are no general changes in mRNA of TonEBP-mediated genes: aldose reductase (AR) does not change in any tissue, betaine transporter (BGT1) decreases only in liver, taurine transporter (TauT) only in brain and thymus, and inositol transporter (SMIT) only in skeletal muscle and liver. Heat shock protein (Hsp)70-1 and Hsp70-2 mRNA increase greatly in most tissues, which cannot be attributed to decreased TonEBP activity. The conclusions are as follows: 1) TonEBP protein or mRNA expression is reduced by hyposmolality in thymus, liver, and brain. 2) TonEBP protein and mRNA expression are differentially regulated in some tissues. 3) Although AR, SMIT, BGT1, and TauT are regulated by TonEBP in renal medullary cells, other sources of regulation may predominate in other tissues. 4) TonEBP abundance and activity are regulated by factors other than tonicity in some tissues. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, Z (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N315, Bethesda, MD 20892 USA. EM Zhangz@nhlbi.nih.gov NR 21 TC 38 Z9 39 U1 0 U2 1 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 OCT 1 PY 2003 VL 285 IS 4 BP F688 EP F693 DI 10.1152/ajprenal.00028.2003 PG 6 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 717RL UT WOS:000185103800011 PM 12824075 ER PT J AU Guralnik, JM Ferrucci, L AF Guralnik, JM Ferrucci, L TI Assessing the building blocks of function utilizing measures of functional limitation SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COMMUNITY-DWELLING ELDERS; LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; OLDER ADULTS; MOBILITY; DISABILITY; VALIDATION; FITNESS; ASSOCIATIONS; DEPENDENCE AB To better understand the health of older people, it is valuable to go beyond conventional measures of disease and self-perceived health and utilize assessments of functional status and disability. Physical decrements can be characterized at the level of organs and body systems (impairments); the organism as a whole (functional limitations); and the person in the context of the environment and its challenges (disability). To understand the dynamics of the pathway leading from disease to disability, it is critical to measure functional limitations that can be assessed through either self-report or standardized objective measures of physical performance. Both of these approaches may be used to evaluate functions such as grasping objects, walking, and climbing stairs. In aging research, measures of functional limitation are utilized as outcomes that indicate the impact of disease, impairments, and other risk factors on function. In turn, measures of functional limitation can be used to characterize the functional status of individuals and populations, and are powerful predictors of various adverse outcomes, including incident disability in people not currently disabled. Functional limitation measures add substantially to our knowledge about older populations, but further work is needed to promote their standardization and use in both clinical and research settings. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Room 3C-301, Bethesda, MD 20892 USA. NR 46 TC 140 Z9 144 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2003 VL 25 IS 3 SU 2 BP 112 EP 121 DI 10.1016/S049-3797(03)00174-0 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 729ZC UT WOS:000185803900003 PM 14552934 ER PT J AU Sansbury, LB Klabunde, CN Mysliwiec, P Brown, ML AF Sansbury, LB Klabunde, CN Mysliwiec, P Brown, ML TI Physicians' use of nonphysician healthcare providers for colorectal cancer screening SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FLEXIBLE SIGMOIDOSCOPY; NURSE-PRACTITIONERS; ENDOSCOPISTS; RECOMMENDATIONS; ASSISTANTS AB Background: Data on the involvement of nonphysician healthcare providers in colorectal cancer (CRC) screening delivery are sparse. This article describes physicians' use of nurse practitioners and physician assistants to provide CRC screening with the fecal occult blood test (FOBT), flexible sigmoidoscopy, and colonoscopy, as well as physicians' attitudes toward using these providers to perform flexible sigmoidoscopy. Methods: Nationally representative samples of primary care physicians, gastroenterologists, and general surgeons were surveyed in 1999-2000. Descriptive statistics and logistic regression were used to estimate the prevalence and predictors of physicians' use of nurse practitioners and physician assistants for CRC screening and to assess physicians' attitudes toward their use in providing CRC screening with flexible sigmoidoscopy. Results: Overall, 24% of primary care physicians reported using a nurse practitioner or physician assistant to provide CRC screening with FOBT. However, only 3% of all physicians surveyed used nurse practitioners and physician assistants for CRC screening with flexible sigmoidoscopy, and less than 1% of gastroenterologists and general surgeons reported rising these providers to perform CRC screening with colonoscopy. Approximately 15% of general surgeons, 40% of primary care physicians, and 60% of gastroenterologists who do not currently use nurse practitioners or physician assistants to perform CRC screening with flexible sigmoidoscopy agreed that these providers could effectively perform the procedure. Conclusions: These results show current involvement of nurse practitioners and physician assistants in the delivery of CRC screening to be limited. Use of nonphysician healthcare providers for CRC screening with FOBT and flexible sigmoidoscopy is one possible Solution to the challenge of boosting low screening rates. However, physician beliefs about the ability of nurse practitioners and physician assistants to perform flexible sigmoidoscopy are a potential barrier to increasing the involvement of nonphysician providers in CRC screening delivery. C1 NCI, Hlth Serv & Econ Branch, Appl Res Program, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Klabunde, CN (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Execut Plaza N Room 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 23 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2003 VL 25 IS 3 BP 179 EP 186 DI 10.1016/S0749-3797(03)00203-4 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 728MD UT WOS:000185720200001 PM 14507523 ER PT J AU Koss, MP Yuan, NP Dightman, D Prince, RJ Polacca, M Sanderson, B Goldman, D AF Koss, MP Yuan, NP Dightman, D Prince, RJ Polacca, M Sanderson, B Goldman, D TI Adverse childhood exposures and alcohol dependence among seven Native American tribes SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SEXUAL-ABUSE; CONDUCT DISORDER; HEAVY DRINKING; UNITED-STATES; INDIAN TRIBE; RISK-FACTORS; WOMEN; RELIABILITY; CHILDREN; NEGLECT AB Background: Alcohol abuse and alcoholism are leading causes of death among Native Americans. Little is known about the impact of negative childhood exposures, including parental alcoholism, childhood maltreatment, and out-of-home placement, on risk of lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis of alcohol dependence in this population. Methods: Face-to-face interviews were conducted with 1660 individuals from seven Native American tribes from 1998 to 2001. Logistic regression was used to estimate the impact of specific types and number of different adverse childhood experiences on alcohol dependence. Relationships between tribe-specific cultural characteristics and alcohol dependence were also examined. Results: There were significant tribal differences in rates of alcohol dependence and several adverse childhood exposures. Lifetime prevalence of alcohol dependence was high among all tribes (men: 21%-56%, women: 17%-30%), but one (men: 1%, women: 2%). High prevalence rates were documented for one or more types of adverse childhood experiences (men: 74%-100%; women: 83%-93%). For men, combined physical and sexual abuse significantly increased the likelihood of subsequent alcohol dependence (odds ratio [OR]=1.58; 95% confidence interval [CI], 1.10-2.27). For women, sexual abuse (OR=1.79; 95% CI, 1.21-2.66) and boarding school attendance increased the odds of alcohol dependence (OR=1.57; 95% CI, 1.03-2.40). Two separate patterns of dose-response relationships were observed for men and women. Significant inter-tribal differences in rates of alcohol dependence remained after accounting for tribe-specific cultural factors and geographic region. Conclusions: Effects of childhood exposures on high-risk behaviors emphasize screening for violence in medical settings and development of social and educational programs for parents and children living on and near tribal reservations. C1 Univ Arizona, Mel & Enid Zuckerman Arizona Coll Publ Hlth, Div Hlth Promot Sci, Tucson, AZ USA. NIAAA, Neurogenet Lab, Bethesda, MD USA. RP Koss, MP (reprint author), 1632 E Lester St, Tucson, AZ 85719 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIAAA NIH HHS [N01AA51012] NR 32 TC 54 Z9 56 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2003 VL 25 IS 3 BP 238 EP 244 DI 10.1016/S0749-3797(03)00195-8 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 728MD UT WOS:000185720200009 PM 14507531 ER PT J AU Meissner, HI Breen, N Yabroff, KR AF Meissner, HI Breen, N Yabroff, KR TI Whatever happened to clinical breast examinations? SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SCREENING MAMMOGRAPHY; SELF-REPORTS; CANCER; WOMEN; GUIDELINES; OLDER; CARE AB Background: The purpose of this study was to examine trends in the use of clinical breast examinations (CBE), mammography, and both tests between the years 1990 and 2000. Methods: Receipt of breast cancer screening tests (CBE, mammography, and both tests combined) for white, black, and Hispanic women in 1990, 1994, 1998, and 2000 were examined by sociodemographic, access, and health risk indicators using data from the National Health Inter-view Survey. Results: The use of mammography increased from 1990 to 2000, but the proportion of women reporting a recent CBE decreased for almost all groups of women. Differential use of CBE by sociodemographic characteristics is consistent with what has been documented for mammography. Conclusions: Although the use of mammography has increased since 1990, there has been a downward trend in the use of CBE. Healthcare providers should be aware of the lower rates of CBE, particularly among women with compromised access to health care, and should not assume that women who get mammograms have received comprehensive screening for breast cancer. C1 NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Meissner, HI (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4102,MSC 7335, Rockville, MD 20852 USA. OI Yabroff, K. Robin/0000-0003-0644-5572 NR 24 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2003 VL 25 IS 3 BP 259 EP 263 DI 10.1016/S0749-3797(03)00189-2 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 728MD UT WOS:000185720200013 PM 14507535 ER PT J AU Daly, RC Danaceau, MA Rubinow, DR Schmidt, PJ AF Daly, RC Danaceau, MA Rubinow, DR Schmidt, PJ TI Concordant restoration of ovarian function and mood in perimenopausal depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GONADOTROPIN; ESTROGEN; HORMONE; WOMEN AB Objective: Despite reports of estradiol's therapeutic efficacy in perimenopausal depression, the relationship between ovarian function and mood in perimenopausal depression remains unclear. The purpose of this study was to examine changes in mood and pituitary-ovarian axis function in women exhibiting perimenopausal depression. Method: Depression ratings (from the Center for Epidemiologic Studies-Depression Scale [CES-D Scale]) and follicle-stimulating hormone (FSH) plasma levels of depressed perimenopausal women (N=110) attending a menopause clinic were obtained at baseline and after a 6-week screening period. Results: Eighteen women experienced an improvement in depression (50% decline in CES-D Scale scores) at week 6, which was associated with a significant decrease in FSH plasma levels (baseline: mean=73.3 IU/liter [SD=42.0]; week 6: mean=42.2 IU/ liter [SD=28.6]). Similarly, those subjects experiencing a 50% drop in FSH plasma levels had significant decreases in CES-D Scale scores (baseline: mean=23.3 [SD6.8]; week 6: mean=18.1 [SD=10.9]). However, between women with CES-D Scale scores greater than or equal to15 and those with CES-D Scale scores <15, no significant differences in FSH levels were observed either at baseline (mean=65.5 IU/liter [SD=35.7] and 60.9 IU/liter [SD=34.9], respectively) or at week 6 (mean=56.2 IU/liter [SD=36.6] and 51.5 IU/liter [SD=34.2]). Conclusions: Mood variability in women with perimenopausal depression may reflect episodic alterations in ovarian function that are best detected by longitudinal study designs. C1 NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, NIH, Bldg 10,Room 2N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. NR 18 TC 31 Z9 33 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2003 VL 160 IS 10 BP 1842 EP 1846 DI 10.1176/appi.ajp.160.10.1842 PG 5 WC Psychiatry SC Psychiatry GA 731JJ UT WOS:000185880300022 PM 14514500 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Shame on you, Uncle! SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2003 VL 93 IS 10 BP 1643 EP 1643 DI 10.2105/AJPH.93.10.1643 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 731JT UT WOS:000185881100014 PM 14534216 ER PT J AU Lucas, JW Barr-Anderson, DJ Kington, RS AF Lucas, JW Barr-Anderson, DJ Kington, RS TI Health status, health insurance, and health care utilization patterns of immigrant Black men SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SELF-RATED HEALTH; NEW-YORK-CITY; CAUSE-SPECIFIC MORTALITY; UNITED-STATES; FOLLOW-UP; BORN; MIGRATION; RACE; ASSIMILATION; RESIDENTS AB Objectives. This study sought to describe the health status, health insurance, and health care utilization patterns of the growing population of immigrant Black men. Methods. We used data from the 1997-2000 National Health Interview Survey to examine and then compare health variables of foreign-born Black men with those of US-born Black and White men. Logistic regression analyses were used to examine health outcomes. Results. Foreign-born Black men were in better overall health than their US-born Black counterparts and were much less likely than either US-born Black or White men to report adverse health behaviors. Despite these health advantages, foreign-born Black men were more likely than either US-born Black or White men to be uninsured. Conclusions. In the long term, immigrant Black men who are in poor health may be adversely affected by lack of health care coverage. C1 NIH, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Div Hlth Interview Stat, Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. RP Kington, RS (reprint author), NIH, Bldg 1,Room 126,1 Ctr Dr, Bethesda, MD 20892 USA. NR 44 TC 55 Z9 55 U1 0 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2003 VL 93 IS 10 BP 1740 EP 1747 DI 10.2105/AJPH.93.10.1740 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 731JT UT WOS:000185881100029 PM 14534231 ER PT J AU Wood, BJ DeFranco, B Ripple, M Topiel, M Chiriboga, C Mani, V Barry, K Fowler, D Masur, H Borio, L AF Wood, BJ DeFranco, B Ripple, M Topiel, M Chiriboga, C Mani, V Barry, K Fowler, D Masur, H Borio, L TI Inhalational anthrax: Radiologic and pathologic findings in two cases SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID BIOTERRORISM EXPOSURE; UNITED-STATES/; MANAGEMENT; PATIENTS/; WOMAN; CT C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. So Maryland Hosp Ctr, Dept Radiol, Clinton, MD 20735 USA. Off Chief Med Examiner State Maryland, Baltimore, MD 21201 USA. Infect Dis Phys PA, Mt Laurel, NJ 08054 USA. So Maryland Hosp Ctr, Intens Care Unit, Clinton, MD 20753 USA. Infect Dis Associates So Maryland, Clinton, MD 20735 USA. Radiol Associates Burlington Cty, Hainesport, NJ 08036 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. Johns Hopkins Ctr Civilian Biodef, Dept Crit Care Med, Baltimore, MD 21202 USA. RP Wood, BJ (reprint author), NIH, Dept Diagnost Radiol, Rm 1C 660,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 19 TC 11 Z9 11 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2003 VL 181 IS 4 BP 1071 EP 1078 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 724NB UT WOS:000185492700032 PM 14500233 ER PT J AU McKenzie, FE Sirichaisinthop, J Miller, RS Gasser, RA Wongsrichanalai, C AF McKenzie, FE Sirichaisinthop, J Miller, RS Gasser, RA Wongsrichanalai, C TI Dependence of malaria detection and species diagnosis by microscopy on parasite density SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID POLYMERASE CHAIN-REACTION; PLASMODIUM-FALCIPARUM; INFECTIONS; DEVICES; THICK AB Giemsa-stained blood smears from each of 2,190 patients from Thai government-operated clinics on the Thailand-Myanmar border were independently examined by the on-duty microscopists at the clinics and by 2-3 research microscopists, each blinded to the clinics' and each other's reports. Using a strictly defined protocol, a consensus reference-standard blood smear interpretation for each sample was produced by the research microscopists. This result was compared with the clinic's diagnostic interpretation for the corresponding sample with respect to detection of parasitemia and diagnosis of infecting species. Reference-standard results reported parasitemia in 13.2% of the samples reported negative by the clinic. Reference-standard results were negative in 24.3% of the samples reported parasite-positive by the clinic. For samples in which both the reference-standard result and the clinic result reported parasitemia, species identification differed for 13.7% of the samples. The likelihood of parasite detection and correct diagnosis at the clinic varied in accordance with the reference-standard estimates of parasite density. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Minist Publ Hlth, Dept Communicable Dis Control, Bangkok, Thailand. Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. Walter Reed Army Inst Res, Silver Spring, MD USA. RP McKenzie, FE (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 TW999999] NR 24 TC 67 Z9 69 U1 0 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD OCT PY 2003 VL 69 IS 4 BP 372 EP 376 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 741QZ UT WOS:000186469900004 PM 14640495 ER PT J AU Caputo, E Moharram, R Martin, BM AF Caputo, E Moharram, R Martin, BM TI Methods for on-chip protein analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE enzymatic hydrolysis; ProteinChip array; surface-enhanced laser desorption/ionization; C-terminal sequencing; carboxypeptidase Y ID FLIGHT-MASS-SPECTROMETRY; 2-DIMENSIONAL ELECTROPHORESIS; CARBOXYPEPTIDASE-Y; IDENTIFICATION; PROTEOMICS; TIME; GENES AB The unambiguous identification of peptides/proteins is crucial for the definition of the proteome. Using ProteinChip Array technology also known as surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS), we developed experimental protocols and probed test conditions required for the protein identification on ProteinChip surfaces. We were able to directly digest peptides/proteins on-chip surfaces by specific proteases, such as trypsin, and to obtain the peptide mass fingerprint of the sample under investigation by its direct analysis on a simple laser desorption/ionization mass spectrometer. Furthermore, tandem mass spectrometry was performed on several of the resulting tryptic peptides by using collision quadrupole time of flight (Qq-TOF) MS/MS via the ProteinChip interface, thus allowing the unambiguous identification of the protein(s) within the sample. In addition, we were able to identify the C-terminal sequence of peptides by their digestion with carboxypeptidase Y directly on ProteinChip surfaces coupled with SELDI-TOF MS analysis of the resulting peptide mass ladders employing the instrument's protein ladder sequence software. Moreover, the removal of up to nine amino acid residues from the C-terminal end of a peptide extends the functional range of Qq-TOF MS/MS sequence determination to over 3000 m/z. The utility of these procedures for the proteome exploration are discussed. (C) 2003 Elsevier Inc. All rights reserved. C1 DHHS, NIMH, LNT, Unit Mol Struct,NIH, Bethesda, MD 20892 USA. RP Martin, BM (reprint author), DHHS, NIMH, LNT, Unit Mol Struct,NIH, 10 Ctr Dr,Bldg 10 3N309, Bethesda, MD 20892 USA. OI CAPUTO, EMILIA/0000-0002-6485-8802 NR 23 TC 65 Z9 68 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 1 PY 2003 VL 321 IS 1 BP 116 EP 124 DI 10.1016/S0003-2697(03)00361-0 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 723BX UT WOS:000185413500014 PM 12963062 ER PT J AU Sturgeon, BE Chen, YR Mason, RP AF Sturgeon, BE Chen, YR Mason, RP TI Immobilized enzyme electron spin resonance: A method for detecting enzymatically generated transient radicals SO ANALYTICAL CHEMISTRY LA English DT Article ID PARAMAGNETIC-RESONANCE; HORSERADISH-PEROXIDASE; BIOCHEMICAL SYSTEMS; HYDROGEN PEROXIDE; LIGNIN PEROXIDASE; OXIDATION; METHEMOGLOBIN; ACETAMINOPHEN; OXYHEMOGLOBIN; SPECTROSCOPY AB The study of enzymatically generated, transient radicals provides valuable information about radical reactivity as well as enzyme function. ESR methods to detect transient radicals are generally based on continuous flow and have the potential to consume large quantities of enzyme, substrate, and buffer. Experimental approaches have been pursued to minimize sample volumes, although none have made the continuous-flow ESR approach generally applicable for enzymes and substrates available in limited quantities. We have developed an alternative approach to the traditional continuous-flow ESR method that provides the same high-resolution ESR spectra, but does not consume large quantities of enzyme, substrate, or buffer. The method utilizes enzyme immobilized onto an inert substrate packed directly into an ESR flat cell. Flowing substrate solution over the immobilized enzyme generates in situ, transient radicals, which can then be observed on the submillisecond time scale. We have termed this method "immobilized enzyme ESR," abbreviated IE-ESR. In this paper, we have described the details of the IE-ESR technique and have presented data collected using the IE-ESR technique for transient radicals from limited quantity enzymes, limited quantity substrates, and D2O buffers. An extension of this technique to ESR spin trapping has also been discussed. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Sturgeon, BE (reprint author), Western Carolina Univ, Dept Chem & Phys, Cullowhee, NC 28723 USA. NR 45 TC 4 Z9 4 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD OCT 1 PY 2003 VL 75 IS 19 BP 5006 EP 5011 DI 10.1021/ac034250k PG 6 WC Chemistry, Analytical SC Chemistry GA 728LB UT WOS:000185717700014 PM 14708772 ER PT J AU Hays, J Hunt, JR Hubbell, FA Anderson, GL Limacher, M Allen, C Rossouw, JE AF Hays, J Hunt, JR Hubbell, FA Anderson, GL Limacher, M Allen, C Rossouw, JE TI The Women's Health Initiative recruitment methods and results SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE clinical trial; cohort study; disease prevention; recruitment; women's health; postmenopausal women ID CLINICAL-TRIALS; FEASIBILITY; PREVENTION; DESIGN; CANCER C1 Baylor Coll Med, WHI Clin Ctr, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. Univ Florida, Dept Cardiol, Gainesville, FL USA. Univ Wisconsin, Dept Prevent Med, Madison, WI 53706 USA. NHLBI, WHI Project Off, Bethesda, MD 20892 USA. RP Hays, J (reprint author), Baylor Coll Med, Ctr Womens Hlth, 6535 Fannin,A701, Houston, TX 77030 USA. OI Anderson, Garnet/0000-0001-5087-7837 NR 14 TC 340 Z9 342 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2003 VL 13 IS 9 SU S BP S18 EP S77 DI 10.1016/S1047-2797(03)00042-5 PG 60 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 739TU UT WOS:000186363200003 PM 14575939 ER PT J AU Jackson, RD LaCroix, AZ Cauley, JA McGowan, J AF Jackson, RD LaCroix, AZ Cauley, JA McGowan, J TI The Women's Health Initiative calcium-vitamin D trial: Overview and baseline characteristics of participants SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE calcium supplements; vitamin D; disease prevention; clinical trials; fractures; osteoporosis; colon cancer; women's health; postmenopausal women ID POSTMENOPAUSAL WOMEN; COLORECTAL-CANCER; BONE LOSS; ELDERLY-WOMEN; COLON-CANCER; SUPPLEMENTATION; DENSITY; FRACTURES; OLDER; MEN C1 Ohio State Univ, Coll Med & Publ Hlth, Columbus, OH 43210 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. NIAMSD, Bethesda, MD 20892 USA. RP LaCroix, AZ (reprint author), Canc Prevent Res, Publ Hlth Sci, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 26 TC 85 Z9 85 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2003 VL 13 IS 9 SU S BP S98 EP S106 DI 10.1016/S1047-2797(03)00046-2 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 739TU UT WOS:000186363200006 PM 14575942 ER PT J AU Rossouw, JE Anderson, GL Oberman, A AF Rossouw, JE Anderson, GL Oberman, A TI Women's health initiative: Baseline summary - Foreword SO ANNALS OF EPIDEMIOLOGY LA English DT Editorial Material C1 NHLBI, NIH, WHI Project Off, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Alabama, Div Prevent Med, Birmingham, AL USA. RP Rossouw, JE (reprint author), NHLBI, NIH, WHI Project Off, Fed Bldg,7550 Wisconsin Ave,H-HV-LA,Room 406, Bethesda, MD 20892 USA. NR 2 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2003 VL 13 IS 9 SU S BP S1 EP S4 DI 10.1016/S1047-2797(03)00041-3 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 739TU UT WOS:000186363200001 ER PT J AU Werhahn, KJ Conforto, AB Kadom, N Hallett, M Cohen, LG AF Werhahn, KJ Conforto, AB Kadom, N Hallett, M Cohen, LG TI Contribution of the ipsilateral motor cortex to recovery after chronic stroke SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; ADULT SQUIRREL-MONKEYS; FUNCTIONAL MRI; MOVEMENT REPRESENTATIONS; SENSORIMOTOR CORTEX; MULTIPLE-SCLEROSIS; BRAIN-STIMULATION; PREMOTOR CORTEX; HAND MOVEMENT; REORGANIZATION AB It has been proposed that the intact (ipsilateral) motor cortex play a significant role mediating recovery of motor function in the paretic hand of chronic stroke patients, but this hypothesis has not been tested experimentally. Here, we evaluated the effects of transcranial magnetic stimulation (TMS) on motor performance of the paretic hand of chronic stroke patients and healthy controls. We hypothesized that, if activity in the intact hemisphere contributes to functional recovery, TMS should result in abnormal motor behavior in the paretic hand. We found that stimulation of the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral healthy hand. RT delays in the paretic hand correlated well with functional recovery. Finger tapping in the paretic hand was affected by TMS of the lesioned but not the intact hemisphere. These results are consistent with the idea that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N229,10 Ctr Dr, Bethesda, MD 20892 USA. OI Kadom, Nadja/0000-0002-7073-956X NR 34 TC 155 Z9 164 U1 0 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2003 VL 54 IS 4 BP 464 EP 472 DI 10.1002/ana.10686 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 727QU UT WOS:000185670600009 PM 14520658 ER PT J AU Bhabu, P Poletto, C Mann, E Bielamowicz, S Ludlow, CL AF Bhabu, P Poletto, C Mann, E Bielamowicz, S Ludlow, CL TI Thyroarytenoid muscle responses to air pressure stimulation of the laryngeal mucosa in humans SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT Meeting of the American-Laryngological-Association CY MAY 02-03, 2003 CL NASHVILLE, TENNESSEE SP Amer Laryngolog Assoc DE air pressure; laryngeal adductor reflex; larynx; sensation; thyroarytenoid muscle ID LONG-LATENCY RESPONSES; BRAIN-STEM REFLEXES; SENSORY DISCRIMINATION; SPASMODIC DYSPHONIA; NERVE-STIMULATION; CAT AB Others have observed glottic adduction in response to air puff stimuli and suggested that this is a reliable indicator of laryngeal sensation. We undertook to determine whether the same thresholds are found if one uses either thyroarytenoid (TA) muscle responses or subjects' reports of laryngeal sensation. We also studied the characteristics of TA responses to unilateral air pressure stimulation of the mucosa overlying the arytenoid cartilages. Ten normal volunteers provided button press responses to air pressure stimuli during bilateral TA electromyography. Similar thresholds were determined by reports of sensation as by electromyographic responses (p < .0005). The early TA responses occurred either around 80 ms or around 125 ms after onset of the air puff, with equal frequency on the ipsilateral and contralateral sides. The TA muscle responses to air pressure stimulation differ in physiological characteristics from the laryngeal adductor reflex that occurs in response to electrical stimulation of the superior laryngeal nerve. C1 Natl Inst Neurol Disorders & Stroke, Laryngeal & Speech Sect, NIH, Bethesda, MD USA. US FDA, Div Ophthalm & Ear Nose & Throat Dev, Rockville, MD USA. George Washington Univ, Ctr Med, Div Otolaryngol Head & Neck Surg, Washington, DC USA. RP Ludlow, CL (reprint author), 10 Ctr Dr,MSC 1416,Bldg 10,Rm 5D38, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 18 TC 16 Z9 16 U1 1 U2 4 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD OCT PY 2003 VL 112 IS 10 BP 834 EP 840 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 731PM UT WOS:000185895700002 PM 14587972 ER PT J AU Rudek, MA Bauer, KS Lush, RM Stinson, SF Senderowicz, AM Headlee, DJ Arbuck, SG Cox, MC Murgo, AJ Sausville, EA Figg, WD AF Rudek, MA Bauer, KS Lush, RM Stinson, SF Senderowicz, AM Headlee, DJ Arbuck, SG Cox, MC Murgo, AJ Sausville, EA Figg, WD TI Clinical pharmacology of flavopiridol following a 72-hour continuous infusion SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE cancer; flavopiridol; pharmacology ID UDP-GLUCURONOSYLTRANSFERASE UGT1A1; DEPENDENT KINASE INHIBITOR; CANCER-PATIENTS; FLAVONOID CHRYSIN; PHARMACOKINETICS; IRINOTECAN; L86-8275; DIARRHEA; CHOLECYSTOKININ; METABOLITES AB BACKGROUND: Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile. OBJECTIVE: To characterize the clinical pharmacology of flavopiridol. METHODS: Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis. RESULTS: Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m(2), respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m(2)/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (f(u) = 6%). CONCLUSIONS: The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m(2)/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m(2)/d, and postinfusional peaks appear to be related to enterohepatic recirculation. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. NCI, Dev Therapeut Program, Clin Trials Unit, Bethesda, MD 20892 USA. NCI, Med Oncol Clin Res Unit, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Clin Pharmacol Res Core,Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Clin Pharmacol Res Core,Med Oncol Clin Res Unit, Bldg 10,Rm 5A01,MSC1910,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 25 TC 33 Z9 33 U1 0 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD OCT PY 2003 VL 37 IS 10 BP 1369 EP 1374 DI 10.1345/aph.1C404 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 727PV UT WOS:000185668100001 PM 14519054 ER PT J AU Oz, MC Gelijns, AC Miller, L Wang, CL Nickens, P Arons, R Aaronson, K Richenbacher, W van Meter, C Nelson, K Weinberg, A Watson, J Rose, EA Moskowitz, AJ AF Oz, MC Gelijns, AC Miller, L Wang, CL Nickens, P Arons, R Aaronson, K Richenbacher, W van Meter, C Nelson, K Weinberg, A Watson, J Rose, EA Moskowitz, AJ TI Left ventricular assist devices as permanent heart failure therapy - The price of progress SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 123rd Annual Meeting of the American-Surgical-Association CY APR 24-26, 2003 CL WASHINGTON, D.C. SP a, Amer Surg Assoc ID SUPPORT; TRIAL AB Background Data: The REMATCH trial evaluated the efficacy and safety of long-term left ventricular assist device (LVAD) support in stage D chronic end-stage heart failure patients. Compared with optimal medical management, LVAD implantation significantly improved the survival and quality of life of these terminally ill patients. To date, however, there have been no analyses of the cost related to the LVAD survival benefit. This paper addresses the cost of hospital resource use, and its predictors, for long-term LVAD patients. Methods: Detailed cost data were available for 52 of 68 RE-MATCH patients randomized to LVAD therapy. We combined the clinical dataset with Medicare data, standard billing forms (UB-92), and line item bills provided directly by clinical centers. Charges were converted to costs by using the Ratio-of-Cost-to-Charges for each major resource category. Results: The mean cost for the initial implant-related hospitalization was $210,187 +/- 193,295. When implantation hospitalization costs are compared between hospital survivors and nonsurvivors the mean costs increase from $159,271 +/- 106,423 to $315,015 +/- 278,713. Sepsis, pump housing infection, and perioperative bleeding are the major drivers of implantation cost, established by regression modeling. In the patients who survived the procedure (n = 35), bypass time, perioperative bleeding, and late bleeding were the drivers of cost. The average annual readmission cost per patient for the overall cohort was $105,326. Conclusions: The cost of long-term LVAD implantation is commensurate with other life-saving organ transplantation procedures like liver transplantation. As an evolving technology, there are a number of opportunities for improvement that will likely reduce costs in the future. C1 Int Ctr Hlth Outcomes & Innovat Res, New York, NY 10032 USA. Columbia Univ, Dept Surg, New York, NY USA. NHLBI, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Iowa, Iowa City, IA USA. Ochsner Med Fdn, New Orleans, LA USA. LDS Hosp, Salt Lake City, UT USA. Univ Minnesota, Minneapolis, MN USA. RP Gelijns, AC (reprint author), Int Ctr Hlth Outcomes & Innovat Res, 600 W 168th St,7th Floor, New York, NY 10032 USA. OI Moskowitz, Alan/0000-0002-4412-9450 FU NHLBI NIH HHS [HL-53986] NR 13 TC 54 Z9 54 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD OCT PY 2003 VL 238 IS 4 BP 577 EP 583 DI 10.1097/01.sla.0000090447.73384.ad PG 7 WC Surgery SC Surgery GA 732DX UT WOS:000185926500026 PM 14530729 ER PT J AU Koh, Y Nakata, H Maeda, K Ogata, H Bilcer, G Devasamudram, T Kincaid, JF Boross, P Wang, YF Ties, YF Volarath, P Gaddis, L Harrison, RW Weber, IT Ghosh, AK Mitsuya, H AF Koh, Y Nakata, H Maeda, K Ogata, H Bilcer, G Devasamudram, T Kincaid, JF Boross, P Wang, YF Ties, YF Volarath, P Gaddis, L Harrison, RW Weber, IT Ghosh, AK Mitsuya, H TI Novel bis-tetrahydrofuranylurethane-containin nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HIV DRUG-RESISTANCE; TYPE-1 VARIANTS; ANTIRETROVIRAL THERAPY; CRYSTAL-STRUCTURES; INFECTION; NELFINAVIR; ZIDOVUDINE; BMS-232632; LAMIVUDINE; SELECTION AB We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC50], similar to0.003 muM; IC90, similar to0.009 muM) with minimal cytotoxicity (50% cytotoxic concentration for CD4(+) MT-2 cells, 74 muM). UIC-94017 blocked the infectivity and replication of each of HIV-1(NL4-3) variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 muM (IC(50)s, 0.003 to 0.029 muM), although it was less active against HIV-1(NL4-3) variants selected for resistance to amprenavir (IC(50)s, 0.22 muM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections. C1 Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8608556, Japan. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. Univ Illinois, Dept Chem, Chicago, IL 60607 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Internal Med 2, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM hm21q@nih.gov FU NIGMS NIH HHS [GM 62920, GM 53386, R01 GM062920-05, R01 GM062920, R01 GM053386, U01 GM062920, R37 GM053386] NR 32 TC 214 Z9 221 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2003 VL 47 IS 10 BP 3123 EP 3129 DI 10.1128/AAC.47.10.3123-3129.2003 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 726RH UT WOS:000185612600015 PM 14506019 ER PT J AU Stadtman, ER Moskovitz, J Levine, RL AF Stadtman, ER Moskovitz, J Levine, RL TI Oxidation of methionine residues of proteins: Biological consequences SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID APOLIPOPROTEIN-A-I; S-OXIDASE ACTIVITY; SULFOXIDE REDUCTASE; ANTIOXIDANT DEFENSE; CELLULAR-REGULATION; KIDNEY MICROSOMES; ESCHERICHIA-COLI; RABBIT LIVER; HIGH-DENSITY; RAT-LIVER AB Most reactive oxygen species (ROS) can oxidize methionine (Met) residues of proteins to methionine sulfoxide (MetO). However, unlike the ROS-dependent oxidation of other amino acid residues of proteins (except cysteine residues), the oxidation of Met residues is readily reversed by the action of methionine sulfoxide reductase (Msr) that catalyzes the thioredoxin-dependent reduction of MetO residues of proteins back to Met. We summarize here results of studies showing that the cyclic interconversion of Met and MetO residues of proteins is involved in several different biological processes: (a) It is the basis of an important antioxidant mechanism for the scavenging of ROS. (b) It is likely involved in the regulation of enzyme activities. (c) It is involved in cell signaling. (d) It can target proteins for proteolytic degradation. Furthermore, a loss in the ability to catalyze the reduction of protein MetO to Met residues leads to a decrease in the maximum life span, whereas overexpression of this activity leads to an increase in the life span of animals. In addition, a decrease in Msr activities in brain tissues is associated with the development of Alzheimer's disease. C1 NHLBI, LB, NIH, Bethesda, MD 20892 USA. RP NHLBI, LB, NIH, Bldg 50,Room 2140,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. EM erstadtman@nih.gov RI Levine, Rodney/D-9885-2011 NR 39 TC 197 Z9 199 U1 2 U2 41 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2003 VL 5 IS 5 BP 577 EP 582 DI 10.1089/152308603770310239 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 735FF UT WOS:000186101200010 PM 14580313 ER PT J AU Kant, AK Graubard, BI AF Kant, AK Graubard, BI TI Predictors of reported consumption of low-nutrient-density foods in a 24-h recall by 8-16 year old US children and adolescents SO APPETITE LA English DT Article DE low nutrient density foods; children; adolescents; dietary patterns; NHANES III ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; CHILDHOOD OBESITY; UNITED-STATES; ENERGY-DENSE; POOR FOODS; POPULATION; BEHAVIOR; PATTERNS; PROFILES AB The purpose of this study was to develop an explanatory model to predict the number of low-nutrient-density (LND) foods reported in a 24-h recall by US children and adolescents using data from the third National Health and Nutrition Examination Survey. The reported number of LND foods was estimated from 24-h dietary recall data for 8-16 year old respondents (n = 4137; 2024 males and 2113 females). The LND foods included-baked and dairy desserts, sweeteners, salty snacks, visible/discretionary fat, and miscellaneous. The predictive ability of socio-demographic. family, weight/dieting related, life-style or food consumption related subject characteristics was determined using multiple linear regression analyses. The strongest independent negative predictor of the reported number of LND foods was the amount of nutrient-dense foods from the five major food groups. In addition, number of eating occasions reported was a significant independent positive predictor, and the weekly frequency of consuming a complete school lunch was a significant independent negative predictor of the reported number of LND foods. These models explained approximately 55% of the variance in LND food reporting in both males and females. Socio-demographic. family, body weight, or lifestyle characteristics contributed little to predicting the number of LND foods reported in a 24-h recall. Published by Elsevier Ltd. C1 CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NR 25 TC 13 Z9 13 U1 1 U2 9 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD OCT PY 2003 VL 41 IS 2 BP 175 EP 180 DI 10.1016/S0195-6663(03)00060-6 PG 6 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 738XG UT WOS:000186312700007 PM 14550315 ER PT J AU Bogdan, JA Yuan, W Long-Rowe, KO Sarwar, J Brucker, EA Blake, MS AF Bogdan, JA Yuan, W Long-Rowe, KO Sarwar, J Brucker, EA Blake, MS TI Identification of peptides that mimic the pertussis toxin binding site on bovine fetuin SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID ISLET-ACTIVATING PROTEIN; BORDETELLA-PERTUSSIS; VACCINE; MODEL; CELLS AB The introduction of acellular pertussis vaccines has greatly enhanced the safety profile of vaccines to prevent whooping cough. Pertussis toxin (Ptx) is one component produced by Bordetella pertussis that is contained in all of these vaccines, either in combination with other known pertussis virulence factors or as the sole pertussis component, combined with tetanus and diphtheria toxoids. A hydrogen peroxide toxoid of Ptx has been shown to be efficacious in preventing pertussis infections in a mass vaccination trial and is presently licensed in the United States and Europe (B. Trollfors, J. Taranger, T. Lagergard, L. Lind, V. Sundh, G. Zackrisson, C. U. Lowe, W. Blackwelder, and J. B. Robbins, N. Engl. J. Med. 333:1045-1050, 1995). The industrial production of Ptx can be performed through the cultivation of B. pertussis in well-defined growth media, in which the components can be well characterized and their origins can be documented. Once the bacteria are removed from the culture, Ptx can be isolated from the supernatant and purified by using the technique described by Sekura et al. (R. D. Sekura, F. Fish, C. R. Manclark, B. Meade, and Y. L. Zhang, J. Biol. Chem. 258:1464714651, 1983). The only drawback of this procedure, which combines two affinity chromatography steps, one with Blue Sepharose and a second with matrix-bound bovine fetuin (BF), is the source and purity of the BF. Concern about vaccine preparations that may possibly risk contamination by material associated with bovine spongioform encephalopathy has continued to increase. We thus sought a replacement for the BF affinity chromatography and, more specifically, for the glycosidic moiety on BF. We describe here the identification of a seven-amino-acid peptide that mimics the glycosidic moiety on BF to which Ptx binds. Furthermore, we have constructed an affinity column containing this peptide that can be used to replace BF in Ptx purification. Finally, we used the X-ray crystallographic structure of Ptx bound to the oligosaccharide moiety of BF as a scaffold and replaced the oligosaccharide with the peptide. C1 Baxter Healthcare Corp, Columbia, MD 21046 USA. Baxter Healthcare Corp, Boulder, CO 80301 USA. RP Bogdan, JA (reprint author), NIAID, 6700-B Rockledge Dr,MSC 7616, Bethesda, MD 20892 USA. NR 18 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2003 VL 69 IS 10 BP 6272 EP 6279 DI 10.1128/AEM.69.10.6272-6279.2003 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 731JV UT WOS:000185881300069 PM 14532091 ER PT J AU Merikangas, KR Zhang, HP Avenevoli, S Acharyya, S Neuenschwander, M Angst, J AF Merikangas, KR Zhang, HP Avenevoli, S Acharyya, S Neuenschwander, M Angst, J TI Longitudinal trajectories of depression and anxiety in a prospective community study - The Zurich cohort study SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID NATIONAL-COMORBIDITY-SURVEY; MAJOR DEPRESSION; YOUNG-ADULTS; SUBTHRESHOLD DEPRESSION; CLINICAL-SIGNIFICANCE; MENTAL-DISORDERS; CO-MORBIDITY; PREVALENCE; PSYCHOPATHOLOGY; CLASSIFICATION AB Background: The dearth of long-term follow-up studies of community-based samples and differences in methodology in existing studies highlight the need for research designed to examine the stability, comorbidity, and diagnostic thresholds of depression and anxiety in the community. Methods: Prospective study of a community-based cohort aged 19 and 20 years from the canton of Zurich, Switzerland. Semistructured diagnostic interviews were administered by clinically experienced interviewers at 5 assessment points during a 15-year period. The format of the interview permitted assessment of major mental disorders at both the diagnostic and subthreshold levels. R Results: Comorbid anxiety and depression tended to be far more persistent than either syndrome alone. Individuals with anxiety states alone tended to develop either depression alone or comorbid anxiety and depression as they progressed through adulthood. In contrast, depression alone and depression comorbid with anxiety tended to be more stable than anxiety alone over time. The patterns of stability were similar for subthreshold and threshold-level disorders. Conclusions: These findings have important implications for classification and treatment of affective disorders. The greater stability of comorbid anxiety and depression than either disorder alone illustrates the importance of further investigation of comorbid states compared with noncomorbid states in etiologic and treatment research. The persistence of subthreshold-level depression and anxiety from early to mid adulthood also suggests the importance of characterizing the continuum of expression of depression and anxiety rather than adhering to strict diagnostic thresholds. C1 NIMH, Mood & Anxiety Disorders Program, Sect Dev Genet,Dept Hlth & Human Serv, Intramural Res Program,NIH, Bethesda, MD 20892 USA. Dept Epidemiol & Publ Hlth, New Haven, CT USA. Brown Univ, Dept Community Hlth, Providence, RI USA. Univ Zurich, Dept Psychiat, Zurich, Switzerland. RP Merikangas, KR (reprint author), NIMH, Mood & Anxiety Disorders Program, Sect Dev Genet,Dept Hlth & Human Serv, Intramural Res Program,NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. FU NIAAA NIH HHS [AA12044]; NIDA NIH HHS [DA12468] NR 77 TC 215 Z9 215 U1 1 U2 21 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2003 VL 60 IS 10 BP 993 EP 1000 DI 10.1001/archpsyc.60.9.993 PG 8 WC Psychiatry SC Psychiatry GA 730DY UT WOS:000185815000006 PM 14557144 ER PT J AU McClelland, JL Plaut, DC Gotts, SJ Maia, TV AF McClelland, JL Plaut, DC Gotts, SJ Maia, TV TI Developing a domain-general framework for cognition: What is the best approach? SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID PAST-TENSE; INTERACTIVE ACTIVATION; GERMAN INFLECTION; SPEECH-PERCEPTION; LANGUAGE DISORDER; TRACE MODEL; DUAL-ROUTE; RULES; MORPHOLOGY; CONTEXT AB We share with Anderson & Lebiere (A&L) (and with Newell before them) the goal of developing a domain-general framework for modeling cognition, and we take seriously the issue of evaluation criteria. We advocate a more focused approach than the one reflected in Newell's criteria, based on analysis of failures as well as successes of models brought into close contact with experimental data. A&L attribute the shortcomings of our parallel-distributed processing framework to a failure to acknowledge a symbolic level of thought. Our framework does acknowledge a symbolic level, contrary to their claim. What we deny is that the symbolic eve is the level at which the principles of cognitive processing should be formulated. Models cast at a symbolic level are sometimes useful as high-level approximations of the underlying mechanisms of thought. The adequacy of this approximation will continue to increase as symbolic modelers continue to incorporate principles of parallel distributed processing. C1 Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. RP McClelland, JL (reprint author), Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. EM jlm@cnbc.cmu.edu; plaut@cmu.edu; gotts@nih.gov; tmaia@cmu.edu RI McClelland, James/F-6004-2011; Gotts, Stephen/J-4842-2012; OI Maia, Tiago/0000-0002-5254-0389 NR 35 TC 5 Z9 5 U1 3 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD OCT PY 2003 VL 26 IS 5 BP 611 EP + PG 11 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 837FJ UT WOS:000222613600032 ER PT J AU Rivas, G Minton, AP AF Rivas, G Minton, AP TI Tracer sedimentation equilibrium: a powerful tool for the quantitative characterization of macromolecular self- and hetero-associations in solution SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Meeting on Intermolecular Associations in 2D and 3D CY JUN 19-20, 2003 CL UNIV NOTTINGHAM, NOTTINGHAM, ENGLAND HO UNIV NOTTINGHAM DE analytical ultracentrifugation; macromolecular interactions ID ANALYTICAL ULTRACENTRIFUGATION; PROTEIN; BINDING; FIBRINOGEN; MONOMER; ACTIN; SITE; FTSZ AB During the last two decades the measurement and analysis of sedimentation equilibrium has been used increasingly as a method for characterizing intermolecular interactions in solution. more recently, a variant of this technique has been developed, in which a trace amount of a single solute component is labelled so that the concentration gradient of that component at sedimentation equilibrium may be measured independently of the gradients of all other components. The dependence of equilibrium tracer gradients upon solution composition may be readily interpreted in the context of models for self- and hetero-association of the labelled component, and, in the case of concentrated solutions, repulsive as well as attractive solute-solute interactions. We present a summary of experimental and analytic methods, a brief review of some previously published applications, and a preview of new applications demonstrating capabilities beyond those afforded by other current techniques for characterizing macromolecular associations in solution. C1 NIDDK, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. CSIC, Ctr Invest Biol, Madrid 28006, Spain. RP Minton, AP (reprint author), NIDDK, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. OI Rivas, German/0000-0003-3450-7478 NR 27 TC 14 Z9 15 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD OCT PY 2003 VL 31 BP 1015 EP 1019 PN 5 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 733RV UT WOS:000186015200027 PM 14505471 ER PT J AU Rikiyama, T Curtis, J Oikawa, M Zimonjic, DB Popescu, N Murphy, BA Wilson, MA Johnson, AC AF Rikiyama, T Curtis, J Oikawa, M Zimonjic, DB Popescu, N Murphy, BA Wilson, MA Johnson, AC TI GCF2: expression and molecular analysis of repression SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE epidermal growth factor receptor; transcription; repression; promoter; lymphoma ID EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR GENE; BREAST-CANCER CELLS; EGF-RECEPTOR; TRANSCRIPTIONAL REPRESSOR; PROTEIN-BINDING; PROMOTER; IDENTIFICATION; RNA; GELSOLIN AB GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. We have mapped the gene for GCF2 by fluorescence in situ hybridization (FISH) to chromosome 2q37. Sequence analysis of the GCF2 gene and cDNA showed that the gene consists of eight exons and introns and spans 73 kbp of DNA. Northern blot analysis showed that GCF2 mRNA was differentially expressed in many human tissues and cell lines. GCF2 mRNA was expressed as a 4.2 kb mRNA in most human tissues with the highest expression level in peripheral blood leukocytes and lowest expression in brain and testis. Additional transcripts of 6.6, 2.9 and 2.4 kb were found in some tissues but the only transcript detected in cancer cell lines was 4.2 kb with high levels found in seven Burkitts' lymphoma cell lines. Western blot analysis showed that GCF2 protein is present at high levels in Burkitts' lymphoma and several other cancer cell lines. GCF2 was found in both nuclear and cytoplasmic compartments in cells. Deletion mutants of GCF2 revealed that amino acids 429-528 are required for both DNA binding and repression of the EGFR promoter. Furthermore, GCF2 was able to substantially decrease activator protein 2 (AP2) enhancement of the EGFR promoter. Thus, GCF2 is a transcriptional repressor overexpressed in cancer cell lines with a role in regulating expression of the EGFR. Published by Elsevier B.V. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Johnson, AC (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Room 5002,Bldg 37,37 Convent Dr MSC-4264, Bethesda, MD 20892 USA. NR 43 TC 21 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD OCT 1 PY 2003 VL 1629 IS 1-3 BP 15 EP 25 DI 10.1016/S0167-4781(03)00156-8 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 731HD UT WOS:000185877500003 PM 14522076 ER PT J AU Gallant, PE AF Gallant, PE TI Axotomy inhibits the slow axonal transport of tubulin in the squid giant axon SO BIOLOGICAL BULLETIN LA English DT Article; Proceedings Paper CT General Scientific Meeting of the Marine-Biological-Laboratory CY AUG 11-13, 2003 CL WOODS HOLE, MASSACHUSETTS SP Marine Biol Lab ID NEUROFILAMENT C1 NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP Gallant, PE (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU MARINE BIOLOGICAL LABORATORY PI WOODS HOLE PA 7 MBL ST, WOODS HOLE, MA 02543 USA SN 0006-3185 J9 BIOL BULL-US JI Biol. Bull. PD OCT PY 2003 VL 205 IS 2 BP 187 EP 188 DI 10.2307/1543244 PG 2 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA 739HJ UT WOS:000186338800015 PM 14583521 ER PT J AU Willeit, M Praschak-Rieder, N Zill, P Neumeister, A Ackenheil, M Kasper, S Bondy, B AF Willeit, M Praschak-Rieder, N Zill, P Neumeister, A Ackenheil, M Kasper, S Bondy, B TI C825T polymorphism in the G protein beta 3-subunit gene is associated with seasonal affective disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE seasonal; depression; signal transduction; G(beta)3; seasonality; association study ID GAMMA-SUBUNIT; MONONUCLEAR LEUKOCYTES; SIGNAL-TRANSDUCTION; ADENYLATE-CYCLASE; LIGHT THERAPY; BETA-SUBUNIT; MOOD; VARIANT; PATHOGENESIS; HYPERTENSION AB Background: Heterotrimeric G proteins play a pivotal role in the intracellular transduction of many transmitter-receptor interactions. Alterations in signal transduction and in G protein concentrations have been reported in seasonal and nonseasonal affective disorder. A single-nucleotide polymorphism (C825T) in the G protein beta3-subunit gene has been shown to influence intracellular response to G protein-coupled stimuli, and the T-allele of this polymorphism has been associated with hypertension and major depression. Methods: We genotyped deoxyribonucleic acid from peripheral mononuclear cells of 172 patients with seasonal affective disorder, winter type (SAD), and 143 healthy control subjects. Results: Patients with SAD were significantly more likely to be either homo- or heterozygous for the G(beta)3 T-allele when compared with healthy control subjects (p =.001), and they displayed a higher frequency of the G(beta)3 C825T T-allele (p =.021). The polymorphism was not associated with seasonality, which is the tendency to experience variations in mood and behavior with changing of the seasons. Conclusions: The G(beta)3 C825T polymorphism was associated with SAD in our study sample. This finding strengthens the evidence for the involvement of G protein-coupled signal transduction in the pathogenesis of affective disorder. (C) 2003 Society of Biological Psychiatry. C1 Univ Hos Psychiat, Dept Gen Psychiat, Vienna, Austria. Univ Munich, Hosp Psychiat, Dept Neurochem, Munich, Germany. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Willeit, M (reprint author), Ctr Addict & Mental Hlth, PET Ctr, 250 Coll St, Toronto, ON M5T 1R8, Canada. NR 28 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2003 VL 54 IS 7 BP 682 EP 686 DI 10.1016/S0006-3223(03)00169-0 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 724RL UT WOS:000185500500003 PM 14512207 ER PT J AU Vermetten, E Vythilingam, M Southwick, SM Charney, DS Bremner, JD AF Vermetten, E Vythilingam, M Southwick, SM Charney, DS Bremner, JD TI Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors ID CHRONIC ANTIDEPRESSANT TREATMENT; RAT HIPPOCAMPUS; COMBAT VETERANS; VIETNAM VETERANS; CHILDHOOD ABUSE; DENTATE GYRUS; SEXUAL ABUSE; PTSD; BRAIN; ATTENTION AB Background: Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. Methods: Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. Results: Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. Conclusions: These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD. (C) 2003 Society of Biological Psychiatry. C1 Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Positron Emiss Tomog Ctr Nucl Med, Atlanta, GA 30322 USA. Vet Affairs Med Ctr, Decatur, GA 30033 USA. NIMH, Program Mood & Anxiety Disorders, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. W Haven Vet Affairs Med Ctr, Natl Ctr Posttraumat Stress Disorder, West Haven, CT USA. RP Vermetten, E (reprint author), Univ Utrecht, Med Ctr, Dept Psychiat, Rudolf Magnus Inst Neurosci, Internal Mailbox B01206, NL-3584 CX Utrecht, Netherlands. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404 FU NIMH NIH HHS [R01 MH56120, R01 MH056120, R01 MH056120-04] NR 68 TC 274 Z9 286 U1 3 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2003 VL 54 IS 7 BP 693 EP 702 DI 10.1016/S0006-3223(03)00634-6 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 724RL UT WOS:000185500500005 PM 14512209 ER PT J AU Vythilingam, M Charles, HC Tupler, LA Blitchington, T Kelly, L Krishnan, KRR AF Vythilingam, M Charles, HC Tupler, LA Blitchington, T Kelly, L Krishnan, KRR TI Focal and lateralized subcortical abnormalities in unipolar major depressive disorder: An automated multivoxel proton magnetic resonance spectroscopy study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE multivoxel proton magnetic resonance spectroscopy; caudate; putamen; choline; N-acetyl-L-aspartate; major depression ID BRAIN METABOLITE CHANGES; MOOD DISORDERS; BASAL GANGLIA; CHOLINE; CAUDATE; INVIVO; MYOINOSITOL; LOCATION; NUCLEUS; CORTEX AB Background: The results of prior proton magnetic resonance spectroscopy (H-1-MRS) studies in unipolar major depressive disorder (MDD) evaluating choline (Cho)/ creatine (Cr) and N-acetyl-L-aspartate (NAA)/Cr ratios are mixed. These single-voxel or one-dimensional chemical-shift imaging (CSI) nonautomated H-1-MRS studies has been unable to evaluate global or lateralized abnormalities in neuronal or membrane function. Using automated multivoxel two-dimensional CSI H-1-MRS techniques, we tested the hypothesis that patients with MDD have focal neuronal and membrane abnormalities localized in the subcortical region. Methods: Whole brain and subcortical measures of Cho, NAA, Cr, and myo-inositol (ml) were obtained in 18 patients with MDD and 20 control subjects using automated two-dimensional CSI H-1-MRS. Results: Compared with control subjects, MDD patients had a significantly lower mean NAA/Cr amplitude in the caudate and a significantly higher mean Cho/Cr amplitude in the putamen, particularly on the right side. No differences were observed for global whole brain measurements. Conclusions: The findings support reduced neuronal viability or function in the caudate and altered membrane phospholipid metabolism in the putamen for patients with MDD. Our results are consistent with prior magnetic resonance imaging, positron emission tomography, and postmortem reports of focal and lateralized abnormalities of the basal ganglia in MDD. (C) 2003 Society of Biological Psychiatry. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Krishnan, KRR (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3950, Durham, NC 27710 USA. RI Charles, Hal/C-7772-2017 OI Charles, Hal/0000-0002-1414-2494 FU NIMH NIH HHS [K08 MH01460] NR 45 TC 43 Z9 47 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2003 VL 54 IS 7 BP 744 EP 750 DI 10.1016/S0006-3223(03)01908-X PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 724RL UT WOS:000185500500011 PM 14512215 ER PT J AU Smith, MJ Adams, LF Schmidt, PJ Rubinow, DR Wassermann, EM AF Smith, MJ Adams, LF Schmidt, PJ Rubinow, DR Wassermann, EM TI Abnormal luteal phase excitability of the motor cortex in women with premenstrual syndrome SO BIOLOGICAL PSYCHIATRY LA English DT Article DE transcranial magnetic stimulation; hormones; menstrual cycle; steroid; GABA; glutamate ID GABA(A) RECEPTOR SUBUNIT; AMINOBUTYRIC-ACID LEVELS; CORTICAL EXCITABILITY; MENSTRUAL-CYCLE; DYSPHORIC DISORDER; ALLOPREGNANOLONE; STEROIDS; MOOD; PROGESTERONE; SENSITIVITY AB Background: Premenstrual syndrome (PMS) involves an aberrant behavioral response to normal hormone secretion. Pathogenetic theories posit abnormal modulation of gamma-aminobutyric acid (GABA) transmission in the brain by neuroactive metabolites of progesterone (neurosteroids). In earlier transcranial magnetic stimulation (TMS) studies of the motor cortex, we showed that inhibition increases in the luteal phase, consistent with neurosteroid action at the GABA(A) receptor. Here, we studied women with PMS to see if their response to endogenous progesterone differed from that of control subjects. Methods: We studied nine women with PMS and 14 control subjects during the midfollicular and luteal phases with paired TMS. Subthreshold conditioning TMS was followed by test stimulation that produced a motor evoked potential (MEP) in a hand muscle. We gave pairs at each of seven intervals (2-10 msec) and unconditioned stimuli, measuring the amplitude ratio of the average MEP from the pairs at each interval to that from the unconditioned stimuli (ratio < 1 = inhibition). Results: Both groups showed the same follicular phase response to paired TMS. Control subjects showed more inhibition in the luteal phase. Women with PMS showed relative facilitation. Conclusions: This is the first physiological evidence for an abnormal brain response to progesterone in PMS. (C) 2003 Society of Biological Psychiatry. C1 NINDS, Brain Stimulat Unit, Bethesda, MD 20892 USA. NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), NINDS, Brain Stimulat Unit, Bldg 10,Room 5N234, Bethesda, MD 20892 USA. NR 37 TC 49 Z9 51 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2003 VL 54 IS 7 BP 757 EP 762 DI 10.1016/S0006-3223(03)01924-8 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 724RL UT WOS:000185500500013 PM 14512217 ER PT J AU Ali, SA Iwabuchi, N Matsui, T Hirota, K Kidokoro, S Arai, M Kuwajima, K Schuck, P Arisaka, F AF Ali, SA Iwabuchi, N Matsui, T Hirota, K Kidokoro, S Arai, M Kuwajima, K Schuck, P Arisaka, F TI Reversible and fast association equilibria of a molecular chaperone, gp57A, of bacteriophage T4 SO BIOPHYSICAL JOURNAL LA English DT Article ID SIZE-DISTRIBUTION ANALYSIS; SHORT TAIL FIBERS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; COILED-COILS; ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION ANALYSIS; SECONDARY STRUCTURE; CIRCULAR-DICHROISM; SELF-ASSOCIATION AB The association of a molecular chaperone, gp57A, of bacteriophage T4, which facilitates formation of the long and short tail fibers, was investigated by analytical ultracentrifugation, differential scanning microcalorimetry, and stopped-flow circular dichroism (CD) to establish the association scheme of the protein. Gp57A is an oligomeric alpha-helix protein with 79 amino acids. Analysis of the sedimentation velocity data by direct boundary modeling with Lamm equation solutions together with a more detailed boundary analysis incorporating association schemes led us to conclude that at least three oligomeric species of gp57A are in reversible and fast association equilibria and that a 3(mer)(mer)(mer)(-6)(-12) model described the data best. On the other hand, differential scanning microcalorimetry revealed a highly reversible two-step transition of dissociation/denaturation, both of which accompanied decrease in CD at 222 nm. The melting curve analysis revealed that it is consistent with a 6(mer)(mer)(mer)(-3)(-1) model. The refolding/association kinetics of gp57A measured by stopped-flow CD was consistent with the interpretation that the bimolecular reaction from trimer to hexamer was preceded by a fast alpha-helix formation in the dead-time. Trimer or hexamer is likely the functional oligomeric state of gp57A. C1 Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Midori Ku, Yokohama, Kanagawa 2268501, Japan. Nagaoka Univ Technol, Dept Bioengn, Niigata, Japan. RIKEN, Genome Sci Ctr, Yokohama, Kanagawa, Japan. Tokyo Inst Technol, Precis & Intelligence Lab, Yokohama, Kanagawa 227, Japan. Natl Inst Adv Ind Sci & Technol, Inst Biol Resources & Funct, Ibaraki, Japan. Univ Tokyo, Grad Sch Sci, Tokyo 113, Japan. NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. RP Arisaka, F (reprint author), Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Midori Ku, 4259 Nagatsuta, Yokohama, Kanagawa 2268501, Japan. RI Arai, Munehito/A-1258-2012; OI Schuck, Peter/0000-0002-8859-6966 NR 44 TC 16 Z9 16 U1 0 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2003 VL 85 IS 4 BP 2606 EP 2618 DI 10.1016/S0006-3495(03)74683-9 PG 13 WC Biophysics SC Biophysics GA 726AQ UT WOS:000185575400049 PM 14507723 ER PT J AU Ma, K Wang, KA AF Ma, K Wang, KA TI Binding of copper(II) ions to the polyproline II helices of PEVK modules of the giant elastic protein titin as revealed by ESI-MS, CD, and NMR SO BIOPOLYMERS LA English DT Article DE PEVK; ESI-MS; CD; NMR; copper ID IONIZATION MASS-SPECTROMETRY; SKELETAL-MUSCLE; DILATED CARDIOMYOPATHY; COMPLEXES; PEPTIDES; ZINC; FRAGMENTATION; SPECTROSCOPY; MUTATIONS; SEQUENCE AB Titin, a family of giant elastic proteins, constitutes an elastic sarcomere matrix in striated muscle. In the 1-band region of the sarcomere, the titin PEVK segment acts as a molecular spring to generate elasticity as well as sites of adhesion with parallel thin filaments. Previously, we reported that PEVK consists of tandem repeats of 28 residue modules and that the "polyproline II-coil" motif is the fundamental conformational motif of the PEVK module. In order to characterize the factors that may affect and alter the PPII-coil conformational motifs, we have initiated a systematic study of the interaction with divalent cations (Cu2+, Ca2+, Zn2+, and Ni2+) and a conformational profile of PEVK peptides (a representative 28-mer peptide PR: PEPPKEVVPEKKAPVAPPKKPEVPPVKV and its subfragments PR1: kvPEPPKEVVPE, PR2: VPEKKAPVAPPK, PR3: KPEVPPVKV). UV-Vis absorption difference spectra and CD spectra showed that Cu2+ bound to PR1 with high affinity (20 muM), while its binding to PR2 and PR3 as well as the binding of other cations to all four peptides were of lower affinity (>100 muM). Conformational studies by CD revealed that Cu2+ binding to PR1 resulted in a polyproline II to turn transition up to a 1:2 PR1/Cu2+ ratio and a coil to turn transition at higher Cu2+ concentration. ESI-MS provided the stoichiometry of PEVK peptide-Cu2+, complexes at both low and high ion strength, confirming the specfic high affinity binding of Ca2+ to PR1 and PR. Furthermore, NMR and ESI-MS/MS fragmentation analysis elucidated the binding sites of the PEVK peptide-Cu2+ complexes at (-2)KVPe(2), (VPE10)-V-8, (13)APV(15) and (EVP24)-E-22. A potential application of Cu2+ binding in peptide sequencing by mass spectrometry was also revealed. We conclude that Cu2+ binds and bends PEVK peptides to a beta-turn-like structure at specific sites. The specfic targeting of Cu2+ towards PPII is likely to be of significant value in elucidating the roles of PPII in titin elasticity as well as in interactions of proline-rich proteins. (C) 2003 Wiley Periodicals, Inc. C1 NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, KA (reprint author), NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NR 46 TC 10 Z9 10 U1 1 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD OCT PY 2003 VL 70 IS 3 BP 297 EP 309 DI 10.1002/bip.10477 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 741AM UT WOS:000186435800002 PM 14579303 ER PT J AU Post, RM Leverich, GS Altshuler, LL Frye, MA Suppes, TM Keck, PE McElroy, SL Kupka, R Nolen, WA Grunze, H Walden, J AF Post, RM Leverich, GS Altshuler, LL Frye, MA Suppes, TM Keck, PE McElroy, SL Kupka, R Nolen, WA Grunze, H Walden, J TI An overview of recent findings of the Stanley Foundation Bipolar Network (Part I) SO BIPOLAR DISORDERS LA English DT Review DE anticonvulsants; antidepressants; bipolar disorder; course of illness; depression; episode sensitization; lithium; mania; mood stabilizers; rapid cycling; Stanley Foundation Bipolar Network ID DEPRESSIVE SYMPTOMATOLOGY IDS; STRESSFUL LIFE EVENTS; CLINICAL CASE SERIES; AFFECTIVE-DISORDER; FOLLOW-UP; LITHIUM PROPHYLAXIS; ANTIDEPRESSANT DISCONTINUATION; PREVIOUS EPISODES; MAJOR DEPRESSION; RATING-SCALE AB Aim and Methods: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. Results: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. Conclusions: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden. C1 NIMH, Biol Psychiat Branch, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Stanley Fdn Bipolar Network, NIH, DHHS, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Ambulatory Clin Res Ctr, Los Angeles, CA USA. VA Med Ctr, Los Angeles, CA USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Med Ctr, Altrecht Inst Mental Hlth, Utrecht, Netherlands. LMU, Psychiat Klin, Munich, Germany. Univ Freiburg Klinikum, Zentrum Innovat Therapie Bipolarer Storungen, Freiburg, Germany. RP NIMH, Biol Psychiat Branch, NIH, DHHS, Bldg 10,Room 3S239,10 Ctr Dr,MSC-1272, Bethesda, MD 20892 USA. EM robert.post@nih.gov RI Nolen, Willem/E-9006-2014 FU NIMH NIH HHS [R01 MH079261] NR 60 TC 111 Z9 113 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD OCT PY 2003 VL 5 IS 5 BP 310 EP 319 DI 10.1034/j.1399-5618.2003.00051.x PG 10 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 728VK UT WOS:000185736900002 PM 14525551 ER PT J AU Bishop, MR AF Bishop, MR TI The evolution of hematopoietic stem cell transplantation for multiple sclerosis SO BLOOD LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bishop, MR (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2003 VL 102 IS 7 BP 2314 EP 2314 DI 10.1182/blood-2003-08-2643 PG 1 WC Hematology SC Hematology GA 727PD UT WOS:000185666500003 ER PT J AU Rosenberg, HF AF Rosenberg, HF TI Human neutrophils and TLRs: 2, 4, and plenty more SO BLOOD LA English DT Editorial Material C1 NIAID, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2003 VL 102 IS 7 BP 2319 EP 2319 DI 10.1182/blood-2003-07-2478 PG 1 WC Hematology SC Hematology GA 727PD UT WOS:000185666500010 ER PT J AU Horwitz, ME Uzel, G Linton, GF Miller, JA Brown, MR Malech, HL Holland, SM AF Horwitz, ME Uzel, G Linton, GF Miller, JA Brown, MR Malech, HL Holland, SM TI Persistent Mycobactetium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency SO BLOOD LA English DT Article ID INTERLEUKIN-12 AB Interferon-gamma receptor-1 (IFNgammaR1) deficiency is a rare inherited immunodeficiency. We performed a nonmyeloablative allogeneic stem cell transplantation on a boy with complete lFNgammaR1 deficiency and refractory disseminated Mycobacterium avium infection. Despite the patient's profound immune defect, early donor stem cell engraftment was low. Full donor engraftment was accomplished only following multiple donor lymphocyte infusions. Detection of IFNgammaR1 expression on peripheral blood monocytes and neutrophils corresponded with establishment of stable, complete donor hematopoletic chimerism. However, expression of, and signaling through IFNgammaR1 disappeared shortly thereafter. Disseminated Mycobacterium avium infection persisted and the patient died. Coculture of Mycobacterium avium with normal myeloid cells resulted in an IFNgamma signaling defect similar to that observed in vivo. Active disseminated Mycobacterium avium infection may significantly compromise normal immune reconstitution following allogeneic stem cell transplantation. Patients with IFNgammaR1 deficiency should receive transplants before developing refractory mycobacterial infections. (C) 2003 by The American Society of Hematology. C1 NIAID, Host Def Lab, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. Childrens Mem Hosp, Div Immunol & Rheumatol, Chicago, IL 60614 USA. RP Horwitz, ME (reprint author), Duke Univ, Med Ctr, Adult Bone Marrow & Stern Cell Transplant Program, 2400 Pratt St,DUMC 3961, Durham, NC 27710 USA. NR 9 TC 23 Z9 24 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2003 VL 102 IS 7 BP 2692 EP 2694 DI 10.1182/blood-2003-04-1268 PG 3 WC Hematology SC Hematology GA 727PD UT WOS:000185666500060 PM 12805054 ER PT J AU Molloy, FM Carr, TD Zeuner, KE Dambrosia, JM Hallett, M AF Molloy, FM Carr, TD Zeuner, KE Dambrosia, JM Hallett, M TI Abnormalities of spatial discrimination in focal and generalized dystonia SO BRAIN LA English DT Article DE focal dystonia; generalized dystonia; spatial discrimination ID SOMATOSENSORY-EVOKED-POTENTIALS; IDIOPATHIC TORSION DYSTONIA; HAND DYSTONIA; CERVICAL DYSTONIA; WRITERS CRAMP; SENSORY DISCRIMINATION; ADULT MONKEYS; BLINK REFLEX; MEDIAN NERVE; CORTEX AB Sensory processing is impaired in focal hand dystonia (FHD), with most previous studies having evaluated only the symptomatic limb. The purpose of this study was to establish whether the sensory system is affected in other types of dystonias and whether the contralateral hand is also involved in FHD. We used a spatial acuity measure (Johnson-Van Boven-Phillips domes) to evaluate sensory spatial discrimination in both hands of patients with different forms of dystonias including primary generalized DYT1 dystonia (associated with a unique deletion in the DYT1 gene) (n=13), FHD (n=15), benign essential blepharospasm (n=9), cervical dystonia (n=10) and in age-matched controls. Clinical evaluation included the Fahn dystonia scale for the focal dystonia groups and the Marsden-Burke-Fahn scale for the generalized dystonia group. Spatial discrimination was normal in patients with DYT1 dystonia, despite all of these patients having hand dystonia. However, spatial discrimination thresholds were significantly increased in both hands in the focal dystonia groups (thresholds were similar for each group) and did not correlate significantly with either severity or duration of dystonic symptoms. Thresholds were significantly increased in the dominant hand compared with the non-dominant hand only within the FHD group. Our observations demonstrate involvement of both the dominant and non-dominant somatosensory cortices, and suggest that abnormal sensory processing is a fundamental disturbance in patients with focal dystonia. These findings of altered sensory processing in idiopathic focal but not generalized DYT1 dystonia suggest both a primary pathophysiological role for the phenomenon in focal dystonia and divergent pathophysiological processes in the two conditions. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (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 58 TC 106 Z9 109 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD OCT PY 2003 VL 126 BP 2175 EP 2182 DI 10.1093/brain/awg219 PN 10 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 721HF UT WOS:000185310400006 PM 12821512 ER PT J AU Pickworth, WB O'Hare, ED Fant, RV Moolchan, ET AF Pickworth, WB O'Hare, ED Fant, RV Moolchan, ET TI EEG effects of conventional and denicotinized cigarettes in a spaced smoking paradigm SO BRAIN AND COGNITION LA English DT Article DE placebo cigarettes; denicotinized cigarettes; smoking; electrocortical; EEG; electroencephalogram ID NICOTINE CHEWING GUM; TOBACCO WITHDRAWAL; HEART-RATE; ABSTINENCE; DEPENDENCE; SMOKERS; MECAMYLAMINE; DEPRIVATION; FREQUENCY; CAFFEINE AB Although there is a documented association between plasma nicotine levels and smoking behavior, recent studies indicate that denicotinized cigarettes reduced craving and symptoms of tobacco withdrawal. Denicotinized cigarettes (that deliver tar but insignificant amounts of nicotine) and conventional cigarettes were compared in a within-subject spaced smoking study. In six sessions, subjects (n = 10) smoked denicotinized cigarettes or conventional cigarettes every 30, 60 or 240min (8, 4 or 1 cigarette(s)). EEG effects of the last cigarette of each session were deduced by comparisons with EEG recordings collected before smoking. Conventional cigarettes increased spectral edge EEG frequency, decreased theta power and increased beta1 power. Denicotinized cigarettes decreased spectral frequency. The EEG effects of both cigarettes depended upon the recentness of smoking. The results indicate that nicotine delivery, recentness and the process of smoking importantly influence the EEG; other, non-nicotine components of tobacco smoke may also exert EEG effects. Published by Elsevier Inc. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Pickworth, WB (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr,POB 5180, Baltimore, MD 21224 USA. NR 39 TC 12 Z9 12 U1 3 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD OCT PY 2003 VL 53 IS 1 BP 75 EP 81 DI 10.1016/S0278-2626(03)00205-7 PG 7 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 738BR UT WOS:000186267300010 PM 14572505 ER PT J AU Sloand, EM Fuhrer, M Keyvanfar, K Mainwaring, L Maciejewski, J Wang, Y Johnson, S Barrett, AJ Young, NS AF Sloand, EM Fuhrer, M Keyvanfar, K Mainwaring, L Maciejewski, J Wang, Y Johnson, S Barrett, AJ Young, NS TI Cytogenetic abnormalities in paroxysmal nocturnal haemoglobinuria usually occur in haematopoietic cells that are glycosylphosphatidylinositol-anchored protein (GPI-AP) positive SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE paroxysmal nocturnal haemoglobinuria; karyotype; genomic instability; progenitor cells; fluorescent in situ hybridization ID T-CELLS; APOPTOSIS; MUTATIONS; GROWTH; GENE AB Some patients with paroxysmal nocturnal haemoglobinuria (PNH) have bone marrow findings characteristic of myelodysplastic syndrome. We studied nine PNH patients to determine whether these karyotypic abnormalities were more likely to occur in glycosylphosphatidylinositol-anchored protein (GPI-AP)-negative cells. Abnormal chromosome patterns were evident only in the GPI-AP-positive populations of the PNH clone in 8 of 9 cases studied. Purified GPI-AP-negative CD34 cells gave rise only to cells of normal karyotype, whereas the progeny of the GPI-AP-positive CD34 cells showed the karyotypic abnormality. These findings suggest that environmental factors, but not genetic instability of the GPI-AP-deficient clone, foster development or survival of haematopoietic cells with chromosomal abnormalities. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Sloand, EM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 14 TC 12 Z9 12 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2003 VL 123 IS 1 BP 173 EP 176 DI 10.1046/j.1365-2141.2003.04562.x PG 4 WC Hematology SC Hematology GA 726JG UT WOS:000185595500026 PM 14510962 ER PT J AU Kidd, KR Weinstein, BM AF Kidd, KR Weinstein, BM TI Fishing for novel angiogenic therapies SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE zebrafish; blood vessels; angiogenesis; arteries; veins; endothelium ID ENDOTHELIAL-GROWTH-FACTOR; ZEBRAFISH DANIO-RERIO; GENE-EXPRESSION; SONIC-HEDGEHOG; TRANSGENIC ZEBRAFISH; VASCULAR DEVELOPMENT; COAGULATION PATHWAY; FACTOR VEGF; IN-VIVO; DIFFERENTIATION AB The zebrafish has recently emerged as an important model for the study of vascular embryogenesis. Its genetic accessibility, external development, and optically clear embryo are just a few of the features that set the zebrafish apart as a particularly well-suited model for studying vascular development. However, there is little precedent for its use as a tool for the experimental study of therapeutic angiogenesis. Here, we review the use of the zebrafish for studying vascular development and patterning, and discuss how the zebrafish might be used more directly as a model for developing and testing effective therapeutic angiogenesis approaches. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 88 TC 28 Z9 33 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD OCT PY 2003 VL 140 IS 4 BP 585 EP 594 DI 10.1038/sj.bjp.0705496 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 737PH UT WOS:000186240600001 PM 14534143 ER PT J AU Aviles, RJ Annex, BH Lederman, RJ AF Aviles, RJ Annex, BH Lederman, RJ TI Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2) SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE angiogenesis; fibroblast growth factor; clinical trials ID CORONARY-ARTERY-DISEASE; PHASE-I TRIAL; INTERMITTENT CLAUDICATION; TISSUE DISTRIBUTION; ENDOTHELIAL-CELLS; AMERICAN-COLLEGE; STABLE ANGINA; NITRIC-OXIDE; DOUBLE-BLIND; TASK-FORCE AB Therapeutic angiogenesis represents an attempt to relieve inadequate blood flow by the directed growth and proliferation of blood vessels. Neovascularization is a complex process involving multiple growth factors, receptors, extracellular matrix glycoproteins, intracellular and extracellular signaling pathways, and local and bone-marrow-derived constituent cells, all responding to a symphonic arrangement of temporal and spatial cues. In cardiovascular disease, patients with refractory angina and lower extremity intermittent claudication seem most amenable to early tests of therapeutic angiogenesis. Monotherapy with the recombinant protein basic fibroblast growth factor (FGF-2) has been tested in six human trials. These have shown provisional safety, and two have provided 'proof of concept' for the strategy of therapeutic angiogenesis. One large randomized phase II trial failed to show significant efficacy in coronary artery disease. Another showed significant efficacy in peripheral artery disease, although the magnitude of benefit was disappointing at the dose tested. This overview details the suitable clinical trial design and further steps toward the clinical development of FGF-2. C1 NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bldg 10,Room 2C713,MSC 1538, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 FU NHLBI NIH HHS [Z01 HL005062-03] NR 61 TC 39 Z9 43 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD OCT PY 2003 VL 140 IS 4 BP 637 EP 646 DI 10.1038/sj.bjp.0705493 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 737PH UT WOS:000186240600007 PM 14534147 ER PT J AU Deutsch, M Land, SR Begovic, M Wieand, HS Wolmark, N Fisher, B AF Deutsch, M Land, SR Begovic, M Wieand, HS Wolmark, N Fisher, B TI The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy - Results of national surgical adjuvant breast and bowel project (NSABP) clinical trials B-04 and B-06 SO CANCER LA English DT Article ID COMPARING TOTAL MASTECTOMY; RADIATION-THERAPY; CONSERVATIVE SURGERY; RADICAL-MASTECTOMY; 2ND MALIGNANCIES; CANCER RISK; CHEST-WALL; FOLLOW-UP; IRRADIATION; WOMEN AB BACKGROUND. in the current study, the authors compared the incidence of subsequent primary lung carcinoma in patients with breast carcinoma who received radiotherapy as part of their treatment and in those patients who did not. The patients were participants in two large National Surgical Adjuvant Breast and Bowel Project (NSABP) breast carcinoma trials, B-04 and B-06, which prospectively randomized women to either undergo surgery alone or to undergo surgery and postoperative radiotherapy. METHODS. The NSABP trial B-04 (1971-1974) randomized patients to undergo radical mastectomy versus total (simple) mastectomy and radiotherapy to the chest wall, axilla, and supraclavicular and internal mammary lymph node areas. For patients with a clinically uninvolved axilla, there was a third randomization arm: total mastectomy without radiotherapy. The B-06 trial (1976-1984) randomized patients between those undergoing total mastectomy versus lumpectomy versus those undergoing lumpectomy and breast irradiation, with all patients undergoing an axillary lymph node dissection. The records of all patients who developed a recurrence in the lung or a new primary lung tumor were reviewed to determine the incidence and laterality of confirmed and probable primary lung carcinoma. RESULTS. For the 1665 evaluable patients on the NSABP B-04 trial (mean follow-up of 21.4 years), there was a total of 23 subsequent confirmed and probable ipsilateral or contralateral primary lung carcinomas. In those patients who had received comprehensive postmastectomy radiotherapy, there was a statistically significant increase in the incidence of these new primary tumors (P = 0.029). With regard to the development of confirmed new primary ipsilateral lung carcinoma alone, the incidence was statistically significantly increased (P = 0.013) in those patients who had received radiotherapy as part of their treatment, and when confirmed and probable ipsilateral lung carcinomas were analyzed, there was a strong trend toward a statistically significant increase in those patients who had received radiotherapy (P = 0.066). For the 1850 evaluable patients on the NSABP trial B-06 (mean follow-up of 19.0 years), there was a total of 30 second primary lung carcinomas but no increase in either ipsilateral or contralateral primary tumors of the lung in those patients who had received radiotherapy. CONCLUSIONS. Extensive postmastectomy irradiation of the chest wall and regional lymphatic node areas, with consequent exposure of a greater volume of lung to higher doses as administered in the NSABP B-04 trial compared with postlumpectomy breast irradiation in the NSABP B-06 trial, was associated with an increased incidence of subsequent primary lung tumors, both ipsilateral and contralateral. Cancer 2003;98:1362-8. (C) 2003 American Cancer Society. C1 Univ Pittsburgh, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. NSABP, Ctr Biostat, Pittsburgh, PA USA. NSABP, Operat Ctr, Pittsburgh, PA USA. RP Deutsch, M (reprint author), Univ Pittsburgh, Presbyterian Med Ctr, Dept Radiat Oncol, 200 Lothrop St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [U10-CA 12027] NR 19 TC 71 Z9 73 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2003 VL 98 IS 7 BP 1362 EP 1368 DI 10.1002/cncr.11655 PG 7 WC Oncology SC Oncology GA 724AM UT WOS:000185464100005 PM 14508821 ER PT J AU Forero, A Meredith, RF Khazaeli, MB Carpenter, DM Shen, S Thornton, J Schlom, J LoBuglio, AF AF Forero, A Meredith, RF Khazaeli, MB Carpenter, DM Shen, S Thornton, J Schlom, J LoBuglio, AF TI A novel monoclonal antibody design for radioimmunotherapy SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE deleted C(H)2CC49; pharmacokinetics; radioimmunotherapy ID TUMOR-ASSOCIATED GLYCOPROTEIN-72; METASTATIC COLORECTAL-CANCER; PHASE-I TRIAL; IMMUNE-RESPONSE; PROSTATE-CANCER; I-131 CC49; B72.3; INTERFERON; CARCINOMA; ANTIGEN AB The generation of chimeric and complementary-determining region (CDR) grafted monoclonal antibodies (MAb) have reduced the immunogenicity problem in the clinical application of radioimmunotherapy with monoclonal antibodies. However, humanization (Hu) has prolonged the circulation (plasma T1/2) of radiolabeled antibodies, resulting in an increased normal tissue exposure to radioactivity and greater dose-limiting bone marrow suppression. To overcome this problem, a tumor-associated glycoprotein (TA G)-72-specific CDR grafted MAb with C(H)2 domain deletion (DeltaC(H)2) was developed from the MAb CC49. Preclinical studies have demonstrated that HuCC49DeltaC(H)2 clears more rapidly from the plasma of mice than HuCC49. This preliminary report describes the initial human experience with HuCC49DeltaC(H)2 radiolabeled with I-131 and administered to patients with metastatic colorectal carcinoma. In this pilot study we enrolled four patients who received a single infusion of 20 mg of HuCC49DeltaC(H)2 (total protein dose) labeled with 10 mCi Of I-131 Pharmacokinetics, biodistribution, dosimetry, and immune response were evaluated over 2-6 weeks. No toxicity was observed in this group of patients. A one-compartment bolus model using the non-linear (NLIN) procedures in Statistical Analysis Software (SAS(R); SAS, Incorporated, Cary, NC) best describes the pharmacokinetics of the I-131-HuCC49DeltaC(H)2 with a plasma mean T1/2 of 20 +/- 3 hours, a mean residence time (MRT) of 29 +/- 4 hours and a clearance rate (0) of 1.5 +/- 0.1 mL/hours/kg. The whole body and marrow radiation dose estimates were 0.55 +/- 0.06 rad/mCi and 1.00 +/- 0.14 rad/mCi, respectively. All patients had positive localization of antibody to metastatic tumor sites. The I-131-HuCC49DeltaC(H)2 biodistribution was similar to murine CC49. Three patients had no evidence of antibody response to HuCC49DeltaC(H)2 over 6 weeks of observation, and one patient had a marginal response by week 6. Intravenous administration of HuCC49DeltaC(H)2 is sale and well tolerated. The deleted C(H)2 construct has a shorter half-life compared with prior studies of murine CC49 but with similar biodistribution and low immunogenicity. These studies support the further clinical investigation of this agent in phase I trials by intravenous and intraperitoneal routes. C1 Univ Alabama, Ctr Comprehens Canc, Wallace Tumor Inst, Dept Med,Div Hematol & Oncol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Comprehens Canc, Dept Radiat Oncol, Birmingham, AL 35294 USA. Natl Canc Inst, Bethesda, MD USA. RP Forero, A (reprint author), Univ Alabama, Ctr Comprehens Canc, Wallace Tumor Inst, Dept Med,Div Hematol & Oncol, 220 1824 6th Ave S, Birmingham, AL 35294 USA. FU NCI NIH HHS [K12-CA76937, R01 CA84152] NR 45 TC 19 Z9 19 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD OCT PY 2003 VL 18 IS 5 BP 751 EP 759 DI 10.1089/108497803770418292 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 743UU UT WOS:000186592600008 PM 14629823 ER PT J AU Mack, WJ Preston-Martin, S Dal Maso, L Galanti, R Xiang, M Franceschi, S Hallquist, A Jin, F Kolonel, L La Vecchia, C Levi, F Linos, A Lund, E McTiernan, A Mabuchi, K Negri, E Wingren, G Ron, E AF Mack, WJ Preston-Martin, S Dal Maso, L Galanti, R Xiang, M Franceschi, S Hallquist, A Jin, F Kolonel, L La Vecchia, C Levi, F Linos, A Lund, E McTiernan, A Mabuchi, K Negri, E Wingren, G Ron, E TI A pooled analysis of case-control studies of thyroid cancer: cigarette smoking and consumption of alcohol, coffee, and tea SO CANCER CAUSES & CONTROL LA English DT Article DE alcohol; caffeine; case-control; smoking; thyroid neoplasms ID POSTMENOPAUSAL WOMEN; HORMONE LEVELS; SEX-HORMONES; RISK-FACTORS; GOITER; PREMENOPAUSAL; PAPILLARY; HISTORY; MEN; PREVALENCE AB Objective: To analyze the role of smoking, alcohol, coffee and tea in relation to thyroid cancer, we conducted a pooled analysis of 14 case - control studies conducted in the United States, Europe, and Asia. Methods: The sample consisted of 2725 thyroid cancer cases ( 2247 females, 478 males) and 4776 controls ( 3699 females, 1077 males). Conditional logistic regression with strati. cation on study, age at diagnosis, and gender was used to compute odds ratios and 95% confidence intervals. Results: Thyroid cancer risk was reduced in persons who had ever smoked. The relationship was more pronounced in current smokers (OR = 0.6, 95% CI = 0.6 - 0.7) than former smokers (OR = 0.9, 95% CI = 0.8 - 1.1). There were significant trends of reduced risk with greater duration and frequency of smoking. For consumption of wine and beer, there was a significant trend of decreasing thyroid cancer risk ( p = 0.02) that was not maintained after adjustment for current smoking (p = 0.12). Thyroid cancer risk was not associated with consumption of coffee or tea. These findings were consistent in both gender-specific and histology-specific (papillary and follicular) analyses. Conclusions: Pooled analyses of these geographically diverse case - control data indicate a reduced thyroid cancer risk associated with current smoking. A reduced risk associated with alcohol was eliminated after adjustment for smoking, and caffeinated beverages did not alter thyroid cancer risk. C1 Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. Ctr Riferimento Oncol, Serv Epidemiol, I-33081 Aviano, Italy. Ctr Tobacco Prevent, Huddinge, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Karolinska Inst, Radiumhemmet, Dept Oncol Pathol, SE-17176 Stockholm, Sweden. Shanghai Canc Inst, Shanghai, Peoples R China. Univ Hawaii Manoa, Canc Res Ctr Hawaii, Honolulu, HI 96822 USA. Univ Milan, Ist Stat Med & Biometria, I-20122 Milan, Italy. CHU Vaudois, Inst Univ Med Sociale & Prevent, Registre Vaudois Tumeurs, Canc Epidemiol Unit, CH-1011 Lausanne, Switzerland. Univ Athens, Dept Epidemiol & Stat, Athens Med Sch, Athens, Greece. Univ Tromso, Inst Community Med, Tromso, Norway. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. NCI, Radiat Epidemiol Branch, Rockville, MD USA. Ist Ric Farmacol Mario Negri, Milan, Italy. Linkoping Univ, Fac Hlth Sci, Div Environm & Occupat Med, Linkoping, Sweden. RP Mack, WJ (reprint author), Univ So Calif, Dept Prevent Med, Keck Sch Med, 1540 Alcazar St,CHP-218, Los Angeles, CA 90089 USA. RI Negri, Eva/B-7244-2013; OI Negri, Eva/0000-0001-9712-8526; La Vecchia, Carlo/0000-0003-1441-897X NR 47 TC 72 Z9 72 U1 0 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2003 VL 14 IS 8 BP 773 EP 785 DI 10.1023/A:1026349702909 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 738DW UT WOS:000186272300010 PM 14674742 ER PT J AU Preston-Martin, S Franceschi, S Ron, E Negri, E AF Preston-Martin, S Franceschi, S Ron, E Negri, E TI Thyroid cancer pooled analysis from 14 case-control studies: what have we learned? SO CANCER CAUSES & CONTROL LA English DT Article ID REPRODUCTIVE FACTORS; HORMONAL FACTORS; RISK-FACTORS; WOMEN; DISEASES; HISTORY; CONSUMPTION; PAPILLARY; CARCINOMA; THERAPY C1 Univ So Calif, Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Int Agcy Res Canc, Unit Field & Intervent Studiews, F-69372 Lyon, France. NCI, Radiat Epidemiol Branch, Rockville, MD USA. Mario Negri Inst Pharmacol Res, Lab Gen Epidemiol, Milan, Italy. RP Preston-Martin, S (reprint author), Univ So Calif, Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, 1441 Eastlake Ave,M-S 44, Los Angeles, CA 90033 USA. RI Negri, Eva/B-7244-2013 OI Negri, Eva/0000-0001-9712-8526 NR 32 TC 27 Z9 29 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2003 VL 14 IS 8 BP 787 EP 789 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 738DW UT WOS:000186272300011 PM 14674743 ER PT J AU Sikder, H Huso, DL Zhang, H Wang, BH Ryu, B Hwang, ST Powell, JD Alani, RM AF Sikder, H Huso, DL Zhang, H Wang, BH Ryu, B Hwang, ST Powell, JD Alani, RM TI Disruption of Id1 reveals major differences in angiogenesis between transplanted and autochthonous tumors SO CANCER CELL LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; SQUAMOUS-CELL CARCINOMA; METASTASIS; EXPRESSION; PROTEINS; VASCULARIZATION; SUPPRESSOR; INHIBITORS; GROWTH; MICE AB Id genes regulate tumor angiogenesis and loss of Id1 inhibits tumor xenograft growth in mice. Here we evaluate the role of Id1 in a more clinically relevant tumor model system using a two-step chemical carcinogenesis protocol. Remarkably, we find that Id1(-/-) mice are more susceptible to skin tumorigenesis compared to their wild-type counterparts. Cutaneous neoplasms in Id1(-/-) mice show increased proliferation without alterations in tumor angiogenesis; however, Id1(-/-) mice possess 50% fewer cutaneous gammadelta T cells than their wild-type counterparts due to an intrinsic migration defect associated with loss of expression of the chemokine receptor, CXCR4. We suggest that there are important differences between the mechanisms of angiogenesis in transplanted and autochthonous tumors and that these findings will have significant implications for the potential utility of antiangiogenic therapies in cancer. C1 Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Comparat Med, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21231 USA. NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Alani, RM (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. FU NCRR NIH HHS [RR000171]; NIAID NIH HHS [AI001773]; NIAMS NIH HHS [AR48246] NR 31 TC 50 Z9 54 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT PY 2003 VL 4 IS 4 BP 291 EP 299 DI 10.1016/S1535-6108(03)00245-9 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 736CY UT WOS:000186154200009 PM 14585356 ER PT J AU Avramis, IA Laug, WE Sausville, EA Avramis, VI AF Avramis, IA Laug, WE Sausville, EA Avramis, VI TI Determination of drug synergism between the tyrosine kinase inhibitors NSC 680410 (adaphostin) and/or STI571 (imatinib mesylate, Gleevec) with cytotoxic drugs against human leukemia cell lines SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ABL GENE MUTATION; IN-VITRO; BCR-ABL; CYTOSINE-ARABINOSIDE AB The primary growth factor receptors involved in angiogenesis and lymphomagenesis can be grouped into the vascular endothelial growth factor (VEGF) receptors and related families. Inhibition of VEGF and other growth factors, including c-Abl, c-Kit, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factor (IGF), or their receptors containing tyrosine kinase domains by antiangiogenesis drugs disrupts cell survival signal transduction pathways and may contribute to the proapoptotic pathways in malignant cells. However, clinical trials suggest that signal transduction inhibitors have considerable antitumor activity when used as single agents only for a short time, most likely due to the development of drug resistance by the host or by the tumor cells. In order to prevent this problem and to augment their antitumor efficacy, these agents could be administered in combination with cytotoxic antineoplastic drugs. We hypothesized that the combination of the antiangiogenesis tyrosine kinase inhibitors with cytotoxic drugs would produce synergistic drug regimens. Two human T-lymphoblastic leukemia cell lines that express VEGF-R1, CEM/0 (wild-type, WT) and the drug-resistant clone CEM/ara-C/I/ASNase-0.5-2, were utilized in the drug combination studies. NSC 680410, a tyrosine kinase inhibitor given at 0.1 to 1 muM for 72 h, inhibited VEGF secretion and leukemic cell growth at 90% of vehicle-treated control cultures with an IC50 value of less than 1 muM. The cytotoxic drugs idarubicin (IDA), fludarabine (Fludara), and cytosine arabinoside (ara-C) were used for the various drug combinations. One-, two-, three-, and four-drug treatments were tested. Cell viability was documented by the MTT assay and photomicrographic estimation of apoptotic cells. Both the combination index (CI) and isobologram evaluations demonstrated strong synergism between these drugs and the tyrosine kinase inhibitor. NSC 680410 was highly synergistic with IDA, IDA + ara-C, and IDA + Fludara + ara-C, over the respective cytotoxic drug regimens at concentrations easily achieved in patient plasma. NSC 680410 potentiated the activity of IDA in both leukemia cell lines by 17.8- and 221.4-fold in the WT and drug-resistant line, respectively. The activity of NSC 680410 + IDA + ara-C was also potentiated by 58.8-fold in the WT line, and the activity of NSC 680410 + IDA + Fludara + ara-C by 2.4- and 6.47x10(6)-fold in the WT and drug-resistant lines, respectively. The results suggest that IDA was not needed for optimal synergistic activity in the CEM/0 cells, but IDA was a necessary component to obtain drug synergism in the drug-resistant clone. Similarly, STI571 (imatinib mesylate, Gleevec), the p210(bcr/abl) tyrosine kinase inhibitor, demonstrated synergism with Fludara + ara-C or IDA + ara-C. Most importantly STI571 showed synergism with NSC 680410, suggesting that these drugs inhibit different tyrosine kinase domains in human leukemia cells. Lastly, pretreatment of leukemic cells with NSC 680410 showed additivity with gamma radiation in comparison to either treatment modality alone. The data, taken together, suggest that by inhibiting the pro-survival signal transduction pathway (VEGF-R1) and DNA replication by cytotoxic drugs, leukemic cells undergo apoptosis in a synergistic manner. In conclusion, the combinations of antiangiogenesis and DNA-damaging cytotoxic drugs are highly synergistic regimens in both WT and drug-resistant leukemic cell lines and they should be examined further. C1 USC Keck Sch Med, Dept Pediat, Div Hematol Oncol, Los Angeles, CA 90027 USA. NCI, Rockville, MD USA. RP Avramis, IA (reprint author), USC Keck Sch Med, Dept Pediat, Div Hematol Oncol, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. NR 44 TC 29 Z9 31 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2003 VL 52 IS 4 BP 307 EP 318 DI 10.1007/s00280-003-0668-y PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 729TK UT WOS:000185790100007 PM 12827297 ER PT J AU Leguizamo, J Quinn, M Takimoto, CH Liang, MD Ismail, ASA Pang, J Dahut, W Grem, JL AF Leguizamo, J Quinn, M Takimoto, CH Liang, MD Ismail, ASA Pang, J Dahut, W Grem, JL TI A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE camptothecin; topoisomerase I; phase I; pharmacokinetics; pharmacodynamics ID METASTATIC COLORECTAL-CARCINOMA; CONTINUOUS INTRAVENOUS-INFUSION; CELL LUNG-CANCER; TRIAL; CAMPTOTHECIN AB Purpose. A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC). Methods. 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 mug/m(2) per hour. Results. Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 mug/m(2) per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 mug/m(2) per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM.h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes. Conclusions. The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 mug/m(2) per hour (1.13 mg/m(2) per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity. C1 Natl Naval Med Res Inst, NCI Navy Oncol, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, NCI Navy Med Oncol, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD USA. RP Grem, JL (reprint author), Natl Naval Med Res Inst, NCI Navy Oncol, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM gremj@mail.nih.gov NR 29 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2003 VL 52 IS 4 BP 333 EP 338 DI 10.1007/s00280-003-0657-1 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 729TK UT WOS:000185790100010 PM 12819941 ER PT J AU Sherman, ME Wang, SS Wheeler, CM Rich, L Gravitt, PE Tarone, R Schiffman, M AF Sherman, ME Wang, SS Wheeler, CM Rich, L Gravitt, PE Tarone, R Schiffman, M TI Determinants of human papillomavirus load among women with histological cervical intraepithelial neoplasia 3: Dominant impact of surrounding low-grade lesions SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; POLYMERASE-CHAIN-REACTION; ASCUS-LSIL TRIAGE; VIRAL LOAD; UNDETERMINED SIGNIFICANCE; INSITU HYBRIDIZATION; RANDOMIZED-TRIAL; COPY NUMBER; HIGH-RISK; HPV TYPES AB Measurement of human papillomavirus (HPV) DNA load has been suggested as a means for improving the positive predictive value of HPV testing for detecting cervical intraepithelial neoplasia 3 and cancer (CIN3+). We hypothesized that lesions surrounding CIN3+ (especially the extent of associated CIN1) are important determinants of load, which limit its clinical use. To test this hypothesis, we reviewed the pathology of women at enrollment in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were managed at enrollment with oncogenic HPV testing using Hybrid Capture 2 (Digene Corp., Gaithersburg, MD) or colposcopy. We focused our analysis on 133 cases of CIN3+ that were identified, stratified by the number of HPV types detected using a PCR-based method (62 single, 71 multiple infections). Infection with multiple types (P < 0.01) and identification of CIN1 or CIN2 in tissues surrounding CIN3 (P = 0.01) were each significantly associated with higher load (two-way ANOVA). Higher load was associated with more extensive CIN1 (P < 0.01), especially when associated with multiple HPV types. Intensive partial rescreening of enrollment thin-layer slides obtained from women with histopathological CIN3+ revealed that ASC-US/LSIL cells were more numerous than ASC-H/HSIL cells. ASC-US/LSIL cell counts were significantly correlated with load (r = 0.31; P < 0.01), whereas counts of ASC-H/HSIL cells were uncorrelated. We conclude that the extent of histopathological CIN1, number of HPV types, and the number of ASC-US/LSIL cells in exfoliative cervical samples vary greatly among cases of CIN3+ and strongly affect HPV load. These factors severely limit the clinical use of load measurements irrespective of HPV testing methodology. C1 NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ New Mexico, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. Informat Management Serv, Silver Spring, MD 20940 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Int Epidemiol Inst, Rockville, MD 20850 USA. RP Sherman, ME (reprint author), NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 52 TC 76 Z9 83 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2003 VL 12 IS 10 BP 1038 EP 1044 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500013 PM 14578140 ER PT J AU Kaufman, DJ Beaty, TH Struewing, JP AF Kaufman, DJ Beaty, TH Struewing, JP TI Segregation analysis of 231 Ashkenazi Jewish families for evidence of additional breast cancer susceptibility genes SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LINKAGE ANALYSIS; OVARIAN-CANCER; STEROID-HORMONE; MAJOR-GENE; HIGH-RISK; BRCA2; MUTATIONS; HISTORY; HETEROGENEITY; LOCALIZATION AB Between 5 and 10% of breast cancer is attributable to inherited cancer susceptibility genes. Mutations in the genes BRCA1 and BRCA2 account for two-thirds of hereditary breast cancer cases. Using segregation analysis, families of cases without BRCA1/2 mutations were studied for statistical evidence of another major breast cancer gene in a community-based sample of Jewish probands tested previously for the presence of three BRCA founder mutations. A total of 231 probands with breast cancer, who do not carry a founder mutation, reported complete data on 602 female first-degree relatives of probands over age 20; 78 of these relatives had breast cancer. Segregation analysis was used to evaluate the likelihood of various genetic and nongenetic models. Sporadic, environmental, and general Mendelian genetic models fit the family data poorly and were rejected. A Mendelian recessive model fit better than dominant and codominant models, although none of these could be rejected. Cumulative incidence curves predicted by the recessive and codominant models fit observed incidence among first-degree relatives well. The assumption of Mendelian transmission of a major recessive gene(s) is compatible with the data. The recessive model predicts that 4% of women would carry the high-risk genotype, with 85% of them developing breast cancer by age 70. There was significant heterogeneity between these families and the 114 BRCA1/2 mutation-positive families from the same study population, implying that this apparent recessive effect is not because of undetected BRCA1/2 mutations. The study adds support for a major autosomal recessive component to breast cancer susceptibility. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, NIH, 41-D702,41 Lib Dr, Bethesda, MD 20892 USA. EM struewij@mail.nih.gov RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 40 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2003 VL 12 IS 10 BP 1045 EP 1052 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500014 PM 14578141 ER PT J AU Sears, SR Stanton, AL Kwan, L Krupnick, JL Rowland, JH Meyerowitz, BE Ganz, PA AF Sears, SR Stanton, AL Kwan, L Krupnick, JL Rowland, JH Meyerowitz, BE Ganz, PA TI Recruitment and retention challenges in breast cancer survivorship research: Results from a multisite, randomized intervention trial in women with early stage breast cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SUPPORT AB The Moving Beyond Cancer trial is a multisite randomized, controlled trial of an individualized psychoeducational intervention for women with early stage breast cancer. Recruitment early in the cancer trajectory and assessment of retention at multiple points are notable features of the research, offering a unique opportunity to examine recruitment, retention, and predictors of participation. Patients were registered for the study within 6 weeks after definitive surgery and followed until primary medical treatment completion, whereupon they were enrolled, administered baseline measures, and randomized to one of three arms. Of 2242 women referred, 41% were ineligible. Of eligible women, 42% elected participation through the point of randomization (n = 558). Participants did not differ from nonparticipants on initial self-reported physical functioning and mental health status, employment status, cancer history, cancer treatment plan, or previous cancer-related research participation. Women who were over 65 years of age, of racial minority status, unmarried, or less educated were less likely to participate through the point, of randomization. Thus, several patient characteristics predicted trial participation, indicating the need for targeted recruitment attempts. C1 Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. Univ Kansas, Dept Psychol, Lawrence, KS 66045 USA. Univ Calif Los Angeles, Div Canc Prevent & Control Res, Sch Publ Hlth, Los Angeles, CA 90095 USA. Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Georgetown Univ, Med Ctr, Dept Psychiat, Washington, DC 20007 USA. Natl Canc Inst, Off Canc Survivorship, Rockville, MD 20852 USA. Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. RP Stanton, AL (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall, Los Angeles, CA 90095 USA. FU NCI NIH HHS [2 R01 CA63028] NR 12 TC 39 Z9 39 U1 0 U2 12 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 OCT PY 2003 VL 12 IS 10 BP 1087 EP 1090 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500020 PM 14578147 ER PT J AU Cho, EY Hildesheim, A Chen, CJ Hsu, MM Chen, IH Mittl, BF Levine, PH Liu, MY Chen, JY Brinton, LA Cheng, YJ Yang, CS AF Cho, EY Hildesheim, A Chen, CJ Hsu, MM Chen, IH Mittl, BF Levine, PH Liu, MY Chen, JY Brinton, LA Cheng, YJ Yang, CS TI Nasopharyngeal carcinoma and genetic polymorphisms of DNA repair enzymes XRCC1 and hOGG1 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID EPSTEIN-BARR-VIRUS; POLY(ADP-RIBOSE) POLYMERASE; SER326CYS POLYMORPHISM; CANCER SUSCEPTIBILITY; ESOPHAGEAL CANCER; CIGARETTE-SMOKING; RISK-FACTORS; DAMAGED DNA; PROTEIN; TAIWAN AB Nitrosamine consumption and polymorphisms in CYP2E1, the product of which is involved in the activation of nitrosamines into reactive intermediates, have been shown to be associated with nasopharyngeal carcinoma (NPC) risk. Given that reactive intermediates created during nitrosamine metabolism are capable of DNA damage, we further hypothesized that differences between individuals in their ability to repair DNA damage might be important in NPC pathogenesis. To evaluate this hypothesis, this study focused on effects of genetic polymorphisms of DNA repair genes hOGG1 and XRCC1 on the development of NPC. We conducted a case-control study to investigate the genotypes of 334 patients with NPC and 283 healthy community controls matched by sex, age, and residence. The PCR-based RFLP assay was used to identify genetic polymorphisms. After adjustment for sex, age, and ethnicity, the odds ratio (OR) of developing NPC for hOGG1 codon 326 genotypes of Ser/Cys and Cys/Cys compared with the Ser/Ser genotype was 1.6 (95% CI, 1.0-2.6). For XRCC1 codon 280 genotypes of Arg/His and His/His compared with the Arg/Arg genotype, the OR was 0.64 (95% CI, 0.43-0.96). Among subjects with putative high-risk genotypes for both hOGG1 and XRCC1, the OR was 3.0 (95% CI, 1.0-8.8). Furthermore, subjects with putative high-risk genotypes for hOGG1, XRCC1, and CYP2E1 had an OR of disease of 25 (95% CI, 3.5-177). Polymorphisms of the DNA repair genes hOGG1 (codon 326) and XRCC1 (codon 280) are associated with an altered risk of NPC. Carriers of multiple putative high-risk genotypes have the highest risk of developing NPC. C1 Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10018, Taiwan. Natl Taiwan Univ, Dept Otorhinolaryngol, Taipei 10018, Taiwan. Natl Taiwan Univ, Grad Inst Microbiol, Coll Med, Taipei 10018, Taiwan. MacKay Mem Hosp, Dept Otorhinolaryngol, Taipei, Taiwan. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Westat Inc, Rockville, MD USA. George Washington Univ, Sch Publ Hlth & Hlth Sci, Washington, DC USA. RP Cheng, YJ (reprint author), Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Room 1552,1 Jen Ai Rd Sect 1, Taipei 10018, Taiwan. RI Chen, Chien-Jen/C-6976-2008; Chen, Jen-Yang/D-2085-2010; Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 42 TC 109 Z9 118 U1 0 U2 1 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 OCT PY 2003 VL 12 IS 10 BP 1100 EP 1104 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500023 PM 14578150 ER PT J AU Hu, N Goldstein, AM Albert, PS Giffen, C Tang, ZZ Ding, T Taylor, PR Emmert-Buck, MR AF Hu, N Goldstein, AM Albert, PS Giffen, C Tang, ZZ Ding, T Taylor, PR Emmert-Buck, MR TI Evidence for a familial esophageal cancer susceptibility gene on chromosome 13 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ALLELIC LOSS; SHANXI-PROVINCE; CHINA; IDENTIFICATION; HISTORY AB Previous segregation analyses of pedigrees from areas of China where esophageal squamous cell carcinoma (ESCC) rates are extraordinarily high suggested a Mendelian mode of transmission. We initiated a search for a major ESCC gene by conducting a genome-wide scan in ESCC tumors. Chromosome 13 showed loss of heterozygosity (LOH) in 95% of microsatellite markers, the highest frequency of LOH on any chromosome. In the current study, we established a high-resolution deletion map using 107 markers on 13q and compared LOH frequency by family history of upper gastrointestinal cancer. Overall allelic loss was-significantly higher in those with a positive (versus negative) family history, suggesting the presence of an inherited tumor suppressor gene on 13q in ESCC. C1 NCI, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD 20904 USA. Shanx Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. RP Emmert-Buck, MR (reprint author), NCI, Pathol Lab, Pathogenet Unit, Bldg 10,Room 2A33,900 Rockville Pike, Bethesda, MD 20892 USA. NR 16 TC 15 Z9 16 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2003 VL 12 IS 10 BP 1112 EP 1115 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500026 PM 14578153 ER PT J AU Landi, MT Baccarelli, A AF Landi, MT Baccarelli, A CA Seveso Study Grp TI Correspondence re: K. Toide et al., Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells: trimodal distribution of Japanese population according to induction of CYP1B1 mRNA by environmental dioxins. 12, 219-222, 2003 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2003 VL 12 IS 10 BP 1116 EP 1117 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 736CR UT WOS:000186153500027 PM 14578154 ER PT J AU Trudel, S Trachtenberg, J Toi, A Sweet, J Li, ZH Jewett, M Tshilias, J Zhuang, LH Hitt, M Wan, YH Gauldie, J Graham, FL Dancey, J Stewart, AK AF Trudel, S Trachtenberg, J Toi, A Sweet, J Li, ZH Jewett, M Tshilias, J Zhuang, LH Hitt, M Wan, YH Gauldie, J Graham, FL Dancey, J Stewart, AK TI A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer SO CANCER GENE THERAPY LA English DT Article DE prostate cancer; IL-2; adenovirus; adjuvant therapy ID RADICAL PROSTATECTOMY; TUMOR-REGRESSION; CLINICAL STAGE; GENE-THERAPY; IMMUNOTHERAPY; ADENOVIRUS; CARCINOMA; VECTOR; PATTERNS; CRITERIA AB Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score >7 or prostate-specific antigen (PSA) >10 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 10(9), 5 x 10(9) and 10(10) PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both gamma-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose ( mean decline of 33.3%, range 17-69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovector-mediated IL-2 gene delivery. C1 Princess Margaret Hosp, Div Hematol Oncol & Urol, Toronto, ON M5G 2M9, Canada. McMaster Univ, Dept Biol & Pathol, Hamilton, ON, Canada. NCI, Rockville, MD USA. RP Stewart, AK (reprint author), Princess Margaret Hosp, Div Hematol Oncol & Urol, 5th Floor,Room 126,610 Univ Ave, Toronto, ON M5G 2M9, Canada. NR 26 TC 39 Z9 45 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD OCT PY 2003 VL 10 IS 10 BP 755 EP 763 DI 10.1038/sj.cgt.7700626 PG 9 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 727TV UT WOS:000185677700003 PM 14502228 ER PT J AU Keezer, SM Ivie, SE Krutzsch, HC Tandle, A Libutti, SK Roberts, DD AF Keezer, SM Ivie, SE Krutzsch, HC Tandle, A Libutti, SK Roberts, DD TI Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin SO CANCER RESEARCH LA English DT Article ID ACTIVATING POLYPEPTIDE-II; DIFFERENTIAL GENE-EXPRESSION; P38 MAP KINASE; FOCAL ADHESION; ACTIN DYNAMICS; TUMOR-GROWTH; LIM-KINASE; IN-VITRO; METHIONINE AMINOPEPTIDASE; ANTIANGIOGENIC THERAPY AB Inhibition of angiogenesis has emerged as a key focus for the treatment of cancer, necessitating a better understanding of the downstream molecular targets of angiogenesis inhibitors. Endostatin, thrombospondin-1, fumagillin, and its synthetic derivative, TNP-470, are potent inhibitors of endothelial cell proliferation and migration in culture and of angiogenesis in vivo. To identify targets that mediate the effects of these inhibitors, we compared two-dimensional gel electrophoresis patterns from lysates of treated and untreated human endothelial cells. Among the proteins identified were cofilin and hsp27, two proteins involved in actin dynamics. Western blotting and immunofluorescence experiments confirmed that the phosphorylation states and subcellular localization of these two proteins were affected by all of the inhibitors tested and that treated cells had a more extensive network of actin stress fibers and more numerous focal adhesion plaques compared with untreated cells. Endothelial monocyte activating polypeptide 11, another angiogenesis inhibitor, elicited the same response in the actin cytoskeleton and focal adhesions of endothelial cells. This more adherent phenotype may explain the shared ability of these inhibitors to block endothelial migratory signals. Starting with a proteomics approach, we have identified common effector molecules used by a panel of angiogenesis inhibitors that perturb the cytoskeleton to prevent endothelial migration. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 79 TC 79 Z9 90 U1 2 U2 9 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 OCT 1 PY 2003 VL 63 IS 19 BP 6405 EP 6412 PG 8 WC Oncology SC Oncology GA 732WC UT WOS:000185967700045 PM 14559830 ER PT J AU Zhang, Z Zhang, ML Goldman, CK Ravetch, JV Waldmann, TA AF Zhang, Z Zhang, ML Goldman, CK Ravetch, JV Waldmann, TA TI Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H SO CANCER RESEARCH LA English DT Article ID HUMAN CD52 ANTIBODY; FC-RECEPTORS; ANTIGEN; CDW52; LYMPHOMA; TARGET AB Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell leukemia virus I-infected individuals. Presently, there is no effective therapy for ATL. A murine model of ATL was produced by introducing leukemic cells (MET-1) from an ATL patient into nonobese diabetic/ severe combined immunodeficient mice. The MET-1 cells are activated T cells that express CD2, CD3, CD4, CD25, CD122, and CD52. We evaluated the efficacy of Campath-1H (alemtuzumab; a humanized monoclonal antibody directed to CD52), alone and in combination with humanized anti-Tac (HAT) directed to CD25 (interleukin 2 receptor a) or with MEDI-507 directed to CD2. We observed that four weekly treatments with 4 mg/kg HAT significantly prolonged survival of MET-1-bearing mice. However, the survival of mice receiving 4 weeks of 4 mg/kg Campath-1H was significantly longer than that of the group receiving four weekly treatments with HAT (P < 0.001). Treatment with Campath-1H for 4 weeks led to a striking prolongation of the survival of MET-I ATL-bearing mice that was comparable with that of tumor-free nontreated controls. Using Fc receptor (FcR) gamma(-/-) mice, we found that FcRgammas on polymorphonuclear leukocytes and monocytes are required for Campath-1H-mediated tumor killing in vivo. These results demonstrate that Campath-1H has therapeutic efficacy on ATL in vivo in that the life span of the Campath-1H treatment group was comparable with that of mice that did not receive a tumor or therapy. The main tumor killing mechanism with Campath-1H in vivo involves FcRgamma-containing receptors (e.g., FcR-gammaIII) on polymorphonuclear leukocytes and macrophages that mediate antibody-dependent cellular cytotoxicity and/or trigger cross-linking induced apoptosis. This study provides support for a clinical trial of Campath-1H in the treatment of patients with T-cell leukemias and lymphomas. C1 NCI, Metab Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, NIH, Ctr Canc Res, Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 75 Z9 76 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 OCT 1 PY 2003 VL 63 IS 19 BP 6453 EP 6457 PG 5 WC Oncology SC Oncology GA 732WC UT WOS:000185967700051 PM 14559836 ER PT J AU Sithanandam, G Smith, GT Masuda, A Takahashi, T Anderson, LM Fornwald, LW AF Sithanandam, G Smith, GT Masuda, A Takahashi, T Anderson, LM Fornwald, LW TI Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3-kinase/Akt pathway SO CARCINOGENESIS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; ERBB SIGNALING NETWORK; C-ERBB-3 PROTEIN EXPRESSION; RECEPTOR TYROSINE KINASES; BREAST-CANCER CELLS; NORMAL HUMAN ADULT; PHOSPHATIDYLINOSITOL 3-KINASE; EPITHELIAL-CELLS; DOWN-REGULATION; GENE AMPLIFICATION AB Although ErbB3, a member of the epidermal growth factor receptor family, has been implicated in mammary tumorigenesis, investigation of its role in lung tumorigenesis has been limited. We found that ErbB3 was present at high levels in five of seven human lung adenocarcinoma cell lines examined, along with its ligands, heregulins alpha and beta, whereas ErbB3 was absent from HPL1D, a non- transformed cell line from human pulmonary peripheral epithelium. Interactions and effects of ErbB3 were studied in detail in adenocarcinoma lines H441 and H1373. Complexes containing phosphorylated ErbB2, phosphorylated ErbB3 and the p85 regulatory subunit of phosphoinositidyl 3-kinase were detected by co-immunoprecipitation experiments and were present constitutively even in the absence of serum-stimulated cell division. Serum treatment increased the pErbB3/p85 complexes and also stimulated phosphorylation of Akt and GSK3beta, increase in cyclin D1 and cell cycle progression, and these events were blocked by the Akt activation inhibitor LY294002. An ErbB3-specific antisense oligonucleotide reduced amounts of ErbB3 protein and p85 complex in both cell lines, and significantly suppressed cell proliferation. These results together suggest involvement of ErbB3 in growth of lung adenocarcinomas, through activation of phosphoinositidyl 3 kinase and Akt, inactivation of GSK3beta and stabilization of cyclin D1 for cell cycle maintenance. It could be a useful therapeutic target. C1 NCI, Basic Res Program, SAIC Frederick, Ft Detrick, MD 21702 USA. NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. Aichi Canc Ctr, Res Inst, Div Mol Oncol, Nagoya, Aichi 4648681, Japan. RP Sithanandam, G (reprint author), NCI, Basic Res Program, SAIC Frederick, Bldg 538, Ft Detrick, MD 21702 USA. RI Takahashi, Takashi/I-7262-2014 FU NCI NIH HHS [N01-CO-12400] NR 78 TC 32 Z9 35 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2003 VL 24 IS 10 BP 1581 EP 1592 DI 10.1093/carcin/bgg125 PG 12 WC Oncology SC Oncology GA 731JD UT WOS:000185879800002 PM 12896906 ER PT J AU Torres-Vaazquez, J Kamei, M Weinstein, BM AF Torres-Vaazquez, J Kamei, M Weinstein, BM TI Molecular distinction between arteries and veins SO CELL AND TISSUE RESEARCH LA English DT Review DE blood vessels; arteries; veins; ephrins; Notch; vascular endothelial growth factor ID ENDOTHELIAL-GROWTH-FACTOR; AUTOSOMAL-DOMINANT ARTERIOPATHY; NEURAL CREST MIGRATION; CELL-CELL INTERACTIONS; SMOOTH-MUSCLE CELLS; NOTCH PATHWAY; VASCULAR MORPHOGENESIS; AXON GUIDANCE; FACTOR VEGF; IN-VIVO AB The vertebrate vascular system is essential for the delivery and exchange of gases, hormones, metabolic wastes and immunity factors. These essential functions are carried out in large part by two types of anatomically distinct blood vessels, namely arteries and veins. Previously, circulatory dynamics were thought to play a major role in establishing this dichotomy, but recently it has become clear that arterial and venous endothelial cells are molecularly distinct even before the output of the first embryonic heartbeat, thus revealing the existence of genetic programs coordinating arterial-venous differentiation. Here we review some of the molecular mechanisms involved in this process. C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Genet Mol Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. OI Kamei, Makoto/0000-0002-1438-0783 FU NHLBI NIH HHS [R01 HL092263] NR 126 TC 73 Z9 75 U1 3 U2 6 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 OCT PY 2003 VL 314 IS 1 BP 43 EP 59 DI 10.1007/s00441-003-0771-8 PG 17 WC Cell Biology SC Cell Biology GA 742WV UT WOS:000186541800007 PM 14505031 ER PT J AU Putney, JW AF Putney, JW TI Capacitative calcium entry in the nervous system SO CELL CALCIUM LA English DT Article DE capacitative calcium entry; calcium signaling; ion channels ID INTRACELLULAR CA2+ STORES; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; ADRENAL CHROMAFFIN CELLS; OPERATED CATION CHANNELS; XENOPUS-OOCYTES; INFLUX FACTOR; ENDOPLASMIC-RETICULUM; DIFFUSIBLE MESSENGER; ADENYLYL CYCLASES; PORE PROPERTIES AB Capacitative calcium entry is a process whereby the depletion of Ca2+ from intracellular stores (likely endoplasmic or sarcoplasmic reticulum) activates plasma membrane Ca2+ channels. Current research has focused on identification of capacitative calcium entry channels and the mechanism by which Ca2+ store depletion activates the channels. Leading candidates for the channels are members of the transient receptor potential (TRP) superfamily, although no single gene or gene product has been definitively proven to mediate capacitative calcium entry. The mechanism for activation of the channels is not known; proposals fall into two general categories, either a diffusible signal released from the Ca2+ stores when their Ca2+ levels become depleted, or a more direct protein-protein interaction between constituents of the endoplasmic reticulum and the plasma membrane channels. Capacitative calcium entry is a major mechanism for regulated Ca2+ influx in non-excitable cells, but recent research has indicated that this pathway plays an important role in the function of neuronal cells, and may be important in a number of neuropathological conditions. This review will summarize some of these more recent findings regarding the role of capacitative calcium entry in normal and pathological processes in the nervous system. Published by Elsevier Ltd. C1 NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 83 TC 97 Z9 99 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD OCT-NOV PY 2003 VL 34 IS 4-5 BP 339 EP 344 DI 10.1016/S0143-4160(03)00143-X PG 6 WC Cell Biology SC Cell Biology GA 714RP UT WOS:000184927500004 PM 12909080 ER PT J AU Mattson, MP Chan, SL AF Mattson, MP Chan, SL TI Neuronal and glial calcium signaling in Alzheimer's disease SO CELL CALCIUM LA English DT Review DE amyloid; apolipoprotein E; apoptosis; astrocytes; microglia; oligodendrocytes; presenilin ID AMYLOID-BETA-PEPTIDE; LIPID-PEROXIDATION PRODUCT; NA+/K+-ATPASE ACTIVITY; NF-KAPPA-B; HIPPOCAMPAL-NEURONS; PRECURSOR PROTEIN; APOLIPOPROTEIN-E; OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; PRESENILIN-1 MUTATION AB Cognitive impairment and emotional disturbances in Alzheimer's disease (AD) result from the degeneration of synapses and death of neurons in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid beta-peptide (Abeta) in the brain. Abeta has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and apoptosis by a mechanism involving disruption of cellular calcium homeostasis. By inducing membrane lipid peroxidation and generation of the aldehyde 4-hydroxynonenal, Abeta impairs the function of membrane ion-motive ATPases and glucose and glutamate transporters, and can enhance calcium influx through voltage-dependent and ligand-gated calcium channels. Reduced levels of a secreted form of APP which normally regulates synaptic plasticity and cell survival may also promote disruption of synaptic calcium homeostasis in AD. Some cases of inherited AD are caused by mutations in presenilins 1 and 2 which perturb endoplasmic reticulum (ER) calcium homeostasis such that greater amounts of calcium are released upon stimulation, possibly as the result of alterations in IP3 and ryanodine receptor channels, Ca2+-ATPases and the ER stress protein Herp. Abnormalities in calcium regulation in astrocytes, oligodendrocytes, and microglia have also been documented in studies of experimental models of AD, suggesting contributions of these alterations to neuronal dysfunction and cell death in AD. Collectively, the available data show that perturbed cellular calcium homeostasis plays a prominent role in the pathogenesis of AD, suggesting potential benefits of preventative and therapeutic strategies that stabilize cellular calcium homeostasis. (C) 2003 Elsevier Ltd. All rights reserved. C1 NIA, Neurosci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Ctr Gerontol Res, 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 130 TC 285 Z9 298 U1 1 U2 33 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD OCT-NOV PY 2003 VL 34 IS 4-5 BP 385 EP 397 DI 10.1016/S0143-4160(03)00128-3 PG 13 WC Cell Biology SC Cell Biology GA 714RP UT WOS:000184927500007 PM 12909083 ER PT J AU DiGiovanna, JJ AF DiGiovanna, JJ TI Dr. Peter M Steinert (1945-2003) - Obituary SO CELL DEATH AND DIFFERENTIATION LA English DT Biographical-Item C1 NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP DiGiovanna, JJ (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD OCT PY 2003 VL 10 IS 10 BP 1117 EP 1117 DI 10.1038/sj.cdd.4401299 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 727UN UT WOS:000185679400001 ER PT J AU Smith, GH Boulanger, CA AF Smith, GH Boulanger, CA TI Mammary epithelial stem cells: transplantation and self-renewal analysis SO CELL PROLIFERATION LA English DT Article ID ADULT HUMAN BREAST; MYOEPITHELIAL CELLS; LIFE SPAN; FUNCTIONAL-DIFFERENTIATION; PRENEOPLASTIC PHENOTYPE; DNA-SYNTHESIS; IN-VIVO; GLAND; CARCINOGENESIS; TUMORIGENESIS AB An entire mammary epithelial outgrowth, capable of full secretory differentiation, may be comprised of the progeny of a single cellular antecedent. This conclusion is based upon the maintenance of retroviral insertion sites within the somatic DNA of successive transplant generations derived from a single mammary fragment. In addition, dissociation of these clonal dominant glands and implantation of dispersed cells at limiting dilution demonstrated that both duct-limited and lobule-limited outgrowths were developed, as well as complete, fully differentiated glands. Thus, transplantation has revealed three distinct mammary epithelial progenitors in the mouse. Similar studies have extended this observation to rat mammary tissue. Recently, using cre-lox conditional activation of reporter genes, a new epithelial progenitor, specific for mammary secretory epithelium in postlactation females has been uncovered. In situ, these cells were shown to regenerate secretory lobules upon successive pregnancies. In transplant studies, they demonstrated the capacity for self-renewal and contributed to the new generation of all of the known epithelial cell types among mammary epithelium. In limiting dilution, the parity-induced progenitors were capable of engendering lobule-limited and duct-limited outgrowths in their entirety, but not completely developed glands. Serial transplant studies indicate that these progenitors have a significant but limited capacity for self-renewal. C1 NCI, Sect Mammary Stem Cell Biol, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), Bldg 10,Room 5B56,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 38 TC 44 Z9 45 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7722 J9 CELL PROLIFERAT JI Cell Prolif. PD OCT PY 2003 VL 36 SU 1 BP 3 EP 15 DI 10.1046/j.1365-2184.36.s.1.2.x PG 13 WC Cell Biology SC Cell Biology GA 739RT UT WOS:000186360800002 PM 14521512 ER PT J AU Lazar, J Szabo, T Kovacs, L Blumberg, PM Biro, T AF Lazar, J Szabo, T Kovacs, L Blumberg, PM Biro, T TI Distinct features of recombinant rat vanilloid receptor-1 expressed in various expression systems SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE vanilloid receptor 1; capsaicin; resiniferatoxin; heterologous expression system; calcium ID ROOT GANGLION NEURONS; CAPSAICIN RECEPTOR; SENSORY NEURONS; PAIN PATHWAY; GLIAL-CELLS; ADULT-RATS; CALCIUM; DESENSITIZATION; RESINIFERATOXIN; VR1 AB In this study, we expressed rat vanilloid receptor 1 (VR1) in various heterologous expression systems using different VR1-encoding vectors, and examined how the VR1 agonists capsaicin and resiniferatoxin affected intracellular calcium. Our results clearly show that the magnitude and kinetics of response as well as the extent of tachyphylaxis differ markedly between systems. Using green fluorescent protein-tagged VR1, we show that much of the VR1 is localized to intracellular membranes. Consistent with this localization, VR1 agonists are able to liberate calcium from intracellular stores in the absence of extracellular calcium. As with other parameters of response, the three expression systems differ in the degree to which, in the absence of extracellular calcium, capsaicin and resiniferatoxin can liberate calcium from the intracellular stores. Our findings emphasize the influence of the expression system on characteristics of the response of VR1 to its ligands and the need for caution in extrapolating such results to other settings. C1 Univ Debrecen, Med & Hlth Sci Ctr, Sch Med, Res Ctr Mol Med,Hungarian Acad Sci,Dept Physiol &, H-4012 Debrecen, Hungary. NCI, Lab Cellular Carcinogenesis & Tumor Promot, Mol Mech Tumor Promot Sect, NIH, Bethesda, MD USA. RP Biro, T (reprint author), Univ Debrecen, Med & Hlth Sci Ctr, Sch Med, Res Ctr Mol Med,Hungarian Acad Sci,Dept Physiol &, Nagyerdei Krt 98,POB 22, H-4012 Debrecen, Hungary. NR 38 TC 17 Z9 17 U1 0 U2 2 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD OCT PY 2003 VL 60 IS 10 BP 2228 EP 2240 DI 10.1007/s00018-003-3230-5 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 742LC UT WOS:000186517400018 PM 14618269 ER PT J AU Armstrong, DM Sheffield, R Mishizen-Eberz, AJ Carter, TL Rissman, RA Mizukami, K Ikonomovic, MD AF Armstrong, DM Sheffield, R Mishizen-Eberz, AJ Carter, TL Rissman, RA Mizukami, K Ikonomovic, MD TI Plasticity of glutamate and GABA(A) receptors in the hippocampus of patients with Alzheimer's disease SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Alzheimer's disease; hippocampus; glutamate; excitotoxicity; GABA ID PERFORANT PATHWAY LESION; SUBTYPE IMMUNOREACTIVITY; DENTATE GYRUS; ENTORHINAL CORTEX; SUBUNITS; CHANNELS; BRAINS; FAMILY; RAT AB 1. Aim: In Alzheimer's disease ( AD) it is well known that specific regions of the brain are particularly vulnerable to the pathologic insults of the disease. In particular, the hippocampus is affected very early in the disease and by end stage AD is ravaged by neurofibrillary tangles and senile plaques (i.e., the pathologic hallmarks of AD). Throughout the past several years our laboratory has sought to determine the molecular mechanisms underlying the selective vulnerability of neurons in AD. 2. Methods: To this end, we employed immunohistochemical, biochemical, and in situ hybrization methods to examine glutamate and gamma-aminobutyric acid (GABA(A)) receptor subtypes in the hippocampus of patients displaying the full spectrum of AD pathology. 3. Results: Despite the fact that the hippocampus is characterized by a marked loss of neurons in the late stages of the disease, our data demonstrate a rather remarkable preservation among some glutamate and GABA(A) receptor subtypes. 4. Conclusions: Collectively, our data support the view that the relatively constant levels of selected receptor subtypes represent a compensatory up-regulation of these receptors subunits in surviving neurons. The demonstration that glutamate and GABA receptor subunits are comparably unaffected implies that even in the terminal stages of the disease the brain is "attempting" to maintain a balance in excitatory and inhibitory tone. Our data also support the concept that receptor subunits are differentially affected in AD with some subunits displaying no change while others display alterations in protein and mRNA levels within selected regions of the hippocampus. Although many of these changes are modest, they do suggest that the subunit composition of these receptors may be altered and hence affect the pharmacokinetic and physiological properties of the receptor. The latter findings stress the importance of understanding the subunit composition of individual glutamate/ GABA receptors in the diseased brain prior to the development of drugs targeted towards those receptors. C1 Jefferson Hlth Syst, Lankenau Inst Med Res, Lab Neuronal Vulnerabil & Aging, Wynnewood, PA USA. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. MCP Hahnemann Univ Sch Med, Grad Program Neurosci, Dept Neurobiol & Anat, Philadelphia, PA USA. Univ Tsukuba, Inst Clin Med, Dept Psychiat, Tsukuba, Ibaraki 305, Japan. Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. RP Armstrong, DM (reprint author), NIH, Brain Disorders & Clin Neurosci IRG, Ctr Sci Review, 6701 Rockledge Dr, Bethesda, MD 20817 USA. FU NIA NIH HHS [AG15472, AG08206] NR 31 TC 21 Z9 23 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD OCT PY 2003 VL 23 IS 4-5 BP 491 EP 505 DI 10.1023/A:1025063811290 PG 15 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 708UX UT WOS:000184589000006 PM 14514010 ER PT J AU Kvale, PA Gohagan, J Marcus, P Fagerstrom, R Pinsky, P Kramer, B Prorok, P AF Kvale, PA Gohagan, J Marcus, P Fagerstrom, R Pinsky, P Kramer, B Prorok, P TI The lung screening study: The national cancer institute's randomized feasibility study of spiral CT versus chest x-ray in lung cancer screening SO CHEST LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Chest-Physicians CY OCT 25-30, 2003 CL ORLAMDO, FLORIDA SP Amer Coll Chest Physicians C1 Henry Ford Hlth Syst, Lung Screening Study Res Grp, Detroit, MI USA. NCI, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2003 VL 124 IS 4 SU S BP 118S EP 118S PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 734RG UT WOS:000186070400152 ER PT J AU Nagorsen, D Scheibenbogen, C Marincola, FM Letsch, A Keilholz, U AF Nagorsen, D Scheibenbogen, C Marincola, FM Letsch, A Keilholz, U TI Natural T cell immunity against cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID CHRONIC MYELOGENOUS LEUKEMIA; TUMOR-ASSOCIATED ANTIGENS; GAMMA-ELISPOT ASSAY; MELANOMA PATIENTS; COLORECTAL-CANCER; HEALTHY DONORS; OVARIAN-CANCER; BREAST-CANCER; BONE-MARROW; EX-VIVO AB It has long been a matter of debate whether tumors are spontaneously immunogenic in patients. With the availability of sensitive methods, naturally occurring T cells directed against tumor-associated antigens (TAAs) can be frequently detected in cancer patients. In this review, we summarize the current data on T cell responses to TAAs in various malignancies, including melanoma, colorectal cancer, leukemia, and breast cancer. T cell responses against various antigens, including melanoma differentiation antigens, carcinoembryonic antigen, epithelial cell adhesion molecule, her-2/neu, Wilms' tumor protein, proteinase 3, NY-ESO-1, and surviving, have been reported in a substantial number of patients. In contrast, other TAAs, including most antigens of the MAGE family, do not usually elicit spontaneous T cell responses. A distinction between direct ex vivo T cell responses and in vitro-generated T cell responses is provided because in vitro stimulation results in quantitative and functional changes of T cell responses. The possible role of TAA-specific T cells in immunosurveillance and tumor escape and the implications for immunological treatment strategies are discussed. Naturally occurring T cells against TAAs are a common phenomenon in tumor patients. Understanding the mechanisms and behavior of natural TAA-specific T cells could provide crucial information for rational development of more efficient T cell-directed immunotherapy. C1 Free Univ Berlin, Univ Hosp Benjamin Franklin, Med Klin 3, D-12200 Berlin, Germany. NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Keilholz, U (reprint author), Free Univ Berlin, Univ Hosp Benjamin Franklin, Med Klin 3, Hindenburgdamm 30, D-12200 Berlin, Germany. NR 88 TC 140 Z9 147 U1 0 U2 7 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 OCT 1 PY 2003 VL 9 IS 12 BP 4296 EP 4303 PG 8 WC Oncology SC Oncology GA 730KV UT WOS:000185830700002 PM 14555498 ER PT J AU Sabichi, AL Xu, H Fischer, S Zou, CC Yang, XL Steele, VE Kelloff, GJ Lotan, R Clifford, JL AF Sabichi, AL Xu, H Fischer, S Zou, CC Yang, XL Steele, VE Kelloff, GJ Lotan, R Clifford, JL TI Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites SO CLINICAL CANCER RESEARCH LA English DT Article ID EMBRYONAL CARCINOMA-CELLS; HUMAN BREAST-CANCER; GROWTH-INHIBITION; MELANOMA-CELLS; HUMAN HEAD; ACID; N-(4-HYDROXYPHENYL)RETINAMIDE; APOPTOSIS; DIFFERENTIATION; EXPRESSION AB Fenretinide (4-HPR) is a retinoid analogue with antitumor and chemopreventive activities. In addition to 4-HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2-carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyi)retinamide, and N-(4-methoxyphenyl)retinamide (4-MPR)]. It is hypothesized that these agents can act independent of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have analyzed the activity of these phenylretinamides in vitro on a panel of F9 murine embryonal carcinoma cell lines, which includes wildtype (F9-WT) and mutant cells that have disrupted genes for both retinoid X receptor alpha and retinoic acid receptor gamma retinoid receptors (F9-KO). The F9-KO cells lack almost all measurable response to all-trans-retinoic acid, the primary biologically active retinoid. Two distinct effects of retinamides were identified. The first is a rapid, dose-dependent induction of cell growth inhibition (reduced cell viability), and the second is a slower induction of differentiation and accumulation of cells in the G(1) phase of the cell cycle that was observed with a concentration of 1 mum, for only those phenylretinamides bearing charged (hydroxyl or carboxyl) groups on the terminal phenylamine ring. The induction of differentiation and G(1) accumulation was only observed in the F9-WT cells, indicating that this effect is receptor dependent. 4-MPR, a major metabolite of 4-HPR, lacks a charged group on the terminal phenylamine ring and did not induce retinoid receptor-dependent effects, but did induce cell growth inhibition. Thus, 4-MPR may play a role in the clinical activity of 4-HPR. This study further reveals the mechanism of action of these novel phenylretinamides and supports continued investigation into their development as chemopreventive drugs. C1 Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. RP Clifford, JL (reprint author), Louisiana State Univ, Hlth Sci Ctr, 1501 Kings Hwy,POB 33932, Shreveport, LA 71130 USA. FU NCI NIH HHS [5 U01 CA77150, R29 CA78560]; NIEHS NIH HHS [5 P30 ES07784] NR 38 TC 21 Z9 21 U1 0 U2 4 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 OCT 1 PY 2003 VL 9 IS 12 BP 4606 EP 4613 PG 8 WC Oncology SC Oncology GA 730KV UT WOS:000185830700040 PM 14555536 ER PT J AU Slavotinek, AM Boles, D Lacbawan, F AF Slavotinek, AM Boles, D Lacbawan, F TI A female infant with duplication of chromosome 2q33 to 2q37.3 SO CLINICAL DYSMORPHOLOGY LA English DT Article DE trisomy 2q3; partial duplication; craniofacial dysmorphism ID PARTIAL TRISOMY 2Q; CHARACTERISTIC PHENOTYPE; LONG ARM; INSERTION; TRANSLOCATION; GENERATIONS; INVERSION; SIBS AB We report a 13-month-old female child with a de-novo inverted duplication of chromosome 2q extending from 2q33 to 2q37.3. She had microcephaly and craniofacial dysmorphism compatible with previously reported cases with overlapping duplications of chromosome 2q. Although a facial phenotype for pure partial trisomy 2q3 has been described, some controversy still exists regarding possible band specificity for the facial findings. We consider this child provides further evidence for a recognizable facial appearance associated with duplication of chromosome band 2q33 to 2q37.3. Other clinical features found with duplication for chromosome 2q3 have been variable and we provide a summary of the findings in previously reported cases. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Inst Mol & Human Genet, Washington, DC 20007 USA. RP Slavotinek, AM (reprint author), Univ Calif San Francisco, Dept Pediat, Div Genet, San Francisco, CA 94143 USA. NR 21 TC 15 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0962-8827 J9 CLIN DYSMORPHOL JI Clin. Dysmorphol. PD OCT PY 2003 VL 12 IS 4 BP 251 EP 256 DI 10.1097/01.mcd.0000081307.64648.5d PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 731DY UT WOS:000185870300008 PM 14564213 ER PT J AU Tao, Q Robertson, KD AF Tao, Q Robertson, KD TI Stealth technology: how Epstein-Barr virus utilizes DNA methylation to cloak itself from immune detection SO CLINICAL IMMUNOLOGY LA English DT Article DE Epstein-Barr virus; EBV; DNA methylation; latent; lytic; transcriptional regulation; ICF syndrome; bisulfite genomic sequencing ID BURKITT-LYMPHOMA CELLS; DE-NOVO METHYLATION; HISTONE DEACETYLASE INHIBITORS; SWITCH GENE BZLF1; TRANSCRIPTION FACTOR; B-CELL; LYMPHOPROLIFERATIVE DISEASE; NUCLEAR ANTIGEN-1; MAMMALIAN DEVELOPMENT; RESPONSIVE ELEMENT AB Epstein-Barr virus (EBV) is a large lymphotrophic DNA virus that establishes life-long residency in the infected host and is associated with a number of human tumors. The EBV genome encodes proteins essential for persistence, an oncoprotein, and proteins that render it vulnerable to the host's immune system; therefore, EBV gene transcription is tightly regulated. One critically important regulatory mechanism utilized by EBV is DNA methylation. Methylation of cytosines within CpG dinucleotides at promoter regions is important for gene silencing and genome integrity. Although most parasitic elements are methylated in mammalian cells never to be reactivated again, EBV has evolved to utilize DNA methylation to maximize persistence and cloak itself from immune detection. EBV's reliance on DNA methylation also provides a unique therapeutic strategy for the treatment of EBV-associated tumors. DNA demethylating agents are capable of reactivating transcription of highly immunogenic viral proteins, rendering tumor cells susceptible to killing by the host immune system, and inducing the viral lytic cycle which culminates in cell lysis. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, LRBGE, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Singapore, Tumor Virol Canc Epigenet Lab, Singapore 117597, Singapore. RP Robertson, KD (reprint author), NCI, LRBGE, Epigenet Gene Regulat & Canc Sect, NIH, Bldg 41,Room B715,41 Lib Dr, Bethesda, MD 20892 USA. NR 98 TC 60 Z9 63 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD OCT PY 2003 VL 109 IS 1 BP 53 EP 63 DI 10.1016/S1521-6616(03)00198-0 PG 11 WC Immunology SC Immunology GA 739AA UT WOS:000186319000008 PM 14585276 ER PT J AU Kearns, GL Robinson, PK Wilson, JT Wilson-Costello, D Knight, GR Ward, RM van den Anker, JN AF Kearns, GL Robinson, PK Wilson, JT Wilson-Costello, D Knight, GR Ward, RM van den Anker, JN CA Pediat Pharma Res Unit Net TI Cisapride disposition in neonates and infants: In vivo reflection of cytochrome P450 3A4 ontogeny SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article; Proceedings Paper CT 102nd Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 06-10, 2001 CL ORLANDO, FLORIDA SP Amer Soc Clin Pharmacol & Therapeut ID CORRECTED QT INTERVAL; POPULATION PHARMACOKINETICS; PRETERM INFANTS; GASTROESOPHAGEAL-REFLUX; PREMATURE NEWBORNS; PEDIATRIC-PATIENTS; DRUG DISPOSITION; MIDAZOLAM; METABOLISM; INHIBITION AB Background: Cisapride, a prokinetic agent and substrate for cytochrome P450 (CYP) 3A4, has been used to treat neonates and infants with feeding intolerance and apnea or bradycardia associated with gastroesophageal reflux. At age 1 month, CYP3A4 activity has been reported to be only 30% to 40% of adult activity. This known developmental delay in the expression of CYP3A4 prompted us to conduct a classical open-label pharmacokinetic study of cisapride in neonates and young infants. Methods: A total of 35 infants with a postconceptional age of 28 to 54 weeks at the time of the study received a single oral cisapride dose (0.2 mg/kg) at a postnatal age of 4 to 102 days, followed by repeated (n = 7) blood sampling over a 24-hour period. Cisapride and norcisapride were quantitated from plasma by HPLC-tandem mass spectrometry and pharmacokinetic data determined (n = 32) by noncompartmental methods. Results: The pharmacokinetic parameters (mean +/- SD) were as follows: time to reach peak plasma concentration (t(max)), 4.4 +/- 2.8 hours (range, 0.9-12 hours); peak plasma concentration (C-max), 29.3 +/- 16.6 ng/mL (range, 5.2-71.7 ng/mL); elimination half-life (t(1/2)), 10.7 +/- 3.7 hours (range, 1.9-18.1 hours); apparent total body clearance (Cl/F), 0.62 +/- 0.43 L (.) h(-1) (.) kg(-1) (range, 0.2-1.9 L (.) h(-1) (.) kg(-1)); and apparent volume of distribution (VDss/F), 9.0 +/- 7.1 L/kg (range, 2.2-30.5 L/kg). The apparent renal clearance (CLR) of cisapride in infants (n = 28) was estimated to be 0.003 +/- 0.003 L (.) h(-1) (.) kg(-1). Substratification of the population based on postconceptional age demonstrated the following findings for cisapride: (1) The mean (+/-SD) C-max for cisapride was higher in the oldest postconceptional age category (44.5 +/- 19.6 ng/mL) than the middle and youngest categories (23.4 +/- 11.7 ng/mL and 30.0 +/- 17.5 ng/mL, respectively); (2) the t(max) for cisapride was shortest in the oldest postconceptional age category (2.2 +/- 1.1 hours) compared with the middle and youngest categories (4.4 +/- 3.3 hours and 5.0 +/- 2.6 hours, respectively); (3) the CL/F for cisapride in the youngest postconceptional age group was significantly lower (0.45 +/- 0.26 L (.) h(-1) (.) kg(-1), P < .05) than in the middle and oldest categories (0.75 +/- 0.46 L (.) h(-1) (.) kg(-1) and 0.85 +/- 0.69 L (.) h(-1) (.) kg(-1), respectively); (4) a positive linear correlation was found between postconceptional age and the apparent terminal elimination rate constant (lambda(z)) for cisapride (P < .001, r(2) = 0.47) but not with CL/F. For norcisapride, the mean apparent C-max was highest and the t(max) was shortest in the oldest postconceptional age group, although no association between postconceptional age and the norcisapride/cisapride area under the curve ratio was observed. All infants tolerated a single dose of cisapride well without significant alteration in QTc. Conclusions: (1) In neonates and infants, cisapride absorption and metabolism to its primary metabolite, norcisapride, were developmentally dependent; (2) approximately 99% of cisapride CL/F in neonates and young infants was nonrenal in nature; (3) CL/F of cisapride in neonates and infants noted in this study was reduced compared with data from older children and adults, likely as a result of developmental reductions in CYP3A4 activity; (4) as reflected by the correlation between postconceptional age and lambda(z), a rapid increase in total CYP3A4 activity occurs in the first 3 months of life. C1 NICHHD, Bethesda, MD 20892 USA. Janssen Pharmaceut Res Fdn, Titusville, NJ 08560 USA. RP Kearns, GL (reprint author), Childrens Mercy Hosp & Clin, Div Pediat Pharmacol & Med Toxicol, 2401 Gillham Rd, Kansas City, MO 64108 USA. NR 39 TC 31 Z9 33 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2003 VL 74 IS 4 BP 312 EP 325 DI 10.1067/S0009-9236(03)00225-X PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 731FH UT WOS:000185873500003 PM 14534518 ER PT J AU Walsh, PJ Bookman, RJ Zaias, J Mayer, GD Abraham, W Bourdelais, AJ Baden, DG AF Walsh, PJ Bookman, RJ Zaias, J Mayer, GD Abraham, W Bourdelais, AJ Baden, DG TI Toxicogenomic effects of marine brevetoxins in liver and brain of mouse SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 6th International Congress of Comparative Physiology and Biochemistry CY FEB 02-07, 2003 CL MT BULLER, AUSTRALIA DE marine brevetoxins; toxic dinoflagellates; Karenia breuis; toxicogenomics; gene arrays; metallothioneins; orosomucoid; lethal shock ID ARYL-HYDROCARBON RECEPTOR; INDUCED LETHAL HEPATITIS; MAJOR URINARY PROTEIN; PTYCHODISCUS-BREVIS; TISSUE DISTRIBUTION; GENE-EXPRESSION; TOXINS; PBTX-3; LIPOCALIN; NECROSIS AB Although the polyether brevetoxins (PbTx's) produced by Karenia brevis (the organism responsible for blooms of the Florida red tide) are known to exert their acute toxic effects through ion-channel mediated pathways in neural tissue, prior studies have also demonstrated that at least one form of the toxin (PbTx-6) is bound avidly by the aryl hydrocarbon receptor (AhR). Since AhR binding of a prototypical ligand such as dioxin is the first step in a cascade pathway producing major changes in gene expression, we reasoned that PbTx-6 might produce similar genomic-wide changes in expression. Mice were injected i.p. with sub-lethal doses of PbTx's (either 1.5 or 3 mg/g body weight of PbTx-6; or 0.15 mg/g body weight of PbTx-2, a toxin not avidly bound by the AhR), and liver and brain tissues were sampled at 8, 24 and 72 h and RNA was isolated. Changes in gene-specific RNA levels were assessed using commercially available mouse cDNA arrays (Incyte) containing > 9600 array elements, including many elements from AhR-mediated genes. Histopathology of the two organs was also assessed. We observed minor histopathological effects and a total of only 29 significant ( > 2.0-fold) changes in gene expression, most of which occurred in the liver, and most of which could be attributable to an 'acute phase' inflammatory response. These results argue against the hypothesis that PbTx-6 acts via a classic AhR-mediated mechanism to evoke gene expression changes. However, given the avidity with which PbTx-6 binds to the AhR, these findings have important implications for how PbTx's may act in concert with other toxicants that are sensed by the AhR. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Univ Miami, Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL USA. Univ N Carolina, Ctr Marine Sci, Wilmington, NC USA. RP Walsh, PJ (reprint author), Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS Marine & Freshwater Biomed Sci Ctr, 4600 Rickenbacker Causeway, Miami, FL 33149 USA. EM pwalsh@rsmas.miami.edu RI Mayer, Gregory/K-4496-2012; Mayer, Gregory/A-8459-2017 OI Mayer, Gregory/0000-0002-2652-9856; Mayer, Gregory/0000-0002-2652-9856 FU NIEHS NIH HHS [ES05705, F32 ES005705, P01 ES010594, P01 ES010594-02, P01 ES10594, P30 ES005705] NR 43 TC 5 Z9 7 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1096-4959 J9 COMP BIOCHEM PHYS B JI Comp. Biochem. Physiol. B-Biochem. Mol. Biol. PD OCT PY 2003 VL 136 IS 2 BP 173 EP 182 DI 10.1016/S1096-4959(03)00223-9 PG 10 WC Biochemistry & Molecular Biology; Zoology SC Biochemistry & Molecular Biology; Zoology GA 731HV UT WOS:000185879000003 PM 14529743 ER PT J AU Rodicio, LP Sternberg, LDL Walsh, PJ AF Rodicio, LP Sternberg, LDL Walsh, PJ TI Metabolic fate of exogenous (NH4Cl)-N-15 in the gulf toadfish (Opsanus beta) SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY LA English DT Article DE gulf toadfish; Opsanus beta; ornithine-urea cycle; hyperammonemia; hepatic encephalopathy; (NH4Cl)-N-15 ID NITROGEN ISOTOPE RATIOS; AMINO-ACID CATABOLISM; AERIAL EXPOSURE; CLARIAS-BATRACHUS; AMMONIA; FISH; EXCRETION; GLUTAMINE; STRATEGY; CATFISH AB This study was undertaken to determine whether gulf toadfish (Opsanus beta) could metabolize ammonia from their environment into other, less toxic products. To this end, gulf toadfish were exposed to 3.8 mM (NH4Cl)-N-15 in seawater for 24 and 48 h. Liver, kidney, gill, brain and muscle samples were analyzed for distribution of N-15 within the tissue and among various nitrogen-containing metabolites (ammonia, amino-N, glutamine-N, urea and protein). The data reported here show that the toadfish can indeed take up and metabolize ammonia. Analysis of individual metabolic products of ammonia indicates that the toadfish can convert this toxic chemical into other less toxic metabolites. Ammonia enrichment is significantly different over controls in the kidney, brain and muscle. Urea enrichment is most significant in the brain, with less significant enrichment occurring in the liver and muscle. While accumulation of ammonia into an amino acid pool was not a significant metabolic fate, protein synthesis was significantly enriched in all tissues (with the highest levels occurring in the gill) indicating that amino acid synthesis may be a pathway of ammonia detoxification en route to protein synthesis, and that environmental ammonia can be 'fixed' into protein. Finally, it was found that glutamine-N synthesis occurs at significant levels in the liver, brain and muscle. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS Marine & Freshwater Biomed Sci Ctr, Div Marine Biol & Fisheries, Miami, FL 33149 USA. Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. RP Walsh, PJ (reprint author), Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS Marine & Freshwater Biomed Sci Ctr, Div Marine Biol & Fisheries, 4600 Rickenbacker Causeway, Miami, FL 33149 USA. FU NIEHS NIH HHS [ES05705, ES11005] NR 27 TC 4 Z9 4 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1532-0456 J9 COMP BIOCHEM PHYS C JI Comp. Biochem. Physiol. C-Toxicol. Pharmacol. PD OCT PY 2003 VL 136 IS 2 BP 157 EP 164 DI 10.1016/S1532-0456(03)00196-0 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Toxicology; Zoology SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Toxicology; Zoology GA 735FR UT WOS:000186102200007 PM 14559297 ER PT J AU Weinstein, JN Pommier, Y AF Weinstein, JN Pommier, Y TI Transcriptomic analysis of the NCI-60 cancer cell lines SO COMPTES RENDUS BIOLOGIES LA English DT Review DE bioinformatics; cancer; genomic; NCI-60 cell lines; pharmacology; proteomics ID DIFFERENTIAL CYTOTOXICITY DATA; GENETIC FUNCTION APPROXIMATION; DRUG DISCOVERY DATABASES; MOLECULAR PHARMACOLOGY; TOPOISOMERASE-II; MULTIDRUG-RESISTANCE; EXPRESSION PATTERNS; ELLIPTICINE ANALOGS; INHIBITORY-ACTIVITY; ANTICANCER AGENTS AB Pharmacogenomics aims at molecular subsetting of patients for more effective therapy. Transcriptomic profiling of the 60 human cancer cell lines (the NCI-60) used by the US National Cancer Institute serves that aim because the cells have been treated with > 100, 000 chemical compounds over the last 13 years. Patterns of potency can be mapped into molecular structures of the compounds or into molecular characteristics of the cells. We discuss conceptual and experimental aspects of the profiling, as well as a number of bioinformatic computer programs that we have developed for biological interpretation of the profiles. (C) 2003 Academie des sciences. Published by Elsevier SAS. All rights reserved. C1 NIH, Mol Pharmacol Lab, Ctr Canc Res, US Natl Canc Inst,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Weinstein, JN (reprint author), NIH, Mol Pharmacol Lab, Ctr Canc Res, US Natl Canc Inst,Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jw4i@nih.gov; pommier@nih.gov NR 54 TC 31 Z9 34 U1 0 U2 5 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1631-0691 J9 CR BIOL JI C. R. Biol. PD OCT-NOV PY 2003 VL 326 IS 10-11 BP 909 EP 920 DI 10.1016/j.crvi.2003.08.005 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 762TC UT WOS:000187997400005 PM 14744097 ER PT J AU Carter, MG Piao, YL Dudekula, DB Qian, Y VanBuren, V Sharov, AA Tanaka, TS Martin, PR Bassey, UC Stagg, CA Aiba, K Hamatani, T Matoba, R Kargul, GJ Ko, MSH AF Carter, MG Piao, YL Dudekula, DB Qian, Y VanBuren, V Sharov, AA Tanaka, TS Martin, PR Bassey, UC Stagg, CA Aiba, K Hamatani, T Matoba, R Kargul, GJ Ko, MSH TI The NIA cDNA Project in mouse stem cells and early embryos SO COMPTES RENDUS BIOLOGIES LA English DT Article DE embryo; genomics; microarray; pre-implantation development; stem cell ID EXPRESSED SEQUENCE TAGS; GENE-EXPRESSION; FUNCTIONAL ANNOTATION; INITIAL ANNOTATION; CLONE SET; GENOME; PCR; VERIFICATION; CONSTRUCTION; COLLECTION AB A catalog of mouse genes expressed in early embryos, embryonic and adult stem cells was assembled, including 250000 ESTs, representing approximately 39000 unique transcripts. The cDNA libraries, enriched in full-length clones, were condensed into the NIA 15 and 7.4K clone sets, freely distributed to the research community, providing a standard platform for expression studies using microarrays. They are essential tools for studying mammalian development and stem cell biology, and to provide hints about the differential nature of embryonic and adult stem cells. (C) 2003 Academie des sciences. Published by Elsevier SAS. All rights reserved. C1 NIA, Dev Genomics & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genomics & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM KoM@grc.nia.nih.gov RI Carter, Mark/B-5089-2010; Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Dudekula, Dawood/0000-0002-4054-1827 NR 40 TC 10 Z9 11 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1631-0691 J9 CR BIOL JI C. R. Biol. PD OCT-NOV PY 2003 VL 326 IS 10-11 BP 931 EP 940 DI 10.1016/j.crvi.2003.09.008 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 762TC UT WOS:000187997400007 PM 14744099 ER PT J AU Sakabe, NJ de Souza, JES Galante, PAF de Oliveira, PSL Passetti, F Brentani, H Osorio, EC Zaiats, AC Leerkes, MR Kitajima, JP Brentani, RR Strausberg, RL Simpson, AJG de Souza, SJ AF Sakabe, NJ de Souza, JES Galante, PAF de Oliveira, PSL Passetti, F Brentani, H Osorio, EC Zaiats, AC Leerkes, MR Kitajima, JP Brentani, RR Strausberg, RL Simpson, AJG de Souza, SJ TI ORESTES are enriched in rare exon usage variants affecting the encoded proteins SO COMPTES RENDUS BIOLOGIES LA English DT Article DE alternative splicing; alternative exon usage; bioinformatics; genome mapping; ORESTES; human transcriptome ID EXPRESSED SEQUENCE TAGS; PRE-MESSENGER-RNA; HUMAN GENOME; HUMAN GENES; HUMAN TRANSCRIPTOME; DIVERSITY AB A significant fraction of the variability found in the human transcriptome is due to alternative splicing, including alternative exon usage (AEU), intron retention and use of cryptic splice sites. We present a comparison of a large-scale analysis of AEU in the human transcriptome through genome mapping of Open Reading Frame ESTs (ORESTES) and conventional ESTs. It is shown here that ORESTES probe low abundant messages more efficiently. In addition, most of the variants detected by ORESTES affect the structure of the corresponding proteins. (C) 2003 Academie des sciences. Published by Elsevier SAS. All rights reserved. C1 Ludwig Inst Canc Res, Sao Paulo Branch, BR-01509010 Sao Paulo, Brazil. Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo, Brazil. Univ Sao Paulo, Curso Posgrad Bioinformat, Sao Paulo, Brazil. Univ Sao Paulo, Inst Coracao, Sao Paulo, Brazil. Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Campinas, Brazil. NCI, Bethesda, MD 20892 USA. RP de Souza, SJ (reprint author), Ludwig Inst Canc Res, Sao Paulo Branch, Rua Prof Antonio Prudente 109,4 Andar, BR-01509010 Sao Paulo, Brazil. EM sandro@compbio.ludwig.org.br RI Oliveira, Paulo/C-1275-2008; Sakabe, Noboru/A-8708-2009; Brentani, Helena/G-6839-2011; Galante, Pedro/C-6564-2012; Passetti, Fabio/D-2422-2009; Oliveira, Paulo/D-5463-2011; Oliveira, Paulo/K-5588-2013 OI Brentani, Helena/0000-0001-5192-4682; Galante, Pedro/0000-0002-4820-4155; Passetti, Fabio/0000-0001-5672-7848; Oliveira, Paulo/0000-0002-1287-8019; NR 27 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1631-0691 J9 CR BIOL JI C. R. Biol. PD OCT-NOV PY 2003 VL 326 IS 10-11 BP 979 EP 985 DI 10.1016/j.crvi.2003.09.027 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 762TC UT WOS:000187997400013 PM 14744104 ER PT J AU Taube, AG Subramanian, S Murugesan, R Devasahayam, N Mitchell, JB Krishna, MC Cook, JA AF Taube, AG Subramanian, S Murugesan, R Devasahayam, N Mitchell, JB Krishna, MC Cook, JA TI An application system for automation of constant-time radio frequency electron paramagnetic resonance imaging SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE constant time imaging; single-point imaging; gyromagnetic ratio; electron paramagnetic resonance; phase encoding; graphical user interface ID SPECTROMETER; RESOLUTION; VISUALIZATION; MICROSCOPY; EPR AB A Windows based application system for data collection, Fourier reconstruction and analysis of pure phase encoded constant-time radio frequency electron paramagnetic resonance (EPR) images, is described. The graphical user interface (GUI) of the system was written in MATLAB version 5.0, using its built-in GUI utilities. Design considerations of the application system included speed, flexibility and user-friendly data display and analysis. To maximize the speed of image data collection, MATLAB's built-in C interface system, MEX was not used for data collection. Instead, MA FLAB programs call the C programs from the DOS prompt directly, based on the data collection parameters entered through the GUI. Computational procedures included various digital signal-processing steps Such as filtering, interpolation etc. for the Fourier reconstruction of 2D, and 3D EPR images from the pure phase encoded data. Examples of 2D images illustrating the performance of the system are presented. Although the application system has been developed for the specific purpose of EPR imaging, it can easily be adapted to other areas such as magnetic resonance microscopy as well. Published by Elsevier Science Ireland Ltd. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3,B69, Bethesda, MD 20892 USA. NR 24 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-2607 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD OCT PY 2003 VL 72 IS 2 BP 127 EP 138 AR PII S0169-2607(02)00124-4 DI 10.1016/S0169-2607(02)00124-4 PG 12 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 721EJ UT WOS:000185303800005 PM 12941517 ER PT J AU Brubaker, L Cundiff, G Fine, P Nygaard, I Richter, H Visco, A Zyczynski, H Brown, MB Weber, A AF Brubaker, L Cundiff, G Fine, P Nygaard, I Richter, H Visco, A Zyczynski, H Brown, MB Weber, A CA Pelvic Floor Disorders Network TI A randomized trial of colpopexy and urinary reduction efforts (CARE): design and methods SO CONTROLLED CLINICAL TRIALS LA English DT Article DE pelvic organ prolapse; sacrocolpopexy; urinary incontinence; paravaginal defect repair; randomized surgical trial; urodynamics ID PELVIC ORGAN PROLAPSE; QUALITY-OF-LIFE; SEXUAL FUNCTION; HEALTH SURVEY; INCONTINENCE; WOMEN; PREVALENCE; SYMPTOMS; SF-36 AB The primary aim of this randomized clinical trial is to evaluate whether a standardized modified Burch colposuspension, when added to planned abdominal sacrocolpopexy for the treatment of pelvic organ prolapse, improves the rate of urinary stress continence in subjects without preoperative symptoms of stress urinary incontinence. Secondary aims include comparison of immediate and short-term complications, overall urinary tract function, and other aspects of pelvic health between subjects with and without a concomitant Burch. The value of preoperative urodynamic testing with prolapse reduction will also be compared between subjects with and without a concomitant Burch. This trial is performed through the Pelvic Floor Disorders Network, which is funded by the National Institutes of Health-National Institute of Child Health and Human Development. Subjects will be enrolled at seven clinical centers across the United States and data will be analyzed by the central data coordinating center. Standardized questionnaires and physical observations and measurements will be obtained. The surgical team is masked to the preoperative urodynamic findings, and the patient and research coordinator are masked to treatment assignment. The primary outcome will be determined at 3 months after surgery. Stress continence is defined as absence of stress incontinence symptoms by questionnaire, a negative standardized stress test, and no treatment for stress incontinence other than the study intervention. Additional follow-up occurs at 6, 12; and 24 months. Accrual began in April 2002 and is projected to take 3 years. As of March 6, 2003, 91 patients have been randomized. This article highlights the scientific aspects of trial design for this pivotal clinical trial. The optimal approach to the urinary tract in women treated surgically for prolapse is not known. This trial is designed to provide pelvic surgeons and their patients with scientific data regarding the utility of urodynamics with and without prolapse reduction and the role of colposuspension with sacrocolpopexy. (C) 2003 Elsevier Inc. All rights reserved. C1 Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. Johns Hopkins Univ, Dept Obstet & Gynecol, Baltimore, MD USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. NICHHD, Bethesda, MD 20892 USA. RP Brubaker, L (reprint author), Loyola Univ, Med Ctr, Dept Obstet & Gynecol, 2160 S 1st Ave, Maywood, IL 60153 USA. FU NICHD NIH HHS [U10 HD041263, U01 HD41249, U10 HD041261, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41267, U10 HD41269, U10 HD41248, U10 HD41268] NR 20 TC 59 Z9 59 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD OCT PY 2003 VL 24 IS 5 BP 629 EP 642 DI 10.1016/S0197-2456(03)00073-4 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 728JG UT WOS:000185713600010 PM 14500059 ER PT J AU Bron, AJ Evans, VE Smith, JA AF Bron, AJ Evans, VE Smith, JA TI Grading of corneal and conjunctival staining in the context of other dry eye tests SO CORNEA LA English DT Article DE grading; cornea; conjunctiva; staining; fluorescein; rose Bengal; lissamine green; filter; clinical trial ID TEAR FLUORESCEIN CLEARANCE; ROSE-BENGAL; SCHIRMER TEST; LISSAMINE GREEN; REFLECTIVE MENISCOMETRY; CHRONIC BLEPHARITIS; MENISCUS; FILM; DIAGNOSIS; THREAD AB Purpose: To describe the Oxford Scheme for grading ocular surface staining in dry eye and to discuss optimization of stain detection using various dyes and filters. Also, to propose a sequence of testing for dry eye diagnosis. Methods: The grading of corneal and conjunctival staining is described, using the Oxford Scheme, including biomicroscopy, optical filters, illumination conditions, and the characteristics of and instillation techniques used for, selected clinical dyes. Results: A series of panels, labeled A-E, in order of increasing severity, reproducing the staining patterns encountered in dry eye, are used as a guide to grade the degree of staining seen in the patient. The amount of staining seen in each panel, represented by punctate dots, increases by 0.5 of the log of the number of dots between panels B to E. The use of the vital dyes fluorescein, lissamine green, and rose Bengal is described; fluorescein and lissamine green, used in conjunction with appropriate absorption filters, are recommended for use in clinical trials. The placement of staining in relation to the sequence of other diagnostic tests is discussed. Conclusions: The monitoring and assessment of corneal and conjunctival staining can be greatly enhanced by the use of a grading scale, controlled instillation of dyes, and standard evaluation techniques. This is of particular benefit in clinical trials, where ocular surface staining is commonly employed as an outcome measure. C1 Univ Oxford, Nuffield Lab Ophthalmol, Oxford OX2 6AW, England. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Bron, AJ (reprint author), Univ Oxford, Nuffield Lab Ophthalmol, Walton St, Oxford OX2 6AW, England. NR 58 TC 293 Z9 304 U1 3 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD OCT PY 2003 VL 22 IS 7 BP 640 EP 650 DI 10.1097/00003226-200310000-00008 PG 11 WC Ophthalmology SC Ophthalmology GA 726BD UT WOS:000185577100008 PM 14508260 ER PT J AU Mattson, MP Haberman, F AF Mattson, MP Haberman, F TI Folate and homocysteine metabolism: Therapeutic targets cardiovascular and neurodegenerative disorders SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Alzheimer's disease; apoptosis; atherosclerosis; dietary folic acid; Parkinson's disease; schizophrenia; stem cells ID AMYLOID BETA-PEPTIDE; PLASMA HOMOCYSTEINE; FOLIC-ACID; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; ENDOTHELIAL FUNCTION; CEREBROSPINAL-FLUID; LIPID-PEROXIDATION; PARKINSONS-DISEASE; GLUCOSE-TRANSPORT AB Individuals with elevated homocysteine levels are at increased risk for cardiovascular disease and stroke, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Homocysteine is a modified form of the amino acid methionine that is tightly regulated by enzymes requiring folate. By impairing DNA repair mechanisms and inducing oxidative stress, homocysteine can cause the dysfunction or death of cells in the cardiovascular and nervous systems. Dietary folate stimulates homocysteine removal and may thereby protect cells against disease processes. The enzymes involved in homocysteine and folate metabolism provide novel targets for drug discovery. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 71 TC 22 Z9 22 U1 1 U2 4 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD OCT PY 2003 VL 10 IS 19 BP 1923 EP 1929 DI 10.2174/0929867033456864 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 721CR UT WOS:000185299900003 PM 12871094 ER PT J AU Su, TP Hayashi, T AF Su, TP Hayashi, T TI Understanding the molecular mechanism of sigma-1 receptors: Towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID METHYL-D-ASPARTATE; CONDITIONED PLACE PREFERENCE; H-3 DOPAMINE RELEASE; GUINEA-PIG BRAIN; RAT-BRAIN; BINDING-SITES; OPIOID ANALGESIA; NOREPINEPHRINE RELEASE; DENDRITIC SPINES; CARDIAC MYOCYTES AB Although sigma receptors were discovered in 1982, the biochemical and physiological roles of sigma receptors have just begun to unveil. Sigma receptors are non-opioid, non-phencyclidine receptors that contain two subtypes: sigma-1 and sigma-2 receptors. The sigma-l receptor has been cloned and its sequence does not resemble that of any mammalian protein. Sigma-2 receptors have not been cloned. The focus of this review will be on sigma-1 receptors. Sigma-1 receptors contain 223 amino acids and reside primarily at the endoplasmic reticulum. Sigma-l receptors exist mainly in the central nervous system, but also in the periphery. Sigma-1 receptor ligands include cocaine, (+)-benzomorphans like (+)-pentazocine and (+)N-allyl-normetazoeine (or (+)-SKF-10047), and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system. C1 NIDA, Cellular Pathobiol Unit, CNRB,IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, CNRB,IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 82 TC 120 Z9 124 U1 0 U2 10 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD OCT PY 2003 VL 10 IS 20 BP 2073 EP 2080 DI 10.2174/0929867033456783 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 721CT UT WOS:000185300000003 PM 12871086 ER PT J AU Kleinman, HK Philp, D Hoffman, MP AF Kleinman, HK Philp, D Hoffman, MP TI Role of the extracellular matrix in morphogenesis SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID ENDOTHELIAL-CELL MORPHOGENESIS; BRANCHING MORPHOGENESIS; BINDING SITE; IN-VITRO; EPITHELIAL MORPHOGENESIS; CAPILLARY MORPHOGENESIS; BIOLOGICAL-ACTIVITY; LAMININ ALPHA-1; DOMAIN; GLAND AB The extracellular matrix is a complex, dynamic and critical component of all tissues. It functions as a scaffold for tissue morphogenesis, provides cues for cell proliferation and differentiation, promotes the maintenance of differentiated tissues and enhances the repair response after injury. Various amounts and types of collagens, adhesion molecules, proteoglycans, growth factors and cytokines or chemokines are present in the tissue- and temporal-specific extracellular matrices. Tissue morphogenesis is mediated by multiple extracellular matrix components and by multiple active sites on some of these components. Biologically active extracellular matrix components may have use in tissue repair, regeneration and engineering, and in programming stem cells for tissue replacement. C1 Natl Inst Dent & Craniofacial Res, Cell Biol Sect, CDBRB, NIH, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, Cell Biol Sect, CDBRB, NIH, 30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. NR 47 TC 222 Z9 226 U1 2 U2 26 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD OCT PY 2003 VL 14 IS 5 BP 526 EP 532 DI 10.1016/j.copbio.2003.08.002 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 741FN UT WOS:000186448200013 PM 14580584 ER PT J AU Catalfamo, M Henkart, PA AF Catalfamo, M Henkart, PA TI Perforin and the granule exocytosis cytotoxicity pathway SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID GRANZYME-B INHIBITOR; CD8(+) T-CELLS; LYMPHOCYTE-MEDIATED CYTOTOXICITY; IN-VIVO; PROTEASE INHIBITOR-9; DENDRITIC CELLS; VIRAL-INFECTION; DEATH PATHWAY; TARGET-CELLS; APOPTOSIS AB Perforin defects have been identified in humans with familial hematophagocytic lymphohistiocytosis. The pathology of these patients has dramatically illustrated an under-appreciated role for perforin in the regulation of T-cell responses in vivo, and experimental studies are shedding light on the mechanisms involved. The detailed molecular mechanisms of perforin's mandatory role in the cytotoxic T lymphocyte (CTL)-mediated granule exocytosis death pathway and of granzyme entry into target cells remain unclear. In model systems measuring apoptosis by granzyme B and sublytic perforin, pore formation is undetectable during granzyme entry. Selfprotection of cytotoxic lymphocytes after degranulation can be explained by surface expression of the granule protease cathepsin B, as shown by suicidal degranulation in the presence of specific inhibitors. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Catalfamo, M (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 53 TC 93 Z9 98 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2003 VL 15 IS 5 BP 522 EP 527 DI 10.1016/S0952-7915(03)00114-6 PG 6 WC Immunology SC Immunology GA 728TE UT WOS:000185731800009 PM 14499260 ER PT J AU Berman, J AF Berman, J TI Current treatment approaches to leishmaniasis SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE liposomal amphotericin B; cutaneous leishmaniasis; miltefosine treatment; visceral leishmaniasis ID INDIAN VISCERAL LEISHMANIASIS; PROPRIETARY SODIUM STIBOGLUCONATE; MEGLUMINE ANTIMONIATE GLUCANTIME; RANDOMIZED CLINICAL-TRIAL; LIPOSOMAL AMPHOTERICIN-B; CUTANEOUS LEISHMANIASIS; PAROMOMYCIN AMINOSIDINE; EFFICACY; ALLOPURINOL; FAILURE AB Purpose of review The leishmaniases consist of cutaneous, mucosal, and visceral syndromes. The classic treatment is with pentavalent antimonials. The disadvantages of the antimonials are their requirement for intramuscular or intravenous injection each day for 20-28 days, their toxicity, and the recent development of resistance in regions such as India. Amphotericin B is a potent secondary agent, but is also compromised by its parenteral nature and toxicity. Clinical investigation of treatment agents from January 2000 to January 2003 is reviewed to determine if there are new agents that can be used. Recent findings A large number of pilot studies on visceral and cutaneous leishmaniasis have been performed. There can be more confidence in the visceral studies because visceral disease is incurable if untreated, and because large numbers of patients have been treated in highly endemic regions such as India. There is less confidence in pilot studies of the cutaneous disease, because most are uncontrolled, and there is a variable, and often high, cure rate without treatment. Summary Liposomal amphotericin B, which is injected infrequently and is easily tolerated, is virtually 100% effective for Indian visceral disease at a total dose of 15 mg/kg and is 90% effective at a dose of 5-10 mg/kg. The oral agent, miltefosine, is more than 95% effective for Indian visceral disease. Fluconazole treatment for 6 weeks speeds up the already-rapid cure rate of cutaneous disease due to Leishmania major. C1 NIH, Natl Ctr Complementary & Alternat Med, Off Clin & Regulatory Affairs, Bethesda, MD 20892 USA. RP Berman, J (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Off Clin & Regulatory Affairs, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. NR 28 TC 123 Z9 125 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD OCT PY 2003 VL 16 IS 5 BP 397 EP 401 DI 10.1097/01.qco.0000092810.64370.65 PG 5 WC Infectious Diseases SC Infectious Diseases GA 736AT UT WOS:000186148600005 PM 14501991 ER PT J AU Aravind, L Anantharaman, V Iyer, LM AF Aravind, L Anantharaman, V Iyer, LM TI Evolutionary connections between bacterial and eukaryotic signaling systems: a genomic perspective SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID AGROBACTERIUM-TUMEFACIENS C58/; HORIZONTAL GENE-TRANSFER; BRADYRHIZOBIUM-JAPONICUM; DOMAIN COMMON; GAF-DOMAIN; PAS KINASE; SEQUENCE; RECEPTORS; PROTEIN; ANCIENT AB Recent advances in microbial genomics suggest that several protein domains are common to bacterial and eukaryotic regulatory proteins. In particular, developmentally and morphologically complex prokaryotes appear to share several signaling modules with eukaryotes. New experimental studies and information from domain architectures point to several similar mechanistic themes in bacterial and eukaryotic signaling proteins. Laterally transferred protein domains, originally of bacterial provenance, appear to have contributed to the evolution of sensory pathways related to light, redox and nitric oxide signaling, and developmental pathways, such as Notch, cytokine and cytokinin signaling in eukaryotes. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 NR 50 TC 35 Z9 37 U1 1 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD OCT PY 2003 VL 6 IS 5 BP 490 EP 497 DI 10.1016/j.mib.2003.09.003 PG 8 WC Microbiology SC Microbiology GA 736DG UT WOS:000186155100012 PM 14572542 ER PT J AU Tisdale, JF Wilson, DR AF Tisdale, JF Wilson, DR TI Clinical applications of gene therapy SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Editorial Material ID SEVERE COMBINED IMMUNODEFICIENCY; DISEASE C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Deborah R Wilson Consulting, Houston, TX 77031 USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N116,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 1 U2 1 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD OCT PY 2003 VL 5 IS 5 BP 456 EP 457 PG 2 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 735GE UT WOS:000186103400001 PM 14601512 ER PT J AU Gordon, CM Nelson, LM AF Gordon, CM Nelson, LM TI Amenorrhea and bone health in adolescents and young women SO CURRENT OPINION IN OBSTETRICS & GYNECOLOGY LA English DT Article DE amenorrhea; osteoporosis; bone mineral density; adolescents; hormonal replacement therapy ID ORAL-CONTRACEPTIVE USE; BIRTH-CONTROL PILLS; ANOREXIA-NERVOSA; PHYSICAL-ACTIVITY; MINERAL DENSITY; HYPOTHALAMIC AMENORRHEA; PREMENOPAUSAL WOMEN; FEMALE ADOLESCENTS; MENSTRUAL-CYCLE; FEMORAL-NECK AB Purpose of review We present an update on amenorrhea in adolescent girls and young women. Amenorrhea may herald the onset of estrogen deficiency, which can adversely affect peak bone mass and ultimate risk of osteoporosis. Recent findings Adolescence is a critical period for bone accretion. Important modifiable factors that optimize bone accretion during this time are calcium intake, vitamin D, nutrition, and exercise. Another modifiable factor in the hands of the clinician is the prompt recognition and therapy of amenorrhea associated with estrogen deficient states, caused by conditions such as hyperprolactinemia and ovarian failure. An important recent observation is that adolescents with amenorrhea who diet, but who do not meet diagnostic criteria for anorexia nervosa, are nonetheless at significant risk for low bone density. Also, multiple factors contribute to the bone loss experienced by patients with anorexia nervosa, and the associated estrogen deficiency may not be the major contributor. Recent evidence also suggests that the contraceptive depot medroxyprogesterone acetate may contribute to impaired bone accretion. While estrogen/progestin replacement therapy has a clear role in the management of girls and young women with primary ovarian insufficiency, the exact role of this therapy in the amenorrhea associated with anorexia nervosa or exercise remains controversial. Summary Increasingly, osteoporosis prevention is recognized as an important role for health care providers of adolescent girls and young women. Viewed from this perspective, there is a need for more aggressive evaluation and management of amenorrhea, and research is needed to define sound and cost effective strategies. C1 Childrens Hosp, Div Adolescent Med, Boston, MA 02115 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp Bone Hlth Ctr, Div Adolescent Young Adult Med, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp Bone Hlth Ctr, Div Endocrinol, Boston, MA USA. Harvard Univ, Sch Med, Dept Pediat, Div Adolescent Young Adult Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pediat, Dept Endocrinol, Boston, MA USA. NICHHD, Sect Womens Hlth Res, Dev Endocrinol Branch, NIH, Bethesda, MD USA. RP Gordon, CM (reprint author), Childrens Hosp, Div Adolescent Med, 300 Longwood Ave, Boston, MA 02115 USA. NR 57 TC 28 Z9 29 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-872X J9 CURR OPIN OBSTET GYN JI Curr. Opin. Obstet. Gynecol. PD OCT PY 2003 VL 15 IS 5 BP 377 EP 384 DI 10.1097/01.gco.0000094698.87578.21 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 734UT UT WOS:000186076900005 PM 14501240 ER PT J AU Watford, WT Moriguchi, M Morinobu, A O'Shea, JJ AF Watford, WT Moriguchi, M Morinobu, A O'Shea, JJ TI The biology of IL-12: coordinating innate and adaptive immune responses SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE IL-12; IL-23; IL-27; T helper 1 cells; interferon-gamma ID IFN-GAMMA-PRODUCTION; NF-KAPPA-B; SEQUENCE-BINDING-PROTEIN; NATURAL-KILLER-CELLS; TOLL-LIKE RECEPTORS; STAT4 SERINE PHOSPHORYLATION; LYMPHOCYTE MATURATION FACTOR; BLOOD MONONUCLEAR-CELLS; MURINE DENDRITIC CELLS; NECROSIS-FACTOR-ALPHA AB Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 is especially important because its expression during infection regulates innate responses and determines the type and duration of adaptive immune response. IL-12 induces interferon-gamma (IFN-gamma) production by NK, T cells, dendritic cells (DC), and macrophages. IL-12 also promotes the differentiation of naive CD4(+) T cells into T helper 1 (Th1) cells that produce IFN-gamma and aid in cell-mediated immunity. As IL-12 is induced by microbial products and regulates the development of adaptive immune cells, IL-12 plays a central role in coordinating innate and adaptive immunity. IL-12 and the recently identified cytokines, IL-23 and IL-27, define a family of related cytokines that induce IFN-gamma production and promote T cell expansion and proliferation. Published by Elsevier Ltd. C1 NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NR 111 TC 295 Z9 314 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD OCT PY 2003 VL 14 IS 5 BP 361 EP 368 DI 10.1016/S1359-6101(03)00043-1 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 725XM UT WOS:000185567700001 PM 12948519 ER PT J AU He, LS Olson, DP Wu, XL Karpova, TS McNally, JG Lipsky, PE AF He, LS Olson, DP Wu, XL Karpova, TS McNally, JG Lipsky, PE TI A flow cytometric method to detect protein-protein interaction in living cells by directly visualizing donor fluorophore quenching during CFP -> YFP fluorescence resonance energy transfer (FRET) SO CYTOMETRY PART A LA English DT Article DE fluorescence resonance energy transfer (FRET); cyan fluorescent protein; yellow fluorescent protein; TNF receptor-associated factor (TRAF); donor quenching; flow cytometry; protein-protein interaction ID NF-KAPPA-B; LIVE CELLS; INDUCED APOPTOSIS; SINGLE-LASER; HUMAN TRAF2; RECEPTOR; MICROSCOPY; ACTIVATION; SURFACES; FAMILY AB Background: Protein interactions at the molecular level can be measured by fluorescence resonance energy transfer (FRET) using a pair of fluorescent proteins, such as CFP and YFP, in which the emission spectrum of CFP significantly overlaps the excitation spectrum of YFP. The resulting energy given off from the donor CFP protein can directly excite the acceptor YFP protein when the proteins are closely approximated. During FRET, there is quenching of the emission of the donor CFP protein that is directly related to the efficiency of energy transfer and inversely proportional to the sixth power of the distance between the donor and acceptor proteins. In this study we describe a new approach to visualize donor CFP quenching during CFP-->YFP FRET and demonstrate how this parameter can be used to calculate FRET efficiency. Methods: A novel flow cytometric method to detect protein-protein interactions in living cells was developed that utilized assessment of CFP donor quenching during CFP-->YFP FRET by comparing CFP intensity between FRET-positive and -negative populations. To accomplish this, we compared the CFP intensity in FRET-positive and FRET-negative cells within the same population transfected with a CFP/YFP fusion protein, in which the molar ratio of CFP:YFP was one. By using separate lasers to excite CFP and YFP, the detection of FRET was separated from that of YFP. Therefore, after direct excitation, the YFP emission spectrum remained constant in all transfected cells, whereas the emission spectrum of CFP varied with the extent of FRET in individual cells. Specific CFP/YFP fusion constructs were prepared to evaluate this approach. The first one consisted of CFP and YFP separated by two caspase cleavage sites (CFP-LEVD-YFP). A second construct consisted of CFP and YFP separated by a structurally restricted 232-amino acid (aa) spacer. No FRET was observed by transfectants expressing this construct. Results: Transfection of CFP-LEVD-YFP into Hela cells resulted in a FRET-positive population and a FRET-negative one. The appearance of the FRET-negative population was inhibited by the caspase inhibitor z-VAD. Moreover, substituting D for A in the caspase cleavage sites of this probe abolished the FRET-negative population, demonstrating the probe's specificity for caspase activity. Comparison of the CFP emission in the FRET-positive and FRET-negative population was used to document the relationship of FRET to donor quenching and permit the calculation of FRET efficiency and relative molecular distance between CFP and YFP. Similar results were noted when cells transfected with the caspase-sensitive probe (in the presence of z-VAD) were mixed with cells expressing the CFP-YFP construct with the 232-aa spacer and therefore were FRET negative. This demonstrated the validity of calculating CFP donor quenching and FRET efficiency by comparing emission spectra of an unknown construct with that of a known positive control, both expressed by the same population of cells. Using this approach, we confirmed that members of the TNF receptor-associated factor (TRAF) family engaged in both homotypic and homotypic interactions. Conclusions: We have established a novel flow cytometric approach to assess donor CFP quenching during CFP-->YFP FRET, which can be used for the calculation of FRET efficiency and relative biological molecular distance between CFP and YFP moieties. This method can be used not only to analyze cells that express a CFP and YFP fusion protein, but also independent CFP-coupled and YFP-coupled interacting proteins. Published 2003 Wiley-Liss, Inc.(dagger) C1 NIAMSD, Flow Cytomet Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD USA. NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP He, LS (reprint author), NIAMSD, Flow Cytomet Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. NR 47 TC 32 Z9 33 U1 2 U2 32 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD OCT PY 2003 VL 55A IS 2 BP 71 EP 85 DI 10.1002/cyto.a.10073 PG 15 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 726JA UT WOS:000185594400002 PM 14505312 ER PT J AU Blackshear, PJ Graves, JP Stumpo, DJ Cobos, I Rubenstein, JLR Zeldin, DC AF Blackshear, PJ Graves, JP Stumpo, DJ Cobos, I Rubenstein, JLR Zeldin, DC TI Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4 SO DEVELOPMENT LA English DT Article DE hydrocephalus; regulatory factor X; winged helix transcription factor; cortex; midline; mouse ID X-LINKED HYDROCEPHALUS; SUBCOMMISSURAL ORGAN; CONGENITAL HYDROCEPHALUS; REISSNERS FIBER; DNA-BINDING; MICE; EXPRESSION; PROTEIN; SYSTEM; REELER AB One line of mice harboring a cardiac-specific epoxygenase transgene developed head swelling and rapid neurological decline in young adulthood, and had marked hydrocephalus of the lateral and third ventricles. The transgene was found to be inserted into an intron in the mouse Rfx4 locus. This insertion apparently prevented expression of a novel variant transcript of RFX4 (RFX4_v3), a member of the regulatory factor X family of winged helix transcription factors. Interruption of two alleles resulted in profound failure of dorsal midline brain structure formation and perinatal death, presumably by interfering with expression of downstream genes. Interruption of a single allele prevented formation of the subcommissural organ, a structure important for cerebrospinal fluid flow through the aqueduct of Sylvius, and resulted in congenital hydrocephalus. These data implicate the RFX4_v3 variant transcript as being crucial for early brain development, as well as for the genesis of the subcommissural. organ. These findings may be relevant to human congenital hydrocephalus, a birth defect that affects similar to0.6 per 1000 newborns. C1 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94143 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Off Clin Res, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIMH NIH HHS [K02 MH01046]; NINDS NIH HHS [R01 NS34661] NR 39 TC 62 Z9 67 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2003 VL 130 IS 19 BP 4539 EP 4552 DI 10.1242/dev.00661 PG 14 WC Developmental Biology SC Developmental Biology GA 755JE UT WOS:000187399100004 PM 12925582 ER PT J AU Escalante-Alcalde, D Hernandez, L Le Stunff, H Maeda, R Lee, HS Cheng, JG Sciorra, VA Daar, I Spiegel, S Morris, AJ Stewart, CL AF Escalante-Alcalde, D Hernandez, L Le Stunff, H Maeda, R Lee, HS Cheng, JG Sciorra, VA Daar, I Spiegel, S Morris, AJ Stewart, CL TI The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning SO DEVELOPMENT LA English DT Article DE lipid phosphate phosphatase; vasculogenesis; Wnt; axis duplication ID VASCULAR ENDOTHELIAL-CELLS; RECEPTOR TYROSINE KINASE; MIGRATING GERM-CELLS; MOUSE FUSED LOCUS; SPHINGOSINE 1-PHOSPHATE; LYSOPHOSPHATIDIC ACID; SIGNAL-TRANSDUCTION; MOLECULAR ANALYSIS; EMBRYONIC AXIS; BETA-CATENIN AB Bioactive phospholipids, which include sphingosine-1-phosphate, lysophosphatidic acid, ceramide and their derivatives regulate a wide variety of cellular functions in culture such as proliferation, apoptosis and differentiation. The availability of these lipids and their products is regulated by the lipid phosphate phosphatases (LPPs). Here we show that mouse embryos deficient for LPP3 fail to form a chorio-allantoic placenta and yolk sac vasculature. A subset of embryos also show a shortening of the anterior-posterior axis and frequent duplication of axial structures that are strikingly similar to the phenotypes associated with axin deficiency, a critical regulator of Wnt signaling. Loss of LPP3 results in a marked increase in beta-catenin-mediated TCF transcription, whereas elevated levels of LPP3 inhibit beta-catenin-mediated TCF transcription. LPP3 also inhibits axis duplication and leads to mild ventralization in Xenopus embryo development. Although LPP3 null fibroblasts show altered levels of bioactive phospholipids, consistent with loss of LPP3 phosphatase activity, mutant forms of LPP3, specifically lacking phosphatase activity, were able to inhibit beta-catenin-mediated TCF transcription and also suppress axis duplication, although not as effectively as intact LPP3. These results reveal that LPP3 is essential to formation of the chorio-allantoic placenta and extra-embryonic vasculature. LPP3 also mediates gastrulation and axis formation, probably by influencing the canonical Wnt signaling pathway. The exact biochemical roles of LPP3 phosphatase activity and its undefined effect on beta-catenin-mediated TCF transcription remain to be determined. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NCI, Regulat & Cell Growth Lab, Div Basic Sci, Frederick, MD 21702 USA. Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. RP Stewart, CL (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RI Lee, Hyun-Shik/G-3555-2011; Morris, Andrew/B-7869-2010 OI Daar, Ira/0000-0003-2657-526X; NR 77 TC 102 Z9 106 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2003 VL 130 IS 19 BP 4623 EP 4637 DI 10.1242/dev.00635 PG 15 WC Developmental Biology SC Developmental Biology GA 755JE UT WOS:000187399100011 PM 12925589 ER PT J AU Mankoo, BS Skuntz, S Harrigan, I Grigorieva, E Candia, A Wright, CVE Arnheiter, H Pachnis, V AF Mankoo, BS Skuntz, S Harrigan, I Grigorieva, E Candia, A Wright, CVE Arnheiter, H Pachnis, V TI The concerted action of Meox homeobox genes is required upstream of genetic pathways essential for the formation, patterning and differentiation of somites SO DEVELOPMENT LA English DT Article DE somite; myogenesis; chondrogenesis; homeobox ID TRANSCRIPTION FACTORS; PARAXIAL MESODERM; SONIC HEDGEHOG; PROTOCADHERIN PAPC; MUSCLE DEVELOPMENT; SIGNALING PATHWAY; LUNATIC FRINGE; MOUSE; SEGMENTATION; SOMITOGENESIS AB The paraxial mesoderm of the somites of the vertebrate embryo contains the precursors of the axial skeleton, skeletal muscles and dermis. The Meox1 and Meox2 homeobox genes are expressed in the somites and their derivatives during embryogenesis. Mice homozygous for a null mutation in Meox1 display relatively mild defects in sclerotome derived vertebral and rib bones, whereas absence of Meox2 function leads to defective differentiation and morphogenesis of the limb muscles. By contrast, mice carrying null mutations for both Meox genes display a dramatic and wide-ranging synthetic phenotype associated with extremely disrupted somite morphogenesis, patterning and differentiation. Mutant animals lack an axial skeleton and skeletal muscles are severely deficient. Our results demonstrate that Meox1 and Meox2 genes function together and upstream of several genetic hierarchies that are required for the development of somites. In particular, our studies place Meox gene function upstream of Pax genes in the regulation of chondrogenic and myogenic differentiation of paraxial mesoderm. C1 Natl Inst Med Res, Dept Neurobiol, London NW7 1AA, England. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA. RP Pachnis, V (reprint author), Natl Inst Med Res, Dept Neurobiol, Mill Hill,Ridgeway, London NW7 1AA, England. NR 50 TC 88 Z9 94 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2003 VL 130 IS 19 BP 4655 EP 4664 DI 10.1242/dev.00687 PG 10 WC Developmental Biology SC Developmental Biology GA 755JE UT WOS:000187399100013 PM 12925591 ER PT J AU Rao, C Foernzler, D Loftus, SK Liu, SM McPherson, JD Jungers, KA Apte, SS Pavan, WJ Beier, DR AF Rao, C Foernzler, D Loftus, SK Liu, SM McPherson, JD Jungers, KA Apte, SS Pavan, WJ Beier, DR TI A defect in a novel ADAMTS family member is the cause of the belted white-spotting mutation SO DEVELOPMENT LA English DT Article DE ADAMTS; white-spotting; melanocyte migration; mouse ID ENDOTHELIN-B RECEPTOR; CAENORHABDITIS-ELEGANS; KIT-LIGAND; BOVINE DERMATOSPARAXIS; COAT COLOR; MOUSE; GENE; MICE; EXPRESSION; AGGRECANASE-1 AB Several features of the pigment defect in belted (bt) mutant mice suggest that it occurs as a result of a defect in melanocyte development that is unique from those described for other classical white-spotting mutations. We report here that bt mice carry mutations in Adamts20, a novel member of the ADAMTS family of secreted metalloproteases. Adamts20 shows a highly dynamic pattern of expression in the developing embryo that generally precedes the appearance of melanoblasts in the same region, and is not expressed in the migrating cells themselves. Adamts20 shows remarkable homology with GON-1, an ADAMTS family protease required for distal tip cell migration in C elegans. Our results suggest that the role of ADAMTS proteases in the regulation of cell migration has been conserved in mammalian development. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02476 USA. Cleveland Clin Fdn, Dept Biomed Engn, Cleveland, OH 44195 USA. Washington Univ, Dept Genet, Bethesda, MD 20892 USA. NHGRI, NIH, Boston, MA 02115 USA. RP Beier, DR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02476 USA. FU NHGRI NIH HHS [HG02155]; NIAMS NIH HHS [AR049930]; NICHD NIH HHS [HD29028] NR 38 TC 44 Z9 45 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2003 VL 130 IS 19 BP 4665 EP 4672 DI 10.1242/dev.00668 PG 8 WC Developmental Biology SC Developmental Biology GA 755JE UT WOS:000187399100014 PM 12925592 ER PT J AU Piotrowski, T Ahn, DG Schilling, TF Nair, S Ruvinsky, I Geisler, R Rauch, GJ Haffter, P Zon, LI Zhou, Y Foott, H Dawid, IB Ho, RK AF Piotrowski, T Ahn, DG Schilling, TF Nair, S Ruvinsky, I Geisler, R Rauch, GJ Haffter, P Zon, LI Zhou, Y Foott, H Dawid, IB Ho, RK TI The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans SO DEVELOPMENT LA English DT Article DE van gogh (vgo); tbx1; endothelin1; pharyngeal arch development; DiGeorge syndrome; endodermal pouches; aortic arches; zebrafish ID PHARYNGEAL ARCH DEVELOPMENT; ULNAR-MAMMARY SYNDROME; BRANCHIAL ARCH; NEURAL-CREST; TRANSCRIPTION FACTOR; DANIO-RERIO; ENDODERMAL FATE; MICE DEFICIENT; SONIC HEDGEHOG; INNER-EAR AB The van gogh (vgo) mutant in zebrafish is characterized by defects in the ear, pharyngeal arches and associated structures such as the thymus. We show that vgo is caused by a mutation in tbx1, a member of the large family of T-box genes. tbx1 has been recently suggested to be a major contributor to the cardiovascular defects in DiGeorge deletion syndrome (DGS) in humans, a syndrome in which several neural crest derivatives are affected in the pharyngeal arches. Using cell transplantation studies, we demonstrate that vgo/tbx1 acts cell autonomously in the pharyngeal mesendoderm and influences the development of neural crest-derived cartilages secondarily. Furthermore, we provide evidence for regulatory interactions between vgo/tbx1 and edn1 and hand2, genes that are implicated in the control of pharyngeal arch development and in the etiology of DGS. C1 NICHD, LMG, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA. Univ Calif Irvine, Dept Cell & Dev Biol, Irvine, CA 92697 USA. Princeton Univ, Dept Biol Mol, Princeton, NJ 08544 USA. Max Planck Inst Dev Biol, D-72076 Tubingen, Germany. Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA. RP Piotrowski, T (reprint author), NICHD, LMG, NIH, Bldg 6B,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [R01 DE013828] NR 51 TC 133 Z9 141 U1 1 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT PY 2003 VL 130 IS 20 BP 5043 EP 5052 DI 10.1242/dev.00704 PG 10 WC Developmental Biology SC Developmental Biology GA 755JG UT WOS:000187399300025 PM 12952905 ER PT J AU Hinton, SD Yang, DZ Eckberg, WR AF Hinton, SD Yang, DZ Eckberg, WR TI Protein tyrosine phosphatases in Chaetopterus egg activation SO DEVELOPMENT GROWTH & DIFFERENTIATION LA English DT Article DE egg activation; fertilization; invertebrate; protein phosphorylation; protein tyrosine phosphatase ID SEA-URCHIN EGG; KINASE-ACTIVITY; CYTOPLASMIC LOCALIZATION; CAENORHABDITIS-ELEGANS; FYN KINASE; PTP-SIGMA; FERTILIZATION; RECEPTOR; CELL; SRC AB Changes in protein tyrosine phosphorylation are an essential aspect of egg activation after fertilization. Such changes result from the net contributions of both tyrosine kinases and phosphatases (PTP). This study was conducted to determine what role(s) PTP may have in egg activation. We identified four novel PTP in Chaetopterus pergamentaceus oocytes, cpPTPNT6, cpPTPNT7, cpPTPR2B, and cpPTPR2A, that have significant homology to, respectively, human PTPsigma, -rho, -D2 and -BAS. The first two are cytosolic and the latter two are transmembrane. Several PTP inhibitors were tested to see if they would affect Chaetopterus pergamentaceus fertilization. Eggs treated with beta-bromo-4-hydroxyacetophenone (PTP inhibitor 1) exhibited microvillar elongation, which is a sign of cortical changes resulting from activation. Those treated with Na3VO4 underwent full parthenogenetic activation, including polar body formation and pseudocleavage and did so independently of extracellular Ca2+, which is required for the Ca2+ oscillations that initiate development after fertilization, Fluorescence microscopy identified phosphotyrosine-containing proteins in the cortex and around the nucleus of vanadate-activated eggs, whereas in fertilized eggs they were concentrated only in the cortex. Immunoblots of vanadate-activated and fertilized eggs showed tyrosine hyperphosphorylation of approximately 140 kDa protein. These results suggest that PTP most likely maintain the egg in an inactive state by dephosphorylation of proteins independent of the Ca2+ oscillations in the activation process. C1 Howard Univ, Dept Biol, Washington, DC 20059 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11274 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Howard Univ, Dept Biol, 415 Coll St NW, Washington, DC 20059 USA. EM weckberg@howard.edu NR 52 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1592 EI 1440-169X J9 DEV GROWTH DIFFER JI Dev. Growth Diff. PD OCT-DEC PY 2003 VL 45 IS 5-6 BP 405 EP 415 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 761KJ UT WOS:000187907700002 PM 14706066 ER PT J AU Maskos, U McKay, RDG AF Maskos, U McKay, RDG TI Neural cells without functional N-methyl-D-aspartate (NMDA) receptors contribute extensively to normal postnatal brain development in efficiently generated chimaeric NMDA R1-/-<->+/+ mice SO DEVELOPMENTAL BIOLOGY LA English DT Article DE embryonic stem cells; chimaeras; differentiation; migration; neurodevelopment; NMDA receptor ID GREEN FLUORESCENT PROTEIN; LONG-TERM POTENTIATION; EMBRYONIC STEM-CELLS; NEURONAL MIGRATION; HIPPOCAMPAL-NEURONS; TARGETED DISRUPTION; GLUTAMATE RECEPTORS; PURKINJE-CELLS; NERVOUS-SYSTEM; MESSENGER-RNA AB Embryonic stem (ES) cells have revolutionised our understanding of animal physiology. Analysis of chimaeric mice generated from these cells allows us to study the role of genes in development and function of the nervous system. The NMDA receptor, one of the two major ionotropic glutamate receptors, has been proposed to play fundamental roles in the survival, migration, differentiation, and activity-dependent maturation of neural cells. The NMDA receptor subunit I (NRI) gene is indispensable for receptor function, and knock-out mice die at birth, inhibiting the study of glutamate signalling in postnatal neurons. Homozygous NR1(-/-) ES cells were derived from matings of heterozygous mice under feeder-free conditions. Chimaeras were made by incorporating these ES cells into wild-type blastocysts and by the classical aggregation of morulae between wild-type and NR1(-/-) embryos. The resulting chimaeras survive and develop normally. NR1(-/-) neurons, identified by their lacZ label, were analysed and quantified in developing and adult brains with varying knock-out contributions in every single brain region. Specifically, postnatal ontogenesis of cerebellum and hippocampus was normal. Accordingly, in chimaeric mice, NMDA receptor-initiated signals are not required for the migration, differentiation, and survival of most types of neurons in the central nervous system, in a cell-autonomous way. (C) 2003 Elsevier Inc. All rights reserved. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Maskos, U (reprint author), Inst Pasteur, CNRS, URA 2182, F-75724 Paris 15, France. NR 51 TC 15 Z9 15 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2003 VL 262 IS 1 BP 119 EP 136 DI 10.1016/S0012-1606(03)00354-3 PG 18 WC Developmental Biology SC Developmental Biology GA 726TR UT WOS:000185616400010 PM 14512023 ER PT J AU Donaldson, JG AF Donaldson, JG TI Myoblasts fuse when loner meets ARF6 SO DEVELOPMENTAL CELL LA English DT Editorial Material ID FUSION C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2503, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT PY 2003 VL 5 IS 4 BP 527 EP 528 DI 10.1016/S1534-5807(03)00298-3 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 731ED UT WOS:000185870800002 PM 14536050 ER PT J AU Coleman, CM Tuan, RS AF Coleman, CM Tuan, RS TI Growth/differentiation factor 5 enhances chondrocyte maturation SO DEVELOPMENTAL DYNAMICS LA English DT Article DE growth/differentiation factor 5; limb development; joint formation; chondrogenesis; chondrocyte hypertrophy ID ALKALINE-PHOSPHATASE; SKELETAL DEVELOPMENT; JOINT DEVELOPMENT; IN-VITRO; DOUBLE MUTATIONS; LIMB; CARTILAGE; COLLAGEN; BONE; CHONDROGENESIS AB Growth/differentiation factor 5 (GDF5) is required for limb mesenchymal cell condensation and joint formation during skeletogenesis. Here, we use a model consisting of long-term, high-density cultures of chick embryonic limb mesenchymal cells, which undergo the entire life history of chondrocyte development, to examine the effects of GDF5 overexpression on chondrocyte maturation. Exposure to GDF5 significantly enhanced chondrocyte hypertrophy and maturation, as determined by the presence of alkaline phosphatase activity, collagen type X protein production, and the presence of a sulfated proteoglycan-rich extracellular matrix. Histologic analysis also revealed an increase in cell volume and cellular encasement in larger lacunae in GDF5-treated cultures. Taken together, these results support a role for GDF5 in influencing chondrocyte maturation and the induction of hypertrophy in the late stages of embryonic cartilage development, and provide additional mechanistic insights into the role of GDF5 in skeletal development. Published 2003 Wiley-Liss, Inc.dagger. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bldg 50,Room 1503,MSC 8022, Bethesda, MD 20892 USA. NR 36 TC 33 Z9 43 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD OCT PY 2003 VL 228 IS 2 BP 208 EP 216 DI 10.1002/dvdy.10369 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 728BC UT WOS:000185694500007 PM 14517992 ER PT J AU Haluzik, M Yakar, S Gavrilova, O Setser, J Boisclair, Y LeRoith, D AF Haluzik, M Yakar, S Gavrilova, O Setser, J Boisclair, Y LeRoith, D TI Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex - Relative roles of growth hormone and IGF-1 in insulin resistance SO DIABETES LA English DT Article ID FACTOR-I; GLUCOSE-TRANSPORT; INDEPENDENT MECHANISMS; MICE; MUSCLE; RECEPTOR; OBESITY; COMBINATION; SENSITIVITY; ADOLESCENTS AB Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice with a gene deletion of the acid-labile subunit (ALSKO) demonstrate a 65% reduction in circulating IGF-1 levels, with normal GH levels and no signs of insulin resistance. To further clarify the relative roles of increased GH and decreased IGF-1 levels in the development of insulin resistance, we crossed the two mouse lines and created a double knockout mouse (LID+ ALSKO). LID+ALSKO mice demonstrate a further reduction in circulating IGF-1 levels (85%) and a concomitant 10-fold increase in GH levels. Insulin tolerance tests showed an improvement in insulin responsiveness in the LID+ALSKO mice compared with controls; LID mice were very insulin insensitive. Surprisingly, insulin sensitivity, while improved in white adipose tissue and in muscle, was unchanged in the liver. The lack of improvement in liver insulin sensitivity may reflect the absence of IGF-1 receptors or increased triglyceride levels in the liver. The present study suggests that whereas GH plays a major role in inducing insulin resistance, IGF-1 may have a direct modulatory role. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Dept Med, Fac Med 1, Prague, Czech Republic. Cornell Univ, Dept Anim Sci, Ithaca, NY USA. RP LeRoith, D (reprint author), NIDDK, Diabet Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 8D12, Bethesda, MD 20892 USA. NR 34 TC 59 Z9 60 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD OCT PY 2003 VL 52 IS 10 BP 2483 EP 2489 DI 10.2337/diabetes.52.10.2483 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729AL UT WOS:000185748500004 PM 14514630 ER PT J AU Humphrey, RK Bucay, N Beattie, GM Lopez, A Messam, CA Cirulli, V Hayek, A AF Humphrey, RK Bucay, N Beattie, GM Lopez, A Messam, CA Cirulli, V Hayek, A TI Characterization and isolation of promoter-defined nestin-positive cells from the human fetal pancreas SO DIABETES LA English DT Article ID EMBRYONIC STEM-CELLS; INTERMEDIATE FILAMENT NESTIN; INSULIN-PRODUCING CELLS; ENDOTHELIAL-CELLS; PROGENITOR CELLS; ENDOCRINE-CELLS; DIFFERENTIATION; EXPRESSION; ISLETS; GROWTH AB Studies using adult human islets and mouse embryonic stem cells have suggested that the neurepithelial precursor cell marker nestin also identifies and can be used to purify beta-cell precursors. To determine whether nestin can be used to identify beta-cell progenitors in the developing human pancreas, we characterized nestin expression from 12 to 24 gestational weeks, purified nestin(+) cells using an enhancer/promoter-driven selection plasmid, and determined whether nestin(+) cells can differentiate into beta-cells. Nestin was visualized in the platelet endothelial cell adhesion molecule and a smooth muscle actin-positive blood vessels and colocalized with vimentin in the interstitium. Nestin was not observed in pan cytokeratin (pCK)-positive ductal epithelium or insulin cells. Purified nestin(+) cells also coexpressed vimentin and lacked pCK immunoreactivity. Purified adult and fetal pancreatic fibroblasts also expressed nestin. The nestin enhancer/promoter used in the selection plasmid was sufficient to drive reporter gene expression, green fluorescent protein, in human fetal pancreatic tissue. Exposure of selected nestin(+) cells to nicotinamide, hepatocyte growth factor/scatter factor, betacellulin, activin A, or exendin-4 failed to induce pancreatic and duodenal homeobox gene-1 or insulin message as determined by RT-PCR. Transplantation of nestin(+) cells and fetal pancreatic fibroblasts into athymic mice also failed to result in the development of beta-cells, whereas nestin(-) fetal pancreatic epithelial cells gave rise to functional insulin-secreting beta-cells. We conclude that nestin is not a specific marker of beta-cell precursors in the developing human pancreas. C1 Univ Calif San Diego, Dept Pediat, Whittier Inst Diabet, Sch Med,Islet Res Lab, La Jolla, CA 92037 USA. NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Hayek, A (reprint author), Univ Calif San Diego, Dept Pediat, Whittier Inst Diabet, Sch Med,Islet Res Lab, 9894 Genesee Ave, La Jolla, CA 92037 USA. FU NIDDK NIH HHS [DK55813S1, R01 DK55183] NR 32 TC 58 Z9 65 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD OCT PY 2003 VL 52 IS 10 BP 2519 EP 2525 DI 10.2337/diabetes.52.10.2519 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729AL UT WOS:000185748500009 PM 14514635 ER PT J AU Meneilly, GS Greig, N Tildesley, H Habener, JF Egan, JM Elahi, D AF Meneilly, GS Greig, N Tildesley, H Habener, JF Egan, JM Elahi, D TI Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes SO DIABETES CARE LA English DT Article ID MEDIATED GLUCOSE-UPTAKE; ENERGY-INTAKE; 7-36 AMIDE; BETA-CELL; INFUSION; DETERMINANTS; MELLITUS; HUMANS; GLP-1 AB OBJECTIVE-Glucagon-like peptide 1 (GLP-1) is an insulinotropic gut hormone that, when given exogenously, may be a useful agent in the treatment of type 2 diabetes. We conducted a 3-month trial to determine the efficacy and safety of GLP-1 in elderly diabetic patients. RESEARCH DESIGN AND METHODS-A total of 16 patients with type 2 diabetes who were being treated with oral hypoglycemic agents were enrolled. Eight patients (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) remained on usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 +/- 1 kg/m(2)), after discontinuing hypoglycemic medications, received GLP-1 delivered by continuous subcutaneous infusion for 12 weeks. The maximum dose was 120 pmol (.) kg(-1) (.) h(-1). Patients recorded their capillary blood glucose (CBG) levels (four times per day, 3 days per week) and whenever they perceived hypoglycemic symptoms. The primary end points were HbA(1c) and CBG determinations. Additionally, changes in beta-cell sensitivity to glucose, peripheral tissue sensitivity to insulin, and changes in plasma ghrelin levels were examined. RESULTS-HbA(1c) levels (7.1%) and body weight were equally maintained in both groups. The usual treatment group had a total of 87 CBG measurements of less than or equal to3.6 mmol/l during the study, and only 1 such measurement (3.5 mmol/l) was recorded in the GLP-1 group. Infusion of GLP-1 enhanced glucose-induced insulin secretion (pre: 119 +/- 21; post: 202 +/- 51 pmol/l; P < 0.05) and insulin-mediated glucose disposal (pre: 29.8 +/- 3.3; post: 35.9 +/- 2.3 mumol (.) kg(-1) (.) min(-1) ; P < 0.01). No effect of GLP-1 treatment was seen on the fasting plasma ghrelin levels. Although plasma ghrelin levels decreased during both portions of the clamp, a drug effect was not present. CONCLUSIONS-A GLP-1 compound is a promising therapeutic option for elderly diabetic patients. C1 Harvard Univ, Geriatr Res Lab, Massachusetts Gen Hosp, Dept Med,Med Sch, Boston, MA 02114 USA. Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. NIA, NIH, Baltimore, MD 21224 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Mol Endocrinol Lab, Boston, MA 02114 USA. RP Elahi, D (reprint author), Harvard Univ, Geriatr Res Lab, Massachusetts Gen Hosp, Dept Med,Med Sch, GRB SB 0015,55 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK-98-02]; PHS HHS [00599] NR 31 TC 65 Z9 66 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2003 VL 26 IS 10 BP 2835 EP 2841 DI 10.2337/diacare.26.10.2835 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729HD UT WOS:000185766900020 PM 14514588 ER PT J AU Chen, LJ Lebetkin, EH Burka, LT AF Chen, LJ Lebetkin, EH Burka, LT TI Metabolism of (R)-(+)-menthofuran in Fischer-344 rats: Identification of sulfonic acid metabolites SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID (R)-(+)-PULEGONE; MENTHOFURAN; HEPATOTOXICITY; GLUTATHIONE; TOXICITY; PULEGONE; MOUSE; FURAN; OIL AB (R)-(+)-Menthofuran is a metabolite of (R)-(+)- pulegone, the chief constituent of pennyroyal oil. Menthofuran has been shown to account for a significant percentage of pulegone toxicity through further metabolism to a reactive intermediate, an enonal (2-Z-(2'-keto-4'-methylcyclohexylidene) propanal). Hydration of the enonal followed by a 1,4-dehydration and rearrangement gives rise to diastereomeric (-)-mintlactone and (+)-isomintlactone (mintlactones). We have conducted disposition studies on pulegone as part of the National Toxicology Program initiative in herbal medicines and dietary supplements, and have reported previously unknown urinary metabolites of pulegone. Comparative metabolism studies of C-14-labeled menthofuran in Fischer-344 (F344) rats were carried out to determine urinary metabolites of pulegone that are derived from the menthofuran pathway. Three sulfonic acid metabolites, namely, hexahydro-3,6-dimethyl-1-(2-sulfoethyl)-2H-indol-2-one, hexahydro-3,6-dimethyl-7a-sulfo-2(3H)-benzofuranone, and 2-sulfomenthofuran, were identified in urine of treated rats. Formation of these metabolites may be derived from reactions of the enonal with taurine or glutathione (GSH) (or sulfite ion). Other identified urinary metabolites of menthofuran could be attributed to further metabolism of mintlactones. Further hydroxylation of mintlactones could give 7a-hydroxymintlactone and 6,7a-dihydroxymintlactone. Glucuronidation or reduction of 7a-hydroxymintlactone could give rise to the major metabolites 7a-hydroxymintlactone glucuronide and 2-[2'-keto-4'-methylcyclohexyl] propionic acids. Glucuronidation or repeated hydroxylation/dehydration of 2-[2'-keto-4'-methylcyclohexyl] propionic acids could result in formation of hexahydro-3,6-dimethyl-7a-hydroxy-2(3H)-benzofuranone glucuronide and 2-(2'-hydroxy-4'-methylphenyl) propionic acid. 2-(Glutathion-S-yl) menthofuran, a GSH conjugate of the enonal that has been partially characterized in bile of rats dosed with pulegone, is at most a minor biliary metabolite of menthofuran in rats. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Chen, LJ (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 18 TC 19 Z9 19 U1 0 U2 4 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 OCT 1 PY 2003 VL 31 IS 10 BP 1208 EP 1213 DI 10.1124/dmd.31.10.1208 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 721RC UT WOS:000185328500003 PM 12975329 ER PT J AU Yan, QS Huang, JQ Fan, T Zhu, HM Muegge, K AF Yan, QS Huang, JQ Fan, T Zhu, HM Muegge, K TI Lsh, a modulator of CpG methylation, is crucial for normal histone methylation SO EMBO JOURNAL LA English DT Article DE chromatin; DNA methylation; histone; Lsh; SNF2 ID H3 LYSINE-9 METHYLATION; DNA METHYLATION; PERICENTRIC HETEROCHROMATIN; NEUROSPORA-CRASSA; ACTIVE CHROMATIN; FAMILY-MEMBER; SNF2 FAMILY; METHYLTRANSFERASE; PROLIFERATION; LOCALIZATION AB Methylation of histone tails and CpG methylation are involved in determining heterochromatin structure, but their cause and effect relationship has not been resolved as yet in mammals. Here we report that Lsh, a member of the SNF2 chromatin remodeling family, controls both types of epigenetic modifications. Lsh has been shown to be associated with pericentromeric heterochromatin and to be required for normal CpG methylation at pericentromeric sequences. Loss of Lsh, in Lsh-deficient mice, results in accumulation of di- and tri-methylated histone 3 at lysine 4 (H3-K4me) at pericentromeric DNA and other repetitive sequences. In contrast, di- or tri-methylation of H3-K9 and distribution of HP1 appear unchanged after Lsh deletion, suggesting independent regulatory mechanisms for H3-K4 or K9 methylation. Experimental DNA demethylation with 5'-azacytidine results in a similar increase of H3-K4me. These results support the model that loss of CpG methylation caused by Lsh deficiency antecedes elevation of H3-K4me. Thus, Lsh is crucial for the formation of normal heterochromatin, implying a functional role for Lsh in the regulation of transcription and mitosis. C1 NCI, Mol Immunoregulat Lab, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, Mol Immunoregulat Lab, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 38 TC 71 Z9 76 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 1 PY 2003 VL 22 IS 19 BP 5154 EP 5162 DI 10.1093/emboj/cdg493 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 728RZ UT WOS:000185731300026 PM 14517253 ER PT J AU Baumann, M Mamais, A McBlane, F Xiao, H Boyes, J AF Baumann, M Mamais, A McBlane, F Xiao, H Boyes, J TI Regulation of V(D)J recombination by nucleosome positioning at recombination signal sequences SO EMBO JOURNAL LA English DT Article DE chromatin remodelling; chromosomal translocation; nucleosome positioning; RAGs; V(D)J recombination ID HISTONE ACETYLATION; CHROMATIN STRUCTURE; IN-VITRO; DNA; PROMOTER; CLEAVAGE; GENE; TRANSCRIPTION; RECEPTOR; ACCESSIBILITY AB A key component in the regulation of V(D)J recombination is control of the accessibility of RAG proteins to recombination signal sequences (RSS). Nucleosomes are known to inhibit this accessibility. We show here that the signal sequence itself represses accessibility by causing nucleosome positioning over the RSS. This positioning is mediated, in vitro and in vivo, by the conserved nonamer of the RSS. Consistent with this strong positioning, nucleosomes at RSSs are resistant to remodelling by nucleosome sliding. In vivo we find that consensus RSSs are preferentially protected, whereas those that lack a consensus nonamer, including some cryptic RSSs, fail to position nucleosomes. Decreased protection of these non-consensus RSSs correlates with their increased use in recombination assays. We therefore suggest that nucleosome positioning by RSSs provides a previously unanticipated level of protection and regulation of V(D)J recombination. C1 Inst Canc Res, London SW3 6JB, England. European Inst Oncol, I-20141 Milan, Italy. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Boyes, J (reprint author), Inst Canc Res, 237 Fulham Rd, London SW3 6JB, England. NR 46 TC 60 Z9 60 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 1 PY 2003 VL 22 IS 19 BP 5197 EP 5207 DI 10.1093/emboj/cdg487 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 728RZ UT WOS:000185731300030 PM 14517257 ER PT J AU Wu, PY Hanlon, M Eddins, M Tsui, C Rogers, RS Jensen, JP Matunis, MJ Weissman, AM Wolberger, CP Pickart, CM AF Wu, PY Hanlon, M Eddins, M Tsui, C Rogers, RS Jensen, JP Matunis, MJ Weissman, AM Wolberger, CP Pickart, CM TI A conserved catalytic residue in the ubiquitin-conjugating enzyme family SO EMBO JOURNAL LA English DT Article DE catalytic mechanism; E2; E3; isopeptide; ubiquitin ID RING FINGER PROTEINS; CRYSTAL-STRUCTURE; POLYUBIQUITIN CHAINS; STRUCTURAL BASIS; DNA-REPAIR; DEUBIQUITINATING ENZYME; SUMO MODIFICATION; LIGASE COMPLEX; SYSTEM; RECOGNITION AB Ubiquitin (Ub) regulates diverse functions in eukaryotes through its attachment to other proteins. The defining step in this protein modification pathway is the attack of a substrate lysine residue on Ub bound through its C-terminus to the active site cysteine residue of a Ub-conjugating enzyme (E2) or certain Ub ligases (E3s). So far, these E2 and E3 cysteine residues are the only enzyme groups known to participate in the catalysis of conjugation. Here we show that a strictly conserved E2 asparagine residue is critical for catalysis of E2- and E2/RING E3-dependent isopeptide bond formation, but dispensable for upstream and downstream reactions of Ub thiol ester formation. In constrast, the strictly conserved histidine and proline residues immediately upstream of the asparagine are dispensable for catalysis of isopeptide bond formation. We propose that the conserved asparagine side chain stabilizes the oxyanion intermediate formed during lysine attack. The E2 asparagine is the first non-covalent catalytic group to be proposed in any Ub conjugation factor. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Biophys & Biophys Chem, Program Mol Biophys, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. NCI, Regulat Prot funct Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Pickart, CM (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, 615 N Wolfe St, Baltimore, MD 21205 USA. OI Matunis, Michael/0000-0002-9350-6611 FU NIDDK NIH HHS [R01 DK046984]; NIGMS NIH HHS [GM60372, GM60980, R01 GM060372, R01 GM060980] NR 52 TC 108 Z9 111 U1 6 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 1 PY 2003 VL 22 IS 19 BP 5241 EP 5250 DI 10.1093/emboj/cdg501 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 728RZ UT WOS:000185731300034 PM 14517261 ER PT J AU Bentov, I Leroith, D Werner, H AF Bentov, I Leroith, D Werner, H TI The WT1 Wilms' tumor suppressor gene: A novel target for insulin-like growth factor-I action SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR GENE; CELLULAR ASPECTS; DNA-BINDING; EXPRESSION; PROMOTER; PROTEIN; PRODUCT; LOCUS; CELLS; TRANSCRIPTION AB IGF-I stimulates cell division in numerous cell types after activation of the IGF-I receptor, a transmembrane heterotetramer linked to the ras-raf-MAPK and phosphatidylinositol 3-kinase signaling pathways. The WT1 Wilms' tumor suppressor is a zinc finger-containing transcription factor that is involved in a number of developmental processes, as well as in the etiology of certain neoplasias. In the present study, we demonstrated that IGF-I reduced WT1 expression in osteosarcoma-derived Saos-2 cells in a time- and dose-dependent manner. This effect was mediated through the MAPK signaling pathway, as shown by the ability of the specific inhibitor UO126 to abrogate IGF-I action. Furthermore, the effect of IGF-I involved repression of transcription from the WT1 gene promoter, as demonstrated using transient transfection assays. Taken together, our results suggest that the WT1 gene is a novel downstream target for IGF-I action. Reduced levels of WT1 may facilitate IGF-I-stimulated cell cycle progression. Most importantly, inhibition of WT1 gene expression by IGF-I may have significant implications in terms of cancer initiation and/or progression. C1 Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Werner, H (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NR 29 TC 10 Z9 10 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT 1 PY 2003 VL 144 IS 10 BP 4276 EP 4279 DI 10.1210/en.2003-0400 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 723JP UT WOS:000185429500010 PM 12960088 ER PT J AU Falcon, J Besseau, L Fazzari, D Attia, J Gaildrat, P Beauchaud, M Boeuf, G AF Falcon, J Besseau, L Fazzari, D Attia, J Gaildrat, P Beauchaud, M Boeuf, G TI Melatonin modulates secretion of growth hormone and prolactin by trout pituitary glands and cells in culture SO ENDOCRINOLOGY LA English DT Article ID RECOMBINANT GOLDFISH PROLACTIN; SALMO-SALAR PARR; RAINBOW-TROUT; ATLANTIC SALMON; PHOTOPERIOD REGULATION; ONCORHYNCHUS-MYKISS; ESCHERICHIA-COLI; PLASMA MELATONIN; GENE-EXPRESSION; BINDING-SITES AB In Teleost fish, development, growth, and reproduction are influenced by the daily and seasonal variations of photoperiod and temperature. Early in vivo studies indicated the pineal gland mediates the effects of these external factors, most probably through the rhythmic production of melatonin. The present investigation was aimed at determining whether melatonin acts directly on the pituitary to control GH and prolactin (PRL) secretion in rainbow trout. We show that 2-[I-125]-iodomelatonin, a melatonin analog, binds selectively to membrane preparations and tissue sections from trout pituitaries. The affinity was within the range of that found for the binding to brain microsomal preparations, but the number of binding sites was 20-fold less than in the brain. In culture, melatonin inhibited pituitary cAMP accumulation induced by forskolin, the adenyl cyclase stimulator. Forskolin also induced an increase in GH release, which was reduced in the presence of picomolar concentrations of melatonin. At higher concentrations, the effects of melatonin became stimulatory. In the absence of forskolin, melatonin induced a dose-dependent increase in GH release, and a dose-dependent decrease in PRL release. Melatonin effects were abolished upon addition of luzindole, a melatonin antagonist. Our results provide the first evidence that melatonin modulates GH and PRL secretion in Teleost fish pituitary. Melatonin effects on GH have never been reported in any vertebrate before. The effects result from a direct action of melatonin on pituitary cells. The complexity of the observed responses suggests several types of melatonin receptors might be involved. C1 Univ Paris 06, CNRS, Unite Mixte Rech 7628, Lab Arago, F-66651 Banyuls sur Mer, France. Univ St Etienne, Lab Biol Anim & Appl, F-42023 St Etienne 02, France. NIH, Lab Dev Neuroendocrinol, Bethesda, MD 20892 USA. RP Univ Paris 06, CNRS, Unite Mixte Rech 7628, Lab Arago, BP 44, F-66651 Banyuls sur Mer, France. EM falcon@obs-banyuls.fr RI FALCON, Jack/I-5302-2013; Besseau, Laurence/O-9942-2015 OI FALCON, Jack/0000-0002-7572-6581; Besseau, Laurence/0000-0002-9617-8190 NR 52 TC 59 Z9 66 U1 1 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT 1 PY 2003 VL 144 IS 10 BP 4648 EP 4658 DI 10.1210/en.2003-0707 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 723JP UT WOS:000185429500052 PM 12960030 ER PT J AU Rice, C Birnbaum, LS Cogliano, J Mahaffey, K Needham, L Rogan, WJ vom Saal, FS AF Rice, C Birnbaum, LS Cogliano, J Mahaffey, K Needham, L Rogan, WJ vom Saal, FS TI Exposure assessment for endocrine disruptors: Some considerations in the design of studies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE developing child; endocrine disruptors; environmental epidemiology; exposure assessment ID VITELLOGENIN GENE-EXPRESSION; TURTLE SEX DETERMINATION; ESTROGENIC ACTIVITY; POLYCHLORINATED-BIPHENYLS; DIETHYLSTILBESTROL DES; REPRODUCTIVE-TRACT; HUMAN SERUM; BINDING-PROTEINS; LEAD-EXPOSURE; UNITED-STATES AB In studies designed to evaluate exposure-response relationships in children's development from conception through puberty, multiple factors that affect the generation of meaningful exposure metrics must be considered. These factors include multiple routes of exposure; the timing, frequency, and duration of exposure; need for qualitative and quantitative data; sample collection and storage protocols; and the selection and documentation of analytic methods. The methods for exposure data collection and analysis must be sufficiently robust to accommodate the a priori hypotheses to be tested, as well as hypotheses generated from the data. A number of issues that must be considered in study design are summarized here. C1 Univ Cincinnati, Environm & Ind Hyg Div, Cincinnati, OH 45267 USA. US EPA, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. US EPA, Quantitat Risk Methods Grp, Natl Ctr Environm Assessment, Washington, DC 20460 USA. US EPA, Exposure Assessment Coordinat & Policy Div, Off Prevent Pesticides & Tox Substances, Washington, DC 20460 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. RP Rice, C (reprint author), Univ Cincinnati, Environm & Ind Hyg Div, 316 Wherry Hall,POB 670056, Cincinnati, OH 45267 USA. EM alerdilr@ucmail.uc.edu RI Needham, Larry/E-4930-2011; Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 96 TC 19 Z9 24 U1 1 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD OCT PY 2003 VL 111 IS 13 BP 1683 EP 1690 DI 10.1289/ehp.5798 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 732JU UT WOS:000185940800038 PM 14527851 ER PT J AU Longnecker, MP Bellinger, DC Crews, D Eskenazi, B Silbergeld, EK Woodruff, TJ Susser, ES AF Longnecker, MP Bellinger, DC Crews, D Eskenazi, B Silbergeld, EK Woodruff, TJ Susser, ES TI An approach to assessment of endocrine disruption in the National Children's Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE chemical actions; child; cohort studies; endocrine disruption; environment; epidemiology; health ID POLYBROMINATED DIPHENYL ETHERS; POLYCHLORINATED-BIPHENYLS PCBS; SERUM DIOXIN CONCENTRATIONS; EXPOSED IN-UTERO; DICHLORODIPHENYL DICHLOROETHENE; BISPHENOL-A; PERINATAL EXPOSURE; THYROID-HORMONE; DUTCH CHILDREN; ENVIRONMENTAL EXPOSURE AB In this article we consider the importance of assessing endocrine disruption in a large new cohort that has been proposed, the National Children's Study (NCS). We briefly review evidence that endocrine disruption is a potentially important hypothesis for human studies and weigh the need to assess endocrine disruption in the NCS. We note the salient features of earlier, similar cohort studies that serve as reference points for the design of the NCS. Finally, we discuss features of the NCS that would allow or enhance assessment of endocrine disruption, even if endocrine disruption were not a primary hypothesis motivating the study. At this time, the evidence supporting endocrine disruption in humans with background-level exposures is not strong. Thus, a compelling rationale for the NCS will probably need to be based on core hypotheses that focus on other issues. Nonetheless, if properly designed, the NCS could serve as an excellent resource for investigating future hypotheses regarding endocrine disruption. C1 NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. Univ Texas, Austin, TX 78712 USA. Univ Calif Berkeley, Sch Publ Hlth, Ctr Childrens Environm Hlth Res, Berkeley, CA 94720 USA. Johns Hopkins Univ, Dept Environm Hlth Sci, Baltimore, MD 21218 USA. US EPA, San Francisco, CA USA. Columbia Univ, Div Epidemiol, Joseph L Mailman Sch Publ Hlth, New York, NY USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM longnecker@niehs.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 NR 121 TC 7 Z9 8 U1 1 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD OCT PY 2003 VL 111 IS 13 BP 1691 EP 1697 DI 10.1289/ehp.5800 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 732JU UT WOS:000185940800039 PM 14527852 ER PT J AU Huang, LS Cox, C Wilding, GE Myers, GJ Davidson, PW Shamlaye, CF Cernichiari, E Sloane-Reeves, J Clarkson, TW AF Huang, LS Cox, C Wilding, GE Myers, GJ Davidson, PW Shamlaye, CF Cernichiari, E Sloane-Reeves, J Clarkson, TW TI Using measurement error models to assess effects of prenatal and postnatal methylmercury exposure in the Seychelles Child Development Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE child development; fish consumption; interaction effects; measurement error models; methylmercury ID MATERNAL FISH DIET; IN-UTERO EXPOSURE; FETAL METHYLMERCURY; NEURODEVELOPMENTAL OUTCOMES; HAIR; MERCURY; POPULATION AB Studies of the effects of environmental exposures on human health typically require estimation of both exposure and outcome. Standard methods for the assessment of the association between exposure and outcome include multiple linear regression analysis, which assumes that the outcome variable is observed with error, while the levels of exposure and other explanatory variables are measured with complete accuracy, so that there is no deviation of the measured from the actual value. The term measurement error in this discussion refers to the difference between the actual or true level and the value that is actually observed. In the investigations of the effects of prenatal methylmercury (MeHg) exposure from fish consumption on child development, the only way to obtain a true exposure level (producing the toxic effect) is to ascertain the concentration in fetal brain, which is not possible. As is often the case in studies of environmental exposures, the measured exposure level is a biomarker, such as the average maternal hair level during gestation. Measurement of hair mercury is widely used as a biological indicator for exposure to MeHg and is the only indicator that has been calibrated against the target tissue, the developing brain. Variability between the measured and the true values in explanatory variables in a multiple regression analysis can produce bias, leading to either over or underestimation of regression parameters (slopes). Fortunately, statistical methods known as measurement error models (MEM) are available to account for measurement errors in explanatory variables in multiple regression analysis, and these methods can provide an (either "unbiased" or "bias-corrected") estimate of the unknown outcome/exposure relationship. In this paper, we illustrate MEM analysis by reanalyzing data from the 5.5-year test battery in the Seychelles Child Development Study, a longitudinal study of prenatal exposure to MeHg from maternal consumption of a diet high in fish. The use of the MEM approach was made possible by the existence of independent, calibration data on the magnitude of the variability of the measurement error deviations for the biomarker of prenatal exposure used in this study, the maternal hair level. Our reanalysis indicated that adjustment for measurement errors in explanatory variables had no appreciable effect on the original results. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. NICHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. Minist Hlth, Victoria, Mahe, Seychelles. Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. RP Huang, LS (reprint author), Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, 601 Elmwood Ave,Box 630, Rochester, NY 14642 USA. RI Myers , Gary /I-4901-2013 OI Myers , Gary /0000-0003-4317-015X FU NIEHS NIH HHS [ES01247, ES-05497, T32 ES007271] NR 25 TC 11 Z9 11 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD OCT PY 2003 VL 93 IS 2 BP 115 EP 122 DI 10.1016/S0013-9351(03)00089-6 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 724WN UT WOS:000185509800002 PM 12963395 ER PT J AU Freedman, LS Barchana, M Al-Kayed, S Qasem, MB Young, JL Edwards, BK Ries, LAG Roffers, S Harford, J Silbermann, M AF Freedman, LS Barchana, M Al-Kayed, S Qasem, MB Young, JL Edwards, BK Ries, LAG Roffers, S Harford, J Silbermann, M TI A comparison of population-based cancer incidence rates in Israel and Jordan SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE Israel; Jordan; leukaemia; lymphoma; neoplasms; registries AB Reliable information about comparative cancer incidence in the Middle East has been lacking. The Middle East Cancer Consortium (MECC) has formed a network of population-based registries with standardized basic data. Here the age-adjusted cancer incidences are compared for four populations: Israeli Jews, Israeli non-Jews, Jordanians and the US Surveillance Epidemiology and End Results (SEER) population, for the years 1996-1997 (Israel) and 1996-1998 (other populations). The all-sites rate of cancer is approximately twice as high in Israeli Jews and SEER, compared with Israeli non-Jews and Jordanians. Rates of lung cancer are similar among Israeli Jews and non-Jews and about twice as high as in Jordanians. Childhood leukaemia rates in Jordan are higher than in Israeli Jews, but lower than SEER. Hodgkin lymphoma rates in Israeli non-Jews and Jordanians are similar to SEER, but non-Hodgkin lymphoma rates are lower than SEER. The previous suspicion of higher overall leukaemia and lymphoma rates in Jordan is thus not confirmed. (C) 2003 Lippincott Williams Wilkins. C1 Middle E Canc Consortium, Ramat Gan, Israel. Bar Ilan Univ, Dept Math & Stat, Ramat Gan, Israel. Israel Canc Registry, MOH, Jerusalem, Israel. Jordan Canc Registry, MOH, Amman, Jordan. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. NCI, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. NCI, SEER Program, NIH, Bethesda, MD 20892 USA. NCI, Off Int Affairs, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Dept Anat & Cell Biol, Haifa, Israel. RP Freedman, LS (reprint author), Bar Ilan Univ, Dept Math Stat & Comp Sci, IL-52900 Ramat Gan, Israel. FU NCI NIH HHS [N02-CN-75003] NR 17 TC 15 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD OCT PY 2003 VL 12 IS 5 BP 359 EP 365 DI 10.1097/01.cej.0000082606.47188.cf PG 7 WC Oncology SC Oncology GA 736FL UT WOS:000186160700003 PM 14512799 ER PT J AU Kiratisin, P Li, L Murray, PR Fischer, SH AF Kiratisin, P Li, L Murray, PR Fischer, SH TI Identification of bacteria recovered from clinical specimens by 16S rRNA gene sequencing SO EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES LA English DT Article ID ENDOCARDITIS; PATHOGENS; PATIENT; GORDONA AB The sequence of the 16S rRNA gene has been used extensively for phylogenetic classification, identification, and genotypic typing of bacteria. Identification of bacterial isolates by 16S rRNA gene sequencing, though generally performed in reference laboratories, has been recently introduced for routine use in clinical laboratories to identify isolates that cannot be identified by conventional methods. Described in this report is the use of 16S rRNA gene sequencing to identify uncommon bacteria, or bacteria with unusual phenotypic properties, with four brief case presentations to illustrate its clinical application. The feasibility, usefulness and limitations of performing this approach in the clinical laboratory are also discussed. C1 NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,Dept Hlth & Human, Bethesda, MD 20892 USA. Mahidol Univ, Siriraj Hosp, Fac Med, Dept Microbiol, Bangkok 10700, Thailand. RP Fischer, SH (reprint author), NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,Dept Hlth & Human, 10 Ctr Dr,Bldg 10,Room 2C-385, Bethesda, MD 20892 USA. NR 12 TC 21 Z9 23 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0934-9723 J9 EUR J CLIN MICROBIOL JI Eur. J. Clin. Microbiol. Infect. Dis. PD OCT PY 2003 VL 22 IS 10 BP 628 EP 631 DI 10.1007/s10096-003-1003-6 PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 734BP UT WOS:000186035600012 PM 14520536 ER PT J AU Akdis, CA Kussebi, F Pulendran, B Akdis, M Lauener, RP Schmidt-Weber, CB Klunker, S Isitmangil, G Hansjee, N Wynn, TA Dillon, S Erb, P Baschang, G Blaser, K Alkan, SS AF Akdis, CA Kussebi, F Pulendran, B Akdis, M Lauener, RP Schmidt-Weber, CB Klunker, S Isitmangil, G Hansjee, N Wynn, TA Dillon, S Erb, P Baschang, G Blaser, K Alkan, SS TI Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE allergy; T cells; IgE; lipopeptide; toll-like receptor 2 ID TOLL-LIKE RECEPTORS; SIGNAL-TRANSDUCTION PATHWAY; AIRWAY HYPERRESPONSIVENESS; IFN-GAMMA; MURINE MACROPHAGES; INTERFERON-GAMMA; IMMUNE-RESPONSES; EXPRESSION; ANTIGEN; CELLS AB In allergy and asthma, the fine balance between the T helper (Th) 1, Th2 and T regulatory cytokine responses appears to be shifted towards Th2. Here, we report that synthetic lipopeptides which contain the typical lipid part of the lipoprotein of gram-negative bacteria stimulate a distinct regulatory cytokine pattern and inhibit several Th2 cell-related phenomena. The most potent analogue of synthetic lipopeptides, lipopeptide CGP 40774 (LP40) was not active in MyD88-deficient mice and stimulated Toll-like receptor (TLR)-2, but not TLR-4. LP40 potentiated the production of IFN-gamma and IL-10, but not IL-4 and IL-5 by human T cells. In addition, triggering of TLR-2 by lipopeptides promoted the in vitro differentiation of naive T cells towards IL-10- and IFN-gamma-producing T cells and suppressed IL-4 production by Th2 cells. Accordingly, LP40 inhibited IgE production induced by allergen, anti-IgD antibody, Nippostrongylus brasiliensis or murine acquired immunodeficiency virus. Furthermore, ovalbumin-induced lung eosinophilic inflammation was abolished and Schistosoma mansoni egg-induced granuloma size and eosinophil counts were suppressed in mice by LP40. These results demonstrate that stimulation of TLR-2 by lipopeptides represents a novel way for possible treatment of allergy and asthma by regulating the disrupted cytokine balance. C1 Swiss Inst Allergy & Asthma Res, CH-7270 Davos, Switzerland. Emory Vaccine Res Ctr, Atlanta, GA USA. Univ Zurich, Childrens Hosp, Zurich, Switzerland. Yeditepe Univ, Sch Med, Istanbul, Turkey. Univ Basel, Inst Med Microbiol, Basel, Switzerland. NIH, Immunobiol Sect, Bethesda, MD 20892 USA. Novartis Pharmaceut, Dept Chem, Basel, Switzerland. Novartis Pharmaceut, Dept Resp Dis, Basel, Switzerland. RP Akdis, CA (reprint author), Swiss Inst Allergy & Asthma Res, Obere Str 22, CH-7270 Davos, Switzerland. RI Dillon, Stephanie/B-8469-2008; Wynn, Thomas/C-2797-2011; Lauener, Roger/O-8612-2016 OI Lauener, Roger/0000-0002-8412-606X FU NIAID NIH HHS [AI48638-01]; NIDDK NIH HHS [DK57665-01] NR 50 TC 80 Z9 85 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD OCT PY 2003 VL 33 IS 10 BP 2717 EP 2726 DI 10.1002/eji.200323329 PG 10 WC Immunology SC Immunology GA 733JG UT WOS:000185996200008 PM 14515255 ER PT J AU Chefer, VI Kieffer, BL Shippenberg, TS AF Chefer, VI Kieffer, BL Shippenberg, TS TI Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE conventional and quantitative microdialysis; mu- and delta-opioid receptors ID OPIOID RECEPTOR KNOCKOUT; VENTRAL TEGMENTAL AREA; EXTRACELLULAR DOPAMINE; QUANTITATIVE MICRODIALYSIS; LOCOMOTOR-ACTIVITY; MOTOR-ACTIVITY; INVIVO MICRODIALYSIS; TRANSIENT CONDITIONS; MESOLIMBIC SYSTEM; INDUCED ANALGESIA AB Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors. Locomotor activity was assessed in these same animals. No difference between genotypes in basal dialysate DA levels was seen. No net flux studies revealed significant decreases in the DA extraction fraction in both MOR- and DOR-knockout mice, indicating decreased basal DA uptake in both genotypes. Extracellular DA, however, was unchanged. Because extracellular neurotransmitter levels are determined by the dynamics of both release and uptake, these findings provide suggestive evidence that basal DA release is decreased in mutant mice. Systemic administration of morphine significantly increased locomotor activity and dialysate DA levels in wild-type mice. MOR-knockout mice failed to exhibit a behavioural response to morphine. The ability of morphine to increase DA levels, however, was reduced but not prevented. No alteration in the effects of morphine was observed in DOR-knockout mice. These data provide genetic evidence for the existence of tonically active MOR and DOR systems that modulate basal DA neurotransmission in the NAc. Furthermore, they demonstrate that in contrast to the locomotor-activating effects of morphine, a small component of morphine-evoked DA release occurs independently of MOR activation. C1 NIH, Integrat Neurosci Sect, DHHS, NIDA,IRP,BNRB,INS, Baltimore, MD 21224 USA. URL, INSERM, CRNS, IGBMC, Illkirch Graffenstaden, France. RP NIH, Integrat Neurosci Sect, DHHS, NIDA,IRP,BNRB,INS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vchefer@intra.nida.nih.gov NR 51 TC 37 Z9 37 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD OCT PY 2003 VL 18 IS 7 BP 1915 EP 1922 DI 10.1046/j.1460-9568.2003.02912.x PG 8 WC Neurosciences SC Neurosciences & Neurology GA 735MK UT WOS:000186119000019 PM 14622224 ER PT J AU Stanley, EF Reese, TS Wang, GZ AF Stanley, EF Reese, TS Wang, GZ TI Molecular scaffold reorganization at the transmitter release site with vesicle exocytosis or botulinum toxin C1 SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium channel; presynaptic; release site; scaffold; transmitter release ID FROG NEUROMUSCULAR-JUNCTION; CALCIUM CHANNELS; FREEZE-FRACTURE; ACTIVE-ZONE AB Neurotransmitter release sites at the freeze-fractured frog neuromuscular junction are composed of inner and outer paired rows of large membrane particles, the putative calcium channels, anchored by the ribs of an underlying protein scaffold. We analysed the locations of the release site particles as a reflection of the scaffold structure, comparing particle distributions in secreting terminals with those where secretion was blocked with botulinum toxin A, which cleaves a small segment off SNAP-25, or botulinum toxin C1, which cleaves the cytoplasmic domain of syntaxin. In the idle terminal the inner and outer paired rows were located approximate to25 and approximate to44 nm, respectively, from the release site midline. However, adjacent to vesicular fusion sites both particle rows were displaced towards the midline by approximate to25%. The intervals between the particles along each row were examined by a nearest-neighbour approach. In control terminals the peak interval along the inner row was approximate to17 nm, consistent with previous reports and the spacing of the scaffold ribs. While the average distance between particles in the outer row was also approximate to17 nm, a detailed analysis revealed short 'linear clusters' with a approximate to14 nm interval. These clusters were enriched at vesicle fusion sites, suggesting an association with the docking sites, and were eliminated by botulinum C1, but not A. Our findings suggest, first, that the release site scaffold ribs undergo a predictable, and possibly active, shortening during exocytosis and, second, that at the vesicle docking site syntaxin plays a role in the cross-linking of the rib tips to form the vesicle docking sites. C1 Univ Hlth Network, Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. Natl Inst Neurol Dis & Hlth, NIH, Bethesda, MD USA. RP Stanley, EF (reprint author), Univ Hlth Network, Toronto Western Res Inst, MP14-320,399 Bathurst St, Toronto, ON M5T 2S8, Canada. NR 17 TC 23 Z9 23 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD OCT PY 2003 VL 18 IS 8 BP 2403 EP 2407 DI 10.1046/j.1460-9568.2003.02948.x PG 5 WC Neurosciences SC Neurosciences & Neurology GA 735ML UT WOS:000186119100033 PM 14622203 ER PT J AU Luster, M Sherman, SI Skarulis, MC Reynolds, JR Lassmann, M Hanscheid, H Reiners, C AF Luster, M Sherman, SI Skarulis, MC Reynolds, JR Lassmann, M Hanscheid, H Reiners, C TI Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE differentiated thyroid carcinoma; iodine-131; ablation; biokinetics; blood dose ID HUMAN THYROTROPIN; REMNANT ABLATION; CANCER; I-131; THERAPY; THYROGLOBULIN; BLOOD; SCAN AB Iodine kinetics were studied in patients with differentiated thyroid cancer while euthyroid under exogenous thyroid stimulating hormone (TSH) and while hypothyroid to detect differences in radioiodine uptake, distribution and elimination. Nine patients with total or near-total thyroidectomy on thyroid hormone suppressive therapy received two or three daily doses of 0.9 mg recombinant human TSH (rhTSH) followed by administration of a diagnostic activity of 2 mCi (74 MBq) iodine-131. After the biokinetics assessments had been performed, patients stopped taking thyroid hormones to become hypothyroid. A second 2 mCi (74 MBq) diagnostic activity of I-131 was administered, followed by a second set of biokinetics assessments. One week later the patients underwent remnant ablation with a therapeutic activity of I-131. A comparison of the I-131 kinetics in the patients while euthyroid and while hypothyroid showed major differences in the doses to the remnant as well as in residence times and radiation exposure to the blood. In the first diagnostic assessment the remnant dose was higher in eight of the nine patients and clearance of the activity from the blood was faster in all of them. The data from this study suggest that radioiodine administration is potent and safe when administered to euthyroid patients following rhTSH administration. Enhanced residence time in the remnant and decreased radiation exposure to the blood were noted when patients were euthyroid compared to when they were rendered hypothyroid. However, all patients received diagnostic activities in the same order: first while euthyroid, followed by hypothyroidism. It is quite possible that "stunning" from the radioiodine administered in the initial uptake study inhibited the subsequent uptake of radioiodine by the remnant lesions in the second uptake study. C1 Univ Wurzburg, Dept Nucl Med, D-97080 Wurzburg, Germany. Univ Texas, MD Anderson Canc Ctr, Sect Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. NIDDK, Div Intramural Res, NIH, Bethesda, MD USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Luster, M (reprint author), Univ Wurzburg, Dept Nucl Med, Josef Schneider Str 2, D-97080 Wurzburg, Germany. RI Lassmann, Michael/B-2284-2013; Sgouros, George/A-6767-2008; OI Lassmann, Michael/0000-0002-2556-1977; Sherman, Steven/0000-0002-3079-5153 NR 28 TC 69 Z9 69 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2003 VL 30 IS 10 BP 1371 EP 1377 DI 10.1007/s00259-003-1230-1 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 731QA UT WOS:000185896900009 PM 12856155 ER PT J AU Davis, WW Graubard, BI Hartman, AM Stillman, FA AF Davis, WW Graubard, BI Hartman, AM Stillman, FA TI Descriptive methods for evaluation of state-based intervention programs SO EVALUATION REVIEW LA English DT Article DE bootstrap; locally weighted regression; random effect; pooled cross-sectional time series ID LOCALLY WEIGHTED REGRESSION; TIME-SERIES AB In this article, the authors discuss program evaluation of intervention studies when the outcome of interest is collected routinely at equally spaced intervals of time. They illustrate concepts using data from the American Stop Smoking Intervention Study, where the outcome is state per capita tobacco consumption. States differ widely in mean tobacco consumption, and these differences should be accounted for in the analysis. A large difference in the variance of the intervention effect may be obtained depending on whether the variation in the between-state effects are considered. The confidence limits obtained by ignoring between-state effects are too optimistic in many cases. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Inst Global Tobacco Control, Baltimore, MD USA. RP Davis, WW (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 25 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-841X J9 EVALUATION REV JI Eval. Rev. PD OCT PY 2003 VL 27 IS 5 BP 506 EP 534 DI 10.1177/0193841X03254405 PG 29 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 719GE UT WOS:000185194600002 PM 14531317 ER PT J AU Watanabe, K Lauwereyns, J Hikosaka, O AF Watanabe, K Lauwereyns, J Hikosaka, O TI Effects of motivational conflicts on visually elicited saccades in monkeys SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE saccade; latency; reward; conflict; monkey ID NIGRA PARS RETICULATA; NEURONAL-ACTIVITY; EYE-MOVEMENTS; CAUDATE NEURONS; COUNTERMANDING SACCADES; FUNCTIONAL-PROPERTIES; AVERAGING SACCADES; REWARD EXPECTATION; PREFRONTAL CORTEX; BASAL GANGLIA AB The prospect of reward evoked by external stimuli is a central element of goal-oriented behavior. To elucidate behavioral effects of reward expectation on saccade latency, we employed a visually guided saccade task with asymmetrical reward schedule. The monkey had to make an immediate saccade to a peripheral visual target in every trial, but was rewarded for a correct saccade to only one of four possible target positions. Reward availability was predictable on the basis of the spatial position of the target throughout a daily session. Compared with the condition where all positions were rewarded with a smaller amount, the mean saccade latency in the asymmetrical reward schedule was significantly shorter when the saccade was made toward the position associated with reward than when it was directed to no-reward positions. Furthermore, a divergence-point analysis on cumulative latency distributions showed that the expectation of reward facilitated saccades at all latency ranges. In contrast, the expected lack of reward delayed the initiation of saccades with latencies longer than about 200 ms, irrespective of whether the saccade was made to a position orthogonal or opposite to the reward position. For saccades with latencies of more than approximately 240 ms, an additional delay was observed when the saccade was made to a position opposite, as compared to orthogonal, to the reward position. These results suggest that the facilitation by predictive reward is mediated by a preparatory process that is location-specific, whereas the inhibition by the absence of reward takes about 200 ms after the target onset to become effective and is initially location nonspecific but turns location-specific over time. C1 Natl Inst Adv Ind Sci & Technol, Inst Human Sci & Biomed Engn, Visual Cognit Grp, Tsukuba, Ibaraki 3058566, Japan. Victoria Univ Wellington, Sch Psychol, Wellington, New Zealand. Tamagawa Univ, Brain Res Inst, Tokyo, Japan. NEI, NIH, Bethesda, MD 20892 USA. RP Watanabe, K (reprint author), Natl Inst Adv Ind Sci & Technol, Inst Human Sci & Biomed Engn, Visual Cognit Grp, Tsukuba Cent 6,1-1-1 Higashi, Tsukuba, Ibaraki 3058566, Japan. EM kw@lsr.nei.nih.gov OI Lauwereyns, Jan/0000-0003-0551-2550 NR 56 TC 23 Z9 24 U1 2 U2 4 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 OCT PY 2003 VL 152 IS 3 BP 361 EP 367 DI 10.1007/s00221-003-1555-9 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 721YQ UT WOS:000185346400010 PM 12904939 ER PT J AU Lee, CH Jang, YS Her, SJ Moon, YM Baek, SJ Eling, T AF Lee, CH Jang, YS Her, SJ Moon, YM Baek, SJ Eling, T TI Nordihydroguaiaretic acid, an antioxidant, inhibits transforming growth factor-beta activity through the inhibition of Smad signaling pathway SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE transforming growth factor-beta; TGF-beta; nordihydroguaiaretic acid; NDG; Smad; antioxidant; cell signal; osteoblast ID CELLS; PROTEIN; BINDING; PROLIFERATION; INVOLVEMENT; SUPERFAMILY; EXPRESSION; PROMOTER; RECEPTOR; ELEMENT AB Transforming growth factor-beta (TGF-beta) and its family are potent and multi-functional cytokines that affect various fundamental biological events. TGF-beta has a unique signaling pathway that is carried by Smad family, and many recent studies showed the extensive crosstalk between Smad pathway and other signaling pathway. There were also clear evidences for the involvement of oxidative events in TGF-beta signaling pathway. To elucidate the role of oxidative events in carrying TGF-beta signals, we examined the effect of various antioxidants on TGF-beta activities in osteoblastic cell line. Among the examined compounds, we found nordihydroguaiaretic acid (NDGA) has a unique and strong inhibitory effect on various TGF-beta activities. Since the majority of TGF-beta activities are mediated by Smad, we questioned whether NDGA blocks the Smad signaling pathway. The result showed that NDGA inhibits the translocation of Smad2 to the nucleus. Further study revealed the strong inhibitory effect of NDGA on the phosphorylation of Smad2. This result may be important for designing chemical modulators of TGF-beta and its family related events and may provide new insights into the action mechanism of antioxidant. (C) 2003 Elsevier Inc. All rights reserved. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Kangnung Natl Univ, Coll Nat Sci, Dept Biol, Gangneung 210702, Gangwon Do, South Korea. RP Eling, T (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Baek, Seung/0000-0001-7866-7778 NR 31 TC 20 Z9 21 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD OCT 1 PY 2003 VL 289 IS 2 BP 335 EP 341 DI 10.1016/S0014-4827(03)00282-9 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 723ZW UT WOS:000185462400014 PM 14499634 ER PT J AU Lu, L Bao, GB Chen, H Xia, P Fan, XL Zhang, JS Pei, G Ma, L AF Lu, L Bao, GB Chen, H Xia, P Fan, XL Zhang, JS Pei, G Ma, L TI Modification of hippocampal neurogenesis and neuroplasticity by social environments SO EXPERIMENTAL NEUROLOGY LA English DT Article DE social environments; neurogenesis; long-term potentiation; synaptic plasticity; hippocampus; isolation; learning and memory ID LONG-TERM POTENTIATION; RAT DENTATE GYRUS; NMDA RECEPTOR ACTIVATION; ADULT-RAT; INCREASES NEUROGENESIS; ENRICHED ENVIRONMENT; SYNAPTIC PLASTICITY; NEURONS; STRESS; MICE AB Synaptic plasticity and neurogenesis in the brain are affected by environmental stimuli. The present study was designed to investigate the effects of social environments on learning and memory, neurogenesis, and neuroplasticity. Twenty-two-day-old rats were housed in isolation or in groups for 4 or 8 weeks and injected intraperitoneally with bromodeoxyuridine to detect proliferation among progenitor cells. The animals were also tested for learning in a water maze and for hippocampal CA1 long-term potentiation in vivo and in vitro. The results show that the number of newborn neurons in the dentate gyrus and the learning in a water maze decreased significantly in rats reared in isolation for 4 or 8 weeks, as compared with grouped controls. Induction of long-term potentiation in the CA1 area of rat hippocampus in vivo and in vitro was also significantly reduced by isolation. Furthermore, the effects of isolation rearing on spatial learning, hippocampal neurogenesis, and long-term potentiation could be reversed by subsequent group rearing. These findings demonstrated that social environments can modify neurogenesis and synaptic plasticity in adult hippocampal regions, which is associated with alterations in spatial learning and memory. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Fudan Univ, Shanghai Med Coll, Natl Lab Med Neurobiol, Shanghai 200032, Peoples R China. Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. NIDA, Behav Neurosci Branch, IPR, NIH, Baltimore, MD 21224 USA. RP Ma, L (reprint author), Fudan Univ, Shanghai Med Coll, Natl Lab Med Neurobiol, 138 Yi Xue Yuan Rd, Shanghai 200032, Peoples R China. RI Zhang, Jisheng/A-1928-2010; Ma, Lan/C-9653-2010; Ma, Lan/B-9295-2009 OI Ma, Lan/0000-0001-9034-5472 NR 48 TC 130 Z9 136 U1 6 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 OCT PY 2003 VL 183 IS 2 BP 600 EP 609 DI 10.1016/S0014-4886(03)00248-6 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 728PB UT WOS:000185724600037 PM 14552901 ER PT J AU Chakrabarti, S Childs, R AF Chakrabarti, S Childs, R TI Allogeneic immune replacement as cancer immunotherapy SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE allogeneic haematopoietic transplantation; graft-versus-leukaemia (GVL); graft-versus-tumour (GVI); haematological malignancy; immunotherapy; metastatic cancer ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; NON-HODGKINS-LYMPHOMA; MINOR HISTOCOMPATIBILITY ANTIGENS; CHRONIC MYELOGENOUS LEUKEMIA; RESTRICTED TISSUE DISTRIBUTION; CHRONIC LYMPHOCYTIC-LEUKEMIA; TREATMENT-RELATED MORTALITY AB The graft-versus-leukaemia (GVL) reaction that occurs after allogeneic haematopoietic cell transplantation (HCT) can cure patients with a variety of haematological malignancies. A heightened appreciation of the GVL effect has resulted in the development of reduced intensity transplant approaches, where antitumour effects occur predominantly as a consequence of the transplanted donor immune system. The recent success of these transplants in patients with acute and chronic leukaemias has led to trials investigating for graft-versus-tumour (GVT) effects in patients with treatment-refractory metastatic solid tumours. This review discusses evidence that immune replacement following allogeneic HCT is a potent form of cancer immunotherapy for patients with haematological and non-haematological malignancies. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Chakrabarti, S (reprint author), NHLBI, Hematol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 69 TC 3 Z9 3 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD OCT PY 2003 VL 3 IS 7 BP 1051 EP 1060 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 734EP UT WOS:000186042500004 PM 14519070 ER PT J AU Cadet, JL Jayanthi, S Deng, XL AF Cadet, JL Jayanthi, S Deng, XL TI Speed kills: cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis SO FASEB JOURNAL LA English DT Review DE Bcl-2 family proteins; cDNA array; IEGs; mitochondria; endoplasmic reticulum; neurodegeneration; terminal apoptosis ID INDUCED DOPAMINERGIC NEUROTOXICITY; DISMUTASE TRANSGENIC MICE; ZINC SUPEROXIDE-DISMUTASE; NITRIC-OXIDE SYNTHASE; TRYPTOPHAN-HYDROXYLASE ACTIVITY; POSITRON-EMISSION-TOMOGRAPHY; PERMEABILITY TRANSITION PORE; BCL-2 FAMILY PROTEINS; RAT-BRAIN; C-FOS AB Methamphetamine (METH) is a drug of abuse that has long been known to damage monoaminergic systems in the mammalian brain. Recent reports have provided conclusive evidence that METH can cause neuropathological changes in the rodent brain via apoptotic mechanisms akin to those reported in various models of neuronal death. The purpose of this review is to provide an interim account for a role of oxygen-based radicals and the participation of transcription factors and the involvement of cell death genes in METH-induced neurodegeneration. We discuss data suggesting the participation of endoplasmic reticulum and mitochondria-mediated activation of caspase-dependent and -independent cascades in the manifestation of METH-induced apoptosis. Studies that use more comprehensive approaches to gene expression profiling should allow us to draw more instructive molecular portraits of the complex plastic and degenerative effects of this drug. C1 NIDA, Mol Neuropsychiat Branch, NIH, Intramural Res Program,DHHS, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, Intramural Res Program,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov NR 208 TC 188 Z9 197 U1 5 U2 20 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD OCT PY 2003 VL 17 IS 13 BP 1775 EP 1788 DI 10.1096/fj.03-0073rev PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 739KH UT WOS:000186343300032 PM 14519657 ER PT J AU Rhen, T Grissom, S Afshari, C Cidlowski, JA AF Rhen, T Grissom, S Afshari, C Cidlowski, JA TI Dexamethasone blocks the rapid biological effects of 17 beta-estradiol in the rat uterus without antagonizing its global genomic actions SO FASEB JOURNAL LA English DT Article DE 17 beta-estradiol; dexamethasone; uterus; microarray ID RETINOIC ACID SYNTHESIS; UTERINE GROWTH; MESSENGER-RNA; ESTROUS-CYCLE; MOUSE UTERUS; GLUCOCORTICOID RECEPTOR; ALCOHOL-DEHYDROGENASE; GENE-EXPRESSION; STRESS; PROGESTERONE AB Estrogens and glucocorticoids have opposing effects on the female reproductive tract, but the molecular basis for this antagonism is poorly understood. We therefore examined the biological and transcriptional programs induced by estrogens and glucocorticoids in the uterus of immature female rats. Estradiol 17beta (E2) rapidly induced morphological changes reminiscent of an acute inflammatory response, including infiltration of eosinophils, edema in the stroma and myometrium, and a decrease in the height of luminal epithelial cells, whereas dexamethasone (Dex) only altered stromal cell morphology. When coadministered with E2, Dex completely blocked the proinflammatory effects of E2. Surprisingly, examination of E2 and Dex effects on gene expression using cDNA microarrays and real-time PCR revealed that these hormones had similar effects on the expression of many genes and that very few genes displayed antagonistic regulation. Together, these results indicate strong discord between the early biologic and genomic actions of estrogens and glucocorticoids and highlight a complex regulatory role for glucocorticoids and GR in the mammalian uterus. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov NR 62 TC 33 Z9 40 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 OCT PY 2003 VL 17 IS 13 BP 1849 EP 1870 DI 10.1096/fj.02-1099com PG 22 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 739KH UT WOS:000186343300039 PM 14519664 ER PT J AU Stratton, P Winkel, C Premkumar, A Chow, C Wilson, J Hearns-Stokes, R Heo, SY Merino, M Nieman, LK AF Stratton, P Winkel, C Premkumar, A Chow, C Wilson, J Hearns-Stokes, R Heo, SY Merino, M Nieman, LK TI Diagnosis of endometriosis: utility of MRI? Reply SO FERTILITY AND STERILITY LA English DT Letter C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), NIH, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD OCT PY 2003 VL 80 IS 4 BP 1072 EP 1072 DI 10.1016/S0015-0282(03)01133-6 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 733BL UT WOS:000185980000047 ER PT J AU Moldin, SO AF Moldin, SO TI Neurobiology of autism: the new frontier SO GENES BRAIN AND BEHAVIOR LA English DT Editorial Material ID DISORDERS; BRAIN C1 Off Human Genet & Genom Resources, Bethesda, MD USA. NIMH, Div Neurosci & Basic Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Moldin, SO (reprint author), Off Human Genet & Genom Resources, Bethesda, MD USA. NR 9 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD OCT PY 2003 VL 2 IS 5 BP 253 EP 254 DI 10.1046/j.1601-183X.2003.00040.x PG 2 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 743QQ UT WOS:000186585400001 PM 14606690 ER PT J AU Masse, E Escorcia, FE Gottesman, S AF Masse, E Escorcia, FE Gottesman, S TI Coupled degradation of a small regulatory RNA and its mRNA targets in Escherichia coli SO GENES & DEVELOPMENT LA English DT Article DE RyhB; Fur; RNase E; RNase III; Hfq; DsrA ID SM-LIKE PROTEIN; DEPENDENT CLEAVAGE; RIBOSOME BINDING; IRON-METABOLISM; ANTISENSE RNA; DSRA RNA; HFQ; EXPRESSION; RPOS; TRANSLATION AB RyhB is a small antisense regulatory RNA that is repressed by the Fur repressor and negatively regulates at least six mRNAs encoding Fe-binding or Fe-storage proteins in Escherichia coli. When Fe is limiting, RyhB levels rise, and target mRNAs are rapidly degraded. RyhB is very stable when measured after treatment of cells with the transcription inhibitor rifampicin, but is unstable when overall mRNA transcription continues. We propose that RyhB turnover is coupled to and dependent on pairing with the target mRNAs. Degradation of both mRNA targets and RyhB is dependent on RNase E and is slowed in degradosome mutants. RyhB requires the RNA chaperone Hfq. In the absence of Hfq, RyhB is unstable, even when general transcription is inhibited; degradation is dependent upon RNase E. Hfq and RNase E bind similar sites on the RNA; pairing may allow loss of Hfq and access by RNase E. Two other Hfq-dependent small RNAs, DsrA and OxyS, are also stable when overall transcription is off, and unstable when it is not, suggesting that they, too, are degraded when their target mRNAs are available for pairing. Thus, this large class of regulatory RNAs share an unexpected intrinsic mechanism for shutting off their action. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM susang@helix.nih.gov NR 54 TC 430 Z9 442 U1 4 U2 26 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 1 PY 2003 VL 17 IS 19 BP 2374 EP 2383 DI 10.1101/gad.1127103 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 729DW UT WOS:000185757800006 PM 12975324 ER PT J AU Ross, KE Cohen-Fix, O AF Ross, KE Cohen-Fix, O TI The role of Cdh1p in maintaining genomic stability in budding yeast SO GENETICS LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; DNA-DAMAGE CHECKPOINT; APC-DEPENDENT PROTEOLYSIS; MITOTIC CYCLIN CLB2; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; S-PHASE; TYROSINE PHOSPHORYLATION; MEDIATED PROTEOLYSIS; SPINDLE CHECKPOINT AB Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G(1) transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1Delta and mad2Delta single mutants, the mad2Delta cdh1Delta double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneons deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinctochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2Delta cdh1Delta and pds1Delta cdh1Delta strains were rescued by overexpressing Swe1p, a G(2)/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1Delta mutant strains with abnormal Cdc28p/ Clb activity that interferes with proper chromosome segregation. C1 NIDDK, NIH, LMCB, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDK, NIH, LMCB, 8 Ctr Dr,Bldg 8,Rm 319, Bethesda, MD 20892 USA. NR 58 TC 21 Z9 21 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD OCT PY 2003 VL 165 IS 2 BP 489 EP 503 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 737HT UT WOS:000186224900005 PM 14573464 ER PT J AU Krylov, DM Wolf, YI Rogozin, IB Koonin, EV AF Krylov, DM Wolf, YI Rogozin, IB Koonin, EV TI Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution SO GENOME RESEARCH LA English DT Article ID COMPLETE GENOMES; GENERATION; NETWORKS; DATABASE; ELEGANS; ORIGIN AB Lineage-specific gene loss, to a large extent, accounts for the differences in gene repertoires between genomes, particularly among eukaryotes. We derived a parsimonious scenario of gene losses for eukaryotic orthologous groups (KOGs) from seven complete eukaryotic genomes. The scenario involves substantial gene loss in fungi, nematodes, and insects. Based on this evolutionary scenario and estimates of the divergence times between major eukaryotic phyla, we introduce a numerical measure, the propensity for gene loss (PGL). We explore the connection among the propensity of a gene to be lost in evolution (PGL value), protein sequence divergence, the effect of gene knockout on fitness, the number of protein-protein interactions, and expression level for the genes in KOGs. Significant correlations between PGL and each of these variables were detected. Genes that have a lower propensity to be lost in eukaryotic evolution accumulate fewer substitutions in their protein sequences and tend to be essential for the organism viability, tend to be highly expressed, and have many interaction partners. The dependence between PGL and gene dispensability and interactivity is much stronger than that for sequence evolution rate. Thus, propensity of a gene to be lost during evolution seems to be a direct reflection of its biological importance. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 43 TC 246 Z9 251 U1 1 U2 12 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD OCT PY 2003 VL 13 IS 10 BP 2229 EP 2235 DI 10.1101/gr.1589103 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 731GR UT WOS:000185876400003 PM 14525925 ER PT J AU Mousses, S Caplen, NJ Cornelison, R Weaver, D Basik, M Hautaniemi, S Elkahloun, AG Lotufo, RA Choudary, A Dougherty, ER Suh, E Kallioniemi, O AF Mousses, S Caplen, NJ Cornelison, R Weaver, D Basik, M Hautaniemi, S Elkahloun, AG Lotufo, RA Choudary, A Dougherty, ER Suh, E Kallioniemi, O TI RNAi microarray analysis in cultured mammalian cells SO GENOME RESEARCH LA English DT Article ID FUNCTIONAL GENOMIC ANALYSIS; DOUBLE-STRANDED-RNA; C-ELEGANS; CAENORHABDITIS-ELEGANS; GENETIC INTERFERENCE; WIDE RNAI; OVARY AB RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) is a powerful new tool for analyzing gene knockdown phenotypes in living mammalian cells. To facilitate large-scale, high-throughput functional genomics studies using RNAi, we have developed a microarray-based technology for highly parallel analysis. Specifically, siRNAs in a transfection matrix were first arrayed on glass slides, overlaid with a monolayer of adherent cells, incubated to allow reverse transfection, and assessed for the effects of gene silencing by digital image analysis at a single cell level. Validation experiments with HeLa cells stably expressing GFP showed spatially confined, sequence-specific, time- and dose-dependent inhibition of green fluorescence for those cells growing directly on microspots containing siRNA targeting the GFP sequence. Microarray-based siRNA transfections analyzed with a custom-made quantitative image analysis system produced results that were identical to those from traditional well-based transfection, quantified by flow cytometry. Finally, to integrate experimental details, image analysis, data display, and data archiving, we developed a prototype information management system for high-throughput cell-based analyses. In summary, this RNAi microarray platform, together with ongoing efforts to develop large-scale human siRNA libraries, should facilitate genomic-scale cell-based analyses of gene function. C1 Translat Genom Res Inst, Canc Drug Dev Lab, Gaithersburg, MD 20878 USA. Canc Genet Branch, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. UNICAMP, Dept Comp Engn & Ind Automat, BR-13081970 Campinas, SP, Brazil. Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. VTT Tech Res Ctr Finland, Med Biotechnol Grp, FIN-20521 Turku, Finland. Turku Univ, FIN-20521 Turku, Finland. RP Mousses, S (reprint author), Translat Genom Res Inst, Canc Drug Dev Lab, Gaithersburg, MD 20878 USA. RI Hautaniemi, Sampsa/A-3122-2009; Lotufo, Roberto/C-1496-2009; Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; Caplen, Natasha/H-2768-2016 OI Hautaniemi, Sampsa/0000-0002-7749-2694; Lotufo, Roberto/0000-0002-5652-0852; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Caplen, Natasha/0000-0002-0001-9460 NR 21 TC 143 Z9 153 U1 0 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD OCT PY 2003 VL 13 IS 10 BP 2341 EP 2347 DI 10.1101/gr.1478703 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 731GR UT WOS:000185876400016 PM 14525932 ER PT J AU Rajeevan, MS Dimulescu, IM Vernon, SD Verma, M Unger, ER AF Rajeevan, MS Dimulescu, IM Vernon, SD Verma, M Unger, ER TI Global amplification of sense RNA: a novel method to replicate and archive mRNA for gene expression analysis SO GENOMICS LA English DT Article DE gene expression profiling; RNA amplification; antisense RNA; sense RNA; biomarkers ID TIME RT-PCR; CDNA LIBRARIES; CELLS; QUANTIFICATION; PROFILES; ARRAYS AB We have developed a procedure to amplify mRNA into sense RNA (sRNA) so as to create a regenerating biorepository representing the complex mRNA profile in the original sample. The procedure exploits the template-switching activity of reverse transcriptase to incorporate RNA polymerase binding sites upstream of single-stranded cDNA (ss cDNA). Limited PCR was used for double-stranded DNA (dsDNA) synthesis. sRNA was synthesized from PCR products by in vitro transcription (IVT). sRNA was evaluated by real-time reverse transcription (RT)-PCR. sRNA synthesis was successful with RNA from human cell lines and tissues, yielding 2000- to 2500-fold amplification of glyceraldeyde-3 phosphate dehydrogenase (G3PDH). The size of sRNA ranged from 3.0 to 0.1 kb. sRNA synthesis preserved the relative differences in plant mRNAs spiked at abundance ranging over 5 orders of magnitude (0.00001-0.1%). This reflects the high fidelity of sRNA synthesis for mRNA as low as 0.3 copies/cell. sRNA is amplified synthetic mRNA in the 5'-->3' direction; the appropriate template for any gene expression analysis. (C) 2003 Elsevier Inc. All rights reserved. C1 CDCP, Viral Exanthems & Herpesvirus Branch, Div Viral & Rickettsial Dis, Natl Ctr Infect Dis,US Dept HHS, Atlanta, GA 30333 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. RP Rajeevan, MS (reprint author), CDCP, Viral Exanthems & Herpesvirus Branch, Div Viral & Rickettsial Dis, Natl Ctr Infect Dis,US Dept HHS, Atlanta, GA 30333 USA. OI Unger, Elizabeth/0000-0002-2925-5635 FU NCI NIH HHS [Y1-CN-0101-01] NR 22 TC 8 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD OCT PY 2003 VL 82 IS 4 BP 491 EP 497 DI 10.1016/S0888-7543(03)00115-0 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 725NY UT WOS:000185550300008 PM 13679029 ER PT J AU Richardson, A Warner, H AF Richardson, A Warner, H TI Nathan Shock Center symposium on molecular aspects of aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Texas, Hlth Sci Ctr, Nathan Shock Ctr Excellence Biol Aging, San Antonio, TX 78229 USA. NIA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 15 EP 15 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100045 ER PT J AU Niederehe, G Niederehe, G Otey, E Oliver, K Light, E AF Niederehe, G Niederehe, G Otey, E Oliver, K Light, E TI Mental health and aging research: Update on NIMH initiatives SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. NIMH, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. EM gniedere@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 22 EP 22 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100059 ER PT J AU Mehrotra, C Laver, G Anagnopoulos, C Singelis, T Barr, R AF Mehrotra, C Laver, G Anagnopoulos, C Singelis, T Barr, R TI Engaging undergraduate students in aging research SO GERONTOLOGIST LA English DT Meeting Abstract C1 Coll St Scholast, Duluth, MN 55811 USA. Calif Polytech State Univ San Luis Obispo, San Luis Obispo, CA 93407 USA. Black Hills State Univ, Dept Psychol, Spearfish, SD 57799 USA. Calif State Univ Los Angeles, Dept Psychol, Chico, CA 95929 USA. NIA, Off Extramural Affairs, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 28 EP 28 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100073 ER PT J AU Chang, M Chang, M Ferrucci, L Cohen-Mansfield, J Guralnik, J AF Chang, M Chang, M Ferrucci, L Cohen-Mansfield, J Guralnik, J TI Predictors of mobility loss over 1.8 years among non-disabled but functionally limited older adults SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 38 EP 38 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100099 ER PT J AU Guralnik, J AF Guralnik, J TI Examiner training for the short physical performance battery SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 39 EP 40 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100105 ER PT J AU Ble', A Volpato, S Guralnik, J Zuliani, G Fellin, R Ferrucci, L AF Ble', A Volpato, S Guralnik, J Zuliani, G Fellin, R Ferrucci, L TI Association between cognitive and lower extremity function in community-dwelling older subjects: The InChianti Study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIA, Geriatr Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 60 EP 60 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100170 ER PT J AU Penninx, B Pahor, M Cesari, M Corsi, A Bandinelli, S Guralnik, J Ferrucci, L AF Penninx, B Pahor, M Cesari, M Corsi, A Bandinelli, S Guralnik, J Ferrucci, L TI Anaemia is independently associated with decreased performance and muscle strength SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RI Cesari, Matteo/A-4649-2008 OI Cesari, Matteo/0000-0002-0348-3664 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 88 EP 88 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100242 ER PT J AU Teri, L Morrison-Bogorad, M AF Teri, L Morrison-Bogorad, M TI Evidence based behavioral training for staff in long-term care SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 94 EP 95 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100259 ER PT J AU Cobb, B Donohue, J Zonderman, A Evans, M Kitner-Triolo, M AF Cobb, B Donohue, J Zonderman, A Evans, M Kitner-Triolo, M TI Age, verbal knowledge, mental status and clock drawing in low SES African Americans: Results from the HANDLS pilot study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Norfolk State Univ, Sch Social Work, Norfolk, VA USA. NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 183 EP 183 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100523 ER PT J AU Hodes, R AF Hodes, R TI Nia symposium: Research initiatives, funding and training opportunities at the national institute on aging SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 229 EP 229 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100656 ER PT J AU Kerns, M AF Kerns, M TI Post-solidarity and postmodern intergenerational relation(ship)s SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 252 EP 252 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100707 ER PT J AU Simonsick, E Newman, A Harris, T Kritchevsky, S Rubin, S Cummings, S AF Simonsick, E Newman, A Harris, T Kritchevsky, S Rubin, S Cummings, S TI Development of a physiological profile of exceptional health in old age: Observations from health ABC SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIA, Bethesda, MD 20892 USA. Wake Forest Univ, Baptist Med Coll, Winston Salem, NC 27109 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 307 EP 307 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100847 ER PT J AU Faulkner, K Cauley, J Redfern, M Rosano, C Kritchevsky, S Landsittel, D Rubin, S Simonsick, E Studenski, S Zmuda, J Newman, A AF Faulkner, K Cauley, J Redfern, M Rosano, C Kritchevsky, S Landsittel, D Rubin, S Simonsick, E Studenski, S Zmuda, J Newman, A TI Do cognitive challenges interfere with walking ability? SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Tennessee, Knoxville, TN 37996 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 311 EP 311 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100855 ER PT J AU Trinidad, G Halpain, M Wetherell, J Olin, J Jeste, D AF Trinidad, G Halpain, M Wetherell, J Olin, J Jeste, D TI Early career development in aging and mental health SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Calif San Diego, San Diego, CA 92103 USA. Natl Inst Mental Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 348 EP 348 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100959 ER PT J AU Quandt, S Arcury, T Bell, R Mellen, B Skelly, A Smith, S Wetmore, L AF Quandt, S Arcury, T Bell, R Mellen, B Skelly, A Smith, S Wetmore, L TI Diabetes education and dietary self-management practices of rural older adults in a multi-ethnic population: Results from the elder study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 357 EP 357 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078100979 ER PT J AU Chernoff, R Wise, P Barrett-Connor, E Resnick, S Pinn, V AF Chernoff, R Wise, P Barrett-Connor, E Resnick, S Pinn, V TI Menopausal hormone therapy: What's new - What's hot SO GERONTOLOGIST LA English DT Meeting Abstract C1 Womens Hlth Initiat, Jackson, MS USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Calif Davis, Davis, CA 95616 USA. Cent Arkansas VA Healthcare Syst, Little Rock, AR 72205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 400 EP 400 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101086 ER PT J AU de Rekeneire, N Pavon, J Simonsick, E Shorr, R Figaro, K Kuller, L Schwartz, A Vellas, B Harris, T AF de Rekeneire, N Pavon, J Simonsick, E Shorr, R Figaro, K Kuller, L Schwartz, A Vellas, B Harris, T TI Glycemic control mediates the association of diabetes with incident functional limitation. the health, aging and body composition (Health ABC) study. SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Univ Tennessee, Memphis, TN USA. Vanderbilt Univ, Nashville, TN USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Toulouse, Toulouse, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 430 EP 431 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101187 ER PT J AU Pavon, J Colbert, L de Rekeneire, N Simonsick, E Kritchevsky, S Bauer, D Rubin, S Studenski, S Tylavsky, F Harris, T AF Pavon, J Colbert, L de Rekeneire, N Simonsick, E Kritchevsky, S Bauer, D Rubin, S Studenski, S Tylavsky, F Harris, T TI The development of functional limitations in elderly cancer survivors: The health, aging, and body composition study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Lab Epidemiol Demog & Biometry, Winter Pk, FL USA. NIA, Baltimore, MD 21224 USA. Univ Tennessee, Memphis, TN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 455 EP 455 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101250 ER PT J AU Brody, E Lebowitz, B Gurland, B AF Brody, E Lebowitz, B Gurland, B TI M. Powell Lawton Award Lecture SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Columbia Univ, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 469 EP 469 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101296 ER PT J AU Bandinelli, S Lauretani, F Bartali, B Corsi, A Ferrucci, L AF Bandinelli, S Lauretani, F Bartali, B Corsi, A Ferrucci, L TI Systolic blood pressure and risk of falls in older women and men: The InChianti study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. NR 1 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 497 EP 497 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101368 ER PT J AU Schulz, R Schulz, R Stahl, S AF Schulz, R Schulz, R Stahl, S TI The reach caregiver intervention trial: Outcomes and transition effects SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIH, Inst Aging, Washington, DC USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM schulz@pitt.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 500 EP 502 PG 3 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101373 ER PT J AU Cesari, M Pahor, M Bartali, B Cherubini, A Penninx, B Williams, R Atkinson, H Guralnik, J Ferrucci, L AF Cesari, M Pahor, M Bartali, B Cherubini, A Penninx, B Williams, R Atkinson, H Guralnik, J Ferrucci, L TI Antioxidants and physical performance in older persons: The inchianti study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Wake Forest Univ Hlth Sci, J Sticht Ctr Aging, Winston Salem, NC USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. Univ Perugia, Dept Gerontol & Geriatr, I-06100 Perugia, Italy. Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RI Cesari, Matteo/A-4649-2008 OI Cesari, Matteo/0000-0002-0348-3664 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 530 EP 531 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101454 ER PT J AU Lee, J Kritchevsky, S Tylavsky, F Rubin, S Newman, A AF Lee, J Kritchevsky, S Tylavsky, F Rubin, S Newman, A TI Weight change, weight change intention, and mobility limitation in well-functioning elderly SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Tennessee, Knoxville, TN 37996 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 531 EP 532 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101457 ER PT J AU Pruchno, R Smith, G Otey, E Stahl, S AF Pruchno, R Smith, G Otey, E Stahl, S TI Beyond convenience: The costs and benefits of sophisticated sampling strategies SO GERONTOLOGIST LA English DT Meeting Abstract C1 Boston Coll, Newton, MA 02459 USA. Kent State Univ, Sch Family & Consumer Studies, Kent, OH 44242 USA. NIMH, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 538 EP 538 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101473 ER PT J AU Weindruch, R Ingram, D Kemnitz, J AF Weindruch, R Ingram, D Kemnitz, J TI Caloric restriction in nonhuman primates: Update on results in two long-term studies SO GERONTOLOGIST LA English DT Meeting Abstract C1 Univ Wisconsin, Madison, WI 53705 USA. VA GRECC, Madison, WI 53705 USA. NIA, Baltimore, MD 21224 USA. Univ Wisconsin, Madison, WI 53715 USA. Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 567 EP 567 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101555 ER PT J AU Boyd, C Xue, Q Tian, J Simonsick, E Blaum, C Guralnik, J Bandeen-Roche, K AF Boyd, C Xue, Q Tian, J Simonsick, E Blaum, C Guralnik, J Bandeen-Roche, K TI Characterization of functional status trajectories among moderately to severely disabled, community-dwelling older women: The women's health and aging study I (WHAS I) SO GERONTOLOGIST LA English DT Meeting Abstract C1 Johns Hopkins Univ, Ctr Aging & Hlth, Div Geriatr Med & Gerontol, Baltimore, MD 21218 USA. NIA, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 571 EP 571 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101567 ER PT J AU Han, B Guralnik, J Phillips, C Ferrucci, L Jylha, M AF Han, B Guralnik, J Phillips, C Ferrucci, L Jylha, M TI Self-rated health and mortality among older women: The Women's Health and Aging Study SO GERONTOLOGIST LA English DT Meeting Abstract C1 Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NIA, Bethesda, MD 20892 USA. Univ Tampere, FIN-33101 Tampere, Finland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 571 EP 572 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101568 ER PT J AU Hicks, G Newman, A Simonsick, E Harris, T Weiner, D Nevitt, M Tylavsky, F AF Hicks, G Newman, A Simonsick, E Harris, T Weiner, D Nevitt, M Tylavsky, F TI Cross-sectional associations between trunk muscle composition, back pain and physical function in the health ABC study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Clin Res Branch, Baltimore, MD 21224 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Tennessee, Memphis, TN 38163 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 583 EP 583 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101598 ER PT J AU Bartali, B Bandinelli, S Corsi, A Lauretani, F Bonafe, M Olivieri, F Ferrucci, L AF Bartali, B Bandinelli, S Corsi, A Lauretani, F Bonafe, M Olivieri, F Ferrucci, L TI Anthropometric measures and IL_6 serum levels in the older population: The InCHIANTI study SO GERONTOLOGIST LA English DT Meeting Abstract C1 NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD OCT PY 2003 VL 43 SI 1 BP 584 EP 584 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 734VF UT WOS:000186078101601 ER PT J AU Mejia-Naranjo, W Yakar, S Bernal, R LeRoith, D Sanchez-Gomez, M AF Mejia-Naranjo, W Yakar, S Bernal, R LeRoith, D Sanchez-Gomez, M TI Regulation of the splenic somatotropic axis by dietary protein and insulin-like growth factor-I in the rat SO GROWTH HORMONE & IGF RESEARCH LA English DT Article DE IGF-I; IGFBP; IGF-IR; GHR; spleen; rat; protein malnutrition; GH/IGF-I axis; nitrogen balance; lymphocytes ID FACTOR-BINDING PROTEINS; IGF-I; NUTRITIONAL REGULATION; HORMONE-RECEPTOR; GENE-EXPRESSION; SOMATOMEDIN-C; MALNUTRITION; LIVER; DEPRIVATION; PROLACTIN AB Protein intake is a critical regulatory factor of the GH/IGF-I axis. Recently, it has been shown that splenic GH/IGF-I may respond to nutritional stress by preserving tissue homeostasis. To study the effects of exogenous administration of rhIGF-I on the splenic GH/IGF-I axis in protein malnourished rats, six-week-old male rats were assigned to one of four isocaloric diets differing in the protein content (0%, 4%, 12% and 20%) for a period of 12 days. Animals in the same dietary group on day 5 were randomly divided into two groups and during 7 days received a continuous subcutaneous infusion of either vehicle or rhIGF-I (300 mug/day). A low protein intake decreased the circulating levels of IGF-I, IGFBP-3, GH and insulin whereas the serum levels of IGFBP-1 were increased. Splenic IGFBP-3, -4 and -6 mRNA expression were up-regulated by protein malnutrition. Similarly, IGF-IR and GHR mRNA expression were significantly increased by the lack of dietary protein, whereas the levels of IGF-1 mRNA remained unchanged. Exogenous rhIGF-I administration increased the circulating levels of IGFBP-1 and -3 in protein malnourished rats and reduced significantly the GH and insulin levels in well-fed rats. Similarly, rhIGF-I increased significantly the expression of the GHR in the spleen and splenic weight in all dietary groups, whereas nitrogen balance was enhanced only in the high-protein diet group. Among the cell subpopulations, B lymphocytes showed the highest GHR expression. These results suggest that in catabolic stress, induced by protein malnutrition the splenic GH/IGF-I axis is an important modulator and contributes to the maintenance of the homeostasis of the immune system. Published by Elsevier Science Ltd. C1 Univ Nacl Colombia, Dept Chem, Bogota, Colombia. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Univ Nacl Colombia, Dept Chem, POB 14490, Bogota, Colombia. EM mygomez@ciencias.unal.edu.co NR 25 TC 7 Z9 7 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1096-6374 EI 1532-2238 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD OCT PY 2003 VL 13 IS 5 BP 254 EP 263 DI 10.1016/S1096-6374(03)00014-5 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 725NG UT WOS:000185548800004 PM 12932746 ER PT J AU Winter, WE Seidman, JD Krivak, TC Chauhan, S Carlson, JW Rose, GS Birrer, MJ AF Winter, WE Seidman, JD Krivak, TC Chauhan, S Carlson, JW Rose, GS Birrer, MJ TI Clinicopathological analysis of c-kit expression in carcinosarcomas and leiomyosarcomas of the uterine corpus SO GYNECOLOGIC ONCOLOGY LA English DT Article DE c-kit; carcinosarcoma; leiomyosarcoma ID STEM-CELL FACTOR; GASTROINTESTINAL STROMAL TUMORS; CHRONIC MYELOID-LEUKEMIA; ABL TYROSINE KINASE; RECEPTOR; TISSUES; UTERUS; EPITHELIUM; CD117; RECURRENCE AB Objective. The purpose of this study was to evaluate the expression of the protooncogene, c-kit, in carcinosarcomas and leiomyosarcomas of the uterine corpus and determine the associations between c-kit expression and clinicopathologic factors, including clinical outcome. Methods and materials. Using a polyclonal anti-KIT-antibody, immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissue blocks from 21 carcinosarcomas, 17 leiomyosarcomas, and 1 endometrial stromal sarcoma. KIT-positive tumors were defined as those tumors demonstrating immunopositivity in greater than or equal to30% of tumor cells examined. KIT-negative lesions demonstrated immunopositivity in <30% of tumor cells. Two authors independently scored the slides as positive or negative. Staining was repeated on all specimens and independently scored, and in the occasion of a mismatch, a third staining was performed. The carcinosarcomas were catalogued as to whether the sarcomatous and/or carcinomatous elements expressed c-kit. Clinical data were abstracted for those patients with uterine carcinosarcomas. The associations between clinicopathologic characteristics and c-kit expression were compared using univariate and multivariate analyses. Kaplan-Meier curves based on c-kit expression were plotted for progression-free and overall survival and compared using the log-rank test. Results. Nine of 21 (43%) carcinosarcomas demonstrated immunopositivity for the KIT receptor, although staining was relatively weak. In contrast, only 1/17 (6%) leiomyosarcomas demonstrated KIT immunopositivity (P = 0.029). The solitary endometrial stromal sarcoma evaluated did not demonstrate significant KIT positivity. The majority of KIT-positive carcinosarcomas (6/9 (67%)) demonstrated KIT presence in the sarcomatous portion as compared to the carcinomatous portion (4/9 (44%)). No clinical factor had a statistically significant association with c-kit expression. The lack of c-kit expression was the only factor that was significantly associated with disease recurrence in univariate and multivariate analyses (P < 0.05), although there appeared to be a trend toward a low stage associated with kit positivity. The median progression-free interval for the KIT-negative cohort was 8 months, while it had not been reached for the KIT-positive cohort after median follow-up of 15 months, (P = 0.0462). Conclusions. A significant proportion of carcinosarcomas of the uterine corpus display immunoreactivity for c-kit. Patients with KIT-positive carcinosarcomas may have an improved progression-free survival compared to KIT-negative tumors; however, further data are needed to determine whether this finding is confounded by stage. (C) 2003 Elsevier Inc. All rights reserved. C1 Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Washington, DC 20307 USA. Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC 20010 USA. NCI, Dept Cell & Canc Biol, Rockville, MD 20850 USA. RP Birrer, MJ (reprint author), Key W Res Ctr, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. NR 27 TC 37 Z9 37 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD OCT PY 2003 VL 91 IS 1 BP 3 EP 8 DI 10.1016/S0090-8258(03)00436-0 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 728RY UT WOS:000185731200002 PM 14529656 ER PT J AU Low, NCP du Fort, GG Cervantes, P AF Low, NCP du Fort, GG Cervantes, P TI Prevalence, clinical correlates, and treatment of migraine in bipolar disorder SO HEADACHE LA English DT Article DE bipolar disorder; migraine; comorbidity; depression; headache ID CANADIAN POPULATION SURVEY; TENSION-TYPE HEADACHE; PSYCHIATRIC-DISORDERS; MAJOR DEPRESSION; YOUNG-ADULTS; COMORBIDITY; ASSOCIATION; IMPACT; COMMUNITY; DIAGNOSIS AB Objective.-To investigate the prevalence, clinical correlates, and treatment of migraine in bipolar disorder. Background.-The relationship between migraine and mood disorders has been of long-standing interest to researchers and clinicians. Although a strong association has been demonstrated consistently for migraine and major depression, there has been less systematic research on the links between migraine and bipolar disorder. Methods.-A migraine questionnaire (based on International Headache Society criteria) was administered to 108 outpatients with bipolar disorder. Information on the clinical course of bipolar illness was also collected. Results.-The overall lifetime prevalence of migraine was 39.8% (43.8% among women and 31.4% among men). In the subgroup of patients with bipolar II disorder, the lifetime prevalence of migraine was 64.7%. The bipolar with migraine group was younger, tended to be more educated, was more likely to be employed or studying, and had fewer psychiatric hospitalizations. Their initial presentation for psychiatric treatment was more often for symptoms of depression, rather than hypomania or mania. They were more likely to have a family history of migraine and psychiatric disorders, and a greater number of affected relatives. They were less likely to use mood stabilizers, and more likely to use atypical antidepressants. Migraine was assessed by a neurologist in only 16% of affected patients. The prevalence of the use of specific antimigraine medications (triptans) was 27.9%. Conclusions.-This study confirms the higher prevalence of migraine among those with bipolar disorder compared to the general population. Migraine in patients with bipolar disorder is underdiagnosed and undertreated. Bipolar disorder with migraine is associated with differences in the clinical course of bipolar disorder, and may represent a subtype of bipolar disorder. C1 NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Sir Mortimer B Davis Jewish Hosp, Ctr Clin Epidemiol & Community Studies, Montreal, PQ, Canada. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. RP Low, NCP (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,US Dept HHS, Bldg 15K,Room 208,MSC 2670,15 K North Dr, Bethesda, MD 20892 USA. NR 50 TC 63 Z9 65 U1 1 U2 6 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0017-8748 J9 HEADACHE JI Headache PD OCT PY 2003 VL 43 IS 9 BP 940 EP 949 DI 10.1046/j.1526-4610.2003.03184.x PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 724ED UT WOS:000185473500001 PM 14511270 ER PT J AU Adler, HJ Belyantseva, IA Merritt, RC Frolenkov, GI Dougherty, GW Kachar, B AF Adler, HJ Belyantseva, IA Merritt, RC Frolenkov, GI Dougherty, GW Kachar, B TI Expression of prestin, a membrane motor protein, in the mammalian auditory and vestibular periphery SO HEARING RESEARCH LA English DT Article DE sensory transduction; hair cell; electromotility ID OUTER HAIR-CELLS; COCHLEAR AMPLIFIER; INNER-EAR; BUNDLE MOVEMENTS; PENDRED-SYNDROME; IDENTIFICATION; CAPACITANCE; MOTILITY; ELECTROMOTILITY; TRANSDUCTION AB Hair cells are specialized mechanoreceptors common to auditory and vestibular sensory organs of mammalian and nonmammalian species. Different hair cells are believed to share common features related to their mechanosensory function. It has been shown that hair cells possess various forms of motile properties that enhance their receptor function. Membrane-based electromotility is a form of hair cell motility observed in isolated outer hair cells (OHCs) of the cochlea. A novel membrane protein, prestin, recently cloned from gerbil and rat tissues, is presumably responsible for electromotility. We cloned prestin from mouse organ of Corti and confirmed strong homology of this protein among different rodent species. We explored whether or not prestin is present in hair cells of the vestibular system. Using reverse transcription-polymerase chain reaction, we demonstrated that prestin is expressed in mouse and rat auditory and vestibular organs, but not in chicken auditory periphery. In situ hybridization and immunolocalization studies confirmed the presence of prestin in OHCs as well as in vestibular hair cells (VHCs) of rodent saccule, utricle and crista ampullaris. However, in the VHCs, staining of varying intensity with anti-prestin antibodies was observed in the cytoplasm, but not in the lateral plasma membrane or in the stereociliary membrane. Whole-cell patch-clamp recordings showed that VHCs do not possess the voltage-dependent capacitance associated with membrane-based electromotility. We conclude that although prestin is expressed in VHCs, it is unlikely that it supports the form of somatic motility observed in OHCs. (C) 2003 Elsevier B.V. All rights reserved. C1 NIH, Sect Struct Cell Biol, Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. RP Adler, HJ (reprint author), NIH, Sect Struct Cell Biol, Natl Inst Deafness & Other Commun Disorders, Bldg 50,Room 4249, Bethesda, MD 20892 USA. OI Frolenkov, Gregory/0000-0002-9810-5024 NR 57 TC 43 Z9 50 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD OCT PY 2003 VL 184 IS 1-2 BP 27 EP 40 DI 10.1016/S0378-5955(03)00192-8 PG 14 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 736EK UT WOS:000186158300004 PM 14553901 ER PT J AU Valent, P Akin, C Sperr, WR Horny, HP Metcalfe, DD AF Valent, P Akin, C Sperr, WR Horny, HP Metcalfe, DD TI Mast cell proliferative disorders: current view on variants recognized by the World Health Organization SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID BLOOD MONONUCLEAR-CELLS; COLONY-FORMING CELL; PROTOONCOGENE C-KIT; SYSTEMIC MASTOCYTOSIS; BONE-MARROW; GENERALIZED MASTOCYTOSIS; CUTANEOUS-MASTOCYTOSIS; RECOMBINANT HUMAN; PERIPHERAL-BLOOD; SMOLDERING MASTOCYTOSIS AB Mastocytosis is a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in one or more organs. Systemic variants of disease can be regarded as myeloproliferative disorders. Similar to other myeloid neoplasms, systemic mastocytosis shows a variable clinical course and prognosis and can progress into frank leukemia. The treatment of mastocytosis must be adjusted to the individual situation in each patient and the subtype of disease. C1 Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria. NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. Med Univ Lubeck, Inst Pathol, D-23538 Lubeck, Germany. RP Valent, P (reprint author), Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Wahringer Gurtel 18-20, Vienna, Austria. OI Akin, Cem/0000-0001-6301-4520 NR 91 TC 49 Z9 49 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD OCT PY 2003 VL 17 IS 5 BP 1227 EP + DI 10.1016/S0889-8588(03)00089-3 PG 16 WC Oncology; Hematology SC Oncology; Hematology GA 726TZ UT WOS:000185617300011 PM 14560784 ER PT J AU Wayne, AS Barrett, AJ AF Wayne, AS Barrett, AJ TI Allogeneic hematopoietic stem cell transplantation for myeloproliferative disorders and myelodysplastic syndromes SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID BONE-MARROW-TRANSPLANTATION; CHRONIC-MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; TOTAL-BODY IRRADIATION; CYTOTOXIC T-LYMPHOCYTES; HLA-IDENTICAL SIBLINGS; DONOR LEUKOCYTE INFUSIONS; MINOR HISTOCOMPATIBILITY ANTIGENS; PRETRANSPLANT INTERFERON-ALPHA AB Allogeneic hematopoietic stem cell transplantation (SCT) is the only proven curative therapy for patients with myeloproliferative diseases. As a stem cell disorder, chronic myelogenous leukemia (CML) has served as a prototypic disease in the development of allogeneic SCT. Since the initial reports of the successful use of bone marrow transplantation for CML, the use of SCT for this disorder has become standard therapy. CML currently is one of the most common indications for allogeneic SCT, and the success of SCT in the treatment of CML has served as a benchmark for transplantation trials in other malignancies. The curative potential of an allogeneic graft-versus-leukemia effect also has been shown in CML, which has fueled major efforts in the study and application of this new approach to anticancer therapeutics. This article highlights the principles and results of allogeneic SCT in the treatment of CML and discusses the use of SCT for other myeloproliferative diseases and myelodysplastic syndromes. C1 NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wayne, AS (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 13N240,10 Ctr Dr,MSC-1928, Bethesda, MD 20892 USA. NR 169 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD OCT PY 2003 VL 17 IS 5 BP 1243 EP + DI 10.1016/S0889-8588(03)00091-1 PG 19 WC Oncology; Hematology SC Oncology; Hematology GA 726TZ UT WOS:000185617300012 PM 14560785 ER PT J AU Thio, CL Mosbruger, T Astemborski, J Goedert , JG O'Brien, S Thomas, DL AF Thio, CL Mosbruger, T Astemborski, J Goedert , JG O'Brien, S Thomas, DL TI An analysis of CTLA4 single nucleotide polymorphismsand haplotypes with hepatitis C virus outcomes. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Natl Canc Inst, Rockville, MD USA. Natl Canc Inst, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 32 BP 171A EP 171A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700033 ER PT J AU Racanelli, V Behrens, SE Aliberti, J Rehermann, B AF Racanelli, V Behrens, SE Aliberti, J Rehermann, B TI Crosspriming of hepatitis C virus specific CD8+T cells in mice by immunization with dendritic cells transfected with self-replicating RNA. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Philadelphia, PA USA. RI Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 34 BP 172A EP 172A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700035 ER PT J AU Heller, T Sobao, Y Mizukoshi, E Rahman, F Sheets, A Gordon, D Sherker, A Kessler, ER Bean, KS Herrine, S Schmitt, J Stevens, M Park, Y Alter, H Hoofnagle, JH Liang, J Rehermann, B AF Heller, T Sobao, Y Mizukoshi, E Rahman, F Sheets, A Gordon, D Sherker, A Kessler, ER Bean, KS Herrine, S Schmitt, J Stevens, M Park, Y Alter, H Hoofnagle, JH Liang, J Rehermann, B TI HCV exposure in humans: Stimulation of cellular, but not humoral immune responses in the absence of detectable viremia. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Washington, DC 20010 USA. Inova Fairfax Hosp, Falls Church, VA USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 57 BP 182A EP 182A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700058 ER PT J AU Jeong, SH Qiao, M Nascimbeni, M Rehermann, B Murthy, K Liang, TJ AF Jeong, SH Qiao, M Nascimbeni, M Rehermann, B Murthy, K Liang, TJ TI Induction of HCV-specific immune responses by hepatitis C virus-like particles in non-human primates: Implications for prevention and therapy of hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Southwest Fdn Biomed Res, San Antonio, TX USA. RI Jeong, Sook-Hyang/D-5726-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 65 BP 186A EP 186A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700066 ER PT J AU Rahman, F Heller, T Sobao, Y Mizukoshi, E Alter, H Herrine, S Hoofnagle, JH Liang, J Rehermann, B AF Rahman, F Heller, T Sobao, Y Mizukoshi, E Alter, H Herrine, S Hoofnagle, JH Liang, J Rehermann, B TI Effect of early antiviral therapy on the cellular immune response in acute hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 64 BP 186A EP 186A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700065 ER PT J AU Gundji, T Manickan, E Hu, ZY Mochizuki, K Mi, LJ Liang, TJ AF Gundji, T Manickan, E Hu, ZY Mochizuki, K Mi, LJ Liang, TJ TI Conditional expression of hepatitis C virus genome induces inflammation, steatosis and hepatocellular injury in a transgenic mouse model. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 105 BP 207A EP 207A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700106 ER PT J AU Mizukoshi, E Eisenbach, C Edlin, B Weiler, C Carrington, M O'Brien, T Rehermann, B AF Mizukoshi, E Eisenbach, C Edlin, B Weiler, C Carrington, M O'Brien, T Rehermann, B TI HCV-specific cellular immune responses in subjects who are antiHCV-negative, HCV RNA-negative despite longterm (> 15 years) injection drug use. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Cornell Univ, Weill Med Coll, Ctr Study Hepatitis C, San Francisco, CA USA. SAIC Frederick Inc, Frederick, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 111 BP 210A EP 210A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700112 ER PT J AU Sakai, A St Claire, M Emerson, SU Purcell, RH Bukh, J AF Sakai, A St Claire, M Emerson, SU Purcell, RH Bukh, J TI The hepatitis C virus p7 protein, a new target for drug development, is critical for infectivity and contains sequences with genotype-specific function. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 110 BP 210A EP 210A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700111 ER PT J AU Lemmer, ER Conner, EA Oe, S Factor, VM Leveen, P Tsai, TL Larsson, J Karlsson, S Thorgeirsson, SS AF Lemmer, ER Conner, EA Oe, S Factor, VM Leveen, P Tsai, TL Larsson, J Karlsson, S Thorgeirsson, SS TI Mice with hepatocyte-specific disruption of transforming growth factor beta (TGF-beta) signaling have enhanced mitogenic response during liver regeneration. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NCI, Bethesda, MD 20892 USA. Univ Lund Hosp, S-22185 Lund, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 113 BP 211A EP 211A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700114 ER PT J AU Sanyal, CA Fontana, R Everhart, J Di Bisceglie, A Wright, E AF Sanyal, CA Fontana, R Everhart, J Di Bisceglie, A Wright, E TI The presence and spectrum of varices in the absence of cirrhosis in patients with chronic hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Virginia Commonwealth Univ, Richmond, VA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NIDDK, Bethesda, MD USA. St Louis Univ, St Louis, MO 63103 USA. New England Res Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 129 BP 218A EP 218A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700130 ER PT J AU Adams, PC Reboussin, D Acton, R Barton, J Gordeuk, V Dawkins, F McLaren, C McLaren, G Harris, E Press, N Speechley, M Mellen, B Thomsen, E Eckfeldt, J Sholinsky, P AF Adams, PC Reboussin, D Acton, R Barton, J Gordeuk, V Dawkins, F McLaren, C McLaren, G Harris, E Press, N Speechley, M Mellen, B Thomsen, E Eckfeldt, J Sholinsky, P TI Prevalence of self-reported symptoms in the HEIRS study: Differences by HFE genotype. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 London Hlth Sci Ctr, London, England. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Univ Alabama, Birmingham, AL USA. So Iron Disorders Ctr, Birmingham, AL USA. Howard Univ, Washington, DC 20059 USA. Univ Calif Irvine, Coll Med, Irvine, CA 92717 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR 97034 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Western Ontario, London, ON, Canada. NHGRI, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 155 BP 230A EP 231A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700156 ER PT J AU Sanchez, A Nagy, P Schroeder, IS Factor, VM Thorgeirsson, SS AF Sanchez, A Nagy, P Schroeder, IS Factor, VM Thorgeirsson, SS TI NF-KB and STAT-3 are required for hepatic stem cell activation. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 264 BP 283A EP 283A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700265 ER PT J AU Schroeder, IS Factor, VM Sanchez, A Lee, JS Hoang, TN Thorgeirsson, SS AF Schroeder, IS Factor, VM Sanchez, A Lee, JS Hoang, TN Thorgeirsson, SS TI In vitro differentiation of adult liver stem cells into the hepatocytic lineage. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 272 BP 287A EP 287A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700274 ER PT J AU Esmat, GH Abouzied, A Abdel-Hamid, M Mohamed, MK Zalata, K El Raziky, MS Ismael, SA Said, M Hasan, A Anwar, M Shaheen, A Abdel-Aziz, F Mikhail, NN Ismail, A Fix, A Strickland, TG Sjogren, MH AF Esmat, GH Abouzied, A Abdel-Hamid, M Mohamed, MK Zalata, K El Raziky, MS Ismael, SA Said, M Hasan, A Anwar, M Shaheen, A Abdel-Aziz, F Mikhail, NN Ismail, A Fix, A Strickland, TG Sjogren, MH TI Results of a randomized clinical trial of genotype-4 infected subjects when treated with standard or pegylated interferon alfa-2b in combination with ribavirin. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Inst Trop Med, Cairo, Egypt. NIH, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 324 BP 314A EP 315A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700325 ER PT J AU Conjeevaram, HS Kleiner, DE Afdhal, N Brown, RS Fried, MW Howell, CD Jeffers, LJ Terrault, N Wiley, TE Cherry, C Belle, S Hoofnagle, JH AF Conjeevaram, HS Kleiner, DE Afdhal, N Brown, RS Fried, MW Howell, CD Jeffers, LJ Terrault, N Wiley, TE Cherry, C Belle, S Hoofnagle, JH TI Race, insulin resistance, visceral adiposity and hepatic steatosis in genotype 1 patients with chronic hepatitis C. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIH, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. New York Presbyterian Med Ctr, New York, NY USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. Miami Univ, Miami, FL USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Illinois, Chicago, IL 60680 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 1 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 388 BP 347A EP 347A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700389 ER PT J AU Balasubramaniyan, N Mirza, MF Sinal, CJ Gonzalez, FJ Suchy, FJ Ananthanarayanan, M AF Balasubramaniyan, N Mirza, MF Sinal, CJ Gonzalez, FJ Suchy, FJ Ananthanarayanan, M TI Farnesoid X receptor (FXR) transactivates mouse organic anion transporting polypeptide 4 (OATP4, SLC21A10, LST-1) promoter: In vitro and in vivo evidence. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Mt Sinai Med Ctr, New York, NY 10029 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 456 BP 380A EP 380A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700460 ER PT J AU Kagawa, T Mochizuki, K Harris, MJ Watanabe, N Mine, T Matsuzaki, S Arias, IM AF Kagawa, T Mochizuki, K Harris, MJ Watanabe, N Mine, T Matsuzaki, S Arias, IM TI Bile acid transport activity and intracellular distribution of PFIC2 mutants in MDCKII cells coexpressing Ntcp and Bsep. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Tokai Univ, Sch Med, Isehara, Kanagawa 25911, Japan. Tufts Univ, Sch Med, Boston, MA 02111 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 475 BP 389A EP 389A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700479 ER PT J AU Fried, MW Kroner, BL Preiss, LR Theodore, D Goedert, JJ AF Fried, MW Kroner, BL Preiss, LR Theodore, D Goedert, JJ TI Hemophilic siblings with chronic hepatitis C: Evidence of a genetic association with disease progression. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Univ N Carolina, Chapel Hill, NC 27515 USA. Res Triangle Inst, Rockville, MD USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 550 BP 424A EP 425A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700554 ER PT J AU Di Bisceglie, AM Dienstag, J Bonkovsky, H Sterling, R Chung, R Everhart, J Wright, E AF Di Bisceglie, AM Dienstag, J Bonkovsky, H Sterling, R Chung, R Everhart, J Wright, E TI Serum alpha-fetoprotein (AFP) levels in patients with advanced hepatitis C-associated liver disease without hepatocellular carcinoma: Results from the HALT-C trial. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NIH, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 567 BP 434A EP 434A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700571 ER PT J AU Lok, AS Everhart, JE Wright, E Chung, R Greenson, JK AF Lok, AS Everhart, JE Wright, E Chung, R Greenson, JK TI Steatosis is common in advanced hepatitis C and related to BMI, hypertriglyceridemia, and genotype 3. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Univ Michigan, Ann Arbor, MI 48109 USA. NIDDK, Bethesda, MD USA. NERI, Watertown, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Lok, Anna /B-8292-2009 NR 0 TC 0 Z9 0 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 574 BP 437A EP 437A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700578 ER PT J AU Nascimbeni, M Shin, EC Chiriboga, L Kleiner, DE Rehermann, B AF Nascimbeni, M Shin, EC Chiriboga, L Kleiner, DE Rehermann, B TI Peripheral blood and intrahepatic CD4/CD8 double positive cells in hepatitis C virus infection. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. NYU, Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 625 BP 462A EP 462A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700629 ER PT J AU Lutchman, GA Promrat, K Soza, A Heller, T Mi, LJ Ghany, M Park, Y Freedman, R Yanovsky, J Kleiner, D Liang, TJ Hoofnagle, J AF Lutchman, GA Promrat, K Soza, A Heller, T Mi, LJ Ghany, M Park, Y Freedman, R Yanovsky, J Kleiner, D Liang, TJ Hoofnagle, J TI Biochemical relapse and continued weight gain in subjects with nonalcoholic steatohepatitis (NASH) after discontinuation of pioglitazone. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 728 BP 510A EP 510A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700732 ER PT J AU Mayo, MJ Combes, B Khilnani, S Al-Halimi, M Jeyarajah, R Lipsky, PE AF Mayo, MJ Combes, B Khilnani, S Al-Halimi, M Jeyarajah, R Lipsky, PE TI Expression of CD40 ligand (CD154) is specifically upregulated in the liver of patients with primary biliary cirrhosis. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. NIAMSD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 742 BP 517A EP 517A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700746 ER PT J AU Factor, VM Huh, CG Sanchez, A Uchida, K Conner, EA Thorgeirsson, SS AF Factor, VM Huh, CG Sanchez, A Uchida, K Conner, EA Thorgeirsson, SS TI Conditional ablation of c-Met reveals an essential role in liver repair after injury. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 819 BP 557A EP 557A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700823 ER PT J AU Jaruga, B Kim, WH Hong, F Gao, B AF Jaruga, B Kim, WH Hong, F Gao, B TI IFN-gamma/STAT1 acts as a pro-inflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: A critical role of IRF-1. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 857 BP 573A EP 573A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700861 ER PT J AU Hafkemeyer, P von Weizsacker, F Kock, J Nassal, M Pastan, IR Blum, HE AF Hafkemeyer, P von Weizsacker, F Kock, J Nassal, M Pastan, IR Blum, HE TI Reverse transcription of a non-viral RNA template by the human hepatitis B-virus polymerase. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 Univ Freiburg, D-7800 Freiburg, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 941 BP 610A EP 610A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700941 ER PT J AU Soza, A Mi, LJ Kleiner, DE Falloon, J Brust, D Hoofnagle, JH Liang, J Heller, T AF Soza, A Mi, LJ Kleiner, DE Falloon, J Brust, D Hoofnagle, JH Liang, J Heller, T TI Hepatitis B core antigen staining in HIV-HBV coinfected patients correlates with serum HBV DNA levels but not HIV RNA levels or CD4 counts. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. RI Soza, Alejandro/C-2907-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 966 BP 622A EP 622A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816700966 ER PT J AU Wagner, M Fickert, P Fuchsbichler, A Silbert, D Gumhold, J Zollner, G Zatloukal, K Marschall, HU Schuetz, JD Gonzalez, FJ Denk, H Trauner, M AF Wagner, M Fickert, P Fuchsbichler, A Silbert, D Gumhold, J Zollner, G Zatloukal, K Marschall, HU Schuetz, JD Gonzalez, FJ Denk, H Trauner, M TI Hepatic and renal ABC transporter expression as critical determinants of ursodeoxycholic acid-induced bile infarcts in bile duct-ligated mice. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 24-28, 2003 CL BOSTON, MA SP Amer Assoc Study Liver Dis C1 Karl Franzens Univ Graz, Graz, Austria. Karolinska Inst, S-10401 Stockholm, Sweden. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 1106 BP 688A EP 689A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816701105 ER PT J AU Mizukoshi, E Sidney, J Livingston, B Ghany, M Hoofnagle, JH Sette, A Rehermann, B AF Mizukoshi, E Sidney, J Livingston, B Ghany, M Hoofnagle, JH Sette, A Rehermann, B TI Cellular immune responses to the hepatitis B virus polymerase decrease during longterm antiviral therapy. SO HEPATOLOGY LA English DT Meeting Abstract CT 54th Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease CY OCT 24-28, 2003 CL BOSTON, MASSACHUSETTS SP Amer Assoc Study Liver Diseases C1 NIH, Bethesda, MD 20892 USA. La Jolla Inst Allergy & Immunol, San Diego, CA USA. Epimmune Inc, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2003 VL 38 IS 4 SU 1 MA 1149 BP 709A EP 709A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730ER UT WOS:000185816701148 ER PT J AU Kino, T Charmandari, E Chrousos, GP AF Kino, T Charmandari, E Chrousos, GP TI Basic and clinical implications of glucocorticoid action - Focus on development - National Institutes of Health, Bethesda, Maryland, June 17-18, 2003 SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE glucocorticoids; glucocorticoid receptor; development; stress C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Charmandari, E (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9D42, Bethesda, MD 20892 USA. RI Charmandari, Evangelia/B-6701-2011 NR 0 TC 4 Z9 4 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD OCT PY 2003 VL 35 IS 10 BP 628 EP 648 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 743RM UT WOS:000186587400013 PM 14606000 ER PT J AU Konheim, YL Wolford, JK AF Konheim, YL Wolford, JK TI Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima Indians SO HUMAN GENETICS LA English DT Article ID INSULIN-SECRETION; ATHEROSCLEROSIS; INTERLEUKIN-6; INFLAMMATION; EXPRESSION; SYNTHASE-2; RISK; PART AB Recent studies have suggested that prostaglandin-endoperoxide synthase-2 (PTGS2), also known as cyclo-oxygenase 2, plays an etiological role in the development of type 2 diabetes mellitus (T2DM). PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response, which is associated with decreased insulin sensitivity. Moreover, the gene encoding this enzyme, PTGS2, is located on 1q25.2, a region that has been linked with early onset T2DM in Pima Indians. To determine the possible role played by PTGS2 in modulating susceptibility to T2DM, we screened approximately 7.0 kb of the gene, corresponding to the promoter, coding sequence, and flanking exon-intron boundaries, and identified five variants, including three single nucleotide polymorphisms (SNPs) in the promoter, one intronic SNP, and one in the 3' untranslated region. With the exception of one rare promoter SNP (minor allele frequency <0.03), all SNPs were typed in similar to1000 Pima Indians. The range of frequencies for the more common alleles was 0.65-0.88, and we found substantial linkage disequilibrium between all PTGS2 SNP pairs (D'greater than or equal to0.95). Variant alleles at two markers, rs20417 and rs2066826, which are located in the promoter and intron 6, respectively, were in strong linkage disequilibrium with each other (D'=0.97) and were associated with a higher prevalence of T2DM. For marker rs20417, individuals with the variant CC genotype had a 30% higher T2DM prevalence compared with subjects with the GG genotype (odds ratio=1.6 per copy of C allele; P=0.01). The variant C allele of rs20417 has been associated with decreased PTGS2 promoter activity, thereby suggesting a possible biological consequence attributable to this polymorphism. These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals. C1 Translat Genom Inst, Tempe, AZ 85281 USA. NIH, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), Translat Genom Inst, 1255 W Washington St, Tempe, AZ 85281 USA. NR 21 TC 47 Z9 48 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2003 VL 113 IS 5 BP 377 EP 381 DI 10.1007/s00439-003-1000-y PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 721YU UT WOS:000185346700002 PM 12920574 ER PT J AU Chiba-Falek, O Touchman, JW Nussbaum, RL AF Chiba-Falek, O Touchman, JW Nussbaum, RL TI Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene SO HUMAN GENETICS LA English DT Article ID SPORADIC PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; SEQUENCE-ANALYSIS; LEWY BODIES; POLYMORPHISM; MUTATION; NOMENCLATURE; ASSOCIATION; JAPAN AB NACP-Rep1, a polymorphic microsatellite upstream of the alpha-synuclein gene (SNCA), consisting of the nucleotides (TC)(x)(T)(2)(TC)(y)(TA)(z)(CA)(w), has five alleles originally defined by 2-bp differences in (CA)(w). Different NACP-Rep1 alleles have been associated with sporadic Parkinson's disease in some, but not all, studies and can effect expression driven by the SNCA promoter over a three-fold range in the neuroblastoma cell line, SH-SY5Y. By analyzing children in CEPH families in which parents appeared to be homozygous for a NACP-Rep1 allele, we found that there are sequence differences within same-sized NACP-Rep1 alleles, contributed mainly by variation of the (TC)(y)(TA)(z) portion of the microsatellite repeat. To test whether these sequence differences might impact on promoter function we determined the effect of two sequence variant alleles, both of size '1', using the luciferase reporter system. There was only a very small expression difference between these two variant alleles. This finding implies that the overall length of the NACP-Rep1 allele plays the main role in the transcription regulation by the NACP-Rep1 element and suggests that functional differences due to sequence heterogeneity within NACP-Rep1 alleles of the same length are probably not confounding factors in association studies based on alleles defined by length. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NIH, NIH Intramural Sequencing Ctr, Gaithersburg, MD 20877 USA. Arizona State Univ, Sch Life Sci, Tempe, AZ 85281 USA. RP Nussbaum, RL (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr MSC 4472, Bethesda, MD 20892 USA. NR 20 TC 57 Z9 59 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2003 VL 113 IS 5 BP 426 EP 431 DI 10.1007/s00439-003-1002-9 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 721YU UT WOS:000185346700008 PM 12923682 ER PT J AU Manolio, TA Barnes, KC Beaty, TH Levett, PN Naidu, RP Wilson, AF AF Manolio, TA Barnes, KC Beaty, TH Levett, PN Naidu, RP Wilson, AF TI Sex differences in heritability of sensitization to Blomia tropicalis in asthma using regression of offspring on midparent (ROMP) methods SO HUMAN GENETICS LA English DT Article ID TOTAL SERUM IGE; SKIN-TEST REACTIVITY; IMMUNOGLOBULIN-E; DERMATOPHAGOIDES-PTERONYSSINUS; ENVIRONMENTAL-FACTORS; MATERNAL INHERITANCE; FAMILIAL RESEMBLANCE; QUANTITATIVE TRAITS; FOUNDER POPULATION; WHITE INDIVIDUALS AB A genetic basis for asthma- and atopy-related quantitative traits, such as allergen-specific immunoglobulin E (IgE) levels, has been suggested by the observed familial aggregation of these traits in temperate climates. Less information is available for tropical climates, where different allergens may predominate. Sensitivity to the mite Blomia tropicalis is related to asthma in tropical climates, but heritability of B. tropicalis sensitivity and the impact of age, sex, and other environmental covariates on heritability have not been widely explored. Total and specific IgE levels were measured by immunochemiluminescent assay in 481 members of 29 Barbadian families (comprised of 340 parent-offspring trios or pairs) ascertained through two asthmatic siblings. Trait heritability was estimated using regression of offspring on mid-parent (ROMP) and pairwise correlation analysis of unadjusted IgE levels and on residual values after adjustment for covariates. Heritability of IgE levels to the major antigen of B. tropicalis (Blo t M) estimated by ROMP in 180 complete parent-offspring trios was 0.56. Heritability was consistently greater for male offspring than for female offspring. Similar sex-specific patterns were observed for specific IgE to Dermatophagoides pteronyssinus and total IgE levels and were relatively unaffected by adjustment for covariates. Pairwise correlational analyses of specific and total IgE levels showed similar results. Moderate heritability of Blo t M IgE levels was detected in these Barbadian families and was greater for sons than daughters. Adjustment for covariates had minimal impact. This suggests that future investigations of genetic determinants of IgE levels should include approaches that allow for potential sex differences in their expression. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Ctr Dis Control & Prevent, Div Bacterial & Mycot Dis, Atlanta, GA USA. Univ W Indies, Sch Clin Med & Res, Bridgetown, Barbados. NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Rm 8160, Bethesda, MD 20892 USA. RI Wilson, Alexander/C-2320-2009 FU NCRR NIH HHS [1 P41 RR03655]; NIAID NIH HHS [1 R01 AI20059] NR 64 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2003 VL 113 IS 5 BP 437 EP 446 DI 10.1007/s00439-003-1005-6 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 721YU UT WOS:000185346700010 PM 12928863 ER PT J AU Kanaan, Y Kpenu, E Utley, K Adams-Campbell, L Dunston, GM Brody, LC Broome, C AF Kanaan, Y Kpenu, E Utley, K Adams-Campbell, L Dunston, GM Brody, LC Broome, C TI Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases SO HUMAN GENETICS LA English DT Article ID GERMLINE MUTATIONS; INDIVIDUALS; PENETRANCE; POPULATION; RISK; GENE; REARRANGEMENTS; PREVALENCE; ASHKENAZI; FREQUENCY AB In order to identify the spectrum of BRCA2 mutations in African Americans, breast or ovarian cancer patients from 74 independent families at elevated risk of germline mutations were investigated. The entire coding regions and flanking introns of BRCA2 were screened for germline mutations by single-stranded conformation polymorphism, protein truncation test, or denaturing high performance liquid chromatography followed by DNA sequencing. Eight distinct protein-truncating mutations were detected in six female patients (average age of onset of breast cancer: 37.6 years) and two male patients, but not in 163 unrelated disease-free controls. Two (1993delAA, 8643delAT) of the eight pathogenic mutations observed in African Americans have not been previously described. The other six pathogenic mutations (1882delT, 1991delATAA, 2001delTTAT, 2816insA, 4075delGT, 4088delA) have been detected in Caucasians; only the 2816insA mutation has been reported previously in African Americans. There were no significant differences in the frequency of deleterious BRCA2 mutations in African Americans compared with Caucasians. Six rare variations, not previously reported, were identified in five breast cancer patients but not in 163 disease-free control subjects. Of 11 different polymorphisms identified in high-risk African-American breast cancer patients, four may be unique to African Americans. An intron 10 polymorphism observed in patients was not detected in 163 disease-free African-American control subjects; this difference is statistically significant. Since many different pathogenic mutations and variants of unknown significance are observed in African Americans, BRCA2 genetic testing in high-risk African-American families must include the entire coding and flanking non-coding regions of the gene. C1 Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. Howard Univ, Ctr Canc, Washington, DC 20059 USA. Howard Univ, Coll Med, Natl Human Genome Ctr, Dept Microbiol, Washington, DC 20059 USA. NHGRI, Bethesda, MD 20892 USA. RP Broome, C (reprint author), Howard Univ, Coll Med, Dept Biochem & Mol Biol, 520 W St NW, Washington, DC 20059 USA. FU NCI NIH HHS [R01 CA557720]; NCRR NIH HHS [G12 RR03048] NR 38 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2003 VL 113 IS 5 BP 452 EP 460 DI 10.1007/s00439-003-0999-0 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 721YU UT WOS:000185346700012 PM 12942367 ER PT J AU Chen, LY Shieh, JJ Lin, BC Pan, CJ Gao, JL Murphy, PM Roe, TF Moses, S Ward, JM Lee, EJ Westphal, H Mansfield, BC Chou, JY AF Chen, LY Shieh, JJ Lin, BC Pan, CJ Gao, JL Murphy, PM Roe, TF Moses, S Ward, JM Lee, EJ Westphal, H Mansfield, BC Chou, JY TI Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter SO HUMAN MOLECULAR GENETICS LA English DT Article ID DISEASE TYPE 1B; COLONY-STIMULATING FACTOR; INFLAMMATORY-BOWEL-DISEASE; GLYCOGEN; GENE; IB; RECEPTOR; MOUSE; EXPRESSION; PROTEIN AB Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT(-/-)) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT(-/-) neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT(-/-) ascites during an inflammatory response. The bone and spleen of G6PT(-/-) mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients. C1 NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Dept Pediat, Los Angeles, CA 90027 USA. Ben Gurion Univ Negev, Div Pediat, IL-84105 Beer Sheva, Israel. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Sci, Frederick, MD 21702 USA. RP Chou, JY (reprint author), NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. RI Lin, Baochuan/A-8390-2009; OI Lin, Baochuan/0000-0002-9484-0785; Mansfield, Brian/0000-0002-8533-2789 NR 47 TC 56 Z9 59 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2003 VL 12 IS 19 BP 2547 EP 2558 DI 10.1093/hmg/ddg263 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 723JT UT WOS:000185429800014 PM 12925567 ER PT J AU Dean, M AF Dean, M TI Approaches to identify genes for complex human diseases: Lessons from Mendelian disorders SO HUMAN MUTATION LA English DT Review DE complex disease; genotype-phenotype; Mendelian; non-Mendelian; mutation analysis ID ADMIXTURE LINKAGE DISEQUILIBRIUM; RECESSIVE RETINITIS-PIGMENTOSA; DOPAMINE-D2 RECEPTOR GENE; EPSTEIN-BARR-VIRUS; CYSTIC-FIBROSIS; CHLAMYDIA-PNEUMONIAE; DIABETES-MELLITUS; STARGARDT-DISEASE; TRANSPORTER GENE; HUMAN GENOME AB The focus of most molecular genetics research is the identification of genes involved in human disease. In the 20th century, genetics progressed from the rediscovery of Mendel's Laws to the identification of nearly every Mendelian genetic disease. At this pace, the genetic component of all complex human diseases could be identified by the end of the 21st century, and rational therapies could be developed. However, it is clear that no one approach will identify the genes for all diseases with a genetic component, because multiple mechanisms are involved in altering human phenotypes, including common alleles with small to moderate effects, rare alleles with moderate to large effects, complex gene-gene and gene-environment interactions, genomic alterations, and noninherited genetic effects. The knowledge gained from the study of Mendelian diseases may be applied to future research that combines linkage-based, association-based, and sequence,based approaches to detect most disease alleles. The technology to complete these studies is at hand and requires that modest improvements be applied on a wide scale. Improved analytical tools, phenotypic characterizations, and functional analyses will enable complete understanding of the genetic basis of complex diseases. Published 2003 Wiley-Liss, Inc. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP Dean, M (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 91 TC 47 Z9 50 U1 3 U2 12 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD OCT PY 2003 VL 22 IS 4 BP 261 EP 274 DI 10.1002/humu.10259 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 726EH UT WOS:000185585200001 PM 12955713 ER PT J AU Kannel, WB Vasan, RS Levy, D AF Kannel, WB Vasan, RS Levy, D TI Is the relation of systolic blood pressure to risk of cardiovascular disease continuous and graded, or are there critical values? SO HYPERTENSION LA English DT Review ID CORONARY HEART-DISEASE; FRAMINGHAM; MORTALITY; IMPACT; STROKE; AGE C1 NHLBI, Framingham Study, Boston, MA USA. Boston Univ, Dept Prevent Med, Boston, MA 02215 USA. RP Kannel, WB (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM billkannel@yahoo.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-25195] NR 20 TC 54 Z9 58 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2003 VL 42 IS 4 BP 453 EP 456 DI 10.1161/01.HYP.0000093382.69464.C4 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 727UJ UT WOS:000185679000004 PM 12975387 ER PT J AU Obarzanek, E Proschan, MA Vollmer, WM Moore, TJ Sacks, FM Appel, LJ Svetkey, LP Most-Windhauser, MM Cutler, JA AF Obarzanek, E Proschan, MA Vollmer, WM Moore, TJ Sacks, FM Appel, LJ Svetkey, LP Most-Windhauser, MM Cutler, JA TI Individual blood pressure responses to changes in salt intake - Results from the DASH-Sodium trial SO HYPERTENSION LA English DT Article DE blood pressure; systole; sodium, dietary; blood pressure determination ID ESSENTIAL-HYPERTENSION; DIETARY-SODIUM; NORMOTENSIVE SUBJECTS; OBSERVATIONAL DATA; SENSITIVITY; RESTRICTION; REPRODUCIBILITY; POPULATIONS; ASSOCIATION; RESISTANCE AB Although group characteristics are known to influence average blood pressure response to changes in salt intake, predictability of individual responses is less clear. We examined variability and consistency of individual systolic blood pressure responses to changes in salt intake in 188 participants who ate the same diet at higher, medium, and lower ( 140, 104, 62 mmol/d) sodium levels for 30 days each, in random order, after 2 weeks of run-in at the higher sodium level. Regarding variability in systolic blood pressure changes over time, changes from run-in to higher sodium ( no sodium level change) ranged from -24 to -25 mm Hg; 8.0% of participants decreased greater than or equal to10 mm Hg. Regarding variability in systolic blood pressure response to change in sodium intake, with higher versus lower sodium levels (78-mmol sodium difference), the range of systolic blood pressure change was -32 to +17 mm Hg; 33.5% decreased greater than or equal to10 mm Hg. Regarding consistency of response, systolic blood pressure change with run-in versus lower sodium was modestly correlated with systolic blood pressure change with higher versus medium sodium; systolic blood pressure change with higher versus lower sodium was similarly correlated with run-in versus medium sodium (combined Spearman r = 0.27, P = 0.002). These results show low-order consistency of response and confirm that identifying individuals as sodium responders is difficult. They support current recommendations for lower salt intake directed at the general public rather than "susceptible" individuals as one of several strategies to prevent and control adverse blood pressures widely prevalent in the adult population. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Boston Univ, Med Ctr, Off Clin Res, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA USA. Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. Duke Univ, Med Ctr, Duke Hypertens Ctr, Durham, NC USA. Duke Univ, Med Ctr, Sarah W Stedman Ctr Nutr Studies, Durham, NC USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Obarzanek, E (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8136,MSC 7936, Bethesda, MD 20892 USA. EM obarzane@nhlbi.nih.gov FU NCRR NIH HHS [RR02635, RR00722]; NHLBI NIH HHS [U01-HL57114, U01-HL57190, U01-HL57156, U01-HL57139, K08-HL03857, U01-HL57173] NR 33 TC 101 Z9 107 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2003 VL 42 IS 4 BP 459 EP 467 DI 10.1161/01.HYP.0000091267.39066.72 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 727UJ UT WOS:000185679000006 PM 12953018 ER PT J AU Zhao, XY Pollock, DM Zeldin, DC Imig, JD AF Zhao, XY Pollock, DM Zeldin, DC Imig, JD TI Salt-sensitive hypertension after exposure to angiotensin is associated with inability to upregulate renal epoxygenases SO HYPERTENSION LA English DT Article; Proceedings Paper CT 15th Scientific Meeting of the Inter-American-Society-of-Hypertension (IASH) CY APR 27-30, 2003 CL SAN ANTONIO, TEXAS SP Inter-Amer Soc Hypertens (IASH) DE endothelium-derived factors; hypertension, sodium-dependent; angiotensin II; kidney; vessels ID ARACHIDONIC-ACID EPOXYGENASE; EPOXYEICOSATRIENOIC ACIDS; 11,12-EPOXYEICOSATRIENOIC ACID; HYPERPOLARIZING FACTORS; EXTRAHEPATIC TISSUES; CYTOCHROME P4502C; METABOLISM; KIDNEY; RAT; IDENTIFICATION AB The current study was designed to determine whether angiotensin II infusion could lead to persistent salt-sensitive hypertension and to examine involvement of renal microvascular epoxygenases in this process. Six groups were studied: rats maintained on a normal salt diet for 4 weeks (NS); rats maintained on a high salt diet for 4 weeks (HS); and all other animals receiving angiotensin II (ANG) infusion and being fed a normal or high salt diet for 2 weeks; then the angiotensin II infusion was stopped and diets were either maintained or switched (ANG/NS-NS, ANG/NS-HS, ANG/HS-HS, ANG/HS-NS). Angiotensin II infusion resulted in a rise in blood pressure and an increase in urinary albumin excretion over the 2-week period. After angiotensin II withdrawal, blood pressure returned to normal in animals receiving a normal salt diet from weeks 2 to 4 (ANG/NS-NS and ANG/HS-NS groups). In contrast, blood pressure remained elevated in the group maintained on a high salt diet throughout the entire 4-week period (ANG/HS-HS group). Renal microvascular CYP2C11 and CYP2C23 protein levels were decreased by 50% to 60% in the ANG/HS-HS group compared with the NS group. Likewise, renal microvascular CYP2J protein was significantly decreased in the ANG/HS-HS group versus the NS group. Renal microvascular CYP2C11 and CYP2C23 mRNA levels were reduced in the ANG/HS-HS group compared with both the NS and HS groups. These results support the hypothesis that angiotensin II infusion induces persistent salt-sensitive hypertension after withdrawal of angiotensin II that may be due to downregulation of CYP2C and CYP2J epoxygenases in renal microvessels. C1 Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA. Med Coll Georgia, Dept Physiol, Augusta, GA 30912 USA. Med Coll Georgia, Dept Surg, Augusta, GA 30912 USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Imig, JD (reprint author), Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA. OI Imig, John/0000-0002-9668-2899 FU NHLBI NIH HHS [HL-64776, HL-59699]; NIDDK NIH HHS [DK-38226] NR 30 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2003 VL 42 IS 4 BP 775 EP 780 DI 10.1161/01.HYP.0000085649.28268.DF PN 2 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 730KC UT WOS:000185829100021 PM 12900436 ER PT J AU Zhao, XY Pollock, DM Zeldin, DC Imig, JD AF Zhao, XY Pollock, DM Zeldin, DC Imig, JD TI Salt-sensitive hypertension after exposure to angiotensin is associated with inability to upregulate renal epoxygenases SO HYPERTENSION LA English DT Article; Proceedings Paper CT 15th Scientific Meeting of the Inter-American-Society-of-Hypertension (IASH) CY APR 27-30, 2003 CL SAN ANTONIO, TEXAS SP Inter-Amer Soc Hypertens (IASH) DE endothelium-derived factors; hypertension, sodium-dependent; angiotensin II; kidney; vessels ID ARACHIDONIC-ACID EPOXYGENASE; EPOXYEICOSATRIENOIC ACIDS; 11,12-EPOXYEICOSATRIENOIC ACID; HYPERPOLARIZING FACTORS; EXTRAHEPATIC TISSUES; CYTOCHROME P4502C; METABOLISM; KIDNEY; RAT; IDENTIFICATION AB The current study was designed to determine whether angiotensin II infusion could lead to persistent salt-sensitive hypertension and to examine involvement of renal microvascular epoxygenases in this process. Six groups were studied: rats maintained on a normal salt diet for 4 weeks (NS); rats maintained on a high salt diet for 4 weeks (HS); and all other animals receiving angiotensin II (ANG) infusion and being fed a normal or high salt diet for 2 weeks; then the angiotensin II infusion was stopped and diets were either maintained or switched (ANG/NS-NS, ANG/NS-HS, ANG/HS-HS, ANG/HS-NS). Angiotensin II infusion resulted in a rise in blood pressure and an increase in urinary albumin excretion over the 2-week period. After angiotensin II withdrawal, blood pressure returned to normal in animals receiving a normal salt diet from weeks 2 to 4 (ANG/NS-NS and ANG/HS-NS groups). In contrast, blood pressure remained elevated in the group maintained on a high salt diet throughout the entire 4-week period (ANG/HS-HS group). Renal microvascular CYP2C11 and CYP2C23 protein levels were decreased by 50% to 60% in the ANG/HS-HS group compared with the NS group. Likewise, renal microvascular CYP2J protein was significantly decreased in the ANG/HS-HS group versus the NS group. Renal microvascular CYP2C11 and CYP2C23 mRNA levels were reduced in the ANG/HS-HS group compared with both the NS and HS groups. These results support the hypothesis that angiotensin II infusion induces persistent salt-sensitive hypertension after withdrawal of angiotensin II that may be due to downregulation of CYP2C and CYP2J epoxygenases in renal microvessels. C1 Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA. Med Coll Georgia, Dept Physiol, Augusta, GA 30912 USA. Med Coll Georgia, Dept Surg, Augusta, GA 30912 USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Imig, JD (reprint author), Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA. OI Imig, John/0000-0002-9668-2899 FU NHLBI NIH HHS [HL-64776, HL-59699]; NIDDK NIH HHS [DK-38226] NR 30 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2003 VL 42 IS 4 BP 775 EP 780 DI 10.1161/01.HYP.000008549.28268.DF PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 727UJ UT WOS:000185679000184 PM 12900436 ER PT J AU Seidel, J Vaquero, JJ Green, MV AF Seidel, J Vaquero, JJ Green, MV TI Resolution uniformity and sensitivity of the NIH ATLAS small animal PET scanner: Comparison to simulated LSO scanners without depth-of-interaction capability SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article DE depth-of-interaction; phoswich detectors; positron emission tomography (PET); small animal PET ID DETECTOR MODULE AB Positron emission tomography (PET) scanners designed to image animals the size of rats and mice should possess simultaneously high and uniform spatial resolution and high sensitivity. ATLAS (Advanced Technology Laboratory Animal Scanner), a 6.0 cm diameter effective transverse field-of-view (FOV), 2 cm axial FOV ring-type research scanner seeks these goals by surrounding the animal with eighteen 15 mm deep, LGSO (7 mm)/GSO (8 mm) phoswich detector modules. A Monte Carlo simulation was used to compare the variation of resolution across the FOV and the absolute central point source sensitivity (ACS) of ATLAS to similar systems comprised only of LSO arrays of different depths with no depth-of-interaction (DOI) capability. For ATLAS radial spatial resolution deteriorated by 27% from the center to 3 cm off-axis. Scanners comprised of 15 mm deep, 10 mm deep and 7 mm deep LSO crystals deteriorated by 100%, 51%, and 20%, respectively, over the same distance. Simulated ACS (absorbed energies greater than or equal to250 keV) for ATLAS was 2.0% and for the 15 nun, 10 mm deep and 7 mm deep LSO scanners 2.4%, 1.5%, and 0.9%, respectively. Radial resolution loss 3 cm off-axis and ACS measured for the actual ATLAS scanner were similar to the values obtained by simulation (27% resolution loss, 1.8% ACS). The phoswich design thus achieves good resolution uniformity over a 6 cm FOV while preserving sensitivity compared to equivalent non-DOI LSO scanners with a range of crystal depths. C1 NIH, Bethesda, MD 20892 USA. RP Seidel, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 9 TC 107 Z9 109 U1 1 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD OCT PY 2003 VL 50 IS 5 BP 1347 EP 1350 DI 10.1109/TNS.2003.817282 PN 2 PG 4 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 732CA UT WOS:000185922200005 ER PT J AU Waldmann, TA AF Waldmann, TA TI A novel means of favorably tipping the balance between cytopathic and regulatory T cells SO IMMUNITY LA English DT Editorial Material ID IL-2 RECEPTOR; ANTIBODIES; CYTOKINES; DISEASES C1 NCI, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 9 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2003 VL 19 IS 4 BP 465 EP 466 DI 10.1016/S1074-7613(03)00273-5 PG 2 WC Immunology SC Immunology GA 734JK UT WOS:000186051900002 PM 14563310 ER PT J AU Buslepp, J Wang, HC Biddison, WE Appella, E Collins, EJ AF Buslepp, J Wang, HC Biddison, WE Appella, E Collins, EJ TI A correlation between TCR V alpha docking on MHC and CD8 dependence: Implications for T cell selection SO IMMUNITY LA English DT Article ID STRUCTURAL BASIS; CRYSTAL-STRUCTURE; HIGH-AFFINITY; RECEPTOR RECOGNITION; CYTOPLASMIC DOMAINS; CORECEPTOR FUNCTION; MAXIMUM-LIKELIHOOD; CLASS-II; COMPLEX; PEPTIDE AB T cell receptors (TCR) adopt a similar orientation when binding with major histocompatibility complex (MHC) molecules, yet the biological mechanism that generates this similar TCR orientation remains obscure. We show here the cocrystallographic structure of a mouse TCR bound to a human MHC molecule not seen by the TCR during thymic development. The orientation of this xenoreactive murine TCR atop human MHC deviates from the typical orientation more than any previously determined TCR/MHC structure. This unique orientation is solely due to the placement of the TCR Valpha domain on the MHC. In light of new information provided by this structure, we have reanalyzed the existing TCR/MHC cocrystal structures and discovered unique features of TCR Valpha domain position on class I MHC that correlate with CD8 dependence. Finally, we propose that the orientation seen in TCR recognition of MHC is a consequence of selection during T cell development. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Collins, EJ (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NR 69 TC 79 Z9 80 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2003 VL 19 IS 4 BP 595 EP 606 DI 10.1016/S1074-7613(03)00269-3 PG 12 WC Immunology SC Immunology GA 734JK UT WOS:000186051900015 PM 14563323 ER PT J AU Tumanov, AV Grivennikov, SI Shakhov, AN Rybtsov, SA Koroleva, EP Takeda, J Nedospasov, SA Kuprash, DV AF Tumanov, AV Grivennikov, SI Shakhov, AN Rybtsov, SA Koroleva, EP Takeda, J Nedospasov, SA Kuprash, DV TI Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting SO IMMUNOLOGICAL REVIEWS LA English DT Review ID TUMOR-NECROSIS-FACTOR; PEYERS PATCH ORGANOGENESIS; DENDRITIC CELL NETWORKS; FOLLICULAR STROMAL CELLS; CXC CHEMOKINE RECEPTOR-5; BETA-DEFICIENT MICE; T-CELL; B-CELL; GERMINAL-CENTERS; SPLENIC ARCHITECTURE AB Mice with inactivation of lymphotoxin beta receptor (LTbetaR) system have profound defects in the development and maintenance of peripheral lymphoid organs. As surface LT is expressed by lymphocytes, natural killer cells, and lymphoid tissue-initiating cells as well as by some other cell types, we dissected cell type-specific LT contribution into the complex LT-deficient phenotype by conditional gene targeting. B-LTbeta knockout (KO) mice displayed an intermediate phenotype in spleen as compared with mice with complete LTbeta deficiency. In contrast, T-LTbeta KO mice displayed normal structure of the spleen. However, inactivation of LTb in both T and B cells resulted in additional defects in the structure of the marginal zone and in the development of follicular dendritic cells in spleen. Structure of lymph nodes (LN) and Peyer's patches (PP) was normal in both B-LTbeta KO and T- and B-LTbeta KO mice, except that PPs were of reduced size. When compared across the panel of lymphocyte-specific LT KOs, the defects in antibody responses to T-cell-dependent antigens correlated with the severity of defects in spleen structure. Expression of CCL21 and CCL19 chemokines was not affected in spleen, LN and PP of B-LTbeta KO and T- and B-LTbeta KO mice, while CXCL13 was slightly reduced only in spleen. Collectively, our data suggest the following: (i) requirements for LT signaling to support architecture of spleen, LN and PP are different; (ii) LT complex expressed by B cells plays a major role in the maintenance of spleen structure, while surface LT expressed by T cells provides a complementary but distinct signal; and (iii) in a non-transgenic model, expression of lymphoid tissue chemokines is only minimally dependent on the expression of surface LT complex on B and T lymphocytes. C1 NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. Osaka Univ, Osaka, Japan. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Mol Immunol, Moscow, Russia. RP Tumanov, AV (reprint author), NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 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; FU PHS HHS [N01-C0-12400] NR 64 TC 75 Z9 76 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2003 VL 195 BP 106 EP 116 DI 10.1034/j.1600-065X.2003.00071.x PG 11 WC Immunology SC Immunology GA 720RU UT WOS:000185274400009 PM 12969314 ER PT J AU Pandeya, SN Sowmyalakshmi, V Panda, SS Pandeya, A Stables, JP AF Pandeya, SN Sowmyalakshmi, V Panda, SS Pandeya, A Stables, JP TI Anticonvulsant activity of semicarbazone derivatives of Mannich bases SO INDIAN JOURNAL OF CHEMISTRY SECTION B-ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY LA English DT Article ID KETONES AB A series of semicarbazones of semicarbazide/p-chlorophenyl semicarbazide and Mannich bases of acetophenone/p-chloroacetophenone has been synthesized and their anticonvulsant activity screened against MES and scPTZ test. p-Chlorophenyl- semicarbazone of N,N-dimethylaminopropiophenone has been found to be the most active in all these tests. C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. Banaras Hindu Univ, Dept Chem, Varanasi 221005, Uttar Pradesh, India. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Pandeya, SN (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NR 15 TC 4 Z9 4 U1 0 U2 5 PU NATL INST SCIENCE COMMUNICATION PI NEW DELHI PA DR K S KRISHNAN MARG, NEW DELHI 110 012, INDIA SN 0376-4699 J9 INDIAN J CHEM B JI Indian J. Chem. Sect B-Org. Chem. Incl. Med. Chem. PD OCT PY 2003 VL 42 IS 10 BP 2657 EP 2661 PG 5 WC Chemistry, Organic SC Chemistry GA 735VP UT WOS:000186135500026 ER PT J AU Lei, BF Liu, MY Prater, CI Kala, SV DeLeo, FR Musser, JM AF Lei, BF Liu, MY Prater, CI Kala, SV DeLeo, FR Musser, JM TI Identification and characterization of HtsA, a second heme-binding protein made by Streptococcus pyogenes SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCUS; CELL-SURFACE PROTEIN; ESCHERICHIA-COLI; GENOME SEQUENCE; IRON ACQUISITION; TRANSPORT; EXPRESSION; HEMOGLOBIN; ENVELOPE; MEMBRANE AB Group A streptococci (GAS) can use heme and hemoproteins as sources of iron. However, the machinery for heme acquisition in GAS has not been firmly revealed. Recently, we identified a novel heme-associated cell surface protein (Shp) made by GAS. The shp gene is cotranscribed with eight downstream genes, including spy1795, spy1794, and spy1793 encoding a putative ABC transporter (designated HtsABC). In this study, spy1795 (designated htsA) was cloned from a serotype M1 strain, and recombinant HtsA was overexpressed in Escherichia coli and purified to homogeneity. HtsA binds I heme molecule per molecule of protein. HtsA was produced in vitro and localized to the bacterial cell surface. GAS up-regulated transcription of htsA in human blood compared with that in Todd-Hewitt broth supplemented with 0.2% yeast extract. The level of the htsA transcript dramatically increased under metal cation-restricted conditions compared with that under metal cation-replete conditions. The cation content, cell surface location, and gene transcription of HtsA were also compared with those of MtsA and Spy0385, the lipoprotein components of two other putative iron acquisition ABC transporters of GAS. Our results suggest that HtsABC is an ABC transporter that may participate in heme acquisition in GAS. C1 Montana State Univ, Bozeman, MT 59717 USA. NIAID, Lab Human Bacteriol Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Lei, BF (reprint author), Montana State Univ, POB 173610, Bozeman, MT 59717 USA. OI DeLeo, Frank/0000-0003-3150-2516 NR 33 TC 57 Z9 57 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2003 VL 71 IS 10 BP 5962 EP 5969 DI 10.1128/IAI.71.10.5962-5969.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 725PH UT WOS:000185551200056 PM 14500516 ER PT J AU Karrow, NA Guo, TL Zhang, LX McCay, JA Musgrove, DL Peachee, VL Germolec, DR White, KL AF Karrow, NA Guo, TL Zhang, LX McCay, JA Musgrove, DL Peachee, VL Germolec, DR White, KL TI Thalidomide modulation of the immune response in female B6C3F1 mice: a host resistance study SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE thalidomide; B6C3F1 mice; host resistance ID LISTERIA-MONOCYTOGENES INFECTION; LOW-DOSE THALIDOMIDE; POLYMORPHONUCLEAR LEUKOCYTES; CELL; NEUTROPHILS; CHEMOTAXIS; INHIBITORS; ACTIVATION; MONOCYTES; TUMORS AB Previously, we have reported that thalidomide (Thd) treatment can modulate the immune responses in female B6C3F1 mice. The present study was designed to evaluate whether or not these immunomodulatory responses were of sufficient magnitude to alter host resistances in a number of pathogen and tumor models. B6C3F1 mice were treated intraperitoneally with Thd (30150 mg/kg) for 14 or 28 days, then inoculated with either Plasmodium yeolii, PYB6 fibrosarcoma tumor cells, B16F10 melanoma tumor cells, Listeria monocytogenes, or Streptococcus pneumoniae. Significant dose-dependent protection against B16F10 and L. monocytogenes was observed in mice that were treated with Thd. Furthermore, time course study using bacterial colony-forming units per spleen and liver as the endpoints indicated that the protective effect of Thd on host resistance to L. monocytogenes was time-dependent. In contrast, Thd treatment did not affect host resistance to R yeolii, S. pneumoniae and PYB6 tumor. Additionally, the effect of Thd on the phagocytic function of the mononuclear phagocyte system (MPS) was evaluated following intravenous injection of Cr-51-labeled sRBCs. The overall phagocytic activity of MPS was not significantly altered by Thd treatment. In conclusion, these results demonstrate that Thd immunomodulation altered host resistance to B16F10 and L. monocytogenes; and selective modulation of Thd on the immune system may be responsible for the pathogen or tumor-specific effect of this compound. (C) 2003 Elsevier B.V. All rights reserved. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Guo, TL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, POB 980613, Richmond, VA 23298 USA. FU NIEHS NIH HHS [ES 55387] NR 42 TC 10 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD OCT PY 2003 VL 3 IS 10-11 BP 1447 EP 1456 DI 10.1016/S1567-5769(03)00143-7 PG 10 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 723HE UT WOS:000185426300010 PM 12946441 ER PT J AU Boccardo, F Ciatto, S Martorana, G AF Boccardo, F Ciatto, S Martorana, G TI Italian National Consensus Conference on Prostate Cancer Screening (Florence, May 17, 2003) - Final consensus document SO INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS LA English DT Editorial Material ID MORTALITY; TRIAL; OVERDIAGNOSIS; CARCINOMA C1 Ctr Studio & Prevenz Oncol, Dept Diagnost Imaging, I-50131 Florence, Italy. Natl Canc Inst, Dept Med Oncol, Genoa, Italy. Univ Bologna, Dept Urol, Bologna, Italy. RP Ciatto, S (reprint author), Ctr Studio & Prevenz Oncol, Dept Diagnost Imaging, Viale A Volta 171, I-50131 Florence, Italy. NR 18 TC 7 Z9 7 U1 0 U2 0 PU WICHTIG EDITORE PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 0393-6155 J9 INT J BIOL MARKER JI Int. J. Biol. Markers PD OCT-DEC PY 2003 VL 18 IS 4 BP 238 EP 240 PG 3 WC Biotechnology & Applied Microbiology; Oncology SC Biotechnology & Applied Microbiology; Oncology GA 762KV UT WOS:000187971600002 PM 14756540 ER PT J AU Kohn, EC Mills, GB Liotta, L AF Kohn, EC Mills, GB Liotta, L TI Promising directions for the diagnosis and management of gynecological cancers SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article ID EPITHELIAL OVARIAN-CANCER; CLINICAL PROTEOMICS; SERUM; IDENTIFICATION; BIOMARKERS; MICROARRAYS; EXPRESSION; CARCINOMA; DIFFERENTIATION; BIOINFORMATICS AB Diagnosis and management of cancer requires tools with both high sensitivity and specificity. The minimally invasive cervical smear has demonstrated how a test, even one with low specificity, can change the public health profile of a cancer from a late stage deadly disease to,early diagnosis with rare tumor-related deaths. The benefit of such a test is best demonstrated by the low frequency of cervix cancer and its good outcome in countries where this test is readily available and used with appropriate secondary follow up. Early and specific symptoms, and identification and prevention for high risk groups has had similar impact for endometrial cancer. Neither a robust test, nor reliable or specific early symptoms are available for ovarian cancer, making clinical and scientific advances in this area a critical world-wide need. Current approaches testing one protein or gene marker at a time will not address this crisis expeditiously. New sensitive, specific, accurate, and reliable technologies that can be implemented using high throughput mechanisms are needed at as low a cost as possible. Ideally, these technologies should be focused on readily available patient resources, such as blood or urine, or as in the case of cervix cancer, minimally invasive informative approaches such as cervical smears. Techniques that allow data mining from a large input database overcome the slow advances of one protein-one gene investigation, and further address the multi-faceted carcinogenesis process occurring even in germ line mutation-associated malignancy. Proteomics, the study of the cellular proteins and their activation states, has led the progress in biomarker development for ovarian and other cancers and is being applied to management assessment. Amenable to high throughput, internet interface, and representative of the proteome spectrum, proteomic technology is the newest and most promising direction for translational developments in gynecologic cancers. C1 NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Gynecol Malignancie Fac, Bethesda, MD USA. MD Anderson Canc Ctr, Div Med, Dept Mol Therapeut, Houston, TX USA. RP Kohn, EC (reprint author), NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. EM ek1b@nih.gov NR 46 TC 15 Z9 16 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD OCT PY 2003 VL 83 SU 1 BP 203 EP 209 DI 10.1016/S0020-7292(03)90122-6 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 742MQ UT WOS:000186521900014 PM 14763176 ER PT J AU Melnick, RL Brody, C DiGangi, J Huff, J AF Melnick, RL Brody, C DiGangi, J Huff, J TI The IARC evaluation of DEHP excludes key papers demonstrating carcinogenic effects SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Letter ID DI(2-ETHYLHEXYL)PHTHALATE; MONOGRAPHS; NEOPLASMS; RATS C1 NIEHS, Res Triangle Pk, NC 27709 USA. Hlth Care Without Harm, Washington, DC 20009 USA. RP Melnick, RL (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. NR 10 TC 13 Z9 13 U1 0 U2 0 PU ABEL PUBLICATION SERVICES PI BURLINGTON PA 1611 AQUINAS COURT, BURLINGTON, NC 27215 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD OCT-DEC PY 2003 VL 9 IS 4 BP 400 EP 402 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 817EY UT WOS:000221162000022 PM 15688552 ER PT J AU Huff, J AF Huff, J TI IARC and the DEHP quagmire SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Editorial Material ID DI(2-ETHYLHEXYL) PHTHALATE DEHP; NATIONAL TOXICOLOGY PROGRAM; ACYL COA OXIDASE; F344 RATS; CARCINOGENESIS BIOASSAYS; RAMAZZINI-FOUNDATION; B6C3F1 MICE; CHEMICALS; MONOGRAPHS; EXPOSURE C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 43 TC 7 Z9 7 U1 0 U2 0 PU ABEL PUBLICATION SERVICES PI BURLINGTON PA 1611 AQUINAS COURT, BURLINGTON, NC 27215 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD OCT-DEC PY 2003 VL 9 IS 4 BP 402 EP 404 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 817EY UT WOS:000221162000023 PM 14664499 ER PT J AU Igishi, T Mikami, M Murakami, K Matsumoto, S Shigeoka, Y Nakanishi, H Yasuda, K Gutkind, JS Hitsuda, Y Shimizu, E AF Igishi, T Mikami, M Murakami, K Matsumoto, S Shigeoka, Y Nakanishi, H Yasuda, K Gutkind, JS Hitsuda, Y Shimizu, E TI Enhancement of cisplatin-induced cytotoxicity by ROCK inhibitor through suppression of focal adhesion kinase-independent mechanism in lung carcinoma cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE ROCK inhibitor; cisplatin; cytotoxicity; focal adhesion kinase ID RHO-ASSOCIATED KINASE; BINDING PROTEIN-RHO; TRANSFORMATION; REORGANIZATION; CYTOSKELETON; METASTASIS; APOPTOSIS; INDUCTION; EFFECTOR; INVASION AB Intracellular signaling through Rho-associated coiled-coil forming kinase (ROCK) is a target of antimetastatic therapy and is proposed to be involved in carcinogenesis. Focal adhesion kinase (FAK) functions downstream of ROCK and participates in anti-apoptotic signaling. We hypothesized that a specific ROCK inhibitor, Y-27632, may exert a pro-apoptotic effect in combination with anticancer agents through the suppression of FAK. A549 lung carcinoma cells were treated with Y-27632 and cisplatin. The simultaneous combination did not exert any additional effect, whereas sequential treatment, in which cisplatin followed Y-27632, enhanced cytotoxicity in concentration- and time-dependent manner. Y-27632 did not suppress tyrosine phosphorylation of FAK in A549-FAK, the active form of FAK expressing A549 cells, as observed in parental cells. Nevertheless, the pretreatment of A549-FAK cells with Y-27632 still enhanced cisplatin-induced cytotoxicity. It was concluded that the ROCK inhibitor enhances cisplatin-induced cytotoxicity through FAK suppression-independent mechanism(s). These observations raise the possibility that the inhibition of the ROCK-mediated signal enhances the effect of anti-cancer agents in addition to its antimetastatic property. C1 Tottori Univ, Fac Med, Dept Internal Med 3, Yonago, Tottori 6838504, Japan. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Igishi, T (reprint author), Tottori Univ, Fac Med, Dept Internal Med 3, Yonago, Tottori 6838504, Japan. RI Gutkind, J. Silvio/A-1053-2009 NR 25 TC 11 Z9 13 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD OCT PY 2003 VL 23 IS 4 BP 1079 EP 1085 PG 7 WC Oncology SC Oncology GA 732QY UT WOS:000185958100025 PM 12963988 ER PT J AU Karimpour, S Gius, D AF Karimpour, S Gius, D TI Those in gene therapy should pay closer attention to lessons from hyperthermia - In response to Drs. van der Zee and Hulshof; And Drs. Dewhirst and Sneed SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter ID NF-KAPPA-B; RADIATION-INDUCED ACTIVATION; HEAT-SHOCK; INHIBITION; RADIOSENSITIZATION; KINASE; HELA C1 NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Karimpour, S (reprint author), NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2003 VL 57 IS 2 BP 599 EP 600 DI 10.1016/S0360-3016(03)00420-6 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 721KH UT WOS:000185315200041 ER PT J AU Gonzalez, OY Teeter, LD Thanh, BT Musser, JM Graviss, EA AF Gonzalez, OY Teeter, LD Thanh, BT Musser, JM Graviss, EA TI Extrathoracic tuberculosis lymphadenitis in adult HIV seronegative patients: a population-based analysis in Houston, Texas, USA SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE Mycobacterium tuberculosis; tuberculosis lymphadenitis; extra-pulmonary tuberculosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; LYMPH-NODE TUBERCULOSIS; EXTRAPULMONARY TUBERCULOSIS; UNITED-STATES; EPIDEMIOLOGY; EXPERIENCE; DIAGNOSIS; INFECTION; SURVIVAL; IMMUNITY AB OBJECTIVE: To evaluate the covariates associated with extrathoracic tuberculosis lymphadenitis (ETBL) among adult HIV-seronegative patients. METHODS: Enrollees were interviewed for TB risk assessment, their medical records were reviewed, and their Mycobacterium tuberculosis isolates underwent molecular characterization. Between 1 October 1995 and 30 September 1999, HIV-negative patients with ETBL were compared with other HIV-negative TB patients. RESULTS: We identified 73 ETBL cases (5%) out of a total of 1371 adult HIV-negative enrollees. Significant variables predicting ETBL in the univariate analysis included age <45 years, female sex, Asian ethnicity, foreign birth, BCG vaccination, and infection with a M. tuberculosis isolate identified in major genetic group 1. Further analysis by birth country revealed increased ETBL risk for persons from countries other than the Americas and with a TB incidence >25 per 100 000 per year. The multivariate model demonstrated increased risk for ETBL for patients of female sex (OR = 2.6, P < 0.01) and birth in Africa or South-east Asia (OR = 4.8; P = 0.03 and OR = 33.6; P = 0.01, respectively). CONCLUSIONS: In adult HIV-negative patients, ETBL occurs more frequently in females and in immigrants from countries other than the Americas; persons from India, South-east Asia and the Eastern Mediterranean exhibited the highest risk among these regions. C1 Baylor Coll Med, Div Infect Dis, Dept Internal Med, Houston, TX 77030 USA. Baylor Coll Med, Infect Dis Sect, Dept Pathol, Houston, TX 77030 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MN USA. RP Gonzalez, OY (reprint author), Baylor Coll Med, Div Infect Dis, Dept Internal Med, 1 Bayor Plaza 209 E, Houston, TX 77030 USA. FU NIAID NIH HHS [N01-AO-02738] NR 31 TC 8 Z9 11 U1 0 U2 1 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD OCT PY 2003 VL 7 IS 10 BP 987 EP 993 PG 7 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 727LE UT WOS:000185659100012 PM 14552570 ER PT J AU Wang, SJ Brechbiel, M Wiener, EC AF Wang, SJ Brechbiel, M Wiener, EC TI Characteristics of a new MRI contrast agent prepared from polypropyleneimine dendrimers, generation 2 SO INVESTIGATIVE RADIOLOGY LA English DT Article DE macromolecule; MRI contrast agent; dendrimer; gadolinium-DTPA; biodistribution ID BIODISTRIBUTION; DTPA; GADOPENTETATE; COMPLEXES; MICE; RATS AB Rationale and objectives: Dendrimer-based magnetic resonance imaging (MRI) contrast agents offer many advantages including high levels of amplification. The objective of this research was to test the adequacy and viability of a new family of dendrimers for use as MRI contrast agents in vitro and in vivo. Methods: Dendrimers based on 1,4-diaminobutane core polypropyleneimine (PPI) generation 2 and ammonia core polyamidoamine dendrimers had the free surface amines conjugated to a diethylenetriaminepentaacetic acid derivative followed by complex formation with gadolinium. Relaxivity measurements were made on an IBM Field Cycling Relaxometer. Biodistribution and pharmacokinetic studies were examined with the radiotracer Gd-153 in rats and a counting window of 95 to 105 keV. MRI images were conducted at 4.7 T. Results: The relaxivity of the PPI agent exceeded that of the corresponding generation polyamidoamine (PAMAM) agent. Uptake occurred in the liver, spleen, and kidney. Pharmacokinetic studies showed a biexponential decay with excretion half-lives of 3 hours and 33.6 days respectively. The agent increased the contrast enhancement, 1 hour after injection, of T1-weighted images by 52%. Conclusions: This PPI agent resulted in significant contrast signal enhancement. This family of agent may also provide a valuable contrast agent backbone. C1 Univ Illinois Urbana, Dept Nucl Plasma & Radiol Engn, Champaign, IL USA. Univ Illinois, Beckman Inst, Champaign, IL 61820 USA. Univ Illinois, Coll Med, Biomed Magnet Resonance Lab, Champaign, IL 61820 USA. Univ Illinois, Dept Mol & Integrat Physiol, Champaign, IL 61820 USA. Univ Illinois, Dept Med Informat Sci, Champaign, IL 61820 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wiener, EC (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, 5117 Ctr Ave,Room 2-26, Pittsburgh, PA 15213 USA. FU NCRR NIH HHS [5 P41 RR05964, IS10RR06243]; PHS HHS [1 R29 C61918] NR 20 TC 50 Z9 53 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD OCT PY 2003 VL 38 IS 10 BP 662 EP 668 DI 10.1097/01.rli.0000084887.47427.75 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 723JV UT WOS:000185430000007 PM 14501494 ER PT J AU Cauley, JA Robbins, J Chen, Z Cummings, SR Jackson, RD LaCroix, AZ LeBoff, M Lewis, CE McGowan, J Neuner, J Pettinger, M Stefanick, ML Wactawski-Wende, J Watts, NB AF Cauley, JA Robbins, J Chen, Z Cummings, SR Jackson, RD LaCroix, AZ LeBoff, M Lewis, CE McGowan, J Neuner, J Pettinger, M Stefanick, ML Wactawski-Wende, J Watts, NB CA Women's Hlth Initiative Investigat TI Effects of estrogen plus progestin on risk of fracture and bone mineral density - The Women's Health Initiative randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HORMONE REPLACEMENT THERAPY; VERTEBRAL FRACTURES; POSTMENOPAUSAL WOMEN; OLDER WOMEN; ESTROGEN/PROGESTIN REPLACEMENT; OSTEOPOROTIC FRACTURES; NONVERTEBRAL FRACTURES; ELDERLY WOMEN; HIP FRACTURE; PREVENTION AB Context In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants Randomized controlled trial (September 1993-July 2002) in which 16608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n=8506) or placebo (n = 8102). Main Outcome Measures All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1,23; 95% Cl, 1.04-1.46; highest tertile, HR, 1.03; 95% Cl, 0.88-1.24) (P for interaction =.54). Conclusions This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture. C1 Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif Davis, Sch Med, Dept Internal Med, Sacramento, CA 95817 USA. Univ Arizona, Mel & Enid Zuckerman Arizona Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ USA. Univ Calif San Francisco, Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. Ohio State Univ, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98104 USA. Brigham & Womens Hosp, Div Endocrine Hypertens, Boston, MA 02115 USA. Univ Alabama, Div Prevent Med, Birmingham, AL USA. NIAMSD, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Ctr Patient Care & Outcomes Res, Milwaukee, WI 53226 USA. Stanford Univ, Dept Med, Stanford Ctr Res Dis Prevent, Palo Alto, CA 94304 USA. SUNY Buffalo, Buffalo, NY 14260 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Cauley, JA (reprint author), Univ Pittsburgh, Dept Epidemiol, Crabtree Hall A524,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 36 TC 529 Z9 553 U1 2 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 1 PY 2003 VL 290 IS 13 BP 1729 EP 1738 DI 10.1001/jama.290.13.1729 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 726NQ UT WOS:000185606100022 PM 14519707 ER PT J AU Brooks, BP Dagenais, SL Nelson, CC Glynn, MW Caulder, MS Downs, CA Glover, TW AF Brooks, BP Dagenais, SL Nelson, CC Glynn, MW Caulder, MS Downs, CA Glover, TW TI Mutation of the FOXC2 gene in familial distichiasis SO JOURNAL OF AAPOS LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 05-10, 2002 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol ID LYMPHEDEMA-DISTICHIASIS; TRANSCRIPTION FACTOR; MFH-1 AB Objective. To examine the FOXC2 gene in a family with hereditary distichiasis. Background. Distichiasis, ie, a second row of eyelashes arising from the meibomian glands of the eyelids, can be inherited either alone (Online Mendelian Inheritance in Man [OMIM] no. 126300) or, more commonly, as part of the lymphedema-distichiasis (LD) syndrome (OMIM no. 153400). More than 45 families with mutations in the FOXC2 gene and LD have been described. Both lymphedema and distichiasis are highly penetrant. Distichiasis without lymphedema is not commonly seen. Methods. We examined three generations of a family (N = nine members) with hereditary distichiasis but without lymphedema or other features of LD syndrome. The FOXC2 gene was polymerase chain reaction-amplified from genomic DNA from all family members and examined for mutations. Results. Clinical examination showed distichiasis of all four lids in two affected family members across two generations. There were no other consistent ophthalmologic abnormalities in the family. A cytosine-to-adenine transversion was identified in DNA from affected study participants at nucleotide position 1076, which would be predicted to cause truncation of the protein at codon 359. This change was not observed in any of the nine unaffected family members participating. Conclusions. This finding suggests that hereditary distichiasis and LD may not be separate genetic disorders but different phenotypic expressions of the same underlying disorder. Ophthalmologists should be aware that LD may present as distichiasis alone and counsel and refer their patients appropriately. C1 Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Ophthalmol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Visual Sci, Ann Arbor, MI 48109 USA. NHGRI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NEI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Glover, TW (reprint author), Univ Michigan, Dept Human Genet, 4909 Buhl,Box 0618,1241 E Catherine St, Ann Arbor, MI 48109 USA. FU NHLBI NIH HHS [HL 71206] NR 22 TC 11 Z9 12 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD OCT PY 2003 VL 7 IS 5 BP 354 EP 357 DI 10.1016/S1091-8531(03)00144-7 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 732BZ UT WOS:000185922100011 PM 14566319 ER PT J AU Fergus, EL Miller, RB Luckenbaugh, DA Leverich, GS Findling, RL Speer, AM Post, RM AF Fergus, EL Miller, RB Luckenbaugh, DA Leverich, GS Findling, RL Speer, AM Post, RM TI Is there progression from irritability/dyscontrol to major depressive and manic symptoms? A retrospective community survey of parents of bipolar children SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE bipolar disorder; child; adolescent; early onset; development ID DEFICIT HYPERACTIVITY DISORDER; ADOLESCENT BIPOLARITY; ONSET; ADHD; PHENOMENOLOGY; COMORBIDITY; PHENOTYPE; CHILDHOOD; FEATURES; VALIDITY AB Background: Although previous studies have discussed age-related changes in the presentation of early onset bipolar illness, the developmental progression of early symptoms remains unclear. The current study sought to trace parents' retrospective report of yearly occurrence of symptoms in a sample of children with and without a diagnosis of bipolar disorder in the community. Methods: Parents retrospectively rated the occurrence of 37 activated and withdrawn symptoms causing dysfunction for each year of their child's life (mean age 12.6 +/- 6.9). Children were divided into three groups based on parent report of diagnosis by a Community clinician: bipolar (n=78); non-bipolar diagnosis (n=38); and well (no psychiatric diagnosis) (n=82). Principal components analysis was performed to understand the relationship among the symptom variables and their potential differences among the three groups as a function of age. Results: Four symptom components were derived and these began to distinguish children with bipolar disorder from the other groups at different ages. Component 11 (irritability/dyscontrol), which included temper tantrums, poor frustration tolerance, impulsivity, increased aggression, decreased attention span, hyperactivity and irritability, began to distinguish bipolar children from the others the earliest (i.e., from ages I to 6). The other components (I, III, and IV) which included symptoms more typical of adult depression (1), mania (111), and psychosis (IV), distinguished the children with a bipolar diagnosis from the others much later (between ages 7 and 12). Limitations: The data were derived from retrospective reports by parents of their children's symptoms on a yearly symptom check list instrument which has not been previously utilized. Parents' ratings were not validated by an outside rater. Moreover, the children were diagnosed in the community and a formal diagnostic interview was not given. Conclusions: By parental report, the cluster of symptoms in the irritability/dyscontrol component may characterize the earliest precursors to an illness eventually associated with more classic manic and depressive components that are diagnosed and treated as bipolar disorder in the community. These retrospective survey data suggesting a longitudinal evolution of symptom clusters in childhood bipolar-like illness identify a number of areas for prospective research and validation. (C) 2002 Elsevier B.V. All rights reserved. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. NR 32 TC 65 Z9 65 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT PY 2003 VL 77 IS 1 BP 71 EP 78 DI 10.1016/S0165-0327(02)00176-3 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 737FA UT WOS:000186218700008 PM 14550937 ER PT J AU Plaut, M Tinkle, SS AF Plaut, M Tinkle, SS TI Risks of smallpox vaccination: 200 Years after Jenner SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE vaccination; smallpox; atopic dermatitis; eczema; immunity ID ATOPIC-DERMATITIS; COMPLICATIONS C1 NIAID, Allerg Mech Sect, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat,NIH,DHHS, Bethesda, MD 20892 USA. RP Plaut, M (reprint author), NIAID, Allerg Mech Sect, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat,NIH,DHHS, 6610 Rockledge Dr,Room 3093,MSC 6601, Bethesda, MD 20892 USA. NR 20 TC 9 Z9 9 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2003 VL 112 IS 4 BP 683 EP 685 DI 10.1067/mai.2003.1776 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 730LA UT WOS:000185831200005 PM 14564344 ER PT J AU Hackett, CJ AF Hackett, CJ TI Innate immune activation as a broad-spectrum biodefense strategy: Prospects and research challenges SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE innate immune defense; adaptive immune system; vaccination; immunotherapeutic approaches ID TOLL-LIKE RECEPTOR-2; MANNOSE-BINDING LECTIN; ANTHRAX LETHAL FACTOR; VIRUS-INFECTED CELLS; NF-KAPPA-B; PATTERN-RECOGNITION; CUTTING EDGE; ANTIMICROBIAL PEPTIDES; MACROPHAGE ACTIVATION; ALVEOLAR MACROPHAGES AB Biodefense strategies require protection against a broad and largely unforeseen spectrum of pathogens-the forte of innate immune system defenses-that have evolved over millennia to function within moments of encountering either ancient or newly emerging pathogens. Although constitutive, the innate immune system is activated by the presence of microbes or their products, providing a rationale for a potential biodefense strategy. Both prophylactic and postexposure strategies involving innate immune stimulation have been shown to be plausible to prevent or ameliorate infections in animal models. Innate immune-activating compounds based on conserved microbial components recognized by toll-like molecules and other receptors could be synthesized and delivered like drugs by using an entirely different strategy from conventional vaccination. However, important theoretic and practical questions, emerge about developing and deploying innate immune protective strategies for biodefense. This rostrum discusses prospects and. problems in the overall approach itself. Important topics include microbe-specific issues about innate immune system effectiveness against highly virulent pathogens and general questions, such as whether innate immune responses will be safe and effective if used in a diverse human population of different age groups and with different genetic makeups. C1 NIAID, Mol & Struct Immunol Sect, Basic Immunol Branch, Div Allergy Immunol & Transplantat,NIH, Bethesda, MD 20892 USA. RP Hackett, CJ (reprint author), NIAID, Mol & Struct Immunol Sect, Basic Immunol Branch, Div Allergy Immunol & Transplantat,NIH, 6610 Rockledge Dr,Room 3009, Bethesda, MD 20892 USA. OI Hackett, Charles/0000-0003-4586-9669 NR 89 TC 40 Z9 43 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2003 VL 112 IS 4 BP 686 EP 694 DI 10.1067/mai.2003.1773 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 730LA UT WOS:000185831200006 PM 14564345 ER PT J AU Chulada, PC Arbes, SJ Zeldin, DC AF Chulada, PC Arbes, SJ Zeldin, DC TI Breast-feeding, passive smoking, and asthma and wheeze in children - Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter C1 NIEHS, Off Clin Res, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Chulada, PC (reprint author), NIEHS, Off Clin Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 4 TC 1 Z9 1 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2003 VL 112 IS 4 BP 808 EP 809 DI 10.1016/S0091-6749(03)02019-0 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 730LA UT WOS:000185831200029 ER PT J AU Cone, EJ Sampson-Cone, AH Darwin, WD Huestis, MA Oyler, JM AF Cone, EJ Sampson-Cone, AH Darwin, WD Huestis, MA Oyler, JM TI Urine testing for cocaine abuse: Metabolic and excretion patterns following different routes of administration and methods for detection of false-negative results SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID MARIJUANA C1 ConeChem Res LLC, Severna Pk, MD 21146 USA. NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Cone, EJ (reprint author), ConeChem Res LLC, 441 Fairtree Dr, Severna Pk, MD 21146 USA. NR 15 TC 43 Z9 45 U1 2 U2 5 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2003 VL 27 IS 7 BP 386 EP 401 PG 16 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 728JW UT WOS:000185714900001 PM 14606991 ER PT J AU Barnes, AJ Kim, I Schepers, R Moolchan, ET Wilson, L Cooper, G Reid, C Hand, C Huestis, MA AF Barnes, AJ Kim, I Schepers, R Moolchan, ET Wilson, L Cooper, G Reid, C Hand, C Huestis, MA TI Sensitivity, specificity, and efficiency in detecting opiates in oral fluid with the Cozart (R) opiate microplate EIA and GC-MS following controlled codeine administration SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID ENZYME-IMMUNOASSAY; GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; POSTMORTEM BLOOD; SALIVA; METHAMPHETAMINE; COCAINE; ABUSE; URINE; DRUGS C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. Cozart Biosci Ltd, Abingdon OX14 4RU, Oxon, England. RP Huestis, MA (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 31 Z9 34 U1 1 U2 4 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2003 VL 27 IS 7 BP 402 EP 406 PG 5 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 728JW UT WOS:000185714900002 PM 14606992 ER PT J AU Kolbrich, EA Kim, I Barnes, AJ Moolchan, ET Wilson, L Cooper, GA Reid, C Baldwin, D Hand, CW Huestis, MA AF Kolbrich, EA Kim, I Barnes, AJ Moolchan, ET Wilson, L Cooper, GA Reid, C Baldwin, D Hand, CW Huestis, MA TI Cozart (R) RapiScan oral fluid drug testing system: An evaluation of sensitivity, specificity, and efficiency for cocaine detection compared with ELISA and GC-MS following controlled cocaine administration SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; HUMAN VOLUNTEERS; SALIVA; PLASMA; ABUSE; URINE; METABOLITES; HUMANS; SWEAT C1 NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Cozart Biosci Ltd, Abingdon OX14 4RU, Oxon, England. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 23 TC 21 Z9 21 U1 1 U2 6 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2003 VL 27 IS 7 BP 407 EP 411 PG 5 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 728JW UT WOS:000185714900003 PM 14606993 ER PT J AU Roth, SM Metter, EJ Lee, MR Hurley, BF Ferrell, RE AF Roth, SM Metter, EJ Lee, MR Hurley, BF Ferrell, RE TI C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE genetics; muscle mass; muscle strength; polymorphism; sex ciliary neurotrophic factor receptor ID CILIARY NEUROTROPHIC FACTOR; AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN SKELETAL-MUSCLE; BONE-MINERAL DENSITY; ALPHA-COMPONENT; MUSCULAR STRENGTH; GRIP STRENGTH; NULL MUTATION; EARLY-ONSET; GENOTYPE AB We performed gene screening of the ciliary neurotrophic factor receptor (CNTFR) gene and genotyped three newly identified polymorphisms: C-1703T in the 5' promoter region, T1069A in intron 5, and C174T in exon 9. We studied the association of these CNTFR variants with muscle strength, mass, and body composition in 465 men and women (20-90 yr) from the Baltimore Longitudinal Study of Aging. Only the C174T variant was significantly associated with muscle-related phenotypes. In the entire cohort, when corrected for age, sex, race, physical activity, and height, homozygotes for the common C allele at C174T ( CC) exhibited lower total body mass and body mass index than carriers of the rare T allele, which appeared to be due to significant differences in total nonosseous fat-free mass (FFM) (48.0 +/- 0.4 vs. 50.0 +/- 0.7 kg; P = 0.011) and lower limb FFM (16.5 +/- 0.1 vs. 17.2 +/- 0.2 kg; P = 0.002). The CC group also exhibited significantly lower quadriceps concentric and eccentric isokinetic strength values at both 30 and 180degrees/s than the T allele carriers (all P < 0.04), but these differences were no longer significant after adjustment for lower limb FFM. There were no significant sex-by-genotype interactions. The results indicate that the C174T polymorphism in exon 9 of CNTFR is significantly associated with FFM in men and women, with concomitant differences in muscular strength. C1 Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. NIA, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Roth, SM (reprint author), Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. OI Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG-05893]; NIDDK NIH HHS [DK-46204] NR 45 TC 33 Z9 38 U1 0 U2 1 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 OCT PY 2003 VL 95 IS 4 BP 1425 EP 1430 DI 10.1152/japplphysiol.00516.2003 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 722QD UT WOS:000185386800012 PM 12807897 ER PT J AU Chaussee, MS Somerville, GA Reitzer, L Musser, JM AF Chaussee, MS Somerville, GA Reitzer, L Musser, JM TI Rgg coordinates virulence factor synthesis and metabolism in Streptococcus pyogenes SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ARGININE DEIMINASE PATHWAY; LACTOBACILLUS-SAKEI L45; GROUP-A STREPTOCOCCUS; CYSTEINE PROTEASE; GENOME SEQUENCE; LACTOCIN-S; TRANSCRIPTIONAL REGULATOR; EXPRESSION; GENE; IDENTIFICATION AB Streptococcus pyogenes is a human-specific pathogen that relies on its host for metabolic substrates. Rgg-like proteins constitute a family of transcriptional regulators present in several gram-positive bacteria. In S. pyogenes, Rgg influences the expression of several virulence-associated proteins localized to the cell wall and extracellular environment. Secreted enzymes may degrade host macromolecules, thereby liberating metabolic substrates. To determine if Rgg regulation of exoprotein expression is associated with altered metabolism, the catabolic activities of S. pyogenes strain NZ131 (serotype M49) and an isogenic rgg mutant strain were analyzed during growth with complex and defined media. As expected, the wild-type strain preferentially used glucose and produced lactic acid during the exponential phase of growth. In contrast, the rgg mutant fermented arginine in the exponential phase of growth, even in the presence of glucose. Arginine degradation was associated with a neutral culture pH and excretion of NH, and ornithine. Arginine, serine, and asparagine were depleted from mutant cultures during growth. The addition of arginine and serine to culture media increased the growth yield and NH, production of mutant but not wild-type cultures. Addition of asparagine had no effect on the growth yield of either strain. Altered metabolism of arginine and serine in the mutant was associated with increased transcript levels of genes encoding arginine deiminase and a putative serine dehydratase. Thus, Rgg coordinates virulence factor synthesis and catabolic activity and may be important in the pathogen's adaptation to changes in the availability of metabolic substrates. C1 Univ S Dakota, Coll Med, Div Basic Biomed Sci, Vermillion, SD 57069 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Texas, Dept Mol & Cell Biol, Richardson, TX 75083 USA. RP Chaussee, MS (reprint author), Univ S Dakota, Coll Med, Div Basic Biomed Sci, Lee Med Bldg,414 E Clark St, Vermillion, SD 57069 USA. RI Somerville, Greg/B-1326-2013; Reitzer, Larry/A-2510-2016 OI Somerville, Greg/0000-0002-0991-8737; FU NCRR NIH HHS [P20 RR016479, P20 RR16479-02] NR 35 TC 67 Z9 69 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 OCT PY 2003 VL 185 IS 20 BP 6016 EP 6024 DI 10.1128/JB.185.20.6016-6024.2003 PG 9 WC Microbiology SC Microbiology GA 730WL UT WOS:000185853100013 PM 14526012 ER PT J AU Boisbouvier, J Wu, ZR Ono, A Kainosho, M Bax, A AF Boisbouvier, J Wu, ZR Ono, A Kainosho, M Bax, A TI Rotational diffusion tensor of nucleic acids from C-13 NMR relaxation SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE anisotropy; C-13 relaxation; Dickerson dodecamer; diffusion anisotropy; nucleic acids; rotational diffusion ID CROSS-CORRELATED RELAXATION; CHEMICAL-SHIFT ANISOTROPY; MODEL-FREE ANALYSIS; B-DNA DODECAMER; BACKBONE DYNAMICS; SPIN RELAXATION; DIPOLAR COUPLINGS; N-15 RELAXATION; INTERNAL DYNAMICS; CRYSTAL-STRUCTURE AB Rotational diffusion properties have been derived for the DNA dodecamer d(CGCGAATTCGCG)(2) from C-13 R-1rho and R-1 measurements on the C-1', C-3', and C-4' carbons in samples uniformly enriched in C-13. The narrow range of C-H bond vector orientations relative to the DNA axis make the analysis particularly sensitive to small structural deviations. As a result, the R-1rho/R-1 ratios are found to fit poorly to the crystal structures of this dodecamer, but well to a recent solution NMR structure, determined in liquid crystalline media, even though globally the structures are quite similar. A fit of the R-1rho/R-1 ratios to the solution structure is optimal for an axially symmetric rotational diffusion model, with a diffusion anisotropy, D-parallel to/D-perpendicular to, of 2.1+/-0.4, and an overall rotational correlation time, (2D(parallel to) + 4D(perpendicular to))(-1), of 3.35 ns at 35degreesC in D2O, in excellent agreement with values obtained from hydrodynamic modeling. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Tokyo Metropolitan Univ, CREST, Tokyo 1920397, Japan. Tokyo Metropolitan Univ, Grad Sch Sci, Tokyo 1920397, Japan. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 54 TC 40 Z9 40 U1 2 U2 11 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2003 VL 27 IS 2 BP 133 EP 142 DI 10.1023/A:1024931619957 PG 10 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 705WM UT WOS:000184419100003 PM 12913409 ER PT J AU Carbone, LD Tylavsky, FA Cauley, JA Harris, TB Lang, TF Bauer, DC Barrow, KD Kritchevsky, SB AF Carbone, LD Tylavsky, FA Cauley, JA Harris, TB Lang, TF Bauer, DC Barrow, KD Kritchevsky, SB TI Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: Impact of cyclooxygenase selectivity SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE nonsteroidal anti-inflammatory drugs; bone; aspirin; cyclo-oxygenase; elderly ID POSTMENOPAUSAL WOMEN; GASTROINTESTINAL TOXICITY; COMPUTED-TOMOGRAPHY; RANDOMIZED-TRIAL; FRACTURE RISK; OLDER WOMEN; IN-VIVO; OSTEOPOROSIS; INHIBITION; PROSTAGLANDINS AB BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis. Introduction: The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of Prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of Prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway. Materials and Methods: NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men; 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of > 1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of < 1 in whole blood. Analysis of covariance, was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status. Results: After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2-7.3 CI) and total hip (4.6%, 0.5-8.8 CI) by DXA and at both trabecular (34.1%, 15.4-52.7 CI) and cortical spine (12.8%, 2.3-23.3 CI) by quantitative computed tomography. Conclusions: Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women. C1 Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NIA, Epidemiol Demography & Biometry Program, Bethesda, MD USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. RP Carbone, LD (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Med, 956 Court Ave,Room E336, Memphis, TN 38163 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]; NIAMS NIH HHS [K23AR02042-01A1] NR 43 TC 57 Z9 65 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2003 VL 18 IS 10 BP 1795 EP 1802 DI 10.1359/jbmr.2003.18.10.1795 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 728LJ UT WOS:000185718400011 PM 14584890 ER PT J AU Domanski, MJ Krause-Steinrauf, H Massie, BM Deedwania, P Follmann, D Kovar, D Murray, D Oren, R Rosenberg, Y Young, J Zile, M Eichhorn, E AF Domanski, MJ Krause-Steinrauf, H Massie, BM Deedwania, P Follmann, D Kovar, D Murray, D Oren, R Rosenberg, Y Young, J Zile, M Eichhorn, E CA Best Investigators TI A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE heart failure; beta-blockers ID LEFT-VENTRICULAR DYSFUNCTION; INTRINSIC SYMPATHOMIMETIC ACTIVITY; RANDOMIZED INTERVENTION TRIAL; RACIAL-DIFFERENCES; BUCINDOLOL; SURVIVAL; METOPROLOL; CARDIOMYOPATHY; MORBIDITY; MORTALITY AB Background: Recent large randomized, controlled trials (BEST [beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure. Methods: To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed. Results: In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR) = 0.77 [95% CI = 0.65, 0.92]), cardiovascular death (HR = 0.71 [0.58, 0.86]), sudden death (HR = 0.77 [0.59, 0.999]), and pump failure death (HR = 0.64 [0.45, 0.91]). Conclusions: Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy. C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. Vet Adm Med Ctr, Dallas, TX 75216 USA. Vet Adm Med Ctr, Charleston, SC 29403 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Iowa, Iowa City, IA USA. San Antonio Clin Ctr, San Antonio, TX USA. Univ Alabama, Birmingham, AL USA. Vet Adm Med Ctr, Fresno, CA USA. Vet Adm Med Ctr, San Francisco, CA 94121 USA. Dept Vet Affairs, Cooperat Studies Program, Palo Alto, CA USA. RP Domanski, MJ (reprint author), NHLBI, Clin Trials Grp, 6701 Rockledge Dr,Room 8146, Bethesda, MD 20892 USA. NR 37 TC 97 Z9 99 U1 3 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD OCT PY 2003 VL 9 IS 5 BP 354 EP 363 DI 10.1054/S1071-9164(03)00133-7 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 739DG UT WOS:000186326500003 PM 14583895 ER PT J AU Kerckhoffs, RCP Faris, OP Bovendeerd, PHM Prinzen, FW Smits, K McVeigh, ER Arts, T AF Kerckhoffs, RCP Faris, OP Bovendeerd, PHM Prinzen, FW Smits, K McVeigh, ER Arts, T TI Timing of depolarization and contraction in the paced canine left ventricle: Model and experiment SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Workshop on Computer Simulation and Experimental Assessment of Cardiac Electrical Function CY DEC 09-10, 2002 CL LAUSANNE, SWITZERLAND DE eikonal-diffusion equation; electromechanics; finite elements ID ENDOCARDIAL ACTIVATION; MECHANICAL ACTIVATION; HUMAN HEART; PURKINJE; PROPAGATION; STIMULATION; EXCITATION; DEFORMATION; MYOCARDIUM; POTENTIALS AB Modeling the Paced LV. Introduction: For efficient pump function, contraction of the heart should be as synchronous as possible. Ventricular pacing induces asynchrony of depolarization and contraction. The degree of asynchrony depends on the position of the pacing electrode. The aim of this study was to extend an existing numerical model of electromechanics in the left ventricle (LV) to the application of ventricular pacing. With the model, the relation between pacing site and patterns of depolarization and contraction was investigated. Methods and Results: The LV was approximated by a thick-walled ellipsoid with a realistic myofiber orientation. Propagation of the depolarization wave was described by the eikonal-diffusion equation, in which five parameters play a role: myocardial and subendocardial velocity of wave propagation along the myofiber c(m) and c(e); myocardial and subendocardial anisotropy a(m) and a(e); and parameter k, describing the influence of wave curvature on wave velocity. Parameters cm, ae, and k were taken from literature. Parameters a and c, were estimated by fitting the model to experimental data, obtained by pacing the canine left ventricular free wall (LVFW). The best fit was found with c(m) = 0.75 m/s, c(e) = 1.3 m/s, a(m) = 2.5, a(e) = 1.5, and k = 2.1 x 10(-4) m(2)/s. With these parameter settings, for right ventricullar apex (RVA) pacing, the depolarization times were realistically simulated as also shown by the wavefronts and the time needed to activate the LVFW. The moment of depolarization was used to initiate myofiber contraction in a model of LV mechanics. For both pacing situations, mid-wall circumferential strains and onset of myofiber shortening were obtained. Conclusion: With a relatively simple model setup, simulated depolarization timing patterns agreed with measurements for pacing at the LVFW and RVA in an LV. Myocardial cross-fiber wave velocity is estimated to be 0.40 times the velocity along the myofiber direction (0.75 m/s). Subendocardial wave velocity is about 1.7 times faster than in the rest of the myocardium, but about 3 times slower than as found in Purkinje fibers. Furthermore, model and experiment agreed in the following respects. (1) Ventricular pacing decreased both systolic pressure and ejection fraction relative to natural sinus rhythm. (2) In early depolarized regions, early shortening was observed in the isovolumic contraction phase; in late depolarized regions, myofibers were stretched in this phase. Maps showing timing of onset of shortening were similar to previously measured maps in which wave velocity of contraction appeared similar to that of depolarization. C1 Eindhoven Univ Technol, Dept Biomed Engn, NL-5600 MB Eindhoven, Netherlands. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Maastricht Univ, Dept Physiol, Maastricht, Netherlands. Medtron Bakken Res Ctr, Dept Lead Modeling, Maastricht, Netherlands. Maastricht Univ, Dept Biophys, Maastricht, Netherlands. RP Bovendeerd, PHM (reprint author), Eindhoven Univ Technol, Dept Biomed Engn, POB 513, NL-5600 MB Eindhoven, Netherlands. EM p.h.m.bovendeerd@tue.nl NR 31 TC 42 Z9 44 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD OCT PY 2003 VL 14 IS 10 SU S BP S188 EP S195 DI 10.1046/j.1540.8167.90310.x PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 743CB UT WOS:000186553900012 PM 14760923 ER PT J AU Beck, GR AF Beck, GR TI Inorganic phosphate as a signaling molecule in osteoblast differentiation SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE inorganic phosphate; osteoblast differentiation; calcium; osteopontin; alkaline phosphatase ID GLYCEROPHOSPHATE-INDUCED MINERALIZATION; SKELETAL ALKALINE-PHOSPHATASE; BONE CELL MINERALIZATION; BETA-GLYCEROPHOSPHATE; MATRIX VESICLES; GENE-EXPRESSION; CARTILAGE CALCIFICATION; MEDIATED MINERALIZATION; COLLAGEN-SYNTHESIS; CALVARIA CELLS AB The spatial and temporal coordination of the many events required for osteogenic cells to create a mineralized matrix are only partially understood. The complexity of this process, and the nature of the final product, demand that these cells have mechanisms to carefully monitor events in the extracellular environment and have the ability to respond through cellular and molecular changes. The generation of inorganic phosphate during the process of differentiation may be one such signal. In addition to the requirement of inorganic phosphate as a component of hydroxyapatite mineral, Ca-10(PO4)(6)(OH)(2), a number of studies have also suggested it is required in the events preceding mineralization. However, contrasting results, physiological relevance, and the lack of a clear mechanism(s) have created some debate as to the significance of elevated phosphate in the differentiation process. More recently, a number of studies have begun to shed light on possible cellular and molecular consequences of elevated intracellular inorganic phosphate. These results suggest a model in which the generation of inorganic phosphate during osteoblast differentiation may in and of itself represent a signal capable of facilitating the temporal coordination of expression and regulation of multiple factors necessary for mineralization. The regulation of protein function and gene expression by elevated inorganic phosphate during osteoblast differentiation may represent a mechanism by which mineralizing cells monitor and respond to the changing extracellular environment. Published 2003 Wiley-Liss, Inc. C1 Natl Canc Inst, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. RP Beck, GR (reprint author), Natl Canc Inst, Ctr Canc Res, Basic Res Lab, Bldg 576,Rm 110, Frederick, MD 21702 USA. FU NCI NIH HHS [CA84573] NR 70 TC 137 Z9 140 U1 5 U2 21 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 1 PY 2003 VL 90 IS 2 BP 234 EP 243 DI 10.1002/jcb.10266 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 729GP UT WOS:000185765100003 PM 14505340 ER PT J AU Oliver, VK Patton, AM Desai, S Lorang, D Libutti, SK Kohn, EC AF Oliver, VK Patton, AM Desai, S Lorang, D Libutti, SK Kohn, EC TI Regulation of the pro-angiogenic microenvironment by carboxyamido-triazole SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INTERLEUKIN-8 GENE-EXPRESSION; MEDIATED SIGNAL-TRANSDUCTION; OVARIAN-CARCINOMA CELLS; HUMAN-MELANOMA CELLS; CALCIUM INFLUX; INDUCED ELEVATION; CANCER-CELLS; IV COLLAGEN; TUMOR-CELLS AB Anti-angiogenic agents regulate tumor growth by inhibiting endothelial cell proliferation and invasion. Carboxyamido-triazole (CAI), an inhibitor of non-voltage-operated calcium entry and calcium influx-mediated pathways, has angiogenesis and invasion inhibitory activity. We hypothesized that CAI may express its anti-angiogenic effects through negative regulation of pro-angiogenic cytokine production and/or function. In vivo, orally administered CAI prevented A2058 human melanoma xenograft growth and concomitantly resulted in a marked reduction in circulating vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In vitro, A2058 cell secretion of VEGF was inhibited by CAI treatment under limiting micronutrient conditions that approximate the tumor microenvironment, media restriction, and acidification to pH 6.8 (P= 0.0003 and P= 0.0006, respectively). VEGF and HIF-1alpha message and protein were also reduced by CAI treatment. Oral CAI treatment reduced vascular ingrowth in vivo into VEGF-containing Matrigel plugs. Commensurate with those findings, human umbilical vein endothelial cell (HUVEC) migration towards VEGF was reduced below background by exposure to CAI in the migration chamber (P< 0.0001). An 88% reduction in circulating IL-8 concentration was measured in CAI-treated animals. However, IL-8 protein secretion and gene expression were increased by CAI treatment in culture (Pless than or equal to 0.01), where CAI caused a dose-dependent acidification of the culture milieu (Pless than or equal to 0.005). This paradox suggests that IL-8 production in vitro may be more sensitive to ambient pH than cytosolic calcium. These observations suggest that CAI inhibition of tumor cell VEGF production and endothelial cell response to VEGF results in disruption of signaling between the tumor and its microenvironment, causing a net anti-angiogenic effect. Published 2003 Wiley-Liss, Inc. C1 NCI, Pathol Lab, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), 10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. NR 55 TC 13 Z9 14 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD OCT PY 2003 VL 197 IS 1 BP 139 EP 148 DI 10.1002/jcp.10350 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 717LL UT WOS:000185090700015 PM 12942550 ER PT J AU Stojilkovic, KS Berezhkovskii, AM Zitserman, VY Bezrukov, SM AF Stojilkovic, KS Berezhkovskii, AM Zitserman, VY Bezrukov, SM TI Conductivity and microviscosity of electrolyte solutions containing polyethylene glycols SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID SEMIDILUTE POLYMER-SOLUTIONS; HYDRODYNAMIC SCALING MODEL; SELF-DIFFUSION; STOKES-EINSTEIN; ION CHANNELS; PARTICLES; TRANSPORT; PORE; SEDIMENTATION; VISCOSITY AB Electrical conductivity of potassium chloride solutions containing polyethylene glycol (PEG) of different molecular mass was measured in a wide range of the polymer concentration up to 33 wt. % for PEG 300, 600, 2000, 4600, and 10 000. The data were used to find the dependence of microviscosity, eta(micro), which characterizes the decrease of the ion mobility compared to that in the polymer-free solution, on the polymer volume fraction, phi. We find that the dependence is well approximated by a simple relation eta(micro)/eta(0)=exp[kphi/(1-phi)], where eta(0) is viscosity of the polymer-free solution and k is a fitting parameter. Parameter k weakly depends on the polymer molecular mass growing from 2.5 for PEG 300 to its limiting value close to 2.9 for long chains. Using the phi-dependence of microviscosity, we give a practical formula for the conductivity of PEG-containing electrolyte solutions. (C) 2003 American Institute of Physics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, CIT, Bethesda, MD 20892 USA. Russian Acad Sci, Inst High Temp, Thermophys Ctr, Moscow 125412, Russia. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Bezrukov, SM (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NR 38 TC 29 Z9 30 U1 1 U2 4 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 1 PY 2003 VL 119 IS 13 BP 6973 EP 6978 DI 10.1063/1.1605096 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 723FH UT WOS:000185421400064 ER PT J AU Nelson, EE McClure, EB Monk, CS Zarahn, E Leibenluft, E Pine, DS Ernst, M AF Nelson, EE McClure, EB Monk, CS Zarahn, E Leibenluft, E Pine, DS Ernst, M TI Developmental differences in neuronal engagement during implicit encoding of emotional faces: an event-related fMRI study SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES LA English DT Article DE memory; adolescent; recognition; affect; emotional bias; child ID DISSOCIABLE NEURAL RESPONSES; ANTERIOR CINGULATE; BRAIN-DEVELOPMENT; HUMAN AMYGDALA; MEMORY; DEPRESSION; MOOD; RECOGNITION; ATTENTION; CHILDREN AB Background: Prior studies document strong interactions between emotional and mnemonic processes. These interactions have been shown to vary across development and psychopathology, particularly mood and anxiety disorders. Methods: The present study used functional neuroimaging to assess the degree to which adolescents and adults differ in patterns of neuronal engagement during implicit encoding of affective stimuli. Subjects underwent rapid event-related fMRI while viewing faces with angry, fearful, happy, and neutral expressions. A surprise post-scan memory test was administered. Results: Consistent with previous findings, both adolescents and adults displayed engagement of left ventrolateral prefrontal cortex when viewing subsequently recognized stimuli. Age differences emerged in patterns of neuronal activation associated with subsequent recognition of specific face-emotion types. Relative to adults, adolescents displayed more activity in the anterior cingulate when viewing subsequently remembered angry faces, and more activity in the right temporal pole when viewing subsequently remembered fear faces. Conversely, adults displayed more activity in the sub-genual anterior cingulate when viewing subsequently remembered happy faces and more activity in the right posterior hippocampus when viewing subsequently remembered neutral faces. These age-related differences emerged in the absence of differences in behavioral performance. Conclusions: These findings document developmental differences in the degree to which engagement of affective circuitry contributes to memory formation. C1 NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY USA. RP Nelson, EE (reprint author), NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RI Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014 OI Nelson, Eric/0000-0002-3376-2453; NR 65 TC 66 Z9 66 U1 8 U2 20 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry Allied Discip. PD OCT PY 2003 VL 44 IS 7 BP 1015 EP 1024 DI 10.1111/1469-7610.00186 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 725ZZ UT WOS:000185573900010 PM 14531584 ER PT J AU Agarwal, AK Simha, V Oral, EA Moran, SA Gorden, P O'Rahilly, S Zaidi, Z Gurakan, F Arslanian, SA Klar, A Ricker, A White, NH Bindl, L Herbst, K Kennel, K Patel, SB Al-Gazali, L Garg, A AF Agarwal, AK Simha, V Oral, EA Moran, SA Gorden, P O'Rahilly, S Zaidi, Z Gurakan, F Arslanian, SA Klar, A Ricker, A White, NH Bindl, L Herbst, K Kennel, K Patel, SB Al-Gazali, L Garg, A TI Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARDIOMYOPATHY; IDENTIFICATION AB Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Div Nutr & Metab Dis, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Ctr Human Nutr, Dallas, TX 75390 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. NIDDKD, Diabet Branch, Bethesda, MD 20892 USA. Addenbrookes Hosp, Cambridge Med Sch, Dept Med, Cambridge CB2 2QR, England. Jinnah Postgrad Med Ctr, Dept Dermatol, Karachi 75510, Pakistan. Hacettepe Univ, Fac Med, Dept Pediat Gastroenterol, TR-06100 Ankara, Turkey. Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15213 USA. Bikur Holim Hosp, Dept Pediat, IL-91004 Jerusalem, Israel. Harvard Univ, Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. Univ Childrens Hosp, Dept Pediat, D-53113 Bonn, Germany. Charles R Drew Univ, Dept Med, Los Angeles, CA 90059 USA. Mayo Clin, Dept Endocrinol, Rochester, MN 55905 USA. Med Univ S Carolina, Div Endocrinol, Charleston, SC 29403 USA. United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Pediat, Al Ain, U Arab Emirates. RP Garg, A (reprint author), Univ Texas, SW Med Ctr, Dept Internal Med, Div Nutr & Metab Dis, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM abhimanyu.garg@utsouthwestern.edu OI Oral, Elif/0000-0002-9171-1144; Patel, Shailendra/0000-0003-0046-5513 FU NCRR NIH HHS [M01-RR00633]; NIDDK NIH HHS [R01-DK54387] NR 23 TC 111 Z9 120 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT 1 PY 2003 VL 88 IS 10 BP 4840 EP 4847 DI 10.1210/jc.2003-030855 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731VC UT WOS:000185906300048 PM 14557463 ER PT J AU Tang, BW Vu, M Booker, T Santner, SJ Miller, FR Anver, MR Wakefield, LM AF Tang, BW Vu, M Booker, T Santner, SJ Miller, FR Anver, MR Wakefield, LM TI TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR-BETA; INVASIVE CARCINOMAS; TRANSGENIC MICE; RECEPTOR; EXPRESSION; CELLS; TUMORIGENESIS; METASTASIS; INHIBITION; MCF10AT AB The TGF-beta signaling network plays a complex role in carcinogenesis because it has the potential to act as either a tumor suppressor or a pro-oncogenic pathway. Currently, it is not known whether TGF-beta can switch from tumor suppressor to pro-oncogenic factor during the course of carcinogenic progression in a single cell lineage with a defined initiating oncogenic event or whether the specific nature of the response is determined by cell type and molecular etiology. To address this question, we have introduced a dominant negative type 11 TGF-beta receptor into a series of genetically related human breast-derived cell lines representing different stages in the progression process. We show that decreased TGF-beta responsiveness alone cannot initiate tumorigenesis but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic cell. line histologically and proliferatively more aggressive. In a high-grade tumorigenic cell line, however, reduced TGF-beta responsiveness has no effect on primary tumorigenesis but significantly decreases metastasis. Our results demonstrate a causal role for loss of TGF-beta responsiveness in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but nonmetastatic disease and suggest that at that point TGF-beta switches from tumor suppressor to prometastatic factor. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Sch Med, Detroit, MI USA. Sci Applicat Int Corp, Pathol Histotechnol Lab, NCI, Frederick, MD USA. RP Wakefield, LM (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. FU PHS HHS [N01-C0-12400] NR 32 TC 252 Z9 265 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2003 VL 112 IS 7 BP 1116 EP 1124 DI 10.1172/JCI200318899 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 729FV UT WOS:000185763100020 PM 14523048 ER PT J AU Palmer, S Wiegand, AP Maldarelli, F Bazmi, H Mican, JM Polis, M Dewar, RL Planta, A Liu, SY Metcalf, JA Mellors, JW Coffin, JM AF Palmer, S Wiegand, AP Maldarelli, F Bazmi, H Mican, JM Polis, M Dewar, RL Planta, A Liu, SY Metcalf, JA Mellors, JW Coffin, JM TI New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; VIRAL LOAD; HIV-1 INFECTION; PROLONGED SUPPRESSION; QUANTITATION; REPLICATION; DNA; PATHOGENESIS; LYMPHOCYTES; RESISTANCE AB More sensitive assays for human immunodeficiency virus type 1 (HIV-1) RNA are needed to detect, quantify, and characterize persistent viremia in patients who are receiving antiretroviral therapy and whose plasma HIV-1 RNA levels are suppressed to less than 50 to 75 copies/ml. We therefore developed an internally controlled real-time reverse transcriptase-initiated PCR assay that quantifies HIV-1 RNA concentrations down to 1 copy per ml of plasma. This assay with single-copy sensitivity (the single-copy assay) generates a reproducible linear regression plot of input copy number versus threshold cycle by using HIV-1 RNA transcripts at copy numbers ranging from 1 to 106 per reaction mixture. The single-copy assay was compared to the ultrasensitive AMPLICOR HIV-1 MONITOR assay and a more sensitive modification of the ultrasensitive assay by repeatedly testing a low-copy-number panel containing 200 to 0.781 copies of HIV-1 RNA per ml of plasma. This comparison showed that the single-copy assay had a greater sensitivity than the other assays and was the only assay that detected HIV-1 RNA at levels as low as 0.781 copies/ml. Testing of plasma samples from 15 patients who were receiving antiretroviral therapy and who had <75 HIV-1 RNA copies/ml revealed persistent viremia in all 15 patients, with HIV-1 RNA levels ranging from 1 to 32 copies/ml (median, 13 copies/ml). The greater sensitivity of the single-copy assay should allow better characterization of persistent viremia in patients who are receiving antiretroviral therapy and whose HIV-1 RNA levels are suppressed to below the detection limits of present assays. C1 NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. Univ Pittsburgh, Pittsburgh, PA USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Palmer, S (reprint author), NCI, HIV Drug Resistance Program, NIH, 1050 Boyles St,Bldg 535,Room 109, Frederick, MD 21702 USA. OI Polis, Michael/0000-0002-9151-2268 FU PHS HHS [5 U01 A1046383-04] NR 32 TC 337 Z9 343 U1 4 U2 28 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 OCT PY 2003 VL 41 IS 10 BP 4531 EP 4536 DI 10.1128/JCM.41.10.4531-4536.2003 PG 6 WC Microbiology SC Microbiology GA 732CH UT WOS:000185922900006 PM 14532178 ER PT J AU Rao, MR Abu-Elyazeed, R Savarino, SJ Naficy, AB Wierzba, TF Abdel-Messih, I Shaheen, H Frenck, RW Svennerholm, AM Clemens, JD AF Rao, MR Abu-Elyazeed, R Savarino, SJ Naficy, AB Wierzba, TF Abdel-Messih, I Shaheen, H Frenck, RW Svennerholm, AM Clemens, JD TI High disease burden of diarrhea due to enterotoxigenic Escherichia coli among rural Egyptian infants and young children SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IMMUNOSORBENT-ASSAY; COHORT; ANTIBODIES; TOXIN; MILK AB The incidence of enterotoxigenic Escherichia coli diarrhea among Egyptian children was 1.5 episodes per child per year and accounted for 66% of all first episodes of diarrhea after birth. The incidence increased from 1.7 episodes per child per year in the first 6 months of life to 2.3 in the second 6 months and declined thereafter. C1 NICHHD, Epidemiol Branch, Bethesda, MD 20892 USA. USN, Med Res Unit 3, Cairo, Egypt. USN, Med Res Ctr, Silver Spring, MD USA. Univ Gothenburg, Dept Med Microbiol & Immunol, Gothenburg, Sweden. Int Vaccine Inst, Seoul, South Korea. RP Rao, MR (reprint author), NIAID, PIPB, NIH, 6610 Rockledge Dr,Room 5044, Bethesda, MD 20892 USA. FU NICHD NIH HHS [Y1-HD-0026-01] NR 16 TC 51 Z9 54 U1 0 U2 2 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 OCT PY 2003 VL 41 IS 10 BP 4862 EP 4864 DI 10.1128/JCM.41.10.4862-4864.2003 PG 3 WC Microbiology SC Microbiology GA 732CH UT WOS:000185922900072 PM 14532244 ER PT J AU Lin, YW Adachi, S Watanabe, KI Umeda, K Nakahata, T AF Lin, YW Adachi, S Watanabe, KI Umeda, K Nakahata, T TI Serial granulocyte transfusions as a treatment for sepsis due to multidrug-resistant Pseudomonas aeruginosa in a neutropenic patient SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DONORS; TRANSPLANTATION; INFECTIONS; THERAPY AB The emergence of multidrug-resistant Pseudomonas aeruginosa (MRPA) has become a major clinical problem. We successfully treated MRPA sepsis in a neutropenic patient undergoing peripheral blood stem cell transplantation with serial granulocyte transfusions. Granulocyte transfusion should be considered as a treatment for severe infection in patients with neutropenia. C1 Kyoto Univ, Grad Sch Med, Dept Pediat, Sakyo Ku, Kyoto 6068507, Japan. RP Lin, YW (reprint author), NCI, ATC, GB, CCR,NIH, 301 N Stonest Ave, Rockville, MD 20892 USA. NR 9 TC 5 Z9 6 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2003 VL 41 IS 10 BP 4892 EP 4893 DI 10.1128/JCM.41.10.4892-4892.2003 PG 2 WC Microbiology SC Microbiology GA 732CH UT WOS:000185922900081 PM 14532253 ER PT J AU Rudek, MA Venitz, J Ando, Y Reed, E Pluda, JM Figg, WD AF Rudek, MA Venitz, J Ando, Y Reed, E Pluda, JM Figg, WD TI Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: Clinical and experimental studies SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE COL-3; metastatic cancer; pharmacokinetics; metabolism ID HUMAN UDP-GLUCURONOSYLTRANSFERASES; PERFORMANCE LIQUID-CHROMATOGRAPHY; 4-DEDIMETHYLAMINO SANCYCLINE; LIVER-MICROSOMES; DRUG-DOSAGE; GLUCURONIDATION; PLASMA; TETRACYCLINE; DOXYCYCLINE; SERUM AB COL-3 is an oral, lipophilic, tetracycline analog that has been administered to patients with metastatic cancer. Preliminary assessment of COL-3 in 35 patients with refractory metastatic carcinoma demonstrated apparent nonlinear pharmacokinetics with highly variable oral clearance (63.9% coefflcient of variance [CV]). To elucidate possible sources of variability of COL-3 pharmacokinetics in vivo, in vitro plasma protein binding and in vitro metabolism were explored along with in vivo pharmacokinetics using compartmental modeling. The variability in the overall clearance and urinary excretion of COL-3 was also assessed. COL-3 had a long terminal half-life (median = 59.8 h), large apparent volume of distribution (median = 50.2 L), and low apparent clearance (median = 9.93 mL/min). Only adjusted ideal body weight decreased the variability in total apparent clearance. There was nonsaturable plasma protein binding of COL-3 (f(u) = 5.5%), with the majority of binding to albumin. The renal route of elimination is negligible, with 0.06% of unchanged COL-3 and 3.31% COL-3 glucuronide excreted in the first 6 days. COL-3 is not metabolized by phase I metabolism but does undergo glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and in vivo, as evidenced by COL-3 glucuronides in the urine (median = 13.6% of the total dose). COL-3 exhibits nonlinear pharmacokinetics, possibly due to dissolution rate-limited absorption. (C) 2003 the American College of Clinical Pharmacology. C1 NCI, Med Oncol Clin Res Unit, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Coll Med, Sch Pharm, Dept Pharmaceut, Richmond, VA USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. RP Figg, WD (reprint author), NCI, Med Oncol Clin Res Unit, Ctr Canc Res, NIH, Bldg 10,Room 5A01,MSC1910,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 46 TC 12 Z9 12 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2003 VL 43 IS 10 BP 1124 EP 1135 DI 10.1177/0091270003256675 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 723AP UT WOS:000185410500007 PM 14517195 ER PT J AU Onder, G Penninx, BWJH Guralnik, JM Jones, H Fried, LP Pahor, M Williamson, JD AF Onder, G Penninx, BWJH Guralnik, JM Jones, H Fried, LP Pahor, M Williamson, JD TI Sexual satisfaction and risk of disability in older women SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID PHYSICAL-ACTIVITY; HEALTH; LIFE; POPULATION; COMMUNITY; ALCOHOL; ADULTS; DEATH AB Background: Most studies evaluating sexuality in older adults have focused on men, and relatively little research has evaluated the relationship between sexual satisfaction and health outcomes in older women. The aims of this study were to describe correlates of sexual satisfaction in community-dwelling older women with moderate to severe levels of disability and to examine the association of sexual satisfaction with progression of disability in this population. Method: A total of 980 moderately to severely disabled women aged 65 years or older who had participated in The Women's Health and Aging Study entered this study. Baseline evaluations took place from 1992 through 1995. Participants rated their satisfaction with their level of sexual activity on a 0-to-10 scale. Women scoring greater than or equal to 8 were considered sexually satisfied. The onset of new severe disability was determined by semiannual assessments, over 3 years, of disability in performing activities of daily living (ADLs) and walking across a room. Results: Of 203 (49.8%) women living with a spouse, 101 were satisfied with their level of sexual activity. In this group, older age, white race, and higher level of physical function were independent predictors of sexual satisfaction. In addition, among women living with a spouse, higher sexual satisfaction was associated with a significantly decreased risk for incident disability in performing ADLs (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.36 to 0.94) and walking across a small room (HR = 0.38, 95% CI = 0.18 to 0.79). Among women not living with a spouse, the response on the sexual satisfaction question showed different determinants and was not associated with disability risk. Conclusion: Sexual satisfaction in community-dwelling, older, disabled women living with their spouse is associated with reduced risk for subsequent new severe disabilities. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sticht Ctr Aging,Sect Gerontol & Geriatr, Winston Salem, NC USA. Univ Sacred Heart, Med Ctr Aging, I-00168 Rome, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. RP Onder, G (reprint author), Univ Cattolica Sacro Cuore, CEMI, Dipartimento Geriatr, Policlin A Gemelli, L Go Francesco Vito 1, I-00139 Rome, Italy. FU NIA NIH HHS [N01 AG 12112, 5P60 AG 10484-07] NR 22 TC 10 Z9 11 U1 2 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2003 VL 64 IS 10 BP 1177 EP 1182 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 739DT UT WOS:000186327500006 PM 14658965 ER PT J AU Ketter, TA Manji, HK Post, RM AF Ketter, TA Manji, HK Post, RM TI Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; STRESSFUL LIFE EVENTS; ANTIEPILEPTIC DRUGS; DOUBLE-BLIND; IN-VITRO; MOOD DISORDERS; KINDLED SEIZURES; HUMAN BRAIN AB Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent lamotrigine, has recently been approved as a maintenance treatment for bipolar I disorder, and has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile. C1 Stanford Univ, Dept Psychiat & Behav Sci, Bipolar Disorders Clin, Stanford, CA 94305 USA. US Dept HHS, NIMH, Bethesda, MD USA. RP Ketter, TA (reprint author), Stanford Univ, Dept Psychiat & Behav Sci, Bipolar Disorders Clin, 401 Quarry Rd,Room 2124, Stanford, CA 94305 USA. NR 128 TC 74 Z9 76 U1 4 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2003 VL 23 IS 5 BP 484 EP 495 DI 10.1097/01.jcp.0000088915.02635.e8 PG 12 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 722XX UT WOS:000185404300011 PM 14520126 ER PT J AU Ishai, A AF Ishai, A TI On representation and reproducibility SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Editorial Material ID TEMPORAL CORTEX; NEURAL SYSTEMS; OBJECTS; FACES; PERCEPTION; IMAGERY; FMRI; AREA C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Ishai, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM alumit@ln.nimh.nih.gov NR 18 TC 2 Z9 2 U1 0 U2 1 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD OCT PY 2003 VL 15 IS 7 BP 946 EP 947 DI 10.1162/089892903770007335 PG 2 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 733MN UT WOS:000186004600004 PM 14614805 ER PT J AU Beauchamp, MS Lee, KE Haxby, JV Martin, A AF Beauchamp, MS Lee, KE Haxby, JV Martin, A TI fMRI responses to video and point-light displays of moving humans and manipulable objects SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID BIOLOGICAL MOTION PERCEPTION; CORTEX ACTIVATION; VISUAL-PERCEPTION; TEMPORAL CORTEX; MACAQUE MONKEY; FROM-MOTION; HUMAN BRAIN; AREAS; FORM; REPRESENTATION AB We used fMRI to study the organization of brain responses to different types of complex visual motion. In a rapid event-related design, subjects viewed video clips of humans performing different whole-body motions, video clips of manmade manipulable objects ( tools) moving with their characteristic natural motion, point-light displays of human whole-body motion, and point-light displays of manipulable objects. The lateral temporal cortex showed strong responses to both moving videos and moving point-light displays, supporting the hypothesis that the lateral temporal cortex is the cortical locus for processing complex visual motion. Within the lateral temporal cortex, we observed segregated responses to different types of motion. The superior temporal sulcus (STS) responded strongly to human videos and human point-light displays, while the middle temporal gyrus (MTG) and the inferior temporal sulcus responded strongly to tool videos and tool point-light displays. In the ventral temporal cortex, the lateral fusiform responded more to human videos than to any other stimulus category while the medial fusiform preferred tool videos. The relatively weak responses observed to point-light displays in the ventral temporal cortex suggests that form, color, and texture ( present in video but not point-light displays) are the main contributors to ventral temporal activity. In contrast, in the lateral temporal cortex, the MTG responded as strongly to point-light displays as to videos, suggesting that motion is the key determinant of response in the MTG. Whereas the STS responded strongly to point-light displays, it showed an even larger response to video displays, suggesting that the STS integrates form, color, and motion information. C1 NIMH, LBC, Bethesda, MD 20892 USA. RP Beauchamp, MS (reprint author), NIMH, LBC, 10 Ctr Dr MSC 1366,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM mbeauchamp@nih.gov RI martin, alex/B-6176-2009; OI Beauchamp, Michael/0000-0002-7599-9934 NR 57 TC 274 Z9 277 U1 2 U2 14 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD OCT PY 2003 VL 15 IS 7 BP 991 EP 1001 DI 10.1162/089892903770007380 PG 11 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 733MN UT WOS:000186004600009 PM 14614810 ER PT J AU Lawrence, NS Ross, TJ Hoffmann, R Garavan, H Stein, EA AF Lawrence, NS Ross, TJ Hoffmann, R Garavan, H Stein, EA TI Multiple neuronal networks mediate sustained attention SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; POSITRON EMISSION TOMOGRAPHY; SHORT-TERM-MEMORY; WORKING-MEMORY; COGNITIVE PERFORMANCE; HUMAN-BRAIN; PARAMETRIC MANIPULATION; SUBCUTANEOUS NICOTINE; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX AB Sustained attention deficits occur in several neuropsychiatric disorders. However, the underlying neurobiological mechanisms are still incompletely understood. To that end, functional MRI was used to investigate the neural substrates of sustained attention ( vigilance) using the rapid visual information processing (RVIP) task in 25 healthy volunteers. In order to better understand the neural networks underlying attentional abilities, brain regions where task-induced activation correlated with task performance were identified. Performance of the RVIP task activated a network of frontal, parietal, occipital, thalamic, and cerebellar regions. Deactivation during task performance was seen in the anterior and posterior cingulate, insula, and the left temporal and parahippocampal gyrus. Good task performance, as defined by better detection of target stimuli, was correlated with enhanced activation in predominantly right fronto-parietal regions and with decreased activation in predominantly left temporo-limbic and cingulate areas. Factor analysis revealed that these performance-correlated regions were grouped into two separate networks comprised of positively activated and negatively activated intercorrelated regions. Poor performers failed to significantly activate or deactivate these networks, whereas good performers either activated the positive or deactivated the negative network, or did both. The fact that both increased activation of task-specific areas and increased deactivation of task-irrelevant areas mediate cognitive functions underlying good RVIP task performance suggests two independent circuits, presumably reflecting different cognitive strategies, can be recruited to perform this vigilance task. C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Trinity Coll Dublin, Dublin, Ireland. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM estein@intra.nida.nih.gov RI Ross, Thomas/B-7469-2008; Stein, Elliot/C-7349-2008; Lawrence, Natalia/A-1588-2010; OI Ross, Thomas/0000-0002-7745-3572; Lawrence, Natalia/0000-0003-1969-6637 FU NCRR NIH HHS [RR00058]; NIDA NIH HHS [DA 09465, DA 14100] NR 52 TC 175 Z9 175 U1 4 U2 21 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD OCT PY 2003 VL 15 IS 7 BP 1028 EP 1038 DI 10.1162/089892903770007416 PG 11 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 733MN UT WOS:000186004600012 PM 14614813 ER PT J AU Lamb, ME Stemberg, KJ Orbach, Y Esplin, PW Stewart, H Mitchell, S AF Lamb, ME Stemberg, KJ Orbach, Y Esplin, PW Stewart, H Mitchell, S TI Age differences in young children's responses to open-ended invitations in the course of forensic interviews SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID INVESTIGATIVE UTTERANCE TYPES; ANATOMICALLY DETAILED DOLLS; SEXUAL-ABUSE VICTIMS; PEDIATRIC EXAMINATION; EYEWITNESS TESTIMONY; PRESCHOOL-CHILDREN; QUESTION TYPE; MEMORY; WITNESSES; EVENT AB To elucidate age differences in responses to free-recall prompts (i.e., invitations and cued invitations) and focused recognition prompts (i.e., option-posing and suggestive utterances), the authors examined 130 forensic interviews of 4- to 8-year-old alleged victims of sexual abuse. There were age differences in the total number of details elicited as well as in the number of details elicited using each of the different types of prompts, especially invitations. More details were elicited from older than from younger children in response to all types of prompts, but there were no age differences in the proportion of details (about 50%) elicited using invitations. Cued invitations elicited 18% of the total details, and the number of details elicited using cued invitations increased with age. Action-based cues consistently elicited more details than other types of cues. C1 NICHD, Sect Social & Emot Dev, NIH, Bethesda, MD 20892 USA. Salt Lake Cty Childrens Justice Ctr, Salt Lake City, UT USA. RP Lamb, ME (reprint author), NICHD, Sect Social & Emot Dev, NIH, Rockledge 1 Ctr,Suite 8048, Bethesda, MD 20892 USA. NR 68 TC 107 Z9 108 U1 4 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2003 VL 71 IS 5 BP 926 EP 934 DI 10.1037/0022-006X.71.5.926 PG 9 WC Psychology, Clinical SC Psychology GA 723HC UT WOS:000185426100008 PM 14516241 ER PT J AU Cassarino, DS Xue, W Shannon, KJ AF Cassarino, DS Xue, W Shannon, KJ TI Widespread cutaneous and perioral metastases of mesothelioma SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID MALIGNANT MESOTHELIOMA; SKIN; DIAGNOSIS AB Background: Cutaneous involvement by mesothelioma represents a rare occurrence from an uncommon neoplasm. Most cases have resulted from local extension of an underlying body cavity mesothelioma or from surgical site contamination. We could only find six previously reported cases of distant cutaneous metastases of mesothelioma. Methods: We describe a case of metastatic mesothelioma involving multiple skin sites and the lip in a 64-year-old man with an underlying primary pleural mesothelioma. Results: A 64-year-old man presented with a lip lesion clinically diagnosed as keratoacanthoma vs. squamous cell carcinoma. Evaluation of the lip biopsy revealed tubulo-glandular and acinar-like arrangements of plump epithelioid cells with a hobnailed appearance, vesicular nuclei, and prominent nucleoli. The initial impression of metastatic carcinoma was revised to probable mesothelioma upon discovery of a previous history of pleural mesothelioma. Positive immunohistochemical stains for anti-cytokeratin, anti-calretinin, and HBME-1 and negative stains for anti-CEA, Leu-M1, B72.3, and Ber-Ep4 confirmed the diagnosis. Conclusion: We report a rare example of multiple cutaneous metastases of mesothelioma. We also demonstrate the usefulness of relatively new and specific immunomarkers for mesothelioma vs. adenocarcinoma. Metastatic mesothelioma to the skin or lip is a very rare occurrence but should be considered in the differential diagnosis of malignant epithelioid neoplasms. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Cassarino, DS (reprint author), Univ Calif Irvine, Irvine Dermatopathol Lab, 101 City Dr S,Bdy 52,Rt 98, Orange, CA 92868 USA. OI Cassarino, David/0000-0001-8875-0858 NR 15 TC 24 Z9 24 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD OCT PY 2003 VL 30 IS 9 BP 582 EP 585 DI 10.1034/j.1600-0560.2003.00110.x PG 4 WC Dermatology; Pathology SC Dermatology; Pathology GA 724EB UT WOS:000185473200010 PM 14507409 ER PT J AU Feng, JQ Huang, H Lu, Y Ye, L Xie, Y Tsutsui, TW Kunieda, T Castranio, T Scott, G Bonewald, LB Mishina, Y AF Feng, JQ Huang, H Lu, Y Ye, L Xie, Y Tsutsui, TW Kunieda, T Castranio, T Scott, G Bonewald, LB Mishina, Y TI The dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE Dmp1 expression; bone; tooth; development; knockout mice ID COMPLEMENT-MEDIATED ATTACK; ACIDIC PHOSPHOPROTEIN; TARGETED DISRUPTION; BONE SIALOPROTEIN; DEFICIENT MICE; GENE; OSTEOPONTIN; LEADS; EVASION; BINDING AB Dentin Matrix Protein I (Dmp1) was originally identified from dentin. However, its expression and function in vivo are not clear. To clarify these two issues, we have generated mice carrying a truncated Dmp1 gene by using gene targeting to replace exon 6 with a lacZ gene. Northern blot analysis shows the expected 5.8-kb Dmp1-lacZ fusion transcript and loss of the wild-type 2.8-kb Dmp1 transcript, confirmed by a lack of immunostaining for the protein. Using heterozygous animals, we demonstrate that Dmp1 is specific for mineralized tissues. Not previously shown, Dmp1 is also expressed in pulp cells. Dmp1-deficient embryos and newborns display no apparent gross abnormal phenotype, although there are a modest expansion of the hypertrophic chondrocyte zone and a modest increase in the long bone diameter. This suggests that DMPI is not essential for early mouse skeletal or dental development. C1 Univ Missouri, Sch Dent, Dept Oral Biol, Kansas City, MO 64108 USA. Third Mil Med Univ, Dept Orthopaed Surg, Inst Surg Res, Daping Hosp, Chongqing, Peoples R China. Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC USA. Okayama Univ, Grad Sch Nat Sci & Technol, Okayama, Japan. RP Feng, JQ (reprint author), Univ Missouri, Sch Dent, Dept Oral Biol, 650 E 25th St, Kansas City, MO 64108 USA. FU NIDCR NIH HHS [DE00455, DE13221, DE13480] NR 24 TC 133 Z9 138 U1 4 U2 9 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2003 VL 82 IS 10 BP 776 EP 780 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 726PQ UT WOS:000185608500003 PM 14514755 ER PT J AU Hoffman, RM Harlan, LC Klabunde, CN Gilliland, FD Stephenson, RA Hunt, WC Potosky, AL AF Hoffman, RM Harlan, LC Klabunde, CN Gilliland, FD Stephenson, RA Hunt, WC Potosky, AL TI Racial differences in initial treatment for clinically localized prostate cancer - Results from the prostate cancer outcomes study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 02-04, 2002 CL ATLANTA, GEORGIA SP Soc Gen Internal Med DE prostatic neoplasms; prostatectomy; radiation therapy; patient selection; African Americans ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; AFRICAN-AMERICAN; WHITE MEN; MEDICARE BENEFICIARIES; RENAL-TRANSPLANTATION; RADIATION-THERAPY; UNITED-STATES; GLEASON SCORE; STAGE AB OBJECTIVE: We examined whether there were racial differences in initial treatment for clinically localized prostate cancer and investigated whether demographic, socioeconomic, clinical, or tumor characteristics could explain any racial differences. DESIGN: Prospective cohort study. SETTING: Population-based tumor registries in Connecticut, Los Angeles, and Atlanta. PARTICIPANTS: We evaluated 1144 African-American and non-Hispanic white men, aged 50 to 74 years, with clinically localized cancer diagnosed between October 1994 and October 1995. MEASUREMENTS AND MAIN RESULTS: We obtained demographic, socioeconomic, and clinical data from patient surveys and medical record abstractions. We reported adjusted percentages for receiving treatment derived from multinomial logistic regression. We found an interaction between race and tumor aggressiveness. Among men with more aggressive cancers (PSA greater than or equal to 20 ng/mL or Gleason score greater than or equal to 8), African Americans were less likely to undergo radical prostatectomy than non-Hispanic whites (35.2% vs 52.0%), but more likely to receive conservative management (38.9% vs 16.3%, P= .003). Among the 71% of subjects with less aggressive cancers, African Americans and non-Hispanic whites were equally likely to receive either radical prostatectomy or radiation therapy (80.0% vs 84.5%, P= .2). CONCLUSIONS: African Americans with more aggressive cancers were less likely to undergo radical prostatectomy and more likely to be treated conservatively. These treatment differences may reflect African Americans' greater likelihood for presenting with pathologically advanced cancer for which surgery has limited effectiveness. Among men with less aggressive cancers-the majority of cases-there were no racial differences in undergoing radical prostatectomy or radiation therapy. C1 New Mexico VA Hlth Care Syst, Med Serv, Albuquerque, NM 87108 USA. Univ New Mexico, Hlth Sci Ctr, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ Utah, Sch Med, Utah Canc Registry, Salt Lake City, UT USA. Univ Utah, Sch Med, Div Urol, Salt Lake City, UT USA. RP Hoffman, RM (reprint author), New Mexico VA Hlth Care Syst, Med Serv, 111GIM,1501 San Pedro Dr SE, Albuquerque, NM 87108 USA. FU NCI NIH HHS [N01 CN067009, N01 PC067010, N01PC67005, N01PC67007, N01PC67010, N01 PC067006, N01PC67000] NR 45 TC 55 Z9 57 U1 1 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2003 VL 18 IS 10 BP 845 EP 853 DI 10.1046/j.1525-1497.2003.21105.x PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 730HF UT WOS:000185823300011 PM 14521648 ER PT J AU Meertens, L Shanmugam, V Gessain, A Beer, BE Tooze, Z Heneine, W Switzer, WM AF Meertens, L Shanmugam, V Gessain, A Beer, BE Tooze, Z Heneine, W Switzer, WM TI A novel, divergent simian T-cell lymphotropic virus type 3 in a wild-caught red-capped mangabey (Cercocebus torquatus torquatus) from Nigeria SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID PAPIO-HAMADRYAS; PAN-PANISCUS; LEUKEMIA; SUBTYPE; EPIDEMIOLOGY; INFECTION; EVOLUTION; CAMEROON; MONKEYS; AFRICA AB We present here a novel, distinct simian T-cell lymphotropic virus (STLV) found in a red-capped mangabey (Cercocebus torquatus) (CTO-NG409), wild-caught in Nigeria, that showed an HTLV-2-like Western blot (WB) seroreactivity. The complete genome (8920 bp) of CTO-NG409 STLV was related to but different from STLV-3/PHA-PH969 (13(.)5%) and STLV-3/PPA-F3 (7(.)6 %), and STLV-3/CTO604 (11(.)3 %), found in Eritrean and Senegalese baboons, and red-capped mangabeys from Cameroon, respectively. Phylogenetic analysis of a conserved tax (1180 bp) sequence and the env gene (1482 bp) confirmed the relatedness of STLV-3/ CTO-NG409 to the STLV-3 subgroup. Molecular clock analysis of env estimated that STLV-3/CTO-NG409 diverged from East and West/Central African STLV-3s about 140 900 +/- 12 400 years ago, suggesting an ancient African origin of STLV-3. Since phylogenetic evidence suggests multiple interspecies transmissions of STLV-1 to humans, and given the antiquity and wide distribution of STLV-3 in Africa, a search for STLV-3 in human African populations with HTLV-2-like WB patterns is warranted. C1 Natl Ctr Infect Dis, CDCP, HIV & retrovirol Branch, Div AIDS STD & TB Lab Res, Atlanta, GA 30333 USA. Inst Pasteur, Dept Ecosyst & Epidemiol Maladies Infect, Unite Epidemiol Physiopathol Virus Oncogenes, F-75724 Paris 15, France. NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. RP Switzer, WM (reprint author), Natl Ctr Infect Dis, CDCP, HIV & retrovirol Branch, Div AIDS STD & TB Lab Res, 1600 Clifton Rd,MS G-19, Atlanta, GA 30333 USA. EM bis3@cdc.gov RI Meertens, Laurent/E-8043-2017 NR 18 TC 24 Z9 24 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD OCT PY 2003 VL 84 BP 2723 EP 2727 DI 10.1099/vir.0.19253-0 PN 10 PG 5 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 777CB UT WOS:000189155700012 PM 13679606 ER PT J AU Zollner, G Fickert, P Fuchsbichler, A Silbert, D Wagner, M Arbeiter, S Gonzalez, FJ Marschall, HU Zatloukal, K Denk, H Trauner, M AF Zollner, G Fickert, P Fuchsbichler, A Silbert, D Wagner, M Arbeiter, S Gonzalez, FJ Marschall, HU Zatloukal, K Denk, H Trauner, M TI Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine SO JOURNAL OF HEPATOLOGY LA English DT Article DE bile acid; cholestasis; orphan nuclear receptor; transcription factor ID SALT EXPORT PUMP; RESISTANCE-ASSOCIATED PROTEIN-3; CONSTITUTIVE ANDROSTANE RECEPTOR; PRIMARY BILIARY-CIRRHOSIS; FOOD-DERIVED CARCINOGEN; NECROSIS-FACTOR-ALPHA; FARNESOID-X-RECEPTOR; RAT-LIVER; OBSTRUCTIVE CHOLESTASIS; HEPATIC INDUCTION AB Background/Aims: Adaptive changes in transporter expression in liver and kidney provide alternative excretory pathways for biliary constituents during cholestasis and may thus attenuate liver injury. Whether adaptive changes in ATP-binding cassette (ABC) transporter expression are stimulated by bile acids and their nuclear receptor FXR is unknown. Methods: Hepatic, renal and intestinal ABC transporter expression was compared in cholic acid (CA)- and ursodeoxycholic acid (UDCA)-fed wild-type (FXR+/+) and FXR knock-out mice (FXR-/-). Expression was assessed by reverse transcription-polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Results: CA feeding stimulated hepatic Mrp2, Mrp3, Bsep and renal Mrp2 as well as intestinal Mrp2 and Mrp3 expression. Lack of Bsep induction by CA in FXR-/- was associated with disseminated hepatocyte necrosis which was not prevented by compensatory induction of Mrp2 and Mrp3. With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity. Conclusions: Toxic CA and non-toxic UDCA induce adaptive ABC transporter expression, independent of FXR with the exception of Bsep. Stimulation of hepatic Mrp3 as well as intestinal and renal Mrp2 by UDCA may contribute to its therapeutic effects by inducing alternative excretory routes for bile acids and other cholephiles. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 Karl Franzens Univ Graz, Dept Med, Div Gastroenterol & Hepatol, A-8036 Graz, Austria. Karl Franzens Univ Graz, Dept Pathol, Graz, Austria. Natl Inst Hlth, Div Basic Sci, Bethesda, MD USA. Huddinge Univ Hosp, Karolinska Inst, Stockholm, Sweden. RP Trauner, M (reprint author), Karl Franzens Univ Graz, Dept Med, Div Gastroenterol & Hepatol, Auenbruggerplatz 15, A-8036 Graz, Austria. OI Zollner, Gernot/0000-0002-8117-6061; Fickert, Peter/0000-0003-0906-4636 NR 53 TC 120 Z9 121 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD OCT PY 2003 VL 39 IS 4 BP 480 EP 488 DI 10.1016/S0168-8278(03)00228-9 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730GD UT WOS:000185820100003 PM 12971955 ER PT J AU Kozlov, SV Dobrovolskaia, MA Rice, NR Stewart, CL Vogel, SN AF Kozlov, SV Dobrovolskaia, MA Rice, NR Stewart, CL Vogel, SN TI A novel cell-based system for the rapid quantitative evaluation of (anti)-inflammatory potential of test substances SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE NF-kappa B; cell-based assay; retroviral gene delivery; high-throughput screening model; TNF; IL-1; LPS ID TUMOR-NECROSIS-FACTOR; ASSAY AB The control of NF-kappaB activation is a proven therapeutic strategy in the treatment of multiple inflammatory disorders. Drug discovery and development for such a therapy demands a battery of assays to reliably demonstrate both clinical effectiveness and biological safety of prospective medications. Unlike traditional in vitro biochemical analyses, cell-based assays more closely mimic the actual in vivo physiologic environment, addressing simultaneously biological activity and toxicity issues. A novel assay system, based solely on the drug resistance of a genetically engineered cell line, has been developed to provide rapid quantitative evaluation of the (anti)-inflammatory potential of test substances. The assay principle is based on the ability of bona fide inflammatory agents to activate the transcription factor NF-kappaB in cultured cells. In our model, expression of a dual drug resistance marker, driven by an NF-kappaB-dependent minimal promoter, provides a selective and highly sensitive scheme with a quantitative readout to detect biochemical agents with pro-or anti -inflammatory properties. The novel cell-based system is inexpensive, simple to perform (requiring only basic cell culture skills), accurate, and provides sensitivity comparable to that of the electrophoretic mobility shift assay and quantitative ELISA. In addition, the dual selection capability of the model provides a powerful tool to discover novel molecular components of the NF-kappaB signal transduction pathway. Published by Elsevier B.V. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NCI, Regulat Cell Growth Lab, Ft Detrick, MD 21702 USA. Uniformed Serv Univ Hlth Sci, Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20814 USA. PPD Inc, Dept Immunochem, Richmond, VA 23230 USA. Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21210 USA. RP Kozlov, SV (reprint author), PPD Inc, Dept Immunochem, 2244 Dabney Rd,Bldg A, Richmond, VA 23230 USA. FU NIAID NIH HHS [AI-44936, AI-18797] NR 21 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 1 PY 2003 VL 281 IS 1-2 BP 51 EP 63 DI 10.1016/S0022-1759(03)00272-2 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 741YG UT WOS:000186487500006 PM 14580881 ER PT J AU Betts, MR Brenchley, JM Price, DA De Rosa, SC Douek, DC Roederer, M Koup, RA AF Betts, MR Brenchley, JM Price, DA De Rosa, SC Douek, DC Roederer, M Koup, RA TI Sensitive and viable identification of antigen-specific CD8+T cells by a flow cytometric assay for degranulation SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE degranulation; T lymphocyte; intraceflular cytokine; CD107a; CD107b ID CYTOTOXIC T-LYMPHOCYTES; RESPONSES; GLYCOPROTEINS; LYSOSOMES; MECHANISM; INFECTION; CYTOKINES; DEATH AB Flow cytometric detection of antigen-specific CD8+ T cells has previously been limited to MHC-class I tetramer staining or intracellular cytokine production, neither of which measure the cytolytic potential of these cells. Here we present a novel technique to enumerate antigen-specific CD8+ T cells using a marker expressed on the cell surface following activation induced degranulation, a necessary precursor of cytolysis. This assay measures the exposure of CD107a and b, present in the membrane of cytotoxic granules, onto the cell surface as a result of degranulation. Acquisition of cell surface CD107a and In is associated with loss of intracellular perform and is inhibited by colchicine, indicating that exposure of CD107a and b to the cell surface is dependent on degranulation. CD107a and b are expressed on the cell surface of CD8+ T cells following activation with cognate peptide, concordant with production of intracellular IFNgamma. Finally, CD107-expressing CD8+ T cells are shown to mediate cytolytic activity in an antigen-specific manner. Measurement of CD107a and b expression can also be combined with MHC-class I tetramer labeling and intracellular cytokine staining to provide a more complete assessment of the functionality of CD8+ T cells expressing cognate T cell receptors (TCR). (C) 2003 Elsevier B.V. All rights reserved. C1 NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Betts, MR (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011; Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 22 TC 935 Z9 967 U1 6 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 1 PY 2003 VL 281 IS 1-2 BP 65 EP 78 DI 10.1016/S0022-1759(03)00265-5 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 741YG UT WOS:000186487500007 PM 14580882 ER PT J AU Sandler, NG Mentink-Kane, MM Cheever, AW Wynn, TA AF Sandler, NG Mentink-Kane, MM Cheever, AW Wynn, TA TI Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MESSENGER-RNA EXPRESSION; SCHISTOSOMA-MANSONI; MATRIX METALLOPROTEINASES; GRANULOMA-FORMATION; EPITHELIAL-CELLS; DEFICIENT MICE; ATOPIC ASTHMA; IFN-GAMMA; IN-VITRO; T-CELLS AB T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated-with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis. C1 NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 50 S Dr,Room 6153,MSC 8003, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 97 TC 168 Z9 177 U1 2 U2 14 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2003 VL 171 IS 7 BP 3655 EP 3667 PG 13 WC Immunology SC Immunology GA 725MY UT WOS:000185548000042 PM 14500663 ER PT J AU Cortez, KJ Fischer, SH Fahle, GA Calhoun, LB Childs, RW Barrett, AJ Bennett, JE AF Cortez, KJ Fischer, SH Fahle, GA Calhoun, LB Childs, RW Barrett, AJ Bennett, JE TI Clinical trial of quantitative real-time polymerase chain reaction for detection of cytomegalovirus in peripheral blood of allogeneic hematopoietic stem-cell transplant recipients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CMV DNA; MARROW TRANSPLANTATION; PCR ASSAY; DISEASE; GANCICLOVIR; PREVENTION; INFECTION AB The preemptive therapy of cytomegalovirus (CMV) reactivation is useful for the prevention of CMV disease in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. We compared results of the pp65 CMV antigenemia test with quantitative touch-down polymerase chain reaction (Q-PCR) on unfractionated whole blood for the detection of CMV reactivation in 51 HSCT recipients. Forty episodes of reactivation in 28 patients were detected by antigenemia and treated by antiviral drugs. Q-PCR detected CMV DNA in 39 (97.5%) of 40 reactivation episodes. False-positive results occurred in 3% of tests, of which 63% were borderline positive. Q-PCR results were positive earlier than antigenemia results in 30 (77%) of 39 episodes detected by antigenemia. Q-PCR remained positive after treatment was discontinued in 14 (36%) of 39 episodes and predicted the return of CMV reactivation in 4 (31%) of 13 episodes. Q-PCR was more sensitive than the antigenemia test and had sufficient specificity for clinical use. C1 NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NHLBI, Stem Cell Allotransplant Unit, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Rm 11C304,10 Ctr Dr, Bethesda, MD 20892 USA. NR 12 TC 48 Z9 51 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2003 VL 188 IS 7 BP 967 EP 972 DI 10.1086/378413 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 726HV UT WOS:000185593900005 PM 14513415 ER PT J AU Kalabokes, V Lavker, R Moshell, AN Price, VH Shapiro, J Stenn, KS Sundberg, J AF Kalabokes, V Lavker, R Moshell, AN Price, VH Shapiro, J Stenn, KS Sundberg, J TI Fourth International Research Workshop on Alopecia Areata - Renaissance Mayflower Hotel and Lister Hill Center, National Library of Medicine - Washington, DC, October 31, November 1 and 2, 2002 - Introduction SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Editorial Material C1 Natl Alopecia Areata Fdn, San Rafael, CA USA. NIAMSD, Bethesda, MD 20892 USA. RP Kalabokes, V (reprint author), Natl Alopecia Areata Fdn, San Rafael, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD OCT PY 2003 VL 8 IS 2 BP 155 EP 156 DI 10.1046/j.1087-0024.2003.00817.x PG 2 WC Dermatology SC Dermatology GA 729CR UT WOS:000185754200001 ER PT J AU Ohyama, M Vogel, JC AF Ohyama, M Vogel, JC TI Gene delivery to the hair follicle SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Article DE hair follicle; gene therapy; hair cycle; anagen ID SONIC HEDGEHOG; STEM-CELLS; EXPRESSION; THERAPY; MICE; SKIN AB Skin and appendages such as hair follicles are attractive candidates for gene therapy targets because they are easily accessible and can be removed and genetically manipulated in culture. Hair follicles are of special interest because our understanding of hair follicle biology and pathophysiology has progressed significantly in recent years, and we now have a much better understanding of how genes, encoding transcription factors, growth factors, and cytokines regulate both hair follicle development and the cycles of hair follicle growth (anagen, catagen, and telogen) (Cotsarelis and Millar, 2001; Millar, 2002). Also important is the characterization of an increasing number of genetic mutations that affect hair growth and can result in hair loss (Cotsarelis and Millar, 2001). Gene therapy could be used to introduce genes that manipulate hair follicle growth and cycling or that replace the mutated defective gene with a normal wildtype gene. As our understanding of the polygenic basis for a number of alopecias improves, gene-based therapies might also be designed to provide more promising treatments than current palliative therapies for hair loss. This review will describe some of the recent progress in gene delivery to hair follicles and discuss examples of how gene delivery can cause phenotypic changes in hair follicles. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RI Ohyama, Manabu/J-5524-2014 OI Ohyama, Manabu/0000-0002-2662-5717 NR 12 TC 16 Z9 16 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD OCT PY 2003 VL 8 IS 2 BP 204 EP 206 DI 10.1046/j.1087-0024.2003.00810.x PG 3 WC Dermatology SC Dermatology GA 729CR UT WOS:000185754200012 PM 14582674 ER PT J AU Diwadkar-Navsariwala, V Novotny, JA Gustin, DM Sosman, JA Rodvold, KA Crowell, JA Stacewicz-Sapuntzakis, M Bowen, PE AF Diwadkar-Navsariwala, V Novotny, JA Gustin, DM Sosman, JA Rodvold, KA Crowell, JA Stacewicz-Sapuntzakis, M Bowen, PE TI A physiological pharmacokinetic model describing the disposition of lycopene in healthy men SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lycopene disposition; carotenoids; physiological model; WinSAAM; human Study; tissue distribution ID CAROTENOID-BINDING-PROTEIN; LOW-DENSITY LIPOPROTEIN; PROSTATE-CANCER RISK; BETA-CAROTENE; INTESTINAL-ABSORPTION; VITAMIN-A; PLASMA; SERUM; TRANSPORT; RETINOL AB A physiological pharmacokinetic model was developed to describe the disposition of lycopene, delivered as a tomato beverage formulation in five graded doses (10, 30, 60, 90, or 120 mg), for a phase I study in healthy male subjects (five per dose). Blood was collected before dose administration (0 h) and at scheduled intervals until 672 h. Serum concentrations of carotenoids and vitamins were measured by high performance liquid chromatography analysis. The model was comprised of seven compartments: gastrointestinal tract, enterocytes, chylomicrons, plasma lipoproteins, fast-turnover liver, slow-turnover tissues, and a delay compartment before the enterocytes. As predicted, the percent absorption at the 10 mg dose (33.9 +/- 8.1%) was significantly greater than at the higher doses; however, the amount of lycopene absorbed (mg) was not statistically different (mean: 4.69 +/- 0.55 mg) between doses, suggesting a possible saturation of absorptive mechanisms. jlr The slow-turnover tissue compartment served as a slow-depleting reservoir for lycopene, and the liver represented the fast-turnover pool. Independent of dose, 80% of the subjects absorbed less than 6 mg of lycopene. This may have important implications for planning clinical trials with pharmacological doses of lycopene in cancer control and prevention if absorption saturation occurs at levels that are already being consumed in the population.-Diwadkar-Navsariwala, V, J. A. Novotny, D. M. Gustin, J. A. Sosman, K. A. Rodvold, J. A. Crowell, M. Stacewicz-Sapuntzakis, and P. E. Bowen. A physiological pharmacokinetic model describing the disposition of lycopene in healthy men. J. Lipid Res. 2003. 44: 1927-1939. C1 Univ Illinois, Dept Human Nutr, Chicago, IL 60612 USA. Univ Illinois, Dept Pharm Practice, Chicago, IL 60612 USA. USDA ARS, Beltsville Human Nutr Res Ctr, Diet & Human Performance Lab, Beltsville, MD 20705 USA. Univ Chicago, Dept Med, Div Hematol Oncol, Chicago, IL 60637 USA. Vanderbilt Univ, Dept Med, Div Hematol Oncol, Nashville, TN 37235 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Bowen, PE (reprint author), Univ Illinois, Dept Human Nutr, Chicago, IL 60612 USA. FU NCI NIH HHS [N01-CN-85081-70]; NCRR NIH HHS [M01-RR-13987] NR 48 TC 35 Z9 37 U1 0 U2 4 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2003 VL 44 IS 10 BP 1927 EP 1939 DI 10.1194/jlr.M200130-JLR200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 734FG UT WOS:000186043900013 PM 12867539 ER PT J AU Ness, SL Ben-Yosef, T Bar-Lev, A Madeo, AC Brewer, CC Avraham, KB Kornreich, R Desnick, RJ Willner, JP Friedman, TB Griffith, AJ AF Ness, SL Ben-Yosef, T Bar-Lev, A Madeo, AC Brewer, CC Avraham, KB Kornreich, R Desnick, RJ Willner, JP Friedman, TB Griffith, AJ TI Genetic homogeneity and phenotypic variability among Ashkenazi Jews with Usher syndrome type III SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID NONSYNDROMIC DEAFNESS; RETINITIS-PIGMENTOSA; HEARING-LOSS; MUTATIONS; PREVALENCE; FREQUENCY; CATARACT; FAMILIES; 167DELT; GJB2 C1 NIDCD, Hearing Sect, NIH, Rockville, MD 20850 USA. Mt Sinai Sch Med, Dept Human Genet, New York, NY USA. NIDCD, Sect Human Genet, NIH, Rockville, MD USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. NIDCD, Sect Gene Struct & Funct, NIH, Rockville, MD USA. RP Griffith, AJ (reprint author), NIDCD, Hearing Sect, NIH, 5 Res Court,Room 2A01, Rockville, MD 20850 USA. RI Madeo, Anne/K-2880-2012 FU NCRR NIH HHS [RR-M01-00071]; NIDCD NIH HHS [1-Z01-DC-00039-04] NR 29 TC 56 Z9 56 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT 1 PY 2003 VL 40 IS 10 BP 767 EP 772 DI 10.1136/jmg.40.10.767 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 734JJ UT WOS:000186051800009 PM 14569126 ER PT J AU Giusti, RM Rutter, JL Duray, PH Freedman, LS Konichezky, M Fisher-Fischbein, J Greene, MH Maslansky, B Fischbein, A Gruber, SB Rennert, G Ronchetti, RD Hewitt, SM Struewing, JP Iscovich, J AF Giusti, RM Rutter, JL Duray, PH Freedman, LS Konichezky, M Fisher-Fischbein, J Greene, MH Maslansky, B Fischbein, A Gruber, SB Rennert, G Ronchetti, RD Hewitt, SM Struewing, JP Iscovich, J TI A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID FOUNDER MUTATIONS; BREAST-CANCER; 185DELAG MUTATION; JEWISH MEN; FREQUENCY; 6174DELT; WOMEN; GENES; JEWS; RISK C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Rabin Med Ctr, Dept Pathol, Petah Tiqwa, Israel. Int Fertil Inst, Raanana, Israel. Selikoff Ctr Environm Hlth & Human Dev, Raanana, Israel. Univ Michigan, Div Med Genet, Ann Arbor, MI 48109 USA. Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. RP Giusti, RM (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Execut Plaza S,Room 7024,6120 Execut Blvd,MSC 723, Rockville, MD 20852 USA. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; Hewitt, Stephen/0000-0001-8283-1788; Rutter, Joni/0000-0002-6502-2361 NR 14 TC 44 Z9 45 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT 1 PY 2003 VL 40 IS 10 BP 787 EP 792 DI 10.1136/jmg.40.10.787 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 734JJ UT WOS:000186051800012 PM 14569130 ER PT J AU D'Costa, J Harvey-White, J Qasba, P Limaye, A Kaneski, CR Davis-Warren, A Brady, RO Bankiewicz, KS Major, EO Arya, SK AF D'Costa, J Harvey-White, J Qasba, P Limaye, A Kaneski, CR Davis-Warren, A Brady, RO Bankiewicz, KS Major, EO Arya, SK TI HIV-2 derived lentiviral vectors: Gene transfer in Parkinson's and Fabry disease models in vitro SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE vector validation; transgene expression; neuronal cells; patient fibroblasts ID IMMUNODEFICIENCY-VIRUS TYPE-2; AMINO-ACID DECARBOXYLASE; PACKAGING SIGNAL; MULTIPLE ORGANS; CELLS; EXPRESSION; THERAPY; ENCAPSIDATION; DELIVERY; INHIBITION AB Lentiviral vectors are prime candidate vectors for gene transfer into dividing and non-dividing cells, including neuronal cells and stem cells. For safety, HIV-2 lentiviral vectors may be better suited for gene transfer in humans than HIV-1 lentiviral vectors. HIV-2 vectors cross-packaged in HIV-1 cores may be even safer. Demonstration of the efficacy of these vectors in disease models will validate their usefulness. Parkinson's disease and Fabry disease provide excellent models for validation. Parkinson's disease is a focal degeneration of dopaminergic neurons in the brain with progressive loss of ability to produce the neurotransmitter dopamine. Current treatment entails administration of increasing doses of L-dopa, with attendant toxicity. We explore here the hypothesis that gene transfer of aromatic acid decarboxylase (AADC), a key enzyme in the pathway, will make neuronal cells more efficiently convert L-dopa into dopamine. Fabry disease on the other hand is a monogenic inherited disease, characterized by alpha-galactosidase A (AGA) deficiency, resulting in glycolipid accumulation in several cell types, including fibroblasts. Animal models for preclinical investigations of both of these diseases are available. We have designed monocistronic HIV-1 and HIV-2 vectors with the AADC transgene and monocistronic and bicistronic HIV-2 vectors with the AGA and puromycin resistance transgenes. They were packaged with either HIV-2 cores or HIV-1 cores (hybrid vectors). Gene transfer of AADC gene in neuronal cells imparted the ability on the transcluced cells to efficiently convert L-dopa into dopamine. Similarly, the AGA vectors induced Fabry fibroblasts to produce high levels of AGA enzyme and caused rapid clearance of the glycolipids from the cells. Both monocistronic and bicistronic vectors were effective. Thus, the insertion of a second gene downstream in the bicistronic vector was not deleterious. In addition, both the self-packaged vectors and the cross-packaged hybrid vectors were effective in gene transfer. (C) 2003 Wiley-Liss, Inc. C1 BRL CCR, Bethesda, MD 20892 USA. DTP DCTD, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Basic Res Lab, NIH, Bethesda, MD USA. Natl Inst Neruol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. Natl Inst Neurol Disorders & Stroke, Dev & Metab Neruol Branch, NIH, Bethesda, MD USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD USA. RP Arya, SK (reprint author), BRL CCR, 6130 Exect Bldv,EPN 8154, Bethesda, MD 20892 USA. OI Kaneski, Christine/0000-0003-1453-2502 NR 39 TC 13 Z9 14 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2003 VL 71 IS 2 BP 173 EP 182 DI 10.1002/jmv.10467 PG 10 WC Virology SC Virology GA 716QL UT WOS:000185039800002 PM 12938190 ER PT J AU Fitch, RW Garraffo, HM Spande, TF Yeh, HJC Daly, JW AF Fitch, RW Garraffo, HM Spande, TF Yeh, HJC Daly, JW TI Bioassay-guided isolation of epiquinamide, a novel quinolizidine alkaloid and nicotinic agonist from an Ecuadoran poison frog, Epipedobates tricolor SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID NEUROBLASTOMA CLONAL LINE; ACETYLCHOLINE-RECEPTORS; DRUG DISCOVERY; LIGAND-BINDING; ION-CHANNEL; CELL-LINE; PHARMACOLOGY; FLUORESCENCE; EPIBATIDINE; EXPRESSION AB Analytical HPLC fractionation, combined with an off-line 96-well fluorescent bioassay screen, has been developed and used for the separation and screening of a natural product extract. This method was used to guide the isolation of a novel quinolizidine alkaloid from the methanolic skin extracts of an Ecuadoran frog, Epipedobates tricolor. The structure was determined on the basis of MS, IR, and NMR analysis as (1R*,10R*)-1-acetamidoquinolizidine (alkaloid 196). We have named this compound epiquinamide, reflecting its origin and structure. The activity of the isolated compound was determined in five cell lines expressing various nicotinic acetylcholine receptor subtypes. The bioactivity of epiquinamide was evaluated on the basis of membrane potential fluorescence and was found to be beta2 selective. This compound represents a new structural class of nicotinic agonists and a potential lead compound for the development of new therapeutics and pharmacological probes for nicotinic receptors. The off-line screening technique was found to be very sensitive for the detection of compounds active at nicotinic receptors. C1 NIDDKD, Lab Bioorgan Chem, Sect Pharmacodynam, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Lab Bioorgan Chem, Sect Pharmacodynam, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. NR 42 TC 52 Z9 52 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2003 VL 66 IS 10 BP 1345 EP 1350 DI 10.1021/np030306u PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 737NC UT WOS:000186237800010 PM 14575435 ER PT J AU Kawakami, M Kawakami, K Puri, RK AF Kawakami, M Kawakami, K Puri, RK TI Interleukin-4-Pseudomonas exotoxin chimeric fusion protein for malignant glioma therapy SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE clinical trials; cpIL-4PE; cytotoxin therapy; malignant glioma; preclinical experimental therapy ID COMMON GAMMA-CHAIN; IL-13 RECEPTOR ALPHA-2; BREAST-CARCINOMA CELLS; INTERLEUKIN-13 RECEPTOR; PSEUDOMONAS EXOTOXIN; IN-VIVO; FUNCTIONAL COMPONENT; SIGNAL-TRANSDUCTION; CANCER-CELLS; ANTITUMOR-ACTIVITY AB Human malignant glioma cell lines, primary cell cultures, and tumor specimens derived from surgical samples have been shown to overexpress high-affinity receptors (R) for interleukin-4 (IL-4) in vitro and in situ. The significance of IL-4R expression on malignant glioma cells is still unclear. However, IL-4 has been reported to mediate functional effects in several solid tumor cell lines. These activities include inhibition of cell proliferation, regulation of adhesion molecules, and induction of signal transduction through the JAK/STAT pathway. To target IL-4Rs on tumor cells, we have produced a chimeric recombinant fusion protein consisting of a binding ligand, circularly permuted IL-4 and a mutated form of Pseudomonas exotoxin. This molecule is termed IL4(38 - 37)-PE38KDEL, cpIL4-PE, or IL-4 cytotoxin. Recombinant cpIL4-PE is highly and specifically cytotoxic to glioma cell lines in vitro, while it is not cytotoxic or less cytotoxic to hematopoietic and normal brain cells. In a nude mouse model, cpIL4-PE showed significant antitumor activity and partial or complete regression of small or large established human glioblastoma tumors. Encouraging preclinical efficacy, safety, and tolerability studies lead to testing of this agent in patients with recurrent glioblastoma. Based on these pilot studies, an extended Phase I/II clinical trial is currently ongoing to determine safety, tolerability, and efficacy of cpIL4-PE when injected stereotactically directly into the recurrent glioma by convection enhanced delivery. Preliminary clinical results suggest that cpIL4-PE can cause pronounced necrosis of recurrent glioma tumors without systemic toxicity. The central nervous system toxicities observed were attributed to the volume of infusion and/or nonspecific toxicity. Ongoing clinical trials will reveal antitumor activities of IL-4 cytotoxin in recurrent malignant glioma. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 51 TC 50 Z9 53 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2003 VL 65 IS 1 BP 15 EP 25 DI 10.1023/A:1026294416718 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 735DE UT WOS:000186096500003 PM 14649882 ER PT J AU Sampson, JH Akabani, G Archer, GE Bigner, DD Berger, MS Friedman, AH Friedman, HS Herndon, JE Kunwar, S Marcus, S McLendon, RE Paolino, A Penne, K Provenzale, J Quinn, J Reardon, DA Rich, J Stenzel, T Tourt-Uhlig, S Wikstrand, C AF Sampson, JH Akabani, G Archer, GE Bigner, DD Berger, MS Friedman, AH Friedman, HS Herndon, JE Kunwar, S Marcus, S McLendon, RE Paolino, A Penne, K Provenzale, J Quinn, J Reardon, DA Rich, J Stenzel, T Tourt-Uhlig, S Wikstrand, C TI Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE brain neoplasms; convection-enhanced delivery; immunotoxin ID FUSION TOXIN DAB486IL-2; FACTOR RECEPTOR GENE; HEMATOLOGIC MALIGNANCIES; MONOCLONAL-ANTIBODY; GLIOBLASTOMA-MULTIFORME; HUMAN GLIOMA; TRIAL; EXPRESSION; CHEMOTHERAPY; INFUSION AB TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks. C1 Duke Univ, Med Ctr, Div Neurosurg, Durham, NC 27710 USA. UCSF, San Francisco, CA USA. IVAX, Miami, FL USA. NCI, Bethesda, MD 20892 USA. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Div Neurosurg, 4th Floor,Blue Zone,4505 Busse Bldg,Box 3807, Durham, NC 27710 USA. RI Yuan, Fan/A-1287-2011 FU NCI NIH HHS [R01 CA097611]; NCRR NIH HHS [K23 RR16065] NR 42 TC 157 Z9 162 U1 1 U2 10 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2003 VL 65 IS 1 BP 27 EP 35 DI 10.1023/A:1026290315809 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 735DE UT WOS:000186096500004 PM 14649883 ER PT J AU Moriguchi, T Salem, N AF Moriguchi, T Salem, N TI Recovery of brain docosahexaenoate leads to recovery of spatial task performance SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE docosahexaenoic acid; functional recovery; infant nutrition; learning ability; Morris water maze; n-3 polyunsaturated fatty acid deficiency ID POLYUNSATURATED FATTY-ACIDS; MORRIS WATER-MAZE; VISUAL-ACUITY DEVELOPMENT; RHESUS-MONKEYS; RAT-BRAIN; OMEGA-3-FATTY-ACID DEFICIENCY; PREFRONTAL CORTEX; PRETERM INFANTS; N-3 DEFICIENCY; TERM INFANTS AB Infants fed vegetable oil-based formulas may have poorer visual function, lower cognitive scores and acquire learning tasks more slowly in comparison with those breast fed or those fed formulas supplemented with docosahexaenoate. The aim of the present study was to determine the reversibility of losses in brain function associated with the loss of brain DHA. Rats were fed very low or adequate levels of n-3 fatty acids through three generations. The n-3 fatty acid deficient animals of the F3 generation were then given an n-3 adequate diet containing alpha-linolenic and docosahexaenoic acids ( DHA) at birth, weaning ( 3 weeks) or young adulthood ( 7 weeks). The spatial task performance of these animals returned to the n-3 adequate diet was then compared using the Morris water at two different ages, at 9 or 13 weeks. Our results indicate that animals repleted since birth or at weaning were able to achieve nearly the same level of brain DHA and spatial task performance as animals maintained for three generations on an n-3 adequate diet. In the case of young adult animals, the degree of DHA and behavioral performance recovery depended upon the duration of dietary repletion with substantial recovery in animals after 6 weeks but little recovery of function after two weeks. The significance of these findings is that they indicate that at least some of the adverse effects of DHA deficiency during neurodevelopment may be reversible with an n-3 fatty acid supplemented diet. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Salem, N (reprint author), 12420 Parklawn Dr,Rooms 1-14, Rockville, MD 20852 USA. NR 57 TC 123 Z9 125 U1 3 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2003 VL 87 IS 2 BP 297 EP 309 DI 10.1046/j.1471-4159.2003.01966.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 726JN UT WOS:000185596100003 PM 14511107 ER PT J AU Furukawa, K Wang, Y Yao, PJ Fu, WM Mattson, MP Itoyama, Y Onodera, H D'Souza, I Poorkaj, PH Bird, TD Schellenberg, GD AF Furukawa, K Wang, Y Yao, PJ Fu, WM Mattson, MP Itoyama, Y Onodera, H D'Souza, I Poorkaj, PH Bird, TD Schellenberg, GD TI Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE calcium; channel; frontotemporal dementia and parkinsonism linked to chromosome 17; neurodegeneration; microtubule; tau ID HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; P301L TAU; CELLS; PROTEIN; PARKINSONISM; MISSENSE; TUBULIN; FTDP-17; TAXOL AB Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (I-Ca) density, and decreases I-Ca rundown. The reduced rundown of I-Ca by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on I-Ca. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA. C1 NIA, Synapt Physiol Unit, Neurosci Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. Tohoku Univ, Sch Med, Dept Neurol, Sendai, Miyagi 980, Japan. Vet Affair Puget Sound Hlth Care Syst, Geriatr Res Educ Clin Ctr, Seattle, WA USA. Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Furukawa, K (reprint author), NIA, Synapt Physiol Unit, Neurosci Lab, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 45 TC 34 Z9 36 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2003 VL 87 IS 2 BP 427 EP 436 DI 10.1046/j.1471-4159.2003.02020.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 726JN UT WOS:000185596100016 PM 14511120 ER PT J AU Hasegawa, T Matsuzaki, M Takeda, A Kikuchi, A Furukawa, K Shibahara, S Itoyama, Y AF Hasegawa, T Matsuzaki, M Takeda, A Kikuchi, A Furukawa, K Shibahara, S Itoyama, Y TI Increased dopamine and its metabolites in SH-SY5Y neuroblastoma cells that express tyrosinase SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dopamine; neuromelanin; oxidative stress; Parkinson's disease; quinone; tyrosinase ID MELANOSOMAL MEMBRANE-PROTEINS; HUMAN SUBSTANTIA-NIGRA; OXIDATIVE STRESS; PARKINSONS-DISEASE; MELANIN; CDNA; HYDROXYLASE; INHIBITION; MUTATION; QUINONES AB Oxidized metabolites of dopamine, known as dopamine quinone derivatives, are thought to play a pivotal role in the degeneration of dopaminergic neurons. Although such quinone derivatives are usually produced via the autoxidation of catecholamines, tyrosinase, which is a key enzyme in melanin biosynthesis via the production of DOPA and subsequent molecules, may potentially accelerate the induction of catecholamine quinone derivatives by its oxidase activity. In the present study, we developed neuronal cell lines in which the expression of human tyrosinase was inducible. Overexpression of tyrosinase in cultured cell lines resulted in (i) increased intracellular dopamine content; (ii) induction of oxidase activity not only for DOPA but also for dopamine; (iii) formation of melanin pigments in cell soma; and (iv) increased intracellular reactive oxygen species. Interestingly, the expressed tyrosinase protein was initially distributed in the entire cytoplasm and then accumulated to form catecholamine-positive granular structures by 3 days after the induction. The granular structures consisted of numerous rounded, dark bodies of melanin pigments and were largely coincident with the distribution of lysosomes. This cellular model that exhibits increased dopamine production will provide a useful tool for detailed analyses of the potentially noxious effects of oxidized catecholamine metabolites. C1 Tohoku Univ, Sch Med, Dept Neurol, Aoba Ku, Sendai, Miyagi 9808574, Japan. NIA, Synapt Physiol Unit, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Tohoku Univ, Sch Med, Dept Mol Biol & Appl Physiol, Sendai, Miyagi 980, Japan. RP Takeda, A (reprint author), Tohoku Univ, Sch Med, Dept Neurol, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. RI Shibahara, Shigeki/M-3644-2014 NR 41 TC 25 Z9 25 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2003 VL 87 IS 2 BP 470 EP 475 DI 10.1046/j.1471-4159.2003.02008.x PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 726JN UT WOS:000185596100020 PM 14511124 ER PT J AU Rusnak, M House, SB Gainer, H AF Rusnak, M House, SB Gainer, H TI Long-term effects of ciliary neurotrophic factor on the survival of vasopressin magnocellular neurones in the rat supraoptic nucleus in vitro SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE axotomy; apoptosis; vasopressin mRNA; hypothalamus; organotypic culture; CNTF ID HYPOTHALAMO-NEUROHYPOPHYSEAL SYSTEM; CENTRAL-NERVOUS-SYSTEM; OXYTOCIN NEURONS; ORGANOTYPIC CULTURES; SUPRACHIASMATIC NUCLEUS; SYMPATHETIC NEURONS; GENE-TRANSCRIPTION; CELL-DEATH; DIFFERENTIATION; LOCALIZATION AB The use of hypothalamic organotypic cultures for the long-term study of mechanisms in magnocellular neurones (MCNs) of the hypothalamic-neurohypophysial system has been limited by the relatively poor maintenance of the vasopressin MCNs in vitro. Recent studies have shown that addition of ciliary neurotrophic factor (CNTF) to the media significantly reduced the apoptosis of both oxytocin and vasopressin MCNs. Here, we studied various temporal factors in the CNTF treatment that can influence the efficacy of MCN survival. Immunohistochemistry was used to identify and count surviving vasopressin and oxytocin MCNs in the supraoptic nucleus (SON) in hypothalamic slices cultured in the presence of CNTF (10 ng/ml media) for various time intervals, and in situ hybridization for vasopressin mRNA was used to evaluate the vasopressin mRNA gene expression in the SON under the same conditions. The presence of CNTF in the medium for 10 days produced a maximal increase in the survival of vasopressin MCNs (by 11-fold) and in the survival of oxytocin-MCNs (by approximately four-fold) over controls. These effects persisted for an additional 7-10 days even in the absence of CNTF. The ability of CNTF to increase survival of the MCNs or increase vasopressin mRNA levels in the SON required that the CNTF be present during the initial 7-10 days of culture. CNTF failed to rescue vasopressin or oxytocin MCNs when added to the media only for the last 7 days of a total of 14 days in vitro. Similar results were observed when SON vasopressin mRNA levels were measured. These results indicate that the presence of CNTF is required at the outset to rescue the vasopressin and oxytocin MCN from axotomy induced apoptosis, and that, after 10 days in CNTF, the MCNs no longer require the CNTF for survival. C1 Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bldg 36,Room 4D-18, Bethesda, MD 20892 USA. NR 41 TC 12 Z9 12 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD OCT PY 2003 VL 15 IS 10 BP 933 EP 939 DI 10.1046/j.1365-2826.2003.01080.x PG 7 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 720RX UT WOS:000185274700005 PM 12969237 ER PT J AU Dalakas, MC AF Dalakas, MC TI Enteroviruses in chronic fatigue syndrome: "now you see them, now you don't'' SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Editorial Material 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 4 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2003 VL 74 IS 10 BP 1361 EP 1362 DI 10.1136/jnnp.74.10.1361 PG 2 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 736UM UT WOS:000186191600002 PM 14570825 ER PT J AU Andringa, G Du, F Chase, TN Bennett, MC AF Andringa, G Du, F Chase, TN Bennett, MC TI Mapping of rat brain using the synuclein-1 monoclonal antibody reveals somatodendritic expression of alpha-synuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE immumohistochemistry; neuron; Parkinson disease; rodent; subcellular distribution; synuclein ID MULTIPLE SYSTEM ATROPHY; GLIAL CYTOPLASMIC INCLUSIONS; SPORADIC PARKINSONS-DISEASE; CENTRAL-NERVOUS-SYSTEM; A-BETA COMPONENT; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; NEURODEGENERATIVE DISORDERS; PRESYNAPTIC PROTEIN; SUBSTANTIA-NIGRA AB The neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson disease and other neurodegenerative diseases. Although many studies report that alpha-synuclein expression is restricted to neuronal presynaptic terminals, this protein aggregates in Lewy bodies in somata that are typically distant from their axon terminals. Few studies have addressed this paradox and there has been no compelling explanation proposed for. the apparent discrepancy between the locus of neuronal alpha-synuclein expression and the loci of Lewy bodies in the majority of Parkinson disease cases. We explored this issue by extensively characterizing the monoclonal antibody Synuclein-1 (Syn-1) and using this highly selective antibody to map the distribution of alpha-synuclein throughout rat brain and in human substantia nigra (SN). Additionally, alpha-synuclein expression in rat SN detected by 2 polyclonal antibodies against alpha-synuclein was compared with that detected by the Syn-1 antibody. In contrast with many previous reports, alpha-synuclein was detected by Syn-1 in neuronal somata and dendrites in restricted brain regions, as well as more ubiquitously in axons and terminals. The strongest alpha-synuclein neuronal expression in rat was found in brainstem and cortical regions that are homologous to regions prone to Lewy body formation in humans. The Syn-1 antibody labeled abundant somatodendritic alpha-synuclein in both rat and human SN, a major locus of Lewy body formation and neurodegeneration in Parkinson disease. By contrast, very few immunoreactive somata in the rat SN were labeled by the 2 polyclonal antibodies. We explore possible explanations for the differences in conflicting reports of patterns of alpha-synuclein expression in brain, including differences among antibodies. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. FD Neurotechnol Inc, Ellicott City, MD USA. Blanchette Rockefeller Neurosci Inst, Rockville, MD USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C-103, Bethesda, MD 20892 USA. NR 62 TC 16 Z9 16 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD OCT PY 2003 VL 62 IS 10 BP 1060 EP 1075 PG 16 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 729UE UT WOS:000185792200008 PM 14575241 ER PT J AU Sohn, YH Dang, NY Hallett, M AF Sohn, YH Dang, NY Hallett, M TI Suppression of corticospinal excitability during negative motor imagery SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; MENTAL MOVEMENT SIMULATION; CORTICAL EXCITABILITY; EVOKED-POTENTIALS; INTRACORTICAL FACILITATION; CORTEX; HUMANS; INHIBITION; ACTIVATION AB To investigate the effect of negative motor imagery on corticospinal excitability, we performed transcranial magnetic stimulation (TMS) studies in seven healthy subjects during imagination of suppressing movements. Subjects were asked to imagine suppression of TMS-induced twitching movement of their nondominant left hands by attempting to increase the amount of relaxation after receiving an auditory NoGo cue ( negative motor imagery), but to imagine squeezing hands after a Go cue (positive motor imagery). Single- and paired-pulse TMS were triggered at 2 s after Go or NoGo cues. Motor-evoked potentials (MEPs) were recorded in the first dorsal interosseus (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles of the left hand. Paired-pulse TMS with subthreshold conditioning stimuli at interstimulus intervals of 2 (short intracortical inhibition) and 15 ms (intracortical facilitation) and that with suprathreshold conditioning stimuli at interstimulus interval of 80 ms (long intracortical inhibition) were performed in both negative motor imagery and control conditions. Compared with the control state (no imagination), MEP amplitudes of FDI (but not APB and ADM) were significantly suppressed in negative motor imagery, but those from all three muscles were unchanged during positive motor imagery. F-wave responses ( amplitudes and persistence) were unchanged during both negative and positive motor imagery. During negative motor imagery, resting motor threshold was significantly increased, but short and long intracortical inhibition and intracortical facilitation were unchanged. The present results demonstrate that excitatory corticospinal drive is suppressed during imagination of suppressing movements. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Coll Med, Dept Neurol, Seoul 120752, South Korea. Yonsei Univ, Coll Med, Inst Brain Res, Seoul 120752, South Korea. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10-5N226,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 43 Z9 43 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT 1 PY 2003 VL 90 IS 4 BP 2303 EP 2309 DI 10.1152/jn.00206.2003 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 729WZ UT WOS:000185799200022 PM 14534268 ER PT J AU Hadfield, WS Baxter, MG Murray, EA AF Hadfield, WS Baxter, MG Murray, EA TI Effects of combined and separate removals of rostral dorsal superior temporal sulcus cortex and perirhinal cortex on visual recognition memory in rhesus monkeys SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID IMPAIRMENT FOLLOWING LESIONS; MEDIAL THALAMIC LESIONS; NONMATCHING-TO-SAMPLE; RHINAL CORTEX; PARAHIPPOCAMPAL CORTICES; HIPPOCAMPAL-FORMATION; DOUBLE DISSOCIATION; ENTORHINAL CORTEX; MACAQUE MONKEY; AREA TE AB The dorsal bank of the superior temporal sulcus (STSd) bears anatomical relations similar to those of perirhinal cortex, an area critical for visual recognition memory. To examine whether STSd makes a similar contribution to visual recognition memory, performance on visual delayed nonmatching-to-sample (DNMS) was assessed in rhesus monkeys with combined or separate ablations of the perirhinal cortex and STSd as well as in unoperated controls. Consistent with previous findings, ablations of perirhinal cortex produced deficits nearly as severe as that found after rhinal (i.e., entorhinal plus perirhinal) cortex lesions. However, combined lesions of perirhinal cortex and STSd produced a deficit no greater than that produced by perirhinal cortex ablation alone, and lesions of STSd alone were without effect on DNMS. We conclude that STSd is not critically involved in visual recognition memory. C1 NIMH, Neuropsychol Lab, 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 OI Murray, Elisabeth/0000-0003-1450-1642 NR 58 TC 7 Z9 7 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT 1 PY 2003 VL 90 IS 4 BP 2419 EP 2427 DI 10.1152/jn.00290.2003 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 729WZ UT WOS:000185799200034 PM 12826654 ER PT J AU Fink-Jensen, A Fedorova, I Wortwein, G Woldbye, DPD Rasmussen, T Thomsen, M Bolwig, TG Knitowski, KM McKinzie, DL Yamada, M Wess, J Basile, A AF Fink-Jensen, A Fedorova, I Wortwein, G Woldbye, DPD Rasmussen, T Thomsen, M Bolwig, TG Knitowski, KM McKinzie, DL Yamada, M Wess, J Basile, A TI Role for M-5 muscarinic acetylcholine receptors in cocaine addiction SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cocaine; muscarinic; self-administration; conditioned place preference; knock-out ID VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; RAT NUCLEUS-ACCUMBENS; SUBSTANTIA-NIGRA; DOPAMINE EFFLUX; KNOCKOUT MICE; BRAIN; STIMULATION; ANXIETY; MORPHINE AB Muscarinic cholinergic receptors of the M-5 subtype are expressed by dopamine-containing neurons of the ventral tegmentum. These M-5 receptors modulate the activity of midbrain dopaminergic neurons, which play an important role in mediating reinforcing properties of abused psychostimulants like cocaine. The potential role Of M-5 receptors in the reinforcing effects of cocaine was investigated using M-5 receptor-deficient mice in a model of acute cocaine self-administration. The M-5-deficient mice self-administered cocaine at a significantly lower rate than wild-type controls. In the conditioned place preference procedure, a classic test for evaluating the rewarding properties of drugs, M-5-deficient mice spent significantly less time in the cocaine-paired compartment than control mice. Moreover, the severity of the cocaine withdrawal syndrome (withdrawal-associated anxiety measured in the elevated plus-maze) was significantly attenuated in mice lacking the M-5 receptor. These results demonstrate that M-5 receptors play an important role in mediating both cocaine-associated reinforcement and withdrawal. (C) 2003 Wiley-Liss, Inc. C1 Univ Copenhagen, Rigshosp, Dept Psychiat, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Rigshosp, Dept Pharmacol, DK-2100 Copenhagen, Denmark. NIDDK, Neurosci Grp, NIH, Bethesda, MD USA. NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bethesda, MD USA. Eli Lilly & Co, Res Labs, Neurosci Res Div, Indianapolis, IN 46285 USA. RP Fink-Jensen, A (reprint author), Univ Copenhagen, Rigshosp, Dept Psychiat, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. NR 27 TC 63 Z9 69 U1 1 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD OCT 1 PY 2003 VL 74 IS 1 BP 91 EP 96 DI 10.1002/jnr.10728 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 725BA UT WOS:000185521700010 PM 13130510 ER PT J AU Polesskaya, OO Haroutunian, V Davis, KL Hernandez, I Sokolov, BP AF Polesskaya, OO Haroutunian, V Davis, KL Hernandez, I Sokolov, BP TI Novel putative nonprotein-coding RNA gene from 11q14 displays decreased expression in brains of patients with schizophrenia SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE psychiatric disorders; noncoding RNA; regulatory RNA; differential display; microarray ID NON-MESSENGER RNAS; SUSCEPTIBILITY LOCI; LINKAGE ANALYSIS; FRONTAL-CORTEX; DIFFERENTIAL DISPLAY; PREFRONTAL CORTEX; BIPOLAR DISORDER; TEMPORAL CORTEX; NONCODING RNAS; GENOME SCAN AB A modified method of differential display was employed to identify a novel gene (named PSZA11q14), the expression of which was reduced in brains from patients with schizophrenia. Decreased expression of PSZA11q14 was identified initially in Brodmann's area (BA) 21 from a small group of patients with schizophrenia (n = 4) and normal controls (n = 6) and was confirmed subsequently using independent RT-PCR assay in BA 21, 22, and 9, and in hippocampus from a larger group of patients with schizophrenia (n = 36) and controls (n = 35). PSZA11q14 is located on chromosome 11q14, an area shown previously to co-segregate with schizophrenia and related disorders in several families. Decreased expression of PSZA11q14 in patients with schizophrenia and its location on 11q14 provide converging lines of evidence indicating that PSZA11q14 may be involved in at least some cases of schizophrenia. PSZA11q14 shows no significant homology with any known gene. It has no introns and produces two RNA transcripts of similar to4.5 and similar to7.0 kb. The largest open reading frame (ORF) in the PSZA11q14 transcripts may potentially encode for a short polypeptide of 71 amino acids. High frequency of rare codons, the short size of this ORF, and low homology with mouse sequences, however, indicate that PSZA11q14 may instead represent a novel member of a family of nonprotein-coding RNA genes that are not translated and that function at the RNA level. PSZA11q14 is located within the first intron of the DLG-2 gene and transcribed in the opposite direction to DLG-2. These results suggest that PSZA11q14 may be considered a candidate gene for schizophrenia acting as an antisense regulator of DLG-2, which controls assembling functional N-methyl-D-aspartate (NMDA) receptors. (C) 2003 Wiley-Liss, Inc. C1 NIDA, Mol Neuropsychiat Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. NIDA, Mol Neurobiol Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. RP Sokolov, BP (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIMH NIH HHS [MH 45212] NR 62 TC 13 Z9 17 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD OCT 1 PY 2003 VL 74 IS 1 BP 111 EP 122 DI 10.1002/jnr.10752 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 725BA UT WOS:000185521700013 PM 13130513 ER PT J AU Weyerbrock, A Walbridge, S Pluta, RM Saavedra, JE Keefer, LK Oldfield, EH AF Weyerbrock, A Walbridge, S Pluta, RM Saavedra, JE Keefer, LK Oldfield, EH TI Selective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival in rats with C6 gliomas SO JOURNAL OF NEUROSURGERY LA English DT Article DE nitric oxide; blood-brain barrier; C6 glioma; chemotherapy; rat ID BRAIN-TUMORS; MICROVASCULAR PERMEABILITY; INTRACAROTID INFUSION; INTRAVENOUS CARBOPLATIN; SUBARACHNOID HEMORRHAGE; VASCULAR-PERMEABILITY; CEREBRAL VASOSPASM; BRADYKININ ANALOG; ENDOTHELIAL-CELLS; RECURRENT GLIOMAS AB Object. The response of brain tumors to systemic chemotherapy is limited by the blood-tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats. Methods. The Proli/NO was infused at a wide dose range (10(-2) to 10(-12) M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (131313) permeability in response to various-sized tracers ([C-14]aminoisobutyric acid, [14C] sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/No (10(-6) M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed. Conclusions. This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors. C1 NINCDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Comparat Carcinogenesis, NIH, Frederick, MD USA. Sci Applicat Int Corp, Instramural Res Support Program, Frederick, MD USA. RP Oldfield, EH (reprint author), NINCDS, Surg Neurol Branch, NIH, 10 Ctr Dr 5D37, Bethesda, MD 20892 USA. RI Weyerbrock, Astrid/E-8493-2014; Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 49 TC 37 Z9 40 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2003 VL 99 IS 4 BP 728 EP 737 DI 10.3171/jns.2003.99.4.0728 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 726XV UT WOS:000185627600015 PM 14567609 ER PT J AU Yamanaka, R Tsuchiya, N Yajima, N Honma, J Hasegawa, H Tanaka, R Ramsey, J Blaese, RM Xanthopoulos, KG AF Yamanaka, R Tsuchiya, N Yajima, N Honma, J Hasegawa, H Tanaka, R Ramsey, J Blaese, RM Xanthopoulos, KG TI Induction of an antitumor immunological response by an intratumoral injection of dendritic cells pulsed with genetically engineered Semliki Forest virus to produce interleukin-18 combined with the systemic administration of interleukin-12 SO JOURNAL OF NEUROSURGERY LA English DT Article DE interleukin-12; interleukin-18; dendritic cell; Semliki Forest virus; immunogene therapy; malignant brain tumor; mouse ID GAMMA-INDUCING FACTOR; CYTOTOXIC T-LYMPHOCYTES; INTERFERON-GAMMA; IFN-GAMMA; IMMUNE-RESPONSES; MURINE TUMORS; GENE-THERAPY; IN-VIVO; COMPLEMENTARY-DNA; SINDBIS VIRUS AB Object. The aim of this study was to investigate further immunogene treatment of malignant brain tumor to improve its therapeutic efficacy. Methods. Intratumoral dendritic cells pulsed with Semliki Forest virus (SFV)-interleukin-18 (IL-18) and/or systemic IL-12 were injected into mice bearing the B16 brain tumor. To study the immune mechanisms involved in tumor regression, we monitored the growth of implanted B 16 brain tumor cells in T cell-depleted mice and IFNgamma-neutralized mice. To analyze the protective immunity created by tumor inoculation, B16 cells were injected into the left thighs of mice that had received an inoculation, and tumor growth was monitored. The local delivery of dendritic cells pulsed with IL-18 bound by SFV combined with the systemic administration of IL-12 enhanced the induction of the T helper type 1 response from tumor-specific CD4(+) and CD8(+) T cells and natural killer cells as well as antitumor immunity. Interferon-gamma is partly responsible for this IL-18-mediated antitumor immunity. Furthermore, the protective immunity is mediated mainly by CD8(+) T cells. Conclusions. Immunogene therapy that combines the local administration of dendritic cells pulsed with IL-18 bound by SFV and the systemic administration of IL-12 may be an excellent candidate for the development of a new treatment protocol. A self-replicating SFV system may therefore open a novel approach for the treatment of malignant brain tumor. C1 Niigata Univ, Inst Brain Res, Dept Neurosurg, Niigata 9518585, Japan. Natl Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. RP Yamanaka, R (reprint author), Niigata Univ, Inst Brain Res, Dept Neurosurg, Asahimachi Dori 1-757, Niigata 9518585, Japan. NR 53 TC 32 Z9 45 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2003 VL 99 IS 4 BP 746 EP 753 DI 10.3171/jns.2003.99.4.0746 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 726XV UT WOS:000185627600017 PM 14567611 ER PT J AU Larner, SF Hayes, RL McKinsey, DM Pike, BR Kalai, M Vandenabeele, P Wang, KKW AF Larner, SF Hayes, RL McKinsey, DM Pike, BR Kalai, M Vandenabeele, P Wang, KKW TI Increased expression and activation of caspase-12 after traumatic brain injury in rats SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 21st Annual National-Neurotrauma-Society Symposium CY NOV 06-07, 2003 CL BILOXI, MISSISSIPPI SP Natl Neurotrama Soc C1 Univ Florida, Ctr Traumat Brain Injury Studies, Dept Neurosci, Gainesville, FL 32611 USA. Univ Florida, McKnight Brain Inst, Dept Psychiat, Gainesville, FL 32611 USA. NIGMS, NIH, Off Sci Review, Bethesda, MD USA. State Univ Ghent VIB, B-9000 Ghent, Belgium. RI Pike, Bruce/K-5562-2014 OI Pike, Bruce/0000-0001-8924-683X NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD OCT PY 2003 VL 20 IS 10 MA P175 BP 1071 EP 1071 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 734RX UT WOS:000186072300087 ER PT J AU Nesic, O Xu, GY Ye, Z Unabia, GC Rafati, DJ Hu, X Bourne, KZ McAdoo, DJ Westlund, KN Hulsebosch, CE Youle, RJ Perez-Polo, JR AF Nesic, O Xu, GY Ye, Z Unabia, GC Rafati, DJ Hu, X Bourne, KZ McAdoo, DJ Westlund, KN Hulsebosch, CE Youle, RJ Perez-Polo, JR TI Spinal cord injury-induced activation of apoptotic gene regulatory networks SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 21st Annual National-Neurotrauma-Society Symposium CY NOV 06-07, 2003 CL BILOXI, MISSISSIPPI SP Natl Neurotrama Soc C1 Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77550 USA. NIH, Bethesda, MD 20892 USA. RI Perez-Polo, Jose/B-6250-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD OCT PY 2003 VL 20 IS 10 MA P195 BP 1076 EP 1076 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 734RX UT WOS:000186072300107 ER PT J AU Li, ST Holmes, C Kopin, IJ Goldstein, DS AF Li, ST Holmes, C Kopin, IJ Goldstein, DS TI Aging-related changes in cardiac sympathetic function in humans, assessed by 6-F-18-fluorodopamine PET scanning SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET; fluorodopamine; aging; sympathetic function ID CONGESTIVE-HEART-FAILURE; POSITRON EMISSION TOMOGRAPHY; MYOCARDIAL BLOOD-FLOW; NERVOUS-SYSTEM; NEURONAL FUNCTION; NOREPINEPHRINE; AGE; 6-FLUORODOPAMINE; INNERVATION; DIHYDROXYPHENYLGLYCOL AB Sympathetic nerves play key roles in cardiac physiology and aging-related cardiovascular diseases. This study examined the effects of normal human aging on cardiac sympathetic innervation and function, including the neuronal uptake of catecholamines (uptake 1) via the cell membrane norepinephrine transporter. Methods: Thirty-three healthy volunteers, 17 under 40 and 16 over 50 y old, underwent thoracic PET scanning after injection of the sympathoneural imaging agent 6-F-18-fluorodopamine. Myocardial perfusion was estimated by (NH3)-N-13 scanning, and arterial blood was sampled for levels of 6-F-18-fluorodopamine and 6-F-18-fluorodopamine-derived radioactivity. Results: The older group had more myocardial 6-F-18-fluorodopamine-derived radioactivity than did the younger group. Myocardial perfusion was also greater in the older group, and arterial blood levels of 6-F-18-fluorodopamine were also higher. After adjustment for delivery of the tracer, the estimated level of myocardial extraction of 6-18F-fluorodopamine was lower in the older group (48%) than in the younger group (74%) (P = 0.02). Conclusion: Cardiac uptake 1 activity decreases with normal human aging. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 34 TC 16 Z9 16 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD OCT PY 2003 VL 44 IS 10 BP 1599 EP 1603 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 730NT UT WOS:000185837400015 PM 14530473 ER PT J AU Hornberger, TA McLoughlin, TJ Leszczynski, JK Armstrong, DD Jameson, RR Bowen, PE Hwang, ES Hou, HL Moustafa, ME Carlson, BA Hatfield, DL Diamond, AM Esser, KA AF Hornberger, TA McLoughlin, TJ Leszczynski, JK Armstrong, DD Jameson, RR Bowen, PE Hwang, ES Hou, HL Moustafa, ME Carlson, BA Hatfield, DL Diamond, AM Esser, KA TI Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth SO JOURNAL OF NUTRITION LA English DT Article DE selenium; Akt/PKB; transgenic; signaling; p70 ribosomal S6 kinase ID ACTIVATED PROTEIN-KINASE; SELENOCYSTEINE TRANSFER-RNA; SKELETAL-MUSCLE; S6 KINASE; SELENIUM; HYPERTROPHY; INDUCTION; PATHWAYS; DISEASE; INHIBITION AB Dietary intake of selenium has been implicated in a wide range of health issues, including aging, heart disease and cancer. Selenium deficiency, which can reduce selenoprotein levels, has been associated with several striated muscle pathologies. To investigate the role of selenoproteins in skeletal muscle biology, we used a transgenic mouse (referred to as i(6)A(-)) that has reduced levels of selenoproteins due to the introduction and expression of a dominantly acting mutant form of selenocysteine transfer RNA (tRNA([Ser]Sec)). As a consequence, each organ contains reduced levels of most selenoproteins, yet these mice are normal with regard to fertility, overall health, behavior and blood chemistries. In the present study, although skeletal muscles from i(6)A(-) mice were phenotypically indistinguishable from those of wild-type mice, plantaris muscles were similar to50% heavier after synergist ablation, a model of exercise overload. Like muscle in wild-type mice, the enhanced growth in the i(6)A(-) mice was completely blocked by inhibition of the mammalian target of rapamycin (mTOR) pathway. Muscles of transgenic mice exhibited increased site-specific phosphorylation on both Akt and p70 ribosomal S6 kinase (p70(S6k)) (p < 0.05) before ablation, perhaps accounting for the enhanced response to synergist ablation. Thus, a single genetic alteration resulted in enhanced skeletal muscle adaptation after exercise, and this is likely through subtle changes in the resting phosphorylation state of growth-related kinases. C1 Univ Illinois, Sch Kinesiol, Chicago, IL 60608 USA. Univ Illinois, Dept Human Nutr, Chicago, IL 60612 USA. NCI, Basic Res Lab, Sect Mol Biol Selenium, NIH, Bethesda, MD 20892 USA. RP Esser, KA (reprint author), Univ Illinois, Sch Kinesiol, Chicago, IL 60608 USA. FU NCI NIH HHS [CA081153]; NIAMS NIH HHS [AR45617] NR 28 TC 58 Z9 59 U1 0 U2 1 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2003 VL 133 IS 10 BP 3091 EP 3097 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 728HH UT WOS:000185711400012 PM 14519790 ER PT J AU Kim, HYP Wallig, MA Picciano, MF AF Kim, HYP Wallig, MA Picciano, MF TI Inorganic selenite supplementation and protection against hyperoxic injury in neonates SO JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY LA English DT Article DE selenite supplementation; neonatal selenium status; hyperoxic lung injury; glutathione peroxidase ID GLUTATHIONE-PEROXIDASE; PREMATURE-INFANTS; RAT; DEFICIENCY; NUTRITION AB This study was designed to determine if oral sodium selenite supplementation to Se-depleted rat pups furnishes protection against hyperoxic lung injury. Twelve female rats were bred and fed a Se-deficient (0.04 ppm Se) diet during pregnancy and lactation. Pups were supplemented either with 0 or 3.2 ng Se/g body weight daily from days 2 to 7. On day 4, two litters were mixed, with half of the pooled litter assigned to an air environment and the other half to an oxygen environment. Dams cross-fostered pups for 4 d. Selenite supplementation increased pup plasma and liver selenium concentration and the liver activity of glutathione peroxidase (GPx). However, lung GPx activity was more affected by oxygen exposure than selenite supplementation. While oral Se supplementation of the pups showed a tendency for decreased incidence of lung injury with oxygen exposure, this apparent effect was not statistically significant. Selenium-supplemented pups also showed a trend toward larger internal surface area and lung volume than selenium-depleted pups. These data indicate that early postnatal selenium repletion via direct oral selenite supplementation may be beneficial to rat pups against hyperoxic lung injury. C1 Yongin Univ, Dept Food & Nutr, Kyonggi Do 449714, South Korea. Univ Illinois, Dept Vet Pathobiol, Urbana, IL 61802 USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Kim, HYP (reprint author), Yongin Univ, Dept Food & Nutr, Kyonggi Do 449714, South Korea. NR 29 TC 0 Z9 0 U1 0 U2 0 PU CENTER ACADEMIC PUBL JAPAN PI TOKYO PA 2-4-16 YAYOI, BUNKYO-KU, TOKYO, 113-0032, JAPAN SN 0301-4800 J9 J NUTR SCI VITAMINOL JI J. Nutr. Sci. Vitaminol. PD OCT PY 2003 VL 49 IS 5 BP 350 EP 356 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 739ED UT WOS:000186328800009 PM 14703311 ER PT J AU Elci, OC Akpinar-Elci, M Blair, A Dosemeci, M AF Elci, OC Akpinar-Elci, M Blair, A Dosemeci, M TI Risk of laryngeal cancer by occupational chemical exposure in Turkey SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID EPIDEMIOLOGIC EVIDENCE; FORMALDEHYDE EXPOSURE; DIESEL EXHAUST; MORTALITY; GASOLINE; CARCINOGENICITY; HYDROCARBONS; SOLVENTS; WORKERS; ALCOHOL AB Laryngeal cancer is the second most common cancer among men in Turkey. In this hospital based case-control study, we evaluated laryngeal cancer risks from occupational chemical exposures. We analyzed 940 laryngeal cancer cases and 1519 controls. Occupational history, tobacco, and alcohol use and demographic information were obtained by a questionnaire. The job and industries were classified by special seven-digit codes. We calculated odds ratios (ORs) and 95% confidence intervals (Us) based on a developed exposure matrix for chemicals, including diesel exhaust, gasoline exhaust, polycyclic aromatic hydrocarbons (PAHs), formaldehyde, and solvents. An excess of laryngeal cancer occurred with diesel exhaust (OR = 1.5, 95 % CI = 1.3 - 1.9), gasoline exhaust (OR 1.6, 95% CI = 1.3 - 2.0), and PAHs (OR = 1.3, 95% CI = 1.1 - 1.6). There was a dose-response relationship for these substances with supraglottic cancers (P < 0.000). The PAH association only occurred among those who also had exposure to diesel exhaust. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Izmir Chest Dis & Surg Training Hosp, Dept Resp Med, Izmir, Turkey. RP Elci, OC (reprint author), NIOSH, Div Resp Dis Studies, Field Studies Branch, MS 2800,1095 Willowdale Rd, Morgantown, WV 26505 USA. NR 49 TC 13 Z9 17 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD OCT PY 2003 VL 45 IS 10 BP 1100 EP 1106 DI 10.1097/01.jom.0000085890.50021.6f PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 731XM UT WOS:000185911800012 PM 14534452 ER PT J AU Charmandari, E Pincus, SM Matthews, DR Johnston, A Brook, CGD Hindmarsh, PC AF Charmandari, E Pincus, SM Matthews, DR Johnston, A Brook, CGD Hindmarsh, PC TI Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE congenital adrenal hyperplasia; synchrony of joint growth hormone-cortisol dynamics ID CORTICOTROPIN-RELEASING HORMONE; CONGENITAL ADRENAL-HYPERPLASIA; (GH)-RELEASING HORMONE; LUTEINIZING-HORMONE; APPROXIMATE ENTROPY; PUBERTAL CHANGES; MESSENGER-RNA; FEMALE RATS; GH RELEASE; SECRETION AB In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/I) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). CrossApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts. C1 UCL, London Ctr Paediat Endocrinol, London, England. Radcliffe Infirm, Diabet Res Labs, Oxford OX2 6HE, England. St Bartholomews Sch Med & Dent, London, England. RP Charmandari, E (reprint author), NICHHD, Pediatr & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Suite 9D42, Bethesda, MD 20892 USA. EM charmane@mail.nih.gov RI Hindmarsh, Peter/C-4964-2008; Charmandari, Evangelia/B-6701-2011 NR 44 TC 2 Z9 2 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD OCT-NOV PY 2003 VL 16 IS 8 BP 1119 EP 1130 PG 12 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 735QN UT WOS:000186126200006 PM 14594172 ER PT J AU Dusenbery, KE Howells, WB Arthur, DC Alonzo, T Lee, JW Kobrinsky, N Barnard, DR Wells, RJ Buckley, JD Lange, BJ Woods, WG AF Dusenbery, KE Howells, WB Arthur, DC Alonzo, T Lee, JW Kobrinsky, N Barnard, DR Wells, RJ Buckley, JD Lange, BJ Woods, WG TI Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia - A report from the children's cancer group SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE extramedullary leukemia; acute myeloid leukemia; radiotherapy; pediatrics ID GRANULOCYTIC SARCOMA CHLOROMA; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; ACUTE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOBLASTIC-LEUKEMIA; CLINICAL-FEATURES; MEDIASTINAL MASS; CELL TUMORS; THERAPY; OOGS AB Objectives: To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). Methods: Among 1,832 patients entered on Children's Cancer Group's chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group I (n = 109) with EML involving skin (with or without other sites of EML), group 2 (n = 90) with EML in sites other than skin, and group 3 (n = 1,633) without EML. Results: The incidence of EML was 10.9%. Group I patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group I the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. Conclusions: Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome. C1 Childrens Oncol Grp, Arcadia, CA 91066 USA. Univ Minnesota, Minneapolis, MN USA. Univ So Calif, Sch Med, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. Childrens Oncol Grp, Arcadia, CA USA. MeritCare Hosp, Fargo, ND USA. IWK Hlth Care, Halifax, NS, Canada. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Childrens Healthcare Atlanta Egleston, Atlanta, GA USA. RP Childrens Oncol Grp, Box 60012, Arcadia, CA 91066 USA. EM dusen001@tc.umn.edu NR 60 TC 58 Z9 62 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1077-4114 EI 1536-3678 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2003 VL 25 IS 10 BP 760 EP 768 DI 10.1097/00043426-200310000-00004 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 729TJ UT WOS:000185790000003 PM 14528097 ER PT J AU Young-Hyman, D Schlundt, DG Herman-Wenderoth, L Bozylinski, K AF Young-Hyman, D Schlundt, DG Herman-Wenderoth, L Bozylinski, K TI Obesity, appearance, and psychosocial adaptation in young African American children SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE African-American children; obesity; appearance; self-esteem ID SELF-ESTEEM; BODY-IMAGE; WEIGHT STATUS; CHILDHOOD OBESITY; PUBERTAL CHANGES; SOCIAL STIGMA; HEALTH-RISK; ADOLESCENTS; GIRLS; OVERWEIGHT AB Objective To evaluate the contributions of weight status, skin tone, peer teasing, and parental appraisals of child's size to self-esteem and psychosocial adjustment in overweight African American children. Method Overweight to very obese 5- to 10-year-old African American children (N=117) completed measures of self-esteem, skin tone satisfaction, peer teasing, and body size perception. Caregivers completed the Child Behavior Checklist and rated their child's body size. Results Overweight was associated with low appearance self-esteem, and body size dissatisfaction with low global self-worth and low appearance self-esteem in children 8 and older. Appearance self-esteem but not global self-worth was lower in girls than boys. Parental perception of child's size as heavier than average was associated with low child appearance self-esteem. Heavier children also had more parental report of behavior and psychosocial problems, but their scores were in the nonclinical range. Child skin tone dissatisfaction was associated with low global self-worth. Weight-related peer teasing was associated with low self-esteem. Conclusions The relationship between obesity and self-esteem in African American children depends upon age, gender, and children's experiences with teasing and parental evaluation of their size. Other factors, like skin tone satisfaction, contribute to a child's sense of self-worth. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. RP Young-Hyman, D (reprint author), NIH, Ctr Sci Review, 6701 Rockledge Dr,Rm 4188 MSC 7848, Bethesda, MD 20892 USA. EM younghyd@csmith.gov FU NIDDK NIH HHS [R01 DK 48201] NR 39 TC 75 Z9 75 U1 3 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD OCT-NOV PY 2003 VL 28 IS 7 BP 463 EP 472 DI 10.1093/jpepsy/jsg037 PG 10 WC Psychology, Developmental SC Psychology GA 729JE UT WOS:000185769400003 PM 12968038 ER PT J AU Gilles, EE McGregor, ML Levy-Clarke, G AF Gilles, EE McGregor, ML Levy-Clarke, G TI Retinal hemorrhage asymmetry in inflicted head injury: A clue to pathogenesis? SO JOURNAL OF PEDIATRICS LA English DT Article ID SHAKEN BABY SYNDROME; INTRACRANIAL-PRESSURE GRADIENTS; SUBARACHNOID HEMORRHAGE; OPTIC-NERVE; CHILD-ABUSE; OCULAR FINDINGS; BRAIN-INJURY; INFANTS; TRAUMA; HYPERTENSION AB Objective To determine whether regional cerebral parenchymal injury patterns correlate with the distribution of retinal hemorrhages after inflicted head injury. Study design Retrospective case series of funduscopic photographs and serial computerized tomographic imaging of 14 children with confirmed inflicted head injury. Main outcome measures: Retinal Hemorrhage Score per eye and per subject, visual field examination, regional patterns of parenchymal injury on computerized tomographic scans and necropsy, and retinal/optic nerve sheath hemorrhage distribution at necropsy. Results Ten of 14 children had retinal hemorrhages (71%); 90% were asymmetric (mean retinal score, 4.89 vs 2.56; P = .006). Retinal hemorrhages were maximal on the side of greatest cerebral injury in seven of 10 children initially. Subsequent imaging asymmetry predicted retinal hemorrhage distribution in all eight survivors. Children's Coma Scores, apnea or cardiorespiratory arrest, initial hemoglobin, and plasma glucose concentration did not predict laterality. Asymmetry was greatest if dilated ophthalmoseopy was performed during the first 24 hours (P = .03). Visual outcome was poor; three had homonymous hemianopia and four had cortical visual loss, all correlating with parenchymal atrophy patterns. Conclusion The distribution of retinal hemorrhages after inflicted head injury correlates with acute and evolving regional cerebral parenchymal injury patterns. C1 Univ Minnesota, Div Pediat Neurol, Dept Pediat, Minneapolis, MN 55455 USA. Univ Minnesota, Div Pediat Neurol, Dept Neurol, Minneapolis, MN 55455 USA. Childrens Hosp, Dept Ophthalmol, Columbus, OH 43205 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Gilles, EE (reprint author), Univ Minnesota, Div Pediat Neurol, Dept Pediat, MMC 486,420 Delaware St SE, Minneapolis, MN 55455 USA. EM gille037@tc.umn.edu NR 41 TC 30 Z9 30 U1 0 U2 0 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 OCT PY 2003 VL 143 IS 4 BP 494 EP 499 DI 10.1067/S0022-3476(03)00416-5 PG 6 WC Pediatrics SC Pediatrics GA 738LQ UT WOS:000186289500019 PM 14571228 ER PT J AU Mitchell, DC Niu, SL Litman, BJ AF Mitchell, DC Niu, SL Litman, BJ TI DHA-rich phospholipids optimize G-protein-coupled signaling SO JOURNAL OF PEDIATRICS LA English DT Article ID ROD OUTER SEGMENT; POLYUNSATURATED FATTY-ACIDS; CRYSTAL-STRUCTURE; CYTOPLASMIC LOOP; METARHODOPSIN-II; RHESUS-MONKEYS; GAMMA-SUBUNITS; RHODOPSIN; RECEPTOR; TRANSDUCIN AB Objective To assess the effects of n-3 polyunsaturated phospholipid acyl chains on the initial steps in G-protein-coupled signaling. Study design Isolated components of the visual signal transduction system, rhodopsin, G protein (G(t)), and phosphodiesterase (PDE), were reconstituted in membranes containing various levels of n-3 polyunsaturated phospholipid acyl chains. In addition, rod outer segment disk membranes containing these components were purified from rats raised on n-3-deficient and n-3-adequate diets. The conformation change of rhodopsin, coupling of rhodopsin to G(t), and PDE activity were each measured separately. Results The ability of rhodopsin to form the active metarhodopsin II conformation and bind G(t) were both compromised in membranes with reduced levels of n-3 polyunsaturated acyl chains. The activity of PDE, directly related to the integrated cellular response, was reduced in all membranes lacking or deficient in n-3 polyunsaturated acyl chains. PDE activity in membranes containing 22:5n-6 PC was 50% lower than in membranes containing either 22:6n-3 PC or 22:5n-3 PC. Conclusions The earliest events in G-protein-coupled signaling; receptor conformation change, receptor-G-protein binding, and PDE activity are reduced in membranes lacking n-3 polyunsaturated acyl chains. Efficient and rapid propagation of G-protein-coupled signaling requires polyunsaturated n-3 phospholipid acyl chains. C1 NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. RP Pk Bldg,Room 158,MSC 8115,12420 Parklawn Dr, Bethesda, MD 20892 USA. NR 37 TC 35 Z9 36 U1 0 U2 3 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 OCT PY 2003 VL 143 IS 4 SU S BP S80 EP S86 DI 10.1067/S0022-3476(03)00405-0 PG 7 WC Pediatrics SC Pediatrics GA 739VC UT WOS:000186366300010 PM 14597917 ER PT J AU Rapoport, SI AF Rapoport, SI TI In vivo approaches to quantifying and imaging brain arachidonic and docosahexaenoic acid metabolism SO JOURNAL OF PEDIATRICS LA English DT Review ID POLYUNSATURATED FATTY-ACIDS; CYTOSOLIC PHOSPHOLIPASE A(2); POSITRON-EMISSION-TOMOGRAPHY; ALPHA-LINOLENIC ACID; RAT-BRAIN; SIGNAL-TRANSDUCTION; NUTRITIONAL DEPRIVATION; CHOLINERGIC STIMULATION; ALZHEIMERS-DISEASE; BIPOLAR DISORDER AB A novel in vivo fatty acid method has been developed to quantify and image brain metabolism of nutritionally essential polyunsaturated fatty acids (PUFAs). In unanesitheitized rodents, a radiolabeled PUFA is injected intravenously, and its rate of incorporation into brain phospholipids is determined by chemical analysis or quantitative autoradiography. Results indicate that about 5% of brain arachidonic acid (20:4 n-6) and of docosahexaenoic acid (22:6 n-3) acid are lost daily by metabolism and are replaced from dietary sources through the plasma. Calculated turnover rates of PUFAs in brain phospholipids, due to deesterification by phospholipase A(2) (PLA(2)) followed by reesterification, are very rapid, consistent with active roles of PUFAs in signal transduction and other processes. Turnover rates of arachidonate and docosahexaenoate are independent of each other and probably are regulated by independent sets of enzymes. Brain incorporation of radiolabeled arachidonate can be imaged in response to drugs that bind to receptors coupled to PLA(2) through G proteins, thus measuring PLA(2)-initiated signal transduction. The in vivo fatty method is being extended for human studies using positron emission tomography. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Room 6N-202, Bethesda, MD 20892 USA. NR 101 TC 65 Z9 68 U1 1 U2 5 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 OCT PY 2003 VL 143 IS 4 SU S BP S26 EP S34 DI 10.1067/S0022-3476(03)00399-8 PG 9 WC Pediatrics SC Pediatrics GA 739VC UT WOS:000186366300004 PM 14597911 ER PT J AU Viswanathan, HL Berry, JE Foster, BL Gibson, CW Li, Y Kulkarni, AB Snead, ML Somerman, MJ AF Viswanathan, HL Berry, JE Foster, BL Gibson, CW Li, Y Kulkarni, AB Snead, ML Somerman, MJ TI Amelogenin: A potential regulator of cementum-associated genes SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE amelogenin; animal studies; cells; mesenchyme-derived; cementoblasts; enamel matrix derivative; epithelial-mesenchymal interactions; periodontium/anatomy and histology; sialoglycoproteins; bone ID PERIODONTAL-LIGAMENT CELLS; ENAMEL MATRIX PROTEINS; EPITHELIAL ROOT SHEATH; BONE SIALOPROTEIN; IN-VITRO; EXTRACELLULAR-MATRIX; CEMENTOBLASTS; MINERALIZATION; EXPRESSION; MICE AB Background: Studies suggest that enamel matrix proteins induce differentiation and mineralization of a variety of mesenchymal cells, including odontoblasts, osteoblasts, and cementoblasts. It has been postulated that this activity could be due to amelogenin-like proteins, known to be present in some mixtures of enamel matrix derivatives. Amelogenins have been reported to induce expression of a mineralized tissue-specific marker, bone sialoprotein (BSP), indicating that epithelial products can regulate the activity of mesenchyme-derived cells. Methods: To explore the molecular mechanisms involved in BSP regulation, a clonal population of immortalized murine cementoblasts (OCCM-30) was exposed to full-length murine amelogenin protein (rp(H)M180), 0.1 mug/ml to 10.0 mug/ml, for 8 days in vitro. To further investigate the potential epithelial-mesenchymal interaction, an amelogenin knockout mouse model was used to examine expression of BSP and other markers, including Type I Collagen, in tissue samples. Results: The lowest dose of amelogenin slightly enhanced BSP expression, whereas at the highest dose, a dramatic decrease (three-fold) in BSP expression was observed. Parallel experiments showed a corresponding decrease in mineral nodule formation in vitro for cells treated with the higher dose of rp(H)M180. In situ hybridization and immunohistochemical analysis of sections from amelogenin null mice revealed a dramatic reduction in expression of BSP mRNA and protein in cementoblasts and surrounding osteoblasts in comparison to age-matched controls. In contrast, the expression of Type I collagen was not significantly different from controls. Conclusion: These data suggest that amelogenin may be a critical signaling molecule required for appropriate development of the periodontium. C1 Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. Univ Michigan, Sch Dent, Dept Periodont Prevent & Geriatr, Ann Arbor, MI 48109 USA. Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD USA. Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA USA. RP Somerman, MJ (reprint author), Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. RI Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU NIDCR NIH HHS [DE11089, DE13045, R01-DE09532, Z01-DE00698-1] NR 43 TC 58 Z9 61 U1 0 U2 3 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD OCT PY 2003 VL 74 IS 10 BP 1423 EP 1431 DI 10.1902/jop.2003.74.10.1423 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 754KN UT WOS:000187315900002 PM 14653387 ER PT J AU Terracciano, A McCrae, RR Hagemann, D Costa, PT AF Terracciano, A McCrae, RR Hagemann, D Costa, PT TI Individual difference variables, affective differentiation, and the structures of affect SO JOURNAL OF PERSONALITY LA English DT Article; Proceedings Paper CT NYAS Conference on Emotions Inside Out: 130 Years after Darwins The expression of the Emotions in Man and Animals CY NOV, 2002 CL NEW YORK, NEW YORK ID NEGATIVE AFFECT; CIRCUMPLEX MODEL; SEX-DIFFERENCES; 5-FACTOR MODEL; PROCRUSTES ROTATION; FACIAL EXPRESSIONS; RESPONSE FORMATS; EXTREME GROUPS; AROUSAL FOCUS; UNITED-STATES AB Methodological arguments are usually invoked to explain variations in the structure of affect. Using self-rated affect from Italian samples (N = 600), we show that individual difference variables related to affective differentiation can moderate the observed structure. Indices of circumplexity (Browne, 1992) and congruence coefficients to the hypothesized target were used to quantify the observed structures. Results did not support the circumplex model as a universal structure. A circular structure with axes of activation and valence was approximated only among more affectively differentiated groups: students and respondents with high scores on Openness to Feelings and measures of negative emotionality. A different structure, with unipolar Positive Affect and Negative Affect factors, was observed among adults and respondents with low Openness to Feelings and negative emotionality. The observed structure of affect will depend in part on the nature of the sample studied. C1 NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Terracciano, A (reprint author), NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z99 AG999999] NR 79 TC 24 Z9 25 U1 3 U2 12 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0022-3506 J9 J PERS JI J. Pers. PD OCT PY 2003 VL 71 IS 5 BP 669 EP 703 DI 10.1111/1467-6494.7105001 PG 35 WC Psychology, Social SC Psychology GA 721DK UT WOS:000185301600001 PM 12932207 ER PT J AU Rothman, RB Vu, N Partilla, JS Roth, BL Hufeisen, SJ Compton-Toth, BA Birkes, J Young, R Glennon, RA AF Rothman, RB Vu, N Partilla, JS Roth, BL Hufeisen, SJ Compton-Toth, BA Birkes, J Young, R Glennon, RA TI In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID INTRACEREBRAL HEMORRHAGE; SALVINORIN-A; AMPHETAMINE; SEROTONIN; POTENT; PHENYLPROPANOLAMINE; (-)EPHEDRINE; FENFLURAMINE; STIMULANTS; ALKALOIDS AB Ephedrine is a long-studied stimulant available both as a prescription and over-the-counter medication, as well as an ingredient in widely marketed herbal preparations, and is also used as a precursor for the illicit synthesis of methamphetamine. Ephedrine is related to phenylpropanolamine, a decongestant removed from the market place due to concerns that its use increased the risk of hemorrhagic stroke. Standard pharmacology texts emphasize that ephedrine is both a direct and indirect adrenergic agonist, activating adrenergic receptors both by direct agonist activity as well as by releasing norepinephrine via a carrier-mediated exchange mechanism. Chemically, ephedrine possesses two chiral centers. In the present study, we characterized the stereoisomers of ephedrine and the closely related compounds pseudoephedrine, norephedrine, pseudonorephedrine (cathine), methcathinone, and cathinone at biogenic amine transporters and a large battery of cloned human receptors (e.g., "receptorome"). The most potent actions of ephedrine-type compounds were as substrates of the norepinephrine transporter (EC50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at alpha(2)-adrenergic and 5-hydroxytryptamine(7) receptors (K-i values 1-10 muM) and no significant activity at beta-adrenergic or alpha(1)-adrenergic receptors. Viewed collectively, these data indicate that the pharmacological effects of ephedrine-like phenylpropanolamines are likely mediated by norepinephrine release, and although sharing mechanistic similarities with, they differ in important respects from those of the phenylpropanonamines methcathinone and cathinone and the phenyisopropylamines methamphetamine and amphetamine. C1 NIDA, Clin Psychopharmacol Sect, Div Intramural Res, NIH, Baltimore, MD 21224 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Div Intramural Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Roth, Bryan/F-3928-2010 FU NIDA NIH HHS [DA01642, R01 DA001642] NR 25 TC 99 Z9 101 U1 1 U2 12 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 1 PY 2003 VL 307 IS 1 BP 138 EP 145 DI 10.1124/jpet.103.053975 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 723VP UT WOS:000185452500015 PM 12954796 ER PT J AU Brodsky, MB McNeil, MR Doyle, PJ Fossett, TRD Timm, NH Park, GH AF Brodsky, MB McNeil, MR Doyle, PJ Fossett, TRD Timm, NH Park, GH TI Auditory serial position effects in story retelling for non-brain-injured participants and persons with aphasia SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE serial position effect; memory; aphasia; story retelling; discourse ID HEARING HANDICAP INVENTORY; SHORT-TERM-MEMORY; ELDERLY SUBJECTS; FREE-RECALL; INFORMATION; RELIABILITY; EXPLICIT; ADULTS; WORDS; SPAN AB Using story retelling as an index of language ability, it is difficult to disambiguate comprehension and memory deficits. Collecting data on the serial position effect (SPE), however, illuminates the memory component. This study examined the SPE of the percentage of information units (%IU) produced in the connected speech samples of adults with aphasia and age-matched, non-brain-injured (NBI) participants. The NBI participants produced significantly more direct and alternate IUs than participants with aphasia. Significant age and gender differences were found in subsamples of the NBI controls, with younger and female participants generating significantly more direct lUs than male and older NBI participants. Alternate IU productions did not generate an SPE from any group. There was a significant linear increase from the initial (primacy) to the final (recency) portion of the recalled alternate lUs for both the NBI group and the group of participants with aphasia. Results provide evidence that individuals with aphasia recall discourse length information using similar memory functions as the nonimpaired population, though at a reduced level of efficiency or quantity. A quadratic model is suggested for the recall of information directly recalled from discourse-length language material. C1 Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Pittsburgh, PA 15260 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP McNeil, MR (reprint author), Univ Pittsburgh, Dept Commun Sci & Disorders, 4033 Forbes Tower, Pittsburgh, PA 15260 USA. NR 49 TC 4 Z9 4 U1 1 U2 2 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT PY 2003 VL 46 IS 5 BP 1124 EP 1137 DI 10.1044/1092-4388(2003/088) PG 14 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 728HD UT WOS:000185711000008 PM 14575347 ER PT J AU Fletcher, BW Broome, KM Delany, PJ Shields, J Flynn, PM AF Fletcher, BW Broome, KM Delany, PJ Shields, J Flynn, PM TI Patient and program factors in obtaining supportive services in DATOS SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE treatment service utilization; supportive services; patient and program factors ID DRUG-ABUSE TREATMENT; METHADONE-MAINTENANCE; ADDICTION TREATMENT; COCAINE DEPENDENCE; TREATMENT OUTCOMES; PRIMARY-CARE; RETENTION; ENGAGEMENT; PREDICTORS; MOTIVATION AB This study examined patient and program factors that influenced the receipt of scheduled supportive services in the Drug Abuse Treatment Outcome Studies (DATOS). Patients (N = 2,932) in 21 long-term residential (LTR) programs, 27 outpatient methadone treatment (OMT), and 25 outpatient drug-free programs were interviewed at admission and at 3 months during treatment. A hierarchical regression analysis was used to examine the relationship between patient-level and program-level factors associated with receiving supportive services in seven categories (medical, psychological, family, legal, educational, vocational, and financial). LTR patients received more services on average than outpatients (especially OMT), but patients overall received few services in the first 3 months of treatment. The patient-level likelihood of receiving services was related to being female and to having higher problem severity at intake. At the program level, outpatient clientele with higher problem severity received more services if they entered a program whose other enrolled patients were less troubled on average. Published by 2003 Elsevier Inc. All rights reserved. C1 Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. Texas Christian Univ, Inst Behav Res, Ft Worth, TX 76129 USA. RP Fletcher, BW (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd,Room 5159, Bethesda, MD 20892 USA. NR 66 TC 7 Z9 7 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2003 VL 25 IS 3 BP 165 EP 175 DI 10.1016/S0740-5472(03)00126-0 PG 11 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 756YU UT WOS:000187514000006 PM 14670522 ER PT J AU Chan, JCC Tycko, R AF Chan, JCC Tycko, R TI Solid-state NMR spectroscopy method for determination of the backbone torsion angle psi in peptides with isolated uniformly labeled residues SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ROTATING SOLIDS; DIHEDRAL ANGLES; PROTEINS; FIELD; CONSTRAINTS; METHANOL; FIBRILS C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Chan, Jerry/F-8075-2010 OI Chan, Jerry/0000-0002-5108-4166 NR 28 TC 39 Z9 41 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 1 PY 2003 VL 125 IS 39 BP 11828 EP 11829 DI 10.1021/ja0369820 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 726BQ UT WOS:000185578500028 PM 14505399 ER PT J AU Lindenfield, J Ghali, JK Krause-Steinrauf, HJ Khan, S Adams, K Goldman, S Peberdy, MA Yancy, C Thaneemit-Chen, S Larsen, RL Young, J Lowes, B Rosenberg, YD AF Lindenfield, J Ghali, JK Krause-Steinrauf, HJ Khan, S Adams, K Goldman, S Peberdy, MA Yancy, C Thaneemit-Chen, S Larsen, RL Young, J Lowes, B Rosenberg, YD CA BEST Investigators TI Hormone replacement therapy is associated with improved survival in women with advanced heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR FUNCTION; ESTROGEN PLUS PROGESTIN; GENDER-DIFFERENCES; POSTMENOPAUSAL WOMEN; AORTIC-STENOSIS; PRESSURE-OVERLOAD; ESSENTIAL-HYPERTENSION; PLASMA NOREPINEPHRINE; CARDIAC ADAPTATION; SEX-DIFFERENCES AB OBJECTIVES We sought to determine whether hormone replacement therapy (HRT) is associated with an improved prognosis in women with advanced heart failure (HF) and systolic dysfunction. BACKGROUND There are about two million postmenopausal women in the U.S. with HE However, limited data are available to assess the effects of HRT on survival in this large group of patients. METHODS A retrospective analysis of women age 50 years and over entered into the Beta-Blocker Evaluation of Survival Trial (BEST) was conducted using Cox regression analysis comparing survival in HRT users and non-users after correcting for baseline variables known to predict survival in women with HF and systolic dysfunction. RESULTS In 493 women age 50 years and older, HRT was associated with a significant reduction in mortality-21% mortality in HRT users and 34% in non-users (p = 0.025). Multivariate analysis demonstrated a hazard ratio for mortality of 0.6 (95% confidence interval = 0.36 to 0.97) (p = 0.039) for HRT users. The benefits of HRT were noted only in women with a nonischemic etiology of HF (n = 237). CONCLUSIONS Hormone replacement therapy is associated with a marked improvement in survival in postmenopausal women with advanced HF. A prospective, randomized trial of HRT should be performed in this large group of patients. (C) 2003 by the American College of Cardiology Foundation. C1 Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. Ctr Womens Hlth Res, Denver, CO USA. Cardiac Ctr Louisiana, Shreveport, LA USA. NHLBI, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Univ N Carolina, Chapel Hill, NC USA. Tucson SAVAHCS, Tucson, AZ USA. Virginia Commonwealth Univ, Med Coll Virgina, Richmond, VA USA. SW Texas State Univ, Dallas, TX USA. VA Palo Alto Hlth Care Syst Cooperat Studies Prog, Palo Alto, CA USA. Duke Clin Res Inst, Durham, NC USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Lindenfield, J (reprint author), Univ Colorado, Hlth Sci Ctr, 4200 E 9th Ave,B-130, Denver, CO 80262 USA. OI Lowes, Brian/0000-0002-5919-2540 NR 46 TC 33 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 1 PY 2003 VL 42 IS 7 BP 1238 EP 1245 DI 10.1016/S0735-1097(03)00938-0 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 726QU UT WOS:000185611200017 PM 14522488 ER PT J AU Balzini, L Vannucchi, L Benvenuti, F Benucci, M Monni, M Cappozzo, A Stanhope, SJ AF Balzini, L Vannucchi, L Benvenuti, F Benucci, M Monni, M Cappozzo, A Stanhope, SJ TI Clinical characteristics of flexed posture in elderly women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE elderly; posture; kyphosis; disability; osteoporosis ID LUMBAR INTERVERTEBRAL DISKS; BONE-MINERAL DENSITY; BACK-PAIN; OLDER WOMEN; POSTMENOPAUSAL WOMEN; OSTEOPOROSIS; BALANCE; KYPHOSIS; MOBILITY; STRENGTH AB OBJECTIVES: To investigate the relationships between the severity of flexed posture ( FP), skeletal fragility, and functional status level in elderly women. DESIGN: Cross-sectional study. SETTING: Geriatric rehabilitation research hospital. PARTICIPANTS: Sixty elderly women (aged 70-93) with FP referred to a geriatric rehabilitation department for chronic back pain without apparent comorbid conditions. MEASUREMENTS: Multidimensional clinical assessment included the severity of FP (standing occiput-to-wall distance) demographic (age) and anthropometric (height, weight) data, clinical profile (number of falls, pain assessment, Mini-Mental State Examination, Comorbidity Severity Index, Geriatric Depression Scale, Multidimensional Fatigue Inventory), measures of skeletal fragility (number of vertebral fractures by spine radiograph, bone mineral density (BMD), and T-score of lumbar spine and proximal femur), muscular impairment assessment (muscle strength and length), motor performance (Short Physical Performance Battery, Performance Oriented Mobility Assessment, instrumented gait analysis), and evaluation of disability (Barthel Index, Nottingham Extended Activities of Daily Living Index). RESULTS: The severity of FP was classified as mild in 11, moderate in 28, and severe in 21 patients. Although there were no differences between FP groups on the skeletal fragility measurements, the moderate and severe FP groups were significantly different from the mild FP group for greater pain at the level of the cervical and lumbar spine. The severe FP group was also significantly different from the mild but not the moderate FP group in the following categories: clinical profile (greater depression, reduced motivation), muscle impairment (weaker spine extensor, ankle plantarflexor, and dorsiflexor muscles; shorter pectoralis and hip flexor muscles), the motor function performance-based tests (lower scores in the balance and gait subsets of the Performance Oriented Mobility Assessment), the instrumented gait analysis (slower and wider base of support), and disability (lower score on the Nottingham Extended Activities of Daily Living Index). The total number of vertebral fractures was not associated with differences in severity of FP, demographic and anthropometric characteristics, clinical profile, muscular function, performance-based and instrumental measures of motor function, and disability, but it was associated with reduced proximal femur and lumbar spine BMD. CONCLUSION: The severity of FP in elderly female patients (without apparent comorbid conditions) is related to the severity of vertebral pain, emotional status, muscular impairments, and motor function but not to osteoporosis, and FP has a measurable effect on disability. In contrast, the presence of vertebral fractures in patients with FP is associated with lower BMD but not patients' clinical and functional status. Therefore, FP, back pain, and mobility problems can occur without osteoporosis. Older women with FP and vertebral pain may be candidates for rehabilitation interventions that address muscular impairments, posture, and behavior modification. Randomized controlled trials are needed to support these conclusions. C1 INRCA I Fraticini, Dipartimento Geriatr, Lab Fisiopatol & Riabilitaz Movimento, I-50125 Florence, Italy. Azienda Sanitaria Firenze, Unita Operat Reumatol, Florence, Italy. Compagnia Assistenza Humanitas, Poliambulatorio, Florence, Italy. Ist Univ Sci Motorie, Rome, Italy. NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. RP Benvenuti, F (reprint author), INRCA I Fraticini, Dipartimento Geriatr, Lab Fisiopatol & Riabilitaz Movimento, Viale Michelanglo 41, I-50125 Florence, Italy. NR 45 TC 52 Z9 57 U1 2 U2 13 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2003 VL 51 IS 10 BP 1419 EP 1426 DI 10.1046/j.1532-5415.2003.51460.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 725GR UT WOS:000185535900011 PM 14511162 ER PT J AU Hansen, PB Castrop, H Briggs, J Schnermann, J AF Hansen, PB Castrop, H Briggs, J Schnermann, J TI Adenosine induces vasoconstriction through Gi-dependent activation of phospholipase C in isolated perfused afferent arterioles of mice SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID SMOOTH-MUSCLE CELLS; BETA-GAMMA-SUBUNITS; ANGIOTENSIN-II; RAT-KIDNEY; ADENYLYL-CYCLASE; A(2A) RECEPTORS; PROTEIN-KINASE; A(1); EXPRESSION; MECHANISM AB Adenosine induces vasoconstriction of renal afferent arterioles through activation of Al adenosine receptors (AlAR). AlAR are directly coupled to Gi/Go, resulting in inhibition of adenylate cyclase, but the contribution of this signaling pathway to smooth muscle cell activation is unclear. In perfused afferent arterioles from mouse kidney, adenosine and the Al agonist N-6-cyclohexyladenosine, when added to the bath, caused constriction in the concentration range of 10(-9) to 10(-6) M (mean diameter: control, 8.8 +/- 0.3 mum; adenosine at 10(-6) M, 2.8 +/- 0.5 mum). Adenosine-induced vasoconstriction was stable for up to 30 min and was most pronounced in the most distal part of the afferent arterioles. Adenosine did not cause vasoconstriction in arterioles from AlAR-/- mice. Pretreatment with pertussis toxin (PTX) (400 ng/ml) for 2 h blocked the vasoconstricting action of adenosine or N-6-cyclo-hexyladenosine. PTX pretreatment did not affect the constriction response to KCl, whereas the angiotensin 11 dose-response relationship was shifted rightward. Reverse transcription-PCR revealed expression of Gi but not Go in kidney cortex and preglomerular vessels. The phospholipase C inhibitor U73122 (4 muM) blocked the constriction responses to both adenosine and angiotensin II. In contrast, the adenylate cyclase inhibitor SQ22536 (10 muM) and the protein kinase A antagonist KT5720 (0.1 and 1 muM) did not induce significant vasoconstriction of afferent arterioles. It is concluded that the constriction response to adenosine in afferent arterioles is mediated by AlAR coupled to a PTX-sensitive Gi protein and subsequent activation of phospholipase C, presumably through betagamma subunits released from Galphai. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. NR 50 TC 65 Z9 67 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2003 VL 14 IS 10 BP 2457 EP 2465 DI 10.1097/01.ASN.0000086474.80845.25 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 725JR UT WOS:000185540800007 PM 14514723 ER PT J AU Dignam, JJ Wieand, K Johnson, KA Fisher, B Xu, L Mamounas, EP AF Dignam, JJ Wieand, K Johnson, KA Fisher, B Xu, L Mamounas, EP TI Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RECEIVING ADJUVANT CHEMOTHERAPY; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; RISK-FACTORS; WEIGHT-GAIN; PROGNOSTIC INDICATORS; MENOPAUSAL STATUS; MENSTRUAL EVENTS; PREMORBID DIET; FAMILY HISTORY AB Background: Obesity is associated with both increased breast cancer risk and poorer prognosis after disease onset. However, little is known about the effect of obesity on treatment efficacy. We evaluated the association of obesity with outcomes and with tamoxifen efficacy in women with early-stage, hormone-responsive breast cancer participating in a multicenter cancer cooperative group clinical trial. Methods: The cohort consisted of 3385 women enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-14, a randomized, placebo-controlled trial evaluating tamoxifen for lymph node-negative, estrogen receptor (ER)positive breast cancer. Hazards of breast cancer recurrence, contralateral breast tumors, other new primary cancers, and several mortality endpoints were evaluated in relation to body mass index (BMI), using statistical modeling to adjust for other prognostic factors. Median follow-up time was 166 months. All statistical tests were two-sided. Results: The hazard of breast cancer recurrence was the same among obese (BMI greater than or equal to30.0 kg/m(2)) women as compared with underweight and normal-weight women (BMI <25.0; hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.80 to 1.18). Contralateral breast cancer hazard was higher in obese women than in underweight/normal-weight women (HR = 1.58, 95% CI = 1.10 to 2.25), as was the risk of other primary cancers (HR = 1.62, 95% C1 = 1.16 to 2.24). Compared with normal-weight women, obese women had greater all-cause mortality (HR = 1.31, 95% C1 = 1.12 to 1.54) and greater risk of deaths due to causes unrelated to breast cancer (HR = 1.49, 95% C1 = 1.15 to 1.92). Breast cancer mortality was not statistically significantly increased for obese women (HR = 1.20, 95% Cl = 0.97 to 1.49). Tamoxifen reduced breast cancer recurrence and mortality, regardless of BMI. Conclusions: For women with lymph node-negative, ER-positive breast cancer, obesity was not associated with a material increase in recurrence risk or a change in tamoxifen efficacy. However, because obesity was associated with increased risks of contralateral breast cancer, of other primary cancers, and of overall mortality, it may influence long-term outcomes for breast cancer survivors. C1 Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA USA. NCI, Breast & Gynecol Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Aultman Hosp, NSABP, Canton, OH USA. Aultman Hosp, Ctr Canc, Canton, OH USA. RP Dignam, JJ (reprint author), Univ Chicago, Dept Hlth Studies, 5841 S Maryland Ave,MC 2007, Chicago, IL 60637 USA. FU NCI NIH HHS [P30 CA014599, U10-CA-69651, R03-CA-99508, R03 CA099508, U10 CA069651, U10 CA012027, P30-CA-14599, U10-CA-12027] NR 84 TC 129 Z9 129 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 1 PY 2003 VL 95 IS 19 BP 1467 EP 1476 DI 10.1093/jnci/djg060 PG 10 WC Oncology SC Oncology GA 725YA UT WOS:000185568900012 PM 14519753 ER PT J AU Friedman, MA Altemus, R Wood, BJ AF Friedman, MA Altemus, R Wood, BJ TI Radiofrequency ablation in a previously irradiated liver SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID RADIATION-THERAPY; HEPATIC-TUMORS; CARCINOMA; HYPERTHERMIA; METASTASES; OCCLUSION; LUNG AB A patient with renal cell carcinoma underwent external-beam radiation therapy (XRT) to treat a painful chest-wall metastasis. One month later, she underwent radiofrequency (RF) ablation of two metastatic deposits within the liver; one of the target lesions was in the recent irradiation zone and the other was outside of the radiation field. RF ablation within the irradiated liver produced a slightly larger ablation zone with prominent needle tract scarring, and required less energy input than treatment in the unirradiated liver. RF ablation and XRT may interact, possibly producing a synergistic effect. Further study of the potentially adjunctive relationship between these two modalities is warranted. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NCI, Surg Branch, Bldg 10,Room 1C660, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 15 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2003 VL 14 IS 10 BP 1345 EP 1348 DI 10.1097/01.RVI.0000092908.31640.81 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 730WX UT WOS:000185854100018 PM 14551284 ER PT J AU Hamer, DH Bocklandt, S McHugh, L Chun, TW Blumberg, PM Sigano, DM Marquez, VE AF Hamer, DH Bocklandt, S McHugh, L Chun, TW Blumberg, PM Sigano, DM Marquez, VE TI Rational design of drugs that induce human immunodeficiency virus replication SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-KINASE-C; CONFORMATIONALLY CONSTRAINED ANALOGS; LATENT HIV-1 EXPRESSION; HIGH BINDING-AFFINITY; CD4(+) T-CELLS; PK-C; DIACYLGLYCEROL DAG; GENE-EXPRESSION; PHORBOL ESTERS; ACTIVATION AB Drugs that induce human immunodeficiency virus type 1 (HIV-1) replication could be used in combination with highly active antiretroviral therapy (HAART) to reduce the size of the latent reservoir that is in part responsible for viral persistence. Protein kinase C (PKC) is a logical target for such drugs because it activates HIV-1 transcription through multiple mechanisms. Here we show that HIV-1 gene expression can be induced by potent synthetic analogues of the lipid second messenger diacylglycerol (DAG) synthesized on a five-member ring platform that reduces the entropy of binding relative to that of the more flexible DAG template. By varying the alkyl side chains of these synthetic DAG lactones, it was possible to maximize their potency and ability to render latently infected T cells sensitive to killing by an anti-HIV-1 immunotoxin while minimizing the side effects of CD4 and CXCR4 downregulation and tumor necrosis factor alpha upregulation. The two lead compounds, LMC03 and LMC07, regulated a series of PKC-sensitive genes involved in T-cell activation and induced viral gene expression in peripheral blood mononuclear cells from HIV-1-infected individuals. These studies demonstrate the potential for the rational design of agents that, in conjunction with HAART and HIV-specific toxins, can be used to decrease or eliminate the pool of latently infected reservoirs by forcing viral expression. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. RP Hamer, DH (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Rm 6002,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 NR 41 TC 32 Z9 33 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10227 EP 10236 DI 10.1128/JVI.77.19.10227-10236.2003 PG 10 WC Virology SC Virology GA 722WE UT WOS:000185400400005 PM 12970407 ER PT J AU Kocisko, DA Baron, GS Rubenstein, R Chen, JC Kuizon, S Caughey, B AF Kocisko, DA Baron, GS Rubenstein, R Chen, JC Kuizon, S Caughey, B TI New inhibitors of scrapie-associated prion protein formation in a library of 2,000 drugs and natural products SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; NEUROBLASTOMA-CELLS; CULTURED-CELLS; TRANSGENIC MICE; HAMSTER PRP; CONGO RED; EXPRESSION; ACCUMULATION; STRAINS; PREVENTION AB Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases associated with the accumulation of a disease-specific form of prion protein (PrP) in the brain. One approach to TSE therapeutics is the inhibition of PrP accumulation. Indeed, many inhibitors of the accumulation of PrP associated with scrapie (PrPSc) in scrapie-infected mouse neuroblastoma cells (ScN(2)a) also have antiscrapie activity in rodents. To expedite the search for potential TSE therapeutic agents, we have developed a high-throughput screening assay for PrPSc inhibitors using ScN(2)a cells in a 96-well format. A library of 2,000 drugs and natural products was screened in ScN(2)a cells infected with scrapie strain RML (Chandler) or 22L. Forty compounds were found to have concentrations causing 50% inhibition (IC(50)s) of PrPSc accumulation of less than or equal to10 muM against both strains. Seventeen had IC(50)s of less than or equal to1 muM against both strains. Several classes of compounds were represented in the 17 most potent inhibitors, including naturally occurring polyphenols (e.g., tannic acid and tea extracts), phenothiazines, antihistamines, statins, and antimalarial compounds. These 17 compounds were also evaluated in a solid-phase cell-free hamster PrP conversion assay. Only the polyphenols inhibited the cell-free reaction, and their IC(50)s were near 100 nM. Several of the new PrPSc inhibitors cross the blood-brain barrier and thus have potential to be effective after TSE infection reaches the brain. The fact that many are either approved human drugs or edible natural products should facilitate their use in animal testing and clinical trials. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. New York State Inst Basic Res Dev Disabil, Lab Mol & Biochem Neurovirol, Staten Isl, NY 10314 USA. Chengdu Jinniu Inst, Food Bur Sichuan Prov, Chengdu, Sichuan, Peoples R China. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 33 TC 144 Z9 152 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10288 EP 10294 DI 10.1128/JVI.77.19.10288-10294.2003 PG 7 WC Virology SC Virology GA 722WE UT WOS:000185400400011 PM 12970413 ER PT J AU Evans, LH Lavignon, M Taylor, M Alamgir, ASM AF Evans, LH Lavignon, M Taylor, M Alamgir, ASM TI Antigenic subclasses of polytropic murine leukemia virus (MLV) isolates reflect three distinct groups of endogenous polytropic MLV-related sequences in NFS/N mice SO JOURNAL OF VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; FOCUS-FORMING VIRUSES; OLIGONUCLEOTIDE PROBES; HETERODUPLEX ANALYSIS; THYMIC LYMPHOMAS; CHROMOSOMAL DNA; INFECTED MICE; PROVIRAL DNA; HOST RANGE; WILD MICE AB Polytropic murine leukemia viruses (MLVs) are generated by recombination of ecotropic MLVs with members of a family of endogenous proviruses in mice. Previous studies have indicated that polytropic MLV isolates comprise two mutually exclusive antigenic subclasses, each of which is reactive with one of two monoclonal antibodies termed MAb 516 and Hy 7. A major determinant of the epitopes distinguishing the subclasses mapped to a single amino acid difference in the SU protein. Furthermore, distinctly different populations of the polytropic MLV subclasses are generated upon inoculation of different ecotropic MLVs. Here we have characterized the majority of endogenous polytropic MLV-related proviruses of NFS/N mice. Most of the proviruses contain intact sequences encoding the receptor-binding region of the SU protein and could be distinguished by sequence heterogeneity within that region. We found that the endogenous proviruses comprise two major groups that encode the major determinant for Hy 7 or MAb 516 reactivity. The Hy 7-reactive proviruses correspond to previously identified polytropic proviruses, while the 516-reactive proviruses comprise the modified polytropic proviruses as well as a third group of polytropic MLV-related proviruses that exhibit distinct structural features. Phylogenetic analyses indicate that the latter proviruses reflect features of phylogenetic intermediates linking xenotropic MLVs to the polytropic and modified polytropic proviruses. These studies elucidate the relationships of the antigenic subclasses of polytropic MLVs to their endogenous counterparts, identify a new group of endogenous proviruses, and identify distinguishing characteristics of the proviruses that should facilitate a more precise description of their expression in mice and their participation in recombination to generate recombinant viruses. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Evans, LH (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 53 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10327 EP 10338 DI 10.1128/JVI.77.19.10327.10338.2003 PG 12 WC Virology SC Virology GA 722WE UT WOS:000185400400015 PM 12970417 ER PT J AU Mascola, JR Lewis, MG VanCott, TC Stiegler, G Katinger, H Seaman, M Beaudry, K Barouch, DH Korioth-Schmitz, B Krivulka, G Sambor, A Welcher, B Douek, DC Montefiori, DC Shiver, JW Poignard, P Burton, DR Letvin, NL AF Mascola, JR Lewis, MG VanCott, TC Stiegler, G Katinger, H Seaman, M Beaudry, K Barouch, DH Korioth-Schmitz, B Krivulka, G Sambor, A Welcher, B Douek, DC Montefiori, DC Shiver, JW Poignard, P Burton, DR Letvin, NL TI Cellular immunity elicited by human immunodeficiency virus type 1/simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1/SIV CHIMERIC VIRUS; CYTOTOXIC T-LYMPHOCYTES; MONOCLONAL-ANTIBODIES; RHESUS-MONKEYS; CD8(+) LYMPHOCYTES; AIDS VACCINE; INFECTION; RESPONSES; MACAQUES; CHALLENGE AB High levels of infused anti-human immunodeficiency virus type 1 (HIV-1) neutralizing monoclonal antibodies (MAbs) can completely protect macaque monkeys against mucosal chimeric simian-human immunodeficiency virus (SHIV) infection. Antibody levels below the protective threshold do not prevent infection but can substantially reduce plasma viremia. To assess if HIV-1/SIV-specific cellular immunity could combine with antibodies to produce sterile protection, we studied the effect of a suboptimal infusion of anti-HIV-1 neutralizing antibodies in macaques with active cellular immunity induced by interleukin-2 (IL-2)-adjuvanted DNA immunization. Twenty female macaques were divided into four groups: (i) DNA immunization plus irrelevant antibody, (ii) DNA immunization plus infusion of neutralizing MAbs 2F5 and 2G12, (iii) sham DNA plus 2F5 and 2G12, and (iv) sham DNA plus irrelevant antibody. DNA-immunized monkeys developed CD4 and CD8 T-cell responses as measured by epitope-specific tetramer staining and by pooled peptide ELISPOT assays for gamma interferon-secreting cells. After vaginal challenge, DNA-immunized animals that received irrelevant antibody became SHIV infected but displayed lower plasma viremia than control animals. Complete protection against SHIV challenge occurred in three animals that received sham DNA plus MAbs 2F5 and 2G12 and in two animals that received the DNA vaccine plus MAbs 2F5 and 2G12. Thus, although DNA immunization produced robust HIV-specific T-cell responses, we were unable to demonstrate that these responses contributed to the sterile protection mediated by passive infusion of neutralizing antibodies. These data suggest that although effector T cells can limit viral replication, they are not able to assist Immoral immunity to prevent the establishment of initial infection. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. So Res Inst, Frederick, MD 21701 USA. US Mil, HIV Res Program, Henry Jackson Fdn, Rockville, MD 20850 USA. Univ Nat Resources & Appl Life Sci, Inst Appl Microbiol, Vienna, Austria. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Merck Res Labs, W Point, PA 19486 USA. Scripps Res Inst, La Jolla, CA 92093 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. RI poignard, pascal/N-6678-2013; Korioth-Schmitz, Birgit/M-7816-2015 OI Korioth-Schmitz, Birgit/0000-0002-5271-9223 FU NHLBI NIH HHS [HL59718]; NIAID NIH HHS [AI33292, AI52057, R01 AI033292, R01 AI052057, R37 AI033292] NR 33 TC 45 Z9 45 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10348 EP 10356 DI 10.1128/JVI.77.19.10348-10356.2003 PG 9 WC Virology SC Virology GA 722WE UT WOS:000185400400017 PM 12970419 ER PT J AU Wu, YT Marsh, JW AF Wu, YT Marsh, JW TI Early transcription from nonintegrated DNA in human immunodeficiency virus infection SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL-ACTIVATION; TYPE-1 INTEGRASE; HIV-1 INFECTION; REV PROTEIN; VIRAL-DNA; HTLV-I; REPLICATION; EXPRESSION; LYMPHOCYTES; MUTATIONS AB Replication of human immunodeficiency virus (HIV) involves obligatory sequential processes. Following viral entry and reverse transcription, the newly synthesized viral DNA integrates into the host chromatin. Integration is mandatory for viral production, yet HIV infection of CD4 T cells in vivo results in high levels of nonintegrated DNA. The biological potential of nonintegrated HIV DNA is unclear; however, prior work has demonstrated a limited transcription of the nef gene by nonintegrated HIV in infected quiescent T-cell populations. In a kinetic analysis of HIV infection of metabolically active transformed and primary CD4 T cells, we find an unexpected transient expression of both early and late message by nonintegrated HIV DNA. However, only the early multiply spliced transcript was measurably translated. This restriction of protein expression was due in part to inadequate Rev function, since expression of Rev in trans resulted in the expression of the late structural gene gag by nonintegrated HIV DNA. C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, Mol Biol Lab, 36 Convent Dr,MSC 4034, Bethesda, MD 20892 USA. NR 36 TC 81 Z9 82 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10376 EP 10382 DI 10.1128/JVI.77.19.10376-10382.2003 PG 7 WC Virology SC Virology GA 722WE UT WOS:000185400400020 PM 12970422 ER PT J AU Labrijn, AF Poignard, P Raja, A Zwick, MB Delgado, K Franti, M Binley, J Vivona, V Grundner, C Huang, CC Venturi, M Petropoulos, CJ Wrin, T Dimitrov, DS Robinson, J Kwong, PD Wyatt, RT Sodroski, J Burton, DR AF Labrijn, AF Poignard, P Raja, A Zwick, MB Delgado, K Franti, M Binley, J Vivona, V Grundner, C Huang, CC Venturi, M Petropoulos, CJ Wrin, T Dimitrov, DS Robinson, J Kwong, PD Wyatt, RT Sodroski, J Burton, DR TI Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gpl120 is sterically restricted on primary human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; INTERMOLECULAR DISULFIDE BOND; HUMAN MONOCLONAL-ANTIBODY; CELL-CELL FUSION; RECEPTOR-BINDING; SOLUBLE CD4; CONFORMATIONAL-CHANGES; VARIABLE LOOPS; GP41 SUBUNITS; HIV-1 AB Anti-human immunodeficiency virus type I (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors. C1 Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. ViroLog Inc, San Francisco, CA USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Div Aids, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21701 USA. Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70118 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol, IMM2,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI poignard, pascal/N-6678-2013 FU NIAID NIH HHS [AI24755, AI31783, AI33292, AI39420, AI41851, AI42848, AI45357, AI49566, P30 AI042848, R01 AI031783, R01 AI033292, R01 AI039420, R01 AI041851, R01 AI045357, R37 AI024755, R37 AI033292] NR 65 TC 267 Z9 272 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10557 EP 10565 DI 10.1128/JVI.77.19.10557-10565.2003 PG 9 WC Virology SC Virology GA 722WE UT WOS:000185400400038 PM 12970440 ER PT J AU Earl, PL Americo, JL Moss, B AF Earl, PL Americo, JL Moss, B TI Development and use of a vaccinia virus neutralization assay based on flow cytometric detection of green fluorescent protein SO JOURNAL OF VIROLOGY LA English DT Article ID CELLS AB A rapid and sensitive neutralization assay is required to evaluate alternative smallpox vaccines. Here we describe the development and use of a 96-well plate, semi-automated, flow cytometric assay that uses a recombinant vaccinia virus expressing enhanced green fluorescent protein and which would be applicable to other viruses. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 11 TC 53 Z9 54 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 19 BP 10684 EP 10688 DI 10.1128/JVI.77.19.10684-10688.2003 PG 5 WC Virology SC Virology GA 722WE UT WOS:000185400400053 PM 12970455 ER PT J AU Igarashi, T Endo, Y Nishimura, Y Buckler, C Sadjadpour, R Donau, OK Dumaurier, MJ Plishka, RJ Buckler-White, A Martin, MA AF Igarashi, T Endo, Y Nishimura, Y Buckler, C Sadjadpour, R Donau, OK Dumaurier, MJ Plishka, RJ Buckler-White, A Martin, MA TI Early control of highly pathogenic simian immunodeficiency virus/human immunodeficiency virus chimeric virus infections in rhesus monkeys usually results in long-lasting asymptomatic clinical outcomes SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL DEPLETION; SIV INFECTION; HIV-INFECTION; SMALL-MOLECULE; DISEASE PROGRESSION; VIRAL REPLICATION; LYMPHOID-TISSUES; MACAQUE MONKEYS; IN-VIVO; AIDS AB In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1- to 2-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause an irreversible and systemic depletion of CD4(+) T lymphocytes in macaque monkeys within weeks of inoculation. Nonetheless, the seemingly more aggressive SHIVs have proven to be easier to control by the same vaccine regimens which fail to contain SIV. Because early events during in vivo infections may determine both the pathogenic consequences of the challenge virus and its sensitivity to interventions that prevent disease, we have evaluated the effects of inoculum size and a potent antiretroviral drug on the development of disease in monkeys infected with SHIVDH12R. The results obtained show that in a majority of inoculated animals, suppression of SHIV replication during the first 2 weeks of infection, which prevents complete loss of CD4(+) T cells, leads to very low to undetectable postpeak viremia and an asymptomatic clinical course for periods up to 4 years. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. NR 52 TC 20 Z9 21 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 10829 EP 10840 DI 10.1128/JVI.77.20.10829-10840.2003 PG 12 WC Virology SC Virology GA 727XL UT WOS:000185686100011 PM 14512533 ER PT J AU Iyasere, C Tilton, JC Johnson, AJ Younes, S Yassine-Diab, B Sekaly, RP Kwok, WW Migueles, SA Laborico, AC Shupert, WL Hallahan, CW Davey, RT Dybul, M Vogel, S Metcalf, J Connors, M AF Iyasere, C Tilton, JC Johnson, AJ Younes, S Yassine-Diab, B Sekaly, RP Kwok, WW Migueles, SA Laborico, AC Shupert, WL Hallahan, CW Davey, RT Dybul, M Vogel, S Metcalf, J Connors, M TI Diminished proliferation of human immunodeficiency virus-specific CD4(+) T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2 SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; HIV-1-INFECTED SUBJECTS; IMMUNE RESTORATION; VIRAL REPLICATION; TYPE-1 INFECTION; HEPATITIS-C; IN-VIVO; RESPONSES; CD8(+) AB Virus-specific CD4(+) T-cell function is thought to play a central role in induction and maintenance of effective CD8(+) T-cell responses in experimental animals or humans. However, the reasons that diminished proliferation of human immunodeficiency virus (HIV)-specific CD4(+) T cells is observed in the majority of infected patients and the role of these diminished responses in the loss of control of replication during the chronic phase of HIV infection remain incompletely understood. In a cohort of 15 patients that were selected for particularly strong HIV-specific CD4(+) T-cell responses, the effects of viremia on these responses were explored. Restriction of HIV replication was not observed during one to eight interruptions of antiretroviral therapy in the majority of patients (12 of 15). In each case, proliferative responses to HIV antigens were rapidly inhibited during viremia. The frequencies of cells that produce IFN-gamma in response to Gag, Pol, and Nef peptide pools were maintained during an interruption of therapy. In a subset of patients with elevated frequencies of interleukin-2 (IL-2)-producing cells, IL-2 production in response to HIV antigens was diminished during viremia. Addition of exogenous IL-2 was sufficient to rescue in vitro proliferation of DR0101 class II Gag or Pol tetramer(+) or total-Gag-specific CD4(+) T cells. These observations suggest that, during viremia, diminished in vitro proliferation of HIV-specific CD4(+) T cells is likely related to diminished IL-2 production. These results also suggest that relatively high frequencies of HIV-specific CD4(+) T cells persist in the peripheral blood during viremia, are not replicatively senescent, and proliferate when IL-2 is provided exogenously. C1 NIAID, LIR, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Montreal, CHUM, Immunol Lab, Montreal, PQ, Canada. Benaroya Res Inst, Virginia Mason Res Ctr, Seattle, WA USA. RP Connors, M (reprint author), NIAID, LIR, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-09,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. RI younes, souheil-antoine/G-4503-2014 OI younes, souheil-antoine/0000-0003-2186-7140 NR 54 TC 142 Z9 143 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 10900 EP 10909 DI 10.1128/JVI.77.20.10900-10909.2003 PG 10 WC Virology SC Virology GA 727XL UT WOS:000185686100018 PM 14512540 ER PT J AU Belliot, G Sosnovtsev, SV Mitra, T Hammer, C Garfield, M Green, KY AF Belliot, G Sosnovtsev, SV Mitra, T Hammer, C Garfield, M Green, KY TI In vitro proteolytic processing of the MD145 norovirus ORF1 nonstructural polyprotein yields stable precursors and products similar to those detected in calicivirus-infected cells SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-DISEASE VIRUS; NORWALK-LIKE VIRUSES; PROTEINASE-POLYMERASE PRECURSOR; 3C-LIKE PROTEASE; CLEAVAGE SITES; SUBSTRATE-SPECIFICITY; GENOME ORGANIZATION; ESCHERICHIA-COLI; CAPSID PRECURSOR; ACTIVE-SITE AB The MD145-12 strain (GII/4) is a member of the genus Norovirus in the Caliciviridae and was detected in a patient with acute gastroenteritis in a Maryland nursing home. The open reading frame 1 (ORF1) (encoding the nonstructural polyprotein) was cloned as a consensus sequence into various expression vectors, and a proteolytic cleavage map was determined. The virus-encoded cysteine proteinase mediated at least five cleavages (Q(330)/G(331) Q(696)/G(697), E-875/G(876), E-1008/A(1009), and E-1189/G(1190)) in the ORF1 polyprotein in the following order: N-terminal protein; nucleoside triphosphatase; 20-kDa protein (p20); virus protein, genome linked (VPg); proteinase (Pro); polymerase (Pol). A time course analysis of proteolytic processing of the MD145-12 ORF1 polyprotein in an in vitro coupled transcription and translation assay allowed the identification of stable precursors and final mapped cleavage products. Stable precursors included p20VPg (analogous to the 3AB of the picornaviruses) and ProPol (analogous to the 3CD of the picornaviruses). Less stable processing intermediates were identified as p20VPgProPol, p20VPgPro, and VPgPro. The MD145-12 Pro and ProPol proteins were expressed in bacteria as active forms of the proteinase and used to further characterize their substrate specificities in trans cleavage assays. The MD145-12 Pro was able to cleave its five mapped cleavage sites in trans and, in addition, could mediate trans cleavage of the Norwalk virus (GI/I) ORF1 polyprotein into a similar proteolytic processing profile. Taken together, our data establish a model for proteolytic processing in the noroviruses that is consistent with nonstructural precursors and products identified in studies of caliciviruses that replicate in cell culture systems. C1 NIAID, DHHS, LID, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Belliot, G (reprint author), NIAID, DHHS, LID, NIH, Bldg 50,Room 6316,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 92 Z9 94 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 10957 EP 10974 DI 10.1128/JVI.77.20.10957-10974.2003 PG 18 WC Virology SC Virology GA 727XL UT WOS:000185686100023 PM 14512545 ER PT J AU McWilliams, MJ Julias, JG Sarafianos, SG Alvord, WG Arnold, E Hughes, SH AF McWilliams, MJ Julias, JG Sarafianos, SG Alvord, WG Arnold, E Hughes, SH TI Mutations in the 5 ' end of the human immunodeficiency virus type 1 polypurine tract affect RNase H cleavage specificity and virus titer SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HIV-1 REVERSE-TRANSCRIPTASE; STRAND DNA-SYNTHESIS; CRYSTAL-STRUCTURE; RIBONUCLEASE-H; ANGSTROM RESOLUTION; IN-VIVO; REPLICATION; POLYMERASE; SEQUENCE AB The RNase H activity of retroviral reverse transcriptases (RTs) degrades viral genomic RNA after it has been copied into DNA, removes the tRNA used to initiate negative-strand DNA synthesis, and generates and removes the polypurine tract (PPT) primer used to initiate positive-strand DNA synthesis. The cleavages that remove the tRNA and that generate and remove the PPT primer must be specific to generate linear viral DNAs with ends that are appropriate for integration into the host cell genome. The crystal structure of human immunodeficiency virus type 1 (HIV-1) RT in a complex with an RNA/DNA duplex derived from the PPT revealed that the 5' end of the PPT deviates from traditional Watson-Crick base pairing. This unusual structure may play a role in the proper recognition of the PPT by HIV-1 RT. We made substitution mutations in the 5' end of the PPT and determined their effects on virus titer. The results indicated that single and double mutations in the 5' end of the PPT had modest effects on virus replication in a single-cycle assay. More complex mutations had stronger effects on virus titer. Analysis of the two-long-terminal-repeat circle junctions derived from infecting cells with the mutant viruses indicated that the mutations affected RNase H activity, resulting in the retention of PPT sequences on viral DNA. The mutants tested preferentially retained specific segments of the PPT, suggesting an effect on cleavage specificity. These results suggest that structural features of the PPT are important for its recognition and cleavage in vivo. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Data Management Serv, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Rm 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [AI 09578, F32 AI009578, R37 AI027690, AI 27690]; NIGMS NIH HHS [GM55609] NR 35 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 OCT PY 2003 VL 77 IS 20 BP 11150 EP 11157 DI 10.1128/JVI.77.20.11150-11157.2003 PG 8 WC Virology SC Virology GA 727XL UT WOS:000185686100040 PM 14512562 ER PT J AU Sato, H Pesnicak, L Cohen, JI AF Sato, H Pesnicak, L Cohen, JI TI Varicella-zoster virus ORF47 protein kinase, which is required for replication in human T cells, and ORF66 protein kinase, which is expressed during latency, are dispensable for establishment of latency SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN TRIGEMINAL GANGLIA; TRANSCRIPTIONAL REGULATORY PROTEIN; INFECTED HUMAN GANGLIA; VIRAL REPLICATION; VZV TRANSCRIPTION; GENE-EXPRESSION; GLYCOPROTEIN-I; SERINE KINASE; CDNA LIBRARY; DNA-SEQUENCE AB Varicella-zoster virus (VZV) results in a lifelong latent infection in human sensory and cranial nerve ganglia after primary infection. VZV open reading frame 47 (ORF47) and ORF66 encode protein kinases that phosphorylate several viral proteins, including VZV glycoprotein gE and ORF32, ORF62, and ORF63 proteins. Here we show that the ORF47 protein kinase also phosphorylates gI. While ORF47 is essential for virus replication in human T cells and skin, we found the gene to be dispensable for establishment of latent infection in dorsal root ganglia of rodents. ORF66 protein is expressed during latency. Rodents infected with VZV unable to express ORF66 developed latent infection at a rate similar to that for the parental virus. ORF63 transcripts, a hallmark of VZV latency, were also detected in similar numbers of animals infected with the ORF47 and ORF66 mutants and with the parental virus. VZV mutants unable to express four of the six genes that do not have herpes simplex virus (HSV) homologs (ORFs 1, 13, 32, 57) were also unimpaired for establishment of latency. While a truncated HSV VP16 mutant was previously reported to be unable to establish latency in, a mouse model, we found that VZV with a deletion of ORF10, the homolog of HSV VP16, was dispensable for establishment of latency. Thus, seven genes, including one expressed during latency, are dispensable for establishing latent VZV infection. C1 NIAID, Med Virol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Clin Invest Lab, Bldg 10,Rm 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. NR 46 TC 21 Z9 22 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 11180 EP 11185 DI 10.1128/JVI.77.20.11180-11185.2003 PG 6 WC Virology SC Virology GA 727XL UT WOS:000185686100043 PM 14512565 ER PT J AU Rhodes, T Wargo, H Hu, WS AF Rhodes, T Wargo, H Hu, WS TI High rates of human immunodeficiency virus type I recombination: Near-random segregation of markers one kilobase apart in one round of viral replication SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; ACTIVATING RETROVIRAL VECTORS; REVERSE-TRANSCRIPTASE; GENETIC-RECOMBINATION; STRAND TRANSFER; PROTEASE INHIBITOR; LENTIVIRAL VECTOR; INTERNAL REGIONS; HIV TYPE-1; SUBTYPE-A AB One of the genetic consequences of packaging two copies of full-length viral RNA into a single retroviral virion is frequent recombination during reverse transcription. Many of the currently circulating strains of human immunodeficiency virus type 1 (HIV-1) are recombinants. Recombination can also accelerate the generation of multidrug-resistant HIV-1 and therefore presents challenges to effective antiviral therapy. In this study, we determined that HIV-1 recombination rates with markers 1.0, 1.3, and 1.9 kb apart were 42.4, 50.4, and 47.4% in one round of viral replication. Because the predicted recombination rate of two unlinked markers is 50%, we conclude that markers 1 kb apart segregated in a manner similar to that for two unlinked markers in one round of retroviral replication. These recombination rates are exceedingly high even among retroviruses. Recombination rates of markers separated by 1 kb are 4 and 4.7% in one round of spleen necrosis virus and murine leukemia virus replication, respectively. Therefore, HIV-1 recombination can be 10-fold higher than that of other retroviruses. Recombination can be observed only in the proviruses derived from heterozygous virions that contain two genotypically different RNAs. The high rates of HIV-1 recombination observed in our studies also indicate that heterozygous virions are formed efficiently during HIV-1 replication and most HIV-1 virions are capable of undergoing recombination. Our results demonstrate that recombination is an effective mechanism to break the genetic linkage between neighboring sequences, thereby reassorting the HIV-1 genome and increasing the diversity in the viral population. C1 NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Frederick, MD 21702 USA. W Virginia Univ, Sch Med & Dent, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. RP Hu, WS (reprint author), NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Bldg 535,Room 336, Frederick, MD 21702 USA. NR 57 TC 101 Z9 101 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 11193 EP 11200 DI 10.1128/JVI.77.20.11193-11200.2003 PG 8 WC Virology SC Virology GA 727XL UT WOS:000185686100045 PM 14512567 ER PT J AU Spann, KM Collins, PL Teng, MN AF Spann, KM Collins, PL Teng, MN TI Genetic recombination during coinfection of two mutants of human respiratory syncytial virus SO JOURNAL OF VIROLOGY LA English DT Article ID REPLICATION IN-VITRO; RNA RECOMBINATION; DENGUE VIRUS; GLYCOPROTEIN; REASSORTMENT; PROTEINS; RSV; TRANSCRIPTION; EVOLUTION; DELETION AB Recombination between coinfecting viruses had not been documented previously for a nonsegmented negative-strand RNA virus (mononegavirus). We investigated the potential of intermolecular recombination by respiratory syncytial virus (RSV) by coinfecting HEp-2 cells with two recombinant RSV (rRSV) mutants lacking either the G gene (DeltaG/HEK) or the NS1 and NS2 genes (DeltaNS1/2). These viruses replicate inefficiently and form pinpoint plaques in HEp-2 cells. Therefore, potential recombined viruses with a growth and/or plaque formation advantage should easily be identified and differentiated from the two parental viruses. Further identification of potential recombinants was aided by the inclusion of point mutation markers in the F and L genes of DeltaG/HEK and the design of reverse transcription-PCR (RT-PCR) primers capable of detecting these markers. Independent coinfections and control single infections by these two rRSV mutants were performed. In one of six coinfections, an RSV variant was identified that produced plaques slightly larger than those of wild-type RSV in HEp-2 cells. RT-PCR and sequencing provided evidence that this variant was a recombined RSV (rec-RSV). The rec-RSV appeared to have been generated by a polymerase jump from the DeltaG/HEK genome to that of DeltaNS1/2 and back again in the vicinity of the SH-G-F genes. This apparently involved nonhomologous and homologous recombination events, respectively. The recombined genome was identical to that of the DeltaG/HEK mutant except that all but the first 12 nucleotides of the SH gene were deleted and replaced by an insert consisting of the last 91 nucleotides of the G gene and its downstream intergenic region. This insert could have come only from the coinfecting DeltaNS1/2 virus. This resulted in the formation of a short chimeric SH:G gene. Northern and Western blot analysis confirmed that the rec-RSV did not express the normal SH and G mRNAs and proteins but did express the aberrant SH:G mRNA. This provides an experimental demonstration of intermolecular recombination yielding a viable, helper-independent mononegavirus. However, the isolation of only a single rec-RSV under these optimized conditions supports the idea that RSV recombination is rare indeed. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, Bldg 50,Room 6503,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. RI Spann, Kirsten/B-4524-2013; Teng, Michael/I-5006-2012 OI Spann, Kirsten/0000-0003-0567-8382; Teng, Michael/0000-0002-0722-3659 NR 27 TC 61 Z9 63 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2003 VL 77 IS 20 BP 11201 EP 11211 DI 10.1128/JVI.77.20.11201-11211.2003 PG 11 WC Virology SC Virology GA 727XL UT WOS:000185686100046 PM 14512568 ER PT J AU Taaffe, DR Simonsick, EM Visser, M Volpato, S Nevitt, MC Cauley, JA Tylavsky, FA Harris, TB AF Taaffe, DR Simonsick, EM Visser, M Volpato, S Nevitt, MC Cauley, JA Tylavsky, FA Harris, TB TI Lower extremity physical performance and hip bone mineral density in elderly black and white men and women: Cross-sectional associations in the health ABC study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID LONG-TERM EXERCISE; MUSCLE STRENGTH; RISK-FACTORS; OSTEOPOROTIC FRACTURES; POSTMENOPAUSAL WOMEN; OLDER WOMEN; BODY-COMPOSITION; MASS; AGE; PREVENTION AB Background. Aging is characterized by declines in physical capacity and bone mineral density (BMD), both of which contribute to increased risk for fracture. However, it is unclear if these factors coexist or are independent in elderly people, and if a relationship does exist, whether it varies by sex and/or race. Methods. Data are from 847 white women, 723 black women, 927 white men, and 544 black men aged 70-79 years participating in the Health Aging and Body Composition (ABC) Study, a cohort of well-functioning community-dwelling elders. BMD (g/cm(2)) of the hip (femoral neck and trochanter) was determined by dual X-ray absorptiometry. Physical capacity measures included knee extensor strength, repeated chair-stands, gait speed (6 m), walking endurance (400 m), and standing balance. Results. In analyses of BMD as a continuous measure, BMD and physical performance were most consistently related at the trochanter in black women, even after adjusting for body size and several covariates including physical activity. For each performance measure, black women in the bottom quartile(s) had lower BMD than those in the top quartile(s). For the femoral neck, there was a significant association with performance tasks, except for the 400-m walk. In comparison, only chair-rise performance was related to BMD at the femoral neck, and knee extensor strength, chair-rise performance, and balance with the trochanter in white women. For white and black men, trends existed only for lower BMD in those with poorer knee extensor strength. Conclusions. In this cohort of well-functioning young-old seniors, physical capacity is only modestly related to BMD at the hip. The association was strongest in black women, who as a group exhibited the poorest functional capacity in the cohort. Our data show that, although both poorer physical performance and low BMD are risk factors for fracture, they remain largely independent in the well-functioning young-old, except in black women. This independence suggests that interventions to reduce fracture incidence should be targeted at improving both physical performance and bone density. C1 Univ Queensland, Fac Hlth Sci, Sch Human Movement Studies, St Lucia, Qld 4072, Australia. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. Natl Inst Aging, Intramural Res Program, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med, Baltimore, MD USA. Vrije Univ Amsterdam, Ctr Med, Inst Res Extramural Med, Amsterdam, Netherlands. Univ Ferrara, Dipartimento Med Clin & Sperimentale, Ferrara, Italy. Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Tennessee, Dept Epidemiol, Memphis, TN USA. RP Taaffe, DR (reprint author), Univ Queensland, Fac Hlth Sci, Sch Human Movement Studies, Connell Bldg, St Lucia, Qld 4072, Australia. RI Cauley, Jane/N-4836-2015; VOLPATO, STEFANO/H-2977-2014 OI Cauley, Jane/0000-0003-0752-4408; VOLPATO, STEFANO/0000-0003-4335-6034 NR 57 TC 16 Z9 18 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2003 VL 58 IS 10 BP 934 EP 942 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 734WF UT WOS:000186080400012 ER PT J AU Garnett, NL Gipson, CA AF Garnett, NL Gipson, CA TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 NIH, OLAW, Bethesda, MD 20892 USA. RP Garnett, NL (reprint author), NIH, OLAW, Bethesda, MD 20892 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2003 VL 32 IS 9 BP 19 EP 19 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 727NH UT WOS:000185664600006 PM 15235657 ER PT J AU Wolff, A Garnett, N Potkay, S Wigglesworth, C Doyle, D Thornton, V AF Wolff, A Garnett, N Potkay, S Wigglesworth, C Doyle, D Thornton, V TI Frequently asked questions about the Public Health Service Policy on Humane Care and Use of Laboratory Animals SO LAB ANIMAL LA English DT Article ID PHS POLICY; USDA; OPRR; WORD AB The Office of Laboratory Animal Welfare (OLAW) of the National Institutes of Health (NIH) develops, implements, and oversees compliance with the US Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals' (Policy). The PHS Policy and the US Department of Agriculture's (USDA`s) Animal Welfare Regulations' are the two principal federal documents that set forth requirements for animal care and use by institutions using animals in research, testing, and education. One of OLAW's primary functions is to assist institutions in implementing PHS Policy by responding to policy-related questions. This is accomplished by collaborating with organizations and individuals in preparing guidance for Institutional Animal Care and Use Committees (IACUCs)(3-5), supporting the publication of monographs on various aspects of animal care and use programs(6,7), and publishing Policy interpretations in articles(8-18) and other formats(19-30). OLAW also sponsors seminars and training that specifically address current topics covering animal care and use, and issues guidance notices in the NIH Guide for Grants and Contracts (formerly as "Dear Colleague" letters), all of which are found on the OLAW website (http://grants.nih.gov/grants/olaw/olaw.htm). The following represent several additional questions frequently asked by institutions and the OLAW responses. C1 NIH, OLAW, Bethesda, MD 20892 USA. RP Wolff, A (reprint author), NIH, OLAW, Suite 360,MSC 7982,6705 Rocklege Dr,RKL 1, Bethesda, MD 20892 USA. NR 33 TC 5 Z9 6 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2003 VL 32 IS 9 BP 33 EP 36 DI 10.1038/laban1003-33 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 727NH UT WOS:000185664600008 PM 15235661 ER PT J AU Akin, C AF Akin, C TI Multilineage hematopoietic involvement in systemic mastocytosis SO LEUKEMIA RESEARCH LA English DT Editorial Material ID C-KIT; ACTIVATING MUTATION; CATALYTIC DOMAIN; MAST-CELLS; MECHANISMS; MICE; GENE C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Akin, C (reprint author), NIAID, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11C210, Bethesda, MD 20892 USA. OI Akin, Cem/0000-0001-6301-4520 NR 15 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD OCT PY 2003 VL 27 IS 10 BP 877 EP 878 DI 10.1016/S0145-2126(03)00093-6 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 702WL UT WOS:000184247700002 PM 12860004 ER PT J AU Ishibe, N Goldin, LR Caporaso, NE Sgambati, MT Dean, M Albitar, M Manshouri, T Gerrard, B Marti, GE AF Ishibe, N Goldin, LR Caporaso, NE Sgambati, MT Dean, M Albitar, M Manshouri, T Gerrard, B Marti, GE TI ATM mutations and protein expression are not associated with familial B-CLL cases SO LEUKEMIA RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MANTLE CELL LYMPHOMA; ATAXIA-TELANGIECTASIA; GENE; INACTIVATION; KINASE C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Lab Genome Divers, FCRDS, Ft Detrick, MD 21702 USA. Univ Texas, MD Anderson Canc Ctr, Hematopathol Dept, Sect Leukemia, Houston, TX 77030 USA. NCI, FCRDC, Intramural Res Support Program, Ft Detrick, MD 21702 USA. US FDA, Flow & image Cytometry Sect, Div Cell & Gene Therapies, Bethesda, MD 20892 USA. RP Ishibe, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Exectu Blvd,MSC 7236, Bethesda, MD 20892 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [N01-CO-12400] NR 18 TC 8 Z9 9 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 OCT PY 2003 VL 27 IS 10 BP 973 EP 975 DI 10.1016/S0145-2126(03)00067-5 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 702WL UT WOS:000184247700019 PM 12860021 ER PT J AU Bazinet, RP McMillan, EG Cunnane, SC AF Bazinet, RP McMillan, EG Cunnane, SC TI Dietary alpha-linolenic acid increases the n-3 PUFA content of sow's milk and the tissues of the suckling piglet SO LIPIDS LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; FORMULA-FED INFANTS; DOCOSAHEXAENOIC ACID; WHOLE-BODY; LACTATING WOMEN; LATE PREGNANCY; SOYBEAN OIL; FISH OIL; TUNA OIL; BRAIN AB alpha-Linolenic acid (18:3n-3) is a precursor to DHA (22:6n-3), which is essential for normal growth and development in the infant. This study was undertaken to assess how a raised I 8:3n-3 intake in sows affects the n-3 PUFA content of the suckling piglet. Sows consumed a high-18:3n-3 or control diet (n-3 PUFA/n-6 PUFA, 0.5 vs. 0.05, respectively) for 10 d prior to parturition and for 14 d postpartum. Piglets suckled from their mothers until 14 d of age, when they were sacrificed. Sows consuming the high-18:3n-3 diet had 141% more 18:3n-3 and 86% more 22:6n-3 in their milk compared to control sows. There was no difference in the proximate composition of the piglets. The n-3/n-6 PUFA ratio was 82% higher in the milk of sows consuming the high-18:3n-3 diet compared to controls. Piglets suckling from sows consuming the high-18:3n-3 diet had 423% more I 8:3n-3 in the carcass as well as a 460% higher n-3/n-6 PUFA ratio than controls. The piglets suckling from sows consuming the high-18:3n-3 diet had 333% more 18:3n-3 and 54% more 22:6n-3 in the liver, as well as a 114% higher n-3/n-6 ratio than control piglets. Piglets suckling from sows consuming a high-18:3n-3 diet also had 24% more 22:6n-3 and a 33% higher n-3/n-6 ratio in the brain compared to control piglets. A high 1 8:3n-3 intake in the sow increases not only the 1 8:3n-3 but also the 22:6n-3 content of sow's milk and the tissues of the suckling piglet. C1 Univ Toronto, Dept Nutrit Sci, Fac Med, Toronto, ON M5S 3E2, Canada. Maple Leaf Foods Agres, Guelph, ON N1G 4T2, Canada. RP Bazinet, RP (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Rm 6N 202,900 Rockville Pike, Bethesda, MD 20892 USA. RI Wilkinson, Stuart/C-2802-2013 NR 34 TC 29 Z9 30 U1 1 U2 6 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD OCT PY 2003 VL 38 IS 10 BP 1045 EP 1049 DI 10.1007/s11745-006-1159-9 PG 5 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 746GZ UT WOS:000186739800005 PM 14669969 ER PT J AU Kobayashi, H Kawamoto, S Choyke, PL Sato, N Knopp, MV Star, RA Waldmann, TA Tagaya, Y Brechbiel, MW AF Kobayashi, H Kawamoto, S Choyke, PL Sato, N Knopp, MV Star, RA Waldmann, TA Tagaya, Y Brechbiel, MW TI Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonance lymphangiography SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; lymphangiography; MRI contrast agents; dendrimers; lymphatic disorder ID LYMPH-NODE METASTASES; IRON-OXIDE PARTICLES; MR-LYMPHOGRAPHY; POLYAMIDOAMINE DENDRIMER; PHARMACOKINETIC PROPERTIES; MONOCLONAL-ANTIBODY; TRANSGENIC MICE; HIGH-GENERATION; IN-VIVO; CORE AB Few methods are currently available to visualize the entire lymphatic system. A method known as micro-magnetic resonance lymphangiography (MRL), which employs a dendrimer-based MRI contrast agent (PAMAM-G8) and a clinical-grade 1.5T MRI instrument, was recently developed for use in mice. In the present study, three dendrimer-based MRI contrast agents (PAMAM-G8, DAB-G5, and PAMAM-G4) with different pharmacokinetic characteristics were compared to determine the best reagent to visualize the lymphatic system under physiological or pathological conditions. In addition, two established MRI contrast agents (Gadomer-17 and Gd-[DTPA]-dimeglumine (Magnevist)) were used as control agents. In experiments with mice, most of the deep lymphatic system was visualized by micro-MRL with all agents except Gd-[DTPA]-dimeglumine. PAMAM-G8 was best for visualizing lymphatic vessels, whereas DAB-G5 was better for visualizing lymph nodes. PAMAM-G4 was intermediate in character between PAMAM-G8 and DAB-G5, except in exhibiting a low background signal (especially in the liver). The lymphatic system was not clearly visualized with Gd-[DTPA]-dimeglumine; however, the lymph nodes were visualized with Gadomer-17, although not as well as with dendrimer-based agents. In conclusion, DAB-G5 and PAMAM-G4 can be used to identify lymph nodes and lymphatic vessels, respectively. Their rapid excretion makes these compounds potentially attractive for human use. Published 2003 Wiley-Liss, Inc. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD USA. NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov NR 40 TC 71 Z9 75 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2003 VL 50 IS 4 BP 758 EP 766 DI 10.1002/mrm.10583 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728CQ UT WOS:000185698000015 PM 14523962 ER PT J AU Markl, M Bammer, R Alley, MT Elkins, CJ Draney, MT Barnett, A Moseley, ME Glover, GH Pelc, NJ AF Markl, M Bammer, R Alley, MT Elkins, CJ Draney, MT Barnett, A Moseley, ME Glover, GH Pelc, NJ TI Generalized reconstruction of phase contrast MRI: Analysis and correction of the effect of gradient field distortions SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE gradient field distortions; phase contrast MRI; velocity encoding; flow quantification; image reconstruction ID GEOMETRIC DISTORTION; MAGNETIC-RESONANCE; SPATIAL DISTORTION; INHOMOGENEITY; DESIGN AB To characterize gradient field nonuniformity and its effect on velocity encoding in phase contrast (PC) MRI, a generalized model that describes this phenomenon and enables the accurate reconstruction of velocities is presented. In addition to considerable geometric distortions, inhomogeneous gradient fields can introduce deviations from the nominal gradient strength and orientation, and therefore spatially-dependent first gradient moments. Resulting errors in the measured phase shifts used for velocity encoding can therefore cause significant deviations in velocity quantification. The true magnitude and direction of the underlying velocities can be recovered from the phase difference images by a generalized PC velocity reconstruction, which requires the acquisition of full three-directional velocity information. The generalized reconstruction of velocities is applied using a matrix formalism that includes relative gradient field deviations derived from a theoretical model of local gradient field nonuniformity. In addition, an approximate solution for the correction of one-directional velocity encoding is given. Depending on the spatial location of the velocity measurements, errors in velocity magnitude can be as high as 60%, while errors in the velocity encoding direction can be up to 45degrees. Results of phantom measurements demonstrate that effects of gradient field nonuniformity on PC-MRI can be corrected with the proposed method. Published 2003 Wiley-Liss, Inc.(dagger) C1 Stanford Univ, Dept Radiol, Lucas MRIS Ctr, Palo Alto, CA 94304 USA. Stanford Univ, Dept Mech Engn, Stanford, CA 94305 USA. NIMH, Clin Brain Disorders Branch, CBDB, Bethesda, MD 20892 USA. RP Markl, M (reprint author), Stanford Univ, Dept Radiol, Lucas MRIS Ctr, Room P284,1201 Welch Rd, Palo Alto, CA 94304 USA. RI Markl, Michael/F-7436-2011 FU NCRR NIH HHS [P41 RR09784]; NHLBI NIH HHS [R01 HL46347] NR 22 TC 67 Z9 68 U1 3 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2003 VL 50 IS 4 BP 791 EP 801 DI 10.1002/mrm.10582 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728CQ UT WOS:000185698000019 PM 14523966 ER PT J AU Klarhofer, M Dilharreguy, B van Gelderen, P Moonen, CTW AF Klarhofer, M Dilharreguy, B van Gelderen, P Moonen, CTW TI A PRESTO-SENSE sequence with alternating partial-Fourier encoding for rapid susceptibility-weighted 3D MRI time series SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE echo-shifting; sensitivity encoding; partial-Fourier; functional imaging ID GRADIENT-ECHO; FUNCTIONAL MRI; FMRI TECHNIQUE; HUMAN BRAIN; REDUCTION; 2D; ACQUISITION; ACTIVATION; EXCITATION; ARTIFACT AB A 3D sequence for dynamic susceptibility imaging is proposed which combines echo-shifting principles (such as PRESTO), sensitivity encoding (SENSE), and partial-Fourier acquisition. The method uses a moderate SENSE factor of 2 and takes advantage of an alternating partial k-space acquisition in the "slow" phase encode direction allowing an iterative reconstruction using high-resolution phase estimates. Offering an isotropic spatial resolution of 4 x 4 x 4 mm(3), the novel sequence covers the whole brain including parts of the cerebellum in 0.5 sec. Its temporal signal stability is comparable to that of a full-Fourier, full-FOV EPI sequence having the same dynamic scan time but much less brain coverage. Initial functional MRI experiments showed consistent activation in the motor cortex with an average signal change slightly less than that of EPI. (C) 2003 Wiley-Liss, Inc. C1 Univ Bordeaux 2, CNRS, Imagerie Mol & Fonctionelle ERT, F-33076 Bordeaux, France. NINDS, NIH, Bethesda, MD 20892 USA. RP Moonen, CTW (reprint author), Univ Bordeaux 2, CNRS, Imagerie Mol & Fonctionelle ERT, 146 Rue Leo Saignat,Case 117, F-33076 Bordeaux, France. RI Moonen, Chrit/K-4434-2016 OI Moonen, Chrit/0000-0001-5593-3121 NR 32 TC 20 Z9 21 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2003 VL 50 IS 4 BP 830 EP 838 DI 10.1002/mrm.10599 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728CQ UT WOS:000185698000023 PM 14523970 ER PT J AU Matsumoto, K Chandrika, B Lohman, JAB Mitchell, JB Krishna, MC Subramanian, S AF Matsumoto, K Chandrika, B Lohman, JAB Mitchell, JB Krishna, MC Subramanian, S TI Application of continuous-wave EPR spectral-spatial image reconstruction techniques for in vivo oxymetry: Comparison of projection reconstruction and constant-time modalities SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE in vivo imaging; oxymetry; EPR imaging; spectral-spatial imaging; tumor ID ELECTRON-PARAMAGNETIC-RESONANCE; FREE-RADICALS; OXYGEN CONCENTRATION; MAGNETIC-RESONANCE; HIGH-RESOLUTION; OXIMETRY; TUMOR; TISSUE; SPECTROMETER; TOMOGRAPHY AB In this study we report the application of continuous-wave (CW) electron paramagnetic resonance (EPR) constant-time spectral spatial imaging (CTSSI) for in vivo oxymetry. 2D and 3D SSI studies of a phantom and live mice were carried out using projection reconstruction (PR) and constant-time (CT) modalities using a CW-EPR spectrometer/imager operating at 300 MHz frequency. Distortion of line shape, which is inherent in the PR method, was minimized by the CTSSI modality. It was also found that CTSSI offers improved noise reduction, restores a smoother line shape, and gives high convergence of estimated values. Spatial resolution was also improved by CTSSI, although fundamental spectral line-width broadening was observed. Although additional corrections are required for accurate estimations of spectral line width, CTSSI was able to demonstrate distinct differences in oxygen tension between a tumor and the normal legs of a C3H mouse. The PR method, on the other hand, was unable to make such a distinction unequivocally with the triarylmethyl spin probes. CTSSI promises to be a more suitable method for quantitative in vivo oxymetric studies using radiofrequency EPR imaging (EPRI). Published 2003 Wiley-Liss, Inc.(dagger) C1 NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Bruker UK Ltd, Coventry, W Midlands, England. RP Krishna, MC (reprint author), NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. NR 39 TC 19 Z9 19 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2003 VL 50 IS 4 BP 865 EP 874 DI 10.1002/mrm.10595 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728CQ UT WOS:000185698000027 PM 14523974 ER PT J AU Thomas, JW Green, ED AF Thomas, JW Green, ED CA NISC Comparative Sequencing Progra TI Comparative sequence analysis of a single-gene conserved segment in mouse and human SO MAMMALIAN GENOME LA English DT Article ID HUMAN-GENOME; DUPLICATIONS; EVOLUTION; MAP AB Comparative mapping and sequencing of the mouse and human genomes have defined large, conserved chromosomal segments in which gene content and order are highly conserved. These regions span megabase-sized intervals and together comprise the vast majority of both genomes. However, the evolutionary relationships among the small remaining portions of these genomes are not as well characterized. Here we describe the sequencing and annotation of a 341-kb region of mouse Chr 2 containing nine genes, including biliverdin reductase A (Blvra), and its comparison with the orthologous regions of the human and rat genomes. These analyses reveal that the known conserved synteny between mouse Chromosome (Chr) 2 and human Chr 7 reflects an interval containing one gene (Blvra/BLVRA) that is, at most, just 34 kb in the mouse genome. In the mouse, this segment is flanked proximally by genes orthologous to human chromosome 15q21 and distally by genes orthologous to human Chr 2q11. The observed differences between the human and mouse genomes likely resulted from one or more rearrangements in the rodent lineage. In addition to the resulting changes in gene order and location, these rearrangements also appear to have included genomic deletions that led to the loss of at least one gene in the rodent lineage. Finally, we also have identified a recent mouse-specific segmental duplication. These finding illustrate that small genomic regions outside the large mouse-human conserved segments can contain a single gene as well as sequences that are apparently unique to one genome. C1 Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Thomas, JW (reprint author), Emory Univ, Sch Med, Dept Human Genet, 615 Michael St,Suite 301, Atlanta, GA 30322 USA. EM jthomas@genetics.emory.edu NR 19 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2003 VL 14 IS 10 BP 673 EP 678 DI 10.1007/s00335-003-2300-1 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 727GL UT WOS:000185650200002 PM 14694903 ER PT J AU Korner, U Bustin, M Scheer, U Hock, R AF Korner, U Bustin, M Scheer, U Hock, R TI Developmental role of HMGN proteins in Xenopus laevis SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Xenopus laevis; early development; chromatin; HMGN1/N2 proteins; gene expression ID GROUP CHROMOSOMAL-PROTEINS; MOBILITY GROUP PROTEIN-14; LINKER HISTONES B4; LAMPBRUSH CHROMOSOMES; CDNA SEQUENCE; TRANSCRIPTIONAL REPRESSION; MITOTIC PHOSPHORYLATION; MORPHOGEN GRADIENT; GENE-TRANSCRIPTION; MULTIGENE FAMILY AB HMGN proteins are architectural chromatin proteins that reduce the compaction of the chromatin fiber, facilitate access to nucleosomes and modulate replication and transcription processes. Here we demonstrate that in Xenopus laevis, the expression and cellular location of the HMGN proteins are developmentally regulated and that their misexpression leads to gross developmental defects in post-blastula embryos. HMGN transcripts and proteins are present throughout oogenesis; however, the proteins stored in the cytoplasm are not associated with lampbrush chromosomes, and are rapidly degraded when oocytes mature into eggs. During embryogenesis, HMGN expression is first detected in blastula stages and progresses to a tissue-specific expression reaching relative high levels in the mesodermal and neuroectodermal regions of tadpoles. Only after midblastula transition (MBT), alterations in the HMGN levels by either microinjection of recombinant proteins or by morpholino-antisense oligo treatments produced embryos with imperfectly closed blastopore, distorted body axis and showed abnormal head structures. Analyses of animal cap explants indicated that HMGN proteins are involved in the regulation of mesoderm specific genes. In addition, HMGN misexpression caused altered expression of specific genes at MBT rather than global changes of transcription rates. Our results demonstrate that proper embryonic development of Xenopus laevis requires precisely regulated levels of HMGN proteins and suggest that these nucleosomal binding proteins modulate the expression of specific genes. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. NCI, DBS, LM, Prot Sect,NIH, Bethesda, MD 20892 USA. RP Hock, R (reprint author), Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, Hubland, D-97074 Wurzburg, Germany. RI Bustin, Michael/G-6155-2015 NR 70 TC 26 Z9 27 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD OCT PY 2003 VL 120 IS 10 BP 1177 EP 1192 DI 10.1016/j.mod.07.001 PG 16 WC Developmental Biology SC Developmental Biology GA 741JV UT WOS:000186455700007 PM 14568106 ER PT J AU Colbert, LH Mai, V Perkins, SN Berrigan, D Lavigne, JA Wimbrow, HH Alvord, WG Haines, DC Srinivas, P Hursting, SD AF Colbert, LH Mai, V Perkins, SN Berrigan, D Lavigne, JA Wimbrow, HH Alvord, WG Haines, DC Srinivas, P Hursting, SD TI Exercise and intestinal polyp development in APC(Min) mice SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE Min mouse; running; colorectal cancer; APC gene; physical activity ID INDUCED COLON CARCINOGENESIS; PHYSICAL-ACTIVITY; COLORECTAL-CANCER; UNITED-STATES; GROWTH-FACTOR; RISK; NEOPLASIA; RATS; ADENOMAS; MOUSE AB Purpose: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APC(Min)) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise X sex interaction on polyp development and to begin to look at potential mechanisms. Methods: Six-week-old APC(Min) mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m(.)min(-1), 5% grade, 45 min(.)d(-1), 5 d(.)wk(-1) (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice. Results: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01). Conclusion: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APC(Min) mice. C1 NIA, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Frederick, MD 21701 USA. NCI, Data Management Serv, Frederick, MD USA. RP Colbert, LH (reprint author), 2000 Observ Dr, Madison, WI 53706 USA. FU NCI NIH HHS [N01 CO 12400] NR 30 TC 41 Z9 41 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD OCT PY 2003 VL 35 IS 10 BP 1662 EP 1669 DI 10.1249/01.MSS.0000089349.54813.41 PG 8 WC Sport Sciences SC Sport Sciences GA 729CX UT WOS:000185754800007 PM 14523302 ER PT J AU Lenfant, C AF Lenfant, C TI Aging: Beneficial effects on patients from recent advances in genetics, neurobiology, and physiology - Introduction SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2003 VL 52 IS 10 SU 2 BP 4 EP 4 DI 10.1053/S0026-0495(03)00293-2 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 732WZ UT WOS:000185969700003 ER PT J AU Singh, VK Moskovitz, J AF Singh, VK Moskovitz, J TI Multiple methionine sulfoxide reductase genes in Staphylococcus aureus: expression of activity and roles in tolerance of oxidative stress SO MICROBIOLOGY-SGM LA English DT Article ID SUBSTRATE STEREOSPECIFICITY; ENZYMATIC REDUCTION; ANTIOXIDANT DEFENSE; MSRA; IDENTIFICATION; CONTRIBUTES; MECHANISM; RESISTANT; PROTEINS; PLASMIDS AB Staphylococcus aureus contains three genes encoding MsrA-specific methionine sulfoxide reductase (Msr) activity (msrA1, msrA2 and msrA3) and an additional gene that encodes MsrB-specific Msr activity. Data presented here suggest that MsrA1 is the major contributor of the MsrA activity in S. aureus. In mutational analysis, while the total Msr activity in msrA2 mutant was comparable to that of the parent, Msr activity was significantly up-regulated in the msrA1 or msrA1 msrA2 double mutant. Assessment of substrate specificity together with increased reactivity of the cell-free protein extracts of the msrA1 mutants to anti-MsrB polyclonal antibodies in Western analysis provided evidence that increased Msr activity was due to elevated synthesis of MsrB in the MsrA1 mutants. Previously, it was reported that oxacillin treatment of S. aureus cells led to induced synthesis of MsrA1 and a mutation in msrA1 increased the susceptibility of the organism to H2O2. A mutation in the msrA2 gene, however, was not significant for the bacterial oxidative stress response. In complementation assays, while the msrA2 gene was unable to complement the msrA1 msrA2 double mutant for H2O2 resistance, the same gene restored H2O2 tolerance in the double mutant when placed under the control of the msrA1 promoter. However, msrA1 which was able to complement the oxidative stress response in msrA1 mutants could not restore the tolerance of the msrA1 msrA2 mutants to H2O2 when placed under the control of the msrA2 promoter. Additionally, although the oxacillin minimum inhibitory concentration of the msrA1 mutant was comparable to that of the wild-type parent, in shaking liquid culture, the msrA1 mutant responded more efficiently to sublethal doses of oxacillin. The data suggest complex regulation of Msr proteins and a more significant physiological role for msrA1/msrB in S. aureus. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Illinois State Univ, Dept Biol Sci, Normal, IL 61790 USA. RP Moskovitz, J (reprint author), NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 36 TC 52 Z9 52 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD OCT PY 2003 VL 149 BP 2739 EP 2747 DI 10.1099/mic.0.26442-0 PN 10 PG 9 WC Microbiology SC Microbiology GA 733NU UT WOS:000186008200006 PM 14523107 ER PT J AU Goldenberg, I Shainberg, A Jacobson, KA Shneyvays, V Grossman, E AF Goldenberg, I Shainberg, A Jacobson, KA Shneyvays, V Grossman, E TI Adenosine protects against angiotensin II-induced apoptosis in rat cardiocyte cultures SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE A(1) and A(3) adenosine receptors; angiotensin II; apoptosis; cardiomyocytes; Feulgen and TUNEL stainings ID CHRONIC HEART-FAILURE; LEFT-VENTRICULAR DYSFUNCTION; ISOLATED RABBIT HEARTS; MYOCYTE CELL-DEATH; CARDIAC MYOCYTES; CONVERTING-ENZYME; MYOCARDIAL-INFARCTION; RECEPTOR ACTIVATION; A(3) RECEPTORS; IN-VITRO AB Adenosine has been found to be cardioprotective during episodes of cardiac ischemia/reperfusion through activation of the A(1) and possibly A(3) receptors. Therefore, we have investigated whether activation of these receptors can protect also against apoptotic death induced by angiotensin II (Ang II) in neonatal rat cardiomyocyte cultures. Exposure to Ang II (10 nM) resulted in a 3-fold increase in programmed cell death (p < 0.05). Pretreatment with the A(3) adenosine receptor agonist 2-chloro-N-6-cyclopentyladenosine (CCPA, 1 μM), abolished the effects of Ang II on programmed cardiomyocyte death. Moreover, exposure of cells to the A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) before pretreatment with CCPA, prevented the protective effect of the latter. Pretreatment with the A(3) adenosine receptor agonist N-6-(3-iodobenzyl) adenosine-5'-N-methyluronamide (IB-MECA, 0.1 μM), led to a partial decrease in apoptotic rate induced by Ang II. Exposure of myocytes to Ang II caused an immediate increase in the concentration of intracellular free Ca2+ that lasted 40-60 sec. Pretreatment of cells with CCPA or IB-MECA did not block Ang II-induced Ca2+ elevation. In conclusion, activation of adenosine A(1) receptors can protect the cardiac cells from apoptosis induced by Ang II, while activation of the adenosine A(3) receptors confers partial cardioprotection. C1 Bar Ilan Univ, Fac Life Sci, Gonda Goldschmied Med Diagnost Res Ctr, IL-52900 Ramat Gan, Israel. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Shainberg, A (reprint author), Bar Ilan Univ, Fac Life Sci, Gonda Goldschmied Med Diagnost Res Ctr, IL-52900 Ramat Gan, Israel. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 29 TC 17 Z9 21 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD OCT PY 2003 VL 252 IS 1-2 BP 133 EP 139 DI 10.1023/A:1025551229566 PG 7 WC Cell Biology SC Cell Biology GA 718BQ UT WOS:000185125600017 PM 14577586 ER PT J AU Kim, KY Cho, YJ Jeon, GA Ryu, PD Nam, MJ AF Kim, KY Cho, YJ Jeon, GA Ryu, PD Nam, MJ TI Membrane-bound alkaline phosphatase gene induces antitumor effect by G2/M arrest in etoposide phosphate-treated cancer cells SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE gene therapy; prodrug-converting system; alkaline phosphatase; etoposide; etoposide phosphate; antitumor activity ID ADVANCED GASTRIC-CANCER; THYMIDINE KINASE GENE; TOPOISOMERASE-II; HEPATOCELLULAR-CARCINOMA; MONOCLONAL-ANTIBODIES; COLORIMETRIC ASSAY; DNA TOPOISOMERASES; MAMMALIAN-CELLS; LUNG-CANCER; PHASE-II AB Gene therapy is used to induce immune responses, regulate tumor growth, or sensitize tumor cells to specific treatment. For sensitizing tumor cells to specific drug, we considered a prodrug-converting system using membrane-bound intestinal alkaline phosphatase (IAP) as the prodrug-activating genes. The IAP is capable of converting a relatively non-cytotoxic prodrug, etoposide phosphate (EP), into etoposide with a significant antitumor activity. We used the retroviral vector for transducing IAP gene into SNU638 gastric cancer cells and EP was prepared by phosphorylation of etoposide. To determine the chromosomal incorporation of membrane-bound IAP gene and AP activity in IAP gene-transduced cells (SNU638/IAP), we performed genomic PCR and AP activity analysis. In genomic DNA of SNU638/IAP cells, full cDNA fragment of a 2.5 kb IAP was detected, and AP activity was shown at most 15 similar to 18-fold increase compared with control cells. According to the in vitro cytotoxicity study, SNU638/IAP cells greatly enhanced the cytotoxic effect in proportion to the concentration of EP, while control cells didn't cause any cytotoxic effects after EP treatment. Especially, the cell population of G2/M phase was increased in EP-treated SNU638/ IAP cells because P4 DNA unknotting activity of topoisomerase II was decreased by EP treatment such as the action mechanism of etoposide. Finally, a strong antitumor response was observed in SNU638/ IAP cancer cells-bearing nude mice that were treated with EP. These results suggest that the prodrug-converting system by membrane-bound IAP gene and EP prodrug is useful as the strong strategy of gene therapy for cancer treatment. C1 Natl Inst Hlth, Dept Biomed Sci, Seoul, South Korea. Seoulin Biosci, Genet Mol Lab, Seoul, South Korea. Seoul Natl Univ, Coll Vet Med, Pharmacol Lab, Seoul, South Korea. Seoul Natl Univ, Sch Agr Biotechnol, Seoul, South Korea. RP Kim, KY (reprint author), NHLBI, Mol Cardiol Lab, NIH, 10 Ctr Dr,Bldg 10,8N206, Bethesda, MD 20892 USA. NR 42 TC 3 Z9 3 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD OCT PY 2003 VL 252 IS 1-2 BP 213 EP 221 DI 10.1023/A:1025572815125 PG 9 WC Cell Biology SC Cell Biology GA 718BQ UT WOS:000185125600026 PM 14577595 ER PT J AU Tomita, S Ueno, M Sakamoto, M Kitahama, Y Ueki, M Maekawa, N Sakamoto, H Gassmann, M Kageyama, R Ueda, N Gonzalez, FJ Takahama, Y AF Tomita, S Ueno, M Sakamoto, M Kitahama, Y Ueki, M Maekawa, N Sakamoto, H Gassmann, M Kageyama, R Ueda, N Gonzalez, FJ Takahama, Y TI Defective brain development in mice lacking the Hif-1 alpha gene in neural cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ENDOTHELIAL GROWTH-FACTOR; FACTOR 1-ALPHA; TUMOR-GROWTH; NUCLEAR TRANSLOCATION; O-2 HOMEOSTASIS; STEM-CELLS; HIF-ALPHA; IN-VIVO; EXPRESSION AB Hypoxia-inducible factor 1alpha (HIF-1alpha) is essential for vascular development during embryogenesis and pathogenesis. However, little is known about its role in brain development. To investigate the function of HIF-1alpha in the central nervous system, a conditional knockout mouse was made with the Cre/LoxP system with a nestin promoter-driven Cre. Neural cell-specific HIF-1alpha-deficient mice exhibit hydrocephalus accompanied by a reduction in neural cells and an impairment of spatial memory. Apoptosis of neural cells coincided with vascular regression in the telencephalon of mutant embryos, and these embryonic defects were successfully restored by in vivo gene delivery of HIF-1alpha to the embryos. These results showed that expression of HIF-1alpha in neural cells was essential for normal development of the brain and established a mouse model that would be useful for the evaluation of therapeutic strategies for ischemia, including hypoxia-mediated hydrocephalus. C1 RIKEN, Res Ctr Allergy & Immunol, Dept Immune Syst Dev, Tokushima 7708503, Japan. Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan. Kagawa Med Univ, Dept Biochem, Miki, Kagawa 7610793, Japan. Kagawa Med Univ, Dept Pathol & Host Def, Miki, Kagawa 7610793, Japan. Kagawa Med Univ, Dept Anesthesiol & Emergency Med, Miki, Kagawa 7610793, Japan. Kyoto Univ, Inst Virus Res, Sakyo Ku, Kyoto 6068507, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Tomita, S (reprint author), RIKEN, Res Ctr Allergy & Immunol, Dept Immune Syst Dev, Tokushima 7708503, Japan. RI Takahama, Yousuke/A-5863-2010 NR 41 TC 140 Z9 150 U1 0 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 OCT PY 2003 VL 23 IS 19 BP 6739 EP 6749 DI 10.1128/MCB.23.6739-6749.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 725CN UT WOS:000185525700003 PM 12972594 ER PT J AU Buchholz, DR Hsia, SCV Fu, LZ Shi, YB AF Buchholz, DR Hsia, SCV Fu, LZ Shi, YB TI A dominant-negative thyroid hormone receptor blocks amphibian metamorphosis by retaining corepressors at target genes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID XENOPUS-LAEVIS METAMORPHOSIS; ADULT EPITHELIAL DEVELOPMENT; BINDING PROTEIN GENE; IN-VIVO ANALYSIS; NUCLEAR RECEPTOR; POSTNATAL-DEVELOPMENT; HISTONE ACETYLATION; N-COR; TRANSCRIPTIONAL ACTIVATION; INTESTINAL DEVELOPMENT AB The total dependence of amphibian metamorphosis on thyroid hormone (T-3) provides a unique vertebrate model for studying the molecular mechanism of T-3 receptor (TR) function in vivo. In vitro transcription and developmental expression studies have led to a dual function model for TR in amphibian development, i.e., TRs act as transcriptional repressors in premetamorphic tadpoles and as activators during metamorphosis. We examined molecular mechanisms of TR action in T-3-induced metamorphosis by using dominant-negative receptors (dnTR) ubiquitously expressed in transgenic Xenopus laevis. We showed that T-3-induced activation of T-3 target genes and morphological changes are blocked in dnTR transgenic animals. By using chromatin immunoprecipitation, we show that dnTR bound to target promoters, which led to retention of corepressors and continued histone deacetylation in the presence of T-3. These results thus provide direct in vivo evidence for the first time for a molecular mechanism of altering gene expression by a dnTR. The correlation between dnTR-mediated gene repression and inhibition of metamorphosis also supports a key aspect of the dual function model for TR in development: during T-3-induced metamorphosis, TR functions as an activator via release of corepressors and promotion of histone acetylation and gene activation. C1 NICHD, LGRD, Unit Mol Morphogenesis, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, LGRD, Unit Mol Morphogenesis, NIH, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. NR 76 TC 73 Z9 74 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2003 VL 23 IS 19 BP 6750 EP 6758 DI 10.1128/MCB.23.6750.6758.2003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 725CN UT WOS:000185525700004 PM 12972595 ER PT J AU Zhang, Y Dufau, ML AF Zhang, Y Dufau, ML TI Repression of the luteinizing hormone receptor gene promoter by cross talk among EAR3/COUP-TFI, Sp1/Sp3, and TFIIB SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR-TFIIB; TATA-BINDING PROTEIN; LONG TERMINAL REPEAT; COUP-TF; THYROID-HORMONE; FACTOR-IIB; N-COR; REGULATE TRANSCRIPTION; PREINITIATION COMPLEX; HISTONE DEACETYLASE AB Transcription of luteinizing hormone receptor (LHR) gene is activated by Sp1/Sp3 at two Sp1 sites and is repressed by nuclear orphan receptors EAR2 and EAR3 through a direct-repeat (DR) motif. To elucidate the mechanism of the orphan receptor-mediated gene repression, we explored the functional connection between the orphan receptors and Sp1/Sp3 complex, and its impact on the basal transcription machinery. The Sp1(I) site was identified as critical for the repression since its mutation reduced the inhibition by EAR2 and abolished the inhibition by EAR3. Cotransfection analyses in SL2 cells showed that both Sp1 and Sp3 were required for this process since EAR3 displayed a complete Sp1/Sp3-dependent inhibitory effect. Functional cooperation between Sp1 and DR domains was further supported by mutual recruitment of EAR3 and Sp1/Sp3 bound to their cognate sites. Deletion of EAR3 N-terminal and DNA-binding domains that reduced its interaction with Sp1 impaired its inhibitory effect on human LHR (hLHR) gene transcription. Furthermore, we demonstrate interaction of TFIIB with Sp1/Sp3 at the Sp1(I) site besides its association with EAR3 and the TATA-less core promoter region. Such interaction relied on Sp1 site-bound Sp1/Sp3 complex and adaptor protein(s) present in the JAR nuclear extracts. We further demonstrated that EAR3 specifically decreased association of TFIIB to the Sp1 (1) site without interfering on its interaction with the hLHR core promoter. The C-terminal region of EAR3, which did not participate in its interaction with Sp1, was required for its inhibitory function and may affect the association of TFIIB with Sp1. Moreover, perturbation of the association of TFIIB with Sp1 by EAR3 was reflected in the reduced recruitment of RNA polymerase II to the promoter. Overexpression of TFIIB counteracted the inhibitory effect of EAR3 and activated hLHR gene transcription in an Sp1 site-dependent manner. These findings therefore indicate that TFIIB is a key component in the regulatory control of EAR3 and Sp1/Sp3 on the initiation complex. Such cross talk among EAR3, TFIIB, and Sp1/Sp3 reveals repression of hLHR gene transcription by nuclear orphan receptors is achieved via perturbation of communication between Sp1/Sp3 at the Sp1-1 site and the basal transcription initiator complex. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. NR 61 TC 33 Z9 34 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2003 VL 23 IS 19 BP 6958 EP 6972 DI 10.1128/MCB.23.19.6958-6972.2003 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 725CN UT WOS:000185525700022 PM 12972613 ER PT J AU Monje, P Marinissen, MJ Gutkind, JS AF Monje, P Marinissen, MJ Gutkind, JS TI Phosphorylation of the carboxyl-terminal transactivation domain of c-Fos by extracellular signal-regulated kinase mediates the transcriptional activation of AP-1 and cellular transformation induced by platelet-derived growth factor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TRANSDUCTION PATHWAYS; GENE-EXPRESSION; JUN PROMOTER; COMPLEX; RAS; ERK; PROLIFERATION; INHIBITOR; SERUM AB Polypeptide growth factors, such as platelet-derived growth factor (PDGF), promote the reinitiation of DNA synthesis and cell growth through multiple intracellular signaling pathways that converge in the nucleus to regulate the activity of transcription factors, thereby controlling the expression of growth-promoting genes. Among them, the AP-1 (activating protein-1) family of transcription factors, including c-Fos and c-Jun family members, plays a key role, as AP-1 activity is potently activated by PDGF and is required to stimulate cell proliferation. However, the nature of the pathways connecting PDGF receptors to AP-1 is still poorly defined. In this study, we show that PDGF regulates AP-1 by stimulating the expression and function of c-Fos through extracellular signal-regulated kinase (ERK). The latter involves the direct phosphorylation by ERK of multiple residues in the carboxyl-terminal transactivation domain of c-Fos, which results in its increased transcriptional activity. Interestingly, the phosphorylation of c-Fos by ERK was required for the ability of PDGF and serum to stimulate the activity of c-Fos as well as AP-1-dependent transcription. Furthermore, we provide evidence that the ERK-dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth. C1 NIDR, Oral & Pharyngeal Canc Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 50 TC 96 Z9 100 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2003 VL 23 IS 19 BP 7030 EP 7043 DI 10.1128/MCB.23.19.7030-7043.2003 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 725CN UT WOS:000185525700028 PM 12972619 ER PT J AU Galban, S Martindale, JL Mazan-Mamczarz, K de Silanes, IL Fan, JS Wang, WG Decker, J Gorospe, M AF Galban, S Martindale, JL Mazan-Mamczarz, K de Silanes, IL Fan, JS Wang, WG Decker, J Gorospe, M TI Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; HIPPEL-LINDAU PROTEIN; ENDOTHELIAL GROWTH-FACTOR; BIOLOGICALLY-ACTIVE PRODUCT; MESSENGER-RNA; PROLINE HYDROXYLATION; SOMATIC MUTATIONS; CDNA ARRAYS; HYPOXIA; TRANSLATION AB A recent analysis of gene expression in renal cell carcinoma cells led to the identification of mRNAs whose translation was dependent on the presence of the von Hippel-Lindau (VHL) tumor suppressor gene product, pVHL. Here, we investigate the finding that pVHL-expressing RCC cells (VHL+) exhibited elevated levels of polysome-associated p53 mRNA and increased p53 protein levels compared with VHL-defective (VHL-) cells. Our findings indicate that p53 translation is specifically heightened in VHL+ cells, given that (i) p53 mRNA abundance in VHL+ and VHL- cells was comparable, (ii) p53 degradation did not significantly influence p53 expression, and (iii) p53 synthesis was markedly induced in VHL+ cells. Electrophoretic mobility shift and immunoprecipitation assays to detect endogenous and radiolabeled p53 transcripts revealed that the RNA-binding protein HuR, previously shown to regulate mRNA turnover and translation, was capable of binding to the 3' untranslated region of the p53 mRNA in a VHL-dependent fashion. Interestingly, while whole-cell levels of HuR in VHL+ and VHL- cells were comparable, HuR was markedly more abundant in the cytoplasmic and polysome-associated fractions of VHL+ cells. In keeping with earlier reports, the elevated cytoplasmic HuR in VHL' cells was likely due to the reduced AMP-activated kinase activity in these cells. Demonstration that HuR indeed contributed to the increased expression of p53 in VHL+ cells was obtained through use of RNA interference, which effectively reduced HuR expression and in turn caused marked decreases in p53 translation and p53 abundance. Taken together, our findings support a role for pVHL in elevating p53 expression, implicate HuR in enhancing VHL-mediated p53 translation, and suggest that VHL-mediated p53 upregulation may contribute to pVHL's tumor suppressive functions in renal cell carcinoma. C1 NIA, IRP, NIH, LCMB,GRC, Baltimore, MD 21224 USA. Biosci Inst, D-55128 Ingelheim, Germany. RP Gorospe, M (reprint author), NIA, IRP, NIH, LCMB,GRC, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Lopez de Silanes, Isabel/K-4962-2015 OI Lopez de Silanes, Isabel/0000-0001-6762-9792 NR 62 TC 80 Z9 83 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 OCT PY 2003 VL 23 IS 20 BP 7083 EP 7095 DI 10.1128/MCB.23.20.7083-7095.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 729CT UT WOS:000185754300001 PM 14517280 ER PT J AU Pramatarova, A Ochalski, PG Chen, K Gropman, A Myers, S Min, KT Howell, BW AF Pramatarova, A Ochalski, PG Chen, K Gropman, A Myers, S Min, KT Howell, BW TI Nck beta interacts with tyrosine-phosphorylated Disabled 1 and redistributes in reelin-stimulated neurons SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PHOTORECEPTOR AXON GUIDANCE; AMYLOID PRECURSOR PROTEIN; LAMINAR ORGANIZATION; SIGNALING PATHWAY; BRAIN-DEVELOPMENT; CORTICAL-NEURONS; ADAPTER PROTEINS; DIRECT BINDING; VLDL RECEPTOR; MOUSE-BRAIN AB The tyrosine phosphorylation sites of the Disabled I (Dab1) docking protein are essential for the transmission of the Reelin signal, which regulates neuronal placement. Here we identify Nckbeta as a phosphorylation-dependent, Dab1-interacting protein. The SH2 domain of Nckbeta but not Nckalpha binds Dab1 phosphorylated on the Reelin-regulated site, Y220, or on Y232. Nckbeta is coexpressed with Dahl in the developing brain and in cultured neurons, where Reelin stimulation leads to the redistribution of Nckbeta from the cell soma into neuronal processes. We found that tyrosine-phosphorylated Dah1 in synergy with Nckbeta disrupts the actin cytoskeleton in transfected cells. In Drosophila melanogaster, exogenous expression of mouse Dahl causes tyrosine phosphorylation site-dependent morphological changes in the compound eye. This phenotype is enhanced by overexpression of the Drosophila Nck protein Dock, suggesting a conserved interaction between the Disabled and Nck family members. We suggest a model in which Dab1 phosphorylation leads to the recruitment of Nckbeta to the membrane, where it acts to remodel the actin cytoskeleton. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Howell, BW (reprint author), NINDS, Neurogenet Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 52 TC 60 Z9 65 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 OCT PY 2003 VL 23 IS 20 BP 7210 EP 7221 DI 10.1128/MCB.23.20.7210-7221.2003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 729CT UT WOS:000185754300012 PM 14517291 ER PT J AU Rosen, ED Kulkarni, RN Sarraf, P Ozcan, U Okada, T Hsu, CH Eisenman, D Magnuson, MA Gonzalez, FJ Kahn, CR Spiegelman, BM AF Rosen, ED Kulkarni, RN Sarraf, P Ozcan, U Okada, T Hsu, CH Eisenman, D Magnuson, MA Gonzalez, FJ Kahn, CR Spiegelman, BM TI Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PPAR-GAMMA; INSULIN-RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; TERMINAL DIFFERENTIATION; GROWTH-FACTOR; COLON-CANCER; EXPRESSION; TROGLITAZONE; SUBSTRATE-1; MICE AB The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is an important regulator of lipid and glucose homeostasis and cellular differentiation. Studies of many cell types in vitro and in vivo have demonstrated that activation of PPARgamma can reduce cellular proliferation. We show here that activation of PPARgamma is sufficient to reduce the proliferation of cultured insulinoma cell lines. We created a model with mice in which the expression of the PPARG gene in beta cells was eliminated (betagammaKO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of beta-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in beta-cell mass, no effect on glucose homeostasis in betagammaKO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and betagammaKO mice revealed that PPARgamma in beta cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPARgamma function in beta-cell proliferation and also indicate that the mechanisms controlling beta-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet. C1 Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr,Dept Cell Biol, Boston, MA USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Vanderbilt Univ, Med Ctr, Dept Physiol & Mol Biophys, Nashville, TN USA. Natl Canc Inst, Lab Metab, Div Basic Sci, Bethesda, MD USA. RP Rosen, ED (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol, 99 Brookline Ave, Boston, MA 02215 USA. RI Magnuson, Mark/B-1335-2009 OI Magnuson, Mark/0000-0002-8824-6499 FU NIDDK NIH HHS [KO8 DK02885, K08 DK002885, KO8 DK02535, R01 DK033201, R01 DK33201, R03 DK58850, R37 DK031405, R37DK31405] NR 47 TC 101 Z9 104 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2003 VL 23 IS 20 BP 7222 EP 7229 DI 10.1128/MCB.23.20.7222-7229.2003 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 729CT UT WOS:000185754300013 PM 14517292 ER PT J AU Gispert, S Del Turco, D Garrett, L Chen, A Bernard, DJ Hamm-Clement, J Korf, HW Deller, T Braak, H Auburger, G Nussbaum, RL AF Gispert, S Del Turco, D Garrett, L Chen, A Bernard, DJ Hamm-Clement, J Korf, HW Deller, T Braak, H Auburger, G Nussbaum, RL TI Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID INCLUSION-BODY FORMATION; MULTIPLE SYSTEM ATROPHY; PARKINSONS-DISEASE; NEURODEGENERATIVE DISORDERS; WILD-TYPE; NUCLEAR-LOCALIZATION; HUNTINGTONS-DISEASE; LEWY BODIES; IN-VITRO; MOUSE AB Alpha-synuclein was implicated in Parkinson's disease when missense mutations in the a-synuclein gene were found in autosomal dominant Parkinson's disease and a-synuclein was shown to be a major constituent of protein aggregates in sporadic Parkinson's disease and other synucleinopathies. We have generated transgenic mice expressing A53T mutant and wild-type human a-synuclein. The mutant transgenic protein was distributed abnormally to the axons, perikarya, and dendrites of neurons in many brain areas. In electron microscopic immunogold studies, no aggregation of alpha-synuclein was found in these mice. However, behavior analysis showed a progressive reduction of spontaneous vertical motor activity in both mutant lines correlating with the dosage of overexpression. In addition, deficits of grip strength, rotarod performance, and gait were observed in homozygous PrPmtB mice. Transgenic animals expressing mutant a-synuclein may be a valuable model to assess specific aspects of the pathogenesis of synucleinopathies. (C) 2003 Elsevier Inc. All rights reserved. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Univ Frankfurt, Dept Anat Expt Neurobiol 2, Frankfurt, Germany. Univ Frankfurt, Dept Anat Clin Neuroanat 1, Frankfurt, Germany. Univ Hosp, Sect Mol Neurogenet, Frankfurt, Germany. RP Auburger, G (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 39 TC 116 Z9 118 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD OCT PY 2003 VL 24 IS 2 BP 419 EP 429 DI 10.1016/S1044-7431(03)00198-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 736HB UT WOS:000186164400013 PM 14572463 ER PT J AU Partridge, JJ Lopreiato, JO Latterich, M Indig, FE AF Partridge, JJ Lopreiato, JO Latterich, M Indig, FE TI DNA damage modulates nucleolar interaction of the Werner protein with the AAA ATPase p97/VCP SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ORGANELLE MEMBRANE-FUSION; TOPOISOMERASE-I; SYNDROME GENE; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; TYROSINE PHOSPHORYLATION; FUNCTIONAL INTERACTION; NUCLEAR-LOCALIZATION; TARGETING SEQUENCE; HELICASE ACTIVITY AB We report a novel nucleolar interaction between the AAA ATPase p97/VCP and the Werner protein (WRNp), a member of the RecQ helicase family. p97/VCP mediates several important cellular functions in eucaryotic cells, including membrane fusion of the endoplasmic reticulum and Golgi and ubiquitin-dependent protein degradation. Mutations in the WRN gene cause Werner syndrome, a genetic disorder characterized by premature onset of aging symptoms, a higher incidence of cancer, and a high susceptibility to DNA damage caused by topoisomerase inhibitors. We observed that both WRNp and valosin-containing protein (VCP) were present in the nucleoplasm and in nucleolar foci in mammalian cells and that WRNp and p97/VCP physically interacted in the nucleoli. Importantly, the nucleolar WRNp/VCP complex was dissociated by treatment with camptothecin, an inhibitor of topoisomerase 1, whereas other WRNp-associated protein complexes, such as WRNp/Ku 80, were not dissociated by this drug. Because WRN syndrome cells are sensitive to topoisomerase inhibitors, these observations suggest that the VCP/WRNp interaction plays an important role in WRN biology. We propose a novel role for VCP in the DNA damage response pathway through modulation of WRNp availability. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Indig, FE (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM-54729] NR 67 TC 49 Z9 51 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2003 VL 14 IS 10 BP 4221 EP 4229 DI 10.1091/mbc.E03-02-0111 PG 9 WC Cell Biology SC Cell Biology GA 727LU UT WOS:000185660900024 PM 12937274 ER PT J AU Coon, M Ball, A Pound, J Ap, S Hollenback, D White, T Tulinsky, J Bonham, L Morrison, DK Finney, R Singer, JW AF Coon, M Ball, A Pound, J Ap, S Hollenback, D White, T Tulinsky, J Bonham, L Morrison, DK Finney, R Singer, JW TI Inhibition of lysophosphatidic acid acyltransferase disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SMOOTH-MUSCLE-CELLS; GROWTH-FACTOR RECEPTOR; PHOSPHATIDIC-ACID; PROTEIN-KINASE; PHOSPHOLIPASE-D; CDNA CLONING; ACTIVATION; RAF-1; RAS; EXPRESSION AB Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysoPA. Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays. We found that ectopic overexpression of LPAAT-beta cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-beta inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-beta activity is suppressed by CT32228 (N-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine-2,4-diamine), an isoform-specific noncompetitive inhibitor, tumor cells undergo mitotic catastrophe while most normal cells simply arrest or become quiescent. The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival. C1 Cell Therapeut, Seattle, WA 98117 USA. NCI, Regulat Cell Growth Lab, Frederick, MD 21701 USA. PanGenex, Seattle, WA USA. RP Coon, M (reprint author), Cell Therapeut, Seattle, WA 98117 USA. EM mcoon@ctiseattle.com NR 41 TC 42 Z9 45 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2003 VL 2 IS 10 BP 1067 EP 1078 PG 12 WC Oncology SC Oncology GA 734KK UT WOS:000186054800015 PM 14578472 ER PT J AU Li, SF Hansman, R Newbold, R Davis, B McLachlan, JA Barrett, JC AF Li, SF Hansman, R Newbold, R Davis, B McLachlan, JA Barrett, JC TI Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus SO MOLECULAR CARCINOGENESIS LA English DT Article DE DES; c-fos gene; mice uteri ID ENDOMETRIAL EPITHELIAL-CELLS; MATERNAL STILBESTROL THERAPY; UTERINE ESTROGEN-RECEPTOR; DE-NOVO METHYLATION; DEVELOPMENTAL EXPOSURE; 3'-FLANKING REGION; TUMOR APPEARANCE; LABORATORY MOUSE; RESPONSE ELEMENT; CPG METHYLATION AB Perinatal exposure to diethylstilbestrol (DES) induces reproductive tract cancers later in life in both humans and animals. Because there is no clear evidence that perinatal DES exposure induces gene mutation, we proposed that perinatal DES exposure causes epigenetic methylation changes that result in persistent alterations in gene expression, leading to tumorigenesis. The proto-oncogene c-fos is one of the immediately induced genes in uterine epithelium after estrogen simulation and a key player in uterine carcinogenesis. Here, we investigated c-fos expression in mice neonatally exposed to DES (2 mug/pup/clay on postnatal days 1-5). The mRNA levels of c-fos in uteri of neonatal DES-treated mice were persistently 1.4-1.9-fold higher than that in the control mice from day 5 to day 60. Overall, the uterine c-fos expression level in the neonatal DES-exposed group was significantly higher than that in the control group. After examination of the methylation status of the c-fos gene, we found that the CpGs in promoter and intron-1 regions were completely unmethylated. In exon-4, from day 17 to day 60, the percentage of unmethylated CpGs was higher in neonatal DES-exposed mice uteri than that in control (42%, 51%, 47%, and 42% in DES-exposed mice vs 33%, 34%, 33%, and 21% in control mice at day 17, 21, 30, and 60, respectively). These results suggest that perinatal DES exposure may permanently alter gene expression and methylation, and the methylation modification may occur in either the promoter regions or other regulatory sites in the gene. Published 2003 Wiley-Liss, Inc.(dagger). C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NCI, Lab Womens Hlth, NIH, Bethesda, MD 20892 USA. Tulane Univ, Ctr Med, Xavier Ctr Bioenvironm Res, New Orleans, LA 70118 USA. Tulane Univ, Ctr Med, Dept Pharmacol, New Orleans, LA 70118 USA. RP Barrett, JC (reprint author), NCI, Lab Biosyst & Canc, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Hansman, Roberta/0000-0003-1525-8509 NR 36 TC 122 Z9 133 U1 2 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2003 VL 38 IS 2 BP 78 EP 84 DI 10.1002/mc.10147 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 771TY UT WOS:000188803200004 PM 14502647 ER PT J AU Cable, PL Wilson, CA Calzone, FJ Rauscher, FJ Scully, R Livingston, DM Li, LP Blackwell, CB Futreal, PA Afshari, CA AF Cable, PL Wilson, CA Calzone, FJ Rauscher, FJ Scully, R Livingston, DM Li, LP Blackwell, CB Futreal, PA Afshari, CA TI Novel consensus DNA-binding sequence for BRCA1 protein complexes SO MOLECULAR CARCINOGENESIS LA English DT Article DE BRCA1; cyclic amplification and selection of targets (CASTing); USF2 ID CANCER SUSCEPTIBILITY GENE; BREAST-CANCER; DAMAGE RESPONSE; TRANSCRIPTIONAL ACTIVATION; PROMOTER ACTIVITY; MESSENGER-RNA; CELL-CYCLE; C-MYC; EXPRESSION; REPAIR AB Increasing evidence continues to emerge supporting the early hypothesis that BRCA1 might be involved in transcriptional processes. BRCA1 physically associates with more than 15 different proteins involved in transcription and is paradoxically involved in both transcriptional activation and repression. However, the underlying mechanism by which BRCA1 affects the gene expression of various genes remains speculative. In this study, we provide evidence that BRCA1 protein complexes interact with specific DNA sequences. We provide data showing that the upstream stimulatory factor 2 (USF2) physically associates with BRCA1 and is a component of this DNA-binding complex. interestingly, these DNA-binding complexes are downregulated in breast cancer cell lines containing wild-type BRCA1, providing a critical link between modulations of BRCA1 function in sporadic breast cancers that do not involve germline BRCA1 mutations. The functional specificity of BRCA1 tumor suppression for breast and ovarian tissues is supported by our experiments, which demonstrate that BRCA1 DNA-binding complexes are modulated by serum and estrogen. Finally, functional analysis indicates that missense mutations in BRCA1 that lead to subsequent cancer susceptibility may result in improper gene activation. In summary, these findings establish a role for endogenous BRCA1 protein complexes in transcription via a defined DNA-binding sequence and indicate that one function of BRCA1 is to co-regulate the expression of genes involved in various cellular processes. Published 2003 Wiley-Liss, Inc.(dagger). C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Amgen Inc, Amgen Ctr, Thousand Oaks, CA 91320 USA. Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Charles A Dana Div Human Canc Genet, Boston, MA 02115 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Wellcome Trust Sanger Inst, Sanger Ctr, Cambridge, England. RP Cable, PL (reprint author), GlaxoSmithKline, RCII 807, Res Triangle Pk, NC 27709 USA. RI Scully, Ralph/F-5008-2013 FU NCI NIH HHS [K01 CA079576] NR 56 TC 22 Z9 22 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2003 VL 38 IS 2 BP 85 EP 96 DI 10.1002/mc.10148 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 771TY UT WOS:000188803200005 PM 14502648 ER PT J AU Liu, ZG AF Liu, ZG TI Adding facets to TNF signaling: The JNK angle SO MOLECULAR CELL LA English DT Article ID PATHWAY; DEATH; ACTIVATION AB In the October 3 issue of Cell, Deng et al. (2003) report that a JNK-dependent mitochondrial signal, the release of Smac/DIABLO, is required for TNF-induced caspase 8 activation and apoptosis. This process is interceded by a novel processed form of the BH3 only protein Bid. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 9 TC 25 Z9 25 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT PY 2003 VL 12 IS 4 BP 795 EP 796 DI 10.1016/S1097-2765(03)00399-X PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 736WL UT WOS:000186196100001 PM 14580328 ER PT J AU Tirumalai, RS Chan, KC Prieto, DA Issaq, HJ Conrads, TP Veenstra, TD AF Tirumalai, RS Chan, KC Prieto, DA Issaq, HJ Conrads, TP Veenstra, TD TI Characterization of the low molecular weight human serum proteome SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID HUMAN PLASMA; MASS-SPECTROMETRY; YEAST PROTEOME; OVARIAN-CANCER; PEPTIDE; ALBUMIN; ONCOGENE; GENE; IDENTIFICATION; EXPRESSION AB Serum potentially carries an archive of important histological information whose determination could serve to improve early disease detection. The analysis of serum, however, is analytically challenging due to the high dynamic concentration range of constituent protein/peptide species, necessitating extensive fractionation prior to mass spectrometric analyses. The low molecular weight (LMW) serum proteome is that protein/peptide fraction from which high molecular weight proteins, such as albumin, immunoglobulins, transferrin, and lipoproteins, have been removed. This LMW fraction is made up of several classes of physiologically important proteins such as cytokines, chemokines, peptide hormones, as well as proteolytic fragments of larger proteins. Centrifugal ultrafiltration of serum was used to remove the large constituent proteins resulting in the enrichment of the LMW proteins/peptides. Because albumin is known to bind and transport small molecules and peptides within the circulatory system, the centrifugal ultrafiltration was conducted under solvent conditions effecting the disruption of protein-protein interactions. The LMW serum proteome sample was digested with trypsin, fractionated by strong cation exchange chromatography, and analyzed by microcapillary reversed-phase liquid chromatography coupled on-line with electrospray ionization tandem mass spectrometry. Analysis of the tandem mass spectra resulted in the identification of over 340 human serum proteins; however, not a single peptide from serum albumin was observed. The large number of proteins identified demonstrates the efficacy of this method for the removal of large abundant proteins and the enrichment of the LMW serum proteome. C1 NCI, Biomed Proteom Program, Lab Proteom & Analyt Technol, Mass Spectrometry Ctr,SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Biomed Proteom Program, Lab Proteom & Analyt Technol, Mass Spectrometry Ctr,SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 32 TC 530 Z9 569 U1 6 U2 71 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT 1 PY 2003 VL 2 IS 10 BP 1096 EP 1103 DI 10.1074/mcp.M300031-MCP200 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 736TV UT WOS:000186190000005 PM 12917320 ER PT J AU Rabadan-Diehl, C Volpi, S Nikodemova, M Aguilera, G AF Rabadan-Diehl, C Volpi, S Nikodemova, M Aguilera, G TI Translational regulation of the vasopressin V1b receptor involves an internal ribosome entry site SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-KINASE-C; FACTOR MESSENGER-RNA; ALTERNATIVE TRANSLATION; INITIATION-FACTOR; CHRONIC STRESS; PHORBOL ESTER; RAT; EXPRESSION; CONTAINS; CELLS AB Posttranscriptional mechanisms play an important role regulating pituitary levels of vasopressin V1b receptors (V1bR) during adaptation to stress. This study investigates the involvement of an internal ribosome entry site (IRES) in the 5' untranslated region (5'UTR) on V1bR translation. Transfection of bicistronic luciferase constructs into MCF-7 cells showed marked increases in translation of the second cistron after insertion of a 499-bp fragment of the V1bR 5'UTR in the intercistronic region, independently of cap-mediated translation, indicating the presence of IRES activity. IRES-mediated translation was potentiated by the protein kinase C activators, 12-O-tetradecanoylphorbol 13-acetate (PMA) and bryostatin 1, and appears to involve phosphorylation of amino terminus of eIF4G. In Chinese hamster ovary cells transfected with pV1bR-green fluorescent protein (pV1bR-GFP), PMA increased V1bR-GFP protein levels when cap-mediated translation was inhibited by rapamycin. The effect of PMA was due to increased translation because it persisted under transcriptional blockade by actinomycin D, and it was completely abolished by cycloheximide. In addition, PMA stimulated [S-35]methionine incorporation into V1bR-GFP but not beta-actin in the absence of mRNA changes. The data show that regulation of IRES activity in the 5'UTR of the V1bR mRNA probably through phosphorylation of eIF4G may serve as a mechanism for rapid changes in V1bR translation to meet physiological demands. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,Mall Stop Code 1862, Bethesda, MD 20892 USA. NR 38 TC 10 Z9 11 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT 1 PY 2003 VL 17 IS 10 BP 1959 EP 1971 DI 10.1210/me.2001-0336 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727DA UT WOS:000185640100006 PM 12869588 ER PT J AU Burns, KH Agno, JE Chen, L Haupt, B Ogbonna, SC Korach, KS Matzuk, MM AF Burns, KH Agno, JE Chen, L Haupt, B Ogbonna, SC Korach, KS Matzuk, MM TI Sexually dimorphic roles of steroid hormone receptor signaling in gonadal tumorigenesis SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID INHIBIN-DEFICIENT MICE; GRANULOSA-CELL TUMORIGENESIS; FOLLICLE-STIMULATING-HORMONE; TRANSGENIC MODELS; TUMOR-DEVELOPMENT; OVARIAN-TUMORS; MESSENGER-RNA; GENE; ALPHA; MOUSE AB Sex steroids control cellular phenotypes by binding to receptor proteins that in turn regulate downstream gene expression. They are important tropic factors in hormonally responsive tissues and have been implicated in the pathogenesis of both benign proliferations and malignancies at some of these sites. Knockout mice lacking inhibins, alpha:beta heterodimeric peptide hormones of the TGFbeta superfamily, develop gonadal tumors that produce sex steroids and depend on pituitary gonadotropin hormones. To better appreciate how sex steroid receptor signaling pathways contribute to the loss of granulosa/Sertoli cell proliferation in the ovary and testis of inhibin alpha (Inhalpha) knockout mice, we are using both pharmacologic and genetic approaches. Roles of androgens in testicular tumor development have been investigated in our previous studies using double-mutant mice lacking inhibins and carrying the null testicular feminization (tfm) mutation of the androgen receptor. Herein, we report that androgens also participate in the development of ovarian tumors, as tumor development is forestalled in mice treated with flutamide, a nonsteroidal inhibitor of androgen actions. Additionally, we generated double-mutant mice lacking estrogen receptor alpha (ERalpha) and Inhalpha or ERbeta and Inhalpha, as well as triple-mutant mice lacking ERalpha, ERbeta, and Inhalpha to determine the effects of individual and combined ER signaling pathways on tumor development. Although estrogens may have proliferative effects during follicle development and are important in specifying the granulosa cell phenotype, ERalpha and ERbeta signaling are not essential for timely granulosa cell tumor development or granulosa cell-like morphological features in ovarian tumors. However, redundant ER signaling through ERalpha and ERbeta in males is critical for testicular tumor formation, as triple-knockout, but not double-knockout, males are protected from early Sertoli cell tumorigenesis and death. Together, these studies indicate important and sexually dimorphic functions of estrogens and androgens in tumor development in this mouse model and indicate, for the first time, overlapping functions of ERalpha and ERbeta in Sertoli cell pathophysiology. C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Baylor Coll Med, Dept Pathol, 1 Baylor Plaza, Houston, TX 77030 USA. EM mmatzuk@bcm.tmc.edu RI Burns, Kathleen/A-3360-2011; OI Korach, Kenneth/0000-0002-7765-418X FU NCI NIH HHS [CA60651]; NICHD NIH HHS [U54 HD28934]; NIGMS NIH HHS [T32GM07330] NR 38 TC 17 Z9 17 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT 1 PY 2003 VL 17 IS 10 BP 2039 EP 2052 DI 10.1210/me.2003-0039 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727DA UT WOS:000185640100013 PM 12855748 ER PT J AU Hewitt, SC Deroo, BJ Hansen, K Collins, J Grissom, S Afshari, CA Korach, KS AF Hewitt, SC Deroo, BJ Hansen, K Collins, J Grissom, S Afshari, CA Korach, KS TI Estrogen receptor-dependent genomic responses in the uterus mirror the biphasic physiological response to estrogen SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID UTERINE LUMINAL EPITHELIUM; GENE-EXPRESSION; CELL-DEATH; BREAST-CANCER; FAMILY; MICE; MICROARRAY; CHECKPOINT; PATTERNS; PROTEINS AB The physiological responses of the rodent uterus to acute estrogen (E) dosing can be divided into early and late events. Examples of early responses include increased RNA transcription, hyperemia, and water imbibition 2 and 6 h following E administration respectively, whereas later responses include cycles of DNA synthesis and mitosis of epithelial cells beginning 10 and 16 h after E. The development of estrogen receptor (ER) knockout (ERKO) mice, combined with microarray technology, has allowed us to design a genomic approach to study the acute response of the rodent reproductive tract to E. To determine whether early and late biological responses are correlated with altered regulation of a single set of genes or distinct sets of genes characteristic of early and late responses, uterine RNA was obtained from ovariectomized mice that were treated with vehicle or with estradiol for 2 h (early) or 24 h (late). Samples were also prepared from identically treated mice that lacked either ERalpha (alphaERKO) or ERbeta (betaERKO) to address the relative contributions of the ERs in the uterine responses. Microarray analysis of the relative expression of 8700 mouse cDNAs indicated distinct clusters of genes that were regulated both positively and negatively by E in the early or late phases as well as clusters of genes regulated at both times. Both early and late responses by the betaERKO samples were indistinguishable from those of WT samples, whereas the alphaERKO showed little change in gene expression in response to E, indicating the predominant role for ERalpha in the genomic response. Further studies indicated that the genomic responses in samples from intermediate time points (6 h, 12 h) fall within the early or late clusters, rather than showing unique clusters regulated in the intermediary period. The use of this genomic approach has illustrated how physiological responses are reflected in genomic patterns. Furthermore, the identification of functional gene families that are regulated by E in the uterus combined with the utilization of genetically altered experimental animal models can help to uncover and define novel mechanisms of E action. C1 NIEHS, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), 111 Alexander Dr,MD E-01, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 60 TC 158 Z9 160 U1 0 U2 2 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 OCT 1 PY 2003 VL 17 IS 10 BP 2070 EP 2083 DI 10.1210/me.2003-0146 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727DA UT WOS:000185640100015 PM 12893882 ER PT J AU Maruyama, K Takigawa, Y Akiyama, Y Hojo, T Nara-Ashizawa, N Cheng, JY Watanabe, M Yamaguchi, K AF Maruyama, K Takigawa, Y Akiyama, Y Hojo, T Nara-Ashizawa, N Cheng, JY Watanabe, M Yamaguchi, K TI Structure and characterization of hamster IL-12 p35 and p40 SO MOLECULAR IMMUNOLOGY LA English DT Article DE hamster; interleukin-12; IL-12 p35 subunit; IL-12 p40 subunit; dendritic cell ID CELL STIMULATORY FACTOR; PANCREATIC-CANCER; ANTITUMOR IMMUNITY; GAMMA PRODUCTION; FACTOR NKSF; IFN-GAMMA; INTERLEUKIN-12; CYTOKINE; CLONING; LYMPHOCYTES AB Complementary DNAs coding for two subunits of hamster interleukin-12 (IL-12), p35 and p40, were cloned from a hamster dendritic cell (DC) cDNA library. The cloning demonstrated that hamster IL-12 consisted of a p35 subunit with 216 amino acid (aa) residues and a p40 subunit with 327 aa. Structural comparison of hamster p35 and p40 at the protein level showed the highest homologies with each counterpart of sigmodon (hispid cotton rat). The gene expressions of hamster IL-12 p35 and p40 in bone marrow (BM) cells cultured in the presence of mouse granulocyte macrophage-colony-stimulating factor (mGM-CSF) and IL-4 were up-regulated during culture. Immunoblot analysis of 293 cells transfected with hamster p35 and p40 expression vectors suggested the presence of a covalently linked p35/p40 heterodimer. Furthermore, supernatant from the 293 cells transfected with both expression vectors induced the up-regulation of interferon-gamma (IFN-gamma) mRNA in hamster splenocytes, indicating that the p35/p40 heterodimer IL-12 protein present in the supernatant was functional. These results suggest that the vectors containing hamster IL-12 cDNA might be suitable tools for developing an immunotherapeutic approach against experimental cancer in a hamster model. (C) 2003 Elsevier Ltd. All rights reserved. C1 Natl Canc Ctr, Res Inst, Div Growth Factor, Chuo Ku, Tokyo 1040045, Japan. Shizuoka Canc Ctr, Div Immunotherapy, Nagaizumi, Shizuoka 4118777, Japan. NCI, Frederick Canc Res & Dev Ctr, Expt Therapeut Sect, Expt Immunol Lab, Frederick, MD 21702 USA. RP Akiyama, Y (reprint author), Natl Canc Ctr, Res Inst, Div Growth Factor, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. NR 25 TC 3 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2003 VL 40 IS 6 BP 319 EP 326 DI 10.1016/S0161-5890(03)00165-2 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 730RD UT WOS:000185843000002 PM 14522013 ER PT J AU Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J Kashmiri, SVS AF Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J Kashmiri, SVS TI Minimizing immunogenicity of the SDR-grafted humanized antibody CC49 by genetic manipulation of the framework residues SO MOLECULAR IMMUNOLOGY LA English DT Article DE antigen-binding affinity; CDRs; frameworks; humanized antibody; HAMA response; immanogenicity; molecular biology; specificity determining residues ID SURFACE-PLASMON RESONANCE; SPECIFICITY-DETERMINING RESIDUES; METASTATIC COLORECTAL-CANCER; MURINE MONOCLONAL-ANTIBODY; SITE-DIRECTED MUTAGENESIS; POLYMERASE CHAIN-REACTION; 3-DIMENSIONAL STRUCTURE; PHASE-II; OVARIAN-CANCER; INTRAPERITONEAL RADIOIMMUNOTHERAPY AB The murine mAb CC49 specifically recognizes a tumor-associated glycoprotein (TAG)-72, which is expressed on the majority of human carcinomas. This Ab has potential applications in the diagnosis and treatment of human carcinomas. However, patients receiving murine CC49 generate human anti-murine Ab (HAMA) responses, preventing repeated administration of the Ab for effective treatment. To minimize the HAMA response, two versions of humanized CC49 (HuCC49) were developed: (a) HuCC49 and (b) HuCC49V10 (V10). HuCC49 was developed by grafting the CC49 CDRs, while V10 was generated by grafting only the specificity determining residues (SDRs) of the CC49 onto the frameworks of the human Abs. During the generation of both HuCC49 and V10, a few murine framework residues that were believed to be essential for the integrity of the Ag-binding site were retained. However, the indispensability of these residues for the Ag-binding activity of CC49 has not been experimentally validated. In this study, an array of V10 variants were generated by replacing, by site-specific mutagenesis, the murine framework residues that were retained in the humanized Ab with their counterparts in the human templates. The variants were tested for their (a) Ag-binding activity and (b) reactivity to sera from patients who were previously administered murine CC49 in a clinical trial. One such variant, V59, compared to the parental V10, shows a significant decrease in its reactivity to the anti-variable region Abs present in the patients' sera, while it binds to the TAG-72 Ag with a slightly higher affinity. Variant 59, which is expected to be minimally immunogenic because of its low sera reactivity, is a potentially useful clinical reagent against human carcinomas. In this study, we show for the first time that experimental validation rather than reliance on the protein data bank (PDB) should be the criterion for the indispensability of framework residues for the humanization of any murine Ab to retain its Ag-binding property and reduce its immunogenicity in patients. Published by Elsevier Ltd. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 59 TC 13 Z9 13 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2003 VL 40 IS 6 BP 337 EP 349 DI 10.1016/S0161-5890(03)00166-4 PG 13 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 730RD UT WOS:000185843000004 PM 14522015 ER PT J AU Ally, RA Ives, KL Traube, E Eltounsi, I Chen, PW Cahill, PJ Battey, JF Hellmich, MR Kroog, GS AF Ally, RA Ives, KL Traube, E Eltounsi, I Chen, PW Cahill, PJ Battey, JF Hellmich, MR Kroog, GS TI Agonist- and protein kinase C-induced phosphorylation have similar functional consequences for gastrin-releasing peptide receptor signaling via G(q) SO MOLECULAR PHARMACOLOGY LA English DT Article ID COUPLED RECEPTORS; BETA-2-ADRENERGIC RECEPTOR; CHOLINERGIC RECEPTORS; SWISS 3T3-CELLS; DOWN-REGULATION; RHODOPSIN; DESENSITIZATION; BINDING; SITES; MECHANISMS AB Acute desensitization of many guanine nucleotide-binding protein-coupled receptors (GPCRs) requires receptor phosphorylation and subsequent binding of an arrestin. GPCRs are substrates for phosphorylation by several classes of kinases. Gastrin-releasing peptide receptor (GRPr) is phosphorylated by a kinase other than protein kinase C (PKC) after exposure to agonist and is also a substrate for PKC-dependent phosphorylation after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA). Using GRPr mutants, we examined receptor domains required for agonist- and TPA-induced phosphorylation of GRPr and consequences of these phosphorylation events on GRPr signaling via G(q). Agonist- and TPA-stimulated GRPr phosphorylation in cells require an intact carboxyl terminal domain (CTD). GRPr is phosphorylated in vitro by GPCR kinase 2 (GRK2) and multiple PKC isoforms. An intact DRY motif is required for agonist- stimulated phosphorylation in cells, and agonist- dependent GRK2 phosphorylation in vitro. Although GRPr CTD mutants do not show enhanced in vitro coupling to G(q) relative to intact GRPr, CTD mutants have more potent G(q)-dependent signaling in cells. Acute desensitization involves CTD-independent processes because desensitization can precede ligand binding in intact GRPr and CTD mutants. TPA-mediated impairment of GRPr-G(q) signaling in cells also requires an intact CTD. Similar to GRK2 phosphorylation, PKC phosphorylation reduces GRPr-G(q) coupling by approximately 80% in vitro. Arrestin translocation to plasma membrane requires agonist, an intact DRY motif, and GRPr phosphorylation. Therefore, agonist- and PKC-induced GRPr phosphorylation sites are in nearby regions of the receptor, and phosphorylation at both sites has similar functional consequences for G(q) signaling. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Univ Texas, Med Branch, Dept Surg, Galveston, TX 77550 USA. Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, NIH, Bethesda, MD USA. RP Kroog, GS (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Chanin 302D,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM gkroog@aecom.yu.edu RI Chen, Pei-Wen/B-7142-2015 NR 40 TC 12 Z9 12 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2003 VL 64 IS 4 BP 890 EP 904 DI 10.1124/mol.64.4.890 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 723KJ UT WOS:000185431300013 PM 14500746 ER PT J AU Hill, F Marchetti, F Liechty, M Bishop, J Hozier, J Wyrobek, AJ AF Hill, F Marchetti, F Liechty, M Bishop, J Hozier, J Wyrobek, AJ TI A new FISH assay to simultaneously detect structural and numerical chromosomal abnormalities in mouse sperm SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE mouse sperm; aneuploidy; structural aberrations; fluorescence in situ hybridization ID IN-SITU HYBRIDIZATION; MULTICOLOR FISH; RECIPROCAL TRANSLOCATIONS; HEALTHY-MEN; GERM-CELLS; MALE-MICE; ANEUPLOIDY; SEGREGATION; ORIGIN AB De novo aberrations in chromosome structure represent important categories of paternally transmitted genetic damage. Unlike numerical abnormalities the majority of de novo structural aberrations among human offspring are of paternal origin. We report the development of a three-color fluorescence in situ hybridization (FISH) assay (CT8) to detect mouse sperm carrying structural and numerical chromosomal abnormalities. The CT8 assay uses DNA probes for the centromeric and telomeric regions of chromosome 2, and a probe for the subcentromeric region of chromosome 8. The CT8 assay was used to measure the frequencies of sperm carrying certain structural aberrations involving chromosome 2 (del2ter, dup2ter, del2cen, dup2cen), disomy 2, disomy 8, and sperm diploidy. Analysis of similar to80,000 sperm from eight B6C3F1 mice revealed an average baseline frequency of 2.5 per 10,000 sperm carrying partial duplications and deletions of chromosome 2. Extrapolated to the entire haploid genome, similar to0.4% of mouse sperm are estimated to carry structural chromosomal aberrations, which is more than fivefold lower than the spontaneous frequencies of sperm with chromosome structural aberrations in man. We validated the CT8 assay by comparing the frequencies of abnormal segregants in sperm of T(2;14) translocation carriers detected by this assay against those detected by chromosome painting cytogenetic analysis of meiosis II spermatocytes. The CT8 sperm FISH assay is a promising method for detecting structural chromosome aberrations in mouse sperm with widespread applications in genetics, physiology, and genetic toxicology. (C) 2003 Wiley-Liss, Inc. C1 Appl Genet Labs, Melbourne, FL USA. Lawrence Livermore Natl Lab, Hlth Effects Genet Div, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Wyrobek, AJ (reprint author), Lawrence Livermore Natl Lab, Hlth Effects Genet Div, Biol & Biotechnol Res Program, L-448, Livermore, CA 94550 USA. OI Marchetti, Francesco/0000-0002-9435-4867 FU NIEHS NIH HHS [Y01-ES-8016] NR 30 TC 9 Z9 10 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 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD OCT PY 2003 VL 66 IS 2 BP 172 EP 180 DI 10.1002/mrd.10299 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 717RP UT WOS:000185104200009 PM 12950105 ER PT J AU Hu, J Kelly, P Bonifacino, A Agricola, B Donahue, R Vanin, E Dunbar, CE AF Hu, J Kelly, P Bonifacino, A Agricola, B Donahue, R Vanin, E Dunbar, CE TI Direct comparison of RD114-pseudotyped versus amphotropic-pseudotyped retroviral vectors for transduction of rhesus macaque long-term repopulating cells SO MOLECULAR THERAPY LA English DT Article ID BLOOD CD34(+) CELLS; HEMATOPOIETIC PROGENITOR CELLS; COLONY-STIMULATING FACTOR; EFFICIENT GENE-TRANSFER; AUTOLOGOUS BONE-MARROW; APE LEUKEMIA-VIRUS; PERIPHERAL-BLOOD; NONHUMAN-PRIMATES; ONCORETROVIRAL VECTOR; STEM-CELLS AB Recently, RD114 (feline endogenous retrovirus envelope protein)-pseudotyped retroviral particles have been shown to transduce human NOD/SCID repopulating cells efficiently. In this study, we compared directly transduction of repopulating cells with RD114-pseudotyped vector to that with standard amphotropic vector in the rhesus macaque model. G-CSF/SCF-mobilized CD34(+) rhesus peripheral blood cells were cultured in the presence of SCF, Flt-3 ligand, and MGDF on Retronectin-coated flasks. To assess directly the ability of the two pseudotypes to transduce primitive cells, both vectors were added simultaneously to the target cells every 24 h, for a total of four exposures in 96 h. The cells were reinfused after the animals received 1000 cGy total body irradiation. At the end of transduction, gene marking efficiency of CFU was higher with amphotropic LNL6 vector (mean 88.4%) vs RD114-G1Na vector (mean 18.5%). After long-term engraftment in three animals, total neo gene marking levels were 4-5% in PBMNCs and 1.5-4% in granulocytes. The RD114-G1Na marking levels were consistently higher in granulocytes than in mononuclear cells, while amphotropic LNL6 marking levels were higher in PBMNCs than in granulocytes. The differential gene marking patterns suggest that RD114 and amphotropic vectors may target distinct progenitor or stem cell populations. There was no clear advantage for RD114-pseudotyped vectors in this predictive preclinical model in terms of overall long-term marking levels; however, optimization of transduction conditions by increasing m.o.i. or inducing the receptor could potentially improve results with this novel vector system. C1 NHLBI, Mol Hematol Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Div Expt Hematol, Memphis, TN 38105 USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematol Sect, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 33 TC 13 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD OCT PY 2003 VL 8 IS 4 BP 611 EP 617 DI 10.1016/S1525-0016(03)00239-9 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 729CU UT WOS:000185754400016 PM 14529834 ER PT J AU Floeter, MK AF Floeter, MK TI Cutaneous silent periods SO MUSCLE & NERVE LA English DT Review DE A-delta fibers; cutaneomuscular reflexes; peripheral silent periods; sensorimotor integration; spinal cord ID MASSETER INHIBITORY REFLEX; MOTOR-NEURON EXCITABILITY; TEMPORALIS MUSCLE-ACTIVITY; UPPER-LIMB MUSCLES; ELECTRICAL-STIMULATION; EXTEROCEPTIVE SUPPRESSION; PARKINSONS-DISEASE; UPPER EXTREMITY; HUMAN HAND; RECURRENT INHIBITION AB The cutaneous silent period (CSP) refers to the brief interruption in voluntary contraction that follows strong electrical stimulation of a cutaneous nerve. The CSP is a protective reflex that is mediated by spinal inhibitory circuits and is reinforced in part by parallel modulation of the motor cortex. This review summarizes current understanding of the afferents and circuits that are responsible for producing CSPs; the utility of the CSP for investigating peripheral and central nervous system disorders; and the relationship between the CSP, other cutaneous reflexes, and peripheral silent periods. C1 Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, 10 Ctr Dr,Bldg 10,Room 5C101, Bethesda, MD 20892 USA. NR 71 TC 59 Z9 59 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD OCT PY 2003 VL 28 IS 4 BP 391 EP 401 DI 10.1002/mus.10447 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 726RN UT WOS:000185613200001 PM 14506711 ER PT J AU Woodruff, ML Wang, ZY Chung, HY Redmond, TM Fain, GL Lem, J AF Woodruff, ML Wang, ZY Chung, HY Redmond, TM Fain, GL Lem, J TI Spontaneous activity of opsin apoprotein is a cause of Leber congenital amaurosis SO NATURE GENETICS LA English DT Article ID PIGMENT ACTIVATES TRANSDUCTION; EQUIVALENT-LIGHT HYPOTHESIS; VITAMIN-A; VISUAL PIGMENT; MOUSE MODEL; RETINITIS-PIGMENTOSA; SALAMANDER RODS; BINDING PROTEIN; NIGHT BLINDNESS; RPE65 GENE AB Mutations in Rpe65 disrupt synthesis of the opsin chromophore ligand 11-cis- retinal and cause Leber congenital amaurosis (LCA), a severe, early-onset retinal dystrophy. To test whether light-independent signaling by unliganded opsin causes the degeneration, we used Rpe65 - null mice, a model of LCA. Dark-adapted Rpe65(-/-) mice behaved as if light adapted, exhibiting reduced circulating current, accelerated response turn-off, and diminished intracellular calcium. A genetic block of transducin signaling completely rescued degeneration irrespective of an elevated level of retinyl ester. These studies clearly show that activation of sensory transduction by unliganded opsin, and not the accumulation of retinyl esters, causes light-independent retinal degeneration in LCA. A similar mechanism may also be responsible for degeneration induced by vitamin A deprivation. C1 Tufts Univ, New England Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. Univ Calif Los Angeles, Dept Physiol Sci, Los Angeles, CA 90095 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Ophthalmol, Los Angeles, CA 90095 USA. Tufts Univ, Sch Med, Dept Ophthalmol, Genet Program, Boston, MA 02111 USA. Tufts Univ, Sch Med, Tufts Ctr Vis Res, Boston, MA 02111 USA. RP Lem, J (reprint author), Tufts Univ, New England Med Ctr, Mol Cardiol Res Inst, 750 Washington St,Box 5045, Boston, MA 02111 USA. OI Redmond, T. Michael/0000-0002-1813-5291 NR 42 TC 115 Z9 115 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2003 VL 35 IS 2 BP 158 EP 164 DI 10.1038/ng1246 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 726WV UT WOS:000185625300012 PM 14517541 ER PT J AU Meetei, AR de Winter, JP Medhurst, AL Wallisch, M Waisfisz, Q van de Vrugt, HJ Oostra, AB Yan, ZJ Ling, C Bishop, CE Hoatlin, ME Joenje, H Wang, WD AF Meetei, AR de Winter, JP Medhurst, AL Wallisch, M Waisfisz, Q van de Vrugt, HJ Oostra, AB Yan, ZJ Ling, C Bishop, CE Hoatlin, ME Joenje, H Wang, WD TI A novel ubiquitin ligase is deficient in Fanconi anemia SO NATURE GENETICS LA English DT Article ID TARGETED DISRUPTION; NUCLEAR-COMPLEX; REDUCED FERTILITY; GROUP-C; PROTEINS; GENE; FANCG/XRCC9; PATHWAY; MICE; HYPERSENSITIVITY AB Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility(1,2). Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 ( also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. Free Univ Amsterdam, Med Ctr, Dept Clin Genet & Human Genet, NL-1081 BT Amsterdam, Netherlands. Oregon Hlth & Sci Univ, Div Mol Med, Portland, OR 97239 USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, 333 Cassell Dr,TRIAD Ctr Room 3000, Baltimore, MD 21224 USA. RI Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 NR 30 TC 377 Z9 392 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2003 VL 35 IS 2 BP 165 EP 170 DI 10.1038/ng1241 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 726WV UT WOS:000185625300013 PM 12973351 ER PT J AU Kelley, MW AF Kelley, MW TI Exposing the roots of hair cell regeneration in the ear SO NATURE MEDICINE LA English DT Editorial Material ID ACOUSTIC TRAUMA; PROLIFERATION; GROWTH; RAT AB Robust regeneration of hair cells, which mediate hearing and balance in the ear, occurs in most vertebrates, with the exception of mammals. Now, the identification of stem cells in the mouse inner ear that can give rise to hair cells raises the prospect of inducing regeneration in mammals as well. C1 NIDCD, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. RP Kelley, MW (reprint author), NIDCD, Sect Dev Neurosci, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 13 TC 4 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2003 VL 9 IS 10 BP 1257 EP 1259 DI 10.1038/nm1003-1257 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 727QK UT WOS:000185669700026 PM 14520370 ER PT J AU Di Pasquale, G Davidson, BL Stein, CS Martins, IS Scudiero, D Monks, A Chiorini, JA AF Di Pasquale, G Davidson, BL Stein, CS Martins, IS Scudiero, D Monks, A Chiorini, JA TI Identification of PDGFR as a receptor for AAV-5 transduction SO NATURE MEDICINE LA English DT Article ID ADENOASSOCIATED VIRUS TYPE-2; GROWTH-FACTOR RECEPTOR; ACTIVATED PROTEIN-KINASE; TUMOR-CELL-LINES; GENE-TRANSFER; SIALIC-ACID; VECTORS; EXPRESSION; INTERNALIZATION; BINDING AB Understanding the process of vector transduction has important implications for the application and optimal use of a vector system for human gene therapy. Recent studies with vectors based on adeno-associated virus type 5 (AAV-5) have shown utility, of this vector system in the lung, central nervous system, muscle and eye. To understand the natural tropism of this virus and to identify proteins necessary for AAV-5 transduction, we characterized 43 cell lines as permissive or nonpermissive for AAV-5 transduction and compared the gene expression profiles derived from cDNA microarray analyses of those cell lines. A statistically significant correlation was observed between expression of the platelet-derived growth factor receptor (PDGFR-alpha-polypeptide) and AAV-5 transduction. Subsequent experiments confirmed the role of PDGFR-alpha and PDGFR-beta as receptors for AAV-5. The tropism of AAV-5 in vivo also correlated with the expression pattern of PDGFR-alpha. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Neurol, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Physiol & Biophys, Iowa City, IA 52242 USA. SAIC Frederick, Frederick, MD 21702 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NR 40 TC 188 Z9 193 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2003 VL 9 IS 10 BP 1306 EP 1312 DI 10.1038/nm929 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 727QK UT WOS:000185669700043 PM 14502277 ER PT J AU Verma, M Kagan, J Sidransky, D Srivastava, S AF Verma, M Kagan, J Sidransky, D Srivastava, S TI Opinion - Proteomic analysis of cancer-cell mitochondria SO NATURE REVIEWS CANCER LA English DT Editorial Material ID DNA MUTATIONS; MASS-SPECTROMETRY; MULTIPLE DELETIONS; MESSENGER-RNA; BREAST-CANCER; PROTEIN; ELECTROPHORESIS; IDENTIFICATION; MARKERS; APOPTOSIS C1 NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. RP Srivastava, S (reprint author), NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. NR 41 TC 62 Z9 69 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD OCT PY 2003 VL 3 IS 10 BP 789 EP 795 DI 10.1038/nrc1192 PG 8 WC Oncology SC Oncology GA 732BJ UT WOS:000185920700016 PM 14570046 ER PT J AU Lewis, W Day, BJ Copeland, WC AF Lewis, W Day, BJ Copeland, WC TI Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID DNA-POLYMERASE-GAMMA; REVERSE-TRANSCRIPTASE INHIBITORS; PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; MANGANESE SUPEROXIDE-DISMUTASE; ANTI-HIV DEOXYNUCLEOTIDES; HUMAN THYMIDINE KINASE-1; VIRUS-INFECTED PATIENTS; RAT-LIVER MITOCHONDRIA; ACUTE-RENAL-FAILURE; OXIDATIVE STRESS AB Highly active antiretroviral therapy (HAART) regimes based on nucleoside reverse transcriptase inhibitors (NRTIs) have revolutionized the treatment of AIDS in recent years. Although HAART can successfully suppress viral replication in the long term, it is not without significant toxicity, which can seriously compromise treatment effectiveness. A major toxicity that has been recognized for more than a decade is NRTI-related mitochondrial toxicity, which manifests as serious side effects such as hepatic failure and lactic acidosis. However, a lack of understanding of the mechanisms underlying mitochondrial toxicity has hampered efforts to develop novel drugs with better side-effect profiles. This review characterizes the pharmacological mechanisms and pathways that are involved in mitochondrial dysfunction caused by NRTIs, and suggests opportunities for future pharmacological research. C1 Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Lewis, W (reprint author), Emory Univ, Dept Pathol, 1639 Pierce Dr,Room 7117, Atlanta, GA 30322 USA. FU NHLBI NIH HHS [HL63666, HL72707, R01 HL59798]; NIAAA NIH HHS [AA13551] NR 156 TC 284 Z9 294 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD OCT PY 2003 VL 2 IS 10 BP 812 EP 822 DI 10.1038/nrd1201 PG 11 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 732BF UT WOS:000185920400014 PM 14526384 ER PT J AU Evdokimov, AG Phan, J Tropea, JE Routzahn, KM Peters, HK Pokross, M Waugh, DS AF Evdokimov, AG Phan, J Tropea, JE Routzahn, KM Peters, HK Pokross, M Waugh, DS TI Similar modes of polypeptide recognition by export chaperones in flagellar biosynthesis and type III secretion SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID SYCE; POLYMERIZATION; COMPLEXES; PROTEINS; FLIT; FLGN AB Assembly of the bacterial flagellum and type III secretion in pathogenic bacteria require cytosolic export chaperones that interact with mobile components to facilitate their secretion. Although their amino acid sequences are not conserved, the structures of several type III secretion chaperones revealed striking similarities between their folds and modes of substrate recognition. Here, we report the first crystallographic structure of a flagellar export chaperone, Aquifex aeolicus FliS. FliS adopts a novel fold that is clearly distinct from those of the type III secretion chaperones, indicating that they do not share a common evolutionary origin. However, the structure of FliS in complex with a fragment of FliC ( flagellin) reveals that, like the type III secretion chaperones, flagellar export chaperones bind their target proteins in extended conformation and suggests that this mode of recognition may be widely used in bacteria. C1 NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. Procter & Gamble Pharmaceut, Hlth Care Res Ctr Discovery, Mason, OH 45040 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. RI ID, IMCACAT/D-5867-2014 NR 22 TC 68 Z9 69 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD OCT PY 2003 VL 10 IS 10 BP 789 EP 793 DI 10.1038/nsb982 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 726WQ UT WOS:000185624900008 PM 12958592 ER PT J AU Lee, HS Kruth, HS AF Lee, HS Kruth, HS TI Accumulation of cholesterol in the lesions of focal segmental glomerulosclerosis SO NEPHROLOGY LA English DT Article DE apolipoprotein B; esterified cholesterol; filipin; glomerulosclerosis; low-density lipoprotein; oil red O; unesterified cholesterol ID HUMAN ATHEROSCLEROTIC LESIONS; LOW-DENSITY-LIPOPROTEIN; INTRAGLOMERULAR LIPID DEPOSITION; UNESTERIFIED CHOLESTEROL; RENAL-DISEASE; FOAM CELLS; APO-B; PARTICLES; FILIPIN; ESTER AB Intraglomerular deposition of low-density lipoprotein (LDL) and oxidized LDL has been described in various human glomerular diseases. Yet it is not clear whether esterified cholesterol (EC) and unesterified cholesterol (UC) carried in LDL are mobilized from deposited LDL particles or accumulate in the diseased human glomeruli, particularly in the segmentally sclerotic lesions. To address this issue, frozen sections of renal biopsies were first immunostained to localize apolipoprotein B (apo B) and then oil red O (ORO) stained to colocalize neutral lipids. By using 124 ORO-positive biopsies and nine ORO-negative ones, UC was visualized directly with filipin staining, and EC was visualized after its enzymatic hydrolysis and staining with filipin. Seventy-seven biopsies (58%) showed filipin staining of accumulated EC and/or UC in the glomeruli. Of these, 11 showed heavy filipin staining for both EC and UC in the segmentally sclerotic lesions. In a group with UC deposits in the sclerotic segments, the percentage of the glomeruli affected by sclerosis and the intensity of filipin fluorescence for UC were significantly higher than biopsies with only mesangial UC deposits. Most filipin-positive biopsies showed apo B staining mainly in the mesangium. Yet in the sclerotic segments, apo B staining was rarely noted. Accumulated apo B-stained lipoprotein was not coincident with ORO-stained lipid in the diseased glomeruli. These results suggest that both EC and UC accumulate in the sclerotic glomerular segments as the glomerular lesions are advanced, and that these EC and UC appear to be derived from altered LDL with progressive loss of apo B. C1 Seoul Natl Univ, Coll Med, Dept Pathol, Seoul, South Korea. NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. RP Lee, HS (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, Yongon Dong 28, Seoul, South Korea. RI Seoul National University, Pathology/B-6702-2012 NR 35 TC 7 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 1320-5358 J9 NEPHROLOGY JI Nephrology PD OCT PY 2003 VL 8 IS 5 BP 224 EP 230 DI 10.1046/j.1440-1797.2003.00160.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 725QB UT WOS:000185552900002 PM 15012708 ER PT J AU Ulloa, A Bullock, D AF Ulloa, A Bullock, D TI A neural network simulating human reach-grasp coordination by continuous updating of vector positioning commands SO NEURAL NETWORKS LA English DT Article DE neural network; reaching and grasping; human prehension; precision grip; reach-grasp coordination; vector-integration-to-endpoint ID ARM MOVEMENTS; PREHENSION MOVEMENTS; SELECTIVE PERTURBATION; TRAJECTORY FORMATION; VISUAL GUIDANCE; PARIETAL CORTEX; MACAQUE MONKEY; OBJECT SIZE; HAND; SPEED AB We developed a neural network model to simulate temporal coordination of human reaching and grasping under variable initial grip apertures and perturbations of object size and object location/orientation. The proposed model computes reach-grasp trajectories by continuously updating vector positioning commands. The model hypotheses are (1) hand/wrist transport, grip aperture, and hand orientation control modules are coupled by a gating signal that fosters synchronous completion of the three sub-goals. (2) Coupling from transport and orientation velocities to aperture control causes maximum grip apertures that scale with these velocities and exceed object size. (3) Part of the aperture trajectory is attributable to an aperture-reducing passive biomechanical effect that is stronger for larger apertures. (4) Discrepancies between internal representations of targets partially inhibit the gating signal, leading to movement time increases that compensate for perturbations. Simulations of the model replicate key features of human reach-grasp kinematics observed under three experimental protocols. Our results indicate that no precomputation of component movement times is necessary for online temporal coordination of the components of reaching and grasping. (C) 2003 Elsevier Ltd. All rights reserved. C1 Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. RP Ulloa, A (reprint author), NCI, 9000 Rockville Pike,Bldg 10,Room 3C716, Bethesda, MD 20892 USA. OI Ulloa, Antonio/0000-0002-7554-4542 NR 50 TC 27 Z9 27 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0893-6080 J9 NEURAL NETWORKS JI Neural Netw. PD OCT PY 2003 VL 16 IS 8 BP 1141 EP 1160 DI 10.1016/S0893-6080(03)00079-0 PG 20 WC Computer Science, Artificial Intelligence SC Computer Science GA 742NR UT WOS:000186524400004 PM 13678619 ER PT J AU Young, WS Gainer, H AF Young, WS Gainer, H TI Transgenesis and the study of expression, cellular targeting and function of oxytocin, vasopressin and their receptors SO NEUROENDOCRINOLOGY LA English DT Review DE oxytocin; vasopressin; oxytocin receptors; vasopressin receptors; magnocellular neurons; paraventricular nucleus; supraoptic nucleus; transgenes; homologous recombination; transcription factors; molecular neuroendocrinology ID GREEN FLUORESCENT PROTEIN; NEURON-SPECIFIC EXPRESSION; MAGNOCELLULAR NEUROSECRETORY-CELLS; HYPOTHALAMIC SUPRAOPTIC NEURONS; CORTICOTROPIN-RELEASING-FACTOR; ADENOASSOCIATED VIRUS VECTOR; MESSENGER RIBONUCLEIC-ACIDS; REGULATED SECRETORY PATHWAY; CILIARY NEUROTROPHIC FACTOR; GENE-EXPRESSION AB The neuropeptides oxytocin and vasopressin and the neurons in the hypothalamus that synthesize them have been a rich source for the exploration and understanding of both the brain and the endocrine system. Because of their large size and compact nuclear organization the magnocellular neurons of the hypothalamoneurohypophysial system have traditionally attracted scientists using state-of-the-art techniques, including the subject of this review, transgenesis. We discuss the role of transgenics in deciphering gene elements necessary for the appropriate expression of oxytocin and vasopressin and to deliver exogenous genes, such as green fluorescent protein, selectively to secretory granules in the neurons in the hypothalamoneurohypophysial system. Finally, we review the studies of mice whose genes for oxytocin and, most recently, for the oxytocin and vasopressin receptors have been knocked out through homologous recombination. Copyright (C) 2003 S. Karger AG, Basel. C1 NIMH, Sect Neural Gene Express, NIH, US Dept HHS, Bethesda, MD 20892 USA. NINDS, Neurochem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Young, WS (reprint author), NIMH, Sect Neural Gene Express, NIH, US Dept HHS, 9000 Rockville Pike,MSC 4068,Bldg 36,Room 2A11, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 NR 185 TC 54 Z9 54 U1 0 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 EI 1423-0194 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD OCT PY 2003 VL 78 IS 4 BP 185 EP 203 DI 10.1159/000073702 PG 19 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 741LH UT WOS:000186459200001 PM 14583651 ER PT J AU Dorling, AA Todman, MG Korach, KS Herbison, AE AF Dorling, AA Todman, MG Korach, KS Herbison, AE TI Critical role for estrogen receptor alpha in negative feedback regulation of gonadotropin-releasing hormone mRNA expression in the female mouse SO NEUROENDOCRINOLOGY LA English DT Article DE gonadal steroid receptor; gonadotropins; gonadotropin-releasing hormone; transgene; mice ID GNRH GENE-EXPRESSION; ANTERIOR HYPOTHALAMIC AREA; BETA ER-BETA; REPRODUCTIVE PHENOTYPES; PROMOTER ACTIVITY; RAT-BRAIN; IN-VIVO; NEURONS; CELLS; MICE AB Estrogen exerts an important regulatory influence upon the functioning of the gonadotropin-releasing hormone (GnRH) neurons. Whether this is mediated by estrogen receptor alpha (ERalpha) or ERbeta or both ERs is presently unclear. Using female mice with targeted disruptions of ERalpha and ERbeta (alphaERKO and betaERKO, respectively) we have investigated the in vivo role of the two ERs in the negative feedback influence of estrogen upon GnRH mRNA expression. Compared with intact wild-type mice, plasma luteinizing hormone (LH) levels were substantially (p < 0.01) higher in intact αERKO females and increased modestly (p < 0.05) in intact betaERKO mice. Three weeks after ovariectomy, LH concentrations were elevated significantly in wild-type (p < 0.01) and βERKO (p < 0.05) mice but not changed in alphaERKO females. Quantitative analysis of GnRH mRNA expression using in situ hybridization revealed that cellular GnRH mRNA content was greater (p < 0.05) in intact αERKO mice compared with intact wild-type and βERKO mice. Following ovariectomy, GnRH mRNA expression was elevated in wild-type (p = 0.06) and βERKO (p < 0.05) females but not alphaERKO mice. These data demonstrate that both ERalpha and ERbeta are involved in inhibiting LH levels at times of estrogen-negative feedback in vivo. However, only ERalpha appears to be critical for the estrogen-negative feedback suppression of GnRH mRNA expression in the female mouse. Copyright (C) 2003 S. Karger AG, Basel. C1 Univ Otago, Sch Med Sci, Dept Physiol, Dunedin, New Zealand. Babraham Inst, Neuroendocrinol Lab, Cambridge, England. NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Raleigh, NC USA. Univ Otago, Sch Med Sci, Ctr Neuroendocrinol, Dunedin, New Zealand. RP Herbison, AE (reprint author), Univ Otago, Sch Med Sci, Dept Physiol, POB 913, Dunedin, New Zealand. OI Korach, Kenneth/0000-0002-7765-418X; Herbison, Allan/0000-0002-9615-3022 NR 28 TC 82 Z9 86 U1 1 U2 5 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD OCT PY 2003 VL 78 IS 4 BP 204 EP 209 DI 10.1159/000073703 PG 6 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 741LH UT WOS:000186459200002 PM 14583652 ER PT J AU Armando, I Tjurmina, OA Li, Q Murphy, DL Saavedra, JM AF Armando, I Tjurmina, OA Li, Q Murphy, DL Saavedra, JM TI The serotonin transporter is required for stress-evoked increases in adrenal catecholamine synthesis and angiotensin II AT(2) receptor expression SO NEUROENDOCRINOLOGY LA English DT Article DE tyrosine hydroxylase; angiotensins; angiotensin receptors; catecholamines; serotonin; serotonin transporter; adrenal medulla; stress; in situ hybridization ID BIOGENIC-AMINE TRANSPORTERS; PERFORMANCE LIQUID-CHROMATOGRAPHY; ANALOG I-125 RTI-55; CHROMAFFIN CELLS; ELECTROCHEMICAL DETECTION; BINDING-SITES; RAT-BRAIN; MICE; 5-HT; GENE AB High numbers of serotonin transporter (SERT) binding sites and high serotonin (5-HT) content are expressed in the adrenal medulla of wild-type (SERT+/+) mice. Acute restraint stress increases adrenomedullary 5-HT, norepinephrine (NE) and epinephrine (E) release, adrenomedullary tyrosine hydroxylase (TH) mRNA, and angiotensin II AT(2) receptor expression. There are no alterations in adrenal catecholamine content during restraint. In litter-mate SERT-/- mice, which do not express SERT binding sites, the basal adrenomedullary 5-HT content is significantly reduced and does not increase after stress. The stress-induced increase in plasma E is higher in SERT-/- than in SERT+/+ animals. In SERT-/- mice, the stress-induced increase in expression of TH mRNA does not occur, and as a consequence, adrenal E content decreases, and adrenal E and NE content are lower than that of SERT+/+ mice during restraint. In addition, instead of increased expression, stress induces a profound decrease in the number of adrenomedullary AT2 receptors in SERT-/- mice. Our results indicate that SERT is necessary for the stress-induced increase in adrenomedullary catecholamine synthesis and AT2 receptor expression. These data further indicate a close relationship between the adrenomedullary 5-HT and angiotensin II systems, and an important role of adrenomedullary AT2 receptors in catecholamine synthesis and release during stress. Copyright (C) 2003 S. Karger AG, Basel. C1 NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Armando, I (reprint author), NIMH, Pharmacol Sect, NIH, Bldg 10,Rm 2D57,10 Ctr Dr,MSC-1514, Bethesda, MD 20892 USA. NR 43 TC 14 Z9 14 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD OCT PY 2003 VL 78 IS 4 BP 217 EP 225 DI 10.1159/000073705 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 741LH UT WOS:000186459200004 PM 14583654 ER PT J AU Brownell, AL Canales, K Chen, YI Jenkins, BG Owen, C Livni, E Yu, MX Cicchetti, F Sanchez-Pernaute, R Isacson, O AF Brownell, AL Canales, K Chen, YI Jenkins, BG Owen, C Livni, E Yu, MX Cicchetti, F Sanchez-Pernaute, R Isacson, O TI Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model SO NEUROIMAGE LA English DT Article DE positron emission tomography; volume rendering; MPTP; Parkinson's disease ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; GLUCOSE METABOLIC-RATE; DOPAMINE D2 RECEPTORS; F-18 FLUORODEOXYGLUCOSE; DIFFERENTIAL-DIAGNOSIS; TREATED MONKEYS; BASAL GANGLIA; NORMAL VALUES; C-11 CFT AB Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [C-11]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [C-11]Raclopride binding of dopamine D-2 receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamocortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration. (C) 2003 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. McLean Hosp, Neurogenerat Lab, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Bartlett Hall 504R, Boston, MA 02114 USA. EM abrownell@partners.org FU NINDS NIH HHS [NS P50-39793] NR 67 TC 38 Z9 43 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2003 VL 20 IS 2 BP 1064 EP 1075 DI 10.1016/S1053-8119(03)00348-3 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 737YV UT WOS:000186260700038 PM 14568476 ER PT J AU Dalakas, MC AF Dalakas, MC TI High-dose intravenous immunoglobulin in inflammatory myopathies: experience based on controlled clinical trials SO NEUROLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT International Workshop on Intravenous Immunoglobulins in Neurological Disorders Present and Future CY JUN 21, 2002 CL MILAN, ITALY ID INCLUSION-BODY MYOSITIS; GAMMA-GLOBULIN; DOUBLE-BLIND; DERMATOMYOSITIS; POLYMYOSITIS; THERAPY AB Controlled clinical trials with high-dose intravenous immunoglobulin (IVIg) have been conducted in patients with DM and IBM, but not PM. A double-blind placebo-controlled study in DM patients, resistant or partially responsive to conventional therapies, showed that IVIg is very effective in improving both the muscle strength and the skin rash. The clinical benefit, which was impressive in patients with early disease, was associated with improvement in the muscle cytoarchitecture. Quantitative histological studies in repeated muscle biopsies showed a statistically significant increased in the size of muscle fibers and the number of capillaries with normalization of the capillary diameter. Resolution of the aberrant immunopathological parameters including interception of complement activation products and downregulation of T cells, ICAM-1, VCAM, TGF-beta and MHC-I molecules was also noted. In IBM, IVIg showed marginal, and non statistically significant, improvements in muscle strength. Up to 20% of patients however, demonstrated clinical improvement with increased activities of daily living while certain muscle groups, such as the muscles of swallowing, showed significant improvements compared to placebo implying mild regional benefits. In PM, small uncontrolled series have shown improvements in muscle strength in up to 70% of the IVIg-treated patients. Because PM, as a stand-alone clinical entity, is a very rare disease, completion of controlled trials will be very difficult. C1 Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. NR 21 TC 19 Z9 21 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1590-1874 J9 NEUROL SCI JI Neurol. Sci. PD OCT PY 2003 VL 24 SU 4 BP S256 EP S259 DI 10.1007/s10072-003-0090-6 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 735FG UT WOS:000186101300010 PM 14598055 ER PT J AU Miap, FJP Green, P Benowitz, N Levine, JD AF Miap, FJP Green, P Benowitz, N Levine, JD TI Vagal modulation of spinal nicotine-induced inhibition of the inflammatory response mediated by descending antinociceptive controls SO NEUROPHARMACOLOGY LA English DT Article DE nociception; inflammation; sympathoadrenal; hypothalamic-pituitary-adrenal; post-ganglionic sympathetic neuron ID INDUCED PLASMA EXTRAVASATION; FEEDBACK NEUROENDOCRINE CONTROL; INTRATHECAL NICOTINE; NEUROGENIC INFLAMMATION; AFFERENT MODULATION; NOCICEPTIVE REFLEX; RAT; BRADYKININ; PAIN; ENDOCRINE AB Noxious stimuli activate neuroendocrine axes, inhibiting inflammation, an effect that is powerfully attenuated by ongoing activity in subdiaphragmatic vagal afferents. To evaluate whether this inhibitory effect of vagal afferent activity is mediated by descending antinociceptive control, we tested whether antagonizing descending antinociceptive controls: (i) enhances the inhibition of inflammation produced by spinal nicotine (which stimulates central terminals of nociceptors) and (ii) occludes the enhancing effect of subdiaphragmatic vagotomy, in the rat. Spinal intrathecal co-administration of the alpha-adrenergic receptor antagonist phentolamine and the non-selective opioid receptor antagonist naloxone, and acute subdiaphragmatic vagotomy each produced enhancement, with similar magnitude, of nicotine-induced inhibition of plasma extravasation, produced by the potent inflammatory mediator, bradykinin. The combination of subdiaphragmatic vagotomy and intrathecal receptor antagonists, however, produced no further enhancement compared to each treatment alone. These findings support the suggestion that activity in descending antinociceptive controls modulates noxious stimulus-induced inhibition of inflammation and the vagal modulation of noxious stimulus-induced inhibition of inflammation is mediated by descending antinociceptive controls. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Calif San Francisco, Sch Med, NIH, Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, NIH, Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Div Clin Pharmacol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, Div Clin Pharmacol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, Div Rheumatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Div Rheumatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Dent, Dept Anat, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, Sch Med, NIH, Pain Ctr, San Francisco, CA 94143 USA. RI Green, Paul/C-5943-2011 NR 40 TC 0 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD OCT PY 2003 VL 45 IS 5 BP 605 EP 611 DI 10.1016/S0028-3908(03)00224-7 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 720MH UT WOS:000185264200005 ER PT J AU Heishman, SJ Singleton, EG Moolchan, ET AF Heishman, SJ Singleton, EG Moolchan, ET TI Tobacco Craving Questionnaire: Reliability and validity of a new multifactorial instrument SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKING URGES; INITIAL VALIDATION; COEFFICIENT-ALPHA; IMAGERY SCRIPTS; ALCOHOL; COCAINE; ACTIVATION; NICOTINE; WITHDRAWAL; MARIJUANA AB This study documented the initial reliability and validity of the Tobacco Craving Questionnaire (TCQ), a new multidimensional questionnaire to assess tobacco craving. Current cigarette smokers (n = 213) not attempting to reduce or quit smoking completed the 47-item TCQ and other forms assessing demographics, tobacco and other drug use history, quit attempts, and current mood. Exploratory factor analyses and structural equation modeling indicated that a four-factor solution best described the item structure. Factor subscales derived from the 17 items with significant loadings had low to high internal consistencies and interitem correlations and exhibited low to moderate, positive intercorrelations. Factor scales were significantly correlated with single-item measures of craving, current mood, and daily cigarette smoking. Results indicated that four specific constructs characterized craving for tobacco: (a) Emotionality, or smoking in anticipation of relief from withdrawal symptoms or negative mood, (b) expectancy, or anticipation of positive outcomes from smoking, (c) compulsivity, or an inability to control tobacco use, and (d) purposefulness, or intention and planning to smoke for positive outcomes. These preliminary data suggest that the TCQ is a reliable and valid instrument for assessing tobacco craving in individuals not attempting to reduce or quit smoking. C1 NIDA, Clin Pharmacol & Therapeut Branch, Intramural Res Program, Baltimore, MD 21224 USA. Howard Univ, Ctr Drug Abuse Res, Washington, DC 20059 USA. RP Heishman, SJ (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, Intramural Res Program, 500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Singleton, Edward G./0000-0003-3442-877X NR 69 TC 48 Z9 48 U1 2 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 645 EP 654 DI 10.1080/1462220031000158681 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200007 PM 14577981 ER PT J AU Lee, EM Malson, JL Waters, AJ Moolchan, ET Pickworth, WB AF Lee, EM Malson, JL Waters, AJ Moolchan, ET Pickworth, WB TI Smoking topography: Reliability and validity in dependent smokers SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CARBON-MONOXIDE EXPOSURE; PUFFING BEHAVIOR; WHITE WOMEN; NICOTINE DEPENDENCE; CIGARETTE-SMOKING; PATTERNS; DETERMINANT; INHALATION; YIELDS AB Data from two studies were analyzed to determine whether smoking through the mouthpiece of a topography unit yields consistent measures over time and to verify that smoking through a mouthpiece results in a similar degree of smoke exposure as conventional smoking. In both studies, subjects smoked their usual brand of cigarette ad libitum. In study A, subjects (n = 7) smoked through a mouthpiece on 4 separate experimental days. In study B, subjects (n = 10) smoked on 2 separate days: Once conventionally and once through a mouthpiece. In both studies, exhaled carbon monoxide (CO) and physiological effects (heart rate and blood pressure) were measured before and after smoking. In study B, plasma nicotine concentrations also were measured. In study A, puff volume, puff duration, interpuff interval, and maximum puff velocity averaged 30.8 ml, .9 s, 19.9 s, and 44.6 ml/s, respectively. Intraclass correlation coefficients computed for puff volume (0.66), puff duration (0.75), and maximum puff velocity (0.68) indicated that these measures showed good reliability. In study B, smoking through the mouthpiece yielded similar topographical (time to smoke and number of puffs per cigarette) measures as conventional smoking. Also similar were changes in biochemical values: Plasma nicotine (18.5 ng/ml vs. 25.5 ng/ml), exhaled CO (4.6 ppm vs. 5.1 ppm), and heart rate (8.6 beats/min vs. 7.4 beats/min) for conventional and topography mouthpiece smoking conditions, respectively. Topography measures did not differ significantly between the two studies. Overall, the data from these two small-sample studies suggest that smoking topography provides a valid and reliable index of conventional smoking and an indirect measure of smoke exposure. C1 NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Pickworth, WB (reprint author), NIDA, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCI NIH HHS [P50CA84718] NR 31 TC 58 Z9 60 U1 2 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 673 EP 679 DI 10.1080/1462220031000158645 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200010 PM 14577984 ER PT J AU Augustson, E Marcus, S AF Augustson, E Marcus, S TI Use of the current population survey to characterize hardcore smokers SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 NCI, DCCPS, TCRB, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 771 EP 771 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200022 ER PT J AU England, L Soule, L Qian, C Yu, K Levine, R AF England, L Soule, L Qian, C Yu, K Levine, R TI Smoking increases risk of gestational diabetes in nulliparous women SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20895 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 776 EP 776 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200033 ER PT J AU Harvey, DM Heishman, SJ Henningfield, JE Goldberg, SR AF Harvey, DM Heishman, SJ Henningfield, JE Goldberg, SR TI Intravenous nicotine self-administration by squirrel monkeys and human volunteers SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 NIDA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 779 EP 779 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200040 ER PT J AU Myers, CS Saha, S Singleton, EG Moolchan, ET Heishman, SJ AF Myers, CS Saha, S Singleton, EG Moolchan, ET Heishman, SJ TI Imagery-induced tobacco craving: Persistent time course and lack of reactivity effects SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 NIDA, IRP, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2003 VL 5 IS 5 BP 788 EP 788 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 734KF UT WOS:000186054200058 ER PT J AU Schou, M Halldin, C Sovago, J Pike, VW Gulyas, B Mozley, PD Johnson, DP Hall, H Innis, RB Farde, L AF Schou, M Halldin, C Sovago, J Pike, VW Gulyas, B Mozley, PD Johnson, DP Hall, H Innis, RB Farde, L TI Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[C-11]MeNER SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE norepinephrine transporter; PET; monkey; autoradiography; MeNER ID SEROTONIN TRANSPORTER; UPTAKE SITES; HUMAN-BRAIN; LOCUS-COERULEUS; H-3 NISOXETINE; HIGH-AFFINITY; AUTORADIOGRAPHY; DESIPRAMINE; POSTMORTEM; DERIVATIVES AB (S,S)-2-(alpha-(2-Methoxyphenoxy)benzyl)morpholine (MeNER), an O-methyl analog of the selective and potent norepinephrine transporter (NET) inhibitor, (S,S)-reboxetine, and its less active enantiomer, (R,R)-MeNER, have each been radiolabeled by O-methylation of their corresponding phenolic precursors in good yields from [C-11]methyl iodide or [C-11]methyl triflate. Radiochemical purities were >99% and specific radioactivity at time of injection was about 74 GBq/mumol. Autoradiographic examination of (SS)-[C-11]MeNER binding to human brain slices post mortem indicated specific binding in a brain region including the locus coeruleus. PET examination of both [C-11]MeNER enantiomers in a cynomolgus monkey demonstrated a higher specific binding of the (SS)-enantiomer with ratios of 1.4-1.6 in the lower brainstem, mesencephalon and thalamus to striatum. Pretreatment with the NET ligand, desipramine, decreased the specific binding of (S,S)-[C-11]MeNER. Labeled metabolites of [C-11]MeNER were all more polar. (SS)-[C-11]MeNER is a good lead compound in the search for a selective radioligand for quantitation of NET in the human brain in vivo. (C) 2003 Elsevier Inc. All rights reserved. C1 Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Karolinska Hosp, S-17176 Stockholm, Sweden. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Halldin, C (reprint author), Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Karolinska Hosp, S-17176 Stockholm, Sweden. RI Sovago, Judit/G-7961-2011; Gulyas, Balazs/F-9508-2015 NR 31 TC 59 Z9 59 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2003 VL 30 IS 7 BP 707 EP 714 DI 10.1016/S0969-8051(03)00079-9 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728ZL UT WOS:000185746200004 PM 14499328 ER PT J AU Michel, RB Rosario, AV Brechbiel, MW Jackson, TJ Goldenberg, DM Mattes, MJ AF Michel, RB Rosario, AV Brechbiel, MW Jackson, TJ Goldenberg, DM Mattes, MJ TI Experimental therapy of disseminated B-Cell lymphoma xenografts with Bi-213-labeled anti-CD74 SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE radiolabeled antibodies; antibody therapy; radioimmunotherapy; alpha-particle emitters ID MONOCLONAL-ANTIBODY; RADIOLABELED ANTIBODIES; EMITTING RADIONUCLIDES; INVARIANT CHAIN; SOLID TUMORS; ALPHA; RADIOIMMUNOTHERAPY; LEUKEMIA; INTERNALIZATION; CYTOTOXICITY AB A Bi-213-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The alpha-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound Bi-213 was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures. (C) 2003 Elsevier Inc. All rights reserved. C1 Ctr Mol Med & Immunol, Belleville, NJ 07922 USA. NIH, Bethesda, MD 20892 USA. RP Mattes, MJ (reprint author), Ctr Mol Med & Immunol, 520 Belleville Ave, Belleville, NJ 07922 USA. FU NCI NIH HHS [CA87059] NR 36 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2003 VL 30 IS 7 BP 715 EP 723 DI 10.1016/S0969-8051(03)00082-9 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728ZL UT WOS:000185746200005 PM 14499329 ER PT J AU Huang, BX Channing, MA Plascjak, PS Kiesewetter, DO Der, M Ma, Y Eckelman, WC AF Huang, BX Channing, MA Plascjak, PS Kiesewetter, DO Der, M Ma, Y Eckelman, WC TI Routine quality control of recycled target [O-18]water by capillary electrophoresis and gas chromatography SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE target [O-18]water; quality control; capillary electrophoresis; gas chromatography ID O-18 WATER TARGET; ANION-EXCHANGE RESIN; F-18 FLUORIDE; WATER; RECOVERY; YIELD; RADIOPHARMACEUTICALS; EXTRACTION AB Recycling of [O-18]water for [F-18]fluoride production can be accomplished with reliable results. We have developed sensitive, robust, and rapid analyses of impurities in [O-18]water. Anions were quantitated by capillary electrophoresis and organic residuals were quantitated by gas chromatography using methods with excellent reproducibility and linearity. Kryptofix 222 (K-222) was quantitated by a sensitive LC-MS-MS technique. Isotopic composition was determined by GC-MS with satisfactory accuracy and precision. These methods were employed to evaluate recovered [O-18]water purified by a novel electrolysis method. 2-[F-18]FDG yields using purified [O-18]water with very low levels of impurities are indistinguishable from newly purchased [O-18]water. High (> 300 ppm) carbonate concentration reduces the fluoride trapping efficiency of QMA. The analyses of anions, organics, and isotopic enrichment were applied routinely for quality control of [O-18]water to predict a satisfactory outcome of 2-[F-18]FDG production. Published by Elsevier Inc. All rights reserved. C1 NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Huang, BX (reprint author), NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. NR 36 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2003 VL 30 IS 7 BP 785 EP 790 DI 10.1016/S0969-8051(03)00083-0 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 728ZL UT WOS:000185746200014 PM 14499338 ER PT J AU Kim, YS Nakanishi, G Lewandoski, M Jetten, AM AF Kim, YS Nakanishi, G Lewandoski, M Jetten, AM TI GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROGRAMMED CELL-DEATH; HEDGEHOG-PATCHED-GLI; TRANSCRIPTION FACTOR; MOUSE DEVELOPMENT; LUNG DEVELOPMENT; SPINAL-CORD; GENE FAMILY; TGF-BETA; EXPRESSION; INDUCTION AB In this study, we describe the identification and characterization of a novel transcription factor GLI-similar 3 (GLIS3). GLIS3 is an 83.8 kDa nuclear protein containing five C2H2-type Kruppel-like zinc finger motifs that exhibit 93% identity with those of GLIS1, however, little homology exists outside their zinc finger domains. GLIS3 can function as a repressor and activator of transcription. Deletion mutant analysis determined that the N- and C-termini are required for optimal transcriptional activity. GLIS3 binds to the GLI-RE consensus sequence and is able to enhance GLI-RE-dependent transcription. GLIS3(DeltaC496), a dominant-negative mutant, inhibits transcriptional activation by GLIS3 and GLI1. Whole mount in situ hybridization on mouse embryos from stage E6.5 through E14.5 demonstrated that GLIS3 is expressed in specific regions in developing kidney and testis and in a highly dynamic pattern during neurulation. From E11.5 through E12.5 GLIS3 was strongly expressed in the interdigital regions, which are fated to undergo apoptosis. The temporal and spatial pattern of GLIS3 expression observed during embryonic development suggests that it may play a critical role in the regulation of a variety of cellular processes during development. Both the repressor and activation functions of GLIS3 may be involved in this control. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 70 TC 55 Z9 58 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2003 VL 31 IS 19 BP 5513 EP 5525 DI 10.1093/nar/gkg776 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726LK UT WOS:000185600400012 PM 14500813 ER PT J AU Tan, PK Downey, TJ Spitznagel, EL Xu, P Fu, D Dimitrov, DS Lempicki, RA Raaka, BM Cam, MC AF Tan, PK Downey, TJ Spitznagel, EL Xu, P Fu, D Dimitrov, DS Lempicki, RA Raaka, BM Cam, MC TI Evaluation of gene expression measurements from commercial microarray platforms SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ART. NO. E15; CDNA MICROARRAY; DNA MICROARRAYS AB Multiple commercial microarrays for measuring genome-wide gene expression levels are currently available, including oligonucleotide and cDNA, single- and two-channel formats. This study reports on the results of gene expression measurements generated from identical RNA preparations that were obtained using three commercially available microarray platforms. RNA was collected from PANC-1 cells grown in serum-rich medium and at 24 h following the removal of serum. Three biological replicates were prepared for each condition, and three experimental replicates were produced for the first biological replicate. RNA was labeled and hybridized to microarrays from three major suppliers according to manufacturers' protocols, and gene expression measurements were obtained using each platform's standard software. For each platform, gene targets from a subset of 2009 common genes were compared. Correlations in gene expression levels and comparisons for significant gene expression changes in this subset were calculated, and showed considerable divergence across the different platforms, suggesting the need for establishing industrial manufacturing standards, and further independent and thorough validation of the technology. C1 NIDDKD, Microarray Core Lab, NIDDK, NIH, Bethesda, MD 20892 USA. Washington Univ, Partek Inc, St Louis, MO 63130 USA. Washington Univ, Dept Math, St Louis, MO 63130 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. NIAID, NIH, SAIC Frederick Inc, Bethesda, MD 20892 USA. NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Cam, MC (reprint author), NIDDKD, Microarray Core Lab, NIDDK, NIH, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 20 TC 501 Z9 523 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2003 VL 31 IS 19 BP 5676 EP 5684 DI 10.1093/nar/gkg763 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726LK UT WOS:000185600400030 PM 14500831 ER PT J AU Lyonnais, S Gorelick, RJ Mergny, JL Le Cam, E Mirambeau, G AF Lyonnais, S Gorelick, RJ Mergny, JL Le Cam, E Mirambeau, G TI G-quartets direct assembly of HIV-1 nucleocapsid protein along single-stranded DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEIC-ACID-CHAPERONE; TERMINAL ZINC-FINGER; GAG GENE-PRODUCTS; IN-VITRO; POSTTRANSLATIONAL MODIFICATIONS; REVERSE TRANSCRIPTION; BINDING-PROPERTIES; TYPE-1; RNA AB The d(TTGGGGGGTACAGTGCA) sequence, derived from the human immunodeficiency virus type 1 (HIV-1) central DNA flap, can form in vitro an intermolecular parallel DNA quadruplex. This work demonstrates that the HIV-1 nucleocapsid protein (NCp) exhibits a high affinity (10(8) M-1) for this quadruplex. This interaction is predominantly hydrophobic, maintained by a stabilization between G-quartet planes and the C-terminal zinc finger of the protein. It also requires 5 nt long tails flanking the quartets plus both the second zinc-finger and the N-terminal domain of NCp. The initial binding nucleates an ordered arrangement of consecutive NCp along the four single-stranded tails. Such a process requires the N-terminal zinc finger, and was found to occur for DNA site sizes shorter than usual in a sequence-dependent manner. Concurrently, NCp binding is efficient on a G'2 quadruplex also derived from the HIV-1 central DNA flap. Apart from their implication within the DNA flap, these data lead to a model for the nucleic acid architecture within the viral nucleocapsid, where adjacent single-stranded tails and NCp promote a compact assembly of NCp and nucleic acid growing from stably and primary bound NCp. C1 Inst Gustave Roussy, CNRS, UMR 8126, Lab Microscopie Mol & Cellulaire, F-94805 Villejuif, France. NCI, AIDS Vaccine Programe, SAIC Frederick Inc, Frederick, MD 21702 USA. CNRS, INSERM, UMR 8646,U565, Museum Natl Hist Nat,Lab Biophys, F-75231 Paris, France. RP Mirambeau, G (reprint author), Inst Gustave Roussy, CNRS, UMR 8126, Lab Microscopie Mol & Cellulaire, 39 Rue Camille Desmoulins, F-94805 Villejuif, France. RI Mergny, Jean-Louis/E-2860-2013; OI Mergny, Jean-Louis/0000-0003-3043-8401; Lyonnais, Sebastien/0000-0002-3154-8568 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 50 TC 40 Z9 40 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2003 VL 31 IS 19 BP 5754 EP 5763 DI 10.1093/nar/gkg716 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726LK UT WOS:000185600400038 PM 14500839 ER PT J AU Pileur, F Andreola, ML Dausse, E Michel, J Moreau, S Yamada, H Gaidamakov, SA Crouch, RJ Toulme, JJ Cazenave, C AF Pileur, F Andreola, ML Dausse, E Michel, J Moreau, S Yamada, H Gaidamakov, SA Crouch, RJ Toulme, JJ Cazenave, C TI Selective inhibitory DNA aptamers of the human RNase H1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 REVERSE-TRANSCRIPTASE; RIBONUCLEASE-H ACTIVITIES; SACCHAROMYCES-CEREVISIAE; RNA HYBRIDS; POLYMERASE; CLONING; ACID; HII; EXPRESSION AB Human RNase H1 binds double-stranded RNA via its N-terminal domain and RNA-DNA hybrid via its C-terminal RNase H domain, the latter being closely related to Escherichia coli RNase HI. Using SELEX, we have generated a set of DNA sequences that can bind efficiently (K-d values ranging from 10 to 80 nM) to the human RNase H1. None of them could fold into a simple perfect double-stranded DNA hairpin confirming that double-stranded DNA does not constitute a trivial ligand for the enzyme. Only two of the 37 DNA aptamers selected were inhibitors of human RNase H1 activity. The two inhibitory oligomers, V-2 and VI-2, were quite different in structure with V-2 folding into a large, imperfect but stable hairpin loop. The VI-2 structure consists of a central region unimolecular quadruplex formed by stacking of two guanine quartets flanked by the 5' and 3' tails that form a stem of six base pairs. Base pairing between the 5' and 3' tails appears crucial for conferring the inhibitory properties to the aptamer. Finally, the inhibitory aptamers were capable of completely abolishing the action of an antisense oligonucleotide in a rabbit reticulocyte lysate supplemented with human RNase H1, with IC50 ranging from 50 to 100 nM. C1 Univ Bordeaux 2, INSERM, U386, F-33076 Bordeaux, France. Univ Bordeaux 2, CNRS, UMR 5097, F-33076 Bordeaux, France. CNRS, Inst Europeen Chim & Biol, F-33402 Talence, France. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Cazenave, C (reprint author), Univ Bordeaux 2, INSERM, U386, 146 Rue Leo Saignat, F-33076 Bordeaux, France. OI Toulme, Jean-jacques/0000-0002-8432-5034 NR 49 TC 55 Z9 57 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2003 VL 31 IS 19 BP 5776 EP 5788 DI 10.1093/nar/gkg748 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726LK UT WOS:000185600400040 PM 14500841 ER PT J AU Kumanyika, SK Obarzanek, E AF Kumanyika, SK Obarzanek, E TI Pathways to obesity prevention: Report of a National Institutes of Health Workshop SO OBESITY RESEARCH LA English DT Article DE health promotion; children; families; interventions; weight control ID AFRICAN-AMERICAN MOTHERS; UNITED-STATES; PHYSICAL-ACTIVITY; WEIGHT-GAIN; INTERVENTIONS; PROGRAM; BEHAVIOR; CHILDREN; TRENDS; MAINTENANCE AB There is an extensive research base on obesity treatment and on the health benefits of weight loss, but relatively little research has focused on obesity prevention. This article summarizes results of a workshop conducted by investigators funded under a National Institutes of Health initiative designed to stimulate novel research for obesity prevention. The 20 pilot studies funded under this initiative involved study populations that were diverse with respect to life stage and ethnicity. were conducted in a variety of natural and research settings, and involved a mix of interventions, including face-to-face group and individual counseling, as well as mail, telephone, and internet-based approaches. The workshop, which occurred approximately halfway through the 3-year funding period, emphasized concepts and experiences related to initiating and conducting obesity prevention studies. Investigators discussed theoretical perspectives as well as various challenges encountered, for example, in study implementation in different clinical and community settings. in working with children and families, and in studying pregnant and postpartum women. Other topics discussed included the difficulty of motivating individuals for prevention of weight gain, relevant cultural and racial/ethnic considerations, and the particular need for valid and practical measures of energy balance, body composition, and physical fitness in obesity prevention research. A key conclusion was that using obesity treatment as the primary paradigm may be a limiting perspective for considering obesity prevention issues. Further insights derived from the workshop deliberations are reflected in a detailed list of recommendations for future obesity prevention research. C1 Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Natl Heart Lung & Blood Inst, Div Epiemiol & Clin Applicat, Prevent Sci Res Grp, NIH, Bethesda, MD USA. RP Kumanyika, SK (reprint author), Ctr Clin Epidemiol & Biostat, 8th Floor,Blockey Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. FU NHLBI NIH HHS [R01 HL065144, R01 HL065132, R01 HL065133, R01HL065134]; NIA NIH HHS [R01 AG018239, R01 AG018238]; NICHD NIH HHS [R01 HD039102, R01 HD039104, R01 HD039103]; NIDDK NIH HHS [R01 DK057486, R01 DK060433, R01 DK057461, R01 DK057492, R01 DK057439, R01 DK057478, R01 DK057446, R01 DK057453, R01 DK057476, R01 DK57384] NR 50 TC 34 Z9 34 U1 0 U2 4 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD OCT PY 2003 VL 11 IS 10 BP 1263 EP 1274 DI 10.1038/oby.2003.172 PG 12 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 735GZ UT WOS:000186105800015 PM 14569052 ER PT J AU Haddad, R Colevas, AD Krane, JF Cooper, D Glisson, B Amrein, PC Weeks, L Costello, R Posner, M AF Haddad, R Colevas, AD Krane, JF Cooper, D Glisson, B Amrein, PC Weeks, L Costello, R Posner, M TI Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study SO ORAL ONCOLOGY LA English DT Article DE salivary gland tumors; Herceptin; Her2/Neu ID MONOCLONAL-ANTIBODY; BREAST-CANCER; CHEMOTHERAPY; HER-2/NEU; CISPLATIN; CYCLOPHOSPHAMIDE; OVEREXPRESSION; MALIGNANCIES; DOXORUBICIN; NEOPLASMS AB Phase II study of Herceptin(R) (Trastuzumab) in patients with advanced salivary gland tumors overexpressing Her2/neu. Patients with advanced, incurable salivary gland tumors and 2+ or 3+ Her2/neu expression in their tumors were enrolled in the study. After an initial dose of 4 mg/kg, patients received 2 mg/kg weekly. Patients were treated until they experienced progression of disease or unacceptable toxicity. The study was closed early when it has become clear that the majority of tumors screened did not overexpress Her2/neu. Fourteen patients were enrolled in the study. A total of 86 cycles of Herceptin were delivered with a median of three cycles per patient (range 1-40). Median time to progression was 4.2 months. One patient with metastatic mucoepidermoid carcinoma has received 40 cycles of Herceptin to date with a documented partial response. Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu. New agents are still needed. (C) 2003 Elsevier Ltd. All rights reserved. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Invest Drug Branch, CTEP, Rockville, MD 20892 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Yale Univ, Ctr Canc, New Haven, CT 06519 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Haddad, R (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, SW430G,44 Binney St, Boston, MA 02115 USA. NR 17 TC 110 Z9 112 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD OCT PY 2003 VL 39 IS 7 BP 724 EP 727 DI 10.1016/S1368-8375(03)00097-6 PG 4 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 721BC UT WOS:000185296300012 PM 12907212 ER PT J AU Jaffe, CL Dwyer, DM AF Jaffe, CL Dwyer, DM TI Extracellular release of the surface metalloprotease, gp63, from Leishmania and insect trypanosomatids SO PARASITOLOGY RESEARCH LA English DT Article ID SECRETED ACID-PHOSPHATASE; PROTEASE GP63; HERPETOMONAS-SAMUELPESSOAI; VISCERAL LEISHMANIASIS; DONOVANI PROMASTIGOTES; CRITHIDIA-FASCICULATA; SANDFLY VECTOR; GENE FAMILY; PROTEINS; GLYCOPROTEINS AB Protease activity was found in spent culture medium collected from Leishmania donovani, L. mexicana, L. major, as well as the insect trypanosomatids, Crithidia luciliae and Leptomonas seymouri. Released protease activity increased linearly over time and was correlated to promastigote density. In SDS-PAGE, zymogram gels showed that the protease's molecular weight ranged from 43-100 kDa. Spent culture medium proteases were blocked by the metallo-protease inhibitors, 1,10-phenanthroline and Z-Tyr-Leu-NHOH, but not by bestatin, leupeptin, ABESF, pepstatin A, E-64 or aprotinin. Monoclonal and/or polyclonal antibodies to the leishmanial gp63 reacted with the released Crithidia, Leptomonas, L. major and L. donovani proteases. Cell surface biotinylation and immune precipitation using gp63-specific antibodies showed that >34% of the released protease originated from the surface. Antibodies against the Trypanosoma brucei variable surface glycoprotein cross-reactive determinant (CRD) did not recognize this activity, suggesting that the gp63 is not cleaved from the cell surface by a parasite phospholipase, but is released by an alternative mechanism. C1 NIAID, Cell Biol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, CL (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Parasitol, POB 12272, IL-91220 Jerusalem, Israel. NR 48 TC 32 Z9 34 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0932-0113 J9 PARASITOL RES JI Parasitol. Res. PD OCT PY 2003 VL 91 IS 3 BP 229 EP 237 DI 10.1007/s00436-003-0960-0 PG 9 WC Parasitology SC Parasitology GA 726MH UT WOS:000185602500007 PM 12923634 ER PT J AU Butter, EM Wynn, J Mulick, JA AF Butter, EM Wynn, J Mulick, JA TI Early intervention critical to autism treatment SO PEDIATRIC ANNALS LA English DT Article ID INTENSIVE BEHAVIORAL TREATMENT; CHILDREN; DIAGNOSIS; DISORDER C1 Ohio State Univ, Nisonger Ctr Dev Disabil, NIMH, Res Units Pediat Psychopharmacol Autism Network, Columbus, OH 43210 USA. Childrens Hosp, Comprehens Autism Ctr, Intens Behav Intervent Clin, Columbus, OH 43205 USA. RP Butter, EM (reprint author), Childrens Hosp, Dept Psychol, 700 Childrens Dr, Columbus, OH 43205 USA. NR 19 TC 23 Z9 23 U1 2 U2 8 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0090-4481 J9 PEDIATR ANN JI Pediatr. Annu. PD OCT PY 2003 VL 32 IS 10 BP 677 EP 684 PG 8 WC Pediatrics SC Pediatrics GA 733AN UT WOS:000185977900007 PM 14606218 ER PT J AU Nelson, KB Grether, JK Dambrosia, JM AF Nelson, KB Grether, JK Dambrosia, JM TI Untitled - Response SO PEDIATRIC RESEARCH LA English DT Letter ID CEREBRAL-PALSY C1 NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. Calif Birth Defects Monitoring Program, Oakland, CA 94612 USA. Calif Dept Hlth Serv, Environm Hlth Invest Branch, Oakland, CA 94612 USA. NINDS, Biostat Branch, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2003 VL 54 IS 4 BP 556 EP 556 DI 10.1203/01.PDR.0000084289.17766.47 PG 1 WC Pediatrics SC Pediatrics GA 725QH UT WOS:000185553500025 ER PT J AU Oh, W Tyson, JE Fanaroff, AA Vohr, BR Perritt, R Stoll, BJ Ehrenkranz, RA Carlo, WA Shankaran, S Poole, K Wright, LL AF Oh, W Tyson, JE Fanaroff, AA Vohr, BR Perritt, R Stoll, BJ Ehrenkranz, RA Carlo, WA Shankaran, S Poole, K Wright, LL CA Natl Inst Child Hlth Human Dev Neo TI Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants SO PEDIATRICS LA English DT Article DE serum bilirubin; hyperbilirubinemia; extremely low birth weight infant; neurodevelopmental outcome ID BLOOD-BRAIN-BARRIER; PREMATURE-INFANTS; NATIONAL-INSTITUTE; CHILD-HEALTH; ANTIOXIDANT ACTIVITY; BOUND BILIRUBIN; NEWBORN-INFANTS; HYPERBILIRUBINEMIA; PHOTOTHERAPY; KERNICTERUS AB Objective. To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. Methods. A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification. Results. The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids ( odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI. Conclusions. PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue. C1 Brown Univ, Women & Infants Hosp, Providence, RI 02905 USA. Univ Texas, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Alabama, Birmingham, AL USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Emory Univ, Atlanta, GA 30322 USA. Wayne State Univ, Detroit, MI USA. Yale Univ, New Haven, CT USA. NICHHD, Rockville, MD USA. RP Oh, W (reprint author), Brown Univ, Women & Infants Hosp, 101 Dudley St, Providence, RI 02905 USA. FU NICHD NIH HHS [U01 HD36790, U10 HD21385, U10 HD34167, U10 HD27880, U10 HD27871, U10 HD34216, U10 HD27904, U10 HD27881, U10 HD21397, U10 HD21373, U10 HD21364, U10 HD21415, U10 HD27853, U10 HD27851] NR 41 TC 72 Z9 74 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT 1 PY 2003 VL 112 IS 4 BP 773 EP 779 DI 10.1542/peds.112.4.773 PG 7 WC Pediatrics SC Pediatrics GA 727NV UT WOS:000185665700016 PM 14523165 ER PT J AU Cheng, TL Schwarz, D Brenner, RA Wright, JL Fields, CB O'Donnell, R Rhee, P Scheidt, PC AF Cheng, TL Schwarz, D Brenner, RA Wright, JL Fields, CB O'Donnell, R Rhee, P Scheidt, PC TI Adolescent assault injury: Risk and protective factors and locations of contact for intervention SO PEDIATRICS LA English DT Article DE adolescent injury; violence; assault; case-control studies ID COMMUNITY VIOLENCE PROJECT; URBAN BLACK-ADOLESCENTS; HIGH-SCHOOL-STUDENTS; YOUTH VIOLENCE; SUBSTANCE USE; SELF-REPORTS; HEALTH-RISK; BEHAVIOR; TELEPHONE; EPIDEMIOLOGY AB Background. Violence is a large contributor to morbidity and mortality among adolescents. Most studies assessing markers for violent injury are cross-sectional. To guide intervention, we conducted a case-control study to explore factors associated with assault injury and locations to reach at-risk adolescents. Objective. 1) To assess risk and protective factors for adolescent assault injury compared with 2 control groups of youth with unintentional injuries and noninjury complaints presenting to the emergency department and 2) to assess locations of contact with assault-injured youth for prevention programs. Methods. Face-to-face and phone interviews were conducted with systematic samples of youth aged 12 to 19 years presenting to the emergency department with assault injury, unintentional injury, and noninjury complaints. Youth with intentional injuries were matched to youth in the 2 control groups on age +/- 1 year, gender, race, and residency. Results. One hundred forty-seven 147 assault-injured youth completed interviews. One hundred thirty-three assault-injured youth were matched to 133 unintentionally injured and 133 noninjured youth presenting to the emergency department. Compared with the 2 control groups, assault-injured youth were more likely to have had more fights in the past year (odds ratio [OR]: 3.91; 95% confidence interval [CI]: 2.02, 7.58; OR: 4.00; 95% CI: 2.23, 7.18) and fights requiring medical treatment (OR: 35.49; 95% CI: 8.71, 144.68; OR: 80.00; 95% CI: 11.13, 574.80). Eighty percent of assault-injured youth had been in 1 or more fights in the last 12 months compared with 55% and 46% in unintentional and noninjured controls, respectively. Assault-injured youth were more likely to have had previous weapon injuries (OR: 9.50; 95% CI: 3.39, 26.6; OR: 8.50; 95% CI: 3.02, 23.95) and have seen someone shot (OR: 2.00; 95% CI 1.12, 3.58; OR: 2.00; 95% CI: 1.12, 3.58). Eighty-six percent of assault-injured youth had a regular health care provider with 82% reporting a visit within the last year. There were no differences between cases and controls with regard to physician contact, extracurricular activity involvement, school or church attendance, police contact, weapon access or weapon-carrying, or witnessing nonweapon-related violence. Conclusions. Fighting was common among all groups. Assault-injured youth were more likely to have had previous weapon injuries and were high-risk for future injury. Past fights, past fight injuries, and seeing someone else shot were markers associated with assault injury. Health providers do have access to at-risk teens for clinical risk assessment and intervention. C1 Childrens Natl Med Ctr, Dept Gen Pediat & Adolescent Med, Washington, DC 20010 USA. Childrens Res Inst, Washington, DC USA. George Washington Univ, Sch Med, Washington, DC USA. Childrens Natl Med Ctr, Dept Emergency Med, Washington, DC 20010 USA. NICHHD, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. MedSTAR, Dept Trauma Surg, Washington, DC USA. RP Cheng, TL (reprint author), 9616 Accord Dr, Potomac, MD 20854 USA. FU ODCDC CDC HHS [R49/CCR331657]; PHS HHS [R40MC00174] NR 44 TC 37 Z9 37 U1 2 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT 1 PY 2003 VL 112 IS 4 BP 931 EP 938 DI 10.1542/peds.112.4.931 PG 8 WC Pediatrics SC Pediatrics GA 727NV UT WOS:000185665700039 PM 14523188 ER PT J AU Tarasov, SG Casas-Finet, JR Cholody, WM Kosakowska-Cholody, T Gryczynski, ZK Michejda, CJ AF Tarasov, SG Casas-Finet, JR Cholody, WM Kosakowska-Cholody, T Gryczynski, ZK Michejda, CJ TI Bisimidazoacridones: 2. Steady-state and time-resolved fluorescence studies of their diverse interactions with DNA SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID MINOR-GROOVE; ACRIDINE-DERIVATIVES; BINDING-PROPERTIES; CYANINE DYES; INTERCALATION; CONFORMATION; DRUGS; ACID; RNA; IMIDAZOACRIDINONES AB Several bisimidazoacridones (BIA) are potent, selective antineoplastic agents, whereas others have potent antihuman immunodeficiency virus activity. BIA are bifunctional agents that consist of two imidazoacridone (TA) chromophores held together by various linkers. Interaction of BIA with DNA has been postulated to be required for their biological activity. Fluorescence data on free and bound BIA suggest that the binding of BIA, and similar drugs to DNA is driven by a transfer of hydrophobic molecules from aqueous media to the more amphiphilic DNA environment. Binding to DNA was sensitive to sequence and depended on the length and rigidity of the linker. Time-resolved fluorescence measurements showed that BIA adopt an extended conformation upon binding and that all of the molecules are tightly associated with DNA. Gel-shift and melting assays indicated that one of the aromatic residues of BIA is intercalated, whereas the other, together with a linker, resides in a groove, probably the minor groove. A continuum of structures may be possible where intercalation and classical minor groove binding are limiting structures. In general, the hypothesis for the mechanism of action of BIA wherein the unintercallated residue, accessible for additional interactions, captures a critical protein involved in repair or transcription, is consistent with this model. C1 NCI, Mol Aspect Drug Design Sect, Struct Biophys Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. Univ Maryland, Sch Med, Ctr Fluorescence Spect, Baltimore, MD 21201 USA. RP Tarasov, SG (reprint author), NCI, Mol Aspect Drug Design Sect, Struct Biophys Lab, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 41 TC 11 Z9 12 U1 0 U2 4 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD OCT PY 2003 VL 78 IS 4 BP 313 EP 322 DI 10.1562/0031-8655(2003)078<0313:BSATFS>2.0.CO;2 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 734YQ UT WOS:000186085900001 PM 14626657 ER PT J AU Krieg, RC Messmann, H Schlottmann, K Endlicher, E Seeger, S Scholmerich, J Knuechel, R AF Krieg, RC Messmann, H Schlottmann, K Endlicher, E Seeger, S Scholmerich, J Knuechel, R TI Intracellular localization is a cofactor for the phototoxicity of protoporphyrin IX in the gastrointestinal tract: In vitro study SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article; Proceedings Paper CT Digestive Disease Week/102nd Annual Meeting of the American-Gastroenterological-Association CY MAY 20-23, 2001 CL ATLANTA, GEORGIA SP Amer Gastroenterol Assoc ID ENDOSCOPIC FLUORESCENCE DETECTION; PHOTODYNAMIC THERAPY; 5-AMINOLEVULINIC ACID; INDUCED APOPTOSIS; CELL-LINES; INTEGRIN EXPRESSION; BARRETTS-ESOPHAGUS; SENSITIZATION; DYSPLASIA; ADHESION AB Photodynamic therapy (PDT) is a new treatment modality for solid tumors as well as for flat lesions of the gastrointestinal tract. Although the use of 5-aminolevulinic acid-induced protoporphyrin IX (PPIX) shows important advantages over other photosensitizers, the main mechanisms of phototoxicity induced are still poorly understood. Three human colon carcinoma cell lines with variable degrees of differentiation and a normal colon fibroblast cell line were used to generate a suitable in vitro model for investigation of photosensitizer concentration as well as the applied light dose. Also, the effects of intracellular photosensitizer localization on efficiency of PDT were examined, and cellular parameters after PDT (morphology, mitochondrial transmembrane potential, membrane integrity and DNA fragmentation) were analyzed to distinguish between PDT-induced apoptosis from necrosis. The fibroblast cell line was less affected by phototoxicity than the tumor cells to a variable degree. Well-differentiated tumor cells showed higher toxicity than less-differentiated cells. After irradiation, cell lines with cytosolic or mitochondrial PPIX localization indicate a loss of mitochondrial transmembrane potential resulting in growth arrest, whereas membrane-bound PPIX induces a loss of membrane integrity and consequent necrosis. Although the absolute amount of intracellular photosensitizer concentration plays the main determining role for PDT efficiency, data indicate that intracellular localization has additional effects on the mode of cell damage. C1 NCI, NIH, Bethesda, MD 20892 USA. Klinikum Augsburg, Dept Internal Med 3, Augsburg, Germany. Univ Regensburg, Dept Internal Med 1, D-8400 Regensburg, Germany. Univ Zurich, Inst Phys Chem, CH-8057 Zurich, Switzerland. Univ Hosp Aachen, Rhein Westfal TH Aachen, Inst Pathol, D-52062 Aachen, Germany. RP Knuechel, R (reprint author), Univ Regensburg, Inst Pathol, Franz Josef Str Allee 11, D-93042 Regensburg, Germany. NR 33 TC 14 Z9 15 U1 0 U2 3 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD OCT PY 2003 VL 78 IS 4 BP 393 EP 399 DI 10.1562/0031-8655(2003)078<0393:ILIACF>2.0.CO;2 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 734YQ UT WOS:000186085900012 PM 14626668 ER PT J AU Insel, TR Volkow, ND Li, TK Battey, JF Landis, SC AF Insel, TR Volkow, ND Li, TK Battey, JF Landis, SC TI Neuroscience networks - Data-sharing in an information age SO PLOS BIOLOGY LA English DT Article C1 NIMH, NIH, Bethesda, MD 20892 USA. NIDA, NIH, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD 20892 USA. NIDOCD, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 5 TC 24 Z9 25 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD OCT PY 2003 VL 1 IS 1 BP 9 EP 11 AR e17 DI 10.1371/journal.pbio.0000017 PG 3 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 772GW UT WOS:000188834700003 PM 14551914 ER PT J AU Vannier, MW Staab, EV Clarke, LP AF Vannier, MW Staab, EV Clarke, LP TI Matching clinical and biological needs with emerging imaging technologies SO PROCEEDINGS OF THE IEEE LA English DT Review DE databases; informatics; medical imaging ID HEALTH-CARE ENTERPRISE; GENOME ANATOMY PROJECT; SHARING PRIMARY DATA; HUMAN BRAIN PROJECT; TERMINOLOGIA ANATOMICA; INFORMATION-MANAGEMENT; MOLECULAR SIGNATURES; DIGITAL MAMMOGRAPHY; NEUROSCIENCE DATA; RESOURCE CENTER AB Acquisition, analysis, and integration of medical images with nonimage biomedical information are essential for research and clinical practice. Individualization of health care, assessment of disease risk, tailoring of therapies, and lifelong monitoring places extraordinary demands on emerging technologies in medical imaging, information management, and molecular medicine. To achieve the anticipated benefits in outcomes that new technology can deliver imaging informatics infrastructure and tools must be available to represent, store, integrate, and present the data in a useful manner Currently, images are not well integrated with other forms of biological knowledge. This paper outlines the clinical and research requirements for imaging, and identifies barriers to progress and links these needs with the current and future informatics technologies that may overcome them. C1 Univ Iowa, Iowa City, IA 52242 USA. NCI, Canc Imaging Program, NIH, Rockville, MD 20852 USA. RP Univ Iowa, Iowa City, IA 52242 USA. OI Vannier, Michael/0000-0001-9898-384X NR 151 TC 5 Z9 5 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9219 EI 1558-2256 J9 P IEEE JI Proc. IEEE PD OCT PY 2003 VL 91 IS 10 BP 1562 EP 1573 DI 10.1109/JPROC.2003.817866 PG 12 WC Engineering, Electrical & Electronic SC Engineering GA 722YP UT WOS:000185405900007 ER PT J AU Ozturk, C Derbyshire, JA McVeigh, ER AF Ozturk, C Derbyshire, JA McVeigh, ER TI Estimating motion from MRI data SO PROCEEDINGS OF THE IEEE LA English DT Review DE cardiac magnetic resonance; displacement encoding with stimulated echoes (DENSE); harmonic phase imaging (HARP); magnetic resonance imaging (MRI); magnetic resonance tagging; motion tracking; phase contrast magnetic resonance imaging; review ID NUCLEAR MAGNETIC-RESONANCE; REGIONAL MYOCARDIAL STRAIN; CEREBROSPINAL-FLUID FLOW; PHASE-CONTRAST MRI; LEFT-VENTRICLE; STIMULATED ECHOES; HUMAN-HEART; TAGGED MRI; 3-DIMENSIONAL MOTION; SPATIAL MODULATION AB Magnetic resonance imaging (MRI) is an ideal imaging modality to measure bloodflow and tissue motion. It provides excellent contrast between soft tissues, and images can be acquired at positions and orientations freely defined by the user From a temporal sequence of MR images, boundaries and edges of tissues can be tracked by image processing techniques. Additionally, MRI permits the source of the image signal to be manipulated. For example, temporary magnetic tags displaying a pattern of variable brightness may be placed in the object using MR saturation techniques, giving the user a known pattern to detect for motion tracking. The MRI signal is a modulated complex quantity, being derived from a rotating magnetic field in the form of an induced current. Well-defined patterns can also be introduced into the phase of the magnetization, and could be thought of as generalized tags. If the phase of each pixel is preserved during image reconstruction, relative phase shifts can be used to directly. encode displacement, velocity and acceleration. New methods for modeling motion fields from MRI have now found application in cardiovascular and other soft tissue imaging. In this review we shall describe the methods used for encoding, imaging, and modeling motion fields with MRI. C1 Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. NHLBI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. RP Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. EM ozturkc@nhlbi.nih.gov; jad11@nih.gov; emcveigh@bme.jhu.edu RI Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 NR 148 TC 24 Z9 24 U1 2 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9219 EI 1558-2256 J9 P IEEE JI Proc. IEEE PD OCT PY 2003 VL 91 IS 10 BP 1627 EP 1648 DI 10.1109/JPROC.2003.817872 PG 22 WC Engineering, Electrical & Electronic SC Engineering GA 722YP UT WOS:000185405900011 ER PT J AU Paruszewski, R Strupinska, M Rostafinska-Suchar, G Stables, JP AF Paruszewski, R Strupinska, M Rostafinska-Suchar, G Stables, JP TI Anticonvulsant activity of benzylamides of some amino acids and heterocyclic acids SO PROTEIN AND PEPTIDE LETTERS LA English DT Article DE anticonvulsants; N-methyle-Glu and N-methyl-Asp derivatives; heterocyclic acid derivaties ID DERIVATIVES; AGENTS; BUTYLOXYCARBONYL; ALA AB A series of new potential anticonvulsants have been synthesized. They are N-methyl benzylamides of N-methyl Asp and N-methyl Glu (R and S), benzylamides of some heterocyclic acids and their N-oxides and benzylamides of two heteroalicyclic acids. The obtained compounds were evaluated in the Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. C1 Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. NINDS, Epilepsy Branch, Rockville, MD 20852 USA. RP Paruszewski, R (reprint author), Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. NR 21 TC 14 Z9 15 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD OCT PY 2003 VL 10 IS 5 BP 475 EP 482 DI 10.2174/0929866033478636 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 725XY UT WOS:000185568700007 PM 14561136 ER PT J AU Krauss, J Arndt, MAE Martin, ACR Liu, HT Rybak, SM AF Krauss, J Arndt, MAE Martin, ACR Liu, HT Rybak, SM TI Specificity grafting of human antibody frameworks selected from a phage display library: generation of a highly stable humanized anti-CD22 single-chain Fv fragment SO PROTEIN ENGINEERING LA English DT Article DE antibody humanization; CD22; human phage display library; single-chain Fv; stability ID VARIABLE DOMAINS; MONOCLONAL-ANTIBODY; FLOW-CYTOMETRY; STABILITY; AFFINITY; ANTIGENS; THERAPY; BINDING; STABILIZATION; CONFORMATION AB A prerequisite for the enrichment of antibodies screened from phage display libraries is their stable expression on a phage during multiple selection rounds. Thus, if stringent panning procedures are employed, selection is simultaneously driven by antigen affinity, stability and solubility. To take advantage of robust pre-selected scaffolds of such molecules, we grafted single-chain Fv (scFv) antibodies, previously isolated from a human phage display library after multiple rounds of in vitro panning on tumor cells, with the specificity of the clinically established murine monoclonal anti-CD22 antibody RFB4. We show that a panel of grafted scFvs retained the specificity of the murine monoclonal antibody, bound to the target antigen with high affinity (6.4-9.6 nM), and exhibited exceptional biophysical stability with retention of 89-93% of the initial binding activity after 6 days of incubation in human serum at 37degreesC. Selection of stable human scaffolds with high sequence identity to both the human germline and the rodent frameworks required only a small number of murine residues to be retained within the human frameworks in order to maintain the structural integrity of the antigen binding site. We expect this approach may be applicable for the rapid generation of highly stable humanized antibodies with low immunogenic potential. C1 NCI, Frederick, MD 21702 USA. Univ Reading, Sch Anim & Microbial Sci, Reading RG6 6AJ, Berks, England. RP Rybak, SM (reprint author), NCI, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 39 TC 28 Z9 28 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD OCT PY 2003 VL 16 IS 10 BP 753 EP 759 DI 10.1093/protein/gzg096 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 743QL UT WOS:000186585000007 PM 14600205 ER PT J AU Ingr, M Uhlikova, T Strisovsky, K Majerova, E Konvalinka, J AF Ingr, M Uhlikova, T Strisovsky, K Majerova, E Konvalinka, J TI Kinetics of the dimerization of retroviral proteases: The "fireman's grip" and dimerization SO PROTEIN SCIENCE LA English DT Article DE retroviral protease; dimerization; HIV protease; fireman's grip; kinetic assay; fluorescence; pressure ID HUMAN-IMMUNODEFICIENCY-VIRUS; MYELOBLASTOSIS ASSOCIATED VIRUS; HIV-1 PROTEASE; ACTIVE-SITE; ASPARTIC PROTEINASE; FOLDED MONOMER; DIMER; DISSOCIATION; SPECIFICITY; INFECTIVITY AB All retroviral proteases belong to the family of aspartic proteases. They are active as homodimers, each unit contributing one catalytic aspartate to the active site dyad. An important feature of all aspartic proteases is a conserved complex scaffold of hydrogen bonds supporting the active site, called the "fireman's grip," which involves the hydroxyl groups of two threonine (serine) residues in the active site Asp-Thr(Ser)-Gly triplets. It was shown previously that the fireman's grip is indispensable for the dimer stability of HIV protease. The retroviral proteases harboring Ser in their active site triplet are less active and, under natural conditions, are expressed in higher enzyme/substrate ratio than those having Asp-Thr-Gly triplet. To analyze whether this observation can be attributed to the different influence of Thr or Ser on dimerization, we prepared two pairs of the wild-type and mutant proteases from HIV and myeloblastosis-associated virus harboring either Ser or Thr in their Asp-Thr(Ser)-Gly triplet. The equilibrium dimerization constants differed by an order of magnitude within the relevant pairs. The proteases with Thr in their active site triplets were found to be -10 times more thermodynamically stable. The dimer association contributes to this difference more than does the dissociation. We propose that the fireman's grip might be important in the initial phases of dimer formation to help properly orientate the two subunits of a retroviral protease. The methyl group of threonine might contribute significantly to fixing such an intermediate conformation. C1 Acad Sci Czech Republ, Inst Organ Chem & Biochem, CR-16610 Prague 6, Czech Republic. Charles Univ, Sch Sci, Dept Biochem, Prague 12843 2, Czech Republic. NCI, Frederick Canc Res & Dev Ctr, SAIC, Biol Testing Branch, Frederick, MD 21784 USA. RP Konvalinka, J (reprint author), Acad Sci Czech Republ, Inst Organ Chem & Biochem, Flemingovo Nam 2, CR-16610 Prague 6, Czech Republic. RI Konvalinka, Jan/G-7518-2014; Ingr, Marek/E-2478-2015; OI Ingr, Marek/0000-0001-6741-9955; Konvalinka, Jan/0000-0003-0695-9266 NR 44 TC 18 Z9 18 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2003 VL 12 IS 10 BP 2173 EP 2182 DI 10.1110/ps.03171903 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723GW UT WOS:000185425500006 PM 14500875 ER PT J AU Dobrodumov, A Gronenborn, AM AF Dobrodumov, A Gronenborn, AM TI Filtering and selection of structural models: Combining docking and NMR SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE protein-protein complexes; domain interfaces; NMR; residual dipolar couplings ID RESIDUAL DIPOLAR COUPLINGS; PHOSPHOCARRIER PROTEIN HPR; LIQUID-CRYSTALLINE PHASE; N-TERMINAL DOMAIN; MACROMOLECULAR STRUCTURE DETERMINATION; ESCHERICHIA-COLI THIOREDOXIN; ENZYME-I; PHOSPHOTRANSFERASE SYSTEM; SOFT-DOCKING; RESOLUTION STRUCTURE AB It is generally accepted that protein structures are more conserved than protein sequences, and 3D structure determination by computer simulations have become an important necessity in the postgenomic area. Despite major successes no robust, fast, and automated ab initio prediction algorithms for deriving accurate folds of single polypeptide chains or structures of intermolecular complexes exist at present. Here we present a methodology that uses selection and filtering of structural models generated by docking of known substructures such as individual proteins or domains through easily obtainable experimental NMR constraints. In particular, residual dipolar couplings and chemical shift mapping are used. Heuristic inclusion of chemical or biochemical knowledge about point-to-point interactions is combined in our selection strategy with the NMR data and commonly used contact potentials. We demonstrate the approach for the determination of protein-protein complexes using the EIN/HPr complex as an example and for establishing the domain-domain orientation in a chimeric protein, the recently determined hybrid human-Escherichia. coli thioredoxin. (C) 2003 WiIey-Liss, Inc. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Phys Chem Lab, NIH, Bldg 5,Rm 130, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 45 TC 26 Z9 27 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD OCT 1 PY 2003 VL 53 IS 1 BP 18 EP 32 DI 10.1002/prot.10439 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717QK UT WOS:000185100700003 PM 12945046 ER PT J AU Elvevag, B McCormack, T Gilbert, A Brown, GDA Weinberger, DR Goldberg, TE AF Elvevag, B McCormack, T Gilbert, A Brown, GDA Weinberger, DR Goldberg, TE TI Duration judgements in patients with schizophrenia SO PSYCHOLOGICAL MEDICINE LA English DT Review ID SUBJECTIVE TIME-ESTIMATION; FRONTAL-LOBE LESIONS; SHORT-TERM-MEMORY; TEMPORAL DISCRIMINATION; INTERNAL CLOCK; PARKINSONS-DISEASE; COGNITIVE DYSMETRIA; MONOZYGOTIC TWINS; WORKING-MEMORY; D-AMPHETAMINE AB Background. The ability to encode time cues underlies many cognitive processes. In the light of schizophrenic patients' compromised cognitive abilities in a variety of domains, it is noteworthy that there are numerous reports of these patients displaying impaired timing abilities. However, the timing intervals that patients have been evaluated on in prior studies vary considerably in magnitude (e.g. 1 s, 1 min, 1 h etc.). Method. In order to obviate differences in abilities in chronometric counting and place minimal demands on cognitive processing, we chose tasks that involve making judgements about brief durations of time (< 1 s). Results. On a temporal generalization task, patients were less accurate than controls at recognizing a standard duration. The performance of patients was also significantly different from controls on a temporal bisection task, in which participants categorized durations as short or long. Although time estimation may be closely intertwined with working memory, patients' working memory as measured by the digit span task did not correlate significantly with their performance on the duration judgement tasks. Moreover, lowered intelligence scores could not completely account for the findings. Conclusions. We take these results to suggest that patients with schizophrenia are less accurate at estimating brief time periods. These deficits may reflect dysfunction of biopsychological timing processes. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Warwick, Dept Psychol, Coventry CV4 7AL, W Midlands, England. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4S235, Bethesda, MD 20892 USA. RI McCormack, Teresa/C-3068-2013 NR 111 TC 87 Z9 89 U1 1 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD OCT PY 2003 VL 33 IS 7 BP 1249 EP 1261 DI 10.1017/S0033291703008122 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 739FL UT WOS:000186334000012 PM 14580079 ER PT J AU Katz, JL Chausmer, AL Elmer, GI Rubinstein, M Low, MJ Grandy, DK AF Katz, JL Chausmer, AL Elmer, GI Rubinstein, M Low, MJ Grandy, DK TI Cocaine-induced locomotor activity and cocaine discrimination in dopamine D-4 receptor mutant mice SO PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT Meeting of the International-Union-of-Pharmacology (IUPHAR) CY JUL 10-14, 2002 CL PORTLAND, OR SP Int Union Pharmacol DE cocaine; locomotor activity; discrimination; dopamine receptors; mouse ID NOVELTY SEEKING; RATS; ASSOCIATION; ANTAGONIST; L-745,870; STIMULI; ALLELES; GENE AB Rationale. Previous studies have found a role for dopamine D-2-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D-2, D-3 and D-4 dopamine receptors, the roles of these specific receptors remain unclear. Objectives. The roles of specific dopamine D-4 receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D-4 receptor knockout (DA D4R KO) and wild-type (WT) mice. Methods. The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D-2-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype. Results. As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D4R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D4R KO mice (ED50 value=0.50 mg/kg) compared to their WT littermates (ED50 value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D4R KO and WT mice, though the shift was greater for the DA D4R KO mice. Conclusions. The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D4R KO mice, and further suggest a role of the DA D4R in vulnerability to stimulant abuse. C1 NIDA, Med Discovery Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. UBA, CONICET, Inst Invest Ingn Genet & Biol Mol, Buenos Aires, DF, Argentina. Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. RP Katz, JL (reprint author), NIDA, Med Discovery Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU NIDA NIH HHS [DA12062] NR 24 TC 28 Z9 28 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2003 VL 170 IS 1 BP 108 EP 114 DI 10.1007/s00213-003-1513-z PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 732YF UT WOS:000185972600014 PM 12783155 ER PT J AU Torchia, DA Ishima, R AF Torchia, DA Ishima, R TI Molecular structure and dynamics of proteins in solution: Insights derived from high-resolution NMR approaches SO PURE AND APPLIED CHEMISTRY LA English DT Article; Proceedings Paper CT IUPAC Polymer Conference on Mission and Challenges of Polymer Science and Technology (IUPAC PC2002) CY DEC 02-05, 2002 CL KYOTO, JAPAN ID MAGNETIC-RESONANCE SPECTROSCOPY; ACANTHAMOEBA PROFILIN-I; SIDE-CHAIN RESONANCES; MODEL-FREE APPROACH; HIV-1 PROTEASE; SECONDARY STRUCTURE; CHEMICAL-SHIFT; DIPOLAR COUPLINGS; TIME-SCALE; TRANSVERSE RELAXATION AB This article reviews heteronuclear NMR techniques that are used to characterize the 3D structures and internal molecular dynamics of proteins in solution. Applications to several proteins that have been studied in our laboratory are presented. Topics discussed include sequential assignments, the use of nuclear Overhauser enhancement spectroscopy (NOESY) and residual dipolar coupling restraints to determine protein structure, and the use of relaxation measurements to obtain information about protein internal motions. Also discussed are recent computational approaches directed at increasing the efficiency of structure determination, as well as new methods for studying large proteins. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NR 53 TC 7 Z9 7 U1 0 U2 5 PU INT UNION PURE APPLIED CHEMISTRY PI RES TRIANGLE PK PA 104 TW ALEXANDER DR, PO BOX 13757, RES TRIANGLE PK, NC 27709-3757 USA SN 0033-4545 J9 PURE APPL CHEM JI Pure Appl. Chem. PD OCT PY 2003 VL 75 IS 10 BP 1371 EP 1381 DI 10.1351/pac200375101371 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 736LK UT WOS:000186172100003 ER PT J AU Preston, DL Shimizu, Y Pierce, DA Suyama, A Mabuchi, K AF Preston, DL Shimizu, Y Pierce, DA Suyama, A Mabuchi, K TI Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997 SO RADIATION RESEARCH LA English DT Article ID NUCLEAR INDUSTRY WORKERS; B SURFACE-ANTIGEN; BREAST-CANCER; IONIZING-RADIATION; MYOCARDIAL-INFARCTION; TUBERCULOSIS PATIENTS; FLUOROSCOPY COHORT; GENERAL MUTAGENS; HODGKINS-DISEASE; POOLED ANALYSIS AB This continues the series of general reports on mortality in the cohort of atomic bomb survivors followed up by the Radiation Effects Research Foundation. This cohort includes 86,572 people with individual dose estimates, 60% of whom have doses of at least 5 mSv. We consider mortality for solid cancer and for noncancer diseases with 7 additional years of follow-up. There have been 9,335 deaths from solid cancer and 31,881 deaths from noncancer diseases during the 47-year follow-up. Of these, 19% of the solid cancer and 15% of the noncancer deaths occurred during the latest 7 years. We estimate that about 440 (5%) of the solid cancer deaths and 250 (0.8%) of the noncancer deaths were associated with the radiation exposure. The excess solid cancer risks appear to be linear in dose even for doses in the 0 to 150-mSv range. While excess rates for radiation-related cancers increase throughout the study period, a new finding is that relative risks decline with increasing attained age, as well as being highest for those exposed as children as noted previously. A useful representative value is that for those exposed at age 30 the solid cancer risk is elevated by 47% per sievert at age 70. There is no significant city difference in either the relative or absolute excess solid cancer risk. Site-specific analyses highlight the difficulties, and need for caution, in distinguishing between site-specific relative risks. These analyses also provide insight into the difficulties in interpretation and generalization of LSS estimates of age-at-exposure effects. The evidence for radiation effects on noncancer mortality remains strong, with risks elevated by about 14% per sievert during the last 30 years of follow-up. Statistically significant increases are seen for heart disease, stroke, digestive diseases, and respiratory diseases. The noncancer data are consistent with some non-linearity in the dose response owing to the substantial uncertainties in the data. There is no direct evidence of radiation effects for doses less than about 0.5 Sv. While there are no statistically significant variations in noncancer relative risks with age, age at exposure, or sex, the estimated effects are comparable to those seen for cancer. Lifetime risk summaries are used to examine uncertainties of the LSS noncancer disease findings. (C) 2003 by Radiation Research Society. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Nagasaki, Japan. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Koen, Hiroshima 7320815, Japan. EM preston@rerf.or.jp NR 87 TC 634 Z9 682 U1 2 U2 19 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2003 VL 160 IS 4 BP 381 EP 407 DI 10.1667/RR3049 PG 27 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 723GL UT WOS:000185424300001 PM 12968934 ER PT J AU Summers, RM AF Summers, RM TI Road maps for advancement of radiologic computer-aided detection in the 21st century SO RADIOLOGY LA English DT Editorial Material DE computers, diagnostic aid; diagnostic radiology; editorials; picture archiving and communication system (PACs); quality assurance ID DIAGNOSIS SYSTEM; PULMONARY NODULES; CHEST RADIOGRAPHS; SPIRAL CT; IMAGES C1 Warren Grant Maguson Clin Ctr, Diagnost Radiol Dept, NIH, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), Warren Grant Maguson Clin Ctr, Diagnost Radiol Dept, NIH, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 17 TC 41 Z9 42 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD OCT PY 2003 VL 229 IS 1 BP 11 EP 13 DI 10.1148/radiol.2291030010 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 723GQ UT WOS:000185424900004 PM 14519863 ER PT J AU Srivastava, SK Csaky, KG AF Srivastava, SK Csaky, KG TI Identification of well-defined intrachoroidal neovascularization by high-speed indocyanine green angiography SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article ID CHOROIDAL NEOVASCULARIZATION; FEEDER VESSELS C1 NEI, NIH, Bethesda, MD 20892 USA. RP Csaky, KG (reprint author), NEI, NIH, Bldg 10,Room 10N119, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD OCT PY 2003 VL 23 IS 5 BP 712 EP 714 DI 10.1097/00006982-200310000-00019 PG 3 WC Ophthalmology SC Ophthalmology GA 736MM UT WOS:000186174600019 PM 14574261 ER PT J AU Elvevag, B Storms, G AF Elvevag, B Storms, G TI Scaling and clustering in the study of semantic disruptions in patients with schizophrenia: a re-evaluation SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; patient; semantics ID FITTING ADDITIVE TREES; THOUGHT-DISORDER; ALZHEIMERS-DISEASE; PROXIMITY DATA; NETWORK; MEMORY; IMPAIRMENT; FLUENCY; SIMILARITY; ALGORITHM AB Some recent studies of semantics in schizophrenia have employed multidimensional scaling and clustering techniques to analyse verbal fluency and triadic comparison data. The conclusions have been: (i) patients generate fewer words in fluency tasks and display more variable similarity groupings of words in triadic tasks, and (ii) this is due to deficits in semantics. We analysed data from both tasks. On the verbal fluency task, patients produced significantly fewer responses than controls. The results also showed little patient-specific inter-individual consistency. Similarly, for triadic comparison data, we did not find much patient-specific inter-individual consistency. When correlating patients' results at different measurement times with means of controls, the data of individual patients (at either of the two measurement times) were not predicted better from their data at the other measurement time than from controls. This latter finding suggests little patient-specific intra-individual consistency and, thus, pleads against idiosyncratic semantic deficits. Our findings do not refute the hypothesis that schizophrenia is associated with semantic disruptions. However, our results demonstrate that because of severe statistical restrictions and requirements associated with some scaling and clustering techniques, these methods may not be as useful in this enterprise as previously thought. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Leuven, Dept Psychol, B-3000 Louvain, Belgium. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4S235,MSC 1379, Bethesda, MD 20892 USA. EM elvevaab@intra.nimh.nih.gov; gert.storms@psy.kuleuven.ac.be NR 43 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD OCT 1 PY 2003 VL 63 IS 3 BP 237 EP 246 DI 10.1016/S0920-9964(02)00331-6 PG 10 WC Psychiatry SC Psychiatry GA 722LT UT WOS:000185376800004 PM 12957703 ER PT J AU Fiedler, TJ AF Fiedler, TJ TI Commentary on 'barking up the wrong tree? Industry funding of academic research' SO SCIENCE AND ENGINEERING ETHICS LA English DT Editorial Material C1 Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Rosenstiel Sch Marine & Atmospher Sci, Coral Gables, FL 33124 USA. RP Fiedler, TJ (reprint author), Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Rosenstiel Sch Marine & Atmospher Sci, Coral Gables, FL 33124 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OPRAGEN PUBLICATIONS PI GUILDFORD PA PO BOX 54, GUILDFORD GU1 2YF, SURREY, ENGLAND SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD OCT PY 2003 VL 9 IS 4 BP 578 EP 582 PG 5 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 745BJ UT WOS:000186667100013 ER PT J AU Meng, QH Zhou, LX Cao, JP Gao, B Shao, RG Li, JY Fan, SJ AF Meng, QH Zhou, LX Cao, JP Gao, B Shao, RG Li, JY Fan, SJ TI Identification and function of coactivator of estrogen receptor: ERIAP SO SCIENCE IN CHINA SERIES C-LIFE SCIENCES LA English DT Article DE estrogen receptor; breast cancer; new gene; ERIAP ID STEROID-HORMONE RECEPTORS; NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVATION; BRCA1 INHIBITION; BREAST-CANCER; ER-ALPHA; BINDING; LXXLL; BETA; RECRUITMENT AB Estrogen receptor (ER), one member of nuclear hormone receptor (NR) family, is an estrogen-dependent transcriptional factor that plays an important role in development, progression and treatment of breast cancer. Transcriptional co-factors (co-activators and co-repressors) are critical for ER to transduce hormone and metabolic signaling to target genes. A number of functional and structural studies have elucidated the precise mechanisms of co-activator interaction with the ligand-inducible activation domain in ER via one and several MILL motifs (where X is any amino acid) known as NR-Box. By the yeast two-hybrid system we have identified a novel ER-a interacting protein ERIAP (Estrogen Receptor Interacting and Activating Protein) which contains two consensus MILL motifs. ERIAP associated with ER-a in a ligand-dependent manner, as demonstrated by in vivo immunoprecipitation and in vitro GST capture assays. The two NR boxes were essential for ERIAP interaction with ER-a. Furthermore, ERIAP specifically enhanced ligand-mediated ER-a transcriptional activity in a dose-dependent fasion and increased the expression of estrogen-responsive gene pS2. Thus, our present findings indicate that ERIAP funcions as a new coactivator for ER-a transcriptional activity, which may play an important role in development and progression of breast cancer. C1 N Shore Long Isl Jewish Res Inst, Mol Oncol Lab, Manhasset, NY 11030 USA. Peking Univ, Beijing Canc Hosp, Dept Pathol, Beijing 100036, Peoples R China. Suzhou Univ, Sch Radiol & Publ Hlth, Suzhou 215007, Peoples R China. NIAAA, Div Liver Biol, NIH, Rockville, MD 20852 USA. Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China. RP Fan, SJ (reprint author), N Shore Long Isl Jewish Res Inst, Mol Oncol Lab, Manhasset, NY 11030 USA. NR 34 TC 0 Z9 0 U1 0 U2 1 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1006-9305 J9 SCI CHINA SER C JI Sci. China Ser. C-Life Sci. PD OCT PY 2003 VL 46 IS 5 BP 546 EP 558 DI 10.1360/03yc0062 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 729GE UT WOS:000185764100011 PM 19448995 ER PT J AU Masi, AT Chrousos, GP AF Masi, AT Chrousos, GP TI Polycystic ovarian syndrome and rheumatoid arthritis: Possible physiopathogenetic clues to hormonal influences on chronic inflammation SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Editorial Material ID ADRENAL ANDROGEN; DEHYDROEPIANDROSTERONE-SULFATE; GLUCOCORTICOID DISSOCIATION; MICROVASCULAR SYSTEMS; PREGNANCY; ONSET; PERSPECTIVES; DISEASES; STEROIDS; SERUM C1 Univ Illinois, Coll Med, Dept Med, Peoria, IL 61605 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Masi, AT (reprint author), Univ Illinois, Coll Med, Dept Med, 1 Illini Dr, Peoria, IL 61605 USA. OI Masi, Alfonse/0000-0002-9695-6634 NR 32 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0049-0172 J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD OCT PY 2003 VL 33 IS 2 BP 67 EP 71 DI 10.1016/S0049-0172(02)70110-8 PG 5 WC Rheumatology SC Rheumatology GA 741GL UT WOS:000186450300001 PM 14625815 ER PT J AU Staudt, LM AF Staudt, LM TI Genomics in hematology: Introduction SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Ctr Canc Res, Metab Branch, 9000 Rockville Pike,Bldg 10,Room 4N114, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2003 VL 40 IS 4 BP 267 EP 267 DI 10.1053/S0037-1963(03)00204-X PG 1 WC Hematology SC Hematology GA 735UE UT WOS:000186132300001 ER PT J AU Wiestner, A Staudt, LM AF Wiestner, A Staudt, LM TI Towards molecular diagnosis and targeted therapy of lymphoid malignancies SO SEMINARS IN HEMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MANTLE-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; TRANSCRIPTION FACTOR XBP-1; GENE-EXPRESSION PROFILE; CD38 EXPRESSION; MESSENGER-RNA; B-CELLS; PROGNOSTIC-SIGNIFICANCE; IMMUNOGLOBULIN GENES C1 NCI, Metab Branch, CCR, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, CCR, NIH, Bldg 10,Room 4N114, Bethesda, MD 20892 USA. NR 80 TC 19 Z9 20 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2003 VL 40 IS 4 BP 296 EP 307 DI 10.1053/S0037-1963(03)00194-X PG 12 WC Hematology SC Hematology GA 735UE UT WOS:000186132300005 PM 14582080 ER PT J AU Chanock, S AF Chanock, S TI Genetic variation and hematology: Single-nucleotide polymorphisms, haplotypes, and complex disease SO SEMINARS IN HEMATOLOGY LA English DT Article ID MANNOSE-BINDING LECTIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; SICKLE-CELL-DISEASE; THIOPURINE METHYLTRANSFERASE ACTIVITY; CHRONIC GRANULOMATOUS-DISEASE; HUMAN-GENOME; CYSTIC-FIBROSIS; COMMON DISEASE; ENVIRONMENTAL-FACTORS; SEQUENCE VARIATION C1 NCI, Sect Genom Variat, Pediat Oncol Branch, Natl Canc Inst,Adv Technol Ctr,NIH, Bethesda, MD 20892 USA. NCI, Core Genotyping Facil, NIH, Bethesda, MD 20892 USA. RP Chanock, S (reprint author), NCI, Sect Genom Variat, Pediat Oncol Branch, Natl Canc Inst,Adv Technol Ctr,NIH, 8717 Grovemont Cir, Bethesda, MD 20892 USA. NR 77 TC 7 Z9 8 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2003 VL 40 IS 4 BP 321 EP 328 DI 10.1053/S0037-1963(03)00198-7 PG 8 WC Hematology SC Hematology GA 735UE UT WOS:000186132300007 PM 14582082 ER PT J AU Smith, RE AF Smith, RE TI A review of selective estrogen receptor modulators and national surgical adjuvant breast and bowel project clinical trials SO SEMINARS IN ONCOLOGY LA English DT Review ID ONCOLOGY TECHNOLOGY-ASSESSMENT; TAMOXIFEN THERAPY; RANDOMIZED TRIAL; CANCER PATIENTS; POSTMENOPAUSAL WOMEN; CONTRALATERAL BREAST; AROMATASE INHIBITORS; ENDOMETRIAL CANCER; PREVENTION; RISK C1 Natl Surg Adjuvant Breast & Bowel Project, Allegheny Ctr 4, Pittsburgh, PA 15212 USA. RP Smith, RE (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Allegheny Ctr 4, 5th Floor, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10-CA-37377, U10-CA-69974] NR 57 TC 9 Z9 11 U1 0 U2 18 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2003 VL 30 IS 5 SU 16 BP 4 EP 13 DI 10.1053/S0093-7754(03)00435-4 PG 10 WC Oncology SC Oncology GA 744PV UT WOS:000186641700002 PM 14613021 ER PT J AU Tan, AR Swain, SM AF Tan, AR Swain, SM TI Ongoing adjuvant trials with trastuzumab in breast cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID HER-2/NEU AMPLIFICATION; PHASE-II; HER2; HERCEPTIN; ONCOGENE; ANTIBODY; EFFICACY; SAFETY C1 NCI, Canc Therapeut Branch, Canc Res Ctr, Bethesda, MD 20889 USA. RP Tan, AR (reprint author), NCI, Canc Therapeut Branch, Canc Res Ctr, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 30 TC 29 Z9 29 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2003 VL 30 IS 5 SU 16 BP 54 EP 64 DI 10.1053/S0093-7754(03)00441-X PG 11 WC Oncology SC Oncology GA 744PV UT WOS:000186641700008 PM 14613027 ER PT J AU Mills, GB Kohn, E Lu, YL Eder, A Fang, XJ Wang, HW Bast, RC Gray, J Jaffe, R Hortobagyi, G AF Mills, GB Kohn, E Lu, YL Eder, A Fang, XJ Wang, HW Bast, RC Gray, J Jaffe, R Hortobagyi, G TI Linking molecular diagnostics to molecular therapeutics: Targeting the Pl3K pathway in breast cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID TUMOR-SUPPRESSOR GENE; ESTROGEN-RECEPTOR-ALPHA; INTEGRIN-LINKED KINASE; HUMAN PROSTATE-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; OVARIAN-CANCER; IN-VIVO; TYROSINE-PHOSPHATASE; PTEN/MMAC1 GENE C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Therapeut, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Med Breast Oncol, Div Med, Houston, TX 77030 USA. NCI, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Calif San Francisco, Ctr Canc, San Francisco, CA 94143 USA. Univ Calif San Francisco, Reprod Endocrinol Ctr, San Francisco, CA 94143 USA. RP Mills, GB (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Mol Therapeut, 1515 Holcombe Blvd,Box 317, Houston, TX 77030 USA. RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 FU NCI NIH HHS [CA82716] NR 96 TC 36 Z9 37 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2003 VL 30 IS 5 SU 16 BP 93 EP 104 DI 10.1053/S0093-7754(03)00444-5 PG 12 WC Oncology SC Oncology GA 744PV UT WOS:000186641700011 PM 14613030 ER PT J AU Hsieh, YH Howell, MR Gaydos, JC McKee, KT Quinn, TC Gaydos, CA AF Hsieh, YH Howell, MR Gaydos, JC McKee, KT Quinn, TC Gaydos, CA TI Preference among female army recruits for use of self-administrated vaginal swabs or urine to screen for Chlamydia trachomatis genital infections SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID LIGASE CHAIN-REACTION; NEISSERIA-GONORRHOEAE INFECTION; SEXUALLY-TRANSMITTED DISEASES; HUMAN-PAPILLOMAVIRUS; DNA AMPLIFICATION; REACTION ASSAY; WOMEN; DIAGNOSIS; SAMPLES; COLLECTION AB Background: Use of self-administered vaginal swabs (SAS) for the detection of Chlamydia trachomatis by nucleic acid amplification tests simplifies specimen collection and transport, especially for women in nonclinical settings. Goal: We investigated the preference and comfort level of military women for the collection of SAS, compared with urine, for the diagnosis of genital chlamydial infections. Study Design: During March through August 1999, female Army recruits in basic training at Fort Jackson, South Carolina, were invited to participate in the study. Participants were requested to complete a questionnaire after providing both first-void urine (FVU) and SAS specimens. Participant characteristics, preferences, and comfort levels were assessed using multivariate logistic regression. Results: From 4496 eligible female recruits, 1403 (31%) completed questionnaires and 1382 provided both specimens; 11.8% (166 of 1403) of participants were infected with chlamydia. The relative sensitivity and specificity of the C. trachomatis Ligase Chain Reaction test on SAS in 1382 matched pairs was 81.1% and 98.6%, respectively, using the test result on urine specimens as the comparison standard. Most of the participants (90.8%) reported that they felt comfortable collecting the FVU specimen, and 69.6% indicated that they felt comfortable collecting SAS. Either specimen collection type received high acceptability at home and in the field, and more women reported that they would collect FVU than reported they would collect SAS in the future (in the field: FVU: 79.4%, SAS: 68.8%, P < 0.001); at home: FVU: 90.9%, SAS: 82.9%, P < 0.001). When questioned about ease of use, 60.4% of women reported that urine was the easier method. Preferences for SAS were associated with being white and having had sexual risk behaviors in the past 3 months. Conclusion: A study of preferences for urine versus self-administered vaginal swabs for the detection of C. trachomatis in military women showed that women generally found SAS acceptable. SAS should be a feasible alternative to urine collection in situations in which specimen storage or transport is an issue. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD USA. Natl Cheng Kung Univ, Coll Med, Dept Publ Hlth, Tainan 70101, Taiwan. US Dept Def, Global Emerging Infect Surveillance & Response Sy, Silver Spring, MD USA. Womack Army Med Ctr, Ft Bragg, NC USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Gaydos, CA (reprint author), 1159 Ross,720 Rutland Ave, Baltimore, MD USA. RI Gaydos, Charlotte/E-9937-2010 NR 35 TC 43 Z9 46 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2003 VL 30 IS 10 BP 769 EP 773 DI 10.1097/01.OLQ.0000079048.11771.46 PG 5 WC Infectious Diseases SC Infectious Diseases GA 728LZ UT WOS:000185719800007 PM 14520176 ER PT J AU Warach, S AF Warach, S TI Measurement of the ischemic penumbra with MRI: It's about time SO STROKE LA English DT Editorial Material DE cerebral blood flow; magnetic resonance imaging; penumbra; randomized controlled trials ID ACUTE STROKE; DIFFUSION; THROMBOLYSIS C1 Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Warach, S (reprint author), Natl Inst Neurol Disorders & Stroke, 10 Ctr Dr,MSC 1063,Bldg 10,Rm B1D733, Bethesda, MD 20892 USA. NR 11 TC 42 Z9 42 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2003 VL 34 IS 10 BP 2533 EP 2534 DI 10.1161/01.STR.0000092395.19554.9A PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 727UK UT WOS:000185679100063 PM 12970511 ER PT J AU Hurley, JH AF Hurley, JH TI Leucine in the sky with diamonds SO STRUCTURE LA English DT Editorial Material ID FOCAL ADHESION KINASE; STRUCTURAL BASIS; RECOGNITION; DOMAINS AB New structures of LD motifs bound to the focal adhesion targeting domain show that the motifs are recognized as amphipathic alpha helices. The structures highlight the structural and functional diversity of leucine and aspartic acid-based targeting motifs. C1 NIDDKD, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NR 9 TC 3 Z9 3 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2003 VL 11 IS 10 BP 1192 EP 1193 DI 10.1016/j.str.2003.09.009 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 729EA UT WOS:000185758500003 PM 14527384 ER PT J AU Mattison, DR AF Mattison, DR TI Sex matters: "Gender" differences in toxicology SO TOXICOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Toxicological-Society CY SEP 09-10, 2002 CL UNIV MANCHESTER INST SCI TECH, MANCHESTER, ENGLAND SP British Toxicolog Soc HO UNIV MANCHESTER INST SCI TECH C1 NICHHD, NIH, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009 NR 5 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD OCT 1 PY 2003 VL 192 IS 1 BP 59 EP 60 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 729JJ UT WOS:000185769800012 ER PT J AU Bolan, CD Wesley, RA Yau, YY Cecco, SA Starling, J Oblitas, JM Rehak, NN Leitman, SF AF Bolan, CD Wesley, RA Yau, YY Cecco, SA Starling, J Oblitas, JM Rehak, NN Leitman, SF TI Randomized placebo-controlled study of oral calcium carbonate administration in plateletpheresis: I. Associations with donor symptoms SO TRANSFUSION LA English DT Article ID IONIZED CALCIUM; PARATHYROID-HORMONE; CITRATE; INFUSION; PLATELETAPHERESIS; TESTS AB BACKGROUND: The effect of oral calcium (Ca) supplements in preventing citrate-induced symptoms during plateletpheresis was evaluated in a randomized, blinded, placebo-control led trial. STUDY DESIGN AND METHODS: Twenty-three donors (12 men, 11 women) underwent four plateletpheresis procedures each, ingesting either 1 or 2 g of oral Ca carbonate or an equivalent placebo 30 minutes before donation. Ten of these subjects subsequently ingested 4 g of open-label Ca before a fifth procedure. All procedures were conducted at the same citrate infusion rate (1.5 mg/kg/min) for 90 minutes. RESULTS: Ingestion of 2 g of oral Ca resulted in a significant reduction in the severity of paresthesias and a significant, though modest, increase in serum ionized calcium (iCa), but no significant improvement in total symptom scores, compared to placebo. Minimal effects were seen with the 1-g dose. The two factors most highly correlated with development of severe symptoms were decreased levels of iCa and ionized magnesium (iMg) at 30 minutes into apheresis. Lower preapheresis serum albumin, creatinine, vitamin D, iMg, and total Mg concentrations were also significantly associated with symptoms. Women experienced more frequent and severe symptoms than men, however, gender was not associated with symptoms after adjustment for lower serum albumin, creatinine, and Mg levels. Ingestion of 4 g of Ca offered no improvement in symptoms or iCa levels compared with the 2-g dose. CONCLUSION: Prophylactic oral Ca was associated with modest improvements in citrate-induced symptoms and laboratory parameters. Baseline albumin and Mg levels were strongly predictive of the development of symptoms. In donors with a prior history of uncomfortable citrate-related effects, a 2-g oral Ca dose before apheresis is recommended. C1 NIH, Dept Transfus Med, Biostat Serv, Dept Lab Med, Bethesda, MD 20892 USA. NIH, Pharm Dept, Warren Grand Magnuson Clin Ctr, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RP Leitman, SF (reprint author), NIH, Dept Transfus Med, Biostat Serv, Dept Lab Med, Bldg 10,Rm 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. NR 19 TC 23 Z9 27 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 OCT PY 2003 VL 43 IS 10 BP 1403 EP 1413 DI 10.1046/j.1537-2995.2003.00514.x PG 11 WC Hematology SC Hematology GA 726NY UT WOS:000185606800011 PM 14507272 ER PT J AU Bolan, CD Cecco, SA Yau, YY Wesley, RA Oblitas, JM Rehak, NN Leitman, SE AF Bolan, CD Cecco, SA Yau, YY Wesley, RA Oblitas, JM Rehak, NN Leitman, SE TI Randomized placebo-controlled study of oral calcium carbonate supplementation in plateletpheresis: II. Metabolic effects SO TRANSFUSION LA English DT Article ID PARATHYROID-HORMONE; IONIZED CALCIUM; CITRATE; PLATELETAPHERESIS; ABSORPTION; INFUSION; SALTS AB BACKGROUND: The metabolic effects of oral calcium (Ca) supplementation during plateletpheresis were evaluated in a randomized, placebo-controlled trial. STUDY DESIGN AND METHODS: Twenty-three donors underwent four plateletpheresis procedures each, receiving in random order, elemental Ca (Ca) 1 or 2 g orally, or a corresponding placebo, 30 minutes before donation. Ten of these donors underwent a fifth procedure using a 4-g Ca dose. All procedures were performed at a fixed citrate infusion rate of 1.5 mg per kg per minute. RESULTS: Oral Ca induced dose-sensitive changes in parathyroid hormone (iPTH), total (tCa), and ionized (iCa) calcium levels. Compared to placebo, the greatest improvement in tCa and iCa levels occurred after the 2-g Ca dose (tCa of 73, 89, and 25% above placebo levels at 60 min, using 1, 2, and 4 g of oral Ca, respectively). Twenty-four hours after apheresis, serum tCa and iCa levels were higher, and iPTH levels lower, in donors who received oral Ca rather than placebo. Marked increases in urinary Ca and magnesium (Mg) excretion occurred at the completion of apheresis, were unaffected by Ca dose, and returned to baseline within 24 hours. Plateletpheresis also induced significant changes in serum alkaline phosphatase, 1,25-dihydroxyvitamin D, and osteocalcin levels immediately and at 24 hours after apheresis. CONCLUSION: Plateletpheresis induces marked acute metabolic effects, with sustained changes evident up to 24 hours after the completion of apheresis. Oral Ca supplementation exerts a significant but clinically modest impact on selected laboratory variables associated with these effects. Further studies are indicated to examine the long-term impact of plateletpheresis, with or without Ca supplementation, on donor Ca balance and bone density. C1 NIH, Dept Transfus Med, Dept Lab Med, Bethesda, MD 20892 USA. NIH, Biostat Serv, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RP Bolan, CD (reprint author), NIH, Dept Transfus Med, Dept Lab Med, Bldg 10,Rm 1C711,MSC 1184, Bethesda, MD 20892 USA. NR 23 TC 23 Z9 24 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 OCT PY 2003 VL 43 IS 10 BP 1414 EP 1422 DI 10.1046/j.1537-2995.2003.00513.x PG 9 WC Hematology SC Hematology GA 726NY UT WOS:000185606800012 PM 14507273 ER PT J AU Bell, JK Mullen, GED Leifer, CA Mazzoni, A Davies, DR Segal, DM AF Bell, JK Mullen, GED Leifer, CA Mazzoni, A Davies, DR Segal, DM TI Leucine-rich repeats and pathogen recognition in Toll-like receptors SO TRENDS IN IMMUNOLOGY LA English DT Article ID GRAM-NEGATIVE FLAGELLIN; GLYCOPROTEIN IB-ALPHA; RIBONUCLEASE INHIBITOR; CRYSTAL-STRUCTURE; LISTERIA-MONOCYTOGENES; ENDOTHELIAL-CELLS; PROTEIN; LIPOPOLYSACCHARIDE; MUTATIONS; COMPLEX AB Toll-like receptors (TLRs) are the major cell-surface initiators of inflammatory responses to pathogens. They bind a wide variety of pathogenic substances through their ectodomains (ECDs). Here, we ask: what is the structural basis for this interaction? Toll-like receptor ECDs comprise 19-25 tandem copies of a motif known as the leucine-rich repeat (LRR). No X-ray structure of a TLR-ECD is currently available but there are several high-resolution LRR-containing proteins that can be used to model TLRs. We suggest that the basic framework of TLRs is a horseshoe-shaped solenoid that contains an extensive P-sheet on its concave surface, and numerous ligand-binding insertions. Together, these insertions and the P-sheet could provide a binding surface that is 10-fold greater in area than binding surfaces in antibodies and T-cell receptors. C1 NCI, Expt Immunol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, Natl Inst Hlth, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. RI Bell, Jessica/I-3893-2013 OI Bell, Jessica/0000-0003-1455-3274 NR 35 TC 403 Z9 445 U1 11 U2 40 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD OCT PY 2003 VL 24 IS 10 BP 528 EP 533 DI 10.1016/S1471-4906(03)00242-4 PG 6 WC Immunology SC Immunology GA 734LY UT WOS:000186058500004 PM 14552836 ER PT J AU Ransom, B Behar, T Nedergaard, M AF Ransom, B Behar, T Nedergaard, M TI New roles for astrocytes (stars at last) SO TRENDS IN NEUROSCIENCES LA English DT Review AB Astrocytes have been presumed to be uninteresting for the better part of a century. Recent findings suggest unexpected new functions for these cells and highlight the importance of viewing most brain activities as a collaboration between astrocytes and neurons. Astrocytes have been implicated in dynamic regulation of neuron production, synaptic network formation, neuron electrical activity and specific neurological diseases. We are only at the threshold of understanding fully the nature and consequences of these new astrocyte functions, and there is still much to be learned about the older and better-known roles. But now, at last, astrocytes have our attention. C1 Univ Washington, Dept Neurol, Seattle, WA 98195 USA. NINDS, Neural Environm Cluster, NIH, Bethesda, MD 20892 USA. New York Med Coll, Valhalla, NY 10595 USA. RP Ransom, B (reprint author), Univ Washington, Dept Neurol, 1959 NE Pacific,Rm RR650,Box 356465, Seattle, WA 98195 USA. OI Ransom, Bruce R./0000-0002-9658-0294 NR 6 TC 180 Z9 190 U1 2 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2003 VL 26 IS 10 BP 520 EP 522 DI 10.1016/j.tins.2003.08.006 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 731AL UT WOS:000185862300003 PM 14522143 ER PT J AU Rahmah, N Shenoy, RK Nutman, TB Weiss, N Gilmour, K Maizels, RM Yazdanbakhsh, M Sartono, E AF Rahmah, N Shenoy, RK Nutman, TB Weiss, N Gilmour, K Maizels, RM Yazdanbakhsh, M Sartono, E TI Multicentre laboratory evaluation of Brugia Rapid dipstick test for detection of brugian filariasis SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE Brugia malayi; dipstick test; multicentre evaluation ID WUCHERERIA-BANCROFTI INFECTION; MALAYI INFECTION; IGG4; DIETHYLCARBAMAZINE; ANTIGEN AB A multicentre evaluation of the Brugia Rapid dipstick test was performed using 1263 serum samples in four international laboratories, i.e. T. D. Medical College (TDMC, India), National Institutes of Health (NIH, USA), Swiss Tropical Institute (STI, Switzerland) and Leiden University Medical Centre (LUMC, Netherlands). In comparison with microscopy, the dipstick demonstrated sensitivities of 97.2% (70 of 72) at TDMC, 91.6% (175 of 191) at LUMC and 100% (six of six) at STI. Sera of chronic patients showed a positivity rate of 11.3% (19 of 168) and 61.2% (71 of 116) at TDMC and LUMC, respectively. All 266 sera of non-endemic normals from STI, NIH and LUMC tested negative with the dipstick. At LUMC, sera of 'endemic normals' (amicrofilaraemics with no clinical disease) from an area with approximately 35% microfilaria positivity showed 60.8% positive results (31 of 51), thus demonstrating the likelihood of many cryptic infections occuring in this population. Specificities of the test with Onchocerca volvulus sera were 98.8% (80 of 81) and 100% (10 of 10) at the NIH and STI, respectively; while specificity with Loa loa sera at the NIH was 84.6% (44 of 52). At the STI, the dipstick test also demonstrated 100% specificity when tested with 75 sera from various protozoan and helminthic infections. C1 Univ Sains Malaysia, Dept Med Microbiol Parasitol, Kubang Kerian, Kelantan, Malaysia. TD Med Coll Hosp, Filariasis Chemotherapy Unit, Allepey 68801, India. NIH, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. Swiss Trop Inst, CH-4051 Basel, Switzerland. Univ Edinburgh, Ashworth Labs, Inst Cell Anim & Populat Biol, Edinburgh EH9 3JT, Midlothian, Scotland. Leiden Univ, Med Ctr, Dept Parasitol, NL-2300 RC Leiden, Netherlands. RP Rahmah, N (reprint author), Univ Sains Malaysia, Dept Med Microbiol Parasitol, Hlth Campus, Kubang Kerian, Kelantan, Malaysia. RI Noordin, Rahmah/A-8277-2011 OI Noordin, Rahmah/0000-0001-7583-0752 NR 13 TC 26 Z9 30 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD OCT PY 2003 VL 8 IS 10 BP 895 EP 900 DI 10.1046/j.1365-3156.2003.01102.x PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 727BD UT WOS:000185635400007 PM 14516300 ER PT J AU Tokumasu, F Jin, AJ Feigenson, GW Dvorak, JA AF Tokumasu, F Jin, AJ Feigenson, GW Dvorak, JA TI Atomic force microscopy of nanometric liposome adsorption and nanoscopic membrane domain formation SO ULTRAMICROSCOPY LA English DT Article; Proceedings Paper CT 4th International Conference on Scanning Probe Microscopy, Sensors and Nanostructures CY MAY 26-29, 2002 CL LAS VEGAS, NEVADA DE atomic force microscopy (AFM); membrane domain; raft; membrane fusion; surface interaction; phase transition; phase behavior; phospholipids; cholesterol ID LIPID-BILAYER; VESICLES; EXTRUSION; SURFACE; TEMPERATURES; TRANSITION; PATCHES; RAFTS; MICA AB Scanning probe microscopy studies of membrane fusion and nanoscopic structures were performed using hydrated single lipids and lipid mixtures. Extruded vesicles of DMPC and mixtures at various concentrations of DLPC, DPPC and cholesterol were deposited on freshly cleaved mica and studied in a fluid environment by AFM. The nanostructures formed by these extruded liposomes ranged from isolated unilamellar vesicles to flat sheet membranes and were marked influenced by thermodynamic phase behavior. For DMPC membrane, intact bilayers exhibited a phase transition process in agreement with large bilayer patches. In the DLPC, DPPC and cholesterol mixtures, nanoscopic domain diameters ranged from similar to 25 to 48 nm with height differences of similar to 1.4 nm; all values were lipid composition-dependent. Our data support and extend previous studies of microscopic domains and phase boundaries of the same mixtures in giant unilamellar vesicles determined by confocal light microscopy. Our approach for preparing and utilizing supported membrane structures is potentially relevant to studies of native cell membranes. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIAID, Lab Malaria & Vestor Res, Biochem & Biophys Parasitol Sect, NIH, Bethesda, MD 20892 USA. NIH, Off Director, ORS, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. RP Dvorak, JA (reprint author), NIAID, Lab Malaria & Vestor Res, Biochem & Biophys Parasitol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Jin, Albert/0000-0003-3826-1081; Tokumasu, Fuyuki/0000-0003-2790-1071 NR 35 TC 68 Z9 69 U1 3 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD OCT-NOV PY 2003 VL 97 IS 1-4 BP 217 EP 227 DI 10.1016/S0304-3991(03)00046-9 PG 11 WC Microscopy SC Microscopy GA 694PP UT WOS:000183783200025 PM 12801674 ER PT J AU Eastham, JA Riedel, E Latkany, L Fleisher, M Schatzkin, A Lanza, E Shike, M AF Eastham, JA Riedel, E Latkany, L Fleisher, M Schatzkin, A Lanza, E Shike, M CA Polyp Prevention Trial Study Grp TI Dietary manipulation, ethnicity, and serum PSA levels SO UROLOGY LA English DT Article ID LOCALIZED PROSTATE-CANCER; BIOPSY SPECIMEN FEATURES; HIGH-FIBER DIET; WHITE MEN; LOW-FAT; AFRICAN-AMERICAN; TRIAL; MORTALITY; SURVIVAL; ANTIGEN AB Objectives. To examine whether a diet low in fat and high in fiber, fruits, and vegetables and ethnicity had any influence on serum prostate-specific antigen (PSA) levels, because serum PSA is a marker for the presence of prostate cancer. The incidence of prostate cancer increases with age, varies by ethnicity, and is greater among men with a first-degree relative who has had the disease. Large international variations in the rates of prostate cancer incidence and mortality, as well as the incidence changes in migrants and their offspring, also suggest that exogenous factors, including diet, have a strong influence on the development of this disease. Methods. We used data and blood samples from the Polyp Prevention Trial, a multicenter randomized trial designed to evaluate the impact of a diet low in fat and high in fiber, fruits, and vegetables on the recurrence of colorectal adenomas. Recruitment was from 1991 through 1994. Participants were followed up from their baseline recruitment date for 4 years. From this group, we identified 1100 white men and 97 black men who were 35 years of age or older, did not have prostate cancer, and had serum samples available for study. Results. At baseline, no difference was present in the fat intake for the black and white men (mean +/- SE, 90 +/- 3.6 g/day and 84 +/- 1.0 g/day, respectively; P = 0.15). The baseline serum PSA levels did not vary by ethnicity. For black men, the mean serum PSA level was 2.2 +/- 0.36 ng/mL compared with 2.0 +/- 0.07 ng/mL for white men (P = 0.64). Although all men assigned to the intervention group markedly reduced their fat intake by approximately 15% and increased their fruit and vegetable intake by approximately 2.25 servings per day, no difference was noted in the kinetics of the serum PSA levels by dietary intervention or race. Conclusions. Although ethnic differences in the incidence of prostate cancer are well defined, we found no difference in the baseline fat intake among black and white men that might have contributed to this difference. Serum PSA, a marker often used in early detection programs for prostate cancer, was not associated with manipulation of the amount of fat in the diet, regardless of ethnicity. (C) 2003 Elsevier Inc. C1 Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Eastham, JA (reprint author), Mem Sloan Kettering Canc Ctr, Dept Urol, 353 E 68h St,Room 527, New York, NY 10021 USA. OI Russo, Lianne/0000-0002-6966-250X NR 28 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD OCT PY 2003 VL 62 IS 4 BP 677 EP 682 DI 10.1016/S0090-4295(03)00576-4 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 765EA UT WOS:000188253100019 PM 14550442 ER PT J AU Xiao, XD Phogat, S Shu, Y Phogat, A Chow, YH Wei, OL Goldstein, H Broder, CC Dimitrov, DS AF Xiao, XD Phogat, S Shu, Y Phogat, A Chow, YH Wei, OL Goldstein, H Broder, CC Dimitrov, DS TI Purified complexes of HIV-1 envelope glycoproteins with CD4 and CCR5(CXCR4): production, characterization and immunogenicity SO VACCINE LA English DT Article DE HIV; AIDS; gp120; gp41; gp140; CD4; CCR5; CXCR4 ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS MOLECULAR CLONE; CELL-SURFACE ASSOCIATION; CROSS-LINKED COMPLEXES; MONONUCLEAR PHAGOCYTES; CONFORMATIONAL-CHANGES; CD4-GP120 COMPLEX; RECEPTOR; BINDING; GP120 AB The ability to readily elicit broadly neutralizing antibodies to HIV-1 remains elusive. We and others have hypothesized that interaction of the viral envelope glycoprotein (Env, gp120-gp41) with its receptor molecules could enhance the exposure of conserved epitopes that may facilitate the elicitation of broadly neutralizing antibodies. The Env-CD4-coreceptor complexes mediate HIV-1 entry into cells and serve as a major target for inhibitors of this process. To begin to evaluate their potential also as vaccine immunogens we produced relatively large amounts of complexes of purified recombinant soluble truncated Env, gp140(89.6) or gp120(89.6), with CD4 and CCR5 or CXCR4. We found that gp140(gp(120))-CD4-CCR5 complexes are stable and immunogenic in mice transgenic for human CD4 and CCR5. They elicited anti-gp 120 and anti-gp 140 antibodies that inhibited an heterologous primary HIV-1 isolate (JR-FL) with two- to threefold higher neutralizing activity than those elicited by gp120 and gp140. The antibodies elicited by the complexes competed better with the antibodies X5 and CG10 but not with b12 for binding to gp120 and gp120-CD4 complexes compared to those elicited with gp 140(120) alone. These findings suggest that stable purified Env-CD4-CCR5(CXCR4) complexes can be produced in relatively large amount sufficient for their further characterization that may help in the development of novel vaccines candidates. Published by Elsevier Ltd. C1 NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Dimitrov, DS (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bldg 469,Rm 246,POB B,Miller Dr, Frederick, MD 21702 USA. RI Chow, Yen-Hung /E-3863-2010 FU NIAID NIH HHS [AI47697] NR 29 TC 10 Z9 11 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 1 PY 2003 VL 21 IS 27-30 BP 4275 EP 4284 DI 10.1016/S0264-410X(03)00494-8 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 747XF UT WOS:000186830800026 PM 14505910 ER PT J AU Lindinger, P Mostbock, S Hammerl, P Hartl, A Thalhamer, J Abrams, SI AF Lindinger, P Mostbock, S Hammerl, P Hartl, A Thalhamer, J Abrams, SI TI Induction of murine ras oncogene peptide-specific T cell responses by immunization with plasmid DNA-based minigene vectors SO VACCINE LA English DT Article DE ras; DNA minigene; T lymphocytes ID COLONY-STIMULATING FACTOR; B SURFACE-ANTIGEN; IMMUNE-RESPONSES; GENE GUN; IN-VIVO; LYMPHOCYTE RESPONSES; ANTITUMOR IMMUNITY; CTL RESPONSES; NUCLEIC-ACID; VACCINES AB In a BALB/c mouse model, we have previously identified a ras oncogene peptide that contained both CD8(+) and CD4(+) T cell epitopes in a nested configuration. In this study, we developed several plasmid DNA minigene vectors encoding these determinants and examined whether they could induce antigen (Ag)-specific CD8(+) cytotoxic and CD4+ lymphoproliferative responses. Furthermore, we compared two different immunization procedures, epidermal gene gun inoculation and intradermal (i.d.) injection of saline plasmid DNA, along with several approaches addressing different aspects of immune modulation. We demonstrated that each DNA plasmid induced the relevant Ag-specific cellular immune response. Gene gun inoculation was superior to that of needle injection for induction of the CTL response. Moreover, DNA plasmids containing both ras epitopes induced the highest CTL response, as compared with vector preparations containing only the CD8(+) epitope. These results suggested that a DNA plasmid expressing nested mutant ras epitope- specific CD4(+) and CD8(+) T cell epitopes can be processed in vivo to induce both subset-specific T cell responses, and that the addition of the helper epitope quantitatively improved the development of the CTL response, which may have implications for DNA-based anti-tumor immunotherapies. Published by Elsevier Ltd. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Salzburg Univ, Inst Chem & Biochem, Immunol Grp, A-5020 Salzburg, Austria. RP Abrams, SI (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 5B46, Bethesda, MD 20892 USA. RI Thalhamer, Josef/E-5787-2011 OI Thalhamer, Josef/0000-0003-2285-6400 NR 36 TC 7 Z9 9 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 1 PY 2003 VL 21 IS 27-30 BP 4285 EP 4296 DI 10.1016/S0264-410X(03)00486-9 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 747XF UT WOS:000186830800027 PM 14505911 ER PT J AU Whitehead, SS Hanley, KA Blaney, JE Gilmore, LE Elkins, WR Murphy, BR AF Whitehead, SS Hanley, KA Blaney, JE Gilmore, LE Elkins, WR Murphy, BR TI Substitution of the structural genes of dengue virus type 4 with those of type 2 results in chimeric vaccine candidates which are attenuated for mosquitoes, mice, and rhesus monkeys SO VACCINE LA English DT Article DE dengue; chimerization; vaccination ID TICK-BORNE ENCEPHALITIS; HUMAN LIVER-CELLS; NONHUMAN-PRIMATES; NONCODING REGION; FEVER; IMMUNOGENICITY; CONSTRUCTION; NEUROVIRULENCE; PROTEIN; RNA AB Antigenic chimeric viruses in which the structural genes of dengue virus type 4 (DEN4) have been replaced with those derived from dengue virus type 2 (DEN2) have been created and evaluated as a first step in generating a live attenuated tetravalent dengue virus vaccine. Specifically, the capsid, membrane precursor, and envelope (CME) or the membrane precursor and envelope (ME) gene regions of DEN2 were substituted for the corresponding genes of wild-type rDEN4 or vaccine candidate rDEN4Delta30 which contains a 30 nucleotide deletion in the 3' untranslated region. The two DEN2/4 chimeric viruses lacking the Delta30 mutation were highly attenuated in tumor-bearing SCID-HuH-7 mice, mosquitoes, and rhesus monkeys, indicating chimerization with either the CME or ME regions lead to attenuation. In mosquitoes and SCID-HuH-7 mice, addition of the Delta30 mutation to the chimeric viruses resulted in comparable or only slightly increased levels of attenuation. In rhesus monkeys, addition of the Delta30 mutation rendered the CME chimeric virus non-infectious, indicating that the attenuation resulting from chimerization and the Delta30 mutation were additive for these animals. In contrast, the attenuation in rhesus monkeys of ME chimeric virus was not significantly modified by the addition of the Delta30 mutation. The satisfactory level of attenuation and immunogenicity achieved by the ME containing DEN2/4Delta30 chimeric virus, as well as its very low infectivity for mosquitoes, make it a vaccine candidate suitable for evaluation in phase I clinical trials. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Entomol, Silver Spring, MD 20955 USA. RP Whitehead, SS (reprint author), NIAID, Infect Dis Lab, NIH, Room 6515,Bldg 50,50 South Dr, Bethesda, MD 20892 USA. NR 41 TC 69 Z9 73 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 1 PY 2003 VL 21 IS 27-30 BP 4307 EP 4316 DI 10.1016/S0264-410X(03)00488-2 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 747XF UT WOS:000186830800029 PM 14505913 ER PT J AU Blaney, JE Manipon, GG Firestone, CY Johnson, DH Hanson, CT Murphy, BR Whitehead, SS AF Blaney, JE Manipon, GG Firestone, CY Johnson, DH Hanson, CT Murphy, BR Whitehead, SS TI Mutations which enhance the replication of dengue virus type 4 and an antigenic chimeric dengue virus type 2/4 vaccine candidate in Vero cells SO VACCINE LA English DT Article DE dengue; vaccine; Vero cells; adaptation ID JAPANESE ENCEPHALITIS-VIRUS; YELLOW-FEVER VIRUS; HUMAN LIVER-CELLS; HEMORRHAGIC-FEVER; ENVELOPE PROTEIN; MOUSE VIRULENCE; RHESUS-MONKEYS; ATTENUATION; STRAIN; IMMUNOGENICITY AB Mutations which increase the replication of dengue viruses in cell culture would greatly facilitate the manufacture of both a live attenuated or inactivated dengue virus vaccine. We have identified eight missense mutations in dengue virus type 4 (DEN4) that increase the plaque size and kinetics of replication of recombinant DEN4 virus in Vero cells. DEN4 viruses bearing these Vero cell adaptation mutations were also evaluated for the level of replication in the brains of mice. Two of these eight recombinant viruses expressing distinct mutations in NS3 were both restricted in replication in the brains of suckling mice. In contrast, six recombinant viruses, each encoding individual mutations in NS4B (five) or in NS5 (one), were not attenuated in mouse brain. Recombinant viruses encoding various combinations of these Vero cell adaptation mutations did not demonstrate enhanced replication in Vero cells over that exhibited by the single mutations. Finally, addition of a subset of the above non-attenuating, adaptation mutations to a DEN2/4 chimeric vaccine candidate was found to increase the virus yield in Vero cells by up to 500-fold. The importance of these Vero cell adaptation mutations in flavivirus vaccine design and development is discussed. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Whitehead, SS (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6515,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM swhitehead@niaid.nih.gov NR 54 TC 44 Z9 44 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 1 PY 2003 VL 21 IS 27-30 BP 4317 EP 4327 DI 10.1016/S0264-410X(03)00487-0 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 747XF UT WOS:000186830800030 PM 14505914 ER PT J AU Chen, H Matsuoka, Y Swayne, D Chen, Q Cox, NJ Murphy, BR Subbarao, K AF Chen, H Matsuoka, Y Swayne, D Chen, Q Cox, NJ Murphy, BR Subbarao, K TI Generation and characterization of a cold-adapted influenza A H9N2 reassortant as a live pandemic influenza virus vaccine candidate SO VACCINE LA English DT Article DE live attenuated vaccines; influenza H9N2; pandemic influenza vaccines ID HONG-KONG; H5N1 VIRUSES; POULTRY; INFECTION; HUMANS; ATTENUATION; CHILDREN; INFANTS; GENES; MICE AB H9N2 subtype influenza A viruses have been identified in avian species worldwide and were isolated from humans in 1999, raising concerns about their pandernic potential and prompting the development of candidate vaccines to protect humans against this subtype of influenza A virus. Reassortant H1N1 and H3N2 human influenza A viruses with the internal genes of the influenza A/Ann Arbor/6/60 (H2N2) (AA) cold-adapted (ca) virus have proven to be attenuated and safe as live virus vaccines in humans. Using classical genetic reassortment, we generated a reassortant virus (G9/AA ca) that contains the hemagglutinin and neuraminidase genes from influenza A/chicken/Hong Kong/G9/97 (H9N2) (G9) and six internal gene segments from the AA ca virus. When administered intranasally, the reassortant virus was immunogenic and protected mice from subsequent challenge with wild-type H9N2 viruses, although it was restricted in replication in the respiratory tract of mice. The G9/AA ca virus bears properties that are desirable in a vaccine for humans and is available for clinical evaluation and use, should the need arise. Published by Elsevier Ltd. C1 CDC, Influenza Branch, Atlanta, GA 30333 USA. USDA ARS, SE Poultry Res Lab, Athens, GA 30613 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), CDC, Influenza Branch, Atlanta, GA 30333 USA. NR 29 TC 53 Z9 61 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 1 PY 2003 VL 21 IS 27-30 BP 4430 EP 4436 DI 10.1016/S0264-410X(03)0043004 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 747XF UT WOS:000186830800042 PM 14505926 ER PT J AU Miura, K Hertle, RW FitzGibbon, EJ Optican, LM AF Miura, K Hertle, RW FitzGibbon, EJ Optican, LM TI Effects of tenotomy surgery on congenital nystagmus waveforms in adult patients. Part I. Wavelet spectral analysis SO VISION RESEARCH LA English DT Article DE congenital nystagmus; oculomotor disorder; tenotomy; wavelet analysis; human ID QUANTITATIVE-EVALUATION; BIOFEEDBACK; WAVEFORMS AB Congenital nystagmus (CN) is an aperiodic oscillatory eye movement disorder. Horizontal rectus tenotomy with simple re-attachment has been proposed as a therapy for CN. This therapy might affect vision and/or eye movements. Another paper deals with improvements in visual acuity. This and the companion paper examine changes in eye movements. In this study, we examined the effect of tenotomy on nystagmus waveforms using wavelet spectral analysis. No common effect was found across the patients on the wavelet spectra of the CN beat, suggesting that tenotomy surgery has no effect, or only a quite small effect, on the waveform structure of CN. Published by Elsevier Ltd. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Optican, LM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. 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 0042-6989 J9 VISION RES JI Vision Res. PD OCT PY 2003 VL 43 IS 22 BP 2345 EP 2356 DI 10.1016/S0042-6989(03)00409-7 PG 12 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 723TL UT WOS:000185447600006 PM 12962991 ER PT J AU Miura, K Hertle, RW FitzGibbon, EJ Optican, LM AF Miura, K Hertle, RW FitzGibbon, EJ Optican, LM TI Effects of tenotomy surgery on congenital nystagmus waveforms in adult patients. Part II. Dynamical systems analysis SO VISION RESEARCH LA English DT Article DE eye movement disorders; congenital nystagmus; tenotomy; non-linear dynamics; correlation dimension ID CORRELATION DIMENSION; OPTOKINETIC NYSTAGMUS; QUANTITATIVE-EVALUATION; EYE-MOVEMENTS; BIOFEEDBACK; PARAMETERS; THERAPY AB Congenital nystagmus (CN) is an aperiodic oscillatory eye movement disorder of unknown etiology. We examined the effect of horizontal rectus tenotomy with simple re-attachment on the dimensionality of the dynamical mechanism underlying CN. The correlation dimensions (CDs) were calculated from eight patients who had tenotomy surgery. We found no significant differences in the CDs that could be associated with the surgery. The change in dimensionality was less than 5% on average. The results suggest that the tenotomy has no effect, or only a quite small effect, on the underlying mechanism of the CN beats. (C) 2003 Elsevier Ltd. All rights reserved. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Optican, LM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 22 TC 7 Z9 9 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD OCT PY 2003 VL 43 IS 22 BP 2357 EP 2362 DI 10.1016/S0042-6989(03)00410-3 PG 6 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 723TL UT WOS:000185447600007 PM 12962992 ER PT J AU Pitcher, WH DeRose, EF Mueller, GA Howell, EE London, RE AF Pitcher, WH DeRose, EF Mueller, GA Howell, EE London, RE TI NMR studies of the interaction of a type II dihydrofolate reductase with pyridine nucleotides reveal unexpected phosphatase and reductase activity SO BIOCHEMISTRY LA English DT Article ID BACKBONE DYNAMICS; ESCHERICHIA-COLI; TERNARY COMPLEX; PROTEIN; ENZYME; R67; RELAXATION; RESONANCE; SITE; CONFORMATION AB The interaction of type II R67 dihydrofolate reductase (DHFR) with its cofactor nicotinamide adenine dinucleotide phosphate (NADP+) has been studied using nuclear magnetic resonance (NMR). Doubly labeled [U-C-13,N-15]DHFR was obtained from Escherichia coli grown on a medium containing [U-C-13]-D-glucose and (NH4Cl)-N-15, and the 16 disordered N-terminal amino acids were removed by treatment with chymotrypsin. Backbone and side chain NMR assignments were made using triple-resonance experiments. The degeneracy of the amide H-1 and 15N shifts of the tetrameric DHFR was preserved upon addition of NADP(+), consistent with kinetic averaging among equivalent binding sites. Analysis of the more titration-sensitive DHFR amide resonances as a function of added NADP(+) gave a K-D of 131 +/- 50 muM, consistent with previous determinations using other methodology. We have found that the H-1 spectrum of NADP(+) in the presence of the R67 DHFR changes as a function of time. Comparison with standard samples and mass spectrometric analysis indicates a slow conversion of NADP(+) to NAD(+), i.e., an apparent NADP(+) phosphatase activity. Studies of this activity in the presence of folate and a folate analogue support the conclusion that this activity results from an interaction with the DHFR rather than a contaminating phosphatase. 1H NMR studies of a mixture of NADP(+) and NADPH in the presence of the enzyme reveal that a ternary complex forms in which the N-4A and N-4B nuclei of the NADPH are in the proximity of the N-4 and N-5 nuclei of NADP(+). Studies using the NADP(+) analogue acetylpyridine adenosine dinucleotide phosphate (APADP(+)) demonstrated a low level of enzyme-catalyzed hydride transfer from NADPH. Analysis of DHFR backbone dynamics revealed little change upon binding of NADP(+). These additional catalytic activities and dynamic behavior are in marked contrast to those of type I DHFR. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Biochem Cell & Mol Biol Dept, Knoxville, TN 37996 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MR-01, Res Triangle Pk, NC 27709 USA. NR 41 TC 18 Z9 18 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 30 PY 2003 VL 42 IS 38 BP 11150 EP 11160 DI 10.1021/bi0349874 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726HC UT WOS:000185592000007 PM 14503865 ER PT J AU Self, WT Wolfe, MD Stadtman, TC AF Self, WT Wolfe, MD Stadtman, TC TI Cofactor determination and spectroscopic characterization of the selenium-dependent purine hydroxylase from Clostridium purinolyticum SO BIOCHEMISTRY LA English DT Article ID NICOTINIC-ACID HYDROXYLASE; ELECTRON-PARAMAGNETIC-RESONANCE; XANTHINE-OXIDASE FAMILY; MOLYBDENUM ENZYMES; DEHYDROGENASE; MECHANISM; BARKERI; OXIDOREDUCTASE; CYLINDROSPORUM; MOLYBDOPTERIN AB Purine hydroxylase (PH) from Clostridium purinolyticum contains a labile selenium cofactor and belongs to a class of enzymes known as the selenium-dependent molybdenum hydroxylases. The presence of approximately 1.1 mol of molybdenum, 0.87 mol of selenium, and 3.3 mol of iron per mol of PH was determined by atomic absorption spectroscopy. Enzyme preparations with lower than stoichiometric amounts of selenium exhibited correspondingly lower hydroxylase activities. Bound FAD, I mol per mol enzyme, was confirmed by UV-vis and fluorescence spectroscopy. CMP, released by acid hydrolysis, indicated the presence of a molybdopterin cytosine dinucleotide cofactor. The fully active PH utilized NADP(+) as an electron acceptor, and kinetic analysis revealed an optimal k(cat) of 412 s(-1) using hypoxanthine as the hydroxylase substrate. Xanthine, NAD(+), and NADPH had no significant effect on this reaction rate. A selenium-independent NADPH oxidase activity was exhibited by native PH. Electron paramagnetic resonance spectroscopy revealed the presence of a Mo(V) desulfo signal, FAD radical, and 2Fe-2S centers in hypoxanthine-reduced PH. No hyperfine coupling of selenium, using Se-77 isotope-enriched PH, was observed in any of the EPR active signals studied. The appearance of the desulfo signal suggests that the ligands of Mo in selenium-dependent molybdenum hydroxylases are different from the well-studied mammalian xanthine oxidoreductases (XOR) and aldehyde oxidoreductases (AOR) and. suggests a unique role for Se in catalysis. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, 50 S Dr MSC 8012, Bethesda, MD 20892 USA. RI Self, William/A-6704-2008 NR 26 TC 12 Z9 13 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 30 PY 2003 VL 42 IS 38 BP 11382 EP 11390 DI 10.1021/bi030136k PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726HC UT WOS:000185592000031 PM 14503889 ER PT J AU Wilson, PWF Grundy, SM AF Wilson, PWF Grundy, SM TI The metabolic syndrome - A practical guide to origins and treatment: Part II SO CIRCULATION LA English DT Article ID CORONARY-HEART-DISEASE; TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; CARDIOVASCULAR RISK; LIFE-STYLE; CHOLESTEROL; ASSOCIATION; PREVENTION; MEN C1 NHLBI, Framingham Heart Study, Boston, MA USA. RP Wilson, PWF (reprint author), Boston Univ, Sch Med, Dept Cardiol, 715 Albany St,Evans 204, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIAMS NIH HHS [AR/AG 41398] NR 32 TC 45 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 30 PY 2003 VL 108 IS 13 BP 1537 EP 1540 DI 10.1161/01.CIR.0000089506.12223.F1 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 726WL UT WOS:000185624500015 PM 14517148 ER PT J AU Xiao, RP Zhang, SJ Chakir, K Avdonin, P Zhu, WZ Bond, RA Balke, CW Lakatta, EG Cheng, HP AF Xiao, RP Zhang, SJ Chakir, K Avdonin, P Zhu, WZ Bond, RA Balke, CW Lakatta, EG Cheng, HP TI Enhanced G(i) signaling selectively negates beta(2)-adrenergic receptor (AR)- but not beta(1)-AR-mediated positive inotropic effect in myocytes from failing rat hearts SO CIRCULATION LA English DT Article DE receptors, adrenergic, beta; heart failure; proteins; contractility ID CARDIAC MYOCYTES; TRANSGENIC MICE; PERTUSSIS-TOXIN; G-PROTEIN; BETA(1)-ADRENERGIC RECEPTOR; CA2+ CURRENT; CELL-DEATH; FAILURE; STIMULATION; CONTRACTION AB Background - Myocardial contractile response to beta(1)- and beta(2)-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G(i) signaling and the ratio of beta(2)/beta(1) are often increased. Because beta(2)-AR but not beta(1)-AR couples to G(s) and G(i) with the G(i) coupling negating the G(s)- mediated contractile response, we determined whether the heart failure-associated augmentation of G(i) signaling contributes differentially to the defects of these beta-AR subtypes and, if so, whether inhibition of G(i) or selective activation of beta(2)-AR/G(s) by ligands restores beta(2)-AR contractile response in the failing heart. Methods and Results - Cardiomyocytes were isolated from 18- to 24-month- old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either beta-AR subtype - mediated inotropic effect was markedly diminished, whereas G(i) proteins and the beta(2)/beta(1) ratio were increased. Disruption of G(i) signaling by pertussis toxin (PTX) enabled beta(2)- but not beta(1)-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of beta(2)-AR ligands revealed that the contractile response mediated by most beta(2)-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G(s) and G(i) activation. In contrast, fenoterol, another beta(2)-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX. Conclusions - We conclude that enhanced G(i) signaling is selectively involved in the dysfunction of beta(2)- but not beta(1)-AR in failing SHR hearts and that disruption of G(i) signaling by PTX or selective activation of beta(2)-AR/G(s) signaling by fenoterol restores the blunted beta(2)-AR contractile response in the failing heart. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Houston, Dept Pharmacol & Pharmacol Sci, Houston, TX USA. Univ Maryland, Dept Physiol, Baltimore, MD 21201 USA. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 45 TC 87 Z9 97 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 30 PY 2003 VL 108 IS 13 BP 1633 EP 1639 DI 10.1161/01.CIR.0000087595.17277.73 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 726WL UT WOS:000185624500031 PM 12975249 ER PT J AU Rausch, JW Qu, J Yi-Brunozzi, HY Kool, ET Le Grice, SFJ AF Rausch, JW Qu, J Yi-Brunozzi, HY Kool, ET Le Grice, SFJ TI Hydrolysis of RNA/DNA hybrids containing nonpolar pyrimidine isosteres defines regions essential for HIV type 1 polypurine tract selection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MURINE LEUKEMIA-VIRUS; SEQUENCE FEATURES IMPORTANT; STRAND DNA-SYNTHESIS; REVERSE-TRANSCRIPTASE; IMMUNODEFICIENCY-VIRUS; RNASE-H; CRYSTAL-STRUCTURE; MINOR-GROOVE; BINDING TRACK; IN-VIVO AB Both x-ray crystallography and chemical footprinting indicate that base; of the HIV type 1 (HIV-1) polypurine tract (PPT)-containing RNA,'DNA hybrid deviate from standard Watson-Crick base pairing. However, the contribution of these structural anomalies to the accuracy of plus-strand primer selection by HIV-1 reverse transcriptase is not immediately clear. To address this issue, DNA templates harboring single and pairwise non-hydrogen-bonding isosteres of cytosine (2-fluoro-4-methyl benzene deoxyribonucleoside) and thymine (2,4-difluoro-5-methyl benzene deoxyribonucleoside) were synthesized and hybridized to PPT-containing RNA primers as a means of locally removing hydrogen bonding and destabilizing paired structure. Cleavage of these hybrids was examined with p66/p51 HIV-1 reverse transcriptase and a mutant carrying an alteration in the p66 RNase H primer shown to specifically impair PPT processing. Analog insertion within the PPT (rG):(dC) and central (rA):(dT) tracts repositioned the RNase H domain such that the RNA/DNA hybrid was cleaved 3-4 bp from the s te of insertion, a distance corresponding closely to the spatial separation between the catalytic center and RNase H primer grip. However, PPT processing was significantly impaired when the junction between these tracts was substituted. Substitutions within the upstream (rA):(dT) tract, where maximum distortion had previously been observed, destroyed PPT processing. Collectively, our scanning mutagenesis approach implicates multiple regions of the PPT in the accuracy with which it is excised from (+) U3 RNA and DNA, and also provides evidence for close cooperation between the RNase H primer grip and catalytic center in achieving this cleavage. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Stanford Univ, Dept Chem, Stanford, CA 94305 USA. RP Le Grice, SFJ (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. FU NIBIB NIH HHS [EB002059]; NIGMS NIH HHS [GM52956] NR 34 TC 23 Z9 24 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11279 EP 11284 DI 10.1073/pnas.1932546100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700021 PM 12972638 ER PT J AU Da Fonseca, F Moss, B AF Da Fonseca, F Moss, B TI Poxvirus DNA topoisomerase knockout mutant exhibits decreased infectivity associated with reduced early transcription SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TEMPERATURE-SENSITIVE MUTANTS; OPEN READING FRAME; VACCINIA VIRUS; RNA-POLYMERASE; ESCHERICHIA-COLI; IDENTIFICATION; GENE; RESOLUTION; PROTEIN; ENZYME AB Vaccinia virus encodes a type I DNA topoisomerase that is highly conserved in all known poxviruses. Although the structure and catalytic activity of the enzyme were well studied, little was known about its biological function. The viral topoisomerase was thought to lie essential, and roles in DNA replication, recombination, conoatemer resolution, and transcription were suggested. Here, we demonstrated that the topoisomerase is not essential for replication of vaccinia virus in cultured cells, although deletion mutants formed fewer and smaller plaques on cell monolayers thar wild-type virus. Purified mutant virus particles were able to binc and enter cells but exhibited reduced viral early transcription and a delay in DNA replication. infecting with a high number of virus particles increased early mRNA and accelerated viral DNA synthesis. Processing of viral DNA concatemers into unit-length genomes was unimpaired at either a low or high multiplicity of infection. The data suggest that the primary, perhaps only, role of the poxvirus topoisomerase is to increase early transcription, which takes place within virus cores in the cytoplasm of infected cells. Because the topoisomerase functions early in infection, drugs capable of penetrating the virus core and irreversibly damaging DNA by trapping nicked DNA-topoisomerase intermediates could make potent antiviral agents. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 37 TC 42 Z9 44 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11291 EP 11296 DI 10.1073/pnas.1534874100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700023 PM 12972642 ER PT J AU Xu, XL Cho, M Spencer, NY Patel, N Huang, Z Shields, H King, SB Gladwin, MT Hogg, N Kim-Shapiro, DB AF Xu, XL Cho, M Spencer, NY Patel, N Huang, Z Shields, H King, SB Gladwin, MT Hogg, N Kim-Shapiro, DB TI Measurements of nitric oxide on the heme iron and beta-93 thiol of human hemoglobin during cycles of oxygenation and deoxygenation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SICKLE-CELL HEMOGLOBIN; RED-BLOOD-CELLS; S-NITROSOHEMOGLOBIN; RELAXING FACTOR; NO; DIFFUSION; BINDING; ERYTHROCYTES; OXIDATION; MODEL AB Nitric oxide has been proposed to be transported by hemoglobin as a third respiratory gas and to elicit vasodilation by an oxygen-linked (allosteric) mechanism. For hemoglobin to transport nitric oxide bioactivity it must capture nitric oxide as iron nitrosyl hem:)globin rather than destroy it by dioxygenation. Once bound to the heme iron, nitric oxide has been reported to migrate reversibly from the heme group of hemoglobin to the beta-93 cysteinyl residue, in response to an oxygen saturation-dependent conformational change, to form an S-nitrosothiol. However, such a transfer requires redox chemistry with oxidation of the nitric oxide or beta-93 cysteinyl residue. in this article, we examine the ability of nitric oxide to undergo this intramolecular transfer by cycling human hemoglobin between oxygenated and deoxygenated states. Under various conditions, we found no evidence for intra molecular transfer of nitric oxide from either cysteine to heme or home to cysteine. In addition, we observed that contaminating nitride can lead to formation of iron nitrosyl hemoglobin in deoxygen ated hemoglobin preparations and a radical in oxygenated hemoglobin preparations. Using N-15-labeled nitrite, we clearly demonstrate that nitrite chemistry could explain previously report d results that suggested apparent nitric oxide cycling from hem to thiol. Consistent with our results from these experiments conducted in vitro, we found no arterial/venous gradient of iron nitrosyl hemoglobin detectable by electron paramagnetic resonance spectroscopy. Our results do not support a role for allosterically controlled intramolecular transfer of nitric oxide in hemoglobin as a function of oxygen saturation. C1 Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. Warren G Magnuson Clin Ctr, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. RP Hogg, N (reprint author), Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. FU NHLBI NIH HHS [R01 HL058091, R29 HL058091, HL58091, R37 HL058091]; NIBIB NIH HHS [P41 EB001980, EB001980]; NIGMS NIH HHS [R29 GM055792, GM55792, R01 GM055792] NR 49 TC 64 Z9 66 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11303 EP 11308 DI 10.1073/pnas.2033883100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700025 PM 14500899 ER PT J AU Boisbouvier, J Delaglio, F Bax, A AF Boisbouvier, J Delaglio, F Bax, A TI Direct observation of dipolar couplings between distant protons in weekly aligned nucleic acids SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIQUID-CRYSTALLINE MEDIUM; PROTEIN BACKBONE STRUCTURE; B-DNA DODECAMER; NMR-SPECTROSCOPY; 2-DIMENSIONAL SPECTROSCOPY; MAGNETIC-RESONANCE; PULSE SEQUENCES; MACROMOLECULES; RESOLUTION; ALIGNMENT AB Under conditions where macromolecules are aligned very weakly with respect to an external magnetic field, Brownian diffusion no longer averages internuclear dipole-dipole interactions to zero. The resulting residual dipolar coupling, although typically 3 orders of magnitude weaker than in a fully aligned sample, can readily be measured by solution NMR methods. To date, application of this idea has focused primarily on pairs of nuclei separated by one or two covalent bonds, where the internuclear separation is known and the measured dipolar coupling provides direct information on the orientation of the internuclear vector. A method is described that allows observation of dipolar interactions over much larger distances. By decoupling nearest-neighbor interactions, it is readily possible to observe direct dipolar interactions between protons separated by upto 12 Angstrom. The approach is demonstrated for the DNA dodecamer d(CGCGAATTCGCG)(2), where direct interactions are observ d between protons up to three base pairs apart. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 52 TC 30 Z9 30 U1 3 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11333 EP 11338 DI 10.1073/pnas.1534664100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700030 PM 12972645 ER PT J AU Lia, G Bensimon, D Croquette, V Allemand, JF Dunlap, D Lewis, DEA Adhya, SC Finzi, L AF Lia, G Bensimon, D Croquette, V Allemand, JF Dunlap, D Lewis, DEA Adhya, SC Finzi, L TI Supercoiling and denaturation in Gal repressor/heat unstable nucleoid protein (HU)-mediated DNA looping SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STRAND BINDING-PROTEIN; SITE-SPECIFIC BINDING; ESCHERICHIA-COLI; HU PROTEIN; TRANSCRIPTION; SPECIFICITY; SEQUENCE; AFFINITY; CONTAINS; MODEL AB The overall topology of DNA profoundly influences the regulation of transcription and is determined by DNA flexibility as well as the binding of proteins that induce DNA torsion, distortion, and/or looping. Gal repressor (GaIR) is thought to repress transcription from the two promoters of the gal operon of Escherichia coli by forming a DNA loop of approximate to40 nm of DNA that encompasses the promoters. Associated evidence of a topological regulatory mechanism of the transcription repression is the requirement for a supercoiled DNA template and the histone-like heat unstable nucleoid protein (HU). By using single-molecule manipulations to generate and finely tune tension in DNA molecules, we directly detected GaIR/HU-mediated DNA looping and characterized its kinetics, thermodynamics, and supercoiling dependence. The factors required for gal DNA looping in single-molecule experiments (HU, GaIR and DNA supercoiling) correspond exactly to those necessary for gal repression observed both in vitro and in vivo. Our sing e-molecule experiments revealed that negatively supercoiled DNA, under slight tension, denatured to facilitate GaIR/HU-mediated DNA loop formation. Such topological intermediates may operate similarly in other multiprotein complexes of transcription, replication, and recombination. C1 Univ Milan, Dipartimento Biol, I-20133 Milan, Italy. Ecole Normale Super, Lab Phys Stat, F-75005 Paris, France. Ecole Normale Super, Dept Biol, F-75005 Paris, France. Ecole Normale Super, Dept Chim, F-75005 Paris, France. San Raffaele Sci Inst, I-20132 Milan, Italy. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Finzi, L (reprint author), Univ Milan, Dipartimento Biol, Via Celoria 26, I-20133 Milan, Italy. RI Bensimon, David/E-7768-2015 OI Bensimon, David/0000-0003-1971-9907 NR 31 TC 81 Z9 82 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 SEP 30 PY 2003 VL 100 IS 20 BP 11373 EP 11377 DI 10.1073/pnas.2034851100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700037 PM 14500788 ER PT J AU Algeciras-Schimnich, A Pietras, EM Barnhart, BC Legembre, P Vijayan, S Holbeck, SL Peter, ME AF Algeciras-Schimnich, A Pietras, EM Barnhart, BC Legembre, P Vijayan, S Holbeck, SL Peter, ME TI Two CD95 tumor classes with different sensitivities to antitumor drugs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-LINES; FAS LIGAND; MONOCLONAL-ANTIBODY; SIGNALING PATHWAYS; INDUCED APOPTOSIS; DOWN-REGULATION; SOLUBLE FORM; II CELLS; INDUCTION; RECEPTOR AB CD95 type I and 11 cells differ in their dependence on mitochondria to execute apoptosis, because antiapoptotic members of the Bcl-2 family render only type 11 cells resistant to death receptor-induced apoptosis. They can also be distinguished by a more efficient formation of the death-inducing signaling complex in type I cells. We have identified a soluble form of CD95 ligand (S2) that is cytotoxic to type 11 cells but does not kill type I cells. By testing 58 tumor cell lines of the National Cancer Institute's anticancer drug-screening panel for apoptosis sensitivity to S2 and performing death-inducing signaling complex analyses, we determined that half of the CD95-sensitive cells are type I and half are type II. Most of the type I cell lines fall into a distinct class of tumor cells expressing mesenchymal-like genes, whereas the type 11 cell lines preferentially express epithelium-like markers. This suggests that type I and 11 tumor cells represent different stages of carcinogenesis that resemble the epithelial-mesenchymal transition. We then screened the National Cancer Institute database of >42,000 compounds for reagents with patterns of growth inhibition that correlated with either type I or type 11 cell lines and found that actin-binding compounds selectively inhibited growth of type I cells, whereas tubulin-interacting compounds inhibited growth of type 11 cells. Our analysis reveals fundamental differences in programs of gene expression between type I and type 11 cells and could impact the way actin- and microtubule-disrupting antitumor agents are used in tumor therapy. C1 Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. NCI, Dev Therapeut Program, Informat Technol Branch, Bethesda, MD 20892 USA. RP Peter, ME (reprint author), Univ Chicago, Ben May Inst Canc Res, 924 E 57th St, Chicago, IL 60637 USA. OI legembre, patrick/0000-0001-6649-8049 FU NCI NIH HHS [5T32CA09594, T32 CA009594]; NIGMS NIH HHS [R01 GM061712, GM61712] NR 26 TC 59 Z9 60 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 SEP 30 PY 2003 VL 100 IS 20 BP 11445 EP 11450 DI 10.1073/pnas.2034995100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700050 PM 14504390 ER PT J AU Woodhouse, EC Fisher, A Bandle, RW Bryant-Greenwood, B Charboneau, L Petricoin, EF Liotta, LA AF Woodhouse, EC Fisher, A Bandle, RW Bryant-Greenwood, B Charboneau, L Petricoin, EF Liotta, LA TI Drosophila screening model for metastasis: Semaphorin 5c is required for I(2)gl cancer phenotype SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR PROTEIN; II HEAVY-CHAIN; LETHAL(2)GIANT LARVAE; GENE; ACTIVATION; DPP; THROMBOSPONDIN-1; EMBRYOGENESIS; PROGRESSION AB Cancer metastasis is a complex process involving many genes and pathways. This complexity hinders the identification of molecules functionally required for this process. We have developed and used a Drosophila screening system to identify genes that are functionally important for tumorigenicity and metastasis. Deletion of Drosophila lethal giant larvae (1(2)gl) leads to highly invasive and widely metastatic tumors on transplantation into adult flies. Random homozygous P element insertions were screened for the ability to modulate the 1(2)gl phenotype. Analysis of metastasis patterns of the lines containing P element insertions and lacking wild-type l(2)gl expression identified three homozygous mutations that dramatically alter tumorigenesis and/or metastasis. Semaphorin Sc (Sema 5c) is required for tumorigenicity, apontic overexpression suppresses metastasis but not tumorigenicity, and pointed up-regulation accelerates lethality of 1(2)gl tumors. Furthermore, class 5 semaphorins are shown to be expressed in cancer cells and localized to the membrane. Drosophila Sema-5c and the mammalian homologs are transmembrane proteins with extracellular thrombospondin type I (Tspl) repeats. Tspl repeats are known in some proteins to bind and activate transforming growth factor (TGF)-beta ligand. Phospho-Mad and the downstream target gene vestigial were elevated in 1(2)gl tumors, thus linking Drosophila neoplasia to the Dpp (TGF-beta-like) signal pathway. The activation of the Dpp pathway in 1(2)gl tumors occurred only in the presence of Sema-5c. This study demonstrates that the power of Drosophila genetics can be applied to screen, identify, and characterize molecules that are functionally required for invasion and metastasis. C1 NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Off Director, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 41 TC 48 Z9 52 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11463 EP 11468 DI 10.1073/pnas.2031202100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700053 PM 14500904 ER PT J AU Moon, C Krawczyk, M Ahn, D Ahmet, I Paik, D Lakatta, EG Talan, MI AF Moon, C Krawczyk, M Ahn, D Ahmet, I Paik, D Lakatta, EG Talan, MI TI Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; MYOCYTE APOPTOSIS; ISCHEMIC-INJURY; HEART-FAILURE; STEM-CELLS; IN-VITRO; RECEPTOR; BRAIN; PHARMACOKINETICS; OCCLUSION AB Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units/kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Hanyang Univ, Dept Anat & Cell Biol, Seoul 133791, South Korea. RP Talan, MI (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. NR 31 TC 215 Z9 238 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11612 EP 11617 DI 10.1073/pnas.1930406100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700079 PM 14500913 ER PT J AU Sakai, A St Claire, MS Faulk, K Govindarajan, S Emerson, SU Purcell, RH Bukh, J AF Sakai, A St Claire, MS Faulk, K Govindarajan, S Emerson, SU Purcell, RH Bukh, J TI The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ION-CHANNEL ACTIVITY; INFLUENZA-A VIRUS; CDNA-CLONE; IN-VIVO; EFFICIENT REPLICATION; FULL-LENGTH; PROTEIN; REGION; CHIMPANZEES; RNA AB The role of the hepatitis C virus (HCV) p7 protein in the virus life cycle is not known. Previous in vitro data indicated that this 63-aa polypeptide is located in the endoplasmic reticulum and has two transmembrane domains (TMDs) connected by a cytoplasmic loop; the amino- and carboxyl-terminal tails are oriented toward the endoplasmic reticulum lumen. Furthermore, recent in vitro studies suggested that HCV p7 could function as a virus-encoded ion channel. It might therefore be a relevant target for future drug development. We studied the role of HCV p7 in vivo. Because HCV does not replicate efficiently in cell culture, we mutagenized p7 of an infectious genotype la cDNA clone and tested RNA transcripts of each mutant for infectivity in chimpanzees by intrahepatic transfection. Appropriate processing of mutant polypeptides was confirmed by studies in transfected mammalian cells. Mutants with deletions of all or part of p7 and a mutant with substitutions of two conserved residues in the cytoplasmic loop were not viable. Thus, p7 is essential for infectivity of HCV. A chimera in which the p7 of the 1 a clone was replaced with p7 from an infectious genotype 2a clone also was not viable. This finding suggests a genotype-specific interaction between p7 and other genomic regions. To define which portions of p7 played the most significant role for this interaction, we tested three chimeras with the 1 a backbone in which only specific domains of p7 had the 2a sequence. A p7 chimera with 2a tails and TMDs and the 1a cytoplasmic loop was not viable. A mutant with 2a tails and cytoplasmic loop and la TMDs also was not viable. However, a p7 chimera with 2a TMDs and cytoplasmic loop and la tails was viable. The transfected chimpanzee became viremic at week 2, and recovered viruses had the chimeric sequence. These data indicate that the amino- and/or carboxyl-terminal intraluminal tails of p7 contain sequences with genotype-specific function. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD 20850 USA. Rancho Los Amigos Med Ctr, Liver Res Lab, Downey, CA 90242 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 50,Room 6529,50 S Dr,MSC 8009, Bethesda, MD 20892 USA. NR 31 TC 161 Z9 172 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11646 EP 11651 DI 10.1073/pnas.1834545100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700085 PM 14504405 ER PT J AU Boylan, JA Posey, JE Gherardini, FC AF Boylan, JA Posey, JE Gherardini, FC TI Borrelia oxidative stress response regulator, BosR: A distinctive Zn-dependent transcriptional activator SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYDROGEN-PEROXIDE; BACILLUS-SUBTILIS; METAL-IONS; BURGDORFERI AB The ability of a pathogen to cause infection depends on successful colonization of the host, which, in turn, requires adaptation to various challenges presented by that host. For example, host immune cells use a variety of mechanisms to control infection by bacterial pathogens, including the production of bactericidal reactive oxygen species. Prokaryotic and eukaryotic cells have developed ways of protecting themselves against this oxidative damage; for instance, Borrelia burgdorferi alters the expression of oxidative-stress-related proteins, such as a Dps/Dpr homolog NapA (BB0690), in response to increasing levels of oxygen and reactive oxygen species. These stress-related genes appear to be regulated by a putative metal-dependent DNA-binding protein (BB0647) that has 50.7% similarity to the peroxide-specific stress response repressor of Bacillus subtilis, PerR. We overexpressed and purified this protein from Escherichia coli and designated it Borrelia oxidative stress regulator, BosR. BosR bound to a 50-nt region 180 bp upstream of the napA transcriptional start site and required DTT and Zn2+ for optimal binding. Unlike the Bacillus subtilis PerR repressor, BosR did not require Fe2+ and Mn2+ for binding, and oxidizing agents, such as t-butyl peroxide, enhanced, not eliminated, BosR binding to the napA promoter region. Surprisingly, transcriptional fusion analysis indicated that BosR exerted a positive regulatory effect on napA that is inducible with t-butyl peroxide. On the basis of these data, we propose that, despite the similarity to PerR, BosR functions primarily as a transcriptional activator, not a repressor of oxidative stress response, in B. burgdorferi. C1 NIAID, NIH, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. TB Brach, Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Gherardini, FC (reprint author), NIAID, NIH, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, 904 S 4th St, Hamilton, MT 59840 USA. NR 17 TC 63 Z9 64 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2003 VL 100 IS 20 BP 11684 EP 11689 DI 10.1073/pnas.2032956100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 727XG UT WOS:000185685700091 PM 12975527 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Small-molecule cyclin-dependent kinase modulators SO ONCOGENE LA English DT Review DE cell cycle; molecular targets; cyclin-dependent kinases; flavopiridol; UCN-01; CYC202; BMS 387032; drug development ID CANCER-CELL-LINES; BREAST-CARCINOMA CELLS; FLAVOPIRIDOL INDUCES APOPTOSIS; HUMAN EPIDERMOID CARCINOMA; SKIN TUMOR-DEVELOPMENT; ACTIVITY IN-VIVO; PROTEIN-KINASE; SELECTIVE INHIBITOR; LUNG-CANCER; ANTITUMOR-ACTIVITY AB Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include. avopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic,. avopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions greater than or equal to24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/ vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus. avopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01(7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks ( in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies. C1 NICDR, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), NICDR, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. NR 185 TC 183 Z9 189 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 29 PY 2003 VL 22 IS 42 BP 6609 EP 6620 DI 10.1038/sj.onc.1206954 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 728DV UT WOS:000185700700018 PM 14528286 ER PT J AU Szentirmay, MN Yang, HX Pawar, SA Vinson, C Sawadogo, M AF Szentirmay, MN Yang, HX Pawar, SA Vinson, C Sawadogo, M TI The IGF2 receptor is a USF2-specific target in nontumorigenic mammary epithelial cells but not in breast cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-II RECEPTOR; TRANSCRIPTION FACTOR USF; FACTOR TYPE-2 RECEPTOR; TUMOR-SUPPRESSOR GENE; PERINATAL LETHALITY; M6P/IGF2 RECEPTOR; PROMOTER ELEMENTS; FETAL OVERGROWTH; BINDING-PROTEINS; CARCINOMA-CELLS AB The antiproliferative activities of the USF proteins and the frequent loss of USF function in cancer cells suggest a role for these ubiquitous transcription factors in tumor suppression. However, the cellular targets that mediate the effects of USF on cellular proliferation and transformation remain uncharacterized. IGF2R, with multiple functions in both normal growth and cancer, was investigated here as a possible USF target in both nontumorigenic and tumorigenic breast cell lines. The 5'-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence. These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A. USF1 and USF2 bound the IGF2R promoter in vitro, and both USF1 and USF2, but not c-Myc, were present within the IGF2R promoter-associated chromatin in vivo. Overexpressed USF2, but not USF1, transactivated the IGF2R promoter, and IGF2R mRNA was markedly decreased by expression of a USF-specific dominant negative mutant, identifying IGF2R as a USF2 target. IGF2R promoter-driven expression was USF-independent in both MCF-7 and MDA-MB-231 breast cancer cell lines, suggesting that a defect in USF function may contribute to down-regulation of IGF2R expression in cancer cells. C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Sawadogo, M (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. FU NCI NIH HHS [CA79578] NR 48 TC 31 Z9 32 U1 5 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2003 VL 278 IS 39 BP 37231 EP 37240 DI 10.1074/jbc.M305791200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723MY UT WOS:000185437200031 PM 12857727 ER PT J AU Dupont, JL Karas, M LeRoith, D AF Dupont, JL Karas, M LeRoith, D TI The cyclin-dependent kinase inhibitor p21C(IP/WAF) is a positive regulator of insulin-like growth factor I-induced cell proliferation in MCF-7 human breast cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CDK INHIBITORS; PHOSPHATIDYLINOSITOL 3-KINASE; MOLECULAR MECHANISMS; SIGNAL-TRANSDUCTION; P21; P21(WAF1/CIP1); RECEPTOR; P21(CIP1/WAF1); EXPRESSION AB To study the role of IGF-I receptor signaling on cell cycle events we utilized MCF-7 breast cancer cells. IGF-I at physiological concentrations increased the level of p21(CIP/WAF) mRNA after 4 h as well as protein after 8 h by 10- and 6-fold, respectively, in MCF-7 cells. This IGF-1 effect was reduced by 50% in MCF-7-derived cells (SX13), which exhibit a 50% reduction in IGF-1R expression, demonstrating that IGF-1 receptor activation was involved in this process. Preincubation with the ERK1/2 inhibitor U0126 significantly reduced the IGF-1 effect on the amount of p21(CIP/WAF) protein in MCF-7 cells. These results were confirmed by the expression of a dominant negative construct for MEK-1 suggesting that the increase of the abundance of p21(CIP/WAF) in response to IGF-1 occurs via the ERK1/2 mitogen-activated protein kinase pathway. Using an antisense strategy, we demonstrated that abolition of p21(CIP/WAF) expression decreased by 2-fold the IGF-1 effect on cell proliferation in MCF-7. This latter result is explained by a delay in G(1) to S cell cycle progression due partly to a reduction in the activation of some components of cell cycle including the induction of cyclin D1 expression in response to IGF-1. MCF-7 cells transiently overexpressing p21 showed increased basal and IGF-I-induced thymidine incorporation. Taken together, these results define p21(CIP/WAF) as a positive regulator in the cell proliferation induced by IGF-1 in MCF-7 cells. C1 NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Rm 8D12,Bldg 10, Bethesda, MD 20892 USA. NR 59 TC 38 Z9 41 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2003 VL 278 IS 39 BP 37256 EP 37264 DI 10.1074/jbc.M302355200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723MY UT WOS:000185437200034 PM 12867429 ER PT J AU Saito, S Yamaguchi, H Higashimoto, Y Chao, C Xu, Y Fornace, AJ Appella, E Anderson, CW AF Saito, S Yamaguchi, H Higashimoto, Y Chao, C Xu, Y Fornace, AJ Appella, E Anderson, CW TI Phosphorylation site interdependence of human p53 post-translational modifications in response to stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; DNA-DAMAGE; IONIZING-RADIATION; UBIQUITIN SYSTEM; GAMMA-RADIATION; UV-RADIATION; MURINE P53; IN-VITRO; ACTIVATION; ATM AB Modification-specific antibodies were used to characterize the phosphorylation and acetylation of human p53 in response to genotoxic (UV, IR, and adriamycin) and non-genotoxic (PALA, taxol, nocodazole) stress in cultured human cells at 14 known modification sites. In A549 cells, phosphorylation or acetylation was induced at most sites by the three DNA damage-inducing agents, but significant differences between agents were observed. IR-induced phosphorylation reached a maximum 2 h after treatment and returned to near pretreatment levels by 72 h; UV light and adriamycin induced a less rapid but more robust and prolonged p53 phosphorylation, which reached a maximum between 8 and 24 h, but persisted ( UV) even 96 h after treatment. Ser(33), Ser(37), Ser(46), and Ser(392) were more efficiently phosphorylated after exposure to UV light than after IR. The non-genotoxic agents PALA, taxol and nocodazole induced p53 accumulation and phosphorylation at Ser(6), Ser(33), Ser(46), and Ser(392). Some phosphorylation at Ser(15) also was observed. Modifications occurred similarly in the HCT116 human colon carcinoma cell line. Analysis of single site mutant p53s indicated clear interdependences between N-terminal phosphorylation sites, which could be classified in four clusters: Ser(6) and Ser(9); Ser(9), Ser(15), Thr(18) and Ser(20); Ser(33) and Ser(37); and Ser(46). We suggest that p53 phosphorylation is regulated through a double cascade involving both the activation of secondary, effector protein kinases as well as intermolecular phosphorylation site interdependencies that check inappropriate p53 inactivation while allowing for signal amplification and the integration of signals from multiple stress pathways. C1 Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Mol Biol Sect, Div Biol, La Jolla, CA 92093 USA. RP Anderson, CW (reprint author), Brookhaven Natl Lab, Dept Biol, 50 Bell Ave, Upton, NY 11973 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 51 TC 158 Z9 162 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2003 VL 278 IS 39 BP 37536 EP 37544 DI 10.1074/jbc.M305135200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723MY UT WOS:000185437200067 PM 12860987 ER PT J AU Yoshida, A Urasaki, Y Waltham, M Bergman, AC Pourquier, P Rothwell, DG Inuzuka, M Weinstein, JN Ueda, T Appella, E Hickson, ID Pommier, Y AF Yoshida, A Urasaki, Y Waltham, M Bergman, AC Pourquier, P Rothwell, DG Inuzuka, M Weinstein, JN Ueda, T Appella, E Hickson, ID Pommier, Y TI Human apurinic/apyrimidinic endonuclease (Ape1) and its N-terminal truncated form (AN34) are involved in DNA fragmentation during apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRAMMED CELL-DEATH; CASPASE-ACTIVATED DNASE; COLI EXONUCLEASE-III; CHROMATIN CONDENSATION; REPAIR ENZYME; DEOXYRIBONUCLEASE-II; BINDING ACTIVITY; RAT THYMOCYTES; ABASIC SITES; TUMOR-CELLS AB We previously isolated a 34-kDa nuclease (AN34) from apoptotic human leukemia cells. Here, we identify AN34 as an N-terminally truncated form of human AP endonuclease (Ape1) lacking residues 1-35 (Delta35-Ape1). Although Ape1 has hitherto been considered specific for damaged DNA (specific to AP site), recombinant AN34 (Delta35-Ape1) possesses significant endonuclease activity on undamaged (normal) DNA and in chromatin. AN34 also displays enhanced 3'-5' exonuclease activity. Caspase-3 activates AN34 in a cell-free system, although caspase-3 cannot cleave Ape1 directly in vitro. We also found that Ape1 itself preferentially cleaves damaged chromatin DNA isolated from cells treated with apoptotic stimuli and that silencing of Ape1 expression decreases apoptotic DNA fragmentation in DFF40/CAD-deficient cells. Thus, we propose that AN34 and Ape1 participate in the process of chromatin fragmentation during apoptosis. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Fukui Med Univ, Dept Chem, Fukui 9101193, Japan. Fukui Med Univ, Dept Internal Med 1, Fukui 9101193, Japan. Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Labs, Oxford OX3 9DS, England. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. RI Waltham, Mark/A-1728-2009 NR 48 TC 36 Z9 39 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2003 VL 278 IS 39 BP 37768 EP 37776 DI 10.1074/jbc.M304914200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723MY UT WOS:000185437200095 PM 12842873 ER PT J AU Pile, LA Spellman, PT Katzenberger, RJ Wassarman, DA AF Pile, LA Spellman, PT Katzenberger, RJ Wassarman, DA TI The SIN3 deacetylase complex represses genes encoding mitochondrial proteins - Implications for the regulation of energy metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; PPAR-ALPHA; MOLECULAR ANALYSIS; HISTONE; EXPRESSION; YEAST; RECEPTOR; IDENTIFICATION AB Deacetylation of histones by the SIN3 complex is a major mechanism utilized in eukaryotic organisms to repress transcription. Presumably, developmental and cellular phenotypes resulting from mutations in SIN3 are a consequence of altered transcription of SIN3 target genes. Therefore, to understand the molecular mechanisms underlying SIN3 mutant phenotypes in Drosophila, we used full-genome oligonucleotide microarrays to compare gene expression levels in wild type Drosophila tissue culture cells versus SIN3-deficient cells generated by RNA interference. Of the 13,137 genes tested, 364 were induced and 35 were repressed by loss of SIN3. The similar to10-fold difference between the number of induced and repressed genes suggests that SIN3 plays a direct role in regulating these genes. The identified genes are distributed throughout euchromatic regions but are preferentially excluded from heterochromatic regions of Drosophila chromosomes suggesting that the SIN3 complex can only access particular chromatin structures. A number of cell cycle regulators were repressed by loss of SIN3, and functional studies indicate that repression of string, encoding the Drosophila homologue of the yeast CDC25 phosphatase, contributes to the G(2) cell cycle delay of SIN3-deficient cells. Unexpectedly, a substantial fraction of genes induced by loss of SIN3 is involved in cytosolic and mitochondrial energy-generating pathways and other genes encode components of the mitochondrial translation machinery. Increased expression of mitochondrial proteins in SIN3-deficient cells is manifested in an increase in mitochondrial mass. Thus, SIN3 may play an important role in regulating mitochondrial respiratory activity. C1 Univ Wisconsin, Sch Med, Dept Pharmacol, Madison, WI 53706 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. NICHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Wassarman, DA (reprint author), Univ Wisconsin, Sch Med, Dept Pharmacol, 1300 Univ Ave, Madison, WI 53706 USA. NR 52 TC 44 Z9 46 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2003 VL 278 IS 39 BP 37840 EP 37848 DI 10.1074/jbc.M305996200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723MY UT WOS:000185437200104 PM 12865422 ER PT J AU Mattson, MP Chan, SL AF Mattson, MP Chan, SL TI Good and bad amyloid antibodies SO SCIENCE LA English DT Letter ID A-BETA NEUROTOXICITY; ALZHEIMER-DISEASE; PEPTIDE; PATHOLOGY; ANTIGENS; VACCINE; MODEL; MOUSE C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 12 TC 12 Z9 13 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 26 PY 2003 VL 301 IS 5641 BP 1847 EP 1849 DI 10.1126/science.301.5641.1847 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 725GW UT WOS:000185536700021 PM 14512605 ER PT J AU O'Brien, SJ Murphy, WJ AF O'Brien, SJ Murphy, WJ TI A dog's breakfast? SO SCIENCE LA English DT Editorial Material ID GENE-THERAPY; HUMAN GENOME; RESOLUTION; EVOLUTION C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. NR 18 TC 20 Z9 20 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 26 PY 2003 VL 301 IS 5641 BP 1854 EP 1855 DI 10.1126/science.1090531 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 725GW UT WOS:000185536700030 PM 14512608 ER PT J AU Hinshaw, JC Suh, DY Garnier, P Buckner, FS Eastman, RT Matsuda, SPT Joubert, BM Coppens, I Joiner, KA Merali, S Nash, TE Prestwich, GD AF Hinshaw, JC Suh, DY Garnier, P Buckner, FS Eastman, RT Matsuda, SPT Joubert, BM Coppens, I Joiner, KA Merali, S Nash, TE Prestwich, GD TI Oxidosqualene cyclase inhibitors as antimicrobial agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 2,3-OXIDOSQUALENE CYCLASE; LANOSTEROL SYNTHASE; TRYPANOSOMA-CRUZI; CHOLESTEROL-BIOSYNTHESIS; CARBON-SOURCES; FATTY-ACID; METABOLISM; STEROLS; CARINII; 4-PIPERIDINOPYRIDINE AB Small-molecule oxidosqualene cyclase (OSC) inhibitors were found to be effective in assays against cloned OSC-like enzymes from human pathogens. A combinatorial library was prepared and used to identify lead compounds that inhibit the growth of Trypanosoma cruzi, Leishmania mexicana amazonensis, and Pneumocystis carinii in culture. Selectivity for the microorganisms in preference to mammalian cells was observed. C1 Univ Utah, Dept Med Chem, Salt Lake City, UT 84108 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Rice Univ, Dept Chem, Houston, TX 77005 USA. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77005 USA. Yale Univ, Sch Med, Infect Dis Sect, Dept Internal Med, New Haven, CT 06520 USA. NYU, Sch Med, Dept Med & Mol Parasitol, New York, NY 10010 USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Prestwich, GD (reprint author), Univ Utah, Dept Med Chem, 419 Wakara Way,Suite 205, Salt Lake City, UT 84108 USA. EM glenn.prestwich@hsc.utah.edu FU NIAID NIH HHS [AI41598, AI48043]; NIGMS NIH HHS [GM 44836] NR 33 TC 30 Z9 32 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 25 PY 2003 VL 46 IS 20 BP 4240 EP 4243 DI 10.1021/jm034126t PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 724AA UT WOS:000185462900003 PM 13678402 ER PT J AU Neckers, L Lee, YS AF Neckers, L Lee, YS TI Cancer - The rules of attraction SO NATURE LA English DT Editorial Material ID HSP90; COMPLEX; TARGET; CELLS C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Mol Modelling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 11 TC 46 Z9 50 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 25 PY 2003 VL 425 IS 6956 BP 357 EP + DI 10.1038/425357a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 724TG UT WOS:000185502300024 PM 14508471 ER PT J AU Houde, M Bertholet, S Gagnon, E Brunet, S Goyette, G Laplante, A Princiotta, MF Thibault, P Sacks, D Desjardins, M AF Houde, M Bertholet, S Gagnon, E Brunet, S Goyette, G Laplante, A Princiotta, MF Thibault, P Sacks, D Desjardins, M TI Phagosomes are competent organelles for antigen cross-presentation SO NATURE LA English DT Article ID MHC CLASS-I; CD8(+) T-CELLS; ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEIN; COMPLEX; PHAGOCYTOSIS; ACTIVATION; PATHWAY; CYTOSOL; LOCALIZATION AB The ability to process microbial antigens and present them at the surface of cells is an important aspect of our innate ability to clear infections. It is generally accepted that antigens in the cytoplasm are loaded in the endoplasmic reticulum and presented at the cell surface on major histocompatibility complex (MHC) class I molecules, whereas peptides present in endo/phagocytic compartments are presented on MHC class II molecules(1,2). Despite the apparent segregation of the class I and class II pathways, antigens from intracellular pathogens including mycobacteria, Escherichia coli, Salmonella typhimurium, Brucella abortus and Leishmania, have been shown to elicit an MHCclass-I-dependent CD8(+) T-cell response(3-7), a process referred to as cross-presentation(2). The cellular mechanisms allowing the cross-presentation pathway are poorly understood. Here we show that phagosomes display the elements and properties needed to be self-sufficient for the cross-presentation of exogenous antigens, a newly ascribed function linked to phagocytosis mediated by the endoplasmic reticulum. C1 Univ Montreal, Dept Pathol & Biol Cellulaire, Montreal, PQ H3C 3J7, Canada. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Caprion Pharmaceut Inc, Montreal, PQ H45 2C8, Canada. RP Desjardins, M (reprint author), Univ Montreal, Dept Pathol & Biol Cellulaire, CP6128,Succ Ctr Ville, Montreal, PQ H3C 3J7, Canada. NR 27 TC 474 Z9 489 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 25 PY 2003 VL 425 IS 6956 BP 402 EP 406 DI 10.1038/nature01912 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 724TG UT WOS:000185502300042 PM 14508490 ER PT J AU Black, DM Greenspan, SL Ensrud, KE Palermo, L McGowan, JA Lang, TF Garnero, P Bouxsein, ML Bilezikian, JP Rosen, CJ AF Black, DM Greenspan, SL Ensrud, KE Palermo, L McGowan, JA Lang, TF Garnero, P Bouxsein, ML Bilezikian, JP Rosen, CJ CA PaTH Study Investigators TI The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BONE-MINERAL DENSITY; VERTEBRAL FRACTURES; WOMEN; TRIAL; METAANALYSIS; RISEDRONATE; TURNOVER; STRENGTH; THERAPY; RISK AB BACKGROUND: Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. METHODS: A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. RESULTS: The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. CONCLUSIONS: There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, Coordinating Ctr, San Francisco, CA 94105 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94105 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Vet Affairs Med Ctr, Dept Med, Minneapolis, MN 55417 USA. Vet Affairs Med Ctr, Dept Epidemiol, Minneapolis, MN USA. Univ Minnesota, Minneapolis, MN USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Synarc, Lyon, France. Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. St Joseph Hosp, Maine Ctr Osteoporosis Res, Bangor, ME USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Black, DM (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, Coordinating Ctr, 74 New Montgomery St,Suite 600, San Francisco, CA 94105 USA. RI Lang, Thomas/B-2685-2012 OI Lang, Thomas/0000-0002-3720-8038 FU NIAMS NIH HHS [N01-AR-9-2245] NR 25 TC 669 Z9 700 U1 1 U2 22 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 25 PY 2003 VL 349 IS 13 BP 1207 EP 1215 DI 10.1056/NEJMoa031975 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 724LJ UT WOS:000185488800003 PM 14500804 ER PT J AU Obungu, VH Burns, AL Agarwal, SK Chandrasekharapa, SC Adelstein, RS Marx, SJ AF Obungu, VH Burns, AL Agarwal, SK Chandrasekharapa, SC Adelstein, RS Marx, SJ TI Menin, a tumor suppressor, associates with nonmuscle myosin II-A heavy chain SO ONCOGENE LA English DT Article DE MEN1; menin; TAP; nonmuscle myosin; cytokinesis ID ENDOCRINE NEOPLASIA TYPE-1; MOLD PHYSARUM-POLYCEPHALUM; MESSENGER-RNAS; NONHISTONE PROTEINS; NUCLEAR-ENVELOPE; GENE-PRODUCT; EXPRESSION; INTERACTS; DROSOPHILA; MORPHOGENESIS AB MEN1 is a likely tumor suppressor gene that encodes a novel protein, menin. Menin is a 610 amino-acid residue protein with as yet unknown function(s). We have used tandem affinity purification and mass spectroscopy to isolate and identify proteins associating with menin from cultured HeLa cell extracts. This strategy has resulted in the isolation and identification of nonmuscle myosin type II-A heavy chain (NMHC II-A) as a menin interacting protein. This interaction was confirmed by glutathione-S-transferase pulldown assays, by coimmunoprecipitation, and by actin selection of myosin. We have further identified the amino-terminal region of menin and the head domain of NMHC II-A to be regions required for this interaction. Moreover menin was seen to colocalize with this myosin isoform in the cleavage furrow of dividing cells by indirect immunofluoresence. These data indicate that menin through binding to NMHC II-A could participate in cell division and in other processes that involve NMHC II-A. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Obungu, VH (reprint author), Eli Lilly & Co, Lilly Res Lab, Lilly Corp Ctr, DC 1505, Indianapolis, IN 46285 USA. RI Agarwal, Sunita/D-1428-2016; OI Agarwal, Sunita/0000-0002-7557-3191; Adelstein, Robert/0000-0002-8683-2144 NR 55 TC 29 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 25 PY 2003 VL 22 IS 41 BP 6347 EP 6358 DI 10.1038/sj.onc.1206658 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 725GK UT WOS:000185535300005 PM 14508515 ER PT J AU Loo, JCY Liu, L Hao, AH Gao, LZ Agatep, R Shennan, M Summers, A Goldstein, AM Tucker, MA Deters, C Fusaro, R Blazer, K Weitzel, J Lassam, N Lynch, H Hogg, D AF Loo, JCY Liu, L Hao, AH Gao, LZ Agatep, R Shennan, M Summers, A Goldstein, AM Tucker, MA Deters, C Fusaro, R Blazer, K Weitzel, J Lassam, N Lynch, H Hogg, D TI Germline splicing mutations of CDKN2A predispose to melanoma SO ONCOGENE LA English DT Article DE splice site mutations; melanoma; genetic predisposition ID MULTIPLE PRIMARY MELANOMAS; FAMILIAL MELANOMA; PRONE FAMILIES; HAPLOTYPE ANALYSIS; P16(INK4A); P19(ARF); FOUNDER AB Coding mutations of the CDKN2A gene on chromosome 9p21 cosegregate with 25-60% of familial melanoma cases, but there remains a number of 9p21-linked kindreds that lack germline coding mutations of CDKN2A. W e sequenced CDKN2A exons 1alpha, 2, 3, and the adjacent intronic regions in 167 melanoma-prone families ( at least two affected first-degree relatives), and detected four splice site variations, three of which cosegregate with the disease. RT-PCR experiments verified that these three variants, including an AGgt to ATgt mutation that demonstrates a founder effect, do affect splicing. While an exon 1alpha splice donor site mutation incompletely abolishes splicing, the correctly spliced mRNA yields a protein (Q50P) that cannot effectively interact with CDK4. We also performed RT-PCR on mRNA from 16 melanoma-prone kindreds to search for cryptic splice sites deep within introns, but identified no splice variants. Meanwhile, we screened 139 affected families using allele specific PCR for the recently discovered IVS2-105A >G mutation, but found only one family that possesses this alteration. We conclude that splice site mutations do predispose to disease in a subset of melanoma-prone kindreds. Characterization of additional splice site variants and other noncoding alterations of CDKN2A should allow us to detect a wider range of mutations in at-risk patients. C1 Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. City Hope Comprehens Canc Ctr, Dept Clin Canc Genet, Duarte, CA 91010 USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. Creighton Univ, Hereditary Canc Inst, Omaha, NE 68178 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. N York Gen Hosp, Dept Genet, Toronto, ON M2K 1E1, Canada. RP Hogg, D (reprint author), Univ Toronto, Dept Med Biophys, Room 7368,Med Sci Bldg, Toronto, ON M5S 1A8, Canada. RI Tucker, Margaret/B-4297-2015 NR 27 TC 21 Z9 21 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 25 PY 2003 VL 22 IS 41 BP 6387 EP 6394 DI 10.1038/sj.onc.1206736 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 725GK UT WOS:000185535300009 PM 14508519 ER PT J AU Chudasama, Y Robbins, TW AF Chudasama, Y Robbins, TW TI Dissociable contributions of the orbitofrontal and infralimbic cortex to Pavlovian autoshaping and discrimination reversal learning: Further evidence for the functional heterogeneity of the rodent frontal cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE rat; autoshaping; orbitofrontal cortex; infralimbic cortex; inhibition; perseveration; reversal learning; discrimination ID ORBITAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; NUCLEUS-ACCUMBENS CORE; BASOLATERAL AMYGDALA; DECISION-MAKING; LESIONS; RAT; MONKEYS; PERFORMANCE; PROJECTIONS AB To examine possible heterogeneity of function within the ventral regions of the rodent frontal cortex, the present study compared the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) and the infralimbic cortex (ILC) on pavlovian autoshaping and discrimination reversal learning. During the pavlovian autoshaping task, in which rats learn to approach a stimulus predictive of reward [ conditional stimulus (CS+)], only the OFC group failed to acquire discriminated approach but was unimpaired when preoperatively trained. In the visual discrimination learning and reversal task, rats were initially required to discriminate a stimulus positively associated with reward. There was no effect of either OFC or ILC lesions on discrimination learning. When the stimulus-reward contingencies were reversed, both groups of animals committed more errors, but only the OFC-lesioned animals were unable to suppress the previously rewarded stimulus-reward association, committing more "stimulus perseverative" errors. In contrast, the ILC group showed a pattern of errors that was more attributable to "learning" than perseveration. These findings suggest two types of dissociation between the effects of OFC and ILC lesions: (1) OFC lesions impaired the learning processes implicated in pavlovian autoshaping but not instrumental simultaneous discrimination learning, whereas ILC lesions were unimpaired at autoshaping and their reversal learning deficit did not reflect perseveration, and (2) OFC lesions induced perseverative responding in reversal learning but did not disinhibit responses to pavlovian CS-. In contrast, the ILC lesion had no effect on response inhibitory control in either of these settings. The findings are discussed in the context of dissociable executive functions in ventral sectors of the rat prefrontal cortex. C1 Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Chudasama, Y (reprint author), NIMH, Neuropsychol Lab, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. NR 56 TC 315 Z9 322 U1 3 U2 30 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 24 PY 2003 VL 23 IS 25 BP 8771 EP 8780 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 725GB UT WOS:000185534500017 PM 14507977 ER PT J AU Ding, KY Gronenborn, AM AF Ding, KY Gronenborn, AM TI Simultaneous and accurate determination of one-bond N-15-C-13 ' and two-bond H-1(N)-C-13 ' dipolar couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LIQUID-CRYSTALLINE PHASE; SENSITIVITY IMPROVEMENT; NMR-SPECTROSCOPY; PROTEINS; N-15-H-1(N) C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 19 TC 10 Z9 11 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 24 PY 2003 VL 125 IS 38 BP 11504 EP 11505 DI 10.1021/ja035954e PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 728HE UT WOS:000185711100025 PM 13129346 ER PT J AU Cohen-Solal, KA Sood, R Marin, Y Crespo-Carbone, SM Sinsimer, D Martino, JJ Robbins, C Makalowska, I Trent, J Chen, S AF Cohen-Solal, KA Sood, R Marin, Y Crespo-Carbone, SM Sinsimer, D Martino, JJ Robbins, C Makalowska, I Trent, J Chen, S TI Identification and characterization of mouse Rab32 by mRNA and protein expression analysis SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE Rab protein; melanosome; transport; storage disease ID GTP-BINDING PROTEIN; MELANOMA-CELLS; MOLECULAR-CLONING; TRANSCRIPTION FACTOR; AMELANOTIC MELANOMA; TRANSGENIC MICE; HUMAN PLATELETS; TYROSINASE; MELANOCYTES; GTPASES AB Rab proteins, a subfamily of the ras superfamily, are low molecular weight GTPases involved in the regulation of intracellular vesicular transport. Cloning of human RAB32 was recently described. Presently, we report the cloning and characterization of the mouse homologue of Rab32. We show that murine Rab32 exhibits a ubiquitous expression pattern, with tissue-specific variation in expression level. Three cell types with highly specialized organelles, melanocytes, platelets and mast cells, exhibit relatively high level of Rab32. We show that in murine amelanotic in vitro transformed melanocytes as well as in human amelanotic metastatic melanoma cell lines, the expression of Rab32 is markedly reduced or absent, in parallel with the loss of expression of two key enzymes for the production of melanin, tyrosinase and Tyrp1. Therefore, in both mouse and human systems, the expression of Rab32 correlates with the expression of genes involved in pigment production. However, in melanoma samples, amelanotic due to a mutation in the tyrosinase gene, the expression of Rab32 remains at levels comparable to those observed in pigmented melanoma samples. Finally, we observed colocalization of Rab32 and the melanosomal proteins, Tyrp1 and Dct, indicating an association of Rab32 with melanosomes. Based on these data, we propose the inclusion of Rab32 to the so-called melanocyte/platelet family of Rab proteins. (C) 2003 Elsevier B.V. All rights reserved. C1 Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, Susan Lehman Cullman Lab Canc Res, Piscataway, NJ 08854 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Chen, S (reprint author), Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, Susan Lehman Cullman Lab Canc Res, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA. FU NCI NIH HHS [R01CA74077-05]; NIEHS NIH HHS [ES05022] NR 40 TC 16 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD SEP 23 PY 2003 VL 1651 IS 1-2 BP 68 EP 75 DI 10.1016/S1570-9639(03)00236-X PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 726GT UT WOS:000185591100008 PM 14499590 ER PT J AU Wilson, PWF Grundy, SM AF Wilson, PWF Grundy, SM TI The metabolic syndrome - Practical guide to origins and treatment: Part I SO CIRCULATION LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; ABDOMINAL OBESITY; DIABETES-MELLITUS; ORLISTAT; FAILURE; ADULTS; RISK C1 NHLBI, Framingham Heart Study, Boston, MA USA. RP Wilson, PWF (reprint author), Boston Univ, Sch Med, 715 Albany St,Evans 204, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIAMS NIH HHS [AR/AG 41398] NR 18 TC 94 Z9 102 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 23 PY 2003 VL 108 IS 12 BP 1422 EP 1424 DI 10.1161/01.CIR.0000089505.34741.E5 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 724BT UT WOS:000185467400002 PM 14504251 ER PT J AU Horner, RD Kamins, KG Feussner, JR Grambow, SC Hoff-Lindquist, J Harati, Y Mitsumoto, H Pascuzzi, R Spencer, PS Tim, R Howard, D Smith, TC Ryan, MAK Coffman, CJ Kasarskis, EJ AF Horner, RD Kamins, KG Feussner, JR Grambow, SC Hoff-Lindquist, J Harati, Y Mitsumoto, H Pascuzzi, R Spencer, PS Tim, R Howard, D Smith, TC Ryan, MAK Coffman, CJ Kasarskis, EJ TI Occurrence of amyotrophic lateral sclerosis among Gulf War veterans SO NEUROLOGY LA English DT Article ID US VETERANS; EPIDEMIOLOGY; MORTALITY; TRAUMA AB Background: In response to Gulf War veterans' concerns of high rates of ALS, this investigation sought to determine if Gulf War veterans have an elevated rate of ALS. Methods: A nationwide epidemiologic case ascertainment study design was used to ascertain all occurrences of ALS for the 10-year period since August 1990 among active duty military and mobilized Reserves, including National Guard, who served during the Gulf War (August 2, 1990, through July 31, 1991). The diagnosis of ALS was confirmed by medical record review. Risk was assessed by the age-adjusted, average, annual 10-year cumulative incidence rate. Results: Among approximately 2.5 million eligible military personnel, 107 confirmed cases of ALS were identified for an overall occurrence of 0.43 per 100,000 persons per year. A significant elevated risk of ALS occurred among all deployed personnel (RR = 1.92; 95% CL = 1.29, 2.84), deployed active duty military (RR = 2.15, 95% CL = 1.38, 3.36), deployed Air Force (RR = 2.68, 95% CL = 1.24, 5.78), and deployed Army (RR = 2;04; 95% CL = 1.10, 3.77) personnel. Elevated, but nonsignificant, risks were observed for deployed Reserves and National Guard (RR = 2.50; 95% CL = 0.88, 7.07), deployed Navy (RR = 1.48, 95% CL = 0.62, 3.57), and deployed Marine Corps (RR = 1.13; 95% CL = 0.27, 4.79) personnel. Overall, the attributable risk associated with deployment was 18% (95% CL = 4.9%, 29.4%). Conclusions: Military personnel who were deployed to the Gulf Region during the Gulf War period experienced a greater post-war risk of ALS than those who were deployed to the Gulf. C1 NINDS, Rockville, MD 20852 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. VA Epidemiol Res & Informat Ctr, Durham, NC 27705 USA. VA Ctr Hlth Serv Res Primary Care, Durham, NC 27705 USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27705 USA. Houston VA Med Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Indiana Univ, Med Ctr, Indianapolis, IN USA. Oregon Hlth & Sci Univ, Portland, OR USA. Durham VA Med Ctr, Durham, NC 27705 USA. USN, Hlth Res Ctr, San Diego, CA 92152 USA. Lexington VA Med Ctr, Lexington, KY 40511 USA. Univ Kentucky, Lexington, KY 40536 USA. RP Horner, RD (reprint author), NINDS, NSC Bldg,Room 2149,6001 Execut Blvd, Rockville, MD 20852 USA. RI Grambow, Steven/E-1422-2015 OI Grambow, Steven/0000-0001-6037-3253 NR 23 TC 141 Z9 143 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 23 PY 2003 VL 61 IS 6 BP 742 EP 749 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 723ZC UT WOS:000185460600006 PM 14504315 ER PT J AU Goldstein, LB Matchar, DB Hoff-Lindquist, J Samsa, GP Horner, RD AF Goldstein, LB Matchar, DB Hoff-Lindquist, J Samsa, GP Horner, RD TI VA stroke study - Neurologist care is associated with increased testing but improved outcomes SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC STROKE; RETROSPECTIVE ASSESSMENT; RANDOMIZED TRIALS; TICLOPIDINE; SPECIALTY; SEVERITY; COMPLICATIONS; INFARCTION; MORTALITY; PHYSICIAN AB Objective: VA Stroke Study (VASt) data were analyzed to determine whether neurologist management affected the process and outcome of care of patients with ischemic stroke. Methods: VASt prospectively identified patients with stroke admitted to nine VA hospitals (April 1995 to March 1997). Demographics, stroke severity (Canadian Neurologic Score), stroke subtype (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] classification), tests/procedures, and discharge status (independent, Rankin less than or equal to 2, vs dead or dependent, Rankin 3 through 5) were compared between patients who were or were not cared for by a neurologist. Results: Of 1,073 enrolled patients, 775 (neurologist care, n = 614; non-neurologist, n = 161) with ischemic stroke were admitted from home. Stroke severity (Canadian Neurologic Score 8.7 +/- 0.1 vs 8.4 +/- 0.2; p = 0.44), TOAST subtype (p = 0.55), and patient age (71.4 +/- 0.4 vs 72.4 +/- 0.7; p = 0.23) were similar for neurologists and non-neurologists. Neurologists more frequently obtained MRI (44% vs 16%; p < 0.001), transesophageal echocardiograms (12% vs 2%; p < 0.001), carotid ultrasounds (65% vs 57%; p = 0.05), cerebral angiography (8% vs 1%; p = 0.001), speech (35% vs 18%; p < 0.001), and occupational therapy (46% vs 33%; p = 0.005) evaluations. Brain CT, transthoracic echocardiogram, 24-hour ambulatory ECG use, and hospitalization durations (18.2 +/- 0.8 vs 19.7 +/- 4.1 days; p = 0.725) were similar. Neurologists' patients were less likely to be dead (5.6% vs 13.5%; OR = 0.38; 95% CI 0.22, 0.68; p = 0.001) and less likely to be dead or dependent (46.1% vs 57.1%; OR = 0.64; 95% CI 0.45, 0.92; p = 0.019) at the time of discharge. The benefit remained after controlling for stroke severity and comorbidity (OR = 0.63; 95% CI 0.42, 0.94; p = 0.025). Conclusion: Neurologist care was associated with more extensive testing, but similar lengths of hospitalization and improved out comes. C1 Duke Univ, Med Ctr,Ctr Clin Hlth Policy Res, Duke Ctr Cerebrovasc Dis, Stroke Policy Program, Durham, NC 27710 USA. Duke Univ, Durham VA Med Ctr, Durham, NC USA. Duke Univ, Dept Med Neurol, Durham, NC USA. NINDS, Off Minor Hlth & Res, Bethesda, MD 20892 USA. RP Goldstein, LB (reprint author), Duke Univ, Med Ctr,Ctr Clin Hlth Policy Res, Duke Ctr Cerebrovasc Dis, Stroke Policy Program, Box 3651, Durham, NC 27710 USA. OI Matchar, David/0000-0003-3020-2108 FU NINDS NIH HHS [K24 NS02165] NR 22 TC 77 Z9 79 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 SEP 23 PY 2003 VL 61 IS 6 BP 792 EP 796 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 723ZC UT WOS:000185460600013 PM 14504322 ER PT J AU Dalakas, MC Hohlfeld, R AF Dalakas, MC Hohlfeld, R TI Polymyositis and dermatomyositis SO LANCET LA English DT Review ID INCLUSION-BODY MYOSITIS; IDIOPATHIC INFLAMMATORY MYOPATHIES; INTERSTITIAL LUNG-DISEASE; NECROSIS-FACTOR-ALPHA; MONOCLONAL-ANTIBODY ANALYSIS; HUMAN MUSCLE-CELLS; MHC CLASS-I; DOSE INTRAVENOUS IMMUNOGLOBULIN; T-CELLS; INTERFERON-GAMMA AB The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders. Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Munich, Klinikum Grosshadern, Inst Clin Neuroimmunol, D-8000 Munich, Germany. Univ Munich, Klinikum Grosshadern, Max Planck Inst Neurobiol, D-8000 Munich, Germany. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. NR 156 TC 598 Z9 666 U1 5 U2 36 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 20 PY 2003 VL 362 IS 9388 BP 971 EP 982 DI 10.1016/S0140-6736(03)14368-1 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 724LT UT WOS:000185489600021 PM 14511932 ER PT J AU Walter, W Kireeva, ML Studitsky, VM Kashlev, M AF Walter, W Kireeva, ML Studitsky, VM Kashlev, M TI Bacterial polymerase and yeast polymerase II use similar mechanisms for transcription through nucleosomes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-DNA HYBRID; ELONGATION COMPLEX; ESCHERICHIA-COLI; ANGSTROM RESOLUTION; TRANSCRIBING POLYMERASE; POSITIONED NUCLEOSOMES; STRUCTURAL BASIS; BINDING PROTEIN; HISTONE OCTAMER; IONIC-STRENGTH AB We have previously shown that nucleosomes act as a strong barrier to yeast RNA polymerase II (Pol II) in vitro and that transcription through the nucleosome results in the loss of an H2A/H2B dimer. Here, we demonstrate that Escherichia coli RNA polymerase (RNAP), which never encounters chromatin in vivo, behaves similarly to Pol II in all aspects of transcription through the nucleosome in vitro. The nucleosome-specific pausing pattern of RNAP is comparable with that of Pol II. At physiological ionic strength or lower, the nucleosome blocks RNAP progression along the template, but this barrier can be relieved at higher ionic strength. Transcription through the nucleosome by RNAP results in the loss of an H2A/H2B dimer, and the histones that remain in the hexasome retain their original positions on the DNA. The results were similar for elongation complexes that were assembled from components (oligonucleotides and RNAP) and elongation complexes obtained by initiation from the promoter. The data suggest that eukaryotic Pol II and E. coli RNAP utilize very similar mechanisms for transcription through the nucleosome. Thus, bacterial RNAP can be used as a suitable model system to study general aspects of chromatin transcription by Pol II. Furthermore, the data argue that the general elongation properties of polymerases may determine the mechanism used for transcription through the nucleosome. C1 Wayne State Univ, Sch Med, Dept Biochem, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. NCI, Ctr Canc Res, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Studitsky, VM (reprint author), Univ Med & Dent New Jersey, Dept Pharmacol, 675 Hoes Lane,Rm 405, Piscataway, NJ 08854 USA. RI Studitsky, Vasily/A-9382-2014 FU NIGMS NIH HHS [GM58650] NR 51 TC 31 Z9 31 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2003 VL 278 IS 38 BP 36148 EP 36156 DI 10.1074/jbc.M305647200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LR UT WOS:000185318300035 PM 12851391 ER PT J AU Baynton, K Otterlei, M Bjoras, M von Kobbe, C Bohr, VA Seeberg, E AF Baynton, K Otterlei, M Bjoras, M von Kobbe, C Bohr, VA Seeberg, E TI WRN interacts physically and functionally with the recombination mediator protein RAD52 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WERNER-SYNDROME PROTEIN; STRAND BREAK REPAIR; DNA HELICASE ACTIVITY; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; SACCHAROMYCES-CEREVISIAE; MITOTIC RECOMBINATION; REPLICATION ARREST; HOLLIDAY JUNCTIONS; IN-VITRO AB Werner syndrome (WS) is a premature aging disorder that predisposes affected individuals to cancer development. The affected gene, WRN, encodes an RecQ homologue whose precise biological function remains elusive. Altered DNA recombination is a hallmark of WS cells suggesting that WRN plays an important role in these pathways. Here we report a novel physical and functional interaction between WRN and the homologous recombination mediator protein RAD52. Fluorescence resonance energy transfer ( FRET) analyses show that WRN and RAD52 form a complex in vivo that co-localizes in foci associated with arrested replication forks. Biochemical studies demonstrate that RAD52 both inhibits and enhances WRN helicase activity in a DNA structure-dependent manner, whereas WRN increases the efficiency of RAD52-mediated strand annealing between non-duplex DNA and homologous sequences contained within a double-stranded plasmid. These results suggest that coordinated WRN and RAD52 activities are involved in replication fork rescue after DNA damage. C1 Univ Oslo, Rikshosp, Ctr Mol Biol & Neurosci, N-0027 Oslo, Norway. Univ Oslo, Rikshosp, Inst Med Microbiol, N-0027 Oslo, Norway. Norwegian Univ Sci & Technol, Inst Canc Res & Mol Biol, N-7005 Trondheim, Norway. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Seeberg, E (reprint author), Univ Oslo, Rikshosp, Ctr Mol Biol & Neurosci, N-0027 Oslo, Norway. NR 81 TC 80 Z9 83 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2003 VL 278 IS 38 BP 36476 EP 36486 DI 10.1074/jbc.M303885200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LR UT WOS:000185318300076 PM 12750383 ER PT J AU Protchenko, O Philpott, CC AF Protchenko, O Philpott, CC TI Regulation of intracellular heme levels by HMX1, a homologue of heme oxygenase, in Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; MEDIATED IRON UPTAKE; CORYNEBACTERIUM-DIPHTHERIAE; HMU-O; ENDOPLASMIC-RETICULUM; OXIDATIVE CLEAVAGE; CRYSTAL-STRUCTURE; CANDIDA-ALBICANS; SIDEROPHORE-IRON; YEAST AB Saccharomyces cerevisiae responds to iron deprivation by increasing the transcription of genes involved in the uptake of environmental iron and in the mobilization of vacuolar iron stores. HMX1 is also transcribed under conditions of iron deprivation and is under the control of the major iron-dependent transcription factor, Aft1p. Although Hmx1p exhibits limited homology to heme oxygenases, it has not been shown to be enzymatically active. We find that Hmx1p is a resident protein of the endoplasmic reticulum and that isolated yeast membranes contain a heme degradation activity that is dependent on HMX1. Hmx1p facilitates the capacity of cells to use heme as a nutritional iron source. Deletion of HMX1 leads to defects in iron accumulation and to expansion of intracellular heme pools. These alterations in the regulatory pools of iron lead to activation of Aft1p and inappropriate activation of heme-dependent transcription factors. Expression of HmuO, the heme oxygenase from Corynebacterium diphtheriae, restores iron and heme levels, as well as Aft1p- and heme-dependent transcriptional activities, to those of wild type cells, indicating that the heme degradation activity associated with Hmx1p is important in mediating iron and heme homeostasis. Hmx1p promotes both the reutilization of heme iron and the regulation of heme-dependent transcription during periods of iron scarcity. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP NIDDK, Liver Dis Sect, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov NR 56 TC 41 Z9 44 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2003 VL 278 IS 38 BP 36582 EP 36587 DI 10.1074/jbc.M306584200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LR UT WOS:000185318300088 PM 12840010 ER PT J AU Miller, DW Ahmad, R Hague, S Baptista, MJ Canet-Aviles, R McLendon, C Carter, DM Zhu, PP Stadler, J Chandran, J Klinefelter, GR Blackstone, C Cookson, MR AF Miller, DW Ahmad, R Hague, S Baptista, MJ Canet-Aviles, R McLendon, C Carter, DM Zhu, PP Stadler, J Chandran, J Klinefelter, GR Blackstone, C Cookson, MR TI L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-SYNUCLEIN; CRYSTAL-STRUCTURE; PROTEIN LIGASE; IN-VITRO; GENE; DEGRADATION; MUTATIONS; FERTILITY; DYSTONIA; PATHWAY AB Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, early-onset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system. A double mutant (K130R, L166P) was more stable than L166P, suggesting that this lysine residue contributes to stability of the protein. Subcellular localization was broadly similar for both wild type and L166P forms of the protein, indicating that the effect of the mutation is predominantly on protein stability. These observations are reminiscent of other recessive gene mutations that produce an effective loss of function. The L166P mutation has the simple effect of promoting DJ-1 degradation, thereby reducing net DJ-1 protein within the cell. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Reprod Toxicol Div, Res Triangle Pk, NC 27711 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Rm 6C103,MSC 1589,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 35 TC 163 Z9 170 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2003 VL 278 IS 38 BP 36588 EP 36595 DI 10.1074/jbc.M304272200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LR UT WOS:000185318300089 PM 12851414 ER PT J AU Bai, F Xi, JH Wawrousek, EF Fleming, TP Andley, UP AF Bai, F Xi, JH Wawrousek, EF Fleming, TP Andley, UP TI Hyperproliferation and p53 status of lens epithelial cells derived from alpha B-crystallin knockout mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DESMIN-RELATED MYOPATHY; HEAT-SHOCK PROTEIN; A-CRYSTALLIN; DNA-DAMAGE; MOLECULAR CHAPERONES; GENOMIC INSTABILITY; MITOTIC SPINDLE; T-ANTIGEN; HA-RAS; V-MOS AB alphaB-Crystallin, a major protein of lens fiber cells, is a stress-induced chaperone expressed at low levels in the lens epithelium and numerous other tissues, and its expression is enhanced in certain pathological conditions. However, the function of alphaB in these tissues is not known. Lenses of alphaB-/- mice develop degeneration of specific skeletal muscles but do not develop cataracts. Recent work in our laboratory indicates that primary cultures of alphaB-/- lens epithelial cells demonstrate genomic instability and undergo hyperproliferation at a frequency 4 orders of magnitude greater than that predicted by spontaneous immortalization of rodent cells. We now demonstrate that the hyperproliferative alphaB-/- lens epithelial cells undergo phenotypic changes that include the appearance of the p53 protein as shown by immunoblot analysis. Sequence analysis showed a lack of mutations in the p53 coding region of hyperproliferative alphaB-/- cells. However, the reentry of hyperproliferative alphaB-/- cells into S phase and mitosis after DNA damage by gamma-irradiation were consistent with impaired p53 checkpoint function in these cells. The results demonstrate that expression of functionally impaired p53 is one of the factors that promote immortalization of lens epithelial cells derived from alphaB-/- mice. Fluorescence in situ hybridization using probes prepared from centromere-specific mouse P1 clones of chromosomes 1 and 9 demonstrated that the hyperproliferative alphaB-/- cells were 30% diploid and 70% tetraploid, whereas wild type cells were 83% diploid. Further evidence of genomic instability was obtained when the hyperproliferative alphaB-/- cells were labeled with anti-beta-tubulin antibodies. Examination of the hyperproliferative alphaB-/- mitotic profiles revealed the presence of cells that failed to round up for mitosis, or arrested in cytokinesis, and binucleated cells in which nuclear division had occurred without cell division. These results suggest that the stress protein and molecular chaperone alphaB-crystallin protects cells from acquiring impaired p53 protein and genomic instability. C1 Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Andley, UP (reprint author), Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, 660 S euclid Ave,Campus Box 8096, St Louis, MO 63110 USA. RI Wawrousek, Eric/A-4547-2008 FU NEI NIH HHS [EY02687, R01EY05681] NR 74 TC 40 Z9 44 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2003 VL 278 IS 38 BP 36876 EP 36886 DI 10.1074/jbc.M304010200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LR UT WOS:000185318300121 PM 12826669 ER PT J AU Marler, JR Goldstein, LB AF Marler, JR Goldstein, LB TI Medicine - Stroke - tPA and the clinic SO SCIENCE LA English DT Editorial Material ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN-ACTIVATOR; PRACTICE GUIDELINES; RT-PA; STATEMENT C1 Natl Inst Neurol Disorders & Stroke, Clin Trials, Bethesda, MD 20817 USA. Duke Univ, Duke Ctr Cerebrovasc Dis, Dept Med Neurol, Durham, NC 27710 USA. Duke Univ, Ctr Clin Hlth Policy Res, Stroke Policy Program, Durham, NC 27710 USA. Vet Adm Med Ctr, Durham, NC 27710 USA. RP Marler, JR (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Trials, Bethesda, MD 20817 USA. EM marlerj@ninds.nih.gov NR 17 TC 38 Z9 39 U1 1 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 SEP 19 PY 2003 VL 301 IS 5640 BP 1677 EP 1677 DI 10.1126/science.1090270 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 722QN UT WOS:000185387700028 PM 14500967 ER PT J AU Vaisman, A Frank, EG Iwai, S Ohashi, E Ohmori, H Hanaoka, F Woodgate, R AF Vaisman, A Frank, EG Iwai, S Ohashi, E Ohmori, H Hanaoka, F Woodgate, R TI Sequence context-dependent replication of DNA templates containing UV-induced lesions by human DNA polymerase iota SO DNA REPAIR LA English DT Article DE Y-family DNA polymerases; mutagenesis; carcinogenesis; xeroderma pigmentosum variant; RAD30B; Pol kappa; DINB1 ID THYMINE-THYMINE DIMER; ERROR-PRONE BYPASS; HUMAN DINB1 GENE; XERODERMA-PIGMENTOSUM; SACCHAROMYCES-CEREVISIAE; TRANSLESION SYNTHESIS; ESCHERICHIA-COLI; IN-VITRO; INSERTION FIDELITY; 6-4 PHOTOPRODUCT AB Humans possess four Y-family polymerases: pols eta, iota, kappa and the Rev1 protein. The pivotal role that poleta plays in protecting us from UV-induced skin cancers is unquestioned given that mutations in the POLH gene (encoding poleta), lead to the sunlight-sensitive and cancer-prone xeroderma pigmentosum variant phenotype. The roles that pols iota, kappa and Rev1 play in the tolerance of UV-induced DNA damage is, however, much less clear. For example, in vitro studies in which the ability of poliota to bypass UV-induced cyclobutane pyrimidine dimers (CPDs) or 6-4 pyrimidine-pyrimidone (6-4PP) lesions has been assayed, are somewhat varied with results ranging from limited misinsertion opposite CPDs to complete lesion bypass. We have tested the hypothesis that such discrepancies might have arisen from different assay conditions and local sequence contexts surrounding each UV-photoproduct and find that poliota can facilitate significant levels of unassisted highly error-prone bypass of a T-T CPD, particularly when the lesion is located in a 3'-A[T-T]A-5' template sequence context and the reaction buffer contains no KCl. When encountering a T-T 6-4PP dimer under the same assay conditions, poliota efficiently and accurately inserts the correct base, A, opposite the 3'T of the 6-4PP by factors of similar to10(2) over the incorporation of incorrect nucleotides, while incorporation opposite the 51 is highly mutagenic. Polkappa has been proposed to function in the bypass of UV-induced lesions by helping extend primers terminated opposite CPDs. However, we find no evidence that the combined actions Of poliota and polkappa result in a significant increase in bypass of T-T CPDs when compared to poliota alone. Our data suggest that under certain conditions and sequence contexts, poliota, can bypass T-T CPDs unassisted and can efficiently incorporate one or more bases opposite a T-T 6-4PP. Such biochemical activities may, therefore, be of biological significance especially in XP-V cells lacking the primary T-T CPD bypassing enzyme, poleta. (C) 2003 Elsevier B.V. All rights reserved. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Sch Engn, Dept Chem & Biotechnol, Bunkyo Ku, Tokyo 1138656, Japan. Kyoto Univ, Inst Virus Res, Kyoto 6068507, Japan. Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bldg 6,Room 1A13,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 NR 77 TC 42 Z9 44 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD SEP 18 PY 2003 VL 2 IS 9 BP 991 EP 1006 DI 10.1016/S1568-7864(03)00094-6 PG 16 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 723QC UT WOS:000185442200005 PM 12967656 ER PT J AU Berger, VW AF Berger, VW TI Preventing fungal infections in chronic granulomatous disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 18 PY 2003 VL 349 IS 12 BP 1190 EP 1190 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 722HQ UT WOS:000185369700027 PM 13679539 ER PT J AU Gallin, JI Wesley, R Holland, SM AF Gallin, JI Wesley, R Holland, SM TI Preventing fungal infections in chronic granulomatous disease - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Gallin, JI (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 18 PY 2003 VL 349 IS 12 BP 1191 EP 1191 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 722HQ UT WOS:000185369700030 ER PT J AU Zhang, ZQ Wang, Y Lantry, LE Kastens, E Liu, GJ Hamilton, AD Sebti, SM Lubet, RA You, M AF Zhang, ZQ Wang, Y Lantry, LE Kastens, E Liu, GJ Hamilton, AD Sebti, SM Lubet, RA You, M TI Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf SO ONCOGENE LA English DT Article DE farnesyltransferase inhibitor; lung cancer; chemoprevention; A/J mice; transgenic mice; P53; Ink4a/Arf ID GERANYLGERANYLTRANSFERASE-I INHIBITORS; PROTEIN TRANSFERASE INHIBITOR; TRANSGENIC MICE; TUMOR-GROWTH; RAS; MOUSE; CARCINOMAS; MUTATION; PATHWAY; MAMMARY AB Mutations in the Kras2 gene are seen in both human and mouse lung adenocarcinomas. The protein product (p21(ras)) encoded by the Kras2 gene must be post-translationally modified at a terminal CAAX motif in order to be biologically active. In this study, we systematically investigated the chemopreventive efficacy of two different farnesyltransferase inhibitors (FTIs): one is a peptidomimetic (FTI-276) and the other is an imidazole (L778 - 123). Both FTIs are designed to inhibit the posttranslational modi. cation of p21ras proteins with a terminal CAAX motif. In a complete chemoprevention study, where the inhibitor was administered before carcinogen was given, and throughout the study, FTI-276 treatment significantly reduced both the tumor multiplicity by 41.7% (P<0.005), and the total tumor volume by 79.4% (P<0.0001). In the late treatment study, where mice were treated with an inhibitor 12 to 20 weeks after carcinogen administration, FTI-276 treatment resulted in a 60% reduction in tumor multiplicity and 58% reduction in tumor volume. Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf. Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an similar to50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes. Interestingly, tumor volume was decreased similar to50% in wildtype mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased similar to75% in animals with a dominant-negative p53 and in mice with both a p53 mutation and heterozygous deletion of Ink4a/ Arf. This result suggests that FTI exhibited a significantly (P<0.05) more efficacious chemopreventive effect in animals with alterations of p53 and Ink4a/ Arf as contrasted with wild-type mice. Thus, FTIs are potent lung chemopreventive agents in both A/J mice and transgenic mice harboring a dominant-negative p53 and heterozygous deletion of Ink4a/Arf. In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. Yale Univ, Dept Chem, New Haven, CT USA. Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Oncol, Drug Discovery Program, Tampa, FL USA. NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Campus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. FU NCI NIH HHS [R01CA78797, R01CA58554] NR 42 TC 27 Z9 28 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 18 PY 2003 VL 22 IS 40 BP 6257 EP 6265 DI 10.1038/sj.onc.1206630 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 724UZ UT WOS:000185506200015 PM 13679864 ER EF